BR112019017915A2 - PROCESSES FOR THE PREPARATION OF FUNGICIDAL COMPOUNDS - Google Patents

Abstract

processes are provided here for the preparation of stereomerically enriched compounds of formulas i-014, i-020, i-064, i-074, i-082, i-089, i-090, i-095, i-171, i -181, i-184, i-186, i-189, i-191, i-192, i-193, i-205, i-206, i-208, i-211, i-212, i-213 , i-220, i-229, i-231, i-233, i-234, i-246, i-251, i-258, i-259, i-262, i-263, i-285, i -323 and i-400. formula v-1 formula v-2-f the compounds described here exhibit activity as pesticides and are useful, for example, in methods for the control of fungal pathogens and diseases caused by fungal pathogens in plants.

Description

Descriptive Report of the Invention Patent for PROCESSES FOR THE PREPARATION OF FUNGICIDAL COMPOUNDS. CROSS REFERENCE TO RELATED ORDERS

[001] This application claims the benefit under 35 U.S.C. § 119 (e) for North American Provisional Application number 62 / 466,944, filed on March 3, 2017, the entirety of which is incorporated herein by reference.

FIELD

[002] Processes are provided here for the preparation of stereomerically enriched compounds that are useful as fungicides. BACKGROUND

[003] Acetyl-CoA carboxylase (ACCase) is an essential catalyst for the rate limiting step of fatty acid biosynthesis in both eukaryotes and prokaryotes. Phytopathogenic fungi can infect crop plants in the field or after harvest, resulting in considerable economic losses for farmers and producers worldwide. In addition to the agricultural impact, when food or feed contaminated with fungi or the toxins they produce are ingested by humans or animals (livestock), several debilitating diseases or death can occur. Approximately 10,000 species of fungi are known to damage crops and affect quality and production. Crop rotation, creation of resistant cultivars, the application of agrochemicals and combinations of these strategies are commonly used to contain the spread of fungal pathogens and the diseases they cause.

[004] Compounds that exhibit fungicidal activity and are useful in the preparation of compositions and methods according to control fungal pathogens, are disclosed in Patent Publications ^Nos North American 2017/0166584, 2017/0166582, 2017 / 0166583, and 2017/0166585, each deposited on November 22, 2016, the

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2/147 all of which are incorporated by reference.

[005] There is a need in the art to provide processes and methods for the synthesis of these and other compounds that exhibit fungal activity.

SUMMARY

[006] Processes are provided here that are useful for the preparation of stereomerically enriched compounds of Formulas I014, I-020, I-064, I-074, I-082, I-089, I-090, I-095, 1 -171, 1-181, 1-184, I186, 1-189, 1-191, 1-192, 1-193, I-205, I-206, I-208, 1-211, 1-212, 1 -213, ΙΣΣΟ, I-229, 1-231, I-233, I-234, I-246, 1-251, I-258, I-259, I-262, I-263, I285, I-323 , and I-400 salts thereof, and intermediates and precursors thereof.

[007] For example, a process for preparing a stereomerically enriched compound of Formula V-1 or V-2-F is provided here:

or a salt thereof, the formula IV-1 or IV-2-F process:

Formula V-2-F comprising contacting a

or a salt thereof, with a hydrogen bridge in the presence of

Petition 870190099157, of 10/03/2019, p. 7/202

3/147 a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or Formula V-1 or V-2-F salt, respectively; where R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3j and R ² is hydrogen or F.

[008] A process for preparing a stereomerically enriched compound of Formula V-3, V-4-F or V-4-F-1a is also provided here:

Formula V-4-F-1a

or a salt thereof, the process comprising contacting a compound of Formula IV-3JV-4-F or IV-4-F-1a:

Formula IV-3 Formula IV-4-F

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or a salt thereof, with a hydrogen bridge in the presence of a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium for providing the stereomerically enriched compound or Formula V-3 or V-4-F salt, respectively ; where R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH2CH3j and R ² is hydrogen or F.

[009] A process for preparing a stereomerically enriched compound of Formula V-5, V-6-F or V-6-F-1a is also provided here:

Formula V-6-F or a salt thereof, the process comprising contacting a compound of Formula IV-5JV-6-F or IV-6-F-1a:

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IV-6-F-1a or a salt thereof, with a hydrogen bridge in the presence of a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium to provide the stereomerically enriched compound or Formula V-5 salt, V-6-F, or V6-F-1a, respectively; where R ¹ is 2H-1,2,3-triazol-2-yl, 1pyrazolyl, or -C (O) OCH2CH3j and R ² is hydrogen or F.

[0010] A process for preparing a stereomerically enriched compound of Formula V-7-F or

V-7-F-1a:

Formula V-7-F-1a or a salt thereof, the process comprising contacting a compound of Formula IV-7-F or IV-7-F-1a:

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Formula IV-1-F-1a or a salt thereof, with a hydrogen bridge in the presence of a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium to provide the stereomerically enriched compound or Formula V-7 salt -F or V-7-F-1a; wherein R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH2CH3.

[0011] A process for preparing a stereomerically enriched compound of Formula I-020, I074, I-064, 1-014, 1-184, 1-211, 1-212, or 1-213 is also provided here:

I-074

I-020

I-064

Petition 870190099157, of 10/03/2019, p. 11/202

1-014

1-184

1-211

1-212

1-213 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-5-F:

Formula V-5-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VI-5-F:

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<_{> a} \ ° ^Ms

Formula VI-5-F or a salt thereof; and reacting the compound or salt of Formula VI-5-F with an alcohol selected from the group consisting of isopropanol, methoxyethanol, ethylene glycol, (R) -3-hydroxy-2-methylpropanonitrile, (S) -3hydroxy-2-methylpropanonitrile , and 3-hydroxy-2,2-dimethylpropanonitrile, thereby providing the stereomerically enriched compound or salt of Formula I-020, I-074, I-064, 1-014, 1-184, 1-211, 1-212 , or 1-213 where R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3.

[0012] A process for preparing a stereomerically enriched compound of Formula I-082 or I171 is also provided here:

I-082

1-171 or a salt thereof, the process comprising:

contact a stereomerically enriched compound of Formula V6-T-F:

Formula V-6-T-F

Petition 870190099157, of 10/03/2019, p. 13/202

9/147 or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VI-6-T-F:

Formula VI-6-T-F or a salt thereof; reacting the Formula VI-6-T-F compound or salt with methoxyethanol, thereby providing the stereomerically enriched compound or Formula I-082 salt; and separating the Formula I-082 compound or salt, thereby providing the stereomerically enriched compound or Formula 1-171 salt.

[0013] A process for preparing a stereomerically enriched compound of Formula I-020, I074, 1-014, 1-211, 1-212, or 1-213 is also provided here:

I-074

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1-211

1-213 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-1-F:

Formula V-1 -F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VI-1-F:

Petition 870190099157, of 10/03/2019, p. 15/202

11/147 or a salt thereof; reacting the compound or salt of Formula VI-1-F with an alcohol selected from the group consisting of isopropanol, methoxyethanol, (S) -3-hydroxy-2-methylpropanonitrile, (R) -3-hydroxy-2-methylpropanonitrile, and 3-hydroxy-2,2-dimethylpropanonitrile, thereby providing a formula VII-1-TF-1, VII-1-TF-2, VII-1 -PF-1, VII-1-TF-3 stereomerically enriched compound , VII-1-TF-4, or VII-1-TF-5:

VII-1-T-F-3 VII-1-T-F-4

VH-1 -T-F-5

Petition 870190099157, of 10/03/2019, p. 16/202

12/147 or a salt thereof; treating the compound or salt of Formula VII-1 -T-F-1,

VII-1-TF-2, VII-1 -PF-1, VII-1-TF-3, VII-1-TF-4, or VII-1-TF-5 with an acid in a deprotection zone, from that so providing a corresponding Formula VIII-1-T-F1, VIII-1-TF-2, VIII-1-PF-1, VIII-1-TF-3, VIII-1-TF-4, carboxylic acid compound, or VIII-1-TF-5:

VIII-1-T-F-1

VIII-1-T-F-2

HIV-1-T-F-5

Petition 870190099157, of 10/03/2019, p. 17/202

13/147 or a salt thereof; and forming an isopropylamine amide in an amide forming zone, thereby providing the stereomerically enriched compound or salt of Formula I-020, I-074, 1-014, I-

211.1-212, or 1-213; wherein R ¹ is 2H-1,2,3-triazol-2-yl or 1-pyrazolyl. [0014] A process for preparing a stereomerically enriched compound of Formula I-082 or Ι-

ου a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-2-T-F:

Formula V-2-T-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VI-2-T-F:

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14/147 or a salt thereof; the Formula VI-2-T-F compound or salt is reacted with methoxyethanol, thereby providing a Formula VII-2-T-F-2 stereomerically enriched compound:

VII-2-T-F-2 or a salt thereof; treating the Formula VII-2-T-F-2 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-2-TF-2 carboxylic acid compound:

VIII-2-T-F-2 or a salt thereof; forming an isopropylamine amide in an amide forming zone, thereby providing the stereomerically enriched compound or Formula I-082 salt; and separating the Formula I-082 compound or salt, thereby providing the stereomerically enriched compound or Formula 1-171 salt.

Also provided here is a process for preparing a stereomerically enriched compound of Formula I-208, I-206, 1-193,

I-095, 1-192, 1-191, I-234, 1-231, I-233, or 1-181:

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I-208 I-206

1-193 I-095

1-192 1-191

I-234 1-231

I-233 1-181 or a salt thereof, the process comprising contacting a Competitor 870190099157, of 10/03/2019, p. 20/202

16/147 stereomerically enriched Formula V-1 post:

Formula V-1 or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VII-1-4 :

or a salt thereof; treating the Formula VII-1-4 compound or salt with an acid in a deprotection zone, thereby providing a corresponding VIII-1-4 carboxylic acid compound:

or a salt thereof; and forming an amide with an amine selected from the group consisting of ethylamine and isopropylamine in an amide forming zone, thereby providing the stereomerically enriched compound or formula I-208, I-206, 1-193, I-095 salt ,

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1- 192, 1-191, I-234, 1-231, I-233, or 1-181; where R ¹ is 2H-1,2,3-triazole-

2- ila, 1-pyrazolyl, or -C (O) OCH2CH3j and R ² is hydrogen or F.

[0015] A process for preparing a stereomerically enriched compound of Formula 1-211, I212, I-262, I-263, I-258, I-259, or 1-213 is also provided here:

Petition 870190099157, of 10/03/2019, p. 22/202

18/147 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-1-F:

Formula V-1 -F or a salt thereof, with an alkenyl compound of CH2 = C (CH3) CN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VII-1-F-5:

Formula VII-1-F-5 or a salt thereof; treating the compound or salt of Formula VII-1-F-5 with an acid in a deprotection zone, thereby providing a corresponding VIII-1-F-5 carboxylic acid compound:

Formula VIII-1-F-5 or a salt thereof;

form an isopropylamine amide in an amide formation zone, thereby providing a compound of Formula

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1-211 / 212, I-262/263, or I-258/259:

Formula 1-211 / 212

Formula I-262/263

I-258/259 or a salt thereof; and separating the compound or salt of Formula I211 / 212, I-262/263, or I-258/259, thereby providing the stereomerically enriched compound or salt of Formula 1-211, 1-212, I-262, I- 263, I-258, or I-259; or reacting the Formula I211 / 212 compound or salt with methyl halide in the presence of base in a methylation zone, thereby providing the stereomerically enriched compound or Formula 1-213 salt; wherein R ¹ is 2H-1,2,3-triazole-2yl, 1-pyrazolyl, or -C (O) OCH2CH3.

[0016] A process for preparing a stereomerically enriched compound of Formula I-205,1-220 or I-229 is also provided here:

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I-220

I-229 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-2-F:

R ¹

‘Bu

F

Formula V-2-F or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VII-2 -F-4:

Formula VII-2-F-4 or a salt thereof; treating the Formula VII-2-F-4 compound or salt with an acid in a deprotection zone, thereby providing a corresponding VIII-2-F-4 carboxylic acid compound:

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Formula VIII-2-F-4 or a salt thereof; form an amide with an amine selected from the group consisting of isopropylamine and / V-methylisopropylamine in an amide formation zone, thereby providing a compound of Formula I-205-RR / RS, I-220-RR / RS, or I-229-RR / RS:

I-220-RR / RS

I-229-RR / RS or a salt thereof; and separating the compound or salt of Formula I-205RR / RS, I-220-RR / RS, or I-229-RR / RS, thereby providing the stereomerically enriched compound or salt of Formula I-205, ΙΣΣΟ, or I -229; wherein R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH ₂ CH ₃ .

A process for preparing a stereomerically enriched compound of Formula I-285 is also provided here:

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I-285 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-1-E-F:

Formula V-1 -EF or a salt thereof, with an alkenyl compound of CH2 = CHSO2CH3 in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VII-1 -E-F6:

Formula VII-1-E-F-6 or a salt thereof; treating the Formula VII-1 -E-F-6 compound or salt with an acid in a deprotection zone, thereby providing a corresponding VIII-1-E-F-6 carboxylic acid compound:

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Formula VIII-1-E-F-6 or a salt thereof; and forming an isopropylamine amide in an amide forming zone, thereby providing the stereomerically enriched compound or Formula I-285 salt.

[0017] A process for preparing a stereomerically enriched compound of Formula I-208, I206, I-234, or 1-231 is also provided here:

I-234 1-231 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-3:

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or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing the stereomerically enriched compound or salt of Formula I-208, I-206 , I-234, or I231; where R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH2CH3j and R ² is hydrogen or F.

[0018] A process for preparing a stereomerically enriched compound of Formula 1-193, 1095, 1-192, 1-191, I-233, or 1-181 is also provided here:

1-193 I-095

1-192 1-191

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or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-5:

Formula V-5 or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing the stereomerically enriched compound or Formula 1-193 salt , I-095, 1-192, 1-191, I-233, or 1-181; where R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or C (O) OCH2CH3j and R ² is hydrogen or F.

A process for preparing a stereomerically enriched compound of Formula 1-211, 1-212, I-262,

I-263, I-258, I-259, or 1-213:

1-211 1-212

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or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-5-F:

Formula V-5-F or a salt thereof, with an alkenyl compound of CH2 = C (CH3) CN in the presence of a base in an addition zone

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Michael comprising the reaction medium, thereby providing a compound of Formula 1-211 / 212.1-262 / 263, or I-258/259:

Formula 1-211 / 212

Formula I-262/263

I-258/259 or a salt thereof; and separating the compound or salt of Formula I211 / 212, I-262/263, or I-258/259, thereby providing the stereomerically enriched compound or salt of Formula 1-211, 1-212, I-262, I- 263, I-258, or I-259; or reacting the Formula I211 / 212 compound or salt with methyl halide in the presence of base in a methylation zone, thereby providing the stereomerically enriched compound or Formula 1-213 salt; wherein R ¹ is 2H-1,2,3-triazole-2yl, 1-pyrazolyl, or -C (O) OCH2CH3.

[0019] A process for preparing a stereomerically enriched compound of Formula I-220 is also provided here:

Petition 870190099157, of 10/03/2019, p. 32/202

28/147 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-6-E-F:

Formula V-6-EF or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a compound of Formula I-220-RR /LOL:

I-220-RR / RS or a salt thereof; and separating the Formula I-220RR / RS compound or salt, thereby providing the stereomerically enriched compound or Formula I-220 salt.

[0020] A process for preparing a stereomerically enriched compound of Formula I-205 or I229 is also provided here:

I-205

I-229

Petition 870190099157, of 10/03/2019, p. 33/202

29/147 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-7-F:

<* \ OH

F

Formula V-7-F or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a compound of Formula 1-205-RR / RS or 1-229-RR / RS:

1-229-RR / RS or a salt thereof; and separating the Formula 1-205RR / RS or 1-229-RR / RS compound or salt, thereby providing the stereomerically enriched compound or Formula 1-205 or 1-229 salt; wherein R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH ₂ CH ₃ .

[0021] A process for preparing a stereomerically enriched compound of Formula I-285 is also provided here:

I-285

Petition 870190099157, of 10/03/2019, p. 34/202

30/147 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-5-E-F:

Formula V-5-EF or a salt thereof, with an alkenyl compound of CH2 = CHSO2CH3 in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing the stereomerically enriched compound or Formula I salt -285. [0022] A process for preparing a stereomerically enriched compound of Formula I-064 is also provided here:

I-064 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-1-T-F:

Formula V-1-T-F

Petition 870190099157, of 10/03/2019, p. 35/202

31/147 or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising the reaction medium; reacting the product with an XCH2C (O) OR3 compound in the α-alkylation zone, thereby providing a formula VII-1-T-F-7 stereomerically enriched compound:

Formula VII-1-T-F-7 or a salt thereof; treating the Formula VII-1-T-F-7 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-1-TF-7 carboxylic acid compound:

The

Formula VIII-1-T-F-7 or a salt thereof; form an isopropylamine amide in an amide formation zone, thereby providing a formula IX-1-T-F-7 stereomerically enriched compound:

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Formula IX-1-TF-7 or a salt thereof; and contacting the Formula IX-1-TF-7 compound or salt with a reducing agent in a reducing zone, thereby providing the stereomerically enriched compound or Formula I-064 salt; where X is Cl or Br, and R ³ is selected from the group consisting of methyl and ethyl.

[0023] A process for preparing a stereomerically enriched compound of Formula I-089 or I090 is also provided here:

or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-2-T-F:

Formula V-2-T-F

Petition 870190099157, of 10/03/2019, p. 37/202

33/147 or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising the reaction medium; react with an XCH2C (O) OR ³ compound in the α-alkylation zone, thereby providing a formula VII-2-TF-7 stereomerically enriched compound:

Formula VII-2-T-F-7 or a salt thereof; treating the Formula VII-2-T-F-7 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-2-TF-7 carboxylic acid compound:

Formula VIII-2-T-F-7 or a salt thereof; form an amide with / V-methylisopropylamine in an amide-forming zone, thereby providing a formula IX-2-T-F-7 stereomerically enriched compound:

Formula IX-2-T-F-7

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34/147 or a salt thereof; contacting the Formula IX-2-T-F7 compound or salt with a reducing agent in a reducing zone, thereby providing a Formula I-I-089/090 compound:

i-089/090 or a salt thereof; and separate the Formula I compound or salt

089/090, thereby providing the stereomerically enriched compound or salt of Formula I-089 or I-090; where X is Cl or Br, and R ³ is selected from the group consisting of methyl and ethyl.

A process for preparing a stereomerically enriched compound of Formula 1-251 is also provided here:

, CN

1-251 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-1-E-F:

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Formula V-1-E-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising the reaction medium; reacting the product with an XCH2CN compound in the α-alkylation zone, thereby providing a formula VII-1-E-F-8 stereomerically enriched compound:

Formula VII-1-E-F-8 or a salt thereof; treating the Formula VII-1-E-F-8 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-1 E-F-8 carboxylic acid compound:

Formula VIII-1-E-F-8 or a salt thereof; and form an isopropylamine amide in a

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36/147 amide formation zone, thereby providing the stereomerically enriched compound or Formula 1-251 salt; where X is Cl or Br.

[0024] A process for preparing a stereomerically enriched compound of Formula I-246 is also provided here:

or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-8-T-F:

Formula V-8-T-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising the reaction medium; reacting the product with an XCH2C (O) OR3 compound in the α-alkylation zone, thereby providing a formula VII-8-T-F-7 stereomerically enriched compound:

Formula VII-8-T-F-7 or a salt thereof; treating the compound or salt of Formula VII-8-T-F-7

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37/147 with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-8-TF-7 carboxylic acid compound:

or a salt thereof; form an isopropylamine amide in an amide forming zone, thereby providing a formula IX-8-T-F-7 stereomerically enriched compound:

Formula IX-8-TF-7 or a salt thereof; and contacting the Formula IX-8-TF-7 compound or salt with a reducing agent in a reduction zone, thereby providing the stereomerically enriched compound or Formula I-246 salt; where X is Cl or Br, and R ³ is selected from the group consisting of methyl and ethyl.

[0025] A process for preparing a stereomerically enriched compound of Formula I-323 is also provided here:

I-323

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38/147 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-3-T-F:

Formula V-3-T-F or a salt thereof, with acetic anhydride or acyl chloride in the presence of a base in an acetylation zone comprising the reaction medium, thereby providing the stereomerically enriched compound or Formula I-323 salt.

[0026] A process for preparing a stereomerically enriched compound of Formula 1-189 is also provided here:

1-189 or a salt thereof, the process comprising separating a compound of Formula V-7-T-F:

Formula V-7-T-F or a salt thereof, thereby providing the stereomerically enriched compound or Formula 1-189 salt.

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[0027] A process for preparing a stereomerically enriched compound of Formula I-400 is also provided here

or a salt thereof, the process comprising contacting a Formula IV-6-T-F-1a post:

Formula IV-6-TF-1a or a salt thereof, with a hydrogen bridge in the presence of a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or Formula I salt -400. Other objectives and characteristics will be partly evident and partly scored hereinafter.

DETAILED DESCRIPTION

[0028] Here are provided processes which are useful for the preparation of stereomerically enriched compounds of Formulas I014, I-020, I-064, I-074, I-082, I-089, I-090, I-095, 1 -171, 1-181, 1-184, I186, 1-189, 1-191, 1-192, 1-193, I-205, I-206, I-208, 1-211, 1-212, 1 -213, ΙΣΣΟ, Ι-ΣΣ9, Ι-Σ31, Ι-Σ33, Ι-Σ34, Ι-Σ46, Ι-Σ51, Ι-Σ58, Ι-Σ59, Ι-Σ6Σ, Ι-Σ63, IΣ85, Ι-3Σ3 , and I-400 and salts thereof.

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Formula 1-014

Formula I-082

Formula I-089

Formula I-090

Formula I-095

Formula 1-181

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Formula 1-186

Formula 1-184

Formula 1-189

Formula 1-191

CN

CN

Formula 1-192

Formula 1-193

Formula I-205

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Formula I-233

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Formula I-259

Formula I-263

Formula I-323

Formula I-400

[0029] As described in Patent Publications North Amer cane ^Nos 2017/0166584, 2017/0166582, 2017/0166583, and 2017/0166585, each of which is deposited on November 22 , 2016, the entirety of which is incorporated here by reference, these compounds exhibit pesticidal activity, and in particular exhibit fungal activity. The compounds can be used, for example, in the preparation of compositions and according to methods for the control of fungal pathogens.

[0030] Processes for the preparation of various intermediates and precursors of the above compounds are also described here.

A. Asymmetric Reduction of a Formula IV Ketone Compound

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[0031] Processes are provided here that are useful for the preparation of stereomerically enriched compounds of Formulas V1, V-2-F, V-3, V-4-F, V-5, V-6-F, and V- 7-F as described here.

[0032] For example, a process is provided here for preparing stereomerically enriched compounds of Formula V-1 or V-2-F, or salts thereof:

Formula V-1 Formula V-2-F where R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3j and R ² is hydrogen or F.

[0033] Generally, the process comprises contacting a compound of Formula IV-1 or IV-2-F:

Formula IV-1 Formula IV-2-F or a salt thereof, with a hydrogen bridge in the presence of a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula V-1 or V-2-F, respectively.

[0034] In the compounds of Formulas V-1, V-2-F, IV-1, and IV-2-F, R ¹ can be 2H-1,2,3-triazole-2yl. Alternatively, R ¹ can be ¹ pyrazolyl. As another alternative, R ¹ can be -C (O) OCH2CH3.

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In the compounds of Formulas V-1 and IV-1, R ² can be hydrogen. Alternatively, R ² can be F.

[0035] For example, in some embodiments, the Formula V-1 stereomerically enriched compound is a Formula V-1-TH, V-1-TF, V-1-PH, V-1-PF, V- 1-EH, or V-1-EF:

Formula V-1 -P-H

Formula V-1 -T-F

Formula V-1 -P-F

Formula V-1 -E-H

Formula V-1 -E-F and the corresponding Formula IV-1 compound is a compound of

Formula IV-1-T-H, IV-1-T-F, IV-1-P-H, IV-1-P-F, IV-1-E-H, or IV-1-E-F:

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Formula IV-1-E-H respectively.

[0036] In other embodiments, the Formula V-2-F stereomerically enriched compound is a Formula V-2-T-F compound or

V-2-E-F:

Formula V-2-T-F

and the corresponding compound of Formula IV-2-F is a compound of

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Formula IV-2-T-F

respectively.

[0037] A process for preparing a stereomerically enriched compound of Formula V-3, V-4-F or V-4-F-1a is also provided here:

Formula V-4-F

Formula V-3

Formula V-4-F-1a or a salt thereof, the process comprising contacting a compound of Formula IV-3, IV-4-F or IV-4-F-1a:

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Formula IV-4-F-1a

or a salt thereof, with a hydrogen bridge in the presence of a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or Formula V-3, V-4-F salt , V-4-F-1a respectively, where R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH2CH3j and R ² is hydrogen or F.

[0038] In the compounds of Formulas V-3, V-4-F, V-4-F-1a, IV-3, IV-

4-F, and IV-4-F-1a R ¹ can be 2H-1,2,3-triazole-2yl. Alternatively, R ¹ can be -C (O) OCH2CH3.

[0039] In the compounds of Formulas V-3 and IV-3, R ² can be hydrogen. Alternatively, R ² can be F.

[0040] For example, in some embodiments, the Formula V-3 or V-4-F stereomerically enriched compound is a Formula V-3-TH, V-3-TF, V-3-EH, V- 3-EF, V-4-TF, V-4-TF-1a or V-4-EF:

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Formula V-3-T-H

Formula V-3-E-H

Formula V-3-T-F

Formula V-4-T-F

Formula V-4-T-F-1a

Formula V-4-EF and the corresponding compound of Formula IV-3 or IV-4-F is a compound of Formula IV-3-TH, IV-3-TF, IV-3-EH, IV-3-EF , IV-4-TF, IV Petition 870190099157, of 10/03/2019, p. 54/202

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4-T-F-1aor IV-4-E-F:

Formula IV-4-E-F

Formula IV-3-T-F

Formula IV-4-T-F-1a respectively.

[0041] A process for preparing documents is also provided here

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Formula V-6-F

Formula V-6-F-1a or a salt thereof, the process comprising contacting a compound of Formula IV-5, IV-6-F or IV-6-F-1a:

Formula IV-6-F

Formula IV-6-F-1a

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52/147 or a salt thereof, with a hydrogen bridge in the presence of a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or Formula V-5 salt, V- 6-F, or V-6-F-1a respectively, where R ¹ is 2H-1,2,3-triazole-2yl, 1-pyrazolyl, or -C (O) OCH2CH3j and R ² is hydrogen or F.

[0042] In the compounds of Formulas V-5, V-6-F, V-6-F-1a, IV-5, IV6-F, and IV-6-F-1a R ¹ can be 2H-1,2 , 3-triazole-2ila. Alternatively, R ¹ can be 1-pyrazolyl. As another alternative, R ¹ can be C (O) OCH ₂ CH ₃ .

[0043] In the compounds of Formulas V-5 and IV-5, R ² can be hydrogen. Alternatively, R ² can be F.

[0044] For example, in some embodiments, the Formula V-5 or V-6-F stereomerically enriched compound is a Formula V-5-TH, V-5-TF, V-5-PH, V- 5-PF, V-5-EH, V-5-EF, V6-TF, V-6-TF-1a or V-6-EF:

Formula V-5-T-H

Formula V-5-T-F

Formula V-5-P-H

Formula V-5-P-F

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Formula V-5-E-H

Formula V-5-E-F (1-186)

Formula V-6-T-F-1a

Formula V-6-T-F

Formula V-6-EF and the corresponding compound of Formula IV-5 or IV-6-F is a compound of Formula IV-5-TH, IV-5-TF, IV-5-PH, IV-5-PF, IV-5-EH, IV-

5-E-F, IV-6-T-F, IV-6-T-F-1a or IV-6-E-F:

Formula IV-5-T-F

Formula IV-5-T-H

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Formula IV-5-P-H

Formula IV-5-P-F

Formula IV-6-T-F

Formula IV-6-E-F respectively.

[0045] A process for preparing a stereomerically enriched compound of Formula V-7-F is also provided here:

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Formula V-7-F or a salt thereof, the process comprising contacting a compound of Formula IV-7-F:

Formula IV-7-F

or a salt thereof, with a hydrogen bridge in the presence of a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or Formula V-7-F salt, where R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH2CH3.

[0046] In the compounds of Formulas V-7-F and IV-7-F, R ¹ can be 2H-1,2,3-triazole-2yl. Alternatively, R ¹ can be -C (O) OCH2CH3.

[0047] For example, in some embodiments, the Formula V-7-F stereomerically enriched compound is a Formula V-7-T-F, V-7-T-F-1a or V-7-E-F compound:

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Formula V-7-T-F

Formula V-7-T-F-1a

Formula V-7-E-F and the corresponding Formula IV-7-F compound is a compound of

Formula IV-7-T-F, IV-7-T-F-1a or IV-7-E-F:

Formula IV-7-E-F

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[0048] In the processes described above, a chiral organometallic catalyst is used to facilitate the preparation of the stereomerically enriched compound of Formulas V-1, V-2-F, V-3, V-4-F, V-5, V-

6-F, and V-7-F. The chiral organometallic catalyst can be a chiral ruthenium catalyst. In some embodiments, the chiral ruthenium catalyst comprises a compound of a chiral complex of (S, S) ruthenium-diamine. By means of a non-limiting example, the chiral complex of (S, S) -ruthenium-diamine can be selected from the group consisting of Formulas X-1 (S, S), X-2 (S, S), X-3 (S, S), and X-4 (S, S).

Formula X-3 (S, S)

'Pr

Formula X-2 (S, S)

Formula X-4 (S, S)

[0049] In other embodiments, the chiral ruthenium catalyst can be selected from, but not limited to, Ru (OTf) [(R, R) -BnSO2 dpen] (p-cymene), RuCI [(R, R) - Ts-dpen] (p-cymene), RuCI [(R, R) -Ts-dpen] (p-cymene), (S) -RUCY ^TM -XilBINAP], RuCI ₂ [(R) -xylyl-Phanephos] [ 1S, 2SDPEN], RuCI ₂ [(S) -xilbinap] [(S, S) -dpen], RuCI2 [(S) -dm-segphos] [(S, S) dpen], RuCI ₂ [(R) - xilbinap] [(R) -daipen], RuCI ₂ [(S) -xilbinap] [(S) -daipen], RuCI ₂ [(S) -binap] [(S) -daipen], RuCI2 [(S) - xyl-PPhos] [(S) -daipen], [NMe ₂ H ₂ ]

[{RuCI (S-TunePhos)} ₂ (p-CI) ₃ ], [NMe ₂ H ₂ ] [{RuCI (MeO-BIPHEP)} ₂ (p-CI) ₃ ], [NMe ₂ H ₂ ] [{ RuCI ((S) -binap)} ₂ (p-CI) ₃ ], [NMe ₂ H ₂ ] [{RuCI ((S) -xilbinap)} ₂ (p-CI) ₃ ], and [NMe ₂ H ₂ ] [{RuCI ((S) -dm-segphos®)} ₂ (p-CI) ₃ ].

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[0050] When the chiral organometallic catalyst is a chiral ruthenium catalyst, the chiral ruthenium catalyst can be present in the reaction medium of the asymmetric reduction zone in an amount of 0.1 mol% to 10% mo, based on in the compound of Formula IV-1, IV-2-F, IV-3, IV-4-F, IV-5, IV-6-F, or IV-7-F.

[0051] In other embodiments, the chiral organometallic catalyst can be a catalyst that does not contain ruthenium. In some embodiments, the chiral organometallic catalyst can be selected from, but not limited to, (S) -2-methyl-CBS-oxazaborolidine, (S, S) -MeDuPhos; Pd ₂ (CF ₃ CO ₂ ) ₂ , [Rh (NBD) (TangPhos)] SbF ₆ .

[0052] In the processes described here, the hydrogen source in the asymmetric reduction zone can be substantially hydrogen gas. Alternatively, the hydrogen source in the symmetric reduction zone can be a hydrogen transfer agent. Non-limiting examples of hydrogen transfer agents include formic acid, formate, and mixtures thereof. Non-limiting examples of suitable formates include alkali metal formates, ammonium formate and trialkylammonium formates. For example, the hydrogen source in the symmetric reduction zone may comprise sodium formate.

[0053] In some embodiments, the hydrogen source in the symmetric reduction zone comprises trialkylammonium formate which is formed in situ by mixing formic acid and trialkylamine in the reaction medium of the asymmetric reduction zone. For example, the trialkylammonium formate may be triethylammonium formate.

[0054] In the processes described above, the enantiomeric excess of the stereomerically enriched compound of Formula V-1, V-2-F, V-3, V-4-F, V-5, V-6-F, or V- 7-F can be at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. For example, the enantiomeric excess of the stereomeric compound

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V-7-F can vary from 60% to 70%, from 70% to 80%, from 80% to 90%, or from 90% to 99%.

B. Alkylation of an Aryl α-halocetone substituted in a Formula IV compound

[0055] Processes are also provided here that are useful for the preparation of compounds of Formulas IV-1,, IV-3, IV-5, and stereomerically enriched compounds of Formulas IV-2-F, IV-4-F, IV -6F, and IV-7-F as described here.

[0056] For example, a process for preparing a compound of Formula IV-1 or IV-2-F is provided here:

0Bu

R ¹

Formula IV-2-F * Bu

Formula IV-1 or a salt thereof, the process comprising contacting a compound of Formula 11-1 or II-2:

The

R ¹

0Bu

Formula 11-1

N

H

R ¹

0Bu

Formula II-2 or a salt thereof, with a compound of Formula III:

Formula III

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60/147 or a salt thereof in the presence of a base in an alkylation zone comprising the reaction medium, thereby providing the compound or salt of Formula IV-1 or IV-2-F, where R ¹ is 2H- 1,2,3triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3j R ² is hydrogen or F; and X is Cl, Br, or I.

[0057] In the compounds of Formulas IV-1, IV-2-F, 11-1, and II-2, R ¹ can be 2H-1,2,3-triazole-2yl. Alternatively, R ¹ can be 1-pyrazolyl. As another alternative, R ¹ can be -C (O) OCH2CH3.

[0058] In the compounds of Formulas IV-1 and III, R ² can be hydrogen. Alternatively, R ² can be F.

[0059] In the compounds of Formula III, X can be Cl. Alternatively, X can be Br. As another alternative, X can be I.

[0060] A process for preparing a compound of Formula IV-3, IV-4-F or IV-4-F-1a is also provided here:

R ¹

H N.

Formula IV-4-F

Formula IV-3

Formula IV-4-F-1a or a salt thereof, the step comprising contacting a compound

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Η Η

Formula ΙΙ-3 Formula ΙΙ-4

Η

Formula 11-4-1 a or a salt thereof, with a compound of Formula III:

Formula III or a salt thereof, in the presence of a base in an alkylation zone comprising the reaction medium, thereby providing the compound or salt of Formula IV-3, IV-4-F, IV-4-F-1a where R ¹ is 2H-

1,2,3-triazol-2-yl or -C (O) OCH2CH3j R ² is hydrogen or F; and X is Cl, Br, or I.

[0059] In the compounds of Formulas IV-3, IV-4-F, IV-4-F-1a, II-3, II4, and 11-4-1 the R ¹ can be 2H-1,2,3- triazole-2ila. Alternatively, R ¹ can be -C (O) OCH ₂ CH ₃ .

[0061] In the compounds of Formulas IV-3 and III, R ² can be hydrogen. Alternatively, R ² can be F.

[0062] In the compounds of Formula III, X can be Cl. Alternatively, X can be Br. As another alternative, X can be I.

[0063] A process for preparing a compound of Formula IV-5JV-6-F or IV-6-F-1a is also provided here:

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Formula IV-6-F-1a

or a salt thereof, the step comprising contacting a compound of Formula II-5, II-6 or 11-6-1 at:

H

Formula II-6

Formula 11-6-1 a or a salt thereof, with a compound of Formula III:

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63/147 or a salt thereof, in the presence of a base in an alkylation zone comprising the reaction medium, thereby providing the compound or salt of Formula IV-5, IV-6-F or IV-6-F- 1a, where R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3j R ² is hydrogen or F; and X is Cl, Br, or I.

[0064] In the compounds of Formulas IV-5, IV-6-F, IV-6-F-1a, II-5, II6, and ll-6-1a R ¹ can be 2H-1,2,3-triazole -2ila. Alternatively, R ¹ can be 1-pyrazolyl. As another alternative, R ¹ can be -C (O) OCH ₂ CH ₃ .

[0065] In the compounds of Formulas IV-5 and III, R ² can be hydrogen. Alternatively, R ² can be F.

[0066] In the compounds of Formula III, X can be Cl. Alternatively, X can be Br. As another alternative, X can be I.

[0067] A process for preparing a compound of Formula IV-7-F or IV-7-F-1a is also provided here:

Formula IV-7-F

Formula IV-7-F-1a or a salt thereof, the step comprising contacting a compound of Formula II-7 or 11-7-1 at:

Formula ll-7-1a or a salt thereof, with a compound of Formula ll-F:

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Formula ll-F or a salt thereof, in the presence of a base in an alkylation zone comprising the reaction medium, thereby providing the compound or salt of Formula IV-7-F or IV-7-F-1a, in that R ¹ is 2H-

1,2,3-triazol-2-yl or -C (O) OCH ₂ CH ₃ ; and X is Cl, Br, or I.

[0068] In the compounds of Formulas IV-7-F, IV-7-F-1a, II-7 and II-71a, R ¹ can be 2H-1,2,3-triazole-2yl. Alternatively, R ¹ can be C (O) OCH ₂ CH ₃ .

[0069] In the compounds of Formula III, X can be Cl. Alternatively, X can be Br. As another alternative, X can be I.

[0070] In some modalities of the processes for preparing the compounds of Formulas IV-1, IV-2-F, IV-3, IV-4-F, IV-4-F-1a, IV-5, IV-6- F, IV-6-F-1a, IV-7-F, and IV-7-F-1a as described above, X is Cl and the reaction medium in the alkylation zone comprises an alkali metal bromide or an iodide of alkali metal. For example, the alkali metal bromide can be sodium bromide or potassium bromide.

[0071] Alkali metal bromide can be present in the reaction medium in an amount of about 1 mol% to about 20 mol%, based on the compound of Formula 11-1, II-2, II-3 , II-4, ll-4-1a, II-5, II-6, ll-6-1a, II-7, or ll-7-1a.

[0072] In some modalities of the processes for preparing the compounds of Formulas IV-1, IV-2-F, IV-3, IV-4-F, IV-4-F-1a, IV-5, IV-6- F, IV-6-F-1a, IV-7-F, and IV-7-F-1a as described above, the base in the alkylation zone comprises an alkali metal carbonate. For example, the alkali metal carbonate can be potassium carbonate.

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[0073] The alkali metal carbonate can be present in the reaction medium in an amount of about 1 equivalent to about 10 equivalents, based on the compound of Formula 11-1, II-2, II-3, II-4 , 11-4-1 a, II-5, II-6, ll-6-1a, II-7, or ll-7-1a.

C. Mesylation and Ether Formation

[0074] Processes are also provided here which are useful for preparing stereomerically enriched compounds of formulas 1-014, I-020, I-064, I-074, I-082, 1-171, and 1-184 as described here .

[0075] For example, a process for preparing a stereomerically enriched compound of Formula I020, I-074, I-064, 1-014, 1-184, 1-211, 1-212, or 1-213 is provided here :

I-020 I-074

I-064

1-014 1-184

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1-213 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-5-F:

Formula V-5-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VI-5-F:

Formula VI-5-F

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67/147 or a salt thereof; and reacting the compound or salt of Formula VI-5-F with an alcohol selected from the group consisting of isopropanol, methoxyethanol, ethylene glycol, (S) -3-hydroxy-2-methylpropanonitrile, (R) -3hydroxy-2-methylpropanonitrile , and 3-hydroxy-2,2-dimethylpropanonitrile, thereby providing the stereomerically enriched compound or salt of Formula I-020, I-074, I-064, 1-014, 1-184, 1-211, 1-212 , or 1-213, where R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3. [0076] In the compounds of formulas V-5-F, and VI-5-F, R ¹ can be 2H-1,2,3-triazole-2-yl. Alternatively, R ¹ can be 1-pyrazolyl. As another alternative, R ¹ can be -C (O) OCH2CH3.

[0077] The compound or salt of Formula VI-5-F can be reacted with isopropanol. Alternatively, the Formula VI-5-F compound or salt can be reacted with methoxyethanol. As another alternative, the Formula VI-5-F compound or salt can be reacted with ethylene glycol. As another alternative, the compound or salt of VI-5-F can be reacted with (S) -3-hydroxy-2-methylpropanonitrile. Alternatively, the VI-5-F compound or salt can be reacted with (R) -3-hydroxy-2-methylpropanonitrile. In yet another alternative, the compound or salt of VI-5-F can be reacted with 3-hydroxy-2,2-dimethylpropanonitrile.

[0078] A process for preparing a stereomerically enriched compound of Formula I-082 or I171 is also provided here:

I-082

1-171 or a salt thereof, a process comprising:

contact a stereomerically enriched compound of Formula V Petition 870190099157, of 10/03/2019, p. 72/202

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6-T-F:

Formula V-6-T-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VI-6-T-F:

Formula VI-6-T-F or a salt thereof; reacting the Formula VI-6-T-F compound or salt with methoxyethanol, thereby providing the stereomerically enriched compound or Formula I-082 salt; and separating the Formula I-082 compound or salt, thereby providing the stereomerically enriched compound or Formula 1-171 salt.

[0078] A process for preparing a stereomerically enriched compound of Formula I-020, I074, 1-014, 1-211, 1-212, or 1-213 is also provided here:

I-020 I-074

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1-212

1-213 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-1-F:

Formula V-1-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising the reaction medium, thereby providing a stereomerically enirPetition compound 870190099157, from 10/03/2019, pg. 74/202

70/147 heated Formula VI-1-F:

Formula VI-1-F or a salt thereof; reacting the compound or salt of Formula VI-1-F with an alcohol selected from the group consisting of isopropanol, methoxyethanol, (S) -3-hydroxy-2-methylpropanonitrile, (R) -3-hydroxy-2-methylpropanonitrile, and 3-hydroxy-2,2-dimethylpropanonitrile, thereby providing a formula VII-1-TF-1 stereomerically enriched compound,

VII-1 -T-F-2, VII-1 -P-F-1, VII-1 -T-F-3, VII-1-T-F-4, or VII-1 -T-F-5:

VII-1 -T-F-2

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VII-1-T-F-3 VII-1-T-F-4

VII-1-T-F-5 or a salt thereof; treating the compound or salt of Formula VII-1 -T-F-1,

VII-1-TF-2, VII-1 -PF-1, VII-1-TF-3, VII-1-TF-4, or VII-1-TF-5 with an acid in a deprotection zone, from that so providing a corresponding Formula VIII-1 -T-F1, VIII-1-TF-2, VIII-1-PF-1, VIII-1-TF-3, VIII-1-TF-4, carboxylic acid compound, or VIII-1-TF-5:

VIII-1-T-F-2

VIII-1 -T-F-1

VIII-1-P-F-1

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VIII-1 -T-F-4 or a salt thereof; and forming an isopropylamine amide in an amide forming zone, thereby providing the stereomerically enriched compound or salt of Formula I-020, I-074, 1-014, I-

211.1-212.1-213; wherein R ¹ is 2H-1,2,3-triazol-2-yl or 1-pyrazolyl.

In the compounds of formulas V-1-F and VI-1-F, R ¹ can be 2H-1,2,3triazole-2-yl. Alternatively, R ¹ can be 1-pyrazolyl.

[0079] A process for preparing a stereomerically enriched compound of Formula I-082 or I171 is also provided here:

I-082

1-171 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-2-T-F:

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Formula V-2-T-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VI-2-T-F:

Formula VI-2-T-F or a salt thereof; the Formula VI-2-T-F compound or salt is reacted with methoxyethanol, thereby providing a Formula VII-2-T-F-2 stereomerically enriched compound:

VII-2-T-F-2 or a salt thereof; treating the Formula VII-2-T-F-2 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-2-TP carboxylic acid compound, option 870190099157, from 10/03/2019, pg. 78/202

74/147

F-2:

VIII-2-T-F-2 or a salt thereof; forming an isopropylamine amide in an amide forming zone, thereby providing the stereomerically enriched compound or Formula I-082 salt; and separating the Formula I-082 compound or salt, thereby providing the stereomerically enriched compound or Formula 1-171 salt.

[0080] In some embodiments of the processes for preparing the compounds of formulas 1-014, I-020, I-064, I-074, I-082, 1-171, I184, 1-211, 1-212, and 1 -213 as described above, the base in the mesylation zone is a pyridine based base. The pyridine-based base can be a substituted pyridine. For example, the substituted pyridine can be 2,6-lutidine. Alternatively, the substituted pyridine can be 2,4,6-collidine.

[0081] In some embodiments of the processes for preparing the compounds of formulas 1-014, I-020, I-064, I-074, I-082, 1-171, I184, 1-211, 1-212, and 1 -213 as described above, the stereochemistry of the fragment

in the stereomerically enriched compound of formulas V-1-F, V2-T-F, V-2-T-F-1a, V-5-F, V-6-T-F, V-6-T-F-1a remains substantial

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75/147 also equal in the stereomerically enriched compound of formulas I-020, I-074, 1-014, 1-184, I-082, 1-171, 1-211, 1-212, or 1-213.

[0082] In some embodiments of the processes for preparing the compounds of formulas 1-014, I-020, I-064, I-074, I-082, 1-171, I184, 1-211, 1-212, and 1 -213, as described above, the acid in the deprotection zone is selected from the group consisting of hydrochloride, formic acid, trifluoroacetic acid, and sulfuric acid. For example, the acid in the deprotection zone can comprise formic acid or sulfuric acid.

[0083] In some embodiments of the processes for preparing the compounds of formulas 1-014, I-020, i-064, I-074, i-082, 1-171, I184, 1-211, 1-212, and 1 -213 as described above, the amide is formed in the presence of an amide coupling reagent in a reaction medium. As a non-limiting example, the amide coupling reagent can be selected from the group consisting of (benzotriazol-1-yloxy) hexafluorophosphate tris (dimethylamino) phosphonium (BOP), 3 (diethoxyphosphoryloxy) -1,2,3-benzotriazin -4 (3H) -one (DEPBT), N, N-dicyclohexylcarbodiimide (DCC), Λ /, Λ / '- diisopropylcarbodiimide (DIC), 1- [bis (dimethylamino) hexafluorophosphate 3-oxide methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium (HATU), 3- [bis (dimethylamino) methyliumyl] -3 / - / - benzotriazole-1-oxide (HBTU) hexafluorophosphate, 3-hydroxytriazolo [4,5-b] pyridine (HOAt), (7-azabenzotriazol-1-yloxy) tripyrrolidinophosphonium (PyAOP) hexafluorophosphate (benzotriazol-1-yloxy) tripyrrolidinophosphonium (PyBOP) and anhydrous (PyBOP) ). For example, the amide coupling reagent can be either HATU or T3P.

Alternatively, the amide can be formed by converting the stereomerically enriched compound of formulas VIII-1-TF-1, VIII-1-TF-2, VIII-1-PF-1, or VIII-2-TF-2 into a corresponding acid chloride and reacting the acid chloride compound with isopropylamine. The conversion of acid halides to amides is well

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76/147 known in the art (see R. C. Larock Comprehensive Organic Tranformations: A Guide to Functional Group Preparations, VCH, New York, 1989, p 979).

D. Addition Michael and Ether Formation

[0085] Processes which are useful for preparing stereomerically enriched compounds of formulas i-095, 1-181, 1-191, 1-192, 1-193, I-205, i-206, i-208 are also provided here , 1-211, 1-212, 1-213, I-220, I-229, 1-231, I-233, I-234, I-258, I-259, I-262, I-263, and I-285 as described here.

[0086] For example, a process is provided here for preparing a stereomerically enriched compound of Formula I208, i-206, 1-193, i-095, 1-192, 1-191, i-234, 1-231, i-233, or 1-181:

i-208

i-206

1-193

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TTIUT

1-234 1-231

I-233 1-181 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-1:

Formula V-1 or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VII-1-4 :

Formula VII-1-4

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78/147 or a salt thereof; treating the Formula VII-1-4 compound or salt with an acid in a deprotection zone, thereby providing a corresponding VIII-1-4 carboxylic acid compound:

Formula VIII-1-4 or a salt thereof; and forming an amide with an amine selected from the group consisting of ethylamine and isopropylamine in an amide forming zone, thereby providing the stereomerically enriched compound or formula I-208, I-206, 1-193, I-095 salt ,

1- 192, 1-191, I-234, 1-231, I-233, or 1-181; where R ¹ is 2H-1,2,3-triazole-

2- ila, 1-pyrazolyl, or -C (O) OCH2CH3j and R ² is hydrogen or F.

In the compounds of formulas V-1, VII-1-4, and VII-1-4, R ¹ can be 2H-

1,2,3-triazole-2-yl. Alternatively, R ¹ can be 1-pyrazolyl. As another alternative, R ¹ can be -C (O) OCH2CH3.

In compounds of formulas V-1, VII-1-4, and VII-1-4, R ² can be hydrogen. Alternatively, R ² can be F.

[0087] A process for preparing a stereomerically enriched compound of Formula 1-211, I212, I-262, I-263, I-258, I-259, or 1-213 is also provided here:

1-212

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I-262

or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-1-F:

Formula V-1-F or a salt thereof, with an alkenyl compound of CH2 = C (CH3) CN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing

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80/147 a stereomerically enriched compound of Formula VII-1-F-5:

Formula VII-1-F-5 or a salt thereof; treating the compound or salt of Formula VII-1-F-5 with an acid in a deprotection zone, thereby providing a corresponding VIII-1-F-5 carboxylic acid compound:

Formula VIII-1-F-5 or a salt thereof;

form an isopropylamine amide in an amide forming zone, thereby providing a compound of Formula 1-211 / 212, I262 / 263, or I-258/259:

Formula 1-211 / 212 Formula I-262/263

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I-258/259 or a salt thereof; and separating the compound or salt of Formula I211 / 212, I-262/263, or I-258/259, thereby providing the stereomerically enriched compound or salt of Formula 1-211, 1-212, I-262, I- 263, I-258, or I-259; or reacting the Formula I211 / 212 compound or salt with methyl halide in the presence of base in a methylation zone, thereby providing the stereomerically enriched compound or Formula 1-213 salt; wherein R ¹ is 2H-1,2,3-triazole-2yl, 1-pyrazolyl, or -C (O) OCH2CH3.

[0088] In the compounds of formulas V-1-F, VII-1-F-5, and VIII-1-F-5, R ¹ can be 2H-1,2,3-triazole-2-yl. Alternatively, R ¹ can be ¹ pyrazolyl. As another alternative, R ¹ can be -C (O) OCH2CH3.

[0089] A process for preparing a stereomerically enriched compound of Formula I-205,1-220 or I-229 is also provided here:

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I-229 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-2-F:

Formula V-2-F or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VII-2 -F-4:

Formula VII-2-F-4 or a salt thereof; treating the Formula VII-2-F-4 compound or salt with an acid in a deprotection zone, thereby providing a corresponding VIII-2-F-4 carboxylic acid compound:

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Formula VIII-2-F-4 or a salt thereof; form an amide with an amine selected from the group consisting of isopropylamine and / V-methylisopropylamine in an amide formation zone, thereby providing a compound of Formula I-205-RR / RS, I-220-RR / RS, or I-229-RR / RS:

I-205-RR / RS

I-220-RR / RS

I-229-RR / RS or a salt thereof; and separating the compound or salt of Formula Ι-Σ05RR / RS, I-220-RR / RS, or I-229-RR / RS, thereby providing the stereomerically enriched compound or salt of Formula Ι-Σ05, ΙΣΣΟ, or Ι -ΣΣ9; wherein R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH2CH3. [0090] In the compounds of formulas V-2-F, VII-2-F-4, and VIII-2-F-4, R ¹ can be 2H-1,2,3-triazole-2-yl. Alternatively, R ¹ can be C (O) OCH2CH ₃ .

[0091] A process for preparing documents is also provided here

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84/147 a stereomerically enriched compound of Formula I-285:

I-285 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-1-E-F:

Formula V-1-EF or a salt thereof, with an alkenyl compound of CH2 = CHSO2CH3 in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VII-1 -E-F6:

Formula VII-1-E-F-6 or a salt thereof; treating the Formula VII-1-E-F-6 compound or salt with an acid in a deprotection zone, thereby providing a corresponding VIII-1-E-F-6 carboxylic acid compound:

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Formula VIII-1-E-F-6 or a salt thereof; and forming an isopropylamine amide in an amide forming zone, thereby providing the stereomerically enriched compound or Formula I-285 salt.

[0092] A process for preparing a stereomerically enriched compound of Formula I-208, I206, I-234, or 1-231 is also provided here:

I-208 I-206

I-234 1-231 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-3:

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or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing the stereomerically enriched compound or salt of Formula I-208, I-206 , I-234, or I231; where R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH2CH3j and R ² is hydrogen or F.

[0093] In the compounds of Formula V-3, R ¹ can be 2H-1,2,3triazole-2-yl. Alternatively, R ¹ can be -C (O) OCH2CH3.

[0094] In the compounds of Formula V-3, R ² can be hydrogen. Alternatively, R ² can be F.

[0095] A process for preparing a stereomerically enriched compound of Formula 1-193, 1095, 1-192, 1-191, I-233, or 1-181 is also provided here:

1-193 I-095

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or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-5:

Formula V-5 or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing the stereomerically enriched compound or Formula 1-193 salt , I-095, 1-192, 1-191, I-233, or 1-181; where R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or C (O) OCH2CH3j and R ² is hydrogen or F.

[0096] In the compounds of Formula V-5, R ¹ can be 2H-1,2,3triazole-2-yl. Alternatively, R ¹ can be 1-pyrazolyl. As another alternative, R ¹ can be -C (O) OCH2CH3.

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[0097] In compounds of Formula V-5, R ² can be hydrogen. Alternatively, R ² can be F.

[0098] A process for preparing a stereomerically enriched compound of Formula 1-211, I212 is also provided here. I-262. I-263. I-258. I-259. or 1-213:

I-262

1-213

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89/147 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-5-F:

Formula V-5-F or a salt thereof, with an alkenyl compound of

CH2 = C (CH3) CN in the presence of a base in an addition zone

Michael comprising the reaction medium, thereby providing a compound of Formula 1-211 / 212.1-262 / 263, or I-258/259:

Formula 1-211 / 212

Formula I-262/263

I-258/259 or a salt thereof; and separating the compound or salt of Formula I211 / 212, I-262/263, or I-258/259, thereby providing the stereomerically enriched compound or salt of Formula 1-211, 1-212, I-262, I- 263, I-258, or I-259; or react the compound or salt of Formula I211 / 212 with methyl halide in the presence of base in a methylation zone, thereby providing the compound stereomerically

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90/147 enriched or Formula 1-213 salt; wherein R ¹ is 2H-1,2,3-triazole-2yl, 1-pyrazolyl, or -C (O) OCH2CH3.

[0099] In the compounds of Formula V-5-F, R ¹ can be 2H-1,2,3triazole-2-yl. Alternatively, R ¹ can be 1-pyrazolyl. As another alternative, R ¹ can be -C (O) OCH2CH3.

[00100] A process for preparing a stereomerically enriched compound of Formula I-220 is also provided here:

I-220 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-6-E-F:

Formula V-6-EF or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a compound of Formula I-220-RR /LOL:

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I-220-RR / RS or a salt thereof; and separating the Formula I-220RR / RS compound or salt, thereby providing the stereomerically enriched compound or Formula I-220 salt.

[00101] A process for preparing a stereomerically enriched compound of Formula I-205 or I is also provided here

or one

I-229 salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-7-F:

F

Formula V-7-F or a salt thereof, with an alkenyl compound of CH2 = CHCN

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92/147 in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a compound of Formula I-205-RR / RS or I-229-RR / RS:

I-229-RR / RS

I-205-RR / RS or a salt thereof; and separating the Formula I-205RR / RS or I-229-RR / RS compound or salt, thereby providing the sterically enriched compound or Formula I-205 or I-229 salt; wherein R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH ₂ CH ₃ .

[00102] In the compounds of Formula V-7-F, R ¹ can be 2H-1,2,3triazole-2-yl. Alternatively, R ¹ can be -C (O) OCH2CH3.

[00103] A process for preparing a stereomerically enriched compound of Formula I-285 is also provided here:

I-285 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-5-E-F:

Formula V-5-E-F

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93/147 or a salt thereof, with an alkenyl compound of CH2 = CHSO2CH3 in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing the stereomerically enriched compound or Formula I-285 salt. [00104] In some embodiments of the processes for preparing the compounds of formulas I-095, 1-181, 1-191, 1-192, 1-193, I-205, I206, I-208, 1-211, 1- 212, 1-213, I-220, I-229, 1-231, I-233, I-234, I-258, I259, I-262, I-263, and I-285 as described above, the basis in the addition zone Michael is an alkali metal hydroxide or a quaternary ammonium hydroxide. In some embodiments, the alkali metal hydroxide is selected from the group consisting of potassium hydroxide, sodium hydroxide, and lithium hydroxide. For example, the alkali metal hydroxide can be potassium hydroxide.

[00105] In some embodiments of the processes for preparing the compounds of formulas I-095, 1-181, 1-191, 1-192, 1-193, I-205, I206, I-208, 1-211, 1- 212, 1-213, I-220, I-229, 1-231, I-233, I-234, I-258, I259, I-262, I-263, and I-285 as described above, the basis is present in the reaction medium in an amount not greater than 1.0 molar equivalent, based on the compound of Formula V-1, V-1-F, V-2-F, V1-EF, V-3, V -5, V-5-F, V-6-EF, V-7-F, or V-5-EF. For example, the base may be present in the reaction medium in an amount of about 0.05 molar equivalent to about 0.9 molar equivalent, from about 0.1 molar equivalent to about 0.5 molar equivalent, or from about 0.1 molar equivalent to 0.3 molar equivalent, based on the compound of Formula V-1, V-1-F, V-2-F, V-1-EF, V-3, V-5 , V-5-F, V-6E-F, V-7-F, or V-5-EF.

[00106] In some embodiments of the processes for preparing the compounds of formulas I-095, 1-181, 1-191, 1-192, 1-193, I-205, I206, I-208, 1-211, 1- 212, 1-213, I-220, I-229, 1-231, I-233, I-234, I-258, I259, I-262, I-263, and I-285 as described above,

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94/147 the stereochemistry of the fragment

in the stereomerically enriched compound of formulas V-1, V-1F, V-2-F, V-1-EF, V-3, V-5, V-5-F, V-6-EF, V-7- F, or V-5-EF remains substantially the same in the stereomerically enriched compound of formulas I-208, I-206, 1-193, I-095, 1-192, 1-191, I-234, I231, I-233 , 1-181, 1-211, 1-212, 1-213, I-262, I-263, I-258, I-259, I-205, I220, I-229, or I-285. R ² can be hydrogen or F as described above. [00107] In some embodiments of the processes for preparing the compounds of formulas I-095, 1-181, 1-191, 1-192, 1-193, I-205, I206, I-208, 1-211, 1- 212, 1-213, I-220, I-229, 1-231, I-233, I-234, I-258, I259, I-262, I-263, and I-285 as described above, the acid in the deprotection zone it is selected from the group consisting of hydrochloride, formic acid, trifluoroacetic acid, and sulfuric acid. For example, in some embodiments, the acid in the deprotection zone comprises formic acid or sulfuric acid.

[00108] In some embodiments of the processes for preparing the compounds of formulas I-095, 1-181, 1-191, 1-192, 1-193, I-205, I206, I-208, 1-211, 1- 212, 1-213, I-220, I-229, 1-231, I-233, I-234, I-258, I259, I-262, I-263, and I-285 as described above, the amide it is formed in the presence of an amide coupling reagent in a reaction medium. As a non-limiting example, the amide coupling reagent can be selected from the group consisting of (benzotriazol-1-yloxy) hexafluorophosphate tris (dimethylamino) phosphonium (BOP), 3 (diethoxyphosphoryloxy) -1,2,3-benzotriazin -4 (3H) -one (DEPBT), Ν, N-dicyclohexylcarbodiimide (DCC), Λ /, Λ / '- diisopropylcarbodiimide (DIC), 1- [bis (dimethylamino) methylene] hexafluorophosphate - 1 H-1,2,3-triazolo [4,5-b]

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95/147 pyridinium 3-oxide (HATU), 3- [bis (dimethylamino) methyliumyl] -3H-benzotriazole-1-oxide (HBTU), 3-hydroxytriazole [4,5-b] pyridine (HOAt), hexafluorophosphate of (7-azabenzotriazol-1-yloxy) tripyrrolidinophosphonium (PyAOP), (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and propylphosphonic anhydride (T3P). For example, the amide coupling reagent can be either HATU or T3P.

[00109] Alternatively, the amide can be formed by converting the stereomerically enriched compound of formulas VIII-1-4, VIII-1-F-5, VIII-2-F-4, or VIII-1-EF-6 to a chloride of corresponding acid and reacting the acid chloride compound with isopropylamine.

E. Alkylation of α-Bromoester and Formation of Ether

[00110] Also provided herein are processes which are useful for preparing stereomerically enriched compounds of formulas I-064, I-089, I-090, I-246, and 1-251 as described here.

[00111] For example, a process for preparing a stereomerically enriched compound of Formula I064 is provided here:

or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-1-T-F:

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Formula V-1-T-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising the reaction medium; react with an XCH2C (O) OR3 compound in the α-alkylation zone, thereby providing a formula VII-1 -T-F-7 stereomerically enriched compound:

Formula VII-1-T-F-7 or a salt thereof; treating the Formula VII-1-T-F-7 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-1-TF-7 carboxylic acid compound:

Formula VIII-1-T-F-7 or a salt thereof; form an isopropylamine amide in an amide forming zone, thereby providing a compound

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97/147 stereomerically enriched Formula IX-1-T-F-7:

Formula IX-1-TF-7 or a salt thereof; and contacting the Formula IX-1-TF-7 compound or salt with a reducing agent in a reducing zone, thereby providing the stereomerically enriched compound or Formula I-064 salt; where X is Cl or Br, and R ³ is selected from the group consisting of methyl and ethyl.

[00112] In the compound of Formula XCH2C (O) OR ³ , X can be Cl. Alternatively, X can be Br.

[00113] In the compounds of formulas XCH ₂ C (O) OR ³ , VII-1-TF-7, VIII-1-TF-7, and IX-1-TF-7, R ³ can be methyl. Alternatively, R ³ can be ethyl.

[00114] A process for preparing a stereomerically enriched compound of Formula I-089 or I090 is also provided here:

I-089

or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-2-T-F:

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Formula V-2-TF or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising the reaction medium; react with an XCH2C (O) OR ³ compound in the α-alkylation zone, thereby providing a formula VII-2-TF-7 stereomerically enriched compound:

Formula VII-2-T-F-7 or a salt thereof; treating the Formula VII-2-T-F-7 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-2-TF-7 carboxylic acid compound:

Formula VIII-2-T-F-7 or a salt thereof; form an amide with / V-methylisopropylamine

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99/147 in an amide-forming zone, thereby providing a formula IX-2-T-F-7 stereomerically enriched compound:

Formula IX-2-T-F-7 or a salt thereof; contacting the Formula IX-2-T-F7 compound or salt with a reducing agent in a reducing zone, thereby providing a Formula I-I-089/090 compound:

or a salt thereof; and separating the Formula I089 / 090 compound or salt, thereby providing the stereomerically enriched compound or Formula I-089 or I-090 salt; where X is Cl or Br, and R ³ is selected from the group consisting of methyl and ethyl.

[00115] In the compound of Formula XCH2C (O) OR ³ , X can be Cl. Alternatively, X can be Br.

[00116] In the compounds of formulas XCH ₂ C (O) OR ³ , VII-2-TF-7, VIII-2-TF-7, and IX-2-TF-7, R ³ can be methyl. Alternatively, R ³ can be ethyl.

[00117] A process for preparing a stereomerically enriched compound of Formula 1-251 is also provided here:

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1-251 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-1-E-F:

Formula V-1-E-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising the reaction medium; reacting the product with an XCH2CN compound in the α-alkylation zone, thereby providing a formula VII-1-E-F-8 stereomerically enriched compound:

Formula VII-1-E-F-8 or a salt thereof; treat the Formula VII-1 -E-F-8 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-1 E-F-8 carboxylic acid compound:

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or a salt thereof; and forming an isopropylamine amide in an amide forming zone, thereby providing the stereomerically enriched compound or Formula 1-251 salt; where X is Cl or Br.

[00118] In the compound of Formula XCH2CN, X can be Cl. Alternatively, X can be Br.

[00119] A process for preparing a stereomerically enriched compound of Formula I-246 is also provided here:

I-246 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-8-T-F:

Formula V-8-T-F or a salt thereof, with a strong deprotonating agent in a

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102/147 α-alkylation zone comprising the reaction medium; reacting the product with an XCH2C (O) OR3 compound in the α-alkylation zone, thereby providing a formula VII-8-T-F-7 stereomerically enriched compound:

Formula VII-8-T-F-7 or a salt thereof; treating the Formula VII-8-T-F-7 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-8-TF-7 carboxylic acid compound:

Formula VIII-8-T-F-7 or a salt thereof; form an isopropylamine amide in an amide forming zone, thereby providing a formula IX-8-T-F-7 stereomerically enriched compound:

Formula IX-8-T-F-7 or a salt thereof; and contacting the Formula IX-8-TF-7 compound or salt with a reducing agent in a reducing zone, thereby providing the stereomerically enriched compound or salt of

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Formula I-246; where X is Cl or Br, and R ³ is selected from the group consisting of methyl and ethyl.

[00120] In the compound of Formula XCH2C (O) OR ³ , X can be Cl. Alternatively, X can be Br.

[00121] In the compounds of formulas XCH ₂ C (O) OR ³ , VII-8-TF-7, VIII-8-TF-7, and IX-8-TF-7, R ³ can be methyl. Alternatively, R ³ can be ethyl.

[00122] In some embodiments of the processes for preparing the compounds of formulas I-064, I-089, I-090, and 1-251 as described above, the strong deprotonating agent comprises alkali metal hydride or an alkali metal hydride earthy. In some embodiments, the alkali metal hydride is sodium hydride or potassium hydride. For example, the alkali metal hydride can be sodium hydride.

[00123] Alternatively, the strong deprotonating agent may comprise sodium f-butoxide or potassium f-butoxide. For example, the strong deprotonating agent can comprise potassium f-butoxide.

[00124] In some embodiments of the processes for preparing the compounds of formulas I-064, I-089, I-090, and 1-251 as described above, where X in the compound of Formula XCH2CN is Cl, the reaction medium in The α-alkylation zone also comprises an alkali metal bromide or an alkali metal iodide. In some embodiments, the alkali metal bromide comprises sodium bromide or potassium bromide.

[00125] In some embodiments of the processes for preparing the compounds of formulas I-064, I-089, I-090, and 1-251 as described above, the stereochemistry of the fragment

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in the stereomerically enriched compound of formulas V-1-T-F, V-2-T-F, or V-1-E-F it remains substantially the same in the stereomerically enriched compound of formulas I-064, I-089, I-090, or I251.

[00126] In some embodiments of the processes for preparing the compounds of formulas I-064, I-089, I-090, and 1-251 as described above, the acid in the deprotection zone is selected from the group consisting of hydrochloride, acid formic, trifluoroacetic acid, and sulfuric acid. For example, where the acid in the deprotection zone may comprise formic acid or sulfuric acid.

[00127] In some embodiments of the processes for preparing the compounds of formulas I-064, I-089, I-090, and 1-251 as described above, the amide is formed in the presence of an amide coupling reagent in a medium reaction. As a non-limiting example, the amide coupling reagent can be selected from the group consisting of (benzotriazol-1-yloxy) hexafluorophosphate tris (dimethylamino) phosphonium (BOP), 3- (diethoxyphosphoryloxy) -1,2,3- benzotriazin-4 (3H) one (DEPBT), Λ /, Λ / '- dicyclohexylcarbodiimide (DCC), N, N-diisopropylcarbodiimide (DIC), 1- [bis (dimethylamino) methylene hexafluorophosphate ] -1 H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU), hexafluorophosphate 3- [bis (dimethylamino) methyliumyl] -3 / - / - benzotriazol-1 oxide ( HBTU), 3-hydroxytriazolo [4,5-b] pyridine (HOAt), (7-azabenzotriazol-1-yloxy) tripyrrolidinophosphonium (PyAOP), (benzotriazol-1-yloxy) tripyrrolidinophosphate (pyridine) and pyridine (TR) propylphosphonic (T3P). For example, the amide coupling reagent can be either HATU or T3P.

[00128] Alternatively, the amide can be formed by converting Petition 870190099157, of 10/3/2019, p. 109/202

105/147 if the stereomerically enriched compound of formulas VIII-1-TF-7, VIII-2-TF-7, or VIII-1 -EF-8 and, a corresponding acid chloride and reacting the acid chloride compound with isopropylamine. [00129] In some embodiments of the processes for preparing the compounds of formulas I-064, I-089, I-090, and 1-251 as described above, the reducing agent in the reducing zone comprises a hydride reducing agent. In some embodiments, the hydride reducing agent is selected from the group consisting of lithium borohydride (LiBFU), lithium triethylborohydride (LiBH ^ Hsb), potassium borohydride (KBFU), sodium borohydride (NaBFE) , sodium cyanoborohydride (NaBHsCN), and calcium borohydride (Ca (BH4) 2). For example, the hydride reducing agent may comprise lithium borohydride (L1BH4).

F. Acetylation to Prepare the compound of Formula I-323

[00130] A process for preparing a stereomerically enriched compound of Formula I-323 is also provided here:

I-323 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-3-T-F:

Formula V-3-T-F or a salt thereof, with acetic anhydride or acyl chloride in the price

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106/147 the presence of a base in an acetylation zone comprising the reaction medium, thereby providing the stereomerically enriched compound or Formula I-323 salt.

[00131] In some modalities, the actilation reaction is carried out with acetic anhydride.

[00132] In some embodiments, the base in the acetylation zone is a substituted tertiary amine. For example, the substituted tertiary amine can comprise diisopropylethylamine. Alternatively, the base in the acetylation zone can be a pyridine based base. For example, in some embodiments, the pyridine-based base is selected from the group consisting of pyridine, 2,6-lutidine, and 2,4,6colidine.

G. Separation to Prepare the compound of Formula 1-189

[00133] A process for preparing a stereomerically enriched compound of Formula 1-189 is also provided here:

1-189 or a salt thereof, a process comprising separating a compound of Formula V-7-T-F:

Formula V-7-T-F

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107/147 or a salt thereof, thereby providing the stereomerically enriched compound or Formula 1-189 salt.

[00134] Having described the invention in detail, it will be evident that modifications and variations are possible without departing from the scope of the invention defined in the appended claims.

EXAMPLES

[00135] The following non-limiting examples are provided to also illustrate the present invention.

Example 1: Description of Synthesis of Compound I-074

[00136] 2- {1 - [(2 /?) - 2- (5-fluoro-2-methoxyphenyl) -2-hydroxyethyl] -5-methyl-

2,4-dioxo-6- (2H-1,2,3-triazol-2-yl) -1,4-dihydrothieno [2,3-d] pyrimidin3 (2H) -yl} -2-methylpropanoate 2-methoxyethyl (Compound I-074) was generally synthesized according to Scheme 1 below. The reactions were monitored by analytical HPLC or 400 MHz ¹ H NMR in CDCh.

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Scheme 1: Synthetic scheme for the preparation of Compound I074

K ₂ CO ₃ cat. NaBr

MeCN

isopropylamine

HATU, DIEA

2MeTHF, rt

2.1 2.2

Me _K Ts ^Ph '^ N l [ ^s / R <Me Ph <y ~ [<h ^H catalyst:

RuCI [(S, S) -Tsdpen] (mesitylene)

MS2O 2,6-lutidine DME, rt;

HO then

OMe

Figure Caption: catalyst - lutidine - mesitylene

HPLC was conducted on an AGILENT 1100 HPLC column, AGILENT XDB-C18 50 x 4.6 mm / 1.8 micron; 1.5 ml / minute; solvent A: water (0.1% TFA), solvent B: acetonitrile (0.07% TFA); gradient: 6 minutes, 95% A to 90% B, then 1 minute maintenance, detection at 210 and 254 nm.

Chiral HPLC conditions: /?, /? - Whelk-01, 5 to 75% ethanol in hexanes, 30 minutes: 1.0 mL / minute, column heater at 30 ° C, injection at 5 pL, detection at 220 nm.

[00137] The reactions were monitored by mass spectrometry under the following conditions. LCMS: ESI +/- Polarity, 120 to 750 amu; AGILENT XDB-C18 50 x 4.6 mm / 1.8 micron column; 1.5 ml / minute; solvent A: water (0.1% formic acid), solvent B: acetonitrile (0.07% formic acid); gradient: 5 minutes, 5 to 95% B, then maintenance for 30 seconds, column heater a

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60 ° C. Loop injection: FIA +/- Polarity, 120 to 750amu, MeOH / water (1: 1), 0.3mL / minute, 1.5 minute cycle.

Example 1.2: Preparation of 2-chloro-1- (5-fluoro-2-methoxyphenyl) ethanone (Compound 1.2)

[00138] Compound 1.2 was prepared according to the following scheme.

Scheme 1A2: Synthetic scheme for the preparation of Compound

1.2

1.1 1.2

[00139] 1-fluoro-4-methoxybenzene (Compound 1.1, 38 mL, 330 mmol, 1.2 equivalent) (HPLC reaction time = 3.535) was added to a 500 mL 4-neck flask containing an anhydride mixture methanesulfonic (48.6 g, 279 mmol, 1 equivalent) and chloroacetic acid (32.0 g, 339 mmol, 1.2 equivalent). The mixture was placed in an oil bath under nitrogen and heated to 80 ° C (bath temperature) with mechanical agitation and internal temperature monitoring. The maximum internal temperature was 75 ° C. HPLC analysis after 1.5 hours showed little conversion to ketone 1.2 compound. HPLC after another hour showed 36% conversion to the desired product (retention time = 3,650 minutes) when adjusted for differences in extinction coefficients between starting material and product. Water (49 mL) was added to the mixture dropwise by means of an addition funnel (the oil bath drips, keeping the internal temperature below 95 ° C). The mixture was allowed to stir for 15 minutes, during which time the internal temperature dropped to 73 ° C. n-propanol (100 ml) was added to the mixture and the temperature was raised to 80 ° C. As the reaction was allowed to cool, additional n-propanol was added to maintain a homogeneous solution (20 mL).

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The reaction was seeded at 50 ° C and also allowed to cool to room temperature overnight with continued slow stirring. Crystallization started at ~ 40 ° C. The reaction was cooled to 0 ° C with an ice bath and allowed to stir an additional 1 hour, then the solid was isolated by suction filtration. The solid was washed with 30% cold water in n-propanol (3 x 50 ml, totally dehumidified) and water (3 x 50 ml). The solid (~ 26 g wet) was placed on the nitrogen press (15 scfh) to dry. After 3 hours, the solid was weighed (22.2 g) and returned to the press for 2 hours. No load on the mass was observed. Compound 1.2 (22.2 g; 39%) was isolated as a white crystalline solid. 33% production based on anisole. ¹ H NMR (300 MHz, CDCh) δ ppm 7.59 (dd, J = 8.8, 3.3 Hz, 1H), 7.23 (m, 1H), 6.96 (dd, J = 9, 1.4.0 Hz, 1H), 4.78 (s, 2H), 3.95 (s, 3H).

Example 1.3: Preparation of / V-isopropyl-2-methyl-2- [5-methyl-2,4-dioxo-6- (2H-1,2,3-triazol-2-yl) -1,4-di -hydrothieno [2,3-d] pyrimidin-3 (2H) -yl] propanamide (compound 2.2)

[00140] A 250 mL round bottom flask was loaded with 2.1 acid (15.4 g, 45.9 mmol, 1 equivalent), HATU (19.2 g, 50.5 mmol, 1.1 equivalent), and 2-MeTHF (50 mL, 500 mmol), in sequence, at room temperature. DIEA (20.0 ml, 115 mmol, 2.5 equivalents) and isopropylamine (9.80 ml, 115 mmol, 2.5 equivalents) were added sequentially in a dropwise manner and the resulting mixture was stirred under ambient conditions. When the complete consumption of 2.1 acid was observed by HPLC, the reaction was quenched with 1M aqueous HCI and transferred to a separating funnel containing 1M aqueous HCI and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (2x). The combined organic phases were washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated. The raw material was recrystallized from hot acetone to produce

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111/147 zir amide 2.2 as a brown solid (2 crops, 13.7 g, 79%). ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 11.96 (s, 1 H), 8.14 (s, 2 H), 7.33 (d, J = 8.1 Hz, 1 H), 3.75-3.90 (m, 1 H), 2.47 (s, 3 H), 1.61 (s, 6 H), 0.99 (s, 3 H), 0.97 (s, 3 H).

Example 1.4: Preparation of / V-isopropyl-2-methyl-2- [5-methyl-2,4-dioxo-6- (2H-1,2,3-triazol-2-yl) -1,4-di -hydrothieno [2,3-d] pyrimidin-3 (2H) -yl] propanamide (compound 3.1)

[00141] A 250 mL round bottom flask was loaded with 2.2 amide (2.76 g, 7.33 mmol, 1.0 equivalent), ketone 1.2 (1.78 g, 8.80 mmol, 1, 2 equivalent), potassium carbonate (2.53 g, 18.3 mmol, 2.5 equivalents), sodium bromide (37.7 mg, 0.366 mmol, 5 mol%), and acetonitrile (24.0 mL, 8, 7 in volume), in sequence, at room temperature. The reaction mixture was heated to 50 ° C and the resulting solution was allowed to stir overnight under an ambient atmosphere. After stirring overnight, the reaction did not achieve complete conversion as determined by HPLC analysis. Additional potassium carbonate (1.01 g, 7.33 mmol) was added and the reaction was continued. Since the reaction mixture remained less than 5% amide 2.2 as judged by HPLC, the reaction was quenched by adding water and the product precipitated from the stirring solution. The heterogeneous solution was vigorously stirred for 1 hour and the precipitate was filtered, washed with water, and dried to provide the crude product as a brown solid. The crude material was dissolved in THF (3 ml) and activated carbon (~ 25 mg) was added. The resulting mixture was stirred overnight under ambient conditions. The mixture was filtered over MAGNESOL, eluting with ethyl acetate. The filtrate was concentrated and the raw material was crystallized from hot hexanes / ethyl acetate to provide ketone 3.1 as a light brown solid (two crops, 2.6 g, 66%). ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 8.13-8.17 (m, 2 H), 7.57 (ddd, J = 9.2, 7.6, 3.4 Hz, 1 H ), 7.50 (dd, J =

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9.1, 3.3 Hz, 1 Η), 7.31-7.37 (m, 2 Η), 5.33 (s, 2 Η), 3.99 (s, 3 Η), 3,763.87 (m, 1 Η), 2.54 (s, 3 Η), 1.62 (s, 6 Η), 1.00 (s, 3 Η), 0.98 (s, 3 Η).

Example 1.5: Preparation of 2- {1 - [(2 /?) - 2- (5-fluoro-2-methoxyphenyl) -2hydroxyethyl] -5-methyl-2,4-dioxo-6- (2H-1,2 , 3-triazol-2-yl) -1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl} -N-sopropyl-2-methylpropanamide (compound 4.1)

[00142] A 500 mL round bottom flask was loaded with ketone 3.1 (17.1 g, 31.5 mmol, 1 equivalent), RuCI [(S, S) Tsdpen] (mesitylene) (196 mg, 0.32 mmol, 1 mol%), sodium formate (10.7 g, 158 mmol, 5.0 equivalents), water (15 mL, 0.9 by volume), and isopropanol (15 mL, 0.9 by volume) in sequence under ambient conditions. The reaction mixture was heated to 75 ° C and the progress of the reaction was monitored by HPLC. After stirring ~ 3 hours, HPLC analysis indicated complete consumption of ketone 3.1. The flask was cooled to room temperature, transferred to a 2 L round bottom flask, diluted with water (~ 90 in volume), and stirred for the night. The precipitated solid was filtered, washed with water, dried, and collected to provide the crude product. The resulting precipitate was purified by MPLC (Silica Gold (Bait, 120 g HP Silica), 5 to 40% ethyl acetate in dichloromethane, 85 ml / minute, 12.5 column volume) to provide 4.1 alcohol as a white foam (13.5 g, 76%, 92% enantiomeric excess). Another purification can be done by recrystallizing the material from tert-butyl methyl ether and hot hexanes. ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 8.16 (s, 2 H), 7.20-7.31 (m, 2 H), 7.05 (td, J = 8.5, 3 , 2 Hz, 1 H), 6.93 (dd, J = 9.1, 4.3 Hz, 1 H), 5.82 (d, J = 4.3 Hz, 1 H), 5.29- 5.36 (m, 1 H), 3.94-4.06 (m, 1 H), 3,793.92 (m, 2 H), 3.71 (s, 3 H), 2.51 (s, 3 H), 1.63 (s, 3 H), 1.63 (s, 3 H), 1.01 (s, 3 H), 0.99 (s, 3 H).

Example 1.6: Preparation of 2- {1 - [(2 /?) - 2- (5-fluoro-2-methoxyphenyl) -2hydroxyethyl] -5-methyl-2,4-dioxo-6- (2H-1,2 , 3-triazol-2-yl) -1,4-dihydrothie

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113/147 in [2,3-d] pjrímjdjn-3 (2H) -jl} -2-methoxypropanoate 2-methoxyethyl (compound I-074)

[00143] Alcohol 4.1 was placed in an amber bottle and dried overnight in a vacuum oven set at 60 ° C. The vessel was removed from the vacuum oven, cooled to room temperature, and subsequently used for the next reaction. Subsequent experiments identified that rogorous drying is not essential for the success of the reaction. The groups used within these examples typically contained 0.5% water or less as determined by KF analysis. [00144] A 20 mL scintillation vial was loaded with 4.1 alcohol (218 mg, 0.400 mmol, 1 equivalent) and 1,2-dimethoxyethane (650 pL, 3.0 by volume) under ambient conditions. It should be noted that the increase in the reaction temperature at any point during the course of the reaction to a greater loss of stereochemical integrity. While increasing the reaction temperature to 5 ° C leads to a marginal improvement in stereochemical erosion (loss of ~ 10% chiral integrity of enantiomeric excess) and decreasing the reaction temperature to -40 ° C does not lead to any observable reaction.

[00145] 2,6-lutidine (139 pL, 1.20 mmol, 3.0 equivalent) and methanesulfonic anhydride (115 mg, 660 pmol, 1.65 equivalent) were added sequentially, each as single charges, under ambient conditions and the reaction was sealed with a screw cap which was fitted with a teflon-coated septum. The resulting reaction mixture was aged 2 hours (at least one hour during this activation period is required for complete conversion) at which time 2 methoxyethanol (950 pL, 12.0 mmol, 30 equivalents) was added in one portion and the resulting solution was stirred under ambient conditions. After 24 hours, the reaction reached complete consumption of starting material as determined by HPLC and MS. The resulting reaction mixture was quenched with 1M aqueous HCI (3 mL, 14 by volume) and

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114/147 also diluted with water (~ 10 mL, 60 by volume) which caused the product to precipitate out of solution. The solid was filtered, washed with water, and dried to provide Compound I-074 as a white solid (223 mg, 91%, 79% enantiomeric excess). Additional purification can be performed by RP-MPLC; C18 _aq Gold (Isco, 50g HP C18), 50-100% MeCN in water containing 0.1% TFA, 40 ml / minute, 12.5 column volume. ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 8.16 (s, 2 H), 7.28 (d, J = 8.1 Hz, 1 H), 7.19 (dd, J = 9, 2, 3.2 Hz, 1 H), 7.06-7.14 (m, 1 H), 6.96 (dd, J = 9.1.4.3 Hz, 1 H), 5.09 ( t, J = 6.4 Hz, 1 H), 4.01 (d, J = 6.1 Hz, 2 H), 3.79-3.90 (m, 1 H), 3.70 (s, 3 H), 3.44-3.53 (m, 1 H), 3,343.44 (m, 2 H), 3.26-3.32 (m, 1 H), 3.11 (s, 3 H ), 2.50 (s, 3 H), 1.64 (s, 3 H), 1.61 (s, 3 H), 1.02 (d, J = 5.8 Hz, 3 H), 0 .99 (d, J = 5.8 Hz, 3 H).

Example 1B: Preparation of Compound V-6-T-F-1a (I-400)

[00146] R) -2- (1 - ((R) -2- (5-fluoro-2-methoxyphenyl) -2-hydroxyethyl) -5-methyl-

2,4-dioxo-6- (2H-1,2,3-triazol-2-yl) -1,4-dihydrothieno [2,3-d] pyrimidin

3 (2H) -yl) -N-isopropylpropanamide (Compound V-6-T-F-1a) was generally synthesized according to Scheme 1A.

Scheme 1B: Preparation of Compound V-6-T-F-1a (I-400)

V-6-T-F-1a (I-400)

Figure Caption: mesitylene

Example 1B.1: Preparation of IV-6-T-F-1a

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[00147] Acetonitrile (230 mL, 4400 mmol) was added to a 2 dram vial containing (2R) -N-isopropyl-2- [5-methyl-2,4-dioxo-6- (2H-

1,2,3-triazol-2-yl) -1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl] propanamide (23.0 g, 63.5 mmol), 2 -bromo-1- (5-fluoro-2-methoxyphenyl) ethanone (19 g, 76 mmol), and potassium carbonate (26 g, 190 mmol). The mixture was allowed to stir with a magnetic bar at 50 ° C overnight. After 12 hours, HPLC indicated 100% conversion to the desired product [Formula IV-6-T-F-1a at R = 4,067). The mixture was diluted with water (~ 600 ml). The mixture was stirred for 30 minutes and the solid it formed was isolated by filtration. The solid was dried by suction and high vacuum providing (2R) -2- {1- [2- (5-fluoro-2-methoxyphenyl) -2-oxoethyl] -5-methyl-2,4dioxo-6- ( 2H-1,2,3-triazol-2-yl) -1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl} N-isopropylpropanamide (28.7 g; Yield = 85 , 6%; The product was isolated as an off-white solid.The NMR spectra were consistent with the desired structure.

Example 1B.2: Preparation of V-6-T-F-1a (I-400)

[00148] To a stirring solution of (2R) -2- {1- [2- (5-fluoro-2-methoxyphenyl) -2-oxoethyl] -5-methyl-2,4-dioxo-6- (2H- 1,2,3-triazol-2-yl) -1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl} -N-isopropylpropanamide (0.20 g, 0.38 mmol ) in THF (0.76 ml) at room temperature, triethylamine (1.05 ml, 7.57 mmol) was added. The RuCI [(S, S) -Tsdpen] catalyst (mesitylene) (2.35 mg, 0.00378 mmol) was added to the stirring solution, followed by the dropwise addition of formic acid (0.285 mL, 7.57 mmol) . The reaction was stirred at room temperature and the progress of the reaction was monitored by HPLC. After 12 hours, complete consumption of starting material was observed. Water was added to make the product precipitate out of the solution. The solid was filtered, washed with water, dried, and collected to provide the crude product. The resulting precipitate was dissolved in ethyl acetate, treated with sodium sulfate and DARCO and filtered through magnesol, eluting with ethyl acetate and followed

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116/147 with DCM wash. After evaporation of solvents, the desired product, (2R) -2- {1 - [(2R) -2- (5-fluoro-2-methoxyphenyl) -2-hydroxyethyl] -5-methyl-2,4-dioxo -6- (2H-1,2,3-triazol-2-yl) -1,4-dihydrothieno [2,3-d] pyrimidin3 (2H) -yl} -N-isopropylpropanamide, I-400, was obtained as a white solid (0.10 g; Yield = 51%). Chiral purity as determined by chiral HPLC was 98.3 to 99.3% enantiomeric excess. The NMR spectra were consistent with the desired structure.

Example 2: Description of the synthesis of Compound i-095

[00149] 2- {1 - [(2R) -2- (2-cyanoethoxy) -2- (5-fluoro-2-methoxyphenyl) ethyl] -5methyl-2,4-dioxo-6- (2H-1, 2,3-triazol-2-yl) -1,4-dihydrothieno [2,3-d] pyrimidin3 (2H) -yl} -N-isopropyl-2-methylpropanamide (compound i-095) was generally synthesized from according to Scheme 3 below. The reactions were monitored by analytical HPLC or 400 MHz ¹ H NMR in CDCh.

Scheme 3: Synthetic scheme for the preparation of Compound I095

2.5 eq. K2CO3 5% NaBr

MeCN 50 ° C, 16h 91%

i-095

catalyst:

RuCI [(S, S) -Tsdpen] (mesitylene)

Figure Caption: catalyst - mesitylene

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Example 2.2: Preparation of 2- {1 - [(2R) -2- (2-cyanoethoxy) -2- (5-fluoro2-methoxyphenyl) ethyl] -5-methyl-2,4-dioxo-6- ( 2H-1,2,3-triazol-2-yl) -1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl} -2-tert-butyl methylpropanoate (compound 24)

[00150] 43% aqueous potassium hydroxide (21 μΙ_, 23 μιτιοΙ, 26 mol%) was added to a stirring solution at 0 ° C of 2- {1 - [(2R) -2 (5-fluoro-2 -methoxyphenyl) -2-hydroxyethyl] -5-methyl-2,4-dioxo-6- (2H-1,2,3-triazol-2-yl) -1,4-dihydrothieno [2,3-d ] tert-butyl pyrimidin-3 (2H) -yl} -2-methylpropanoate (compound 23, 50 mg, 89 pmol) (HPLC reaction time = 4.870 minutes) and 2-propenonitrile (600 μΙ_, 9.13 mmol , 5 equivalents) in acetonitrile (5 ml). The mixture was allowed to stir for 1.5 hours. HPLC indicated 97% conversion to ether 24 (retention time = 4.978 minutes) with a small starting alcohol 23 remaining (3%). The mixture was allowed to stir an additional hour at 0 ° C. HPLC indicated similar conversion, so the reaction was quenched with water (10 mL) at 0 ° C. The mixture was allowed to stir 30 minutes. The solid that formed was isolated by filtration and dried under ambient conditions overnight to provide Compound 24 (50 mg; 91%) as a brown solid. HPLC indicated 95% purity. ¹ H NMR (300 MHz, DMSO-cfe) δ ppm 8.16 (s, 2H), 7.16 (m, 2H), 7.00 (m, 1H), 5.16 (t, J = 6, 1 Hz, 1H), 4.08 (m, 2H), 3.72 (s, 3H), 3.51 (m, 2H), 2.69 (t, J = 5.7 Hz, 2H), 2 , 53 (s, 3H), 1.59 (s, 3H), 1.63 (s, 3H), 1.38 (s, 9 H).

Example 2.3: Preparation of 2- {1 - [(2R) -2- (2-cyanoethoxy) -2- (5fluoro-2-methoxyphenyl) ethyl] -5-methyl-2,4-dioxo-6- (2H -1,2,3-triazol-2-yl) -

1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl} -2-methylpropanoic (compound 25)

[00151] Formic acid (3.0 mL, 80 mmol, 5 by volume) was added to a 2 dram vial containing a mixture of Compound 24 (0.580 g, 0.947 mmol) and ethanol (3.0 mL, 51 mmol, Volume). THE

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The mixture was allowed to stir on a heating block at 80 ° C overnight. HPLC after 18 hours indicated 96% conversion. After another 6 hours, the conversion reached 99%. The mixture was concentrated to half the original volume, diluted with water (5 ml), and allowed to stir overnight. The light brown solid that formed was isolated by filtration and washed with water to provide Compound 25 (465 mg; 88%) as a brown solid. ¹ H NMR (300 MHz, DMSO-cfe) δ ppm 12.38 (br, s., 1H), 8.17 (m, 2H), 7.16 (m, 2H), 6.99 (m, 1H ), 5.15 (t, J =

6.2 Hz, 1H), 4.08 (m, 2H), 3.72 (s, 3H), 3.52 (m, 2H), 2.69 (t, J = 5.9 Hz, 2H) , 2.52 (br, s., 3H), 1.64 (d, J = 3.8 Hz, 6 H).

Example 2.4: Preparation of 2- {1 - [(2 /?) - 2- (2-cyanoethoxy) -2- (5-fluoro2-methoxyphenyl) ethyl] -5-methyl-2,4-dioxo-6- ( 2H-1,2,3-triazol-2-yl) -1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl} -N-isopropyl-2-methylpropanamide (Compound 1-095)

[00152] Compound 24 (252 mg, 0.45 mmol) (HPLC reaction time = 3.913 min) and HATU (207 mg, 0.54 mmol, 1.2 equivalent) were added to a 1 dram vial, followed by by methylene chloride (0.76 ml) and 2-propanamine (116 pL, 1.35 mmol, 3 equivalents). The mixture was allowed to stir at room temperature overnight. The reaction became very dark on the addition of the amine. HPLC after 18 hours indicated ~ 95% conversion. The mixture was allowed to stir for 4 hours. HPLC indicated complete conversion. The mixture was diluted with ethyl acetate (30 ml) and washed with water. 1N aqueous HCI, water, saturated sodium bicarbonate, and brine (10 mL each). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was loaded onto diatomaceous earth with dichloromethane and dried by suction. The material was purified by reverse phase MPLC (C18 _aq Gold (Bait, 50g HP C18), 35 to 100% MeCN in water containing 0.1% TFA, 40 ml / minute, 13 in column volume). The purest fractions containing the product were

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119/147 combined and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with saturated sodium bicarbonate and brine (20 ml each). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. The pure product was dissolved in a small amount of methanol and concentrated to remove the residual solvent. The material was placed under high vacuum overnight. Compound I-095 (160 mg, 59%) was isolated as a white amorphous solid. An HPLC provides very high purity and chiral HPLC showed 98.6% enantiomeric excess for the R. ¹ H NMR (300 MHz, DMSO-cfe) δ ppm 8.15 (s, 2H), 7.24 (dd) enantiomer , J = 9.2, 3.1 Hz, 1H), 7.13 (m, 2H), 6.99 (m, 1H), 5.15 (t, J = 6.4 Hz, 1H), 4 , 04 (d, J = 6.3 Hz, 2H), 3.85 (m, 1H), 3.72 (s, 3H), 3.52 (m, 2H), 2.69 (t, J = 5.8 Hz, 2H), 2.51 (s, 3H), 1.63 (d, J = 8.9 Hz, 6 H), 1.00 (d, J = 4.8 Hz, 3H), 1.02 (d, J = 4.8 Hz, 3H).

Example 3: Description of Synthesis of Compound 1-181

[00153] 1 - [(2R) -2- (2-cyanoethoxy) -2- (5-fluoro-2-methoxyphenyl) ethyl] -3- [2 (isopropylamino) -1, 1-dimethyl-2-oxoethyl] Ethyl -5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate (compound 1-181) was generally synthesized according to Scheme 4 below . The reactions were monitored by analytical HPLC or 400 MHz ¹ H NMR in CDCh.

[00154] Analytical HPLC conditions used an AGILENT 1100 HPLC column, AGILENT ZORBAX XDB C18 50x4.6 mm, 1.8 micron. Solvent A: water (0.1% TFA); solvent B: acetonitrile (0.07% TFA); gradient: 5 minutes, 95% A to 90% B, 1 minute maintenance, then recycling to 95% A; UV detection at 214 and 254 nm. The reported percentage area was determined at 214 nm.

[00155] Chiral determination was performed in intermediates on a CHIRALCEL IA-3 column, with conditions in 2 to 12% of

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IPA / hexanes, 30 minutes, 1.0 mL / minute, column temperature at 30 ° C, detection at 220 nm.

[00156] Chiral determination was performed on the final product 1-181 on a (R, R) -Whelk-01 column with conditions at 5 to 75% EtOH / hexanes, 30 minutes, 1.0 mL / minute, column temperature at 30 ° C, detection at 220 nm.

Scheme 4: Synthetic scheme for the preparation of Compound I181

o 1.CDI, Et ₃ N

CH ₃ CN, 50 ° C

K ₂ CO ₃ , cat. NaBr

MeCN, 60 ° C

HCI o

catalyst:

RuCI [(S, S) -Tsdpen] (mesitylene)

Figure Caption: catalyst - oxalyl chloride - next - or Isopropylamine - propylphosphonic anhydride - mesitylene

Example 3.2: Preparation of diethyl 5 - {[(2-tert-butoxy-1,1-dimethyl-2-oxoethyl) carbamoyl] amino} -3-methylthiophene-2,4-dicarboxylate (compound 3)

[00157] A stirred heterogeneous mixture of diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate (compound 2, 9.00 g, 35.0 mmol) in dry acetonitrile (45 mL) under nitrogen was treated with ICD (7.09 g, 43.7 mmol) followed by triethylamine (24.4 mL, 175 mmol). The mixture was heated to 50 ° C. The resulting homogeneous mixture was stirred at

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50 ° C for 4 hours, during which time HPLC indicated complete conversion to the acyl imidazole intermediate. HPLC was performed in aliquots of the mixture satiated with morpholines. Tert-butyl 2-methylalaninate hydrochloride (8.56 g, 43.7 mmol) was added to form a slightly heterogeneous mixture. The mixture was stirred at 50 ° C for 1.5 hours. Stirring was continued overnight at room temperature. The mixture was diluted with water (100 ml), and the resulting solids were filtered, washed with water (6 x 30 ml), and dried in a vacuum oven at 40 ° C over the weekend to provide Compound 3 ( 15.55 g, 100%) as a white solid. HPLC indicated a purity greater than 99% (retention time 5.44 minutes). ¹ H NMR (300 MHz, DMSO-c / e) δ ppm 10.60 (s, 1H), 8.41 (s, 1H), 4.33 (q, J = 6.9 Hz, 2H), 4 , 22 (q, J = 6.9 Hz, 2H), 2.66 (s, 3H), 1.37 (s, 9H), 1.38-1.24 (m, 12H).

Example 3.3: Preparation of 3- (2-tert-butoxy-1,1-dimethyl-2-oxoethyl) 5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3- d] ethyl-pyrimidine-6carboxylate (compound 4)

[00158] A stirred heterogeneous mixture of Compound 3 (12.00 g, 27.12 mmol) in dry acetonitrile (120 mL) under nitrogen was treated with potassium tert-butoxide (6.08 g, 54.2 mmol). The brown mixture, almost homogeneous, was stirred at room temperature. Within minutes, the mixture became cloudy. HPLC, after a retention time of 12 minutes, showed ~ 2% Compound 3 remaining, with 80% Compound 4 and ~ 8% acid by-product resulting from hydrolysis of Compound 4 ethyl ester. After 20 minutes reacting, the The reaction was quenched quickly with 0.05 M aqueous citric acid (~ 550 mL, ~ 27 mmol). The mixture cleared during this addition, and the product precipitated to provide a coarse suspension. The mixture was stirred for 8 to 10 minutes, and the solids were filtered, washed with water (5 x 120 ml) and dried in a vacuum oven at 45 ° C during the

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122/147 weekend to provide Compound 4 (8.75 g, 77%) as a white solid. HPLC indicated a purity of 94.1% (retention time 4.75 minutes). ¹ H NMR (300 MHz, DMSO-cfe) δ ppm 12.38 (s, 1H), 4.26 (q, J = 6.9 Hz, 2H), 2.70 (s, 3H), 1.63 (s, 6H), 1.36 (s, 9H), 1.28 (t, J = 6.9 Hz, 3H).

Example 3.4: Preparation of 3- (2-tert-butoxy-1,1-dimethyl-2-oxoethyl) 1- [2- (5-fluoro-2-methoxyphenyl) -2-oxoethyl] -5-methyl-2, Ethyl 4-dioxo-1,2,3,4tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate (compound 5)

[00159] A stirring, thick suspension of Compound 4 (2.00 g, 5.04 mmol) in dry acetonitrile (36 mL) under nitrogen was treated sequentially with 2-chloro-1- (5-fluoro-2-methoxyphenyl) ) ethanone (Compound 1, 1.23 g, 6.05 mmol), NaBr (52 mg, 0.50 mmol) and K2CO3 (1.74 g, 12.6 mmol) while being heated to 60 ° Ç. During the heating, it was necessary to keep the reaction stirred. The resulting pale yellow heterogeneous mixture was stirred at 60 ° C overnight and monitored by HPLC for consumption of Compound 4. In 24 hours, the mixture was cooled to room temperature, diluted with water (40 ml) and extracted with EtOAc (50 ml + 25 ml). The combined organic phase was washed with water (25 ml) and brine (15 ml), dried over MgSO4, and concentrated and dried in vacuo to provide the crude product. The crude product was then triturated with EtOH (12 ml) with sonication and filtered. The solids were washed with EtOH (4x3 ml) and dried in a vacuum oven at 40 ° C for the weekend to provide Compound 5 (2.51 g, 88%) as a weak yellow solid. HPLC indicated 98.5% purity (retention time 5.87 minutes). ¹ H NMR (300 MHz, DMSO-cfe) δ ppm 7.58 (m, 1H), 7.50 (dd, J = 9.0, 3.3 Hz, 1H), 7.35 (dd, J = 9.0, 3.9 Hz, 1H), 5.35 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 3.99 (s, 3H), 2.75 ( s, 3H), 1.63 (s, 6H), 1.35 (s, 9H), 1.26 (t, J = 7.2 Hz, 3H).

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Example 3.5: Preparation of 3- (2-tert-butoxy-1,1-dimethyl-2-oxoethyl) 1 - [(2R) -2- (5-fluoro-2-methoxyphenyl) -2-hydroxyethyl] -5- methyl-2,4-dioxo-

1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate (compound 6)

[00160] A stirred, thick suspension of Compound 5 (5.40 g, 9.60 mmol) in isopropyl alcohol / water (1: 1, 22 mL) under nitrogen was heated to 50 ° C and treated with sodium formate (3.26 g, 48.0 mmol) and RuCI [(S, S) -Tsdpen] (mesitylene) (60.0 mg, 0.0964 mmol). The resulting mixture was heated to 75 ° C, at which time most of the solids dissolved. The mixture was stirred vigorously for 2 hours, at which time HPLC indicated complete reaction. The mixture was cooled to room temperature, added portionwise to water (~ 150 ml), and stirred for 15 minutes. The resulting solids (some viscous material also formed) were isolated by filtration, rinsing and washing with ~ 5% acetonitrile / water (2 x 50 mL). Filtration became slow, and a significant amount of viscous residue was established. Because of the viscous residue, it may be necessary to perform an aqueous analysis and then stimulate using a MAGNESOL pad. The solids were dried in the vacuum oven at 40 ° C overnight to provide Compound 6 (5.24 g, 97%) as a light brown foam. A portion of this solid (2.41

g) was absorbed in a minimum of dichloromethane and stimulated through a MAGNESOL pad (7.5 g) using dichloromethane (~ 75 mL) as an eluent. The filtrate was concentrated and dried under high vacuum to provide a quantitative recovery of the product as a beige foam (dark impurities removed). HPLC indicated 98.9% purity (retention time 5.59 minutes). Chiral HPLC, 96.3% enantiomeric excess. ¹ H NMR (300 MHz, DMSO-cfe) δ ppm 7.24 (dd, J = 9.3, 3.0 Hz, 1H), 7.07 (m, 1H), 6.92 (dd, J = 9.3, 4.5 Hz, 1H), 5.84 (d, J = 4.5 Hz, 1H), 5.30 (m, 1H), 4.28 (m, 2H), 3.98 ( m, 2H), 3.69

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124/147 (s, 3H), 2.72 (s, 3H), 1.60 (s, 3H), 1.58 (s, 3H), 1.37 (s, 9H), 1.30 (t , J = 7 Hz, 3H).

Example 3.6: Preparation of 3- (2-tert-butoxy-1,1-dimethyl-2-oxoethyl) 1 - [(2R) -2- (2-cyanoethoxy) -2- (5-fluoro-2-methoxy- phenyl) ethyl] -5-methyl-2,4dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate (compound 7)

[00161] A stirred mixture of Compound 6 (2.77 g, 4.90 mmol) in acetonitrile (28 mL) under nitrogen was cooled to 0 to 5 ° C and treated with acrylonitrile (1.61 mL, 24.5 mmol ) followed by 40% aqueous KOH (150 pL, 1.5 mmol). The resulting mixture was stirred at 0 to 5 ° C and monitored by HPLC for consumption of Compound 6. In 3 hours, the mixture was diluted dropwise with water (80 ml) and extracted with EtOAc (80 ml). The organic phase was washed with water (50 ml) and brine (25 ml), dried over MgSO4, and concentrated and dried in vacuo. The crude product [3.01 g of light brown foam at 93.8% HPLC purity, 93% yield] was combined with a similar batch of product and purified by silica gel chromatography (40 g cartridge, 10 to 30% EtOAc / hexanes eluent) to provide 86% (average combined production) of Compound 7 as a white foam. Chromatography on silica gel was used to provide an update in purity at this stage, as initial attempts to crush or crystallize failed in the chiral series. HPLC indicated 96.4% purity (retention time 5.67 minutes). Chiral HPLC, 96.8% enantiomeric excess. ¹ H NMR (300 MHz, DMSO-cfe) δ ppm 7.20 (dd, J = 9.3, 3.0 Hz, 1H), 7.14 (m, 1H), 7.00 (dd, J = 9.0, 4.2 Hz, 1H), 5.15 (m, 1H), 4.28 (m, 2H), 4.23 (m, 1H), 4.00 (m, 1H), 3, 71 (s, 3H), 3.50 (m, 2H), 2.71 (s, 3H), 2.68 (m, 2H), 1.60 (s, 3H), 1.57 (s, 3H ), 1.37 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H).

Example 3.7: Preparation of 2- {1 - [(2R) -2- (2-cyanoethoxy) -2- (5fluoro-2-methoxyphenyl) ethyl] -6- (ethoxycarbonyl) -5-methyl-2,4- dioxo-2,4-di

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125/147 hjdrotjeno [2,3-d] pjrímjdjn-3 (2H) -jl} -2-metjlpropanojco (compound 8)

[00162] Compound 8 was prepared as described below, by methods using formic acid (Example 3.7a) or sulfuric acid (Example 3.7b).

Example 3.7a: Preparation of Compound 8 using formic acid [00163] A stirred mixture of Compound 7 (4.87 g, 7.88 mmol) in EtOH (24 ml) under nitrogen was treated with formic acid (24 ml), and the mixture was heated to mild reflux (78-80 ° C) and monitored by HPLC for consumption of Compound 7. In 48 hours, the mixture was cooled to room temperature and stirred overnight to let the product precipitate. The resulting solids were isolated by filtration, rinsing with water (3 x 15 ml) and washing with water (4 x 20 ml), and dried in the vacuum oven at 45 ° C overnight to provide Compound 8 (3.33 g, 75%) as a white solid. HPLC indicated 98.1% purity (retention time 4.49 minutes). The filtrate was extracted with EtOAc (50 ml), and the organic phase was washed with water (25 ml) and brine (20 ml), dried over MgSO4 and concentrated and dried in vacuo to provide additional crude product (77% pure). HPLC). These solids were suspended in isopropyl alcohol (9.5 ml, 10 V) for 1 hour, filtered, washed with isopropyl alcohol (4 x 1 ml), and dried in a vacuum oven at 45 ° C overnight to provide the Additional compound 8 (655 mg, 14%) as a white solid. HPLC, 93.2% purity (4.48 minutes retention time).

Example 3.7b: Preparation of Compound 8 using sulfuric acid [00164] A stirred mixture of Compound 7 (199 mg, 0.322 mmol) in isopropyl alcohol (1 mL) in a small vial was treated with 9 M sulfuric acid (1 mL) dropwise. The resulting thick, white suspension was stirred at room temperature and monitored

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126/147 regarding the consumption of Compound 7. Additional isopropyl alcohol (0.5 mL) and concentrated H2SO4 (2 to 3 drops) were added to fine-tune the suspension and bring the reaction to completion. In 44 hours, the reaction mixture was added dropwise to the water (8 ml), rinsing with additional water (4 ml), and the suspension was stirred for several minutes. The solids were isolated by filtration, washed with water (4x3 ml) and dried in a vacuum oven at 45 ° C overnight to provide Compound 8 (165 mg, 91%) as a white solid. HPLC indicated 97.3% purity (4.47 minutes retention time). ¹ H NMR (300 MHz, DMSO-cfe) δ ppm 12.39 (s, 1H), 7.20 (dd, J = 9.3, 3.0 Hz, 1H), 7.14 (td, J = 8.4, 3.0 Hz, 1H), 6.99 (dd, J = 9.0, 4.2 Hz, 1H), 5.14 (m, 1H), 4.28 (m, 2H), 4.18 (m, 1H), 3.97 (m, 1H), 3.72 (s, 3H), 3.50 (m, 2H), 2.70 (s, 3H), 2.68 (m , 2H), 1.63 (s, 3H), 1.62 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

Example 3.8: Preparation of 1 - [(2R) -2- (2-cyanoethoxy) -2- (5-fluoro-2methoxyphenyl) ethyl] -3- [2- (isopropylamino) -1,1-dimethyl-2-oxoethyl ] -5-methyl-

Ethyl 2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate (1-181)

[00165] Compound 1-181 was prepared with methods using acid chloride (Example 3.8a) and propylphosphonic anhydride (Example 3.8b). Example 3.8a: Preparation of Compound 1-181 using acid chloride

[00166] A flame-dried vial was loaded with Compound 8 (225 mg, 0.401 mmol) and dry dichloromethane (2.2 mL) under nitrogen, and the stirred white suspension was treated with oxalyl chloride (35.6 pL, 0.421) mmol) dropwise, followed by catalytic DMF (6.2 pL, 0.080 mmol). Gas evolution occurred, the mixture initially thinned, and then a precipitate began to form. The resulting suspension was vigorously stirred at room temperature for 2 hours, during which time HPLC (aliquot quenched in MeOH to form

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127/147 methyl ester) indicated <5% remaining compound 8. The mixture was treated with isopropylamine (171 μΙ_, 2.00 mmol) quickly using a syringe below the solvent line to provide a homogeneous mixture. The frasconette was sealed, and the mixture was allowed to stir at room temperature overnight, although the HPLC indicated an almost complete reaction in 15 minutes. The reaction was diluted with dichloromethane (20 ml), washed with water (2x15 ml) and brine (10 ml), dried over Na2SO4, and concentrated and dried in vacuo. The crude product was purified by silica gel chromatography (40 g cartridge, 3555% EtOAc / hexanes eluant) and the product fractions were mixed, concentrated and removed from MeOH several times to provide Compound 1-181 (226 mg, 94%) as a white solid. HPLC indicated 99.7% purity (retention time 4.76 minutes). Chiral HPLC,> 99% enantiomeric excess.

Example 3.8b: Preparation of Compound 1-181 using propylphosphonic anhydride

[00167] A stirred suspension of Compound 8 (100 mg, 0.178 mmol) in dry dichloromethane (1.0 mL) under nitrogen was treated with triethylamine (74.4 pL, 0.534 mmol) dropwise. Once the mixture was cleared, isopropylamine (75.8 pL, 0.890 mmol) and propylphosphonic anhydride (50% in EtOAc, 159 pL, 0.267 mmol) were added dropwise (a slight exotherm was created), and the mixture The resulting mixture was stirred at room temperature. HPLC indicated ~ 88% conversion in 15 minutes, but little change overnight. In 18 hours, additional isopropylamine (15 pL, 1 equivalent) and propylphosphonic anhydride (53 pL, 0.5 equivalent) were added, and the mixture was stirred for 1.5 hours, diluted with dichloromethane (15 ml), washed with water (2x10 ml) and brine (5 ml), dried over Na2SO4, and concentrated and dried in vacuo. Purification by radial chromatography (2000 silica gel rotor, 60% EtOAc / hexanes eluant) provides Compound 1-181

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128/147 (108 mg, 100%) as a white film. HPLC indicated 99.7% purity (4.75 minutes retention time). Chiral HPLC,> 99% enantiomeric excess. ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 7.20 (dd, J = 9.2, 3.2 Hz, 1H), 7.15 (m, 2H), 6.99 (dd, J = 9.2, 4.4 Hz, 1H), 5.13 (m, 1H), 4.28 (m, 2H), 4.10 (m, 1H), 4.00 (m, 1H), 3, 83 (m, 1H), 3.71 (s, 3H), 3.53 (m, 1H), 3.46 (m, 1H), 2.70 (s, 3H), 2.68 (m, 2H ), 1.62 (s, 3H), 1.60 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H), 0.99 (t, J = 6.2 Hz, 6H ).

Example 3.9: Two-Step Preparation of 2-chloro-1- (5-fluoro-2methoxyphenyl) ethanone (Compound 1)

[00168] Compound 1 in Scheme 4 was generally prepared in a two-step procedure according to Scheme 5 below.

Scheme 5: Synthetic scheme for the preparation of Compound 1 of Scheme 4

OMe

1.2 eq AICI ₃

1.4 eq AcCI

DCM, 0-5 ° C (89%)

SO2CI2

DCM (80%)

[00169] Step 1. A jacketed, three-necked 125 mL reaction flask equipped with a temperature probe and nitrogen flask was loaded with ammonium chloride (12.7 g, 95.1 mmol) and dichloromethane (50 mL) . This mixture was cooled to 1 to 2 ° C and 4 fluoroanisole (compound 9, 8.98 mL, 79.3 mmol) was added slowly over a period of 30 minutes to maintain the temperature below 5 ° C. After the mixture again cooled to 1 to 2 ° C, pure acetyl chloride (7.89 ml, 111 mmol) was added dropwise over a period of 30 minutes, keeping the temperature below 5 ° C. The reaction was then allowed to stir at 1 to 2 ° C for 18 hours.

[00170] A round bottom flask of three 1 L necks equipped with a temperature probe and mechanical stirrer was loaded with sodium hydroxide (20.2 g, 504 mmol) and water (200 mL)

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129/147 followed by slow addition of acetic acid (28.7 mL, 504 mmol) while cooling in an ice bath. The homogeneous Friedel-Crafts mixture was diluted with dichloromethane (25 mL) and slowly added dropwise via cannula to this cold solution (0 to 5 ° C) of sodium acetate at a rate that kept the temperature below 8 ° C. Dichloromethane (100 ml) was added after the addition was complete and the mixture allowed to warm to room temperature and stirred for 60 minutes. This solution was transferred to an addition funnel, the layers were separated and the aqueous layer was extracted with dichloromethane (2 x 100 ml). The organic materials were combined, washed with 1N NaOH (3 x 75 mL), dried with anhydrous sodium sulfate and concentrated. This provided 11.9 g (89% yield, 96% area) of Compound 10 as an oil. ¹ H NMR (400 MHz, CDCh) δ ppm 2.64 (s, 3 H) 3.92 (s, 3 H) 6.94 (dd, J = 9.09, 4.04 Hz, 1 H) 7 , 18 (ddd, J = 9.09, 7.33, 3.28 Hz, 1 H) 7.48 (dd, J = 8.97, 3.16 Hz, 1 H); HPLC reaction time: 3.39 min; MS (ESI +) for C9H ₉ FO ₂ m / z 169.1 (M + H) ⁺ .

[00171] Step 2. A three-neck, 100-ml round-bottom flask equipped with a pressure equalized addition funnel, temperature probe and a nitrogen flask was loaded with Compound 10, Scheme 5 (11.9 g, 70 , 8 mmol), methanol (11 mL), and dichloromethane (36 mL). This solution was cooled in an ice bath to ~ 5 ° C and a solution of sulfuryl chloride (8.0 mL, 99 mmol) in dichloromethane (14 mL) was added dropwise at a rate to maintain the reaction temperature below 15 ° C. After the addition was complete, the ice bath was removed and the reaction was allowed to warm to room temperature for 1 hour. This mixture was cooled to 0 to 5 ° C and a solution of water (12 ml) and ethanol (47.6 ml) was added dropwise over a period of 20 minutes. This material was transferred to a 500 mL vial and concentrated in vacuo

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130/147 cuo until the dichloromethane is removed, resulting in a suspension containing a white precipitate. This solid was collected and washed with 75% ethanol / water (2 x 20 ml) and water (2 x 20 ml). The material was dried in a nitrogen press to provide 11.6 g (80% yield, 98% area) of Compound 1 as a white solid. ¹ H NMR (400 MHz, CDCh) δ ppm 3.96 (s, 3 H) 4.80 (s, 2 H) 6.98 (dd, J = 9.09, 4.04 Hz, 1 H) 7 , 17 - 7.32 (m, 1 H) 7.62 (dd, J = 8.84, 3.28 Hz, 1 H); HPLC reaction time: 3.73 minutes. MS (ESI +) for C9H8CIFO2 m / z 203.0 (M + H) ⁺ .

Example 3.10: Preparation of Three Steps of 2-chloro-1- (5-fluoro-2methoxyphenyl) ethanone (Compound 1)

[00172] Compound 1 in Scheme 4 was generally prepared in a three step procedure according to Scheme 6 below.

Scheme 6: Synthetic scheme for the preparation of Compound 1 of Scheme 4

OMe

1.2 eq AICI3

1.4 eq AcCI

DCM, 0-5 ° C (97%)

DMS, K ₂ CO ₃

Acetone, Δ (98%)

SO2CI2

DCM (89%)

[00173] Step 1. A three-necked, 125-mL jacketed reaction flask equipped with a temperature probe and nitrogen flask was loaded with ammonium chloride (12.7 g, 95.1 mmol) and dichloromethane (50 mL) . This mixture was cooled to 1 to 2 ° C and 4 fluoroanisole (compound 9, 8.98 mL, 79.3 mmol) was added slowly over a period of 30 minutes to maintain the temperature below 5 ° C. After the mixture again cooled to 1 to 2 ° C, pure acetyl chloride (7.89 ml, 111 mmol) was added dropwise over a period of 30 minutes, keeping the temperature below ° C. The reaction was then allowed to stir at 1 to 2 ° C for 18 hours

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131/147 ras.

[00174] A three-necked, 1 L round-bottom flask equipped with a temperature probe and mechanical stirrer was charged with sodium hydroxide (20.2 g, 504 mmol) and water (200 mL) followed by slow addition of acid acetic (28.7 mL, 504 mmol) while cooling in an ice bath. The homogeneous Friedel-Crafts mixture was diluted with dichloromethane (25 mL) and slowly added dropwise via cannula to this cold solution (0 to 5 ° C) of sodium acetate at a rate that kept the temperature below 8 ° C. Dichloromethane (100mL) was added after the addition was complete and the mixture allowed to warm to room temperature and stirred for 60 minutes. This solution was transferred to an addition funnel, the layers were separated, and the aqueous layer was extracted with dichloromethane (2 x 100 ml). The organic materials were combined, dried with anhydrous sodium sulfate, and concentrated. This provided 13.0 g (97% yield, 98% area) of a 4.1: 1 mixture of 1- (5-fluoro-2-methoxyphenyl) ethanone (Compound 10) and 1- (5-fluoro -2-hydroxyphenyl) ethanone (Compound 11) as an oil.

Compound 10: ¹ H NMR (400 MHz, CDCh) δ ppm 2.64 (s, 3 H) 3.92 (s, 3 H) 6.94 (dd, J = 9.09, 4.04 Hz, 1 H) 7.18 (ddd, J = 9.09, 7.33, 3.28 Hz, 1 H) 7.48 (dd, J = 8.97, 3.16 Hz, 1 H); HPLC reaction time: 3.39 minutes; MS (ESI +) for C9H ₉ FO ₂ m / z 169.1 (M + H) ⁺ .

Compound 11: ¹ H NMR (400 MHz, CDCh) δ ppm 2.64 (s, 3 H) 6.98 (dd, J = 9.09, 4.55 Hz, 1 H) 7.17 - 7.30 (m, 1 H) 7.42 ( dd, J = 8.84, 3.03 Hz, 1 H) 12.00 (s, 1 H); HPLC reaction time: 3.37 min; MS (ESI +) for C ₈ H ₇ FO ₂ m / z 153.0 (M + H) ⁺ .

[00175] Step 2. The mixture of 4.1: 1 of Compound 10 (10.4 g, 61.8 mmol) and Compound 11 (2.54 g, 16.5 mmol) was dissolved in acetone (50 mL) and potassium carbonate (2.50 g, 18.1 mmol) and dimethyl sulfate (0.25 mL, 2.6 mmol) were added. The reaction was refluxed du

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132/147 for 18 hours, cooled to room temperature, and water (20 mL) added. This mixture was stirred at room temperature for 3 hours and divided between dichloromethane and brine (50 ml each). The layers were separated and the aqueous layer was extracted with dichloromethane (3 x 50 ml). The organic materials were combined, dried with anhydrous sodium sulfate, and concentrated. This provided 13.0 g (98% yield, 97 area%) of Compound 10 as a yellow oil. ¹ H NMR (400 MHz, CDCh) δ ppm 2.64 (s, 3 H) 3.92 (s, 3 H) 6.94 (dd, J = 9.09, 4.04 Hz, 1 H) 7 , 18 (ddd, J = 9.09, 7.33, 3.28 Hz, 1 H) 7.48 (dd, J = 8.97, 3.16 Hz, 1 H); HPLC reaction time: 3.39 minutes; MS (ESI +) for C9H9FO2 m / z 169.1 (M + H) ⁺ .

[00176] Step 3. A three-neck, 100-ml round-bottom flask equipped with a pressure equalized addition funnel, temperature probe and a nitrogen flask was loaded with Compound 10 (13.0 g, 77.3 mmol ), methanol (12 ml), and dichloromethane (40 ml). This solution was cooled in an ice bath to 5 ° C and a solution of sulfuryl chloride (8.8 mL, 110 mmol) in dichloromethane (16 mL) was added dropwise at a rate to maintain the reaction temperature below 10 ° C. After the addition was completed, the ice bath was removed and the reaction was allowed to warm to room temperature over 1 hour. The reaction mixture was cooled to 0 to 5 ° C and a mixture of water (13 ml) and ethanol (52.0 ml) was added dropwise over a period of 20 minutes. This material was transferred to a 500 ml vial and concentrated in vacuo until the dichloromethane was removed resulting in a suspension containing a white precipitate. This solid was collected, washed with 75% ethanol / water (2 x 20 ml) and water (2 x 20 ml). The material was dried in a nitrogen press to provide 14.0 g (89% yield, 99% area) of Compound 1 as a white solid. ¹ H NMR (400 MHz, CDCh) δ ppm 3.96 (s, 3 H) 4.80 (s, 2 H) 6.98 (dd, J = 9.09, 4.04

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Hz, 1 Η) 7.17 - 7.32 (m, 1 Η) 7.62 (dd, J = 8.84, 3.28 Hz, 1 H); HPLC reaction time: 3.73 minutes. MS (ESI +) for C9H8CIFO2 m / z 203.0 (M + H) ⁺ .

Example 4: Description of Synthesis of Compound 1-191

[00177] 2- {1 - [(2R) -2- (2-cyanoethoxy) -2- (5-fluoro-2-methoxyphenyl) ethyl] -5methyl-2,4-dioxo-6- (1 H-pyrazole -1 -yl) -1,4-d i-hydrothieno [2,3-d] pyrimidin3 (2H) -yl} -N-isopropyl-2-methylpropanamide (compound 1-191) was generally synthesized according to

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Scheme 7 below. The reactions were monitored by analytical HPLC or 400 MHz ¹ H NMR in CDCh.

[00178] Analytical HPLC conditions used an AGILENT 1100 HPLC column, AGILENT ZORBAX XDB C18 50 x 4.6 mm, 1.8 micron. Solvent A: water (0.1% TFA); solvent B: acetonitrile (0.07% TFA); gradient: 5 minutes, 100% A to 100% B, maintenance for 1 minute, then recycling; UV detection at 210 and 254 nm. The reported percentage area was determined at 210 nm.

[00179] Chiral determination was performed for intermediates on a CHIRALCEL IA-3 column, with conditions at 5 to 75% IPA / hexanes, 30 minutes, 1.0 mL / minute, column temperature at 30 ° C, detection at 220 nm. The R / S ratio was 97: 3.

[00180] Chiral determination was performed for the final product I191 on a (R, R) -Whelk-01 column with conditions at 5 to 75% EtOH / hexanes, 30 minutes, 1.0 mL / minute, column temperature at 30 ° C, detection at 220 nm. The R / S ratio was 97.5: 2.5.

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Scheme 7: Synthetic scheme for the preparation of Compound I191

K ₂ CO ₃ , cat. NaBr

MeCN (92%)

40% KOH / H ₂ O MeCN, 0'C (96%)

9M H ₂ SO ₄

ÍPrOH, rt (98%)

T ₃ P, TEA DCM, rt (78%, 95% ee)

KXN Sample NC1233, 95% ee

Reference NC1233, 97% ee

NC1233

Figure caption: dioxane - catalyst - KXN sample - reference Example 4.2: Preparation of 2 - {[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl) carbamoyl] amino} -4-methyl-5- ( 1 H-pyrazol-1-yl) thiophene-3-carboxylate (Compound 13)

[00181] To a well stirred suspension of ethyl 2-amino-4-methyl-5- (1Hpyrazol-1-yl) thiophene-3-carboxylate (Compound 12, 1.0 g, 4.0 mmol) and CDI ( 0.806 g, 4.97 mmol) in dry acetonitrile (5.0 mL) under nitrogen, triethylamine (2.77 mL, 19.9 mmol) was added via syringe. The reaction was then heated to 50 ° C for 3 hours.

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Solid tert-butyl 2-methylalaninate hydrochloride (0.973 g, 4.97 mmol) was then added and stirring at 50 ° C continued for 1 hour, followed by cooling to room temperature and stirring for 72 hours. The reaction was diluted with water (5 ml), stirred for 2 hours, and a precipitate formed. The solids were collected by filtration, washed with water (3x5 mL), and dried under vacuum. This provided 1.59 g (92% yield, 96% area) of Compound 13 as an off-white solid. ¹ H NMR (400 MHz, CDCh) δ ppm 1.41 (t, J = 7.07 Hz, 3 H) 1.49 (s, 9 H) 1.59 (s, 3 H) 1.61 (s , 3 H) 2.22 (s, 3 H) 4.37 (q, J = 7.07 Hz, 2 H) 5.70 (s, 1 H) 6.42 (t, J = 2.15 Hz , 1 H) 7.56 (dd, J = 2.27, 0.51 Hz, 1 H) 7.71 (dd, J = 2.02, 0.51 Hz, 1 H) 10.76 (s, 1 H); HPLC reaction time: 4.68 minutes; MS (ESI ⁺ ) for C20H28N4O5S m / z 437.1 (M + H) ⁺ .

Example 4.3: Preparation of 2-methyl-2- [5-methyl-2,4-dioxo-6- (1Hpyrazol-1-yl) -1,4-dihydrothieno [2,3-d] pyrimidin-3 ( 2H) tert-butyl propylate (Compound 14)

[00182] To a well-stirred suspension of Compound 13 (2.00 g, 4.58 mmol) in dry 1,4-dioxane (60.0 mL) at room temperature under nitrogen was added solid potassium tert-butoxide (2 , 57 g, 22.9 mmol). This mixture was briefly sonicated to provide a coarse suspension and heated to 80 ° C for 30 minutes. Complete conversion was observed. The reaction was cooled to room temperature and diluted with acetic acid (1.43 ml, 25.2 mmol) in water (60 ml). This mixture was stirred at room temperature for 1 hour and a precipitate formed over 0 time. The mixture was then concentrated in vacuo to approximately half the volume and the precipitate was collected, washed with water (3x10 mL) and air dried overnight to provide 1.17 g (65% yield, 99% area) of Compound 14 as a brown solid. ¹ H NMR (400 MHz, CDCh) δ ppm 1.48 (s, 9 H) 1.81 (s, 6 H) 2.41 (s, 3 H) 6.48 (dd, J = 2.40, 1.89

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Hz, 1 Η) 7.68 (dd, J = 2.53, 0.51 Hz, 1 H) 7.75 (dd, J = 2.02, 0.51 Hz, 1 H) 9.77 (brs , 1 H); HPLC reaction time: 3.98 minutes. MS (ESI ⁺ ) for C18H22N4O4S m / z 391.2 (M + H) ⁺ .

Example 4.4: Preparation of 2- {1- [2- (5-fluoro-2-methoxyphenyl) -2oxoethyl] -5-methyl-2,4-dioxo-6- (1 H-pyrazol-1-i 1 ) Tert-Butyl -1,4-dihydrothieno [2,3d] pyrimidin-3 (2H) -yl} -2-methylpropanoate (Compound 15)

[00183] A suspension of 2-chloro-1- (5-fluoro-2-methoxyphenyl) ethanone (Compound 1) (3.61 g, 17.8 mmol), compound 14 (5.81 g, 14.9 mmol ), K2COs (5.13 g, 37.1 mmol) and NaBr (306 mg, 2.97 mmol) in dry acetonitrile (60 mL) was stirred at 50 ° C under nitrogen. After 18 hours, the mixture was allowed to cool to room temperature, diluted with water (60 ml) and stirred at room temperature for 2 hours. The precipitated product was isolated by filtration, washed with water (3 x 30 ml), and dried in vacuo. This provided 7.63 g (92% yield, 99% area) of Compound 15 as a white solid. ¹ H NMR (400 MHz, CDCh) δ ppm 1.47 (s, 9 H) 1.81 (s, 6 H) 2.46 (s, 3 H) 4.01 (s, 3H) 5.25 ( s, 2 H) 6.46 (dd, J = 2.53, 2.02 Hz, 1 H) 7.02 (dd, J = 9.22, 3.92 Hz, 1 H) 7.25 - 7 , 34 (m, 1 H) 7.64 (dd, J = 8.84, 3.28 Hz, 1 H) 7.67 (dd, J = 2.53, 0.51 Hz, 1 H) 7, 68 - 7.71 (m, 1 H); HPLC reaction time: 5.12 minutes. MS (ESI ⁺ ) for C27H29FN4O6S m / z 557.1 (M + H) ⁺ .

Example 4.5: Preparation of 2- {1 - [(2R) -2- (5-fluoro-2-methoxyphenyl) -2hydroxyethyl] -5-methyl-2,4-dioxo-6- (1 H-pyrazol-1 - il) tert-butyl -1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl} -2-methylpropanoate (Compound 16)

[00184] To a well stirred mixture of Compound 15 (7.00 g, 12.6 mmol), RuCI [(S, S) -Tsdpen] (mesitylene) (79 mg, 0.13 mmol), sodium formate ( 4.29 g, 63.1 mmol) and water (28 mL) under nitrogen wasopropyl alcohol (28 mL, 360 mmol) was added. The reaction was then heated to 75 ° C for 60 minutes. The reduction was complete and the mis

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138/147 mixture was added to a vial containing water (200 ml) and allowed to stir at room temperature overnight. The precipitate that formed was filtered, washed with water (3 x 30 ml), and air-dried to provide 7.01 g (99% yield, 99% area) of Compound 16 as an off-white solid. ¹ H NMR (400 MHz, CDCh) δ 1.49 (s, 9 H) 1.81 (s, 6 H) 2.43 (s, 3 H) 3.74 (d, J = 6.32 Hz, 1 H) 3.90 (s, 3 H) 4.01 - 4.17 (m, 1 H) 4.19 - 4.31 (m, 1 H) 5.2 - 5.4 (m „1 H ) 6.50 (dd, J = 2.40, 1.89 Hz, 1 H) 6.83 (dd, J = 8.97, 4.17 Hz, 1 H) 6.92 - 7.04 (m , 1H) 7.22 7.32 (m, 1H) 7.64 - 7.72 (m, 1 H) 7.72 - 7.79 (m, 1 H); HPLC reaction time: 4.84 minutes. Chiral HPLC: 94% enantiomeric excess; MS (ESI ⁺ ) for C27H31FN4O6S m / z 559.2 (M + H) ⁺ .

Example 4.6: Preparation of 2- {1 - [(2R) -2- (2-cyanoethoxy) -2- (5-fluoro2-methoxyphenyl) ethyl] -5-methyl-2,4-dioxo-6- (1 H -pyrazol-1 -11) -1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl} -2-tert-butyl methylpropanoate (Compound 17)

[00185] To a well stirred mixture of Compound 16 (1.0 g, 1.8 mmol) and acrylonitrile (2.50 mL, 38.0 mmol) in dry acetonitrile (10.0 mL) at 0 ° C were added 40% aqueous KOH (1.20 mL, 12.0 mmol). This mixture is allowed to stir at 0 to 5 ° C for 18 hours. The mixture was allowed to warm to room temperature and water (10 ml) was added. The mixture was partitioned between dichloromethane (50 ml) and brine (20 ml), the layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 20 ml). The organic materials were combined, dried with anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel chromatography (Silicycle, 230400 mesh, 100 g, elution with 20 to 50% ethyl acetate / hexane) to provide 1.04 g (96% of production, 99% of area) of Compound 17 as a white foam. ¹ H NMR (400 MHz, CDCh) δ ppm 1.49 (s, 9 H) 1.77 (s, 3 H) 1.80 (s, 3 H) 2.41 (s, 3 H) 2.58 (t, J = 6.69 Hz, 2 H) 3.55 (dt, J = 9.47, 6.38 Hz, 1 H) 3.68 (dt, J = 9.47, 6.51 Hz, 1 H) 3.80 (s, 3

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Η) 4.01 - 4.13 (m, 2Η) 5.26 (m, 1 Η) 6.49 (dd, J = 2.40, 1.89 Hz, 1 H) 6.81 (dd, J = 8.97, 4.17 Hz, 1 H) 7.01 (ddd, J = 8.91, 7.89, 3.16 Hz, 1 H) 7.19 (dd, J = 8.72, 3 , 16 Hz, 1 H) 7.68 (dd, J = 2.53, 0.51 Hz, 1 H) 7.75 (dd, J = 2.02, 0.51 Hz, 1 H); HPLC reaction time: 5.00 minutes. MS (ESI ⁺ ) for C30H34FN4O6S m / z 612.3 (M + H) ⁺ .

Example 4.7: Preparation of 2- {1 - [(2R) -2- (2-cyanoethoxy) -2- (5fluoro-2-methoxyphenyl) ethyl] -5-methyl-2,4-dioxo-6- (1 H-pyrazol-1 -11) -1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl} -2-methylpropanoic (Compound 18)

[00186] To a well stirred solution of Compound 17 (275.0 mg, 0.45 mmol) in isopropyl alcohol (1.4 mL) at room temperature was added 9.0 sulf sulfuric acid (1.4 mL). The reaction was allowed to stir at room temperature for 2 hours and water (2.8 ml) was added. The mixture was partitioned between brine and dichloromethane (20 ml each), the layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 20 ml). The organic materials were combined, dried with anhydrous sodium sulfate, and concentrated. The obtained solid was suspended with heptane and concentrated in vacuo to remove the residual solvent and provide 245 mg (98% yield, 94% area) of Compound 18 as a white solid. ¹ H NMR (400 MHz, CDCh) δ ppm 1.87 (s, 3 H) 1.88 (s, 3 H) 2.42 (s, 3 H) 2.59 (t, J = 6.32 Hz , 2 H) 3.53 (dt, J = 9.60, 6.44 Hz, 1 H) 3.70 (dt, J = 9.66, 6.28 Hz, 1H) 3.82 (s, 3 H) 4.01 - 4.09 (m, 1 H) 4.15 - 4.24 (m, 1 H) 5.28 (dd, J = 8.21, 4.67 Hz, 1 H) 6, 46 - 6.51 (m, 1 H) 6.82 (dd, J = 9.09, 4.04 Hz, 1 H) 7.01 (ddd, J = 8.97, 7.83, 3.16 Hz, 1 H) 7.20 (dd, J = 8.72, 3.16 Hz, 1 H) 7.68 (d, J = 2.27 Hz, 1H) 7.73 - 7.78 (m, 1 H) (0 carboxylate proton was not observed in ¹ H NMR); HPLC reaction time: 3.91 minutes. MS (ESI ⁺ ) for C26H26FN4O6S m / z 556.3 (M + H) ⁺ .

Example 4.8: Preparation of 2- {1 - [(2R) -2- (2-cyanoethoxy) -2- (5-fluoro2-methoxyphenyl) ethyl] -5-methyl-2,4-dioxo-6- ( 1 H-pyrazol-1 -11) -1,4-diPetition 870190099157, from 10/03/2019, p. 144/202

140/147 hjdrotjeno [2,3-d] pjrjmjdjn-3 (2H) -jl} -N-jsopropjl-2-metjlpropanamjda (compound 1-191)

[00187] To a well stirred solution of Compound 18 (240 mg, 0.43 mmol), TEA (180.6 uL, 1.29 mmol), and isopropyl amine (110.4 uL, 1.29 mmol) in dichloromethane (5.0 mL) at room temperature under nitrogen, 1.57 M propylphosphonic anhydride in ethyl acetate (0.55 mL, 0.86 mmol) was added dropwise over several minutes. The reaction was then stirred at room temperature overnight. The reaction mixture was quenched by the addition of 10% citric acid (5.0 ml) and stirring was continued for 30 minutes. The mixture was partitioned between dichloromethane and brine (30 ml each). The layers were separated and the aqueous layer was extracted with dichloromethane (3x10 ml). The organic materials were combined, dried with anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel chromatography (Silicycle, 230-400 mesh, 40g, eluting with 20 to 70% ethyl acetate / hexane) to provide 203 mg (78% of production, 99% of area) of Compound 1-191 as a white foam. ¹ H NMR (400 MHz, CDCh) δ ppm 1.14 (d, J = 6.82 Hz, 6 H) 1.82 (s, 3 H) 1.84 (s, 3 H) 2.42 (s , 3 H) 2.53 - 2.70 (m, 2 H) 3.39 - 3.48 (m, 1 H) 3.76 - 3.85 (m, 1 H) 3.88 (s, 3 H) 4.02 (d, J = 10.11 Hz, 1 H) 4.07 - 4.19 (m, 2 H) 5.34 (dd, J = 9.60, 3.54 Hz, 1 H ) 6.04 (d, J = 8.08 Hz, 1 H) 6.50 (dd, J = 2.53, 2.02 Hz, 1 H) 6.86 (dd, J = 8.97, 4 , 17 Hz, 1 H) 7.03 (ddd, J = 8.91, 7.89, 3.16 Hz, 1 H) 7.22 (dd, J = 8.84, 3.03 Hz, 1 H ) 7.68 - 7.72 (m, 1 H) 7.76 (dd, J = 2.02, 0.51 Hz, 1 H); Chiral HPLC: 95% enantiomeric excess; HPLC reaction time: 4.18 minutes; MS (ESI ⁺ ) for C29H33FN6O5S m / z 597.3 (M + H) ⁺ .

Example 5: Description of Synthesis of Compound 1-193

[00188] Starting from 1- (2-methoxyphenyl) ethan-1-one and 2-methyl-2- (5methyl-2,4-dioxo-6- (2H-1,2,3-triazol-2-yl) Tert-butyl -1,4-dihydrothieno [2,3-d] pyrimidin3 (2H) -yl) propanoate, the synthesis of (R) -2- (1- (2- (2-cyano)

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141/147 ethoxy) -2- (2-methoxyphenyl) ethyl) -5-methyl-2,4-dioxo-6- (2H-1,2,3-triazol-2-yl) -

1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) -N-isopropyl-2-methylpropanamide (compound 1-193) was performed as diagrammed below:

Scheme 8: Synthetic scheme for the preparation of Compound I193

Br

Br ₂ , ACN | ^ ₀

ÇJ] ^ste P ¹

MW: 150.17

1.1

MW: 229.07

1.2

MW: 376.43

3.1

MW: 579.23

Final Product

Figure Caption: stage - final product

[00189] The synthesis was contemplated twice to produce a total of 203 g of the Formula 1-193 product. Each step in the synthetic scheme is described in more detail in the following examples 5.1 to 5.6.

Example 5.1: Preparation of 2-bromo-1- (2-methoxyphenyl) ethan-1-one (Compound 1.2)

Br ₂ , ACN rt

Step 1

- (2-methoxyphenyl) ethan-1-one

MW: 150.17

2-bromo-1 - (2-methoxyphenyl) ethan-1-one

MW: 229.07

[00190] 1- (2-methoxyphenyl) ethanone, 1.1, (300 g, 1.0 equivalent) was

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142/147 added to a reactor containing acetonitrile (1.2 L, 4.0 V). Br2 (319.62 g, 1.0 equivalent) was added below 25 ° C. The reaction mixture was stirred for 4 hours at 20 to 25 ° C and sampled for IPC until the 1- (2-methoxyphenyl) ethanone content was 6.5%. NaHSOs (600 ml, 2V) were added to quench the reaction and then stirred for another 0.5h at 20 to 25 ° C. The product was extracted with tert-butyl methyl ether (600 ml, 2V), three times, to produce a dark oil (418 g, crude), which was purified using a column to produce 330 g of 2-bromo1- (2 -methoxyphenyl) ethan-1-one, 1.2, as an off-white solid (98% pure).

Example 5.2: Preparation of 2-methyl-2- (5-methyl-2,4-dioxo-6 (2H-1,2,3-triazol-2-yl) -1,4-dihydrothienoic acid [2, 3-d] pyrimidin-3 (2H) yl) propanoic (Compound 2.2).

2.1

fert-butyl 2-methyl-2- (5-methyl-2,4-dioxo-6 (2 / - / - 1,2,3-triazol-2-yl) 1,4-di hyd roth ieno [2, 3- d] pyrim id i n3 (2 / - /) - yl) propanoate

MW: 391.44

2.2

2-methyl-2- (5-methyl-2,4dioxo-6- (2 / - / - 1,2,3-triazol-2yl) -1,4-dihydrothieno [2,3d] pyrimidin-3 (2 / - /) yl) propanoic acid

MW: 335.34

Figure Caption: 2-methyl-2- (5-methyl-2,4-dioxo-6 (2 / - / - 1,2,3-triazo-2yl) -1,4-dihydrothieno [2,3 -d] tert-butyl pyrimidin-3 (2 / - / - yl) propanoate

2-Methyl-2- (5-methyl-2,4-dioxo-6 (2 / 7-1,2,3-triazo-2-yl) -1,4-dihydrothieno [2,3-d ] pyrimidin-3 (2/7) -yl) propanoic

[00191] Compound 2.1 (580.0 g, 1.0 equivalent) was added to a reactor containing dichloromethane (5.8L, 10V). Trifluoroacetic acid (1.2 L, 2 V) was added dropwise and the reaction was stirred for 18 hours at 20 ± 5 ° C. The samples were taken for HPLC until the content of Compound 2.1 <1.0%. The reaction was cooled to <10 ° C and H2O (23.2 L, 40V) was added dropwise. The reaction was stirred for 2

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143/147 hours at 5 to 10 ° C and then filtered. The resulting solid was washed with water (580 ml, 1 V) before drying under vacuum at 35 ± 5 ° C to obtain 448 g of Compound 2.2 (98% purity) as an off-white solid.

Example 5.3: Preparation of N-isopropyl-2-methyl-2- (5-methyl-2,4dioxo-6- (2H-1,2,3-triazol-2-yl) -1,4-di- hydrothieno [2,3-d] pyrimidin3 (2H) -yl) propanamide (Compound 3.1)

2.2

CDI.ACN step 3 h ₂ n

3.1

H

A / -isopropyl-2-methyl-2- (5-methyl2,4-dioxo-6- (2 / 7-1,2,3-triazol-2yl) -1,2-dihydrothieno [2,3- c! 7pyrimidin-3 (2 / - /) - yl) propanamide

MW: 376.43

[00192] A reactor was charged with acetonitrile (4.5L, 10V) under a nitrogen atmosphere before the addition of Compound 2.2 (15.0g, 1.0 equivalent). The reaction mixture was cooled to 0 to 10 ° C and 1, Tcarbonildi-imidazole (433.3 g, 2.0 equivalent) was added between 510 ° C. The reaction was heated to 25 ± ° C and stirred for 1 hour at the new temperature. IPC samples were taken until the NDI-012080-2 content was 0. The reaction was cooled to 0 to 10 ° C before the addition of isopropylamine (315.9 g, 4 equivalents). The reaction was again heated to 25 ± 5 ° C and stirred for 1 hour at the new temperature with samples taken for IPC until the content of Compound 2.2 was 0. H2O (9.0L, 20 V) was added followed by concentrated HCI (111 , 3 ml, 4.0 equivalents), dropwise, at 0 to 25 ° C. The reaction was stirred for 2 hours at 0 ~ 25 ° C, filtered, and the resulting filter mass washed with water (896 ml, 2V) and then with ceric ammonium nitrate (896 ml, 2V). 442 g of Compound 3.1 (purity: 98.8%, yield: 87.9%) were obtained as an off-white solid.

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Example 5.4: Preparation of N-isopropyl-2- (1- (2- (2-methoxyphenyl) -2oxoethyl) -5-methyl-2,4-dioxo-6- (2H-1,2,3-triazole-2 -i I) -1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) -2-methylpropanamide (compound

4.1)

3.1

H

Br 1-2

/ V-isopropyl-2- (1- (2- (2-methoxyphenyl) 2-oxoethyl) -5-methyl-2,4-dioxo-6- (2H1,2,3-triazol-2-yl) -1 , 4-d ih id roethylene [2,3-d] pyrimidin-3 (2H) -yl) -2methylpropanamide

MW: 524.29

[00193] Compound 3.1 (430g, 1.0 equivalent) and N-methyl-2 pyrrolidone (2.2 L, 5 V) were added in such order to a reactor and stirred at 20 ± 5 ° C until the solid had dissolved . Compound 1.1 (282.6 g, 1.08 eq) and then K2CO3 (5.51 G, 3 eq) were added before stirring an additional 2 hours at 25 ± 5 ° C. The samples for IPC were seized until the content of Compound 3.1 was 3.1%. H2O (4.3L, 10V) was added and the reaction mixture was filtered. The filtered mass was suspended with water (4.3L, 10V) twice and with petroleum ether (4.3L, 10V) once before drying under vacuum at 40 ± 5 ° C to obtain 642.8 g of Compound 4.1 (Purity: 97.2%, QRMN: 79.2%, production: 85%).

Example 5.5: Preparation of (R) -2- (1- (2-hydroxy-2- (2-methoxyphenyl) ethyl) -5-methyl-2,4-dioxo-6- (2H-1,2,3- triazol-2-yl) -1,4-dihydrothieno [2,3d] pyrimidin-3 (2H) -yl) -N-isopropyl-2-methylpropanamide (compound 5.1)

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Ru-cat

Step 5

(R) -2- (1- (2-hydroxy-2- (2-methoxyphenyl) ethyl) -5-methyl-2,4-dioxo-6 (2 / 7-1,2,3-triazole-2- il) -1,4-dihydrothieno [2,3-cy] pyrimidin-3 (2/7) yl) - / V-isopropyl-2-methylpropanamide

MW: 526.61

[00194] Compound 4.1 (645.0 g, 1.0 equivalent) was added to a reactor containing tetrahydrofuran (1.9L, 3.0v) at 20 to 25 ° C. Triethylamine (20.0 equivalents) was added at 20 to 25 ° C. RuCI [(S, S) -Tsdpen] (p-cymene) (10% by volume / volume) was added at the same temperature followed by formic acid (20.0 eq), dropwise, at 20 to 25 ° C. The reaction was stirred at 20 to 30 ° C for 4 days and sampled for HPLC until the content of Compound 4.1 was not more than 3.0%. The reaction product was concentrated at 4 ~ 5v under vacuum at 35 ± 5 ° C and then added, dropwise, in water (12.0L, ~ 20.0V). The reaction was filtered and washed with water (2.5L, 4.0 V) and then suspended with MTBE / heptane (1: 1, 4.0L). The suspension was filtered and washed with heptane (2.5L, 4.0 V) to obtain 430.0 g of Compound 5.1 as a not entirely white solid (purity: 96.3%).

Example 5.6: Preparation of (R) -2- (1- (2- (2-cyanoethoxy) -2- (2-methoxyphenyl) ethyl) -5-methyl-2,4-dioxo-6- (2H-1, 2,3-triazol-2-yl) -1,4-dihydrothieno [2,3-d] pyrimidin-3 (2H) -yl) -N-isopropyl-2-methylpropanamide (compound 1-193).

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^ GN

Step 6

Formula 1-193

MW: 579.23

[00195] Compound 5.1 (130.0 g, 1.0 equivalent) was added to a reactor containing tetrahydrofuran (1.3 L, 10.0 V) and then cooled to -5 ~ 0 ° C. A solution of 50% KOH in water (130.0 ml, 1.0V) followed by acrylonitrile (260.0 ml, 2.0v) was added and the reaction mixture was stirred for 20 hours at -5 ~ 0 ° C . The samples were seized for HPLC until the NDI-012080-5 content was no more than 5.0%. Ethyl acetate (1.3L, 10.0V) was then added. The organic phase was separated, collected, and washed with 20% NaCI (650.0 ml, 5.0 V) twice before being concentrated under vacuum at 35 ± 5 ° C. The concentrate was suspended with isopropyl alcohol (650.0 ml, 5.0 V) and then recrystallized with isopropyl alcohol to obtain 61.0 g of the final product (compound 1-193) as a not entirely white solid (purity : 98.7%).

[00196] When introducing the elements of the present invention or the modality (s) of the same, the articles one / a, one / an, the aforementioned are intended to mean one or more of the elements. The terms comprising, including and having are intended to be inclusive and mean that they may be additional elements other than those listed.

[00197] In view of the above, it will be observed that the various objectives of the invention are obtained and other advantageous results al

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[00198] Since several changes can be made in the above processes without departing from the scope of the Invention, it is understood that the whole matter contained above should be interpreted as illustrative and not in a limiting sense.

Claims (45)

1. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula V-1 or V-2-F:

Formula V-1 Formula V-2-F or a salt thereof, the process comprising contacting a compound of Formula IV-1 or IV-2-F:

Formula IV-1 Formula IV-2-F or a salt thereof, with a hydrogen bridge in the presence of a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or Formula V-1 salt or V-2-F, respectively; on what: R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3j R ² is hydrogen or F. 2. Process characterized by the fact that it is for preparing Petition 870190099157, of 10/03/2019, p. 153/202 2/45 tion of a stereomerically enriched compound of Formula V-3, V-4-F, or V-4-F-1a:

Formula V-4-F-1a or a salt thereof, a process comprising contacting a compound of Formula IV-3, IV-4-F, or IV-4-F-1a: R '

R ² Formula IV-3

or a salt thereof, with a hydrogen bridge in the presence of Petition 870190099157, of 10/03/2019, p. 154/202 3/45 a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or Formula V-3, V-4-F, or V-4-F-1a salt, respectively ; on what: R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH ₂ CH ₃ ; and R ² is hydrogen or F. 3. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula V-5, V-6-F, or V-6-F-1a:

Formula V-5

Formula V-6-F-1a or a salt thereof, a process comprising contacting a compound of Formula IV-5, IV-6-F, or IV-6-F-1a:

Formula IV-6-F Petition 870190099157, of 10/03/2019, p. 155/202 4/45

Formula IV-6-F1a or a salt thereof, with a hydrogen bridge in the presence of a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or Formula V-5 salt , V-6-F, or V-6-F-1a, respectively; on what: R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3j and R ² is hydrogen or F. 4. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula V7-F or V-7-F-1a:

Formula V-7-F-1a or a salt thereof, a process comprising contacting a compound of Formula IV-7-F or IV-7-F-1a:

Formula IV-7-F

Formula IV-1-F-1a Petition 870190099157, of 10/03/2019, p. 156/202 5/45 or a salt thereof, with a hydrogen bridge in the presence of a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or Formula V-7-F salt or V-7-F-1a; where: R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH2CH3. Process according to claim 1, characterized in that the process also comprises a step of preparing the compound of Formula IV-1 or IV-2-F:

Formula IV-1 Formula IV-2-F or a salt thereof, the step comprising contacting a compound of Formula 11-1 or II-2:

Formula 11-1 Formula II-2 or a salt thereof, with a compound of Formula III:

Formula III or a salt thereof in the presence of a base in an alkylation zone comprising the reaction medium, thereby providing the compound or salt of Formula IV-1 or IV-2-F; on what: R ² is hydrogen or F; and X is Cl, Br, or I. Petition 870190099157, of 10/03/2019, p. 157/202 6/45 Process according to claim 2, characterized in that the process also comprises a step of preparing the compound of Formula IV-3, IV-4-F or IV-4-F-1a:

or a salt thereof, the step comprising contacting a compound of Formula II-3, II-4 or II-4-

Formula II-3 R ¹ - s

or a salt thereof, with a compound of Formula III: Petition 870190099157, of 10/03/2019, p. 158/202 7/45

Formula III or a salt thereof, in the presence of a base in an alkylation zone comprising the reaction medium, thereby providing the compound or salt of Formula IV-3, IV-4-F or IV-4-F-1a ; on what: R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH ₂ CH ₃ ; R ² is hydrogen or F; and X is Cl, Br, or I. Process according to claim 3, characterized in that the process also comprises a step of preparing the compound of Formula IV-5JV-6-F or IV-6-F-1a:

Formula IV-5 Formula IV-6-F

Formula IV-6-F-1a or a salt thereof, the step comprising contacting a compound of Formula II-5JI-6 or 11-6-1 at: Petition 870190099157, of 10/03/2019, p. 159/202 8/45

Formula 11-5 Formula 11-6

H Formula 11-6-1 a or a salt thereof, with a compound of Formula III:

Formula III or a salt thereof, in the presence of a base in an alkylation zone comprising the reaction medium, thereby providing the compound or salt of Formula IV-5JV-6-F or IV-6-F-1a; on what: R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3j R ² is hydrogen or F; and X is Cl, Br, or I. Process according to claim 4, characterized in that the process also comprises a step of preparing the compound of Formula IV-7-F or IV-1-F-1a:

Formula IV-7-F

Formula IV-1-F-1a Petition 870190099157, of 10/03/2019, p. 160/202 9/45 or a salt thereof, the step comprising contacting a compound of Formula 11-7 or 11-7-1 at:

Formula II-7 Formula ll-7-1a or a salt thereof, with a compound of Formula ll-F:

Formula ll-F or a salt thereof, in the presence of a base in an alkylation zone comprising the reaction medium, thereby providing the compound or salt of Formula IV-7-F or IV-1 -F-1 a; on what: R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH ₂ CH ₃ ; and X is Cl, Br, or I. 9. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I020, I-074, I-064, 1-014, 1-184, 1-211, 1-212, or 1-213:

I-020 I-074 Petition 870190099157, of 10/03/2019, p. 161/202 10/45

1-014 1-184

1-211

CN

I | 1-212 1-213 or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-5-F: Petition 870190099157, of 10/03/2019, p. 162/202 11/45

Formula V-5-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VI-5-F:

Formula VI-5-F or a salt thereof; and reacting the compound or salt of Formula VI-5-F with an alcohol selected from the group consisting of isopropanol, methoxyethanol, ethylene glycol, (S) -3-hydroxy-2-methylpropanonitrile, (R) -3-hydroxy-2 -methylpropanonitrile, and 3-hydroxy-2,2-dimethylpropanonitrile, thereby providing the stereomerically enriched compound or salt of Formula I020, I-074, I-064, 1-014, 1-184, 1-211, 1-212 , or 1-213; on what: R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3. 10. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I082 or 1-171: Petition 870190099157, of 10/03/2019, p. 163/202 12/45

1-171 I-082 or a salt thereof, a process comprising: contact of a stereomerically enriched compound of Formula V-6-T-F:

Formula V-6-T-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VI-6-T-F:

or a salt thereof; Petition 870190099157, of 10/03/2019, p. 164/202 13/45 reacting the Formula VI-6-T-F compound or salt with methoxyethanol, thereby providing the stereomerically enriched compound or Formula I-082 salt; and separating the Formula I-082 compound or salt, thereby providing the stereomerically enriched compound or Formula 1-171 salt. 11. Process characterized by the fact that it is for preparing a stereomerically enriched compound of Formula I020, I-074, 1-014, 1-211, 1-212, or 1-213:

I-020 I-074

1-014

1-211 1-212 Petition 870190099157, of 10/03/2019, p. 165/202 14/45

1-213 or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-1-F:

Formula V-1 -F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VI-1-F:

Formula VI-1 -F or a salt thereof; react the Formula VI-1-F compound or salt with an alcohol Petition 870190099157, of 10/03/2019, p. 166/202 15/45 selected from the group consisting of isopropanol, methoxyethanol, (S) - 3-hydroxy-2-methylpropanonitrile, (R) -3-hydroxy-2-methylpropanonitrile, and 3-hydroxy-2,2-dimethylpropanonitrile thereby providing a formula VII-1 -TF-1, VII-1-TF stereomerically enriched compound -2, VII-1 -P-F-1, VII-1 -T-F-3, VII-1-T-F-4, or VII-1-T-F-5:

VII-1-T-F-1 VII-1-T-F-2

VII-1-P-F-1

VII-1-T-F-3 VII-1-T-F-4 Petition 870190099157, of 10/03/2019, p. 167/202 16/45

CN X ⁰ VII-1-T-F-5 or a salt thereof; treating the compound or salt of Formula VII-1-TF-1, VII-1-T-F2, VII-1-PF-1, VII-1-TF-3, VII-1-TF-4, or VII- 1-TF-5 with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-1-TF-1, VIII-1-TF-2, VIII-1-PF-1, VIII carboxylic acid compound -1-TF-3, VIII-1-TF-4, or VIII-1-TF-5:

VIII-1 -T-F-2 HIV-1-T-F-1

Petition 870190099157, of 10/03/2019, p. 168/202 17/45

VIII-1-T-F-3

HIV-1-T-F-5 or a salt thereof; and forming an isopropylamine amide in an amide forming zone, thereby providing the stereomerically enriched compound or salt of Formula I-020, I-074, 1-014, 1-211, I212, or 1-213; on what: R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3. 12. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I082 or 1-171:

I-082

or a salt thereof, a process comprising: contact a stereomerically enriched compound of Petition 870190099157, of 10/03/2019, p. 169/202 18/45 Formula V-2-T-F:

Formula V-2-T-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VI-2-T-F:

Formula VI-2-T-F or a salt thereof; the Formula VI-2-T-F compound or salt is reacted with methoxyethanol, thereby providing a Formula VII-2-T-F-2 stereomerically enriched compound:

VII-2-T-F-2 or a salt thereof; Petition 870190099157, of 10/03/2019, p. 170/202 19/45 treating the Formula VII-2-T-F-2 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-2-T-F-2 carboxylic acid compound:

VIII-2-T-F-2 or a salt thereof; forming an isopropylamine amide in an amide forming zone, thereby providing the stereomerically enriched compound or Formula I-082 salt; and separating the Formula I-082 compound or salt, thereby providing the stereomerically enriched compound or Formula 1-171 salt. 13. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I208, I-206, 1-193, I-095, 1-192, 1-191, I-234, 1-231, I- 233, or 1-181:

I-208 I-206 Petition 870190099157, of 10/03/2019, p. 171/202 20/45

1-193 I-095

1-192 1-191

I-234 1-231

I-233 1-181 or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-1: Petition 870190099157, of 10/03/2019, p. 172/202 21/45

Formula V-1 or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VII-1-4 :

Formula VII-1-4 or a salt thereof; treating the Formula VII-1-4 compound or salt with an acid in a deprotection zone, thereby providing a corresponding VIII-1-4 carboxylic acid compound:

Formula VIII-1-4 or a salt thereof; and Petition 870190099157, of 10/03/2019, p. 173/202 22/45 form an amide with an amine selected from the group consisting of ethylamine and isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-208, 1-206, 1-193, I -095, 1-192, 1-191, I- 234.1-231, I-233, or 1-181; on what: R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3j R ² is hydrogen or F. 14. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I211, 1-212, I-262, I-263, I-258, I-259, or 1-213:

1-212

Petition 870190099157, of 10/03/2019, p. 174/202 23/45

1-213 or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-1-F:

O'Bu Formula V-1 -F or a salt thereof, with an alkenyl compound of CH2 = C (CH3) CN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VII-1-F-5:

or a salt thereof; treating the compound or salt of Formula VII-1-F-5 with an acid Petition 870190099157, of 10/03/2019, p. 175/202 24/45 in a deprotection zone, thereby providing a corresponding VIII-1-F-5 carboxylic acid compound:

Formula VIII-1-F-5 or a salt thereof; form an isopropylamine amide in an amide forming zone, thereby providing a compound of Formula 1-211 / 212, I-262/263, or I-258/259:

I-258/259 or a salt thereof; and separating the compound or salt of Formula 1-211 / 212,1-262 / 263, or I-258/259, thereby providing the stereomerically enriched compound or salt of Formula 1-211, 1-212, I-262, I-263, I-258, or IPetição 870190099157, of 10/03/2019, p. 176/202 25/45 259; or reacting the Formula 1-211 / 212 compound or salt with methyl halide in the presence of base in a methylation zone, thereby providing the stereomerically enriched compound or Formula 1-213 salt; on what: R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3. 15. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I205, I-220 or I-229:

I-220 I-229 or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-2-F:

Formula V-2-F or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising Petition 870190099157, of 10/03/2019, p. 177/202 26/45 giving the reaction medium, thereby providing a formula VII-2-F-4 stereomerically enriched compound:

Formula VII-2-F-4 or a salt thereof; treating the compound or salt of Formula VII-2-F-4 with an acid in a deprotection zone, thereby providing a corresponding VIII-2-F-4 carboxylic acid compound:

Formula VIII-2-F-4 or a salt thereof; and forming an amide with an amine selected from the group consisting of isopropylamine and / V-methylisopropylamine in an amide forming zone, thereby providing a compound of Formula 1-205-RR / RS, 1-220-RR / RS, or 1-229-RR / RS:

Petition 870190099157, of 10/03/2019, p. 178/202 27/45

1-220-RR / RS

1-229-RR / RS or a salt thereof; and separating the Formula 1-205-RR / RS, 1-220RR / RS, or 1-229-RR / RS compound or salt, thereby providing the stereomerically enriched compound or Formula 1-205, 1-220 salt, or 1-229; on what: R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH ₂ CH ₃ . 16. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I285:

I-285 or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-1-E-F:

Formula V-1 -E-F Petition 870190099157, of 10/03/2019, p. 179/202 28/45 or a salt thereof, with an alkenyl compound of CH2 = CHSO2CH3 in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a stereomerically enriched compound of Formula VII-1-EF- 6:

Formula VII-1-EF-6 or a salt thereof, treat the Formula VII-1 compound or salt with an acid in a deprotection zone, thereby providing a corresponding VIII-1 carboxylic acid compound -EF-6:

Formula VIII-1-E-F-6 or a salt thereof; and forming an isopropylamine amide in an amide forming zone, thereby providing the stereomerically enriched compound or Formula I-285 salt. 17. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I208, I-206, I-234, or 1-231: Petition 870190099157, of 10/03/2019, p. 180/202 29/45

or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-3:

Formula V-3 or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing the stereomerically enriched compound or Formula 1-208 salt , 1-206, 1-234, or I231; on what: R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH ₂ CH ₃ ; and R ² is hydrogen or F. Petition 870190099157, of 10/03/2019, p. 181/202 30/45 18. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I193, I-095, 1-192, 1-191, I-233, or 1-181:

or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-5:

or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in an addition zone. Petition 870190099157, of 10/03/2019, p. 182/202 31/45 providing the reaction medium, thereby providing the stereomerically enriched compound or salt of Formula 1-193, I-095, 1-192, 1-191, I-233, or 1-181; on what: R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3j R ² is hydrogen or F. 19. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I211, 1-212, I-262, I-263, I-258, I-259, or 1-213:

1-211 1-212

I-262 I-263

I-258 I-259

1-213 Petition 870190099157, of 10/03/2019, p. 183/202 32/45 or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-5-F:

Formula V-5-F or a salt thereof, with an alkenyl compound of CH2 = C (CH3) CN in the presence of a base in an addition zone Michael comprising the reaction medium, thereby providing a compound of Formula 1-211 / 212,1-262 / 263, or I-258/259:

I-258/259 or a salt thereof; and separating the compound or salt of Formula 1-211 / 212,1-262 / 263, or I-258/259, thereby providing the stereomerically enriched compound or salt of Formula 1-211, 1-212, I-262, I-263, I-258, or I259; or react the compound or salt of Formula 1-211 / 212 with methyl halide in the presence of base in a methylation zone, thereby providing the stereomerically enriched compound or salt of Petition 870190099157, of 10/03/2019, p. 184/202 33/45 Formula 1-213; on what: R ¹ is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C (O) OCH2CH3 ;. 20. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I220:

or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-6-E-F:

Formula V-6-EF or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a compound of Formula I-220-RR /LOL:

I-220-RR / RS Petition 870190099157, of 10/03/2019, p. 185/202 34/45 or a salt thereof; and separating the Formula 1-220-RR / RS compound or salt, thereby providing the stereomerically enriched compound or Formula 1-220 salt. 21. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I205 or I-229:

I-205 I-229 or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-7-F:

or a salt thereof, with an alkenyl compound of CH2 = CHCN in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing a compound of Formula I-205-RR / RS or I-229 -RR / RS:

I-205-RR / RS I-229-RR / RS Petition 870190099157, of 10/03/2019, p. 186/202 35/45 or a salt thereof; and separating the Formula 1-205-RR / RS or I229-RR / RS compound or salt, thereby providing the stereomerically enriched compound or Formula 1-205 or 1-229 salt; on what: R ¹ is 2H-1,2,3-triazol-2-yl or -C (O) OCH ₂ CH ₃ . 22. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I285:

I-285 or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-5-E-F:

or a salt thereof, with a CH ₂ alkenyl compound = CHSO ₂ CH ₃ in the presence of a base in a Michael addition zone comprising the reaction medium, thereby providing the stereomerically enriched compound or Formula I-285 salt . 23. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I064: Petition 870190099157, of 10/03/2019, p. 187/202 36/45

or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-1-T-F:

Formula V-1 -T-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising the reaction medium; reacting the product with an XCH2C (O) OR3 compound in the α-alkylation zone, thereby providing a formula VII-1 -T-F-7 stereomerically enriched compound:

Formula VII-1-T-F-7 or a salt thereof; treating the Formula VII-1-T-F-7 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-1-T-F-7 carboxylic acid compound: Petition 870190099157, of 10/03/2019, p. 188/202 37/45

or a salt thereof; form an isopropylamine amide in an amide formation zone, thereby providing a formula IX-1-T-F-7 stereomerically enriched compound:

Formula IX-1-T-F-7 or a salt thereof; and contacting the Formula IX-1-T-F-7 compound or salt with a reducing agent in a reducing zone, thereby providing the stereomerically enriched compound or Formula I-064 salt; where: X is Cl or Br, and R ³ is selected from the group consisting of methyl and ethyl. 24. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I089 or I-090:

I-089 I-090 Petition 870190099157, of 10/03/2019, p. 189/202 38/45 or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-2-T-F:

Formula V-2-T-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising the reaction medium; reacting the product with an XCH2C (O) OR ³ compound in the α-alkylation zone, thereby providing a formula VII-2-TF-7 stereomerically enriched compound:

Formula VII-2-T-F-7 or a salt thereof; treating the Formula VII-2-T-F-7 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-2-T-F-7 carboxylic acid compound:

Formula VIII-2-T-F-7 Petition 870190099157, of 10/03/2019, p. 190/202 39/45 or a salt thereof; form an amide with / V-methylisopropylamine in an amide-forming zone, thereby providing a formula IX-2-T-F-7 stereomerically enriched compound:

Formula IX-2-T-F-7 or a salt thereof; contacting the Formula IX-2-T-F-7 compound or salt with a reducing agent in a reducing zone, thereby providing a Formula I-1-089 / 090 compound:

1-089 / 090 or a salt thereof; and separating the Formula 1-089 / 090 compound or salt, thereby providing the stereomerically enriched compound or Formula 1-089 or 1-090 salt; where: X is Cl or Br, and R ³ is selected from the group consisting of methyl and ethyl. 25. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I251: Petition 870190099157, of 10/03/2019, p. 191/202 40/45

or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V1-E-F:

Formula V-1 -E-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising the reaction medium; reacting the product with an XCH2CN compound in the α-alkylation zone, thereby providing a formula VII-1-E-F-8 stereomerically enriched compound:

Formula VII-1-E-F-8 or a salt thereof; treating the Formula VII-1-E-F-8 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-1-E-F-8 carboxylic acid compound: Petition 870190099157, of 10/03/2019, p. 192/202 41/45

or a salt thereof; forming an isopropylamine amide in an amide forming zone, thereby providing the stereomerically enriched compound or Formula 1-251 salt; where: X is Cl or Br. 26. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I246:

I-246 or a salt thereof, a process comprising contacting a stereomerically enriched compound of Formula V-8-T-F:

Formula V-8-T-F or a salt thereof, with a strong deprotonating agent in a Petition 870190099157, of 10/03/2019, p. 193/202 42/45 α-alkylation zone comprising the reaction medium; reacting the product with an XCH2C (O) OR3 compound in the α-alkylation zone, thereby providing a formula VII-8-T-F-7 stereomerically enriched compound:

or a salt thereof; treating the Formula VII-8-T-F-7 compound or salt with an acid in a deprotection zone, thereby providing a corresponding Formula VIII-8-T-F-7 carboxylic acid compound:

or a salt thereof; form an isopropylamine amide in an amide forming zone, thereby providing a formula IX-8-T-F-7 stereomerically enriched compound:

or a salt thereof; and Petition 870190099157, of 10/03/2019, p. 194/202 Contacting the Formula IX-8-T-F-7 compound or salt with a reducing agent in a reducing zone, thereby supplying the stereomerically enriched compound or Formula 1-246 salt; where X is Cl or Br, and R ³ is selected from the group consisting of methyl and ethyl. 27. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I323:

1-323 or a salt thereof, a process comprising: contact a stereomerically enriched compound of Formula V-3-T-F:

Formula V-3-T-F or a salt thereof, with acetic anhydride or acyl chloride in the presence of a base in an acetylation zone comprising the reaction medium, thereby providing the stereomerically enriched compound or Formula 1-323 salt. 28. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula I189: Petition 870190099157, of 10/03/2019, p. 195/202 44/45

1-189 or a salt thereof, a process comprising: separate a compound of Formula V-7-T-F:

Formula V-7-T-F or a salt thereof, thereby providing the stereomerically enriched compound or Formula 1-189 salt. 29. Process characterized by the fact that it is for the preparation of a stereomerically enriched compound of Formula V-6-T-F-1a (I-400):

V-6-T-F-1a (I-400) or a salt thereof, the process comprising contacting a compound of Formula IV-6-T-F-1a:

Formula IV-6-T-F-1a Petition 870190099157, of 10/03/2019, p. 196/202 45/45 or a salt thereof, with a hydrogen bridge in the presence of a chiral organometallic catalyst in an asymmetric reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or Formula V-6-TF- salt 1a (I-400).