WO2019200114A1

WO2019200114A1 - Methods for preparing substituted dihydroindene-4-carboxamide compounds

Info

Publication number: WO2019200114A1
Application number: PCT/US2019/027011
Authority: WO
Inventors: Andrew G. Cole; Steven Kultgen; Ganapati Reddy Pamulapati; Jan Michelle SPINK
Original assignee: Arbutus Biopharma Corporation
Priority date: 2018-04-12
Filing date: 2019-04-11
Publication date: 2019-10-17
Also published as: TW201943707A

Abstract

The invention relates to novel, scalable methods of making substituted bicyclic compounds that are useful to treat and/or prevent HBV and/or HDV infection and related conditions in a subject.

Description

TITLE OF THE INVENTION

Methods for Preparing Substituted Dihydroindene-4-Carboxamide Compounds

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Applications No. 62/656,614, filed April 12, 2018, and No. 62/700,503, filed July 19, 2018, all of which are hereby incorporated by reference herein in their entireties.

BACKGROUND OF THE INVENTION

Hepatitis B is one of the world’s most prevalent diseases. Although most individuals resolve the infection following acute symptoms, approximately 30% of cases become chronic. 350-400 million people worldwide are estimated to have chronic hepatitis B, leading to 0.5-1 million deaths per year, due largely to the development of hepatocellular carcinoma, cirrhosis, and/or other complications. Hepatitis B is caused by hepatitis B virus (HBV), a noncytopathic, liver tropic DNA virus belonging to Hepadnaviridae family.

A limited number of drugs are currently approved for the management of chronic hepatitis B, including two formulations of alpha-interferon (standard and pegylated) and five nucleoside/nucleotide analogues (lamivudine, adefovir, entecavir, telbivudine, and tenofovir) that inhibit HBV DNA polymerase. At present, the first-line treatment choices are entecavir, tenofovir, or peg-interferon alfa-2a. However, peg-interferon alfa-2a achieves desirable serological milestones in only one third of treated patients, and is frequently associated with severe side effects. Entecavir and tenofovir require long-term or possibly lifetime administration to continuously suppress HBV replication, and may eventually fail due to emergence of drug-resistant viruses.

Hepatitis D virus (HDV) is a small circular enveloped RNA virus that can propagate only in the presence of HBV. In particular, HDV requires the HBV surface antigen protein to propagate itself. Infection with both HBV and HDV results in more severe complications compared to infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased chance of developing liver cancer in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest mortality rate of all the hepatitis infections. The routes of transmission of HDV are similar to those for HBV. Infection is largely restricted to persons at high risk of HBV infection, particularly injecting drug users and persons receiving clotting factor concentrates. Currently, there is no effective antiviral therapy available for the treatment of acute or chronic type D hepatitis. Interferon-alfa, given weekly for 12 to 18 months, is the only licensed treatment for hepatitis D. Response to this therapy is limited-in only about one- quarter of patients is serum HDV RNA undetectable 6 months post therapy.

Much research has been dedicated to the identification of novel agents that can be used to effectively treat and/or prevent HBV and/or HDV infection in a subject. Such agents should be easily and reproducibly prepared in large scale, so that they can be used to treat large number of patients infected with, or at risk on being infected with, HBV and/or HDV. There is thus a need to identify scalable synthetic routes for those anti-HBV and/or HDV antiviral agents (as well as certain intermediates useful for preparing the same). The present invention addresses this need.

BRIEF SUMMARY OF INVENTION

The present invention provides methods of preparing (1 -methyl- 1H-1, 2, 4-triazol-3- yl)methyl (_<S)-(4-((3-chloro-4-fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden-l-

yl)carbamate

salt or solvate thereof. The present invention further provides methods of preparing intermediates useful for the synthesis of [9] or related compounds, such as but not limited to R group-substituted 7 -fluoro-l-oxo-2, 3-dihydro- 1H-

indene-4-carboxylate

wherein R is Ci-C₆ alkyl, C₃-C₈ cycloalkyl, or benzyl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates, in certain aspects, to synthetic routes that allow for reproducible preparation of certain substituted bicyclic compounds (and certain intermediates useful for preparing the same) that can be used to treat and/or prevent HBV and/or HDV infection and related conditions in a subject. In certain embodiments, the methods of the invention allow for large scale (i.e.. multigram and/or multikilo) synthesis of 9 and related compounds. In other embodiments, the methods of the invention allow for enantiospecific synthesis of 9 and related compounds. In other embodiments, the methods of the invention allow for isolation of 9 and related compounds in high purity (i.e., >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >97.5%, >98%, >98.5%, >99%, >99.5%, >99.75%, >99.9%, or >99.5% purity, as determined by an analytical method, such as high-performance liquid chromatography (HPLC) or any other chromatographic method, IR, UV, NMR, and the like). Certain related compounds were originally described in PCT Application Publication No. WO2018/172852A1, which is incorporated herein in its entirety by reference.

Synthetic Methods

In one aspect, the present invention provides methods of preparing (l-methyl-lH- l,2,4-triazol-3-yl)methyl (5)-(4-((3-chloro-4-fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-

lH-inden-l-yl)carbamate F [9], or a salt or solvate thereof.

In certain embodiments, any of the alkyl, cycloalkyl, phenyl, and/or benzyl groups recited herein are independently optionally substituted. As used herein, an ester can be described interchangeably as a“carboxylate” or a“carboxylic ester” As a non-limiting example, C₆H₅C(=0)0CH₃ can be described interchangeably as methyl benzoate and/or benzoic methyl ester. In certain embodiments, compounds of the invention are prepared according to the illustrative synthetic methods outlined in Scheme I.

Scheme I

Scheme I, Step 6: Synthesis of (1-methyl- 1H- 1,2, 4- triazol-3-yl)methyl (L')-(4-((3- chloro-4-fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden- l-yl)carbamate [9].

In certain embodiments, the invention provides a method of preparing [9] In other embodiments, the method comprises contacting (l-methyl-l,2,4-triazol-3-yl)methanol [8], or a salt or solvate thereof, (5)-l-amino-N-(3-chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-lH-

indene-4-carboxamide

salt or solvate thereof, and at least one coupling agent.

In certain embodiments, [7], [8], and at least one coupling agent are contacted. In other embodiments, the contacting is in the presence of a solvent, which may form a solution of [7], [8], and the at least one coupling agent. In other embodiments, the solution comprises at least one organic solvent selected from the group consisting of 2-methyl tetrahydrofuran, tetrahydrofuran, dimethylformamide, dichloromethane, chloroform, dimethylacetamide, and N-methyl-2-pyrrolidone.

In certain embodiments, the at least one coupling agent is a carbonyl equivalent (a carbonyl equivalent coupling agent), allowing for the coupling of an amine and an alcohol to form a carbamate (also known as urethane). In other embodiments, the at least one coupling agent is selected from the group consisting of carbonyldiimidazole, phosgene, diphosgene, triphosgene, and disuccinimidyl carbonate.

In certain embodiments, [7], [8], and at least one coupling agent are further contacted with at least one base. In other embodiments, the at least one base is a tertiary amine or tertiary aniline. In yet other embodiments, the at least one base is selected from the group consisting of N,N-diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine, or any other tertiary amine or tertiary aniline.

In certain embodiments, [7], [8], and at least one coupling agent are reacted at temperature from about 20 °C to about 80 °C. In other embodiments, [7], [8], and at least one coupling agent are contacted at an initial temperature of about 20 °C, and then heated to about 80 °C.

In certain embodiments, [7], [8], and at least one coupling agent are contacted for about 5 hours to about 48 hours. In other embodiments, [7], [8], and at least one coupling agent are contacted for a period of time sufficient to reach reaction completion, as monitored and determined by one or more chemical characterization methods common in the art.

In certain embodiments, [7] and [8]are contacted in a molar ratio of about 1: 1 to about 3: 1.

In certain embodiments, the method further comprises recry stallizing [9] from a solution comprising isopropanol and/or 2-methyltetrahydrofuran.

In certain embodiments, [7] is an acid addition salt of (S)- 1 -amino-N-(3-chloro-4- fluorophenyl)-7-fluoro-2,3-dihydro-lH-indene-4-carboxamide. In other embodiments, [7] is (<S -l-amino-N-(3-chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-lH-indene-4-carboxamide hydrochloride.

Scheme I, Step 5: Synthesis of (( ')-1 -amino- IN-(3-chloro-4-fluorophenyl)-7-fluoro- 2, 3-dihydro- lH-indene-4-carboxamide [7].

In certain embodiments, [7] is prepared by a process comprising contacting (S')- 1 - (((<S)-/e/7-butylsulfmyl)amino)-N-(3-chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-lH-indene- 4-carboxamide [6] with an acid. In certain embodiments, [6] is in a solution. In other embodiments, the solution comprising [6] comprises at least one solvent selected from the group consisting of methanol, ethanol, isopropanol, dioxane, and cyclopentyl methyl ether.

In certain embodiments, the acid is in a solution comprising at least one solvent selected from the group consisting of methanol, ethanol, isopropanol, dioxane, and cyclopentyl methyl ether.

In certain embodiments, the acid comprises at least one acid selected from the group consisting of hydrochloric acid, sulfuric acid, and phosphoric acid. In other embodiments, the acid is generated in situ from one or more acid generating compounds. In yet other embodiments, the one or more acid generating compounds comprise an acid chloride and/or a silyl chloride. In yet other embodiments, the acid is generated from acetyl chloride and/or trimethylsilyl chloride in the presence of at least one alcohol.

In certain embodiments, [6] and the acid are contacted at a temperature of about 10 °C to about 30 °C.

Scheme I, Step 4: Synthesis of fV)- l-((fV)-fe/i-butylsulfinyl)amino)-IN-(3-chloro-4- fluorophenyl)-7-fluoro-2,3-dihydro-lH-indene-4-carboxamide [6] .

In certain embodiments, [6] is prepared by a process comprising contacting 3-chloro- 4-fluoroaniline with (5 -l-(((ri)-/er/-butylsulfmyl)amino)-7-fluoro-2,3-dihydro-lH-indene-4-

carboxylic acid

[5], or an acid anhydride or acyl halide (such as but not limited to acyl chloride or acyl bromide) thereof.

In other embodiments, [6] is prepared through an amide coupling reaction between [5] and 3-chloro-4-fluoroaniline.

In certain embodiments, [5], or an acid anhydride or acyl halide thereof, and 3-chloro- 4-fluoroaniline are contacted in a solution comprising at least one organic solvent. In other embodiments, the at least one organic solvent is selected from the group consisting of 2- methyl tetrahydrofuran, tetrahydrofuran, dimethylformamide, ethyl acetate, dichloromethane, chloroform, dimethylacetamide, and N-methyl-2-pyrrolidone.

In certain embodiments, [5] and 3-chloro-4-fluoroaniline are further contacted by at least one amide coupling agent. In other embodiments, the at least one amide coupling agent is selected from the group consisting of carbonyldiimidazole (CDI), (l-[bis(dimethylamino) methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 4-(4,6- dimethoxy-l,3,5-triazin-2-yl)-4-methyl morpholinium chloride, propanephosphonic acid anhydride (T3P), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC or EDCI) / hydroxybenzotriazole (HOBt), N,N,N',N'-tetramethyl-0-(lH-benzotriazol-l -yl)uronium hexafluorophosphate (HBTU), 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), (benzotriazol- 1 -y loxy)tris(dimethy lamino)phosphonium hexafluorophosphate (BOP), chlorotripyrrolidinophosphonium hexafluorophosphate (PyClOP), benzotriazol- l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N’-dicyclohexylcarbodiimide (DCC) / HOBt, l-cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholinocarbenium hexafluorophosphate (COMU), EDCI / ethyl 2-cyano- 2-(hydroxyimino)acetate (Oxyma), and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium tetrafluoroborate.

In certain embodiments, [5], or an acid anhydride or acyl halide thereof, and 3-chloro- 4-fluoroaniline are further contacted by at least one base. In other embodiments, the at least one base is a tertiary amine or tertiary aniline. In yet other embodiments, the at least one base is selected from the group consisting ofN,N-diisopropylethylamine, triethylamine, and 4- dimethylaminopyridine, or any other tertiary base or aniline.

In certain embodiments, the system formed after contacting [5], or an acid anhydride or acyl halide thereof, and 3-chloro-4-fluoroaniline, and the at least one base is further contacted with an acidic solution. In other embodiments, the acidic solution is an aqueous solution comprising at least one acid selected from the group consisting of citric acid and acetic acid.

In certain embodiments, [5], or an acid anhydride or acyl halide thereof, and 3-chloro- 4-fluoroaniline are contacted at a temperature from about 0 °C to about 40 °C.

In certain embodiments, [5], or an acid anhydride or acyl halide thereof, and 3-chloro- 4-fluoroaniline are contacted in a molar ratio of about 1 : 1 to about 1: 1.2.

In certain embodiments, the acid anhydride of [5] is a mixed acid anhydride. In other embodiments, the acid anhydride of [5] is a mixed acid anhydride prepared from (L')- 1 -(((L')- ter/-butylsulfinyl)amino)-7-fluoro-2,3-dihydro-lH-indene-4-carboxylic acid and a C2-C6 carboxylic acid.

Scheme I, Step 3: Synthesis of R group-substituted (A)-l-(((A)-tert-butylsulfinyl) amino)-7-fluoro-2, 3-dihydro- lH-indene-4-carboxylate [5].

In certain embodiments, [5] is prepared by a process comprising contacting a hydrolyzing base with R group-substituted (ri)-l-(((ri -/er/-butylsulfinyl)amino)-7-fluoro-2,3- dihydro- lH-indene-4-carboxylate

wherein R is C₁-C₆ alkyl, C₃-C_! cycloalkyl, or benzyl. In other embodiments, [5] is prepared by a process comprising converting the ester [4] into the carboxylic acid [5] using a hydrolyzing base.

In certain embodiments, the solution comprises at least one solvent selected from the group consisting of 2-methyl tetrahydrofuran, tetrahydrofuran, methanol ethyl acetate, ethanol, and isopropanol. In other embodiments, the at least one hydrolyzing base is selected from the group consisting of NaOH, LiOH, KOH, Na^C'O,. and K₂CO₃.

In certain embodiments, [4] after being contacted with at least one hydrolyzing base is further contacted by an acidic solution. In other embodiments, the acidic solution is an aqueous solution comprising at least one acid selected from the group consisting of citric acid and acetic acid.

In certain embodiments, [4] is contacted with the at least one hydrolyzing base at a temperature from about 0 °C to about 40 °C.

Scheme I, Step 2: Synthesis of R group-substituted (^^)-l-((tert-butylsulfinyl)

imino)-7-fluoro-2, 3-dihydro- lH-indene-4-carboxylate [4].

In certain embodiments, [4] is prepared by a process comprising contacting a reducing agent with R group-substituted (_<S',£)-l-((Ye/7-butylsulfmyl)imino)-7-fluoro-2,3-dihydro-lH-

indene-4-carboxylate

wherein R is Ci-C₆ alkyl, C₃-C₈ cycloalkyl, or benzyl. In other embodiments, [4] is prepared by a process comprising stereospecifically reducing the imine bond of [3]

In certain embodiments, the reducing agent is at least one selected from the group consisting of a borohydride salt, triacetoxyborohydride salt, and cyanoborohydride salt. In other embodiments, the reducing agent is at least one selected from the group consisting of sodium borohydride, sodium triacetoxyborohydire, sodium cyanoborohydride, and lithium borohydride. In yet other embodiments, the reducing agent is hydrogen gas, and the imine reduction is accomplished through catalytic hydrogenation, which is optionally enantioselective and/or enantiospecific.

In certain embodiments, [3] is contacted with the reducing agent in a solution comprising at least one organic solvent. In other embodiments, the at least one organic solvent is selected from the group consisting of 2-methyl tetrahydrofuran and

tetrahydrofuran.

In certain embodiments, [3] is contacted with the reducing agent at a temperature from about -78 °C to about 20 °C.

In certain embodiments, [3] after being contacted with the reducing agent is further contacted with a solution comprising an acid. In other embodiments, the solution comprising an acid is an aqueous solution comprising at least one acid, such as but not limited to citric acid and/or acetic acid.

In certain embodiments, the reducing agent and [3] are contacted in a molar ratio of about 1: 1 to about 1 : 1.5.

Scheme I, Step 1: Synthesis of R group-substituted (^^)-l-((tert-butylsulfinyl)

imino)-7-fluoro-2,3-dihydro-lH-indene-4-carboxylate [3].

In certain embodiments, [3] is prepared by a process comprising contacting ( S)-2 - methylpropane-2-sulfmamide, at least one Lewis acid, and R group-substituted 7-fluoro-l-

oxo-2, 3-dihydro-lH-indene-4-carboxylate

wherein R is C1-C6 alkyl, C3-C8 cycloalkyl, or benzyl.

In certain embodiments, [2] is contacted with 0V)-2-methyl propan e-2-sulfinamide and the at least one Lewis acid in a solution comprising at least one organic solvent. In other embodiments, the at least one organic solvent is selected from the group consisting of 2- methyl tetrahydrofuran, tetrahydrofuran, toluene, dichloromethane, and dioxane.

In certain embodiments, the at least one Lewis acid is selected from the group consisting of Ti(OEt)₄, Ti(OiPr)₄, TiCl₄, TiCl₂(OCH(CH₃)2)2, and TiCl(OCH(CH₃)₂)₃.

In certain embodiments, [2] is contacted with fV)-2-methyl propan e-2-sulfinamide and the at least one Lewis acid at a temperature from about 0 °C to about 120 °C.

In certain embodiments, [2] is contacted with fV)-2-methyl propan e-2-sulfinamide at a molar ratio of about 1 : 1.5. In other embodiments, [2] is contacted with the at least one Lewis acid at a molar ratio of about 1 :3. Scheme I, Steps 1-2: One-pot synthesis of R group-substituted (SJ )-l-((tert- butylsulfmyl)imino)-7-fluoro-2, 3-dihydro- lH-indene-4-carboxylate

[4] from R group-substituted 7-fluoro-l-oxo-2, 3-dihydro- 1H- indene-4-carboxylate [2].

In certain embodiments, Steps 1-2 of Scheme I as described herein can be performed under one-pot reaction conditions. In such case, [2] is contacted with fV)-2-methylpropane-2- sulfmamide and the at least one Lewis acid in a system under conditions that allow for formation of [3], at which time the system is further treated with a reducing agent under conditions that allow for formation of [4] Reaction progress can be monitored using techniques and methods known to those skilled in the art, some of which are exemplified elsewhere herein. The reaction mixture can be subjected to a work-up so as to isolate [4], which can then be hydrolyzed to yield [5]

In certain embodiments, compounds of the invention are prepared according to the illustrative synthetic methods outlined in Scheme II.

Scheme II.

Scheme II, Step 3: Synthesis of (1-methyl- 1H- 1,2, 4- triazol-3-yl)methyl (L')-(4-((3- chloro-4-fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden- l-yl)carbamate [9].

In certain embodiments, [9] is prepared by a process comprising contacting 3-chloro- 4-fluoroaniline with fY)-7-fluoro- 1 -(((( 1 -methyl- 1 H- 1.2.4-tria/ol-3-yl)metho\y)carbonyl)

amino)-2,3-dihydro-lH-indene-4-carboxylic acid

acid anhydride or acyl halide (such as but not limited to, acyl chloride or acyl bromide) thereof.

In other embodiments, [9] is prepared through an amide coupling reaction between [12] and 3-chloro-4-fluoroaniline.

In certain embodiments, [12], or an acid anhydride or acyl halide thereof, and 3- chloro-4-fluoroaniline are contacted in a solution comprising at least one organic solvent. In other embodiments, the at least one organic solvent is selected from the group consisting of 2-methyl tetrahydrofuran, tetrahydrofuran, dimethylformamide, ethyl acetate,

dichloromethane, chloroform, dimethylacetamide, and N-methyl-2-pyrrolidone.

In certain embodiments, [12] and 3-chloro-4-fluoroaniline are further contacted by at least one coupling agent. In other embodiments, the at least one coupling agent is selected from the group consisting of carbonyldiimidazole, HATU, 4-(4,6-dimethoxy-l,3,5-triazin-2- yl)-4-methyl morpholinium chloride, T₃P, EDC/HOBt, HBTU, TBTU, BOP, PyClOP, PyBOP, DCC/HOBt, COMU, EDC/Oxyma, and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium tetrafluoroborate.

In certain embodiments, [12], or an acid anhydride or acyl halide thereof, and 3- chloro-4-fluoroaniline are further contacted by at least one base. In other embodiments, the at least one base is a tertiary amine or tertiary aniline. In yet other embodiments, the at least one base is selected from the group consisting of N,N-diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine, or any other tertiary amine or tertiary aniline.

In certain embodiments, the system formed after contacting [12], or an acid anhydride or acyl halide thereof, and 3-chloro-4-fluoroaniline, and the at least one base is further contacted with an acidic solution. In other embodiments, the acidic solution is an aqueous solution comprising at least one acid selected from the group consisting of citric acid and acetic acid.

In certain embodiments, [12], or an acid anhydride or acyl halide thereof, and 3- chloro-4-fluoroaniline are contacted at a temperature from about 0 °C to about 40 °C.

In certain embodiments, [12], or an acid anhydride or acyl halide thereof, and 3- chloro-4-fluoroaniline are contacted in a molar ratio of about 1: 1 to about 1 : 1.2.

In certain embodiments, the acid anhydride of [12] is a mixed acid anhydride. In other embodiments, the acid anhydride of [12] is a mixed acid anhydride prepared from ( S )- l-(((<S)-/e/7-butylsulfmyl)amino)-7-fluoro-2,3-dihydro-lH-indene-4-carboxylic acid and a C₂- Ce carboxylic acid.

Scheme II, Step 2: Synthesis of fV)-7-fluoro- 1 -((((I -methyl- 1 H-l ,2,4-triazol-3- yl)methoxy)carbonyl)amino)-2,3-dihydro-lH-indene-4-carboxylic acid [12].

In certain embodiments, [12] is prepared by a process comprising contacting a hydrolyzing base with R group-substituted (<S)-7-fluoro- !-((((! -methyl- 1H- 1,2, 4-triazol-3-

yl)methoxy)carbonyl)amino)-2,3-dihydro-lH-indene-4-carboxylate

[11], wherein R is C1-C6 alkyl, C3-C8 cycloalkyl, or benzyl. In other embodiments, [12] is prepared by a process comprising converting the ester [11] into the carboxylic acid [12] using a hydrolyzing base.

In certain embodiments, the hydrolysis is run in a solvent, wherein the solvent comprises at least one selected from the group consisting of 2-methyl tetrahydrofuran, tetrahydrofuran, methanol ethyl acetate, ethanol, and isopropanol. In other embodiments, the at least one hydrolyzing base is selected from the group consisting of NaOH, LiOH, KOH, Na C0₃, and K C0₃.

In certain embodiments, the system formed after contacting [11] and at least one hydrolyzing base is further contacted by an acidic solution. In other embodiments, the acidic solution is an aqueous solution comprising at least one acid selected from the group consisting of citric acid and acetic acid.

In certain embodiments, [11] is contacted with the at least one hydrolyzing base at a temperature from about 0 °C to about 40 °C.

Scheme II, Step 1: Synthesis of R group-substituted fV)-7-fluoro- l-(((( l-methyl- l 11-

1, 2,· 4- triazol-3-yl)methoxy)carbonyl)amino)-2, 3-dihydro- 1H- indene-4-carboxylate [11].

In certain embodiments, [11] is prepared by a process comprising contacting (1- methyl-l,2,4-triazol-3-yl)methanol [8], R group-substituted fV)- l -amino-7-fluoro-2.3- dihydro- lH-indene-4-carboxylate

, wherein R is Ci-C₆ alkyl, C₃-C₈

cycloalkyl, or benzyl, and at least one coupling agent, or a salt or solvate thereof.

In certain embodiments, [8], [10], and at least one coupling agent are contacted in a solution. In other embodiments, the solution comprises at least one organic solvent selected from the group consisting of 2-methyl tetrahydrofuran, tetrahydrofuran, dimethylformamide, dichloromethane, chloroform, dimethylacetamide, and N-methyl-2-pyrrolidone.

In certain embodiments, the at least one coupling agent is a carbonyl equivalent (carbonyl equivalent coupling agent), allowing for the coupling of an amine and an alcohol to form a carbamate (or urethane). In other embodiments, the at least one coupling agent is selected from the group consisting of carbonyldiimidazole, phosgene, diphosgene, triphosgene, and disuccinimidyl carbonate.

In certain embodiments, [8], [10], and at least one coupling agent are further contacted with at least one base. In other embodiments, the at least one base is a tertiary amine or tertiary aniline. In yet other embodiments, the at least one base is selected from the group consisting of N,N-diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine, or any other tertiary amine or tertiary aniline.

In certain embodiments, [8], [10], and at least one coupling agent are reacted at temperature from about 20 °C to about 80 °C. In other embodiments, [8], [10], and at least one coupling agent are contacted at an initial temperature of about 20 °C, and then heated to about 80 °C.

In certain embodiments, [8], [10], and at least one coupling agent are contacted for about 5 hours to about 48 hours. In other embodiments, [8], [10], and at least one coupling agent are contacted for a period of time sufficient to reach reaction completion, as monitored and determined by one or more chemical characterization methods common in the art.

In certain embodiments, [8] and [10], are contacted in a molar ratio of about 1 : 1 to about 3: 1.

In certain embodiments, the method further comprises recry stallizing [11] from a solution comprising isopropanol and/or 2-methyltetrahydrofuran.

In certain embodiments, [10] is an acid addition salt of R group-substituted (<S -l- amino-7-fluoro-2,3-dihydro-lH-indene-4-carboxylate. In other embodiments, [10] is R group-substituted fV)- 1 -amino-7-fluoro-2.3-dihydro- 1 H-indene-4-carbo\ylate hydrochloride. In certain embodiments, [2] is prepared according to Scheme III, wherein X is Br or I.

Scheme III.

Scheme III: Synthesis of R group-substituted (X,£)-l-((tert-butylsulfinyl)

imino)-7-fluoro-2, 3-dihydro- lH-indene-4-carboxylate [2].

In certain embodiments, [2] is prepared by a process comprising contacting 4-halo-7- fluoro-2,3-dihydro-lH-inden-l-one [1], wherein X is Br or I, with at least one base, at least one esterification catalyst, carbon monoxide, and alcohol ROH, wherein R is C1-C6 alkyl, CN- Cg cycloalkyl, or benzyl.

In certain embodiments, the at least one base is selected from the group consisting of triethylamine, NaOAc, KOAc, and K₃PO₄.

In certain embodiments, the at least one esterification catalyst is a palladium catalyst. In other embodiments, the at least one catalyst is a palladium catalyst selected from the group consisting of PdCf.dppf (dppf = l,l'-Ferrocenediyl-bis(diphenylphosphine)), Pd(dppf)Cl2, PdiOAcf-dppp. and PdCl2(PPh₃)₂. In yet other embodiments, the at least one catalyst is contacted with [1] in a molar ratio of about 1 : 100 to about 1: 10.

In certain embodiments, the carbon monoxide pressure ranges from about 50 psi to about 150 psi.

In certain embodiments, [1] is contacted with the at least one base, the at least one catalyst, the carbon monoxide, and the alcohol at a temperature from about 40 °C to about 100 °C.

In certain embodiments, 2 is prepared according to Scheme IV.

Scheme IV.

Scheme IV, Step 4a: Synthesis of R group-substituted 7-fluoro-l-oxo-2,3-dihydro-lH- indene-4-carboxylate [2].

In certain embodiments, [2] is prepared by a process comprising converting 3-(2- (Alkoxycarbonyl)-5-fluorophenyl)propanoic acid [18] to its corresponding acyl halide (such as acyl chloride or acyl bromide) and then allowing it to undergo an intramolecular Friedel- Craft acylation, wherein R is C1-C6 alkyl or C3-C8 cycloalkyl.

In certain embodiments, [2] is prepared by a process comprising contacting [18] with a strong acid, such as but not limited to poly phosphoric acid and/or trifluoroacetic acid, with optional heating, optionally in solution, whereby intramolecular cyclization takes place. In certain embodiments, the method comprises contacting [18] with a chlorinating reagent selected from the group consisting of oxalyl chloride, phosgene, diphosgene, triphosgene, and thionyl chloride. In other embodiments, the chlorinating reagent and [18] are contacted in the presence of DMF and/or DMAc.

In certain embodiments, the product of the reaction between [18] and the chlorinating reagent is then contacted with a Lewis acid, such as but not limited to an aluminum salt, such as but not limited to AICI₃, whereby an intramolecular Friedel-Crafts reaction takes place to form 2.

In certain embodiments, the intramolecular Friedel-Crafts reaction takes place at a temperature from about 10 °C to about 50 °C.

Scheme IV, Step 3a: Synthesis of 3-(2-((R group-substituted)-oxycarbonyl)-5- fluorophenyl)propanoic acid [18]:

In certain embodiments, 18 is prepared by a process comprising reducing R group- substituted (7/)-2-(3-(alko\y)-3-o\oprop- 1 -en- 1 -yl)-4-fluorobenzoate [16], wherein R is Ci- Ce alkyl or C₃-C₈ cycloalkyl, and R’ is benzyl.

In certain embodiments, the method comprises contacting [16] with at least one hydrogenation catalyst and hydrogen gas.

In certain embodiments, the at least one hydrogenation catalyst is a palladium or platinum catalyst. In other embodiments, the at least one hydrogenation catalyst is palladium on carbon (Pd/C). In yet other embodiments, the at least one hydrogenation catalyst is contacted with 16 in a molar ratio of about 1 : 100 to about 1: 10.

In certain embodiments, [16] is contacted with the hydrogenation catalyst and hydrogen gas at a temperature from about 20 °C to about 30 °C.

In certain embodiments, [16] is contacted with hydrogen gas under a pressure of about 10 psi to about 50 psi.

In certain embodiments, [16] is contacted with the hydrogenation catalyst and hydrogen gas in a solution. In other embodiments, the solution comprises at least one alcohol. In yet other embodiments, the solution comprises methanol. Scheme IV, Steps 3al & 3a2: Synthesis of 3-(2-((R group-substituted)- oxycarbonyl)-5-fluorophenyl)propanoic acid [18]:

Alternatively, instead of using Step 3a as described herein, conversion of [16] into

[18] can be performed in two steps, which can be run as a one-pot reaction. In this alternative procedure, [16] can be hydrolyzed to acid [20] (Step 3al), using for example and acid or a base as described elsewhere herein. Acid [20] can then be hydrogenated to bis-acid [18]

(Step 3a2) using hydrogenation conditions as described elsewhere herein. In certain embodiments, R’ is Ci-C₆ alkyl, C3-C8 cycloalkyl, or benzyl.

Scheme IV, Steps 3bl & 3b2: Synthesis of 3-(2-((R group-substituted)- oxycarbonyl)-5-fluorophenyl)propanoic acid [18]:

Altematively, instead of using Step 3a as described herein, conversion of [16] to [18] can be performed in two steps, which can be run as a one-pot reaction. In this alternative procedure, [16] with at least one hydrogenation catalyst and hydrogen gas (Step 3b 1) to yield bis-ester [21], and contacting [21] with an acid under conditions that allow for hydrolysis of R’ but not of R, as described elsewhere herein (Step 3b2; see, for example, Scheme IV, Step 3’). In certain embodiments, R’ is Ci-C₆ alkyl or C3-C8 cycloalkyl. In other embodiments,

R’ is tert- butyl. In yet other embodiments, R is not tert- butyl.

Scheme IV, Step 2a: Synthesis of R,R’ groups-substituted (£)-2-(3-(alkoxy)-3-oxoprop- l-en-l-yl)-4-fluorobenzoate [16].

In certain embodiments, [16] is prepared by a process comprising coupling an acrylate

[15] with a R group-substituted 2-halo-4-fluorobenzoate [14], wherein X is selected from the group consisting of Cl, Br, and I, R is C1-C6 alkyl or C3-C8 cycloalkyl, and R’ is C1-C6 alkyl, C3-C8 cycloalkyl, or benzyl.

In certain embodiments, the method comprises contacting [14] with at least one base, at least one catalyst, and [15] to form a reaction mixture.

In certain embodiments, a phase transfer agent, such as but not limited to a tetraalkylammonium halide (such as but not limited to tetrabutylammoniun bromide), can be used in the reaction.

In certain embodiments, the at least one catalyst is a palladium catalyst. In yet other embodiments, the at least one catalyst is a catalyst selected from the group consisting of Pd(OAc)₂, PdCl₂(PPh₃)₂, Pd(PPh₃)₄, and Pd/C. In yet other embodiments, the catalyst comprises a ligand, such as but not limited to a triphosphine, such as but not limited to triphenylphosphine, tris-(o-tolyl)phosphine, and/or tris-(4-fluorophenyl)phosphine. In yet other embodiments, the at least one catalyst is contacted with [14] in a molar ratio of about 1: 100 to about 1 : 10.

In certain embodiments, [14] is contacted with the at least one base, the at least one catalyst, and [15] in a solution. In other embodiments, the solution comprises at least one solvent selected from the group consisting of dimethyl sulfoxide (DMSO),

dimethylformamide (DMF), and dimethyl acetamide (DMAc).

In certain embodiments, [14] is contacted with the at least one base, the at least one catalyst, and [15] at a temperature from about 80 °C to about 120 °C. In other embodiments,

[14] is contacted with the at least one base, the at least one catalyst and [15] at about 100 °C.

In certain embodiments, the reaction mixture further comprises at least one coupling promoter. In other embodiments, the coupling promoter is a tetrabutylammonium salt, such as tetrabutylammonium bromide.

Scheme IV, Step 4b: Synthesis of R group-substituted 7-fluoro-l-oxo-2,3-dihydro-lH- indene-4-carboxylate [2].

In certain embodiments, [2] is prepared by a process comprising converting 3-(5- fluoro-2-([R group-substituted]oxycarbonyl)phenyl)propanoic acid [18] to its corresponding acyl chloride and then allowing it to undergo an intramolecular Friedel-Craft acylation, wherein R is Ci-C₆ alkyl or C3-C8 cycloalkyl. In other embodiments, [2] is prepared by a process comprising contacting [18], with a strong acid, such as but not limited to

polyphosphoric acid and/or trifluoroacetic acid, with optional heating, optionally in solution, whereby intramolecular cyclization takes place.

In certain embodiments, the method comprises contacting [18] with a chlorinating reagent selected from the group consisting of oxalyl chloride, phosgene, diphosgene, triphosgene, and thionyl chloride. In other embodiments, the chlorinating reagent and [18] are contacted in the presence of DMF.

Scheme IV, Step 3b: Synthesis of 3-(5-fluoro-2-([R group-substituted] oxycarbonyl) phenyl) propanoic acid [18]

In certain embodiments, [18] is prepared by a process comprising contacting R group- substituted 4-fluoro-2-(3-[R’-substituted]oxy-3-oxopropyl)benzoate [17] with an acid, wherein R is Ci-C₆ alkyl or C₃-C₈ cycloalkyl, and R’ is Ci-C₆ alkyl or C₃-C₈ cycloalkyl. In other embodiments, R’ is tert-butyl. In yet other embodiments, R is not tert- butyl.

In certain embodiments, 17 is contacted with the acid in a solvent, which may be an aprotic solvent, such as but not limited to 2-methyl tetrahydrofuran, tetrahydrofuran, dimethylformamide, dichloromethane, chloroform, dimethylacetamide, and N-methyl-2- pyrrolidone.

In certain embodiments, the acid comprises at least one selected from the group consisting of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, and the like.

In certain embodiments, the step is run at a temperature from about 0 °C to about 40 °C.

In certain embodiments, the system formed after contacting [17] and the acid is concentrated to at least near dryness, and then purified by methods known to those skilled in the art, such as chromatography, solvent extraction, and/or crystallization.

Scheme IV, Step 2b: Synthesis of R group-substituted 4-fluoro-2-(3-[R’-substituted]oxy- 3-oxopropyl)benzoate [17].

In certain embodiments, [17] is prepared by a process comprising coupling aromatic halide [14] with R-substituted 3-halopropanoate [19], wherein each X is independently selected from the group consisting of Cl, Br, and I, R is Ci-C₆ alkyl or C3-C8 cycloalkyl, and R’ is Ci-C₆ alkyl or C3-C8 cycloalkyl. In other embodiments, R’ is tert- butyl. In yet other embodiments, R is not tot-butyl.

In certain embodiments, the coupling of [14] and [19] is performed using a transition metal catalyst. In other embodiments, the coupling of [14] and [19] is performed using Negishi coupling conditions. In yet other embodiments, the transition metal comprises nickel or palladium. In yet other embodiments, the transition metal comprises at least one of Pd₂(dba)3, Pd(OAc)₂, PdCl₂(PPh₃)₂, Pd(PPh₃)₄, and the like. In yet other embodiments, the coupling is performed in the presence of a ligand, such as but not limited to a triphosphine, such as but not limited to triphenylphosphine, tris-(o-tolyl)phosphine, tris-(4-fluorophenyl) phosphine, l,2-bis(diphenylphosphino)ethane (dppe), 2,2'-bis(diphenylphosphino)-l,T- binaphthyl (BINAP), (2N,3ri)-(-)-bis(diphenylphosphino)butane, (2//.3//)-(+)-bis

(diphenylphosphino)butane, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-(2-dicyclohexylphosphanyl phenyl)-N¹,N¹,N³,N³-tetramethyl-benzene-l, 3-diamine (CPhos), and the like. In yet other embodiments, the coupling is run in the presence of catalytic amounts of iodine. In yet other embodiments, the coupling is run in the presence of elemental zinc. In yet other

embodiments, the coupling is performed in a solvent, which may be an aprotic solvent, such as but not limited to 2-methyl tetrahydrofuran, tetrahydrofuran, dimethylformamide, dichloromethane, chloroform, dimethylacetamide, and N-methyl-2-pyrrolidone. In yet other embodiments, the coupling is performed under oxygen-free conditions. In yet other embodiments, the coupling is performed under anhydrous conditions. In yet other embodiments, the coupling reaction is run at a temperature from about -20 °C to about 60 °C.

In yet other embodiments, after the coupling reaction is complete, the system is filtered, and the solute is washed with an acidic aqueous solution and/or a basic aqueous solution. The resulting solute can then be concentrated and purified using conditions known to those skilled in the art to yield 17. Scheme IV, Step 1: Synthesis of R group-substituted 2-halo-4-fluorobenzoate [14]

In certain embodiments, [14] is prepared by a process wherein an alcohol (ROH) is

contacted with an acid and 2-halo-4-fluorobenzoic acid

wherein X is selected from the group consisting of Cl, Br, and I, and R is Ci-C₆ alkyl or C3-C8 cycloalkyl.

In certain embodiments, the alcohol is ethanol. In other embodiments, the alcohol, acid, and [13] are contacted in a solution that does not comprise any additional solvent besides the alcohol.

In certain embodiments, the acid is at least one selected from the group consisting of sulfuric acid (H2SO4), p-toluenesulfonic acid, and hydrochloric acid. In other embodiments, the acid is contacted with [13] in a molar ratio of about 1 :1 to about 1:5.

In certain embodiments, [14] is prepared by a process comprising converting [13] to the corresponding acid halide (for example, by treating [13] with a chlorinating agent such as but not limited to oxalyl chloride, phosgene, diphosgene, triphosgene, and/or thionyl chloride), and reacting the acyl halide formed with an alcohol ROH.

In certain embodiments, the alcohol, acid, and [13] are contacted at a temperature from about 60 °C to about 120 °C. In other embodiments, the alcohol, acid, and [13] are contacted at about 80 °C. In yet other embodiments, the alcohol, acid, and [13] are contacted at a temperature about equivalent to the boiling point of the alcohol.

A non-limiting synthetic scheme to prepare [9] and certain compounds of the invention is provided herein.

Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It should be contemplated that the invention includes each and every one of the synthetic schemes described and/or depicted herein.

It is appreciated that where typical or preferred process conditions (i.e.. reaction temperatures, times, mole ratios of reactants, solvents, pressures, and so forth) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein.

The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 'H or ¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatography (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

Preparation of the compounds can involve protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al. , Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out in suitable solvents that can be readily selected by one skilled in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, /. e.. temperatures that can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

Salts

The compounds described herein may form salts with acids or bases, and such salts are included in the present invention. The term“salts” embraces addition salts of free acids or bases that are useful within the methods of the invention. The term“pharmaceutically acceptable salt” refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications. In certain embodiments, the salts are pharmaceutically acceptable salts. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the invention.

Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include sulfate, hydrogen sulfate, hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4- hydroxybenzoic, phenylacetic, mandebc, embonic (or pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, sulfanibc, 2-hydroxyethanesulfonic, trifluoromethanesulfonic, p-toluenesulfonic, cyclohexylaminosulfonic, stearic, alginic, b- hydroxybutyric, salicylic, galactaric, galacturonic acid, glycerophosphonic acids and saccharin (e.g., saccharinate, saccharate). Salts may be comprised of a fraction of one, one or more than one molar equivalent of acid or base with respect to any compound of the invention.

Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, ammonium salts and metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene- diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (or N- methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.

Definitions

As used herein, each of the following terms has the meaning associated with it in this section.

Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in animal pharmacology, pharmaceutical science, separation science and organic chemistry are those well-known and commonly employed in the art. It should be understood that the order of steps or order for performing certain actions is immaterial, so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously or not.

As used herein, the articles“a” and“an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example,“an element” means one element or more than one element.

As used herein, the term“alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined elsewhere herein, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, l-propoxy, 2-propoxy (or isopropoxy) and the higher homologs and isomers. A specific example is (Ci-C3)alkoxy, such as, but not limited to, ethoxy and methoxy.

As used herein, the term“alkyl” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbon atoms) and includes straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. A specific embodiment is (Ci-C₆)alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, «-pentyl, «-hexyl and cyclopropylmethyl.

As used herein, the term“cycloalkyl” by itself or as part of another substituent refers to, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (i.e., G-G, refers to a cyclic group comprising a ring group consisting of three to six carbon atoms) and includes straight, branched chain or cyclic substituent groups.

Examples of (G-G, (cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl rings can be optionally substituted. Non-limiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5- dichlorocyclohexyl, 4-hydroxy cyclohexyl, 3,3,5-trimethylcyclohex-l-yl,

octahydropentalenyl, octahydro- 1 //-indeny 1. 3a.4.5.6.7.7a-he\ahydro-3//-inden-4-yl.

decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro- 1//- fluorenyl. The term“cycloalkyl” also includes bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2. l. l]hexanyl, bicyclo[2.2. l]heptanyl,

bicyclo[3. l. l]heptanyl, l,3-dimethyl[2.2. l] heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

As used herein, the term“halide” refers to a halogen atom bearing a negative charge. The halide anions are fluoride (F ), chloride (CE), bromide (Br ). and iodide (G).

As used herein, the term“halo” or“halogen” alone or as part of another substituent refers to, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

As used herein, the language“pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and/or bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates (including hydrates) and clathrates thereof.

As used herein, the term“substituted” refers to that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

As used herein, the term“substituted alkyl” or“substituted cycloalkyl” refers to alkyl or cycloalkyl, as defined elsewhere herein, substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, alkoxy, tetrahydro-2-H- pyranyl, -NH₂, -NH(C_I-C₆ alkyl), -N(C_I-C₆ alkyl)₂, 1 -methyl-imidazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=0)OH, -C(=0)0(Ci-C₆)alkyl, trifluoromethyl, -CºN, - C(=0)NH₂, -C(=0)NH(Ci-C₆)alkyl, -C(=0)N((Ci-C₆)alkyl)₂, -S0₂NH₂, -S0₂NH(Ci-C₆ alkyl), -S0₂N(C_I-C₆ alkyl)₂, -C(=NH)NH₂, and -N0₂, in certain embodiments containing one or two substituents independently selected from halogen, -OH, alkoxy, -NH₂, trifluoromethyl, -N(CH₃)₂, and -C(=0)OH, in certain embodiments independently selected from halogen, alkoxy and -OH. Examples of substituted alkyls include, but are not limited to, 2,2- difluoropropyl, 2-carboxy cyclopentyl and 3-chloropropyl.

For benzyl and phenyl groups, the term“substituted” as applied to the rings of these groups refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In certain embodiments, the substituents vary in number between one and four. In other embodiments, the substituents vary in number between one and three. In yet another embodiments, the substituents vary in number between one and two. In yet other embodiments, the substituents are independently selected from the group consisting of C1-C6 alkyl, -OH, Oi-Ob alkoxy, halo, amino, acetamido and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic.

Whenever a term or either of their prefix roots appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, whenever the term“alkyl” or“aryl” or either of their prefix roots appear in a name of a substituent ( e.g ., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given elsewhere herein for“alkyl” and“aryl” respectively.

In certain embodiments, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term“Ci_₆ alkyl” is specifically intended to individually disclose Ci, C₂, C₃, C₄, C₅, C₆, Ci-C₆, C1-C5, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆ alkyl.

Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual and partial numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

The following non-limiting abbreviations are used herein: CPME, cyclopentyl methyl ether; DCM, dichloromethane; dppp, l,3-Bis(diphenylphosphino)propane; dppf, 1,1'- Ferrocenediyl-bis(diphenylphosphine); DMAc, dimethylacetamide; DMAP, 4- dimethylaminopyridine; DMF, dimethylformamide; EDC or EDCI, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide; EtOAc, ethyl acetate; EtOH, ethanol; Et₃N or TEA, trimethylamine; HATU, (l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate; HBV, hepatitis B virus; HDV, hepatitis D virus; HPLC, high performance liquid chromatography; MeOH, methanol; NaBH₄, sodium borohydride; NMP, N-methyl-2-pyrolidone; TBAB, tetrabutylammonium bromide; THF, tetrahydrofuran; 2-MeTHF, 2-methyl tetrahydrofuran.

The following examples further illustrate aspects of the present invention. However, they are in no way a limitation of the teachings or disclosure of the present invention as set forth herein.

EXAMPLES

The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only, and the invention is not limited to these Examples, but rather encompasses all variations that are evident as a result of the teachings provided herein.

Materials and Methods

All commercially available reagents and solvents were purchased from commercial sources and used without further purification unless noted otherwise.

' H and ¹³C NMR spectra were obtained on Bruker (400 MHz) and Agilent Magnetic Resonance System (600 MHz, Agilent Technologies). Chemical shifts were measured in parts per million or ppm (d), referenced to tetramethylsilane (TMS) as the internal standard or to the residual solvent peak (CDCh, 1H: 7.26, 13C: 77.16). Multiplicities were indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), dd (doublet of doublets), brs (broad singlet), and so on. Coupling constants were reported in hertz (Hz).

Low resolution mass spectra (LRMS) were analyzed on Waters Q-TOF using the electrospray ionization (ESI) method.

The reaction conversion was monitored by thin-layer chromatography (TLC) (Merck Kiselgel 60 F254 plates).

Products were purified by flash column chromatography on Merck Kieselgel 60 (230- 400 mesh).

EXAMPLE 1: Synthesis of (l-methyl-lH-l,2,4-triazol-3-yl)methyl (S)-(4-((3-chloro-4- fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden-l-yl)carbamate [9], according to Scheme I.

Step: Preparation of ethyl 7-fluoro-l-oxo-2, 3-dihydro- lH-indene-4-carboxylate

[2a]:

A solution of 4-bromo-7-fluoro-2,3-dihydro-lH-inden-l-one [la] (50 g, 218.3 mmol) in EtOH (900 mL) and Et₃N (355 mL) was degassed and backfilled with nitrogen gas three times in a 2L pressure vessel. PdCl₂.dppf (17.8 g, 21.8 mmol) was added. The solution was degassed and backfilled with nitrogen gas three times. The vessel was sealed, pressurized with CO (100 psi), and heated at 80 °C overnight. The contents were cooled to room temperature and released the pressure. The reaction mixture was filtered through pad of CELITE®, and the filter cake was washed with EtOAc (3 x 1L). The combined filtrate was concentrated under vacuum and diluted with EtOAc (1 L). The solution was washed with water two times (2 x 500 mL). The organic layer was concentrated under vacuum to give 93 g as a brown wax. The crude material was recrystallized from CPME (1.5 mL/g) and dried to give ethyl 7-fluoro-l-oxo-2,3-dihydro-lH-indene-4-carboxylate [2a], R=Et (58 g, 80 %) as a pale brown powder. ^XH NMR (400 MHz, DMSO-d₆): 8.2 (dd, J = 4.8, 3.6 Hz, 1H), 7.3 (t, J = 9.0 Hz, 1H), 4.34 (q, J = 7.2, 6.9 Hz, 2H), 3.41-3.37 (m, 2H), 2.70-2.66 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of triethylamine, bases such as but not limited to KOAc or K3PO4, or other trialky lamines can be used. Alternative catalysts to PdCT.dppf can include Pd(dppf)Cl2-DCM, Pd(OAc)₂-dppp and PdCl₂(PPh₃)₂.

Alternative alcohols such as methanol or isopropanol can be used in lieu of ethanol to provide corresponding alkyl esters. These alkyl esters can also be used in following steps leading to intermediate (5)-l-(((5 -/er/-butylsulfmyl)amino)-7-fluoro-2,3-dihydro-lH-indene- 4-carboxylic acid (5).

Steps 1-3: Preparation of (S)- l-(((A)-tert-butylsulfinyl)amino)-7-fluoro-2, 3-dihydro- 1H- indene-4-carboxylic acid [5]:

To a stirred solution of fV)-2-methylpropane-2-sulfinamide (l59g, 1.31 mol) in 2- MeTHF (970 mL) was added titanium tetraethoxide (597.4 g, 2.62 mol). The contents were heated to 65-70 °C. To the hot reaction mixture was added a hot solution (40 °C) of ethyl 7- fluoro-l -oxo-2, 3-dihydro-lH-indene-4-carboxylate [2a] (194 g, 0.873 mmol) in 1: 1 mixture of 2-MeTHF/THF (1940 mL) over 11 hours. The contents were heated for additional 3 hours and cooled to -12 °C. Sodium borohydride (33.0 g, 873 mmol) was added to the reaction mixture in two portions. The mixture was warmed to 0 °C and stirred for additional 1 hour at 0 °C. The reaction mixture was quenched in to a 15 wt% citric acid/sodium citrate solution (prepared by dissolving 582 g of citric acid and 97 g of sodium hydroxide and 3.2 L of water) while maintaining the internal temperature below 15 °C (addition is highly exothermic with a significant off-gassing). The mixture was warmed to 20 °C and stirred for additional 2 hours. The mixture was filtered through a pad of CELITE® and the layers were separated. The organic layer was washed with water (970 mL) followed by brine (970 mL). The organic layer was concentrated to a minimum volume and co-evaporated with methanol (2 x 970 mL) to a final volume of approximately 970 mL. To the mixture was added additional methanol (776 mL) and cooled to 10 °C. A solution of sodium hydroxide (34.9 g in 388 mL water) was added while maintaining the internal temperature below 15 °C. Contents were warmed to 20 °C and stirred for 18 hours. The mixture was concentrated under reduced pressure and diluted with water (388 mL). Ethyl acetate (1.16 L) was added, and the contents were cooled to 10 °C. 50 wt% citric acid solution (350 mL) in water was slowly added while maintaining the internal temperature below 20 °C. The slurry was cooled to 5 °C and stirred for 2 hours. The product was filtered, washed with water (2 x 500 mL) and cold ethyl acetate (194 mL, 0- 5 °C). The product was dried under vacuum at 40 °C to give (ri -l-(((<S)-/e/7-butylsulfmyl) amino)-7-fluoro-2,3-dihydro-lH-indene-4-carboxylic acid [5] as solid (113.7 g, 43 % yield). ^XH NMR (400 MHz, DMSO-d₆) d 12.89 (s, 1H), 7.88 (dd, J= 8.6, 5.1 Hz, 1H), 7.10 (t, J = 8.7 Hz, 1H), 5.70 (d, = 5.8 Hz, 1H), 4.93-4.89 (m, 1H), 3.33 (dd, J= 8.8, 8.3 Hz, 1H), 3.17 (ddd, J = 17.7, 8.9, 3.1 Hz, 1H), 2.34-2.24 (m, 1H), 2.14-2.07 (m, 1H), 1.04 (s, 9H).

d crop isolation·. The filtrate was washed with water two times (390 mL each) and concentrated to a final volume of approximately 350 mL. The slurry was heated at 40 °C for 2 hours and cooled to 20 °C. After stirring for additional 2 hours, product was collected by filtration and washed with cold ethyl acetate (0-5 °C) two times with 75 mL each time. The product was dried under vacuum at 40 °C to give (5)-l-(((5)-/er/-butylsulfmyl)amino)-7- fluoro-2,3-dihydro-lH-indene-4-carboxylic acid [5] as solid (25.3 g, 9.7%). Analytical data was identical to the I^st crop.

Alternative reagents and reaction conditions to those disclosed above may also be employed. Various conditions for the formation of R group-substituted (S,E)-\-((tert- butylsulfmyl)imino)-7-fluoro-2,3-dihydro-lH-indene-4-carboxylate [3] are well known to those skilled in the art and include those disclosed in Chem. Rev. 2010 (110):3609, hereby incorporated by reference in its entirety. For example, a wide range of Lewis acids can be used, including but not limited to titanium(IV) isopropoxide, titanium(IV) chloride, TiCl₂(OCH(CH₃)₂)2, and TiCl(OCH(CH₃)₂)₃.

A wide range of solvents can be employed, including but not limited to toluene, dichloromethane and dioxane. The reaction can proceed at temperatures ranging from 0 to 120 °C.

A wide range of reducing agents may also be used in lieu of sodium borohydride. Examples include sodium triacetoxyborohydride, sodium cyanoborohydride, and lithium borohydride. The reaction can proceed at temperatures ranging from -78 °C to 20 °C.

Alternative solvents and bases may be used for hydrolysis of R group-substituted ( S )- 1 -((CS')-/cT/-butylsuirinyl)amino)-7-fluoro-2.3-dihydro- 1 H-indene-4-carbo\ylate [4a]

Alternative bases for hydrolysis can include LiOH, KOH, Na₂C0₃, and K₂C0₃. The reaction can proceed in various solvents that include, but are not limited to, THF, ethanol, and isopropanol.

Step 4: Preparation of (S)-l-(((S)-fe/7-butylsulfinyl)amino)-IN-(3-chloro-4- fluorophenyl)-7-fluoro-2, 3-dihydro- lH-indene-4-carboxamide [6] :

A mixture of (5 -l-(((5 -/er/-butylsulfinyl)amino)-7-fluoro-2,3-dihydro-lH-indene-4- carboxylic acid [5] (130 g, 0.43 mol), HATU (167.2 g, 0.52 mol), and dimethylacetamide (520 mL) was stirred at ambient temperature (21 °C) for 30 min. N,N-diisopropylethyl amine (112.3 g, 0.87 mol) was added to the reaction mixture, and the contents were stirred for an additional 30 min. A solution of 3-chloro-4-fluoroaniline (75.9 g, 0.52 mol) in DMAc (130 mL) was added and the contents stirred until the reaction was deemed complete (less than 1.0 % (5)-l-(((5)-/er/-butylsulfmyl)amino)-7-fluoro-2,3-dihydro-lH-indene-4- carboxylic acid [5] remaining by HPLC). Ethyl acetate (520 mL) was added to the reaction mixture followed by a 15 wt% citric acid solution (1.3 L) in water while maintaining the internal temperature below 25 °C. The slurry was stirred at ambient temperature (20-25 °C) for 2 hours and then cooled to 5 °C stirred for 2 hours. The product was filtered and washed with water (650 mL). The wet product was washed with cold ethyl acetate (2 x 130 mL) and dried at 40 °C under vacuum to give (5)-l-(((5)-/er/-butylsulfmyl)amino)-N-(3-chloro-4- fluorophenyl)-7-fluoro-2,3-dihydro-lH-indene-4-carboxamide [6] as solid (174 g, 94% yield). ^XH NMR (400 MHz, DMSO-d₆) d 10.41 (s, 1H), 8.03 (dd, J = 6.9, 2.6 Hz, 1H), 7.71 (dd, J= 8.5, 4.8 Hz, 1H), 7.65 (ddd, J = 9.1, 4.4, 2.6 Hz, 1H), 7.39 (t, J= 9.1 Hz, 1H), 7.16 (t, J= 8.7 Hz, 1H), 5.71 (d , J = 5.7 Hz, 1H), 4.96-4.92 (m, 1H), 3.38-3.25 (m, 1H), 3.05 (ddd, J = 17.2, 8.7, 3.3 Hz, 1H), 2.36-2.26 (m, 1H), 2.17-2.10 (m, 1H), 1.06 (s, 8H).

Alternative reagents and reaction conditions to those disclosed above can also be employed. For example, other coupling reagents in lieu of HATU can be used. Non-limiting examples include 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride, carbonyldiimidazole, propylphosphonic anhydride, 3-(ethyliminomethyleneamino)-N,N- dimethylpropan-l -amine/hydroxybenzotriazole, (2-( 1 //-benzotriazol- 1 -yl)- 1. 1.3.3- tetramethyluronium hexafluorophosphate), (2-( 1 //-benzotriazol- 1 -yl)- 1. 1.3.3- tetramethy luronium tetrafluoroborate), (benzotriazol- 1 -y loxy )tris(dimethy lamino) phosphonium hexafluorophosphate, chlorotripyrrolidinophosphonium hexafluorophosphate, (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate,

dicyclohexylcarbodiimide / hydroxybenzotriazole, (l-cyano-2-ethoxy-2- oxoethy lidenaminooxy )dimethy lamino-morpholino-carbenium hexafluorophosphate, 1 -ethy 1- 3-(3-dimethylaminopropyl)carbodiimide / ethyl cyanohydroxyiminoacetate, and 4-(4,6- dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholiniumtetrafluoroborate. Alternative amide couplings via activation of carboxylic acid through mixed anhydride followed by reacting with 3-chloro-4-fluoroaniline can also be utilized. Alternative bases that can be employed in place of N,N-diisopropylethyl amine are triethylamine or 4-dimethylaminopyridine (DMAP). Various solvents, such as dimethylformamide (DMF), N-methyl-2-pyrolidone (NMP), ethyl acetate and dichloromethane, can be employed, and the reaction can proceed at temperatures of about 0 °C to about 40 °C.

Step 5: Preparation of (A)-l-amino-IN-(3-chloro-4-fluorophenyl)-7-fluoro-2,3- dihydro-lH-indene-4-carboxamide hydrochloride [7.HC1]:

Acetyl chloride (93.7 g, 85 mL, 1.19 mol) was added slowly to methanol (500 mL) while maintaining the internal temperature below 30 °C. The contents were cooled to 10 °C with stirring and external cooling. The resulting methanolic hydrogen chloride solution was added to a solution of (_<S)-l-(((_<S)-/e/7-butylsulfmyl)amino)-N-(3-chloro-4-fluorophenyl)-7- fluoro-2,3-dihydro-lH-indene-4-carboxamide [6] (170 g, 0.398 mol) in methanol (350 mL) while keeping the contents below 25 °C. The solution was stirred at ambient temperature (20-25 °C) until the reaction is deemed complete (2-3 hours, <1.0% [6] remaining by HPLC). The reaction mixture was concentrated under reduced pressure to approximately 340 mL, and then CPME added (850 mL). The mixture was concentrated to about 340 mL, CPME was added (850 mL), and the system was concentrated to a final volume of about 850 mL. The slurry was stirred at 20 °C for 16 hours and then cooled to 0 °C. The product was filtered, washed with CPME (340 mL), and dried under vacuum to give (S)- 1 -amino-N-(3-chloro-4- fluorophenyl)-7-fluoro-2,3-dihydro-lH-indene-4-carboxamide hydrochloride [7.HC1] as solid (152 g, 108 % yield, contaminated with residual CPME and methyl /er/-butylsulfinate). ' H NMR (400 MHz, DMSO-d₆) d 10.67 (s, 1H), 8.63 (s, 3H), 8.08 (dd, J= 6.9, 2.6 Hz, 1H),

7.89 (dd, J= 8.6, 4.9 Hz, 1H), 7.71 (ddd, = 9. l, 4.4, 2.6 Hz, 1H), 7.40 (t, = 9.1 Hz, 1H), 7.27 (t, J= 8.7 Hz, 1H), 3.44-3.36 (m, 1H), 3.21-3.09 (m, 1H), 2.48-2.36 (m, 1H), 2.18-2.11 (m, 1H).

Alternative reagents and reaction conditions to those disclosed above can also be employed. For example, the methanolic hydrochloric acid can be replaced with acid solutions in alternative solvents such, but not limited to, isopropanol, ethanol, CPME, and dioxane. Step 6: Preparation of (1-methyl- 1H-1, 2, 4-triazol-3-yl)methyl (A)-(4-((3-chloro-4- fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden-l-yl)carbamate [9]:

A mixture of carbonyldiimidazole (CDI) (97 g, 0.6 mol), (l-methyl-l,2,4-triazol-3- yl)methanol [8] (67.7 g, 0.6 mol), and 2-MeTHF (1150 mL) was stirred at room temperature (20 °C) for 2 hours. The reaction mixture was added to a stirred mixture of (S)- 1 -amino-N- (3-chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-lH-indene-4-carboxamide hydrochloride [7.HC1] (143.3 g, 0.4 mol), 2-MeTHF (860 mL), and N,N-diisopropylethylamine (129 g, 1 mol). The mixture was heated to 60 °C and the contents maintained at 60 °C for 6 hours.

The contents were cooled to 20 °C, water (285 mL) was added, and the mixture was stirred for 15 min. The layers were separated and the organic layer was washed with water two times (285 mL each time). The organic layer was filtered through a pad of CELITE®, and rinsed with 145 mL 2-MeTHF (1 volume). The solution was concentrated to about 700 mL under vacuum. 2-propanol (710 mL) was added and the mixture concentrated to about 700 mL. Additional 2-propanol (710 mL) was added and the mixture concentrated to

approximately 1000 mL. The slurry was heated at 45 °C for 2 hours and cooled to 20 °C over 1 hour. The slurry was stirred at 20 °C for 2 hours, and the product filtered. The product was washed with 2-propanol two times (286 mL each wash), and the wet product was dried under vacuum to give (l-methyl-lH-l,2,4-triazol-3-yl)methyl fV)-(4-((3-chloro-4- fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden-l-yl)carbamate [9] as solid (144.5 g, 78.4% yield). ^XH NMR (400 MHz, DMSO-d₆) d 10.39 (s, 1H), 8.42 (s, 1H), 8.06-7.99 (m,

1H), 7.81 (d, J = 8.8 Hz, 1H), 7.71-7.59 (m, 2H), 7.39 (t, J = 9.1 Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 5.26 (q, J = 7.7 Hz, 1H), 4.99 (dd, J = 20.0, 12.0 Hz, 1H), 3.83 (s, 2H), 3.21 (ddd, J = 17.1, 8.8, 5.1 Hz, 1H), 3.04-2.96 (m, 1H), 2.46-2.33 (m, 1H), 1.92-1.83 (m, 1H). mp: 185.9- 186.9 °C.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative solvents can include, DMAc, DMF, NMP, THF and dichloromethane. The product can be crystallized from wet 2-MeTHF and isopropanol mixture.

EXAMPLE 2: Synthesis of (l-methyl-lH-l,2,4-triazol-3-yl)methyl (X)-(4-((3-chloro-4- fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden-l-yl)carbamate [9], according to Scheme I.

Synthesis of (X)-l-(((X)-feri-butylsulfmyl)amino)-7-fluoro-2, 3-dihydro- lH-indene-4- carboxylic acid [2a]— one-pot reaction:

To a solution of fV)-2-methylpropane-2-sulfinamide [2a] (11 kg, 87 mol) in 2-MeTHF (66 L) at 30 °C was added Ti(OEt)4 (40 kg, 175 mol) and then the reaction mixture was heated to 65-75 °C. A heated solution of ethyl 7-fluoro-l-oxo-2,3-dihydro-lH-indene-4- carboxylate (13 kg, 58 mol) in THF (65 L) and 2-MeTHF (66 L) at 40 °C was charged slowly over 11 hours to the above solution at 65-75 °C.

Upon complete conversion of starting material, the reaction mixture was cooled to -15 °C and NaBH₄ (2.2 kg, 58 mol) was added. The reaction mixture was warmed to 0 °C and stirred. To the reaction mixture a solution of citric acid (39 kg) and NaOH (6.5 kg) in purified water (215 L) was slowly added, followed by 2-MeTHF (66 L). The reaction mixture was heated to 20 °C and filtered through a pad of CELITE® (13 kg) rinsing with additional 2-MeTHF (66 L). The filtrate was collected, and the organic layer was washed with purified water (65 L) and a solution of NaCl (3.4 kg) in purified water (63 L). The organic phase was concentrated under vacuum. The residue was dissolved in MeOH (52 L) and cooled to 0 °C.

A solution of NaOH (2.3 kg) in purified water (26 L) was added and the reaction mixture was heated to 20 °C and stirred until the reaction was complete. The reaction was concentrated, EtO Ac (78 L) was added, and the mixture was cooled to 0-10 °C. A solution of citric acid (15 kg) in purified water (15 L) was added to the reaction mixture to afford a pH of 4.5-5.5. The mixture was cooled to 0 °C and stirred. The product slurry was filtered, the wet cake was washed with purified water (68 L) and cold EtO Ac (13 L). The solid was dried under vacuum to afford (_<S)-l-(((_<S)-/e/7-butylsulfmyl)amino)-7-fluoro-2,3-dihydro-lH- indene-4-carboxylic acid [5] (6.5 kg, 38% yield). *H NMR (400 MHz, DMSO-d₆) d 12.89 (s, 1H), 7.88 (dd, J = 8.6, 5.1 Hz, 1H), 7.10 (t, J = 8.7 Hz, 1H), 5.70 (d, J = 5.8 Hz, 1H), 4.93- 4.89 (m, 1H), 3.33 (dd, J = 8.8, 8.3 Hz, 1H), 3.17 (ddd, J = 17.7, 8.9, 3.1 Hz, 1H), 2.34-2.24 (m, 1H), 2.14-2.07 (m, 1H), 1.04 (s, 9H).

Synthesis of fV)-l-(((A)-fe/i-butylsulfinyl)amino)-IN-(3-chloro-4-fluorophenyl)-7-fluoro- 2,3-dihydro- lH-indene-4-carboxamide [6] :

To a solution of (5 -l-(((5 -/er/-butylsulfmyl)amino)-7-fluoro-2,3-dihydro-lH- indene-4-carboxylic acid (6.5 kg, 22 mol) and HATU (8.3 kg, 22 mol) in DMAc (26 L) at room temperature was slowly added DIEA (5.6 kg, 44 mol). The reaction mixture was stirred at room temperature and then a solution of 3-chloro-4-fluoroaniline (3.8 kg, 26 mol) in DMAc (6 L) was added slowly. The reaction was stirred at room temperature until completion. EtOAc (26 L) was added followed by a solution of citric acid (10 kg) in purified water (58 L) at room temperature. The reaction mixture was cooled to 0 °C and filtered. The wet cake was washed with purified water (32 L) and cold EtOAc (13 L). The filtered cake was dried under vacuum to afford (5 -l-(((5 -/er/-butylsulfmyl)amino)-N-(3-chloro-4- fluorophenyl)-7-fluoro-2,3-dihydro-lH-indene-4-carboxamide [6] (8.0 kg, 86% yield) ' H NMR (400 MHz, DMSO-d₆) d 10.41 (s, 1H), 8.03 (dd, J = 6.9, 2.6 Hz, 1H), 7.71 (dd, J = 8.5, 4.8 Hz, 1H), 7.65 (ddd, J = 9.1, 4.4, 2.6 Hz, 1H), 7.39 (t, J = 9.1 Hz, 1H), 7.16 (t, J = 8.7 Hz, 1H), 5.71 (d, J = 5.7 Hz, 1H), 4.96-4.92 (m, 1H), 3.38-3.25 (m, 1H), 3.05 (ddd, J = 17.2, 8.7, 3.3 Hz, 1H), 2.36-2.26 (m, 1H), 2.17-2.10 (m, 1H), 1.06 (s, 8H).

Synthesis of fV)-l-amino-IN-(3-chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-l H-indene- 4-carboxamide [7]:

To MeOH (23 L) at 0-10 °C, acetyl chloride (4.4 kg, 56 mol) was slowly added drop wise to prepare the MeOH-HCl solution. To a solution of (S)-l-(((S)-tert- butylsulfmyl)amino)-N-(3-chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-lH-indene-4- carboxamide [6] (8.0 kg, 19 mol) in MeOH (16 L) at 0-10 °C the prepared MeOH-HCl solution was slowly added dropwise. The mixture was stirred at 20-30 °C until reaction was complete. The mixture was concentrated under vacuum maintaining the temperature at or below 35 °C. To the residue purified water (80 L) was added, followed by EtOAc (80 L), and the system was stirred. The organic layer was discarded, and the aqueous layer was washed with EtOAc (40 L) again. To the aqueous layer, 2-MeTHF (44 L) and a solution of NaHC0₃ (9.3 kg) and purified water (107 L) were charged at room temperature. The mixture was stirred and then the layers separated. The pH of the aqueous layer was adjusted to 7.5-8.5 and again extracted with 2-MeTHF (44 L). The combined organic layers were washed with purified water (20 L) and then concentrated under vacuum while maintaining the temperature at or below 40 °C. The residue was treated with CPME (51 L) and concentrated to a volume of approximately 16 L. The slurry was cooled to 0-5 °C and filtered. The filter cake was dried under vacuum at or below 40 °C to afford (_<S)-l-amino-N-(3-chloro-4-fluorophenyl)-7- fluoro-2,3-dihydro-lH-indene-4-carboxamide [7] (3.9 kg, 65% yield). ^XH NMR (400 MHz, DMSO-de) d 10.67 (s, 1H), 8.63 (s, 3H), 8.08 (dd, J= 6.9, 2.6 Hz, 1H), 7.89 (dd, J= 8.6, 4.9 Hz, 1H), 7.71 (ddd, J= 9.1, 4.4, 2.6 Hz, 1H), 7.40 (t, J= 9.1 Hz, 1H), 7.27 (t, J= 8.7 Hz,

1H), 3.44-3.36 (m, 1H), 3.21-3.09 (m, 1H), 2.48-2.36 (m, 1H), 2.18-2.11 (m, 1H).

Synthesis of (1-methyl- 1H-1, 2, 4-triazol-3-yl)methyl (A)-(4-((3-chloro-4-fluorophenyl) carbamoyl)-7-fluoro-2, 3-dihydro- lH-inden-l-yl)carbamate [9] :

To a solution of CDI (3.0 kg, 18 mol) and (l-methyl-lH-l,2,4-triazol-3-yl)methanol [8] (2.2 kg, 19 mol) in 2-MeTHF (30 L) at room temperature was added fS')- l -amino-N-(3- chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-lH-indene-4-carboxamide [7] (3.9 kg, 12 mol) and DIEA (1.6 kg, 12 mol). The reaction was heated to 60-70 °C and stirred until completion. The reaction was cooled to room temperature, 2-MeTHF (30 L) and purified water (20 L) were added. The mixture was filtered through CELITE® (7.9 kg) and rinsed with 2-MeTHF (8.8 L). The collected filtrate was stirred, and the phases were separated.

The organic layer was washed with a solution of citric acid (2.0 kg) in purified water (18 L) followed by purified water washes (2 x 10 L) at 35-45 °C. The organic layer was polish filtered and concentrated under vacuum at or below 40 °C. To the residue IPA (28 L) was charged, the slurry was warmed to 40-50 °C, cooled to 15-25 °C and filtered. The wet cake was washed with IPA (10 L) and then dried under vacuum at or below 40 °C to afford (1- methyl-lH-l,2,4-triazol-3-yl)methyl fV)-(4-((3-chloro-4-n uorophenyl (carbamoyl )-7-fluoro- 2,3-dihydro-lH-inden-l-yl)carbamate [9] (4.4 kg, 78% yield) ' H NMR (400 MHz, DMSO- d₆) d 10.39 (s, 1H), 8.42 (s, 1H), 8.06-7.99 (m, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.71-7.59 (m, 2H), 7.39 (t, J = 9.1 Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 5.26 (q, J = 7.7 Hz, 1H), 4.99 (dd, J = 20.0, 12.0 Hz, 1H), 3.83 (s, 2H), 3.21 (ddd, J = 17.1, 8.8, 5.1 Hz, 1H), 3.04-2.96 (m, 1H), 2.46-2.33 (m, 1H), 1.92-1.83 (m, 1H). mp: 185.9-186.9 °C.

EXAMPLE 3: Synthesis of (l-methyl-lH-l,2,4-triazol-3-yl)methyl (X)-(4-((3-chloro-4- fluorophenyl)carbamoyl)-7-fluoiO-2,3-dihydro-lH-inden-l-yl)carbamate [9], according to Scheme II.

Step 1: Methyl fV)-7-fliioro-l-((((l-methyl-l H-l, 2, 4-triazol-3-yl)methoxy (carbonyl) amino)-2, 3-dihydro- lH-indene-4-carboxylate [11a], R=Me:

A mixture of carbonyldiimidazole (CDI, 4.62 g, 28.5 mmol), ( 1 -methyl- 1,2, 4-triazol- 3-yl)methanol (3.45g, 30.53 mmol), and 2-MeTHF (50 mL) was stirred at room temperature (20 °C) for 3 hours. To the mixture was added methyl (5)-l-amino-7-fluoro-2,3-dihydro-lH- indene-4-carboxylate hydrochloride [lOa.HCl] (5.0 g, 20.35 mmol) followed by N,N- diisopropylethylamine (6.58 g, 50.9 mmol). The contents were heated to 60 °C and stirred for 15 hours. The mixture was cooled to 20 °C, charged with water (50 mL), and stirred for 30 min. The slurry was filtered, washed with 2-MeTHF (2 x 5 mL) and dried under vacuum to give methyl fV)-7-riuoro- 1 -(((( 1 -methyl- 1 H- 1.2.4-triazol-3-yl)metho\y)carbonyl)amino)- 2,3-dihydro-lH-indene-4-carboxylate [11a] as white crystalline solid (5.8g, 81.8% yield). 'H NMR (400 MHz, DMSO-d₆) d 8.41 (s, 1H), 7.87 (dd, J = 8.6, 5.0 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.11 (t, J = 8.8 Hz, 1H), 5.28-5.22 (m, 1H), 4.98 (q, J = 10 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.31 (ddd, J = 17.6, 8.8, 5.5 Hz, 1H), 3.06 (ddd, J = 17.6, 8.7, 6.3 Hz, 1H), 2.44- 2.35 (m, 1H), 1.94-1.81 (m, 1H).

Step 2: 0V)-7-fluoro-l-((((l-methyl-l H-l,2,4-triazol-3-yl)methoxy)carbonyl)amino)- 2, 3-dihydro- lH-indene-4-carboxylic acid [12]:

To a stirred solution of methyl 0Y)-7-iluoro- 1 -(((( 1 -methyl- 1 H- 1 2.4-triazol-3- yl)methoxy) carbonyl)amino)-2,3-dihydro-lH-indene-4-carboxylate [11a] (4.0 g, 11.48 mmol) in methanol (40 mL) was added a solution of lithium hydroxide (0.69 g, 28.7 mmol) in water (10 mL). The mixture was heated at 45 °C for 18 hours. The contents were cooled to 20 °C and concentrated. To the residue was added ethyl acetate (8 mL) and the system was then treated with 10 wt% aqueous citric acid solution in water (4 mL). The slurry was stirred for 1 hour, filtered, washed with water followed by methanol (4 mL). The wet product was dried under vacuum to give (Y)-7-fluoro- 1 -(((( 1 -methyl- 1 H- 1.2.4-triazol-3-yl)metho\y) carbonyl)amino)-2,3-dihydro-lH-indene-4-carboxylic acid [12a] as white solid (2.3g, 60% yield). 1H NMR (400 MHz, DMSO-d₆) d 12.91 (s, 1H), 8.41 (s, 1H), 7.85 (dd, J = 8.6, 5.1

Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.08 (t, J = 8.8 Hz, 1H), 5.26-5.21 (m, 1H), 4.98 (q, J 10.0 Hz, 2H), 3.82 (s, 3H), 3.31 (ddd, J = 17.6, 8.8, 5.6 Hz, 1H), 3.07 (ddd, J = 17.6, 8.7, 6.2 Hz, 1H), 2.45-2.31 (m, 1H), 1.92-1.79 (m, 1H).

Step 3: (l-methyl-lH-l,2,4-triazol-3-yl)methyl (X)-(4-((3-chloro-4-fluorophenyl) carbamoyl)-7-fluoro-2,3-dihydro-lH-inden-l-yl)carbamate (9)

A mixture of LY)-7-fluoro- 1 -(((( 1 -methyl- 1 H- 1 2.4-triazol-3-yl)methoxy)carbonyl) amino)-2,3-dihydro-lH-indene-4-carboxylic acid [12] (l.Og, 2.99 mmol), HATU (l.36g, 3.59 mmol), and DMAc (7 mL) was stirred at room temperature for 20 min. The system was charged with 3-chloro-4-fluoroaniline (0.52 g, 3.59 mmol), followed by N,N- diisopropylethylamine (0.46g, 3.59 mmol), and the mixture was stirred at room temperature for 24 hours. The system was charged with water (10 mL) and ethyl acetate (25 mL). The mixture was stirred for 15 min and then allowed to settle. The layers were separated and the organic layer was washed with water (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to a minimum volume. 2-Propanol was charged into the mixture (25 mL), which was then concentrated to a final volume of 10 mL. The slurry was stirred for 2 hours and the product was filtered and washed with 2- propanol (5 mL). The wet product was dried under vacuum to give (l-methyl-lH-l,2,4- triazol-3-yl)methyl (_<S -(4-((3-chloro-4-fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH- inden-l-yl)carbamate [9] as off-white solid (l.02g, 74% yield). 'H NMR (400 MHz, DMSO- d₆) d 10.39 (s, 1H), 8.42 (s, 1H), 8.06-7.99 (m, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.71-7.59 (m, 2H), 7.39 (t, J = 9.1 Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 5.26 (q, J = 7.7 Hz, 1H), 4.99 (dd, J = 20.0, 12.0 Hz, 1H), 3.83 (s, 2H), 3.21 (ddd, J = 17.1, 8.8, 5.1 Hz, 1H), 3.04-2.96 (m, 1H), 2.46-2.33 (m, 1H), 1.92-1.83 (m, 1H).

EXAMPLE 4: Preparation of ethyl 7-fluoro-l-oxo-2,3-dihydro-lH-indene-4- carboxylate [2], according to Scheme IV.

18a, R=Et 2a, R=Et

Step 1: Preparation of ethyl 2-bromo-4-fluorobenzoate [14a]:

13a, X=Br 14a, X=Br, R=Et

To a 2-bromo-4-fluorobenzoic acid [13a] (22.8 mmol, 5.0 g) in ethanol (50 mL) was added sulfuric acid (22.8 mmol, 2.2 g) at 15 to 25 °C. The reaction mixture was stirred at 80 to 85 °C overnight, and the reaction was monitored by TLC. After completion, the reaction mixture was quenched with 10 wt% aq. Na^CO, solution and extracted with DCM three times. The combined organic layers were dried over anhydrous Na^SCft. The solvent was evaporated under reduced pressure to afford ethyl 2-bromo-4-fluorobenzoate [14a] in 97.2% yield (5.5 g) as a yellow oil, which was used for the next step without further purification. 'H NMR (600 MHz, CDCft) d 7.87 (dd, J = 8.4, 6.0 Hz, 1H), 7.41 (dd, J = 8.4, 2.4 Hz, 1H), 7.07-7.10 (m, 1H), 4.40 (q, J= 7.2 Hz, 2H), 1.41 (t, J= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCft) d 165.0, 163.6 (d, _CF = 255.2 Hz), 133.2 (d, _CF = 9.3 Hz), 128.3 (d, _CF = 3.5 Hz), 122.9 (d, _CF = 9.9 Hz); 121.7 (d, _CF = 24.5 Hz), 114.4 (d, _CF = 21.2 Hz), 61.6, 14.1; ¹⁹F

NMR (564 MHz, CDC13) d -106.1.

Step 2a: Preparation of ethyl (£)-2-(3-(benzyloxy)-3-oxoprop-l-en-l-yl)-4- fluorobenzoate [16a]:

Method A:

To a schlenk tube were added Pd(PPh₃)₂Cl₂ (0.89 mmol, 625 mg), benzyl acrylate (15a, 35.6 mmol, 5.35 mL), triethylamine (89.1 mmol, 12.4 mL), ethyl 2-bromo-4- fluorobenzoate [14a], (17.8 mmol, 4.4 g), and DMSO (88 mL) at room temperature under a nitrogen atmosphere. Then the reaction mixture was stirred at 95 to 105 °C for 20 hours. The reaction mixture was quenched with 10 wt % aqueous NaCl solution and extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous Na^SCL. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel by eluting with ethyl acetate/hexanes (v/v, 1/5) to afford ethyl (¾⁾-2-(3-(benzyloxy)-3-oxoprop-l-en-l-yl)-4-fluorobenzoate [16a] in 84.0% yield (4.9 g) as a yellow oil.

Method B:

To a schlenk tube were added NaOAc (24.3 mmol, 2.0 g), tetrabutylammonium bromide (TBAB) (0.8 mmol, 260 mg), and Pd(OAc)₂ (0.2 mmol, 54.5 mg) at room temperature under nitrogen atmosphere. A solution of ethyl 2-bromo-4-fluorobenzoate [14a] (8.1 mmol, 2.0 g) and benzyl acrylate [15a] (16.2 mmol, 2.6 g) in DMAc (40 mL) was added to the reaction mixture. The reaction mixture was stirred at 100 to 105 °C for 5 hours and then cooled to room temperature. The reaction mixture was quenched with purified water and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous Na₂S04. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel by eluting with ethyl acetate/hexanes (v/v, 1/5) to afford ethyl (E)-2-(3-(benzyloxy)-3-oxoprop-l-en-l-yl)-4-fluorobenzoate [16a] in 94.0 % yield (2.5 g) as ayellow oil. ^XH NMR (600 MHz, CDCl₃) d 8.48 (d, J= 16.2 Hz, 1H), 8.01 (dd, J= 9.0, 6.0 Hz, 1H), 7.42 (d, J= 6.6 Hz, 2H), 7.38 (t , J= 7.8 Hz, 2H), 7.33 (t, J= 3.0 Hz, 3H), 7.25 (dd, J= 9.6, 3.0 Hz, 1H), 7.10-7.13 (m, 1H), 6.32 (d, J= 15.6 Hz, 1H), 5.26 (s, 2H), 4.37 (q, J= 7.2 Hz, 2H), 1.37 (t, J= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) d 165.9, 165.8, 164.7 (d, J_{C F} = 252.2 Hz), 143.3 (d, J_{C F} = 1.8 Hz), 139.2 (d, J_{C F} = 8.6 Hz), 135.9, 133.5 (d, _CF = 9.2 Hz), 128.6, 128.3, 128.2, 126.3 (d, _CF = 3.0 Hz), 121.6, 116.4 (d, CF ⁼ 21.6 Hz), 114.7 (d, _CF = 22.7 Hz), 66.5, 61.6, 14.2; ¹⁹F NMR (564 MHz, CDC13) d - 106.3; LRMS (ESI) m/z calcd for C_I9H_I7F0₄ [M+H]⁺: 329.11; Found: 329.13.

Step 3a: Preparation of 3-(2-(Ethoxycarbonyl)-5-fluorophenyl)propanoic acid [18a]:

, ,

To a schlenk tube were added ethyl (¾)-2-(3-(benzyloxy)-3-oxoprop-l-en-l-yl)-4- fluorobenzoate [16a] (2.0 mmol, 2.9 g), 10% Pd/C (0.9 g, 30 wt%), and MeOH (29 mL) at room temperature under hydrogen gas. The reaction mixture was stirred for 18 hours under hydrogen gas, filtered through a CELITE® pad and washed with MeOH. After removal of the solvent under reduced pressure, 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid

[18a] was obtained in 94.0 % yield (1.9 g) as a gray solid, which was used for the next step without further purification. ^XH NMR (600 MHz, CDCl₃) d 9.9 (brs, 1H), 7.97 (dd, J= 8.4, 6.0 Hz, 1H), 7.00 (dd, J= 9.6, 2.4 Hz, 1H), 6.95-6.96 (m, 1H), 4.35 (q, J= 7.2 Hz, 2H), 3.28 (t, J= 7.8 Hz, 2H), 2.72 (t, J= 7.8 Hz, 2H), 1.38 (t, J= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCI₃) d 178.8, 166.3, 164.7 (d, J_{C F} = 252.0 Hz), 145.6 (d, J_{C F} = 8.3 Hz), 133.7 (d, J_{C F} = 9.2 Hz), 125.7 (d, JCF = 3.2 Hz), 117.9 (d, J_{C F} = 21.3 Hz), 113.6 (d, J_{C F} = 21.2 Hz), 61.1, 35.3, 29.7, 14.2; ¹⁹F NMR (564 MHz, CDCI₃) d -106.9; LRMS (ESI) m/z calcd for C₁₂H₁₃FO₄ [M+H]⁺: 241.08; Found: 241.10.

Step 4a: Preparation of ethyl 7-fluoro-l-oxo-2, 3-dihydro- lH-indene-4-carboxylate

(2a):

Method A:

To a solution of 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid [18a] (7.91 mmol, 1.9 g) in DCM (38 mL), oxalyl chloride (39.5 mmol, 5.0 g) was slowly added at 10 to 15 °C. After stirring at 15 to 20 °C for 2 hours, the reaction mixture was concentrated under reduced pressure. To the residue, were added AICI₃ (23.7 mmol, 3.2 g) and DCM (38 mL). The reaction mixture was stirred for 20 hours at 45 °C. After cooling to room temperature, the reaction mixture was filtered through a CELITE® pad and washed with water and DCM. The aqueous layer was extracted with DCM three times and the combined organic layers were dried over anhydrous Na2SC>4. After the solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel by eluting with ethyl acetate/hexanes (v/v, 1/2) to afford ethyl 7-fluoro-l-oxo-2, 3-dihydro- lH-indene-4- carboxylate [2a] in 43.2% yield (0.8 g) as a light yellow solid.

Method B:

To a solution of 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid [18a] (6.07 mmol, 1.5 g) and DMF (0.61 mmol, 44 mg) in DCM (30 mL), oxalyl chloride (30.4 mmol,

3.9 g) was slowly added at 10 to 15 °C. After stirring at 20 to 25 °C for 2 hours, the reaction mixture was concentrated under reduced pressure. To the residue, were added AICI₃ (18.2 mmol, 2.4 g) and DCM (30 mL). The reaction mixture was stirred for 6 hours at 40 °C.

After cooling to room temperature, the reaction mixture was quenched with purified water. The product was extracted with DCM three times and the combined organic layers were dried over anhydrous Na₂S04. After the solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel by eluting with ethyl acetate/hexanes (v/v, 1/2) to afford ethyl 7-fluoro-l-oxo-2,3-dihydro-lH-indene-4-carboxylate [2a] in 66.2 % yield (0.9 g) as a white solid.

NMR (600 MHz, CDCl₃) d 8.24 (dd, J= 7.8, 4.8 Hz, 1H), 7.02 (t, J= 9.0 Hz, 1H), 4.35 (q, J= 12 Hz, 2H), 3.45-3.47 (m, 2H), 2.68-2.70 (m, 2 H), 1.37 (t, .7= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCI₃) d 202.6, 164.7, 161.5 (d, J_CF = 224.1), 159.7 (d, J _F = 3.0 Hz), 138.8 (d, J_{C F} = 8.1 Hz), 125.5 (d, J_{C F} = 13.3 Hz), 124.5 (d, J_{C F} = 3.4 Hz), 114.6 (d, J _F = 16.4 Hz), 61.2, 36.5, 27.4, 14.2; ¹⁹F NMR (564 MHz, CDCI₃) d -108.4;

LRMS (ESI) m/z calcd for C12H11FO3 [M+H]⁺: 223.07; Found: 223.11.

EXAMPLE 5: Synthesis of ethyl 7-fluoro-l-oxo-2, 3-dihydro- lH-indene-4-carboxylate

[2a], R=Et.

Method A: Carbonylation of 4-bromo-7-fluoro-2,3-dyhydro-lH-inden-l-one (la), according to Scheme III:

Example I:

To a solution of 4-bromo-7-fluoro-2,3-dihydro-lH-inden-l-one [la] (16 kg, 70 mol) in ethanol (99.5%, 160 L) was added triethylamine (42 kg, 415 mol) slowly at room temperature. To the stirred reaction mixture, Pd(dppf)Cl2 (2.6 kg, 3.6 mol) was added and then CO(g) was charged to the reactor to maintain 1.4 to 1.8 bar pressure. The reaction was heated to 65-75 °C and stirred until completion. The reaction was cooled to 25-35 °C and the solvent was concentrated under reduced pressure to dryness. The crude residue was dissolved in DCM (128 L) and washed with 0.5 N HC1 solution (67 L), 5 wt% NaHCC solution (67 L) and 5 wt% NaCl solution (67 L). To the organic layer, silica gel (16 kg) and N-Charcoal (6.4 kg) were added. The mixture was filtered through CELITE® (16 kg), silica gel (48 kg), and then Na^SCE (16 kg). The filtrate was concentrated, and then IPA (80 L) was added with agitation. Hexane (170 L) was heated to 55-65 °C and added to the IPA solution at 55-65 °C. The slurry was cooled to -5 to 5 °C, filtered and washed with heptane (29 L).

The solid was dried under vacuum to afford ethyl 7-fluoro-l-oxo-2,3-dihydro-lH-indene-4- carboxylate [2a] (13 kg, 83% yield).

Example II:

To a 25 L pressure reactor were added 4-bromo-7-fluoro-2,3-dihydro-lH-inden-l-one [la] (1 Kg, 4.38 mol, 1.0 eq.) in EtOH (10 L, 10 vol), triethylamine (3.67 L, 26.32 mol, 6 eq.) slowly and Pd(dppf)Cl2.DCM complex (160 g, 0.195 mol, 4.5 mol %), and the mixture was stirred under nitrogen atmosphere for 10 minutes. The reactor was evacuated and backfilled with CO(g). The pressure was adjusted to 25-30 psi and released to a scrubber (CuCl/HCl solution). This process was preformed three times. The internal temperature was adjusted to 70-75 °C and stirred the contents until the reaction was completed (monitored by HPLC). After 10 hours, the reaction mixture was cooled to 25-35 °C and then released CO gas to the scrubber. The mixture was purged with nitrogen (bubble through solution), and then evaporated under reduced pressure at <45 °C. The mixture was diluted with ethyl acetate (15 L) and treated with thiourea (167 g, 2.19 mol) for 2 hours and filtered through CELITE® pad. The filtrate was washed with water (2 x 6 L) and brine solution (4 L). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at < 45 °C. Isopropyl alcohol (4 L) was added to the mixture and heated at 60-65 °C for 1 hour to give a clear solution. n-Heptane (8 L) was added slowly while maintaining the temperature and then cooled to 30-35 °C for 2 hours. The mixture was cooled down to 0 °C and stirred for 2 hours at 0-5 °C. The resulting solid was filtered and washed with additional heptane (1 L). Wet product was dried at 45-50 °C to give ethyl 7-fluoro-l-oxo-2,3-dihydro-lH-indene-4- carboxylate [2a] as pale brown solid (71 lg, 73% yield). ^XH NMR (400 MHz, CDCI₃): d 8.29 (dd, J = 8.4, 4.8 Hz, 1H), 7.06 (t, J = 9.0 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 3.53-3.50 (m, 2H), 2.76-2.73 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): d 202.88, 165.01, 163.11, 160.42, 159.88, 139.09, 138.99, 125.87, 125.74, 124.71, 114.99, 114.79, 61.40,

36.78, 27.60, 14.46.

Method B: Intramolecular Friedel-C rafts acylation, according to Scheme IV, Step 4a or Step 4b:

To a solution of 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid [18a] (6.0 g, 25.0 mmol) in CH2CI2 (60 mL) was added thionyl chloride (3.71 g, 31.2 mmol, 1.25 eq.) slowly at room temperature. After being stirred for 2 hours, the solvent was concentrated under reduced pressure to dryness. It was further dissolved in CH2CI2 (25 mL) and added to a pre-stirred solution of AICI3 (9.97 g, 75.0 mmol, 3 eq.) in CH2CI2 (35 mL) dropwise and stirred for 20 hours at 40 °C. The reaction mixture was brought to room temperature, quenched with water (50 mL) and separated into two layers. The aqueous layer was extracted with CH2CI2 (2 x 15 mL). The combined organic layer was washed with saturated NaHCC solution (50 mL), dried over anhydrous Na2S0₄ and filtered. The filtrate was concentered under reduced pressure to dryness. The residue was further recry stallized with isopropyl ether (2 vol) to afford ethyl 7-fluoro-l-oxo-2,3-dihydro-lH-indene-4-carboxylate [2a] as an off white solid.

EXAMPLE 6: Synthesis of 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid 18a; according to Scheme IV, Steps 2a, 3al & 3a2.

18a, R=Et

Synthesis of (E)-ethyl 2-(3-(fe/i-butoxy)-3-oxoprop-l-en-l-yl)-4-fluorobenzoate [16b], R=Et, R’-tBu:

Method A:

A 500 mL two neck round bottom flask was charged with ethyl 2-bromo-4- fluorobenzoate [14a] (10.0 g, 40.48 mmol) and tert- butyl acrylate [15b], R’=tBu, 10.36 g, 80.96 mmol, 2 eq.) in acetonitrile (200 mL). To it was added Pd(OAc)₂ (900 mg, 4.08 mmol, 10 mol%) and Et₃N (2l.6g, 202.0 mmol, 5.0 eq), followed by P(o-tolyl)₃ (2.4 g, 8.16 mmol, 20 mol%). The flask was evacuated and then filled with nitrogen gas twice. The resulting mixture was stirred at 45 °C. The reaction was monitored by TLC. After being stirred for 20 hours, reaction mixture was cooled to room temperature and filtered through CELITE® pad. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layer was dried over Na^SCf and filtered, concentrated under reduced pressure to dryness. The crude was purified by silica gel column chromatography using 3% ethyl acetate in hexane as an eluent to give semi pure (A^’)-ethyl 2-(3-(/ -buto\y)-3-o\oprop- l-en-l-yl)-4-fluorobenzoate [16b] as a light-yellow color liquid ' H NMR (400 MHz, CDCl₃): d 8.34 (dd, J = 4.0, 1.2 Hz, 1H), 8.01-7.97 (q, J = 7.2 Hz, 2H),), 7.26-7.23(dd, J = 2.8, 2.4 Hz, lH)7. l l (m, 1H), 6.23 (d, J = 16 Hz, 1H) 4.41 ( m, 2H) 1.56 (s, 9H) 1.42 (t, J = 7.2 Hz, 3H).

Method B:

A 500 mL two neck round bottom flask was charged with ethyl 2-bromo-4- fluorobenzoate [14a], R=Et, 10.0 g, 40.48 mmol) and /er/-butyl acrylate [15b], R’=tBu, 10.36 g, 80.96 mmol, 2 eq.) in DMSO (150 mL) and to it was added Pd(PPh₃)₂Cl2 (1.41 g, 2.02 mmol, 5 mol%) and Et₃N (20.4 g, 202.0 mmol, 5.0 eq). The flask was evacuated and then filled with nitrogen gas twice. Then the resulting mixture was stirred at 90 °C for 20 hours. The reaction was monitored by TLC. After 20 hours, the reaction mixture was cooled to room temperature and quenched with 10% NaCl solution (100 mL) slowly, then extracted with ethyl acetate (2x150 mL). The combined organic layers were washed with ice water (2 x 100 mL), separated and dried over Na₂S04 and filtered, concentrated under reduced pressure to dryness. The crude compound was used in next step without further purification. Synthesis of (E)-3-(2-(ethoxycarbonyl)-5-fluorophenyl)acrylic acid [20a], R=Et:

To a solution of ethyl 2-(3-(/er/-butoxy)-3-oxopropyl)-4-fluorobenzoate [16a], R=Et, R’-tBu, (8.0 g crude, 77% by HPLC, 27.2mmol) in CH2CI2 (80 mL) was added trifluoroacetic acid (13.95 g, 122.4 mmol, 4.5 eq.) slowly at room temperature, and the reaction mixture was stirred at room temperature for 16-20 hours. The solvent was then concentrated under reduced pressure to dryness giving a light brown solid (having pH = 4.0). This solid was stirred in a mixture of isopropyl etherhexane (1: 1) (2 vol) for 30 min at 50 °C. then cooled to 20-25 °C and stirred for 30 min. The solid was filtered and dried under vacuum to yield (£)- 3-(2-(ethoxycarbonyl)-5-fluorophenyl)acrylic acid [20a] as ash color solid ' H NMR (400 MHz, CDCI₃): d 8.29 (dd, J = 8.4, 4.8 Hz, 1H), 7.06 (t, J= 9.0 Hz, 1H), 4.40 (q, J= 7.2 Hz, 2H), 3.53-3.50 (m, 2H), 2.76-2.73 (m, 2H), 1.42 (t, J= 7.2 Hz, 3H).

Synthesis of ethyl 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid [18a], R=Et:

To a solution of (£)-3-(2-(ethoxycarbonyl)-5-fluorophenyl)acrylic acid [20a] (400 mg, 1.68 mmol) in ethyl acetate (8.0 mL) was added 10% Pd/C wet (120 mg, 30% w/w) at room temperature, and the reaction mixture stirred for 24 hours under hydrogen gas atmosphere (60 psi) [completion of the reaction was monitored by TLC] After completion of the reaction, the reaction mixture was filtered through CELITE® pad, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure giving 3-(2- (ethoxycarbonyl)-5-fluorophenyl)propanoic acid [18a], R=Et, as an off-white solid, which was directly used in the next step without any further purification. 'H NMR (400 MHz, CDCI₃): d 8.29 (dd, J= 8.4, 4.8 Hz, 1H), 7.06 (t, J= 9.0 Hz, 1H), 4.40 (q, J= 7.2 Hz, 2H), 3.53-3.50 (m, 2H), 2.76-2.73 (m, 2H), 1.42 (t, J= 12 Hz, 3H).

EXAMPLE 7: Synthesis of 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid 18a, according to Scheme IV, Steps 2a & 3a.

Synthesis of (E)-ethyl 2-(3-(benzyloxy)-3-oxoprop-l-en-l-yl)-4-fluorobenzoate [16a]:

A 500-mL two neck round bottom flask was charged with ethyl 2-bromo-4- fluorobenzoate [14a] (10.0 g, 40.48 mmol) and benzyl acrylate [15a] (13.2 g, 80.96 mmol, 2 eq.) in DMSO (150 mL) and to it was added Pd(PPh₃)₂Cl2 (1.41 g, 2.02 mmol, 5 mol%) and Et₃N (20.4 g, 202.0 mmol, 5.0 eq). The flask was evacuated and then filled with nitrogen gas twice. The resulting mixture was stirred at 90 °C for 20 hours. Reaction was monitored by TLC. After 20 hours, the reaction mixture was cooled to room temperature and quenched with 10% NaCl solution (100 mL) slowly, then extracted with ethyl acetate (2 x 150 mL).

The combined organic layer was washed with ice water (2 x 100 mL), and the organic layer was separated, dried over anhydrous Na^SCf. filtered, and concentrated under reduced pressure to dryness. The crude residue was purified by silica gel column chromatography using 3% ethyl acetate in hexane as an eluent to give pure (£)-ethyl 2-(3-(benzyloxy)-3- oxoprop-l-en-l-yl)-4-fluorobenzoate [16a] as a pale-yellow color liquid. ^XH NMR (400 MHz, CDCl₃): d 8.50 (dd, J = 1.2, 1.2 Hz, 1H), 8.02-7.98 (m, 1H) 7.43-7.26 (m, 5H), 7.25 (dd, J = 0.8 Hz, 1H), 7.13-7.08 (td, 1H) 6.34 (d, 1H) 5.29-5.26 (d, 2H) 4.39-4.34(q, J = 2.0 2H)), 1.38 (t, J = 7.2 Hz, 3H).

Synthesis of 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid [18a]:

To a solution of (A^’)-ethyl 2-(3-(benzyloxy)-3-oxoprop-l-en-l-yl)-4-fluorobenzoate

[16a] (8.0 g, 24.3 mmol) in methanol (80 mL) was added 10% Pd/C wet (2.4 g, 30% w/w) at room temperature and stirred the reaction mixture for 24 hours under hydrogen gas pressure (60 psi) [completion of the reaction was monitored by TLC] After completion of the reaction, the reaction mixture was filtered through CELITE® pad, washed with methanol, and the filtrate was concentrated under reduced pressure to give crude residue as a brown liquid. This liquid was further dissolved and stirred at room temperature for 30 min. The resulting precipitate was filtered and dried under vacuum to afford 3-(2-(ethoxycarbonyl)-5- fluorophenyl)propanoic acid [18a] as an off white solid ' H NMR (400 MHz, CDCl₃): d

8.00-7.96 (dd, J = 6.0, 4.8 Hz, 1H), 7.02-6.94 (m, 2H), 4.38-4.33 (q, J = 6.8 Hz, 2H), 3.30- 3.27 (t, 2H), 2.75-2.71 (t, 2H), 1.40-1.37 (t, 3H). EXAMPLE 8: Synthesis of 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid 18, according to Scheme IV, Steps 3b 1 & 3b2.

Synthesis of ethyl 2-(3-(fe/i-butoxy)-3-oxopropyl)-4-fluorobenzoate [21a], R=Et, R’=tBu:

To a solution of (£)-ethyl 2-(3-(/e/ /-butoxy)-3-oxoprop- 1 -en- 1 -yl)-4-fluorobenzoate

[16b] (10.5 g, 35.7 mmol) in methanol (105 mL) was added 10% Pd/C wet (2.5 g, 30% w/w) at room temperature and stirred the reaction mixture for 24 hours under hydrogen gas atmosphere (60 psi) (completion of the reaction was monitored by TLC). After completion of the reaction, the reaction mixture was filtered through CELITE® pad and washed with methanol. The filtrate was concentrated under reduced pressure giving (ethyl 2-(3 -(tert- butoxy)-3-oxopropyl)-4-fluorobenzoate [21a] as a light brown liquid. 'H NMR (400 MHz, CDC ): d 7.97 (q, .7= 2.8, Hz, 1H), 7.01 (m, 2H), 4.37 (q, J= 6.8 Hz, 2H), 3.25 (t, J= 7.6 Hz, 2H), 2.59-2.55 (m, 2H), 1.42 (m, 12H).

Synthesis of 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid [18a]:

To a solution of (ethyl 2-(3-(/er/-butoxy)-3-oxopropyl)-4-fluorobenzoate [21a] (9.2g, 3l.0mmol) in CH2CI2 (92 mL) was added trifluoroacetic acid (8.3 mL, 108.7 mmol, 3.5 eq.) slowly at room temperature. After being stirred the reaction mixture for 5 hours, the solvent was concentrated under reduced pressure to crude residue as a light brown liquid (pH 4). To this residue was added water and the system was stirred for 30 min to give precipitate, filtered and dried under vacuum giving 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid

[18a] as an off white solid. ^XH NMR (400 MHz, CDCl₃): d 8.00-7.96 (dd, J= 6.0, 4.8 Hz, 1H), 7.02-6.94 (m, 2H), 4.38-4.33 (q, J= 6.8 Hz, 2H), 3.30-3.27 (t, 2H), 2.75-2.71 (t, 2H), 1.40-1.37 (t, 3H).

EXAMPLE 9: Synthesis of 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid 18a, according to Scheme IV, Steps 2b & 3b.

Synthesis of ethyl 2-(3-(fe/i-butoxy)-3-oxopropyl)-4-fluorobenzoate [17a]:

A 250 mL two neck round bottom flask was charged with tot-butyl 3- bromopropanoate [19a] (12.3 g, 69 mmol, 2 eq.) and Zn (6.7 g, 103.5 mmol, 3.0 eq.) in dry DMF (50 mL). To it was added catalytic amount of iodine (54 mg, 0.426 mmol) at 0 °C. After being stirred at room temperature for 2 hours, ethyl 2-bromo-4-fluorobenzoate [14a], (8.5 g, 34.5 mmol), Pd₂(dba)3 (1.3 g, 1.38 mmol, 0.04 eq.), and XPhos (2.62 g, 5.52 mmol, 0.16 eq.) were added and the resulting mixture was stirred at 90 °C for 16 hours (monitored by TLC). Then the reaction mixture was cooled to room temperature and filtered through CELITE® pad. The filtrate was diluted with ethyl acetate (300 mL) and washed with NH₄Cl (200 mL) and aqueous ammonia (250 mL). The organic layers were separated, dried over anhydrous Na^SCf. filtered, and concentrated under reduced pressure to dryness. The crude residue was purified by silica-gel column chromatography using 3% ethyl acetate in hexane as an eluent giving semi pure ethyl 2-(3-(/er/-butoxy)-3-oxopropyl)-4-fluorobenzoate [17a] as a pale-yellow color liquid.

Synthesis of 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid [18a]:

To a solution of (ethyl 2-(3-(/er/-butoxy)-3-oxopropyl)-4-fluorobenzoate [17a] (4.4 g, 14.8 mmol) (8.0 g, 27.2mmol) in CTl₂Cl₂ (45 mL) was added trifluoroacetic acid (3 mL) slowly at room temperature, and the reaction mixture was stirred at room temperature for 4.5 hours. Then the solvent was concentrated under reduced pressure to dryness. The crude residue was further purified from silica gel column chromatography to yield [18a] (900 mg; 75% pure by HPLC). Further, purity was enriched from Combi-flash chromatography (in reverse phase mode) to get pure 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid [18a]

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations. Enumerated Embodiments:

The following enumerated embodiments are provided, the numbering of which is not to be construed as designating levels of importance.

Embodiment 1 provides a method of preparing (l-methyl-lH-l,2,4-triazol-3- yl)methyl (5)-(4-((3-chloro-4-fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden-l-

yl)carbamate [9], or a salt or solvate thereof:

the method

/^¾N

comprising coupling (l-methyl-l,2,4-triazol-3-yl)methanol ^' N ^ ^ ^0H i [8], or a salt or solvate thereof, and (5)-l-amino-N-(3-chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-lH-

indene-4-carboxamide

salt or solvate thereof, under conditions whereby a carbamate group comprising the hydroxyl group of [8] and the amino group of [7] is formed.

Embodiment 2 provides the method of Embodiment 1, wherein [8] and [7] are contacted in a molar ratio of about 1 : 1 to about 3: 1.

Embodiment 3 provides the method of any of Embodiments 1-2, wherein [8] and [7] is first contacted with a carbonyl equivalent coupling agent before being contacted with [7] and [8], respectively.

Embodiment 4 provides the method of Embodiment 3, wherein the carbonyl equivalent coupling agent comprises at least one of carbonyldiimidazole, phosgene, diphosgene, triphosgene, and disuccinimidyl carbonate.

Embodiment 5 provides the method of any of Embodiments 1-4, wherein the coupling is performed in the presence of a base.

Embodiment 6 provides the method of Embodiment 5, wherein the base comprises at least one of N,N-diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine. Embodiment 7 provides the method of any of Embodiments 1-6, wherein [9] is further recrystallized from a solvent system comprising at least one of isopropanol and 2-methyl- tetrahydrofuran.

Embodiment 8 provides the method of any of Embodiments 1-7, wherein [9] is isolated as its hydrochloride salt.

Embodiment 9 provides the method of any of Embodiments 1-8, wherein [7] is prepared by a process comprising contacting (ri -l-(((ri)-tert-butylsulfmyl)amino)-N-(3-

[6] with an acidic solution.

Embodiment 10 provides the method of Embodiment 9, wherein the acidic solution comprises at least one of hydrochloric acid, phosphoric acid, and sulfuric acid.

Embodiment 11 provides the method of any of Embodiments 9-10, wherein [6] is prepared by a process comprising contacting (ri)-l-(((S)-tert-butylsulfmyl)amino)-7-fluoro-

2,3-dihydro- lH-indene-4-carboxy lie acid

acid anhydride or acyl

halide thereof, with 3 -chloro-4-fluoroaniline ^F

Embodiment 12 provides the method of Embodiment 11, wherein [5] and 3-chloro-4- fluoroaniline are further contacted with an amide coupling agent.

Embodiment 13 provides the method of Embodiment 12, wherein the amide coupling agent comprises at least one of carbonyldiimidazole (CDI), (l-[bis(dimethylamino) methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 4-(4,6- dimethoxy-l,3,5-triazin-2-yl)-4-methyl morpholinium chloride, propanephosphonic acid anhydride (T3P), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC or EDCI) / hydroxybenzotriazole (HOBt), N,N,N',N'-tetramethyl-0-(lH-benzotriazol-l -yl)uronium hexafluorophosphate (HBTU), 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), (benzotriazol- 1 -y loxy)tris(dimethy lamino)phosphonium hexafluorophosphate (BOP), chlorotripyrrolidinophosphonium hexafluorophosphate

(PyClOP), benzotriazol- l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N’-dicyclohexylcarbodiimide (DCC) / HOBt, l-cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholinocarbenium hexafluorophosphate (COMU), EDCI / ethyl 2-cyano- 2-(hydroxyimino)acetate (Oxyma), and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium tetrafluoroborate.

Embodiment 14 provides the method of any of Embodiments 11-13, wherein [5], or an acid anhydride or acyl halide thereof, and 3-chloro-4-fluoroaniline are further contacted with a base.

Embodiment 15 provides the method of Embodiment 14, wherein the base comprises at least one of N,N-diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine.

Embodiment 16 provides the method of any of Embodiments 11-15, wherein [5] is prepared by a process comprising hydrolyzing R group-substituted (S')- 1 -((fV)-tert-

butylsulfinyl)amino)-7-fluoro-2,3-dihydro-lH-indene-4-carboxylic acid

[4], wherein R is Ci-C₆ alkyl, C3-C8 cycloalkyl, or benzyl, with a hydrolyzing base.

Embodiment 17 provides the method of Embodiment 16, wherein the hydrolyzing base comprises at least one of NaOH, LiOH, KOH, Na^CO,. and K₂CO₃.

Embodiment 18 provides the method of any of Embodiments 16-17, wherein the hydrolysis product of [4] is further contacted by an acidic solution so as to yield [5]

Embodiment 19 provides the method of any of Embodiments 16-18, wherein [4] is prepared by a process comprising contacting a reducing agent with R group-substituted (S //)- l-((tert-butylsulfmyl) imino)-7-fluoro-2,3-dihydro-lH-indene-4-carboxylate

wherein R is C1-C6 alkyl, C3-C8 cycloalkyl, or benzyl.

Embodiment 20 provides the method of Embodiment 19, wherein the reducing agent comprises at least one of a borohydride salt, a triacetoxyborohydride salt, and a

cyanoborohydride salt.

Embodiment 21 provides the method of any of Embodiments 19-20, wherein the reduction product of [3] is further contacted with an acidic solution so as to yield [4]

Embodiment 22 provides the method of any of Embodiments 19-21, wherein the reducing agent and [3] are contacted in a molar ratio of about 1 : 1 to about 1: 1.5.

Embodiment 23 provides the method of any of Embodiments 19-22, wherein [3] is prepared by a process comprising contacting R group-substituted 7-fluoro-l-oxo-2,3-dihydro-

lH-indene-4-carboxylate

-methylpropane-2-sulfina ide, and a Lewis acid, wherein R is C1-C6 alkyl, C3-C8 cycloalkyl, or benzyl.

Embodiment 24 provides the method of Embodiment 23, wherein the Lewis acid comprises at least one of Ti(OEt)4, Ti(OiPr)₄, TiCU, TiCl2(OCH(CH₃)₂)2, and

TiCl(OCH(CH₃)2)3.

Embodiment 25 provides the method of any of Embodiments 23-24, wherein [2] is contacted with fV)-2-methylpropane-2-sulfinamide at a molar ratio of about 1 : 1.5.

Embodiment 26 provides the method of any of Embodiments 23-25, wherein [2] is contacted with the Lewis acid at a molar ratio of about 1 :3.

Embodiment 27 provides the method of any of Embodiments 16-26, wherein R is selected from the group consisting of methyl, ethyl, «-propyl, and isopropyl.

Embodiment 28 provides a method of preparing (l-methyl-lH-l,2,4-triazol-3- yl)methyl (5)-(4-((3-chloro-4-fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden-l- yl)carbamate [9], or a salt or solvate thereof:

the method contacting

3-chloro-4-fluoroaniline with fY)-7-iluoro- 1 -(((( 1 -methyl- 1 H- 1.2.4-tria/ol-3-yl)metho\y)

carbonyl) amino)-2,3-dihydro-lH-indene-4-carboxylic acid

acid anhydride or acyl halide, under conditions whereby an amide bond is formed between the carboxylic acid of [12] and the amine of 3-chloro-4-fluoroaniline.

Embodiment 29 provides the method of Embodiment 28, wherein [12] and 3-chloro- 4-fluoroaniline are further contacted with an amide coupling agent.

Embodiment 30 provide the method of Embodiment 29, wherein the amide coupling agent comprises carbonyldiimidazole (CDI), (l-[bis(dimethylamino) methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 4-(4,6-dimethoxy-l,3,5- triazin-2-yl)-4-methyl morpholinium chloride, propanephosphonic acid anhydride (T3P), 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC or EDCI) / hydroxybenzotriazole (HOBt), N,N,N',N'-tetramethyl-0-(lH-benzotriazol-l -yl)uronium hexafluorophosphate (HBTU), 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), (benzotriazol-l -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), chlorotripyrrolidinophosphonium hexafluorophosphate (PyClOP), benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N’- dicyclohexylcarbodiimide (DCC) / HOBt, l-cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholinocarbenium hexafluorophosphate (COMU), EDCI / ethyl 2-cyano-

2-(hydroxyimino)acetate (Oxyma), or 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium tetrafluoroborate.

Embodiment 31 provides the method of any of Embodiments 28-30, wherein [12] and

3-chloro-4-fluoroaniline are further contacted with a base.

Embodiment 32 provides the method of Embodiment 31 , wherein the base comprises at least one of N,N-diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine. Embodiment 33 provides the method of any of Embodiments 28-32, wherein [12] is prepared by a process comprising hydrolyzing the ester group in R group-substituted (S)-7- fluoro- 1 -((((1 -methyl- 1E1- 1 ,2, 4-triazol-3-y l)methoxy)carbonyl)amino)-2, 3-dihydro- 1E1-

indene-4-carboxylate

wherein R is Ci-C alkyl, C -C cycloalkyl, or benzyl.

Embodiment 34 provides the method of Embodiment 33, wherein the hydrolysis comprises contacting [11] with a hydrolyzing base.

Embodiment 35 provides the method of Embodiment 34, wherein the hydrolyzing base comprises at least one of NaOH, LiOH, KOH, Na^CCh. and K₂CO₃.

Embodiment 36 provides the method of any of Embodiments 33-35, wherein [11] is prepared by a process comprising contacting (l-methyl-l,2,4-triazol-3-yl)methanol [8], or a salt or solvate thereof, and R group-substituted (S')- 1 -amino-7-fluoro-2.3-dihydro- 1 H-indene-

4-carboxylate

salt or solvate thereof, wherein R is Ci-C₆ alkyl, C -C cycloalkyl, or benzyl, under conditions whereby a carbamate group comprising the hydroxyl group of [8] and the amino group of [10] is formed.

Embodiment 37 provides the method of Embodiment 36, wherein [8] and [10] are contacted in a molar ratio of about 1 : 1 to about 3: 1.

Embodiment 38 provides the method of any of Embodiments 36-37, wherein [8] and [10] is first contacted with a carbonyl equivalent coupling agent before being contacted with [10] and [8], respectively.

Embodiment 39 provides the method of Embodiment 38, wherein the carbonyl equivalent coupling agent comprises at least one of carbonyldiimidazole, phosgene, diphosgene, triphosgene, and disuccinimidyl carbonate.

Embodiment 40 provides the method of any of Embodiments 36-39, wherein the coupling is performed in the presence of a base.

Embodiment 41 provides the method of Embodiment 40, wherein the base comprises at least one of N,N-diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine.

Embodiment 42 provides the method of any of Embodiments 36-41, wherein [11] is isolated as its hydrochloride salt.

Embodiment 43 provides the method of any of Embodiments 36-42, wherein [2] is prepared by a process comprising promoting esterification of 4-halo-7-fluoro-2, 3-dihydro-

lH-inden-l-one

wherein X is Br or I.

Embodiment 44 provides the method of Embodiment 43, wherein [1] is contacted with a base, an esterification catalyst, carbon monoxide, and alcohol ROH, wherein R is Ci- Ce alkyl, C3-C8 cycloalkyl, or benzyl.

Embodiment 45 provides the method of Embodiment 44, wherein the base comprises at least one of triethylamine, NaOAc, KOAc, and K3PO4.

Embodiment 46 provides the method of any of Embodiments 44-45, wherein the catalyst comprises a palladium catalyst comprising at least one of PdCl₂.dppf (dppf = 1,1'- Ferrocenediyl-bis(diphenylphosphine)), Pd(dppf)Cl2, Pd(OAc)₂-dppp, and PdCl2(PPh₃)₂.

Embodiment 47 provides the method of any of Embodiments 44-46, wherein the carbon monoxide pressure during esterification ranges from about 50 psi to about 150 psi.

Embodiment 48 provides the method of any of Embodiments 36-42, wherein [2] is prepared by a process comprising cyclizing 3-(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic

acid

wherein R is Ci-C₆ alkyl or C3-C8 cycloalkyl.

Embodiment 49 provides the method of Embodiment 48, comprising : (i) converting [18] to the corresponding acyl halide, which undergoes intramolecular acylation to yield [2]; or (ii) treating [18] with an acid, thus promoting intramolecular acylation to yield [2]

Embodiment 50 provides the method of Embodiment 49, wherein in (i) [18] is contacted with a chlorinating reagent comprising at least one of oxalyl chloride, phosgene, diphosgene, triphosgene, and thionyl chloride, so as to yield [18]’s acyl chloride.

Embodiment 51 provides the method of Embodiment 50, wherein the chlorinating reagent and [18] are contacted in the presence of dimethylformamide (DMF).

Embodiment 52 provides the method of any of Embodiments 50-51, wherein [18]’s acyl chloride is contacted with a Lewis acid, thus undergoing cyclization to form [2] Embodiment 53 provides the method of Embodiment 52, wherein the Lewis acid comprises an aluminum salt.

Embodiment 54 provides the method of any of Embodiments 48-53, wherein [18] is prepared by a process comprising hydrolyzing R group-substituted 4-fluoro-2-(3-[R’-

substituted]oxy-3-oxopropyl)benzoate

acid, wherein R is

Ci-C₆ alkyl or C3-C8 cycloalkyl, and R’ is Ci-C₆ alkyl or C3-C8 cycloalkyl.

Embodiment 55 provides the method of Embodiment 54, wherein R’ is tert-butyl and R is not tert- butyl.

Embodiment 56 provides the method of any of Embodiments 54-55, wherein [17] is

prepared by a process comprising coupling

wherein each X is independently selected from the group consisting of Cl, Br, and I, R is Ci-C₆ alkyl or C3-C8 cycloalkyl, and R’ is Ci-C₆ alkyl or C3-C8 cycloalkyl.

Embodiment 57 provides the method of Embodiment 56, wherein the coupling is catalyzed by a transition metal comprising nickel or palladium.

Embodiment 58 provides the method of Embodiment 57, wherein the transition metal comprises at least one of Pd₂(dba)3, Pd(OAc)₂, PdCl₂(PPh₃)₂, and Pd(PPh₃)₄.

Embodiment 59 provides the method of any of Embodiments 56-58, wherein the coupling is run in the presence of a triphosphine.

Embodiment 60 provides the method of Embodiment 59, wherein the triphosphine comprises at least one of triphenylphosphine, tris-(o-tolyl)phosphine, tris-(4-fluorophenyl) phosphine, l,2-bis(diphenylphosphino)ethane (dppe), 2,2'-bis (diphenylphosphino)-l,l'- binaphthyl (BINAP), (2N,3ri)-(-)-bis(diphenylphosphino)butane, (2R.3R)-(+)- bis(diphenylphosphino)butane, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), and 2-(2- dicyclohexylphosphanylpheny^-N^N^N^N^tetramethyl-benzene-l, 3-diamine (CPhos).

Embodiment 61 provides the method of any of Embodiments 56-60, wherein the coupling is run in the presence of iodine. Embodiment 62 provides the method of any of Embodiments 56-61, wherein the coupling is run in the presence of elemental zinc.

Embodiment 63 provides the method of any of Embodiments 56-62, wherein the coupling is run in oxygen-free and anhydrous conditions.

Embodiment 64 provides the method of any of Embodiments 48-63, wherein [18] is prepared by a process comprising one of the following: (i) reducing R group-substituted (£)-

2-(3-(alkoxy)-3-oxoprop-l-en-l-yl)-4-fluorobenzoate

wherein R’

is benzyl; (ii) hydrolyzing

acid

reducing [20] to yield [18], wherein R’ is Ci-C₆ alkyl, C₃-C₈ cycloalkyl, or benzyl; (iii)

reducing [16] to bis-ester

contacting [21] with an acid under conditions that allow for hydrolysis of R’ but not of R, wherein R’ is Ci-C₆ alkyl or C₃-C₈ cycloalkyl.

Embodiment 65 provides the method of Embodiment 64, wherein in (iii) R’ is tot- butyl and R is not tert- butyl.

Embodiment 66 provides the method of any of Embodiments 64-65, wherein 16 is

prepared by a process comprising coupling

wherein X is selected from the group consisting of Cl, Br, and I, R is Ci-C₆ alkyl or C₃-C₈ cycloalkyl, and R’ is as defined in Embodiment 64.

Embodiment 67 provides the method of Embodiment 66, comprising contacting [14],

[15], a base, and a catalyst.

Embodiment 68 provides the method of Embodiment 67, wherein the base comprises at least one of triethylamine, NaOAc, KOAc, and K3PO4.

Embodiment 69 provides the method of any of Embodiments 67-68, wherein the catalyst comprises at least one of Pd(OAc)₂, PdCl2(PPh₃)₂, Pd(PPh₃)₄, and Pd/C.

Embodiment 70 provides the method of any of Embodiments 67-69, wherein the catalyst is contacted with [14] in a molar ratio of about 1 : 100 to about 1 : 10.

Embodiment 71 provides the method of any of Embodiments 67-70, wherein [14], [15], the base, and the catalyst are further contacted with a tetraalkylammonium halide.

Embodiment 72 provides the method of any of Embodiments 66-71, wherein [14] is

prepared by esterifying

Claims

CLAIMS What is claimed is:

1. A method of preparing (l-methyl-lH-l,2,4-triazol-3-yl)methyl (_<S)-(4-((3-chloro-4- fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden-l-yl)carbamate [9], or a salt or solvate thereof:

the method comprising coupling (1 -methyl- 1, 2, 4-triazol-3-yl)methanol

or a salt or solvate thereof, and (<S)-l-amino-N-(3-chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-

lH-indene-4-carboxamide

2. The method of claim 1, wherein [8] and [7] are contacted in a molar ratio of about 1 : 1 to about 3: 1.

3. The method of claim 1, wherein [8] and [7] is first contacted with a carbonyl equivalent coupling agent before being contacted with [7] and [8], respectively.

4. The method of claim 3, wherein the carbonyl equivalent coupling agent comprises at least one of carbonyldiimidazole, phosgene, diphosgene, triphosgene, and disuccinimidyl carbonate.

5. The method of claim 1, wherein the coupling is performed in the presence of a base.

6. The method of claim 5, wherein the base comprises at least one of N,N- diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine.

7. The method of claim 1, wherein [9] is further recrystallized from a solvent system comprising at least one of isopropanol and 2-methyl-tetrahydrofuran.

8. The method of claim 1, wherein [9] is isolated as its hydrochloride salt.

9. The method of claim 1, wherein [7] is prepared by a process comprising contacting

(ri -l-(((ri)-tert-butylsulfmyl)amino)-N-(3-chloro-4-fluorophenyl)-7-fluoro-2,3-dihydro-lH-

indene-4-carboxamide

acidic solution.

10. The method of claim 9, wherein the acidic solution comprises at least one of hydrochloric acid, phosphoric acid, and sulfuric acid.

11. The method of claim 9, wherein [6] is prepared by a process comprising contacting (S)- 1 -(((S)-tert-butylsuirinyl)amino)-7-nuoro-2.3-dihydro- 1 H-indene-4-carbo\ylic acid

f

uoroan ne

12. The method of claim 11, wherein [5] and 3-chloro-4-fluoroaniline are further contacted with an amide coupling agent.

13. The method of claim 12, wherein the amide coupling agent comprises at least one of carbonyldiimidazole (CDI), (l-[bis(dimethylamino) methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU), 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4- methyl morpholinium chloride, propanephosphonic acid anhydride (T₃P), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC or EDCI) / hydroxybenzotriazole (HOBt), N,N,N',N'-tetramethyl-0-(lH-benzotriazol-l-yl)uronium hexafluorophosphate (HBTU), 2- (lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), (benzotriazol-

1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP),

chlorotripyrrolidinophosphonium hexafluorophosphate (PyClOP), benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N’- dicyclohexylcarbodiimide (DCC) / HOBt, l-cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholinocarbenium hexafluorophosphate (COMU), EDCI / ethyl 2-cyano-

2-(hydroxyimino)acetate (Oxyma), and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium tetrafluoroborate.

14. The method of claim 11, wherein [5], or an acid anhydride or acyl halide thereof, and

3-chloro-4-fluoroaniline are further contacted with a base.

15. The method of claim 14, wherein the base comprises at least one of N,N- diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine.

16. The method of claim 11, wherein [5] is prepared by a process comprising hydrolyzing R group-substituted (5 -l-(((5)-tert-butylsulfmyl)amino)-7-fluoro-2, 3-dihydro- lH-indene-4-

carboxylic acid

wherein R is C1-C6 alkyl, C₃-Cg cycloalkyl, or benzyl, with a hydrolyzing base.

17. The method of claim 16, wherein the hydrolyzing base comprises at least one of NaOH, LiOH, KOH, Na₂C0₃, and K₂C0₃.

18. The method of claim 16, wherein the hydrolysis product of [4] is further contacted by an acidic solution so as to yield [5]

19. The method of claim 16, wherein [4] is prepared by a process comprising contacting a reducing agent with R group-substituted (S. K)- 1 -((tert-butylsulfinyl) imino)-7-fluoro-2,3-

dihy dro- lH-indene-4-carboxylate

wherein R is C1-C6 alkyl, C₃-Ci cycloalkyl, or benzyl.

20. The method of claim 19, wherein the reducing agent comprises at least one of a borohydride salt, a triacetoxyborohydride salt, and a cyanoborohydride salt.

21. The method of claim 19, wherein the reduction product of [3] is further contacted with an acidic solution so as to yield [4]

22. The method of claim 19, wherein the reducing agent and [3] are contacted in a molar ratio of about 1: 1 to about 1 : 1.5.

23. The method of claim 19, wherein [3] is prepared by a process comprising contacting

R group-substituted 7-fluoro-l-oxo-2,3-dihydro-lH-indene-4-carboxylate

(S)-2-methylpropane-2-sulfmamide, and a Lewis acid, wherein R is Ci-C₆ alkyl, C3-C8 cycloalkyl, or benzyl.

24. The method of claim 23, wherein the Lewis acid comprises at least one of Ti(OEt)4, Ti(OiPr)₄, TiCl₄, TiCl₂(OCH(CH₃)₂)2, and TiCl(OCH(CH₃)₂)₃.

25. The method of claim 23, wherein [2] is contacted with fY)-2-methyl propan e-2- sulfmamide at a molar ratio of about 1 : 1.5.

26. The method of claim 23, wherein [2] is contacted with the Lewis acid at a molar ratio of about 1:3.

27. The method of claim 16, wherein R is selected from the group consisting of methyl, ethyl, «-propyl, and isopropyl.

28. A method of preparing (l-methyl-lH-l,2,4-triazol-3-yl)methyl fV)-(4-((3-chloro-4- fluorophenyl)carbamoyl)-7-fluoro-2,3-dihydro-lH-inden-l-yl)carbamate [9], or a salt or solvate thereof:

the method contacting 3-chloro-4-fluoroaniline with fV)-7-fluoro- 1 -(((( 1 -methyl- 1 H- 1.2.4- triazol-3-yl)methoxy)carbonyl) amino)-2,3-dihydro-lH-indene-4-carboxylic acid

acid anhydride or acyl halide, under conditions whereby an amide bond is formed between the carboxylic acid of [12] and the amine of 3-chloro-4- fluoroaniline.

29. The method of claim 28, wherein [12] and 3-chloro-4-fluoroaniline are further contacted with an amide coupling agent.

30. The method of claim 29, wherein the amide coupling agent comprises

carbonyldiimidazole (CDI), (l-[bis(dimethylamino) methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU), 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4- methyl morpholinium chloride, propanephosphonic acid anhydride (T₃P), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC or EDCI) / hydroxybenzotriazole (HOBt), N,N,N',N'-tetramethyl-0-(lH-benzotriazol-l-yl)uronium hexafluorophosphate (HBTU), 2- (lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU), (benzotriazol-

1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP),

31. The method of claim 28, wherein [12] and 3-chloro-4-fluoroaniline are further contacted with a base.

32. The method of claim 31, wherein the base comprises at least one of N,N- diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine.

33. The method of claim 28, wherein [12] is prepared by a process comprising hydrolyzing the ester group in R group-substituted fV)-7-fluoro- 1 -(((( 1 -methyl- 1 H- 1.2.4- triazol-3-yl)methoxy)carbonyl)amino)-2,3-dihydro-lH-indene-4-carboxylate

wherein R is C1-C6 alkyl, C₃-C₈ cycloalkyl, or benzyl.

34. The method of claim 33, wherein the hydrolysis comprises contacting [11] with a hydrolyzing base.

35. The method of claim 34, wherein the hydrolyzing base comprises at least one of NaOH, LiOH, KOH, Na₂C0₃, and K₂C0₃.

36. The method of claim 33, wherein [11] is prepared by a process comprising contacting (l-methyl-l,2,4-triazol-3-yl)methanol [8], or a salt or solvate thereof, and R group-substituted

(S)- 1 -amino-7-fluoro-2.3-dihydro- 1 H-indene-

salt or solvate thereof, wherein R is C1-C6 alkyl, C₃-C₈ cycloalkyl, or benzyl, under conditions whereby a carbamate group comprising the hydroxyl group of [8] and the amino group of [10] is formed.

37. The method of claim 36, wherein [8] and [10] are contacted in a molar ratio of about 1 : 1 to about 3: 1.

38. The method of claim 36, wherein [8] and [10] is first contacted with a carbonyl equivalent coupling agent before being contacted with [10] and [8], respectively.

39. The method of claim 38, wherein the carbonyl equivalent coupling agent comprises at least one of carbonyldiimidazole, phosgene, diphosgene, triphosgene, and disuccinimidyl carbonate.

40. The method of claim 36, wherein the coupling is performed in the presence of a base.

41. The method of claim 40, wherein the base comprises at least one of N,N- diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine.

42. The method of claim 36, wherein [11] is isolated as its hydrochloride salt.

43. The method of claim 23, wherein [2] is prepared by a process comprising promoting

esterification of 4-halo-7-fluoro-2,3-dihydro-lH-inden-l-one

wherein X is Br or I.

44. The method of claim 43, wherein [1] is contacted with a base, an esterification catalyst, carbon monoxide, and alcohol ROH, wherein R is C1-C6 alkyl, C3-C8 cycloalkyl, or benzyl.

45. The method of claim 44, wherein the base comprises at least one of triethylamine, NaOAc, KOAc, and K3PO4.

46. The method of claim 44, wherein the catalyst comprises a palladium catalyst comprising at least one of PdCl₂.dppf (dppf = l,T-Ferrocenediyl-bis(diphenylphosphine)), Pd(dppf)Cl2, Pd(OAc)₂-dppp, and PdCl2(PPh₃)₂.

47. The method of claim 44, wherein the carbon monoxide pressure during esterification ranges from about 50 psi to about 150 psi.

48. The method of claim 23, wherein [2] is prepared by a process comprising cyclizing 3-

(2-(ethoxycarbonyl)-5-fluorophenyl)propanoic acid

wherein R is C1-C6 alkyl or C3-C8 cycloalkyl.

49. The method of claim 48, comprising :

(i) converting [18] to the corresponding acyl halide, which undergoes intramolecular acylation to yield [2]; or

(ii) treating [18] with an acid, thus promoting intramolecular acylation to yield [2]

50. The method of claim 49, wherein in (i) [18] is contacted with a chlorinating reagent comprising at least one of oxalyl chloride, phosgene, diphosgene, triphosgene, and thionyl chloride, so as to yield [18]’s acyl chloride.

51. The method of claim 50, wherein the chlorinating reagent and [18] are contacted in the presence of dimethylformamide (DMF).

52. The method of claim 50, wherein [18]’s acyl chloride is contacted with a Lewis acid, thus undergoing cyclization to form [2]

53. The method of claim 52, wherein the Lewis acid comprises an aluminum salt.

54. The method of claim 48, wherein [18] is prepared by a process comprising hydrolyzing R group-substituted 4-fluoro-2-(3-[R’-substituted]oxy-3-oxopropyl)benzoate

acid, wherein R is C₁-C₆ alkyl or C₃-C₈ cycloalkyl, and R’ is

Ci-C₆ alkyl or C₃-C₈ cycloalkyl.

55. The method of claim 54, wherein R’ is fer/-butyl and R is not tert- butyl.

56. The method of claim 54, wherein [17] is prepared by a process comprising coupling

57. The method of claim 56, wherein the coupling is catalyzed by a transition metal comprising nickel or palladium.

58. The method of claim 57, wherein the transition metal comprises at least one of Pd₂(dba)3, Pd(OAc)₂, PdCl₂(PPh₃)₂, and Pd(PPh₃)₄.

59. The method of claim 56, wherein the coupling is run in the presence of a triphosphine.

60. The method of claim 59, wherein the triphosphine comprises at least one of triphenylphosphine, tris-(o-tolyl)phosphine, tris-(4-fluorophenyl)phosphine, 1,2- bis(diphenylphosphino)ethane (dppe), 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (BINAP), (2N,35)-(-)-bis(diphenylphosphino)butane, (2//.3//)-(+)-bis(diphenylphosphino)butane. 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos), 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (SPhos), and 2-(2-dicyclohexylphosphanylphenyl)-N¹,N¹,N³,N³- tetramethyl-benzene- 1 ,3-diamine (CPhos).

61. The method of claim 56, wherein the coupling is run in the presence of iodine.

62. The method of claim 56, wherein the coupling is run in the presence of elemental zinc.

63. The method of claim 56, wherein the coupling is run in oxygen-free and anhydrous conditions.

64. The method of claim 48, wherein [18] is prepared by a process comprising one of the following: (1) reducing R group-substituted (£)-2-(3-(alkoxy)-3-oxoprop-l-en-l-yl)-4-

fluorobenzoate

wherein R’ is benzyl;

(11) hydrolyzing

reducing [20] to yield [18], wherein R’ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, or benzyl;

(iii) reducing [16] to bis-ester

contacting [21] with an acid under conditions that allow for hydrolysis of R’ but not of R, wherein R’ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl.

65. The method of claim 64, wherein in (iii) R’ is /e/V-butyl and R is not tert- butyl.

66. The method of claim 64, wherein 16 is prepared by a process comprising coupling

wherein X is selected from the group consisting of Cl,

Br, and I, R is C₁-C₆ alkyl or C₃-C₈ cycloalkyl, and R’ is is benzyl in (i), R’ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, or benzyl in (ii), or R’ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl in (iii).

67. The method of claim 66, comprising contacting [14], [15], a base, and a catalyst.

68. The method of claim 67, wherein the base comprises at least one of triethylamine, NaOAc, KOAc, and K₃PO₄.

69. The method of claim 67, wherein the catalyst comprises at least one of Pd(OAc)₂, PdCl₂(PPh₃)₂, Pd(PPh₃)₄, and Pd/C.

70. The method of claim 67, wherein the catalyst is contacted with [14] in a molar ratio of about 1 : 100 to about 1 : 10.

71. The method of claim 62, wherein [14], [15], the base, and the catalyst are further contacted with a tetraalkylammonium halide.

72. The method of claim 66, wherein [14] is prepared by esterifying

ROH, wherein X is selected from the group consisting of Cl, Br, and I, and R is Ci-C₆ alkyl or C₃-C₈ cycloalkyl.