WO2025240809A1 - Processes related to preparation of triazole oxathiazolidine derivatives - Google Patents

Abstract

Disclosed herein is a process for the preparation of compounds of formula Z:

Description

PROCESSES RELATED TO FORMATION OF OXATHIAZOLIDINE DERIVATIVES

BACKGROUND

[001] This disclosure relates to processes to prepare oxathiazolidine urea derivatives having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda.

[002] oxathiazolidine ureas of specific interest have been disclosed in WO 2021/011722

[003] The protection of crops from insects and nematodes which inhibit crop growth is a constantly recurring problem in agriculture. To help combat this problem, researchers in the field of synthetic chemistry have produced an extensive variety of chemicals and chemical formulations effective in controlling such insects and nematodes. Chemical insecticides and nematicides of many types have been disclosed in the literature and a large number are in commercial use. However, there remains a need for compositions and methods that are effective in controlling undesirable insects and nematodes and methods to prepare such.

SUMMARY

[004] This disclosure provides processes to make and use compounds having the following formula Z: where Ri is selected from the group consisting of F, -(Ci-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(Ci-C₄)alkoxy, -CHF₂, -CH₂F, -CF₃, -OCF₃, -OCF₂H, -OCF₂CF₃ and - OCH₂F;

A is selected from the group consisting of -F, -Cl, -(Ci-C4)alkyl, and -(Ci-C4)haloalkyl; R₂ is selected from the group consisting of -CH₂OCH₂CH₃, -CH₂OCH₂CF₃, - CH₂OCH₂CHF₂, -CH₂OCH₂CH₂F, -OCF₃, -OCH₂CH₂CH₃, -OCH₂CH₂CF₃ and - OCH₂CF₃, -(Cl-C4)alkyl; and R₃ is selected from the group consisting of -(C1-C4)alkyl, -(Ci-C4)alkoxy, -(C1- C₄)alkylhalo, -CH₃, -CH2CH3, -OCH₃, and -OCH2CH3.

DETAILED DESCRIPTION

[005] Examples provided herein are not exhaustive and should not be construed as limiting. It is understood that a substituent should comply with chemical bonding rules and steric compatibility constraints in relation to the particular molecule to which it is attached. These definitions are only to be used for the purposes of this disclosure.

[006] The term “alkyl” means an acyclic, saturated, branched, or unbranched, substituent consisting of carbon and hydrogen, for example, methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, and tert-butyl.

[007] The term "halogen" or "halo" or derivative terms such as “halide” refers to one or more halogen atoms, defined as F, Cl, Br, and I.

[008] The term “ambient pressure” refers to pressures from about 80 kilopascals (kPa) to about 105 kPa.

[009] The term “ambient temperature” or “room temperature” refers to temperatures ranging from about 20 °C to about 24 °C.

[0010] The term “catalyst” refers to any substance that increases the rate of a reaction without itself being consumed.

[0011] “Continuous flow”, “flow”, “continuous formation”, “continuous process”, or other derivative terms as used herein means methods that produce a minimum amount of a reactive intermediate at any given time and provide reduced cycle times in comparison to conventional methods. For example, U.S. Patent 9,145,428 B2 describes methods and systems using continuous flow. Processes disclosed herein can be conducted according to conventional batch processes or continuous flow processes.

[0012] All references, including publications, patent applications, and patents, referred to herein are incorporated by reference herein to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety.

The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0013] The term “crystalline” refers to a solid state form where the molecules are arranged to form a crystal lattice comprising distinguishable unit cells. A certain crystalline form can be identified by the specific diffraction peaks when subjected to X-ray radiation.

[0014] Throughout the disclosure, in a solvate of Y2b or an acceptable salt thereof, the ratio of solvent molecules to the compound of Y2b or an acceptable salt thereof may be, but is not limited to, 1:2, 1 : 1, or 2: 1.

[0015] Throughout the disclosure, in a hydrate of Y2b or an acceptable salt or solvate thereof, the ratio of water molecules to the compound of Y2b or an acceptable salt or solvate thereof may be, but is not limited to, 1 :2 (hemi-hydrate), 1 : 1 (monohydrate), 2: 1 (dihydrate). [0016] Throughout the disclosure, reference to the compound of Y2b or compounds of Y2b is read as also including acceptable salts, solvates, or hydrates thereof, unless otherwise indicated herein or clearly contradicted by context.

[0017] Throughout the disclosure, reference to compounds of the present disclosure is read as also including all regioisomers, structural isomers, geometrical isomers, rotational isomers, tautomers, and stereoisomers, for example diastereomers, enantiomers, and mixtures thereof. [0018] The compounds of the disclosure may also contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage e.g., restriction resulting from the presence of a ring or a double bond. Accordingly, any cis/trans and E/Z isomers are expressly included in the present disclosure.

[0019] The compounds of the disclosure may also be present in multiple tautomeric forms. Where one or more tautomeric forms exist, the disclosure expressly includes all such tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented.

[0020] The compounds of the present disclosure may exist in an amorphous solid form or as an oil. The compounds of the present disclosure may exist in one or more crystalline or polymorphic forms. All crystalline forms and polymorphs of the compounds of the disclosure are expressly included in the present disclosure.

BRIEF DESCRIPTION OF DRAWINGS

[0021] FIGURE 1 is an X-ray diffractogram (XRD) of crystalline form A of Y2b recorded using Cu-Ka radiation at 25 °C;

[0022] FIGURE 2 is a Differential Scanning Calorimetry (DSC) profile of crystalline form A of Y2b;

[0023] FIGURE 3 is an X-ray diffractogram (XRD) of crystalline form B of Y2b recorded using Cu-Ka radiation at 25 °C;

[0024] FIGURE 4 is a Differential Scanning Calorimetry (DSC) profile of crystalline form B of Y2b;

[0025] A molecule, Z having the following formula:

Z and processes to make and use a molecule of formula Z, and stereoisomers thereof are provided.

In a particular aspect, a molecule of formula Z is Zl.

Z1

[0026] Compounds of formula Z have pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda.

[0027] The following are processes related to the preparation of Z and intermediates related to such processes.

Scheme 1 shows the general process for the preparation of a compound of formula Z via a series of reactions between a compound of formula XI and a compound of formula Y, wherein L is a leaving group, for example, halides such as -Cl, -Br, -I, - or sulfonates such as -OSCLCeLLMe, - OSChPh, -OSO₂Me.

Scheme 1 [0028] Scheme 2 shows a general process for the preparation of Y as disclosed in W02021/011722A1.

Scheme 2

[0029] Scheme 3 shows a general process for preparation of XI as disclosed in W02021/011722A1.

Scheme 3

[0030] Scheme 4 shows a process for the preparation of Z as disclosed in WO

2021/011722A1. This process comprises first converting Y to the intermediate Yl, followed by isolating Y1 via an aqueous and/or chromatographic purification, and then adding the isolated Yl to XI in the presence of a suitable carbonyl (CO) derivative to obtain Z. The process illustrated in Scheme 4 as illustrated in WO 2021/011722A1 calls for isolation of Y via a chromatographic purification.

[0031]

Scheme 4

[0032] The improved process disclosed herein focuses on improving the overall yield of all processes leading up to Z where such improvements are easily amenable to large scale synthesis. They can be conducted via a batch-process or a continuous process.

[0033] In one aspect, one of the objectives of the processes disclosed herein is to improve the overall yields by preventing/circumventing the degradation of unstable intermediates. For example, Y1 is either synthesized in situ and carried through to the next coupling step, or isolated via means that prevent potential degradation (for example, Y1 may be susceptible to degradation during chromatographic purification). Accordingly, in one aspect, the improved process encompasses isolation of crystalline forms of Y1 via crystallization processes, , selecting appropriate reagents and solvents, and optimizing other process conditions. In another aspect of the process improvement disclosed herein, the intermediate Y1 is synthesized in situ, and carried through to the next step without isolation. “In situ” in some instances, means Y1 is prepared from Y in the first step in solution, generally in an organic solvent/solvent mixture, and taken to the next step. In one aspect, an optional aqueous work-up can be carried out to remove any inorganic byproducts, and Y1 can be taken on to the coupling step. This involves a careful selection of appropriate solvents. For example, synthesis of Y1 can be carried out in the same solvent as in the final coupling reaction between Y1 and XI. In some instances, for further optimization of the yield and to facilitate process operations, synthesis of Y1 and the final coupling can be carried out in separate solvents. In such instances, following the formation of Y1 and after an aqueous work-up, the solvent can be removed and exchanged with the solvents to be used in the final coupling of Y1 and XI. Generally polar aprotic solvents are used in the synthesis of Yl and found to be beneficial in improving the yield. Suitable solvents include ketones, esters, ethers, nitriles and halogenated C1-C4 alkyls. Specific examples are ethyl acetate, /.w-propyl acetate, //-propyl acetate, /.w-butyl acetate, //-butyl acetate, .sec-butyl acetate, acetonitrile, tetrahydrofuran, acetone, di chloromethane and mixtures thereof. The choice of the solvent plays an important role in preventing the degradation of the intermediate Yl. Suitable solvents for the final coupling to prepare Z are aromatic hydrocarbons, aliphatic hydrocarbons, ketones, esters, ethers, nitriles and halogenated C1-C4 alkanes. Specific examples are ethyl acetate, acetonitrile, tetrahydrofuran, acetone, toluene, xylenes and dichloromethane. In some embodiments, the solvent is an acetate selected from the group consisting of iso-propyl acetate, n-propyl acetate, iso-butyl acetate, n-butyl acetate and sec-butyl acetate. In some cases, the final coupling to prepare Z can be carried out with water as a co-solvent. In some cases, mixtures of suitable solvents can be used at some point during the process, including the reaction, work-up and crystallization. Suitable anti-solvents include water and aliphatic hydrocarbons such as hexane, heptane, octane, nonane, decane, cyclohexane and methylcyclohexane.

[0034] In another aspect, Yl is isolated using crystallization after completion of the reaction and aqueous workup without chromatographic purification. The crystalline forms of Yl can be obtained by concentrating the solution and/or cooling the solution and/or adding an anti-solvent followed by filtration. In some instances, the crystallization process is achieved by seeding with crystalline Yl. In some instances, the filter cake can be washed with an appropriate solvent and dried. Suitable reaction solvents include ketones, esters, ethers, nitriles and halogenated C1-C4 alkyls. Specific examples are acetone, ethyl acetate, /.w-propyl acetate, //-propyl acetate, isobutyl acetate, //-butyl acetate, .scc-butyl acetate, tetrahydrofuran, acetonitrile, and dichloromethane. Suitable anti-solvents include aliphatic hydrocarbons such as hexane, heptane, octane, nonane, decane, cyclohexane and methylcyclohexane. In some instances, the solvent or anti-solvent contains water. In some aspects, some of the crystalline forms are anhydrous and in other instances, the crystalline forms are in the form of hydrates. The isolated crystalline forms can be used in the final coupling of crystalline forms of Yl and XI.

[0035] The improved procedure disclosed herein resulted in higher yields and high purity of Z. In addition, Z can be isolated from the reaction mixture via crystallization without the need for additional purifications.

[0036] Synthesis of Z [0037] Scheme 5 shows the general scheme for the synthesis of Z. Compound of formula Y is treated with a thiocyanate salt in the presence of an appropriate base to generate a compound of formula Yl. The base can be either organic or inorganic and can be used in catalytic or stoichiometric amounts. The organic bases can be selected from the group consisting of amines, amidines, carboxylates, guanidines, phosphines and N-oxides and the inorganic bases can be selected from the group consisting of carbonates, bicarbonates, phosphates and amides. Yl is then added to a mixture comprising a compound of formula XI and an appropriate coupling agent and optionally an acid and/or base. Suitable coupling reagents are carbonyl (CO) derivatives such as chloroformates, phosgene derivatives, carbonates, carboxylic acid derivatives and ureas. Specific reagents, for example, are dimethyl carbonate, diethyl carbonate, bis(2,5- dioxopyrrolidin-l-yl)carbonate, phenyl chloroformate, /%/ra-nitrophenyl chloroformate, methyl chloroformate, ethyl chloroformate, carbonyl diimidazole, carbonyl ditriazole, oxalyl chloride, phosgene, diphosgene and triphosgene. The coupling reaction of Yl and XI generates a compound of Formula Z.

Scheme 5

The first reaction between Y and a thiocyanate salt is carried out in an appropriate solvent or solvent mixture. Suitable solvents can be from various classes of solvents such as ketones (acetone), esters (ethyl acetate), ethers (tetrahydrofuran), halogenated organic solvents (dichloromethane), alkanes and aprotic polar nitriles (acetonitrile). Any thiocyanate salt can be used. A particular example of a thiocyanate salt is potassium thiocyanate. The reaction is carried out at ambient pressure and at a temperature range of 0 °C to 100 °C. In some instances, the first reaction for preparation of the Y1 intermediate can be carried out using the same solvent used for the second coupling reaction between Y1 and XI. In some instances, a polar, aprotic solvent such as ethyl acetate, /.w-propyl acetate, //-propyl acetate, /.w-butyl acetate, //-butyl acetate, secbutyl acetate, tetrahydrofuran, acetonitrile, acetone or dichloromethane can be used. In some instances, the first reaction is carried out in a different solvent than that of the second coupling reaction. In one embodiment, the solvents can be of different polarity. For example, the first reaction can be carried out in ethyl acetate, and the second reaction can be carried out in toluene. In such an instance, a solvent exchange is carried out. After the first reaction is complete, an aqueous wash is done to remove any inorganic and organic byproducts and the excess solvent is removed by distillation or by rotary evaporation. The Y1 intermediate is dissolved in a solvent that is used for the second coupling reaction, for example, toluene, and transferred into a mixture comprising XI and a CO derivative. In a specific embodiment, the Y1 intermediate is taken through to the second coupling reaction between XI without any isolation, either in the same solvent, or via a solvent exchange in a telescopic manner. This way, any degradation products arising from the unstable intermediates can be avoided.

[0039] The first reaction between a thiocyanate salt and Y is carried out in the presence of a base. In specific instances, any thiocyanate salt can be used. The base can either be used in catalytic or stoichiometric amounts. A base consisting of an anion and a cation, where the anion can be carboxylate, carbonate, and bicarbonate and the cation can be lithium, sodium, potassium and cesium can be used in this reaction. Exemplary bases include sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate and potassium acetate. The base can be added anytime during the course of the reaction. For example, the base can be added at the outset of the reaction or in other cases the base can be added after step 1 has been started. In the latter instance, the intermediate Ya shown below is generated and observed. Accordingly, the intermediate Ya shown below is within the scope of the process disclosed herein. In some instances, the intermediate Ya is isolated and in some other instances the intermediate is processed through the final coupling step without any isolation. In the latter instance, a suitable work-up or an appropriate crystallization can be used to remove any byproducts and excess reagents.

[0040]

[0041] Suitable CO derivatives are selected from the group consisting of chloroformates, ureas, phosgene or phosgene derivatives, carboxylic acid derivatives, and carbonates. A particular example is phosgene. Optionally, a base and/or acid can also be used. Bases can be organic or inorganic bases such as amines (triethylamine), alkoxides (sodium tert-butoxide), carbonates (sodium carbonate) and/or bicarbonates (sodium bicarbonate). Acids can be Lewis acids and Bronsted acids such as methanesulfonic acid, hydrochloric acid or boron trichloride. In some instances, the coupling reaction can be carried out without any acid or base in an appropriate solvent, such as when the CO derivative is carbonyl ditriazole. In some other instances, the coupling reaction can be carried out in the presence of both an acid and a base, such as boron trichloride and triethylamine when the CO derivative is a carbonate or chloroformate. Suitable solvents for the coupling reaction include aprotic solvents such as ethyl acetate, tetrahydrofuran, acetonitrile, acetone, toluene, xylenes, dichloromethane and mixtures thereof. Suitable anti-solvents include water and aliphatic hydrocarbons such as hexane, heptane, octane, nonane, decane, cyclohexane and methylcyclohexane. The reaction is typically carried out at ambient pressure and at a temperature between 0 °C and 150 °C. The final coupling step can be carried out by 1) mixing the CO derivative/coupling agent with Yl, 2) mixing the CO derivative/coupling agent with XI, 3) mixing the CO derivative/coupling agent with a mixture comprising XI and Yl. Accordingly, any of the intermediates Yl-COJ, Yl-NCO, Xl-NCO and Xl-COJ shown below is within the scope of the processes disclosed herein, where J is selected from the group consisting of -F, -Cl, -Br, -I, -triazole, -imidazole, -(Ci-C4)alkoxy, -COCI, -0- aryl or -O-succinimidyl. In some instances, these intermediates are isolated and in some other instances they are processed through the final coupling step without any isolation. In the latter instance, a workup or an appropriate crystallization can be used to remove any byproducts and excess reagents.

[0042]

X1-C0J X1-NC0

[0043] One specific embodiment of the process disclosed herein is a process for the preparation of a compound of formula Z1 (Scheme 7). In such an embodiment, the compound of formula Y2 is first treated with a thiocyanate salt and a base to obtain the intermediate Y2b. In one aspect, an aqueous work-up was conducted to remove the inorganic byproducts and Y2b is carried through to the next step. Y2b can then be added to a mixture comprising X2 and an appropriate CO derivative. Alternatively, a mixture comprising X2 and an appropriate CO derivative in a suitable solvent can be added to the Y2b intermediate. In another alternative, an appropriate CO derivative in a suitable solvent can be added to the mixture of Y2b and X2, or a mixture of Y2b and X2 in a suitable solvent can be added to an appropriate CO derivative. Generally, the mixing step of the coupling reaction is conducted in solution. However, in some instances, the reagents can exist as solids, or semi-solids, partially dissolved, or as slurries.

[0044] In another specific embodiement, Y2b is isolated using crystallization after completion of the reaction and an optional aqueous workup without chromatographic purification. In particular aspects, the crystalline form produced is crystalline form A of Y2b. In some aspects, the crystalline form produced is crystalline form B of Y2b. In some aspects, the isolated material is a mixture of form A and form B. The crystalline forms of Y2b can be obtained by concentrating the solution and/or cooling the solution and/or adding an anti-solvent followed by filtration. In some instances, the crystallization process is achieved by seeding with crystalline Y2b. In some instances, the filtercake can be washed with an appropriate solvent or anti-solvent and then dried. Suitable reaction solvents include ketones, esters, ethers, nitriles and halogenated C1-C4 alkyls. Specific examples are acetone, ethyl acetate, zso-propyl acetate, n- propyl acetate, /.w-butyl acetate, //-butyl acetate, .sec-butyl acetate, tetrahydrofuran, acetonitrile, and dichloromethane. Suitable anti-solvents include aliphatic hydrocarbons such as hexane, heptane, octane, nonane, decane, and cyclohexane. In some instances, the solvent or anti-solvent contains water. In some aspects, some of the crystalline forms are anhydrous and in other instances, the crystalline forms are in the form of hydrates. Under certain conditions, the crystalline forms of A and B can be interconverted; for example, the hydrate crystalline form can be converted to the anhydrous form and vice versa. Both isolated crystalline forms can be used in the final coupling through coupling of crystalline forms of Y2b and X2. In a specific embodiment, crystalline form A is used in the final coupling step.

[0045] The crystalline form A of Y2b exhibits an X-ray powder diffractogram (X-RPD) recorded using Cu-Ka radiation at 25 °C substantially as shown in Figure 1.

[0046] Crystalline form A of Y2b typically has a melting onset temperature in the range from 50 to 100 °C, in particular in the range from 70 to 90 °C, and especially in the range from 72 to 82 °C. It is noted that melting points of the crystalline forms disclosed herein can vary depending on impurities and the conditions being used to generate the DSC curves.

[0047] In one specific aspect, the crystalline form A of Y2b can also be characterized by its melting point. Accordingly, also provided herein is a crystalline form A of Y2b exhibiting a differential scanning calorimetry (DSC) profile having an endothermic peak at 81.3 °C with onset temperature of 77.1 °C and preferably with a melting enthalpy in the range of 50-90 J/g (Joules per gram) as shown in Figure 2.

[0048] In one aspect, disclosed herein are various crystalline forms of Y2b. In another aspect, the crystalline form is crystalline form A of Y2b. In one aspect, the crystalline form A comprises at least three of the following reflexes in any combination as 20 + 0.20 in an X-ray powder diffractogram (X-RPD) recorded using Cu-Ka radiation at 25 °C:

[0049] In another aspect, the crystalline form is crystalline form B of Y2b. The crystalline form B of Y2b exhibits an X-ray powder diffractogram (X-RPD) recorded using Cu-Ka radiation at 25 °C substantially as shown in Figure 3.

[0050] Crystalline form B of Y2b typically has a melting onset temperature in the range from 40 to 90 °C, in particular in the range from 50 to 80 °C, and especially in the range from 60 to 70 °C. It is noted that melting points of the crystalline forms disclosed herein can vary depending on impurities and the conditions being used to generate the DSC curves.

[0051] In one specific aspect, the crystalline form B of Y2b can also be characterized by its melting point. Accordingly, also provided herein is a crystalline form B of Y2b exhibiting a differential scanning calorimetry (DSC) profile having two endothermic peaks with melting onset temperatures of 66.7 °C and 77.8 °C preferably with a melting enthalpy in the range of 65- 105 J/g (Joules per gram) as shown in Figure 4.

[0052] In another aspect, the crystalline form is crystalline form B of Y2b. In one aspect, the crystalline form B of Y2b comprises at least three of the following reflexes in any combination as 26 + 0.20 in an X-ray powder diffractogram (X-RPD) recorded using Cu-Ka radiation at 25 or. [0053] In some instances, Z1 can be isolated from the reaction mixture in excellent yields with high purity. For example, the second coupling reaction can be conducted in acetonitrile, and after the reaction is complete as indicated by the high-performance liquid chromatography (HPLC) analysis, the reaction mixture is cooled, water was added, and the precipitated solids are isolated via filtration. The filter cake is washed with acetonitrile:water and methanol, and dried under vacuum to obtain crystalline Z1 in high purity. In other instances, suitable anti-solvents such as aliphatic hydrocarbons such as hexane, heptane, octane, nonane, decane, cyclohexane and methyl cyclohexane can be added to reaction mixture, and crystalline Z1 can be isolated from the reaction medium. This is another advantage of the improved process disclosed herein.

X2

Scheme 7

[0054] In light of the above, the following details are additionally provided: dl . A process for preparation of a compound of formula Z: comprising the steps of: la. reaction of a compound of formula Y, a base, a thiocyanate salt, mixed in a solvent to form a compound of formula Yl; lb. combining a) a crystalline-form of compound of formula Y1 or b) Y1 formed in situ, with a compound of formula XI, and a CO derivative compound to form Z;

Y1 xi wherein

L is a leaving group selected from the group consisting of -Cl, -Br, -I, OSO2C6H4Me, OSO₂Ph, and -OSO₂Me;

Ri is selected from the group consisting of -OCF3, -OCHF₂, -OCH₂F, and OCF₂CFs;

A is selected from the group consisting of F, Cl, -(Ci-C4)alkyl;

R₂ is selected from the group consisting of -CH₂OCH₂CH3, -CH₂OCH₂CF3, - CH₂OCH₂CHF₂, -CH₂OCH₂CH₂F, -OCF3, -OCH₂CH₂CH₃, -OCH₂CH₂CF₃ , -(Cl- C4)alkyl and -OQLCF3; and

R3 is selected from the group consisting of -(Ci-C4)alkyl, -(Ci-C4)alkoxy, -(Ci- C₄)haloalkyl, -CH₃, -CH₂CH₃, and -OCH₂CH₃. d2. The process according to dl, wherein in step la: the thiocyanate salt is a thiocyanate salt selected from the group consisting of sodium thiocyanate and potassium thiocyanate; the base is a base that consists of an anion and cation, where the anion is carboxylate, carbonate, or bicarbonate and the cation is lithium, sodium, potassium or cesium ; and the solvent is selected from the group consisting of ketones, esters, ethers, halogenated C1-C4 solvents, , aprotic polar solvents, aliphatic hydrocarbons and mixtures thereof. d3. The process according to dl, wherein in step lb an optional acid, base or acid and base is present; and wherein the base is selected from the group consisting of organic and inorganic bases; the acid is selected from the group consisting of Lewis acids and Br0nsted acids. d4. The process according to dl, wherein in step lb: the solvent is an aprotic solvent selected from the group consisting of ethyl acetate, tetrahydrofuran, acetonitrile, acetone, toluene, xylenes, dichloromethane and mixtures thereof. d5. The process according to dl, wherein in step lb: the CO derivative is selected from the group consisting of phosgene, phosgene derivatives, carbonates, chloroformates, carbonyl derivatives and ureas. d6. The process according to d5, wherein the CO derivative is selected from the group consisting of dimethyl carbonate, diethyl carbonate, bis(2,5-dioxopyrrolidin-l-yl)carbonate, methyl chloroformate, ethyl chloroformate, phenyl chloroformate, /%/ra-nitropheriyl chloroformate, carbonyl diimidazole, carbonyl ditriazole, oxalyl chloride, phosgene, diphosgene and triphosgene. d7. The process according to dl, wherein in step lb, the combining of Y1 and XI is carried out by: a. adding the compound of formula Y1 to a mixture of a compound of formula XI, and a CO derivative; b. adding a mixture of a compound of formula Yl, and a CO derivative compound to the compound of formula XI, or c. adding a compound of formula Y 1 and a compound of formula XI, simultaneously or sequentially in any order to a CO derivative. d8. The process according to dl, wherein combining a) the compound of formula Yl, b) the compound of formula XI, and c) the CO derivative comprises mixing a), b) and c) components together in any order. d9. The process according to dl, wherein step la is carried out in a solvent selected from the group consisting of ethyl acetate, /.w-propyl acetate, //-propyl acetate, /.w-butyl acetate, //-butyl acetate, sec-butyl acetate, acetonitrile, tetrahydrofuran, acetone, dichloromethane and mixtures thereof. dlO. The process according to dl, wherein the step lb further comprising a solvent exchange step which comprises: a. removing the solvent of step la; and b. adding the solvent used in step lb. dl 1. The process according to dlO, further comprising an aqueous wash prior to removing the solvent of step la. dl2. The process according to any of dl - 11, wherein Y1 is isolated by crystallization. dl 3. The process according to dl for the preparation of a compound of formula Zl:

Zl comprising the steps of: a. reaction of a compound of formula Y2, a thiocyanate salt in a polar, aprotic solvent to form a compound of formula Y2b b. combining a) a crystalline-form of the compound of Formula Y2b or b) compound of formula Y2b formed in situ, with mixture of a compound of formula X2, and a CO derivative to form Zl;

X2. d 14. The process according to d 13 , wherein combining the compound of formula Y2b with the compound of formula X2 and a CO derivative comprises any of a) adding the compound of formula Y2b to a mixture of the compound of formula X2 and a CO derivative; or b) adding the compound of formula X2 to a mixture of the compound of formula Y2b and a CO derivative; or c) adding a CO derivative to a mixture of the compound of formula Y2b and the compound of formula X2; or d) adding CO derivative, the compound of formula Y2b and the compound of formula X2 sequentially or simultaneously in any order. dl 5. The process according to dl 3-dl4, wherein the compound of formula Y2b is a crystalline form of the compound of Formula Y2b, or a crystalline form of acceptable salts, solvates, isotopes or tautomers of Y2b. dl 6. A compound of formula Zl, prepared according to any of dl -dl 5.

[0055] Starting materials, reagents, and solvents that were obtained from commercial sources were used without further purification. Anhydrous solvents were purchased and were used as received. Melting points were obtained on a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated Melting Point System from Stanford Research Systems and are uncorrected. Some melting points were obtained using a Thermal Analysis (TA) Q2500 DSC instrument. After loading the sample in the sample pan, the DSC instrument is heated and the resulting heat flow into (endotherm) or out of (exotherm) the sample is measured via comparison to a blank reference cell. Molecules are given their known names, named according to the naming program within ChemDraw (version 21.0.0.28)), IUPAC guidelines, or using conventional naming rules. ¹ H NMR spectral data are in ppm (8) and were recorded at 400 MHz or 500 MHz, and ¹³C NMR spectral data are in ppm (8) and were recorded at 101 MHz or 126 MHz, unless otherwise stated.

[0056] In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

A% = area percent

AcOH = acetic acid aq = aqueous

BF3-OEt2 = boron trifluoride etherate

Boc = tert-butyloxycarbonyl

BOC2O = di-tert-butyl decarbonate cone. = concentrated

DCM = dichloromethane

DI = deionized

DMF = AA-dimethylformamide

DMSO = dimethyl sulfoxide

DSC = differential scanning calorimetry equiv = equivalent

EtaN = triethylamine

ESIMS = electrospray ionization mass spectrometry

EtOAc = ethyl acetate

EtOH = ethanol g = gram

GC-MS = gas chromatography-mass spectrometry h = hours

H2 = hydrogen

HC1 = hydrochloric acid

HPLC = high-performance liquid chromatography

IP A = isopropanol zPrOAc = isopropyl acetate

K2CO3 = potassium carbonate

KSCN = potassium thiocyanate

KOH = potassium hydroxide kPa = kilopascals

L = liter

LC = liquid chromatography

M = molar

MeCN = acetonitrile mg = milligrams

MgSO4 = magnesium sulfate min = minutes mL = milliliters mL/min = milliliters per minute mmol = millimoles mol = moles mp = melting point

MS = mass spectrometry

MTBE = methyl /c/7-butyl ether m/z = mass to charge ratio

N = normal

N2 = nitrogen (gas)

NaBH4 = sodium borohydride

NaCl = sodium chloride

NaHCCE = sodium bicarbonate

NaOEt = sodium ethoxide

NaO/Bu = sodium te/7-butoxide n-BuOAc = //-butyl acetate

NH4CI = ammonium chloride

Ni = nickel

NMR = nuclear magnetic resonance

NaOH = sodium hydroxide

Na2SOs = sodium sulfite

Na2S2C>3 = sodium thiosulfate Na₂SO₄ sodium sulfate

PBr₃ = phosphorus tribromide

Pd(OH)2/C = palladium hydroxide on carbon PhSChCl = benzenesulfonyl chloride psi = pounds per square inch rpm = revolutions per minute

RT, rt = room temperature sat = saturated

SM = starting material

SOBr2 = thionyl bromide

SOCh = thionyl chloride

TBAB = tetrabutylammonium bromide

/-BuOH = tert-butanol

TEAB = tetraethylammonium bromide

THF = tetrahydrofuran

TMAB = tetramethylammonium bromide

TMEDA = tetramethylethylenediamine

TMSC1 = trimethyl silyl chloride

TsCl = p-toluenesulfonyl chloride pL = microliter

UPLC = ultra-performance liquid chromatography wt% = weight percent w/v = weight per volume V volumes

[0057]

[0058] EXAMPLES

[0059] Example 1. Synthesis of 2- fluoro-4-(l-(4-trifluoromethoxy)phenyl)-l/7-l,2,4-triazol-

3-yl)aniline (X2)

X2

[0060] A round bottom flask equipped with a stir bar, reflux condenser, temperature probe and nitrogen inlet was charged with 3,4-difluorobenzonitrile (3.48 grams (g), 25 millimoles (mmol)) and potassium l,3-dioxoisoindolin-2-ide (5.79 g, 31.3 mmol). Anhydrous DMF (25 milliliters (mL)) was then added and the reaction was heated to 130 °C. After 8 hours, the reaction was sampled and analyzed, showing high conversion by high-performance liquid chromatography (HPLC). The reaction was cooled to 40 °C and a thick suspension was present. The mixture was poured into water (35 mL) and stirred for 5 minutes. The mixture was then filtered through a fritted glass funnel and washed with water (20 mL) to afford the desired product, 4-( 1,3 -di oxoisoindolin-2-yl)-3 -fluorobenzonitrile (6.13 g, 21.2 mmol, 85% yield), as an off-white solid after drying in 92% purity: ^!H NMR (400 MHz, Chloroform -J) 6 8.00 (dd, J = 5.5, 3.1 Hz, 2H), 7.85 (dd, J= 5.5, 3.0 Hz, 2H), 7.74 - 7.45 (m, 3H). ¹⁹F NMR (376 MHz, Chloroform-t/) 6 -113.51.

[0061] A 40 mL vial was equipped with a stir bar and charged with 4-(l,3-dioxoisoindolin-2- yl)-3 -fluorobenzonitrile (2.0 g, 7.51 mmol) and an 8.2 molar (M) solution of anhydrous HC1 in ethanol (15 mL) and the reaction was heated to 35 °C and stirred overnight. After 19 hours, the reaction was a white suspension and the reaction was sampled by ¹⁹F NMR to confirm complete conversion had been achieved. The reaction was cooled to room temperature, and the solids were collected by filtration, washed with several mL of anhydrous EtOH, and dried in a 50 °C vacuum oven overnight to yield ethyl 4-(l,3-dioxoisoindolin-2-yl)-3-fluorobenzimidate hydrochloride as a white solid (2.38 g, 6.76 mmol, 91% yield): 'H NMR (400 MHz, CDC1₃) δ 8.61 - 8.50 (m, 1H), 8.32 - 8.22 (m, 1H), 8.06 - 7.93 (m, 2H), 7.90 - 7.80 (m, 2H), 7.71 - 7.58 (m, 1H), 5.00 (q, J= 7.0 Hz, 2H), 1.66 (t, J= 7.0 Hz, 3H; ¹⁹F NMR (376 MHz, Chloroform - ) 8 -113.35.

[0062] A jacketed reactor equipped with a stir rod, temperature probe, and nitrogen inlet was charged with ethyl 4-(l,3-dioxoisoindolin-2-yl)-3-fluorobenzimidate hydrochloride (3 g, 8.60 mmol) and pyridine (34.4 mL, 0.25 M). The mixture was cooled to 2 °C and (4- (trifluoromethoxy)phenyl)hydrazine hydrochloride (2.36 g, 10.3 mmol) was added and allowed to stir for 1 hour and then heated to 25 °C over 30 minutes and allowed to stir for an additional three hours. Triethyl orthoformate (2.15 mL, 12.9 mmol, 1.5 equivalents (equiv)) was then added and the reaction was heated to 100 °C and allowed to continue stirring overnight. The reaction was cooled to room temperature, diluted with water (30 mL), solids were collected by filtration, and washed with additional water to give a light yellow/off-white solid that was dried in a vacuum oven overnight, yielding the desired product, 2-(2-fluoro-4-(l-(4-

(trifluorom ethoxy )phenyl)- 1/7-1, 2, 4-triazole-3-yl)phenyl)isoindoline-l, 3-dione (3.88 g, 8.28 mmol, 96% yield): 'H NMR (400 MHz, Chloroform-t/) 8 8.60 (s, 1H), 8.17 - 8.08 (m, 2H), 8.00 (dd, J= 5.5, 3.1 Hz, 2H), 7.89 - 7.75 (m, 4H), 7.49 (t, J= 7.7 Hz, 1H), 7.46 - 7.35 (m, 2H). ¹⁹F NMR (376 MHz, Chloroform^) 8 -58.00, -117.73.

[0063] Into 500 mL 2-neck round bottom flask (RBF) equipped with a stir bar, thermocouple, and reflux condenser, 2-(2-fluoro-4-(l-(4-(trifluoromethoxy)phenyl)-l/f-l,2,4- triazol-3-yl)phenyl)isoindoline-l, 3-dione (5.0 g, 10.68 mmol), and EtOH (21.35 ml) were added and the flask was flushed with nitrogen gas (N2). In a separate flask, sodium hydroxide (NaOH, 5.12 g, 128 mmol) was dissolved in water (21.35 mL). The NaOH solution was added to the flask with the reaction and stirred at 84 °C for 23 hours. The reaction mass was cooled to room temperature and 100 mL of water was slowly added with stirring to induce precipitation of product. The solids were collected by filtration, washed with additional water, and dried in a vacuum oven (50 °C) overnight to yield 2-fluoro-4-(l-(4-(trifluorom ethoxy jphenyl)- 1H- 1,2,4- triazol-3-yl)aniline (X2) as a white solid (3.58 g, 10.56 mmol, 99% yield): ¹HNMR (400 MHz, Chloroform-d ) 8 8.51 (s, 1H), 7.89 - 7.69 (m, 4H), 7.47 - 7.33 (m, 2H), 6.85 (t, J= 8.6 Hz, 1H), 3.93 (br, 2H). ¹⁹F NMR (376 MHz, CDCI3) 8 -58.02, -135.33. ESIMS m/z 339.1 ([M+H]⁺). [0064] Example 2. Synthesis of 2-chloro-A^r-(5-methyl-2-((2, 2, 2- trifluoroethoxy)methyl)phenyl)acetamide (Y2).

Y2

[0065] A 5 liter (L) reactor was fit with a nitrogen inlet, vacuum port, condenser with collection flask, overhead stir rod, thermocouple, and pump feed tube. The reactor was charged with ///-toluidine (433.3 g) and //-heptane (1,621 g). The reactor was sparged with nitrogen for 20 minutes and brought to an internal temperature of 55 °C. A separate vessel was charged with di- //'/7-butyl di carbonate (BOC2O, 882.6 g) and //-heptane (214 g). The solution of B0C2C) was pumped into the reactor over a period of 180 minutes. After the addition of BOC2O was complete, the bottle and pump line were rinsed with //-heptane (41 g). After an additional 30 minutes, the temperature was set to 80 °C. Once the temperature had stabilized, the pressure in the reactor was reduced under vacuum to begin removing solvent via a series of distillation operations. After the bulk solvent was removed, //-heptane (825 g) was added to the reactor and a subsequent distillation operation was conducted to remove /-butyl alcohol (7-BuOH). After distillation, the reactor was rapidly cooled to an internal temperature of 35 °C and the solution was diluted to an approximate concentration of 25 w/w% product in //-heptane (1,327 g of additional //-heptane were added). The internal temperature was then adjusted to 2 °C. When the internal temperature reached ~30 °C, the crystallization was seeded (2.5 g product). After the temperature was held at 2 °C for 6 hours, the reactor was drained into a vacuum filter. The filtrate was used to rinse the reactor. The wet filter cake was dried under static vacuum and the collected solid was transferred to drying dishes. The solid was dried in a vacuum oven at 50 °C for 48 h. This afforded tert-butyl /w-tolylcarbamate (725 g of material less the 2.5 g seed weight = 722 g, 86%): 'H NMR (500 MHz, Chloroform-//) 5 7.25 (d, J = 2.7 Hz, 1H), 7.15 (t, J= 7.8 Hz, 1H), 7.09 (dd, J = 8.0, 2.2 Hz, 1H), 6.84 (d, J= 7.4 Hz, 1H), 6.49 (s, 1H), 2.31 (s, 3H), 1.51 (s, 9H). ¹³C NMR (126 MHz, Chloroform-//) 5 152.85, 138.90, 138.30, 128.78, 123.84, 119.18, 115.64, 80.40, 28.38, 21.53. LRMS (ESI-quad): [M+H-^rBu] calculated for C₈HioN0₂ ⁺, 152.1; found, 152.0. [0066] A 1 L reactor was equipped with nitrogen inlet, mechanical stirrer, thermocouple, and septa, and sealed under a positive pressure of nitrogen. The vessel was charged with sec-butyl lithium (260 mL, 1.4 M in cyclohexane, 364 mmol, 2.5 equiv). Mechanical stirring was set to 300 revolutions per minute (rpm). The vessel was cooled to an internal temperature of -28 °C. A solution of the substrate was prepared by charging a 250 mL flask with tert-butyl m- tolylcarbamate (30 g, 144.6 mmol), which was then dissolved into THF (15 mL, 184.5 mmol, 1.275 equiv) and tetramethylethylenediamine (TMEDA, 22 mL 144.6 mmol, 1.0 equiv). The solution of substrate was added dropwise to the reactor over 30 minutes. The internal temperature was maintained below -20 °C over the course of the addition. After an additional 60 minutes, DMF (23 mL, 289 mmol, 2 equiv) was added dropwise over 15 minutes. The internal temperature was maintained below -20 °C over the course of the addition. The reaction was quenched with 150 mL of water and the phases were separated. The organic layer was washed with another 100 mL of water and the phases were separated. The organic phase was distilled under vacuum to remove cyclohexane. Isopropyl alcohol was added and the mixture was distilled to remove residual cyclohexane and afford a solution of tert-butyl (2-formyl-5- methylphenyl)carbamate (-140 mmol) in 150 mL of IPA.

[0067] A 250 mL cylindrical jacketed reactor containing -140 mmol of tert-butyl (2-formyl- 5-methylphenyl)carbamate in 150 mL of IPA was cooled to -10 °C. To the reaction was added 2.8 g of solid sodium borohydride (NaBHf). The reaction mass was then heated to an external set temperature to 20 °C. After monitoring by HPLC, the reaction was quenched with 24 mL acetic acid (AcOH) and 50 mL water. The reaction mass was stirred for 5 minutes and then 80 mL of toluene were added. To the reaction mass was added more water (20 mL) and the layers were separated. The organic layer was distilled and 60 mL of toluene were added to afford a solution of tert-butyl (2-(hydroxymethyl)-5-methylphenyl)carbamate (-140 mmol) in 150 mL of toluene. [0068] A 250 mL jacketed reactor containing tert-butyl (2-(hydroxymethyl)-5- methylphenyl)carbamate (-140 mmol) in toluene (150 mL) was agitated. 120 mL of 45 wt% potassium hydroxide (KOH) solution was added. The reaction was heated at 95 °C overnight. After stirring overnight, the reaction mass was cooled to 75 °C and then slowly cooled to -8 °C. The solids were collected via vacuum filtration and washed with toluene (100-125 mL) to produce (2-amino-4-methylphenyl)methanol as an off-white solid (11.4 g, 57% yield over three steps) upon drying overnight in a vacuum oven: 'H NMR (500 MHz, DMSO-de) 5 6.90 (d, J = 7.5 Hz, 1H), 6.43 (d, J= 1.7 Hz, 1H), 6.32 (dd, J= 7.5, 1.7 Hz, 1H), 4.91 (d, J= 4.6 Hz, 1H), 4.81 (s, 2H), 4.33 (d, J= 4.1 Hz, 2H), 2.14 (s, 3H). ¹³C NMR (126 MHz, DMSO-<A) 5 146.77, 137.06, 128.37, 123.13, 117.09, 115.68, 61.55, 21.42. LRMS (ESI-quad): [M-OH] calculated for C₈HION⁺, 120.1; found, 120.0.

[0069] Methanesulfonic acid (11.83 mL, 182 mmol) was added to (2-amino-4- methylphenyl)methanol (5 g, 36.4 mmol) in trifluoroethanol (65 mL) at 40 °C. The reaction was stirred at 40 °C for 24 hours to afford the methanesulfonic acid salt of 5-methyl-2-((2,2,2- tri fluoroethoxy )methyl)aniline.

[0070] The reaction mixture was then cooled to room temperature (rt) and transferred to a 500 mL flask and concentrated on a rotary evaporator. Isopropyl acetate (zPrOAc, 109 mL) was added, and the reaction mixture was cooled in an ice bath. Chloroacetyl chloride (4.09 mL, 51.0 mmol) was then added dropwise followed by the dropwise addition of aqueous (aq) 2 normal (N) sodium hydroxide (120 mL, 241 mmol). The reaction was allowed to stir in the ice bath for ~15 minutes while checking HPLC. The layers were separated. The organic layer was washed with saturated sodium bicarbonate (NaHCCL, 100 mL). The reaction mixture was concentrated to ~50 wt% solution and heptane was added to make ~1:4 w/w zPrOAc/heptane solution at ~5 wt%. The mixture was seeded at rt, cool to 0 °C for 2 hours and filtered. The wet cake was washed with heptane to afford desired product (Y2) as an off-white solid (8.71 g, 81% yield) upon drying: 'H NMR (400 MHz, Chloroform^) 6 9.16 (s, 1H), 7.94 (s, 1H), 7.12 (d, J= 7.7 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 4.70 (s, 2H), 4.20 (s, 2H), 3.84 (q, J= 8.6 Hz, 2H), 2.38 (s, 3H). ¹⁹F NMR (376 MHz, Chloroform-t/) 5 -73.57.

[0071] Example 3: Synthesis of 2-imino-3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b)

Y2b

[0072] Example 3a: A round bottom flask equipped with a magnetic stir bar, nitrogen inlet, and reflux condenser was charged with Y2 (7 g, 23.7 mmol, 1 equiv), potassium thiocyanate (KSCN, 4.6 g, 47.3 mmol, 2 equiv), and ethyl acetate (EtOAc, 35 mL, 5 V). The reaction mixture was heated at 55 °C for 2 hours. Cesium carbonate (CS2CO3, 0.37 g, 1.18 mmol, 0.05 equiv) was then added, and the reaction continued to stir at 55 °C for 1 hour or until complete conversion was observed. Water (50 mL) was added, and the layers were separated. The organic layer was washed with 10% sodium chloride (NaCl, 30 mL) and concentrated. The remaining ethyl acetate was replaced with hexanes by adding hexanes (2 x 50 mL) and concentrating. Hexanes (50 mL) was added, and the mixture was stirred at rt overnight. The solids were filtered and dried to give Y2b as a tan solid (7.34 g, 97% yield). NMR (400 MHz, ChloroformW) 6 7.40 (d, J= 7.8 Hz, 1H), 7.30 (d, J= 7.8 Hz, 1H), 7.04 (d, J= 1.8 Hz, 1H), 4.61 (d, J= 12.6 Hz, 1H), 4.49 (d, J= 12.5 Hz, 1H), 4.06 (d, J= 3.7 Hz, 2H), 3.70 (qd, J= 8.7, 1.9 Hz, 2H), 2.40 (s, 3H); ¹⁹F NMR (376 MHz, Chloroform- 8 -73.78; ESIMS mlz 319 ([M+H]⁺).

[0073] Example 3b: A round bottom flask equipped with a magnetic stir bar, nitrogen inlet, and reflux condenser was charged with Y2 (3 g, 10.2 mmol, 1 equiv), KSCN (1.97 g, 20.3 mmol, 2 equiv), and EtOAc (15 mL, 5 V). The reaction mixture was heated at 60 °C for 16 hours. Potassium carbonate (K2CO3, 70 mg, 0.51 mmol, 0.05 equiv) was then added, and the reaction continued to stir at 60 °C for 40 minutes or until complete conversion was observed. The reaction mixture was washed with water and aq NaCl and concentrated. The remaining ethyl acetate was replaced with hexanes by adding heptane (2 x 25 mL) and concentrating. Heptane (25 mL) was added, and the mixture was stirred at rt overnight. The solids were filtered and dried to give Y2b as a tan solid (2.97 g, 92% yield, still containing heptane by 'H NMR): Analytical data matched that from above.

[0074] Example 3c: A reactor equipped with stirring capability and nitrogen inlet was charged with EtOAc (53.9 g), Y2 (12.2 g, 98 wt% purity, 40.4 mmol, 1 equiv) and KSCN (4.39 g, 98.5 wt% purity, 45 mmol). Potassium bicarbonate (202 mg, 2 mmol) was added, and the reaction mixture was heated at 60 °C overnight. The reaction mixture was cooled and was washed sequentially with water (75 g) and 10% aq NaCl (80 g). The organic layer was concentrated and then heptane (8.6 g) was added over 30 minutes. The mixture was seeded with Y2b (0.17 g) and stirred for 3 hours. Heptane (8.1 g) was added, and the mixture was stirred overnight. Two additional portions of heptane (16.8 g, 7.4 g) were added sequentially. The mixture was filtered and was washed with heptane (23.2 g) and dried to give Y2b as a tan solid (10.6 g, 82% yield): Analytical data matched that from above. [0075] Example 3 d: A solution containing Y2 (81.6 g, 276 mmol) in n-BuOAc (405 g) was charged into a reactor. Potassium thiocyanate (32.3 g, 1.2 equiv, 332 mmol) was added followed by potassium bicarbonate (1.38 g, 0.05 equiv, 13.8 mmol). The reaction mixture was warmed to 60 °C, stirred under a nitrogen atmosphere and monitored by HPLC analysis. After 20 h, the mixture was cooled to RT. To the reaction mixture was added water (324 g) and the layers were separated. The organic layer was then washed with 10% brine (243 g), concentrated and heated to 60 °C. The mixture was crystallized by adding heptane (575 g) and cooling to 10 °C. The mixture was filtered and the wetcake was washed with heptane (162 g). The solids were dried to yield Y2b-Form A (78.0 g, 245 mmol, 83.5% yield, 93 wt% purity). Analytical data matched that from above and PXRD matched that of Form A.

[0076] Example 3e: A vial with stir bar was charged with 2 g of Y2b and 15 g de-ionized water to produce a slurry. The slurry was agitated vigorously on a stir plate for 5 hours. The slurry was filtered to isolate the solids and PXRD analysis of the wetcake matched the pattern corresponding to Form B.

[0077] Example 3f: A vial equipped with a magnetic stir bar was charged with compound Y2 (0.50 g, 1.7 mmol, 1 equiv), sodium thiocyanate (0.19 g, 2.4 mmol, 1.4 equiv), potassium carbonate (12 mg, 0.85 mmol, 0.05 equiv), and EtOAc (2.5 mL). The reaction was heated at 60 °C for 17 hr. The reaction was cooled to rt and then washed with water (2.5 mL). The layers were separated, and the organic layer was washed with brine (2.5 mL). Yield of Y2b was determined by HPLC using benzamide as an internal standard (86% yield). Analytical data matched that from above.

[0078] Example 4: Synthesis of (Z)-l-(2-fluoro-4-(l-(4-(trifluoromethoxy)phenyl)-17/-l,2,4- tri azol -3-yl)phenyl)-3-(3-(5-methyl-2-((2, 2, 2-tri fluoroethoxy )methyl)phenyl)-4-oxothi azolidin-2- ylidene)urea (Zl)

Z1

[0079] Example 4a: A round bottom flask equipped with a magnetic stir bar, nitrogen inlet, and reflux condenser was charged with 2-chloro-A-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)acetamide (Y2, 1.5 g, 5.1 mmol, 1 equiv), KSCN (0.69 g, 7.1 mmol, 1.4 equiv), K2CO3 (35 mg, 0.25 mmol, 0.05 equiv), and EtOAc (7.5 mL, 5 V). The reaction mixture was heated at 60 °C for 19 hours. The reaction mixture was washed with water (10 mL) and 10% NaCl (10 mL). Solvent exchange from EtOAc to acetonitrile (MeCN) provided 2-imino-3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b) as a 35.9 wt% solution in MeCN (96% yield). The MeCN solution of 2-imino-3-(5-methyl-2- ((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b) was used directly in the final coupling step.

[0080] A flask equipped with a nitrogen inlet and mechanical stirrer was charged with 2- fluoro-4-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)aniline (X2, 677 mg, 1 equiv, 2.00 mmol), di(l/Al,2,4-triazol-l-yl)methanone (383 mg, 90% Wt, 1.05 equiv, 2.10 mmol) and acetonitrile (12.0 mL) and stirred at 29-30 °C overnight. 2-Imino-3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b, 1.95 g, 35.9% Wt, 1.1 equiv, 2.20 mmol) in MeCN was added to the reaction mixture, then heated at 40 °C overnight. After the reaction was complete as judged by HPLC analysis, the reaction mixture was cooled to rt, then 15 mL of water were added. The suspension was stirred overnight at rt. After filtration, the cake was washed with 15 mL of MeCN-water (1:2), water (10 mL) and MeOH (3 mL). The cake was dried in an oven at 50 °C under vacuum to afford the product, (Z)-l-(2-fluoro-4-(l-(4- (trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)phenyl)-3-(3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)-4-oxothiazolidin-2-ylidene)urea (Zl, 1.27 g, 1.86 mmol, 93.0% yield): ^NMR (400 MHz, Chloroform-6/) 8 8.53 (s, 1H), 8.47 (t, J= 8.4 Hz, 1H), 7.96 (dd, J= 8.6, 1.8 Hz, 1H), 7.88 (dd, <7= 12.0, 1.9 Hz, 1H), 7.86 - 7.73 (m, 2H), 7.49 (d, J= 3.1 Hz, 1H), 7.45 - 7.29 (m, 4H), 7.04 (d, ./ = 1.8 Hz, 1H), 4.62 (d, J= 12.4 Hz, 1H), 4.50 (d, J= 12.4 Hz, 1H), 3.95 (d, J= 2.7 Hz, 2H), 3.83 - 3.59 (m, 2H), 2.44 (s, 3H). ¹⁹F NMR (376 MHz, Chloroform-^/) 5 58.02, -73.78, -131.31.

[0081] Example 4b: A reactor was charged with 2-chloro-A-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)acetamide (Y2, 10.5 g, 95% purity, 33.8 mmol), KSCN (4.67 g, 50 mmol, 1.4 equiv), K2CO3 (233 mg, 2 mmol, 0.05 equiv), and EtOAc (45.3 g). The reaction mixture was heated at 60 °C for 24 hours. The reaction mixture was cooled to room temperature and washed with water (62 g). The layers were separated, and the organic layer was washed with a 10% aqueous solution of NaCl (67 g). Solvent exchange from EtOAc to toluene provided 2- imino-3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b) as a 11.6 wt% solution in toluene (87.8 g, 95% yield). The toluene solution of 2-imino-3-(5-methyl-2- ((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b) was used directly in the final coupling step.

[0082] A separate reactor was charged with toluene (158 g) and 15 wt% phosgene in toluene (44.4 g, 67.4 mmol). A solution containing 2-fluoro-4-(l-(4-(trifluoromethoxy)phenyl)-l//- 1,2,4- triazol-3-yl)aniline (X2) in toluene (167 g, 5.46 wt% solution, 26.9 mmol) was added over ~20 minutes at rt to the reactor containing the phosgene solution. This mixture was stirred for 60 minutes. Tri ethylamine (6.8 g, 67 mmol) was added, and the mixture was stirred at rt. Upon complete consumption of starting material, the reactor was heated to 40-45 °C and phosgene/toluene were removed by distillation. The reaction mixture was then cooled to rt and the previously prepared solution of 2-imino-3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b) in toluene (87.8 g, 11.6 wt%) was added over ~10 minutes at rt. This reaction mixture was stirred for 60 minutes. The reaction mixture was quenched with water (100 g) and the mixture was stirred for 2 hours. The mixture was filtered, and the mother liquor phases were separated. The organic layer was washed with an aqueous solution of 1 N HC1 (100 g) and the resulting biphasic mixture was filtered. The mother liquor phases were separated, and the organic layer was concentrated in-vacuo. Methanol (100 g) was added, and the reaction mixture was cooled to 10 °C. The mixture was filtered and washed with methanol (20 g) followed by water (14.6 g). The isolated solid was dried in a vacuum oven (55-60 °C, 100-250 Torr) to afford the title compound (Zl) as a pale brown solid (14.6 g, 97 wt% purity, 77% yield): Analytical data matched that from above.

[0083] Example 4c: A jacketed reactor equipped with a nitrogen inlet, reflux condenser, temperature probe, and overhead stirrer was charged with 2-fluoro-4-(l-(4-

(trifluorom ethoxy )phenyl)- l/7- l, 2, 4-triazol-3-yl)aniline (X2, 2 g, 5.91 mmol) in tetrahydrofuran (59 mL). The mixture was heated to 50 °C and then 4-nitrophenyl chloroformate (1.311 g, 6.50 mmol, 1.1 equiv) was added in one portion and the reaction was stirred at 50 °C overnight. After stirring at 50 °C for 16 hours, full conversion was observed based on HPLC analysis.

Triethylamine (0.907 mL, 6.50 mmol, 1.1 equiv) was added to the reaction and immediately after 2-imino-3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one Y2b (2.070 g, 6.50 mmol) was added in one portion. After an additional 1 hour, full conversion was observed based on HPLC analysis. The reaction was concentrated under reduced pressure, dissolved in EtOAc (50 mL), and washed with a solution of 20% potassium carbonate (50 mL). The organic layer was collected, dried over sodium sulfate, filtered and concentrated to give a red/brown crude solid. The crude mixture was purified through precipitation, adding 10 mL of EtOAc and heating the mixture to 70 °C to dissolve the crude solid, adding heptane (30 mL) to precipitate out the product and then slowly letting the suspension cool to room temperature with stirring overnight. The product was isolated by cooling the mixture in an ice-water bath to 0-5 °C with stirring for 30 minutes and collecting the solids by filtration and washing with additional cold solvent (10 mL x 2, 3: 1 heptane/EtOAc). The desired product (Zl) was isolated as an off-white solid that was dried (3.61 g, 5.29 mmol, 89% yield): 'H NMR (400 MHz, Chloroform-t/) 6 8.53 (s, 1H), 8.47 (t, 8.4 Hz, 1H), 7.96 (dd, J= 8.6, 1.8 Hz, 1H), 7.88 (dd, J = 12.0, 1.9 Hz, 1H),

7.86 - 7.73 (m, 2H), 7.49 (d, J = 3.1 Hz, 1H), 7.45 - 7.29 (m, 4H), 7.04 (d, J= 1.8 Hz, 1H), 4.62 (d, J= 12.4 Hz, 1H), 4.50 (d, J= 12.4 Hz, 1H), 3.95 (d, J= 2.7 Hz, 2H), 3.83 - 3.59 (m, 2H), 2.44 (s, 3H). ¹⁹F NMR (376 MHZ, Chloroform-t/) 5 58.02, -73.78, -131.31.

[0084] Example 4d: A flask equipped with a nitrogen inlet and stir bar was charged with 2- fluoro-4-(l-(4-(trifluoromethoxy)phenyl)-l#-l,2,4-triazol-3-yl)aniline (X2, 0.25 g, 0.739 mmol) and THF (7.39 mL). Phenyl chloroformate (0.10 mL, 0.81 mmol) was added to the reaction mixture in one portion and the reaction was heated to 50 °C in a heating block and stirred overnight. After 21 hours, full conversion was observed. The reaction was cooled to 30 °C, and triethylamine (0.113 mL, 0.813 mmol) was added to the reaction, stirred for 30 seconds to give a thin, brown solution. 2-Imino-3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin- 4-one (Y2b, 0.259 g, 0,813 mmol) was added, and the mixture was heated to 50 °C and stirred. After 41 hours high conversion was observed and the reaction was cooled to 35 °C and diluted with water (10 mL). The mixture was cooled to 0-5 °C in an ice/water bath to give a purple suspension. The suspension was filtered through a fritted glass funnel, and the solids were washed with cold water (10 mL) and collected to give a purple solid that was dried in a vacuum oven to give a light brown solid as the desired product (Zl, 0.490 g, 89% purity, 0.639 mmol, 86% yield). Analytical data matched that from above.

[0085] Example 4e: A flask equipped with a nitrogen inlet and mechanical stir was charged with 2-fluoro-4-(l-(4-(trifluoromethoxy)phenyl)-17/-l,2,4-triazol-3-yl)aniline (X2, 3.38 g, 10 mmol), di(l#-l,2,4-triazol-l-yl)methanone (2.13 g, 13 mmol) and MeCN (60 mL). The reaction mixture was stirred at 28-30 °C overnight. After the reaction was complete as judged by HPLC analysis, the reaction mixture was filtered and washed with additional MeCN, then dried over air to give the active intermediateA-(2-fluoro-4-(l-(4-(trifluoromethoxy)phenyl)-l#-l,2,4-triazol-3- yl)phenyl)- TH- 1, 2, 4-triazole-l -carboxamide (4.19 g, 9.67 mmol, 97% yield): 'H NMR. (400 MHz, Chloroform-t/) 8 9.20 (d, J= 3.0 Hz, 1H), 8.99 (s, 1H), 8.58 (s, 1H), 8.39 (t, J= 8.2 Hz, 1H), 8.14 - 7.97 (m, 3H), 7.87 - 7.74 (m, 2H), 7.47 - 7.35 (m, 2H). ¹⁹F NMR (376 MHz, Chloroform -J) 6 -57.96, -57.97, -58.07, -58.12, -129.87, -129.98, -129.99, -130,01, -130,03, - 130.07, -130.38. MS/ES+: 434.2 (M+l).

[0086] The isolated intermediate above (4.19 g, 9.67 mmol) was added to the solution of 2- imino-3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b, 3.50 g, 10 mmol) in MeCN (60 mL) at rt, then heated to 38-40 °C. After the reaction was complete as judged by HPLC analysis, the reaction mixture was cooled to 25 °C and diluted with water (70 mL). The mixture was stirred for 3-4 hours at rt. The suspension was filtered through a fritted glass funnel and the solids were washed with pre-mixed MeCN (10 mL)-water (20 mL) and water (10 mL). A solid was collected and dried in a vacuum oven at 45 °C to give a light brown solid as the desired product (Zl, 6.48 g, >98% purity, 9.49 mmol, 95% yield overall in two steps): Analytical data matched that from above. [0087] Example 4f: A 3 -neck round-bottom flask equipped with a nitrogen inlet, temperature probe and stir bar was charged with 2-fluoro-4-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol- 3-yl)aniline (X2, 1.0 g, 2,96 mmol) and EtOAc (14.8 mL) that was cooled to 0-5 °C in an ice/water bath. A solution of HC1 (4 M in dioxane, 0.96 mL, 3.84 mmol) was then added and the mixture was stirred for 30 minutes. Oxalyl chloride (0.34 mL, 3.84 mmol) was then added dropwise over 1 minute, keeping the temperature below 10 °C. After two hours, 1,2- di chlorobenzene (5 mL) was added to the reaction and then it was heated to 150 °C in a heating block to reach an internal temperature of 130-135 °C. After 4.5 hours, the reaction was cooled to 40-50 °C, 2-imino-3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b, 1.04 g, 3.25 mmol) was added, and the mixture was cooled to room temperature. After six hours, the reaction was diluted with dichloromethane (DCM, 20 mL), an internal standard was added, and the reaction was analyzed to give an assay yield of 18%.

[0088] Example 4g: A vial equipped with a nitrogen inlet and stir bar was charged with 2- fluoro-4-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)aniline (X2, 4 g, 11.8 mmol) and potassium fert-butoxide (1.59 g, 14.2 mmol). Dimethyl carbonate (29.9 mL, 355 mmol) was then added, and the reaction was stirred and placed in a heating block set to 105 °C. After 15 minutes, the mixture was cooled to room temperature. The reaction mixture was sampled and showed high conversion by HPLC. The reaction was diluted with water (10 mL) and poured into additional water (150 mL) to give a biphasic mixture. The mixture was extracted with EtOAc (200 mL), and the organic layer was collected and washed with water (50 mL x2), dried over sodium sulfate, filtered and concentrated to give a solid that was dried on house vacuum. The material was isolated as an off-white solid as the desired product, methyl (2-fluoro-4-(l-(4- (trifluorom ethoxy )phenyl)- 1/7-1, 2, 4-triazol-3-yl)phenyl)carbamate (4.5 g, 11.4 mmol, 96% yield): 'H NMR (400 MHz, Chloroform -J) 6 8.55 (s, 1H), 8.23 (s, 1H), 8.01 - 7.95 (m, 1H), 7.91 (dd, J= 12.0, 1.9 Hz, 1H), 7.83 - 7.75 (m, 2H), 7.39 (d, J= 8.5 Hz, 2H), 6.96 (br, 1H), 3.83 (s, 3H). ¹⁹E NMR (376 MHz, Chloroform-c/) 6 -58.02, -132.40. LCMS/UPLC-MS (ESIMS) m/z 397.2 ([M+H]⁺).

[0089] A vial equipped with a nitrogen inlet, reflux condenser and stir bar was charged with methyl (2-fluoro-4-(l-(4-(trifluoromethoxy)phenyl)-17/-l,2,4-triazol-3-yl)phenyl)carbamate (1 g, 2.52 mmol), triethylamine (0.39 mL, 2.78 mmol) and toluene (10 mL) and the mixture was placed in a heating block that was heated to 105 °C. Then, boron trichloride (1 M in />-xylene) (0.93 mL, 0.93 mmol) was added in one portion and the mixture was stirred. After 15 minutes 2- imino-3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b, 0.88 g, 2.78 mmol) was added in one portion and stirred. After a combined 30 minutes, the reaction was cooled to 50 °C and quenched with water (5 mL). The reaction was cooled to room temperature and transferred to a separatory funnel with EtOAc (10 mL) and water (10 mL). The organic layer was collected, dried over sodium sulfate, filtered and concentrated to give a mixture as the desired product (Zl), (Z)-l-(2-fhioro-4-(l-(4-(trifluoromethoxy)phenyl)-lZ/-l,2,4-triazol-3- yl)phenyl)-3-(3-(5-methyl-2-((2, 2, 2-tri fluoroethoxy )methyl)phenyl)-4-oxothiazolidin-2- ylidene)urea (1.72 g, 84% purity, 2.12 mmol, 84% yield): Analytical data matched.

[0090] Example 4h: A vial equipped with a stir bar and nitrogen inlet was charged with 2- fluoro-4-(l-(4-(trifluoromethoxy)phenyl)-l/7-l,2,4-triazol-3-yl)aniline (X2, 1 g, 2.3 mmol), pyridine (0.29 ml, 3.6 mmol) and DCM (10 mL). The mixture was cooled to 0-5 °C in an ice/water bath. Ethyl chloroformate (0.31 mL, 3.3 mmol) was then added to the reaction in one portion and the reaction was allowed to stir in the ice bath and slowly warm to room temperature overnight. After stirring overnight, the reaction mixture was transferred to a separatory funnel with DCM (15 mL), water (10 mL) and a saturated solution of sodium bicarbonate (5 mL). The organic layer was collected, dried over sodium sulfate, filtered, concentrated under reduced pressure and placed under vacuum to dry overnight. The mixture was purified by column chromatography (gradient from 0-75% EtOAc/hexanes), affording the desired product as a white solid, ethyl (2-fluoro-4-(l-(4-(trifluorom ethoxy )phenyl)- 1/7-1, 2, 4-triazol-3-yl)phenyl)carbamate (1.05 g 2.56 mmol, 87% yield): ^XH NMR (400 MHz, Chloroform- 8 8.55 (s, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.01 - 7.94 (m, 1H), 7.91 (dd, J= 12.0, 1.9 Hz, 1H), 7.83 - 7.75 (m, 2H), 7.39 (d, J = 8.7 Hz, 2H), 6.95 (br, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). ¹⁹F NMR (376 MHz, Chloroform-^/) 8 -58.02, -132.50. GCMS (EIMS) m/z 364.1.

[0091] A vial equipped with a nitrogen inlet, reflux condenser and stir bar was charged with ethyl (2-fluoro-4-(l-(4-(trifluoromethoxy)phenyl)-l//-l,2,4-triazol-3-yl)phenyl)carbamate (75 mg, 0.18 mmol), triethylamine (28 pL, 0.201 mmol) and toluene (0.73 mL) and the mixture was placed in a heating block set to 105 °C. Then, boron trichloride (1 M in j»-xylene) (67.6 pL, 0.068 mmol) was added in one portion and the mixture was stirred. After 1 hour, 2-imino-3-(5- methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b, 64 mg, 0.201 mmol) was added in one portion. After a combined 1 hour and 30 minutes, the reaction was cooled to room temperature, an internal standard was added, and the reaction was analyzed to give an assay yield of 60%.

[0092] Example 4i: A reactor was charged with 2-chloro-A-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)acetamide (Y2, 51.2 g, 98% purity, 170 mmol), KSCN (18.4 g, 190 mmol, 1.1 equiv), potassium bicarbonate (KHCO3, 846 mg, 8 mmol, 0.05 equiv), and EtOAc (226.4 g). The reaction mixture was heated at 60 °C for 15 hours. The reaction mixture was cooled to rt and washed with water (314 g). The layers were separated, and the organic layer was washed with a 10% aqueous solution of NaCl (336 g). Solvent exchange from EtOAc to toluene provided 2-imino-3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b) as a 11.6 wt% solution in toluene (441 g, 95% yield). The toluene solution of 2-imino-3-(5- methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b) was used directly in the final coupling step.

[0093] A separate reactor was charged with toluene (214 g) and 15 wt% phosgene in toluene (60.3 g, 91.5 mmol). A solution containing 2-fluoro-4-(l-(4-(trifluoromethoxy)phenyl)- \H- 1,2,4- triazol-3-yl)aniline (X2) in toluene (227 g, 5.5 wt% solution, 36.5 mmol) was added at rt to the reactor containing the phosgene solution. This mixture was stirred for 60 minutes. Triethylamine (9.3 g, 91 mmol) was added, and the mixture was stirred at rt. Upon complete consumption of starting material, the reactor was heated to 40-45 °C and phosgene/toluene were removed by distillation. The reaction mixture was then cooled to rt and a portion of the previously prepared solution of 2-imino-3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b) in toluene (105 g, 11.6 wt%) was added at rt. This reaction mixture was stirred for 120 minutes.

[0094] The reaction mixture was quenched with water (136 g) and the mixture was stirred and degassed for 2 hours. The mixture was heated to 65-70 °C and the layers were separated. The organic layer was washed with an aqueous solution of 1 N HC1 (136 g) and the resulting biphasic mixture was separated. The organic layer was concentrated m-vacuo Heptane (137 g) was added, and the reaction mixture was cooled to 0 °C. The mixture was filtered and washed with heptane (35 g) followed by water (56 g). The isolated solid was dried in a vacuum oven to afford the title compound (Zl) as a brown solid (22.4 g, 98 wt% purity, 88% yield): Analytical data matched that from above.

[0095] Example 4j : A reactor was charged with 2-chloro-A-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)acetamide (Y2, 12.2 g, 98% purity, 40.4 mmol), KSCN (4.4 g, 45 mmol, 1.1 equiv), potassium bicarbonate (202 mg, 2 mmol, 0.05 equiv), and EtOAc (54.0 g).

The reaction mixture was heated at 60 °C for 15 hours. The reaction mixture was cooled to rt and washed with water (75 g). The layers were separated, and the organic layer was washed with a 10% aqueous solution of NaCl (80 g). Solvent exchange from EtOAc to toluene provided 2- imino-3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b) as a 11.6 wt% solution in toluene (105 g, 95% yield). The toluene solution of 2-imino-3-(5-methyl-2- ((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b) was used directly in the final coupling step.

[0096] A separate reactor was charged with toluene (214 g) and a 15 wt% solution of triphosgene in toluene (57.9 g, 29.3 mmol). A solution containing 2-fluoro-4-(l-(4- (trifluorom ethoxy )phenyl)- 1/7-1, 2, 4-triazol-3-yl)aniline (X2) in toluene (227 g, 5.5 wt% solution, 36.5 mmol) was added at rt to the reactor containing the triphosgene solution. This mixture was stirred for 60 minutes. Triethylamine (9.3 g, 91 mmol) was added, and the mixture was stirred at rt. Upon complete consumption of starting material, the reactor was heated to 40- 45 °C and volatiles were removed by distillation. The reaction mixture was then cooled to rt and the previously prepared solution of 2-imino-3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b) in toluene (105 g, 11.6 wt%) was added at rt. This reaction mixture was stirred for 120 minutes.

[0097] The reaction mixture was quenched with water (136 g) and the mixture was stirred and degassed for 2 hours. The mixture was heated to 65-70 °C and the layers were separated. The organic layer was washed with an aqueous solution of 1 N HC1 (136 g) and the resulting biphasic mixture was separated. The organic layer was concentrated in-vacuo. Heptane (137 g) was added, and the reaction mixture was cooled to 0 °C. The mixture was filtered and washed with heptane (35 g) followed by water (56 g). The isolated solid was dried in a vacuum oven to afford the title compound (Zl) as a brown solid (22.3 g, 97 wt% purity, 87% yield): Analytical data matched that from above.

[0098] Example 4k: A 3 -neck flask equipped with a nitrogen inlet, overhead stirrer and temperature probe was charged with 2-fluoro-4-( l-(4-(trifluorom ethoxy Jphenyl )-!//- 1,2,4- triazol-3-yl)aniline (10.1 g, 29.8 mmol) and DCM (305 mL). Pyridine (2.9 mL, 35.8 mmol) and bis(2,5-dioxopyrrolidin-l-yl) carbonate (9.17 g, 1.2 equiv, 35.8 mmol) were added and the reaction was stirred for 30 minutes at room temperature. 2-Imino-3-(5-methyl-2-((2,2,2- trilfuoroethoxy)methyl)phenyl)thiazolidin-4-one (10 g, 29.8 mmol) was added, followed by addition of sodium bicarbonate (20.1 g, 239 mmol) and deionized water (305 mL) and the mixture was stirred and slowly converted from a brown suspension to a brown biphasic mixture. After four hours full conversion of the intermediate was observed, and the reaction was transferred to a separatory funnel. The organic layer was collected, and the aqueous layer was extracted with DCM (50 mL x 4). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid as crude that was purified by flash column chromatography (gradient from 0-60% EtOAc/hexanes) to give the desired product as a light yellow solid (17.5 g, 90% purity, 23.07 mmol, 77% yield): Analytical data matched that from above.

[0099] Example 41: To a jacketed reactor was added 2-imino-3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b, 6.1 g, 18.21 mmol), carbonyl diimidazole (CDI, 3.04 g, 18.21 mmol) and acetonitrile (80 mL). The red solution was cooled to 10 °C. To the solution was added methanesulfonic acid (3.50 g, 36.4 mmol) slowly in a dropwise manner. It was exothermic. It took 13 minutes to finish the addition in order to keep the temperature <20 °C. The mixture was heated to 20 °C and stirred for 30 minutes. The 2-fluoro-4-(l-(4- (trifluorom ethoxy jphenyl)- 1/7-1, 2, 4-triazol-3-yl)aniline (X2, 6.48 g, 18.21 mmol) was added last in one portion. It was endothermic. The temperature dropped to 16.6 °C. The reaction mixture was a dark brown suspension. It was stirred at 50 °C for 18 hours and 80 °C for 23 hours. The suspension was filtered and the solid was washed with acetonitrile (2 x 15 mL). The filtrate was concentrated to a volume of ~70 mL. While the red dark solution was stirred at 600 rpm, water was added (40 mL) dropwise resulting in the formation of solids. The mixture was stirred at 20 °C for 18 hours. The product was isolated by vacuum filtration, washed with water and dried to give the title compound (Zl) as a light tan solid (8.94 g, 72% yield): Analytical data matched that from above.

[00100] Example 4m: To a jacketed reactor were added 2-imino-3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (Y2b, 6.4 g, 19.11 mmol), N, N’ -carbonyl -di- (1,2,4-triazole) CDT (3 g, 18.2 mmol) and acetonitrile (60 mL). After 1 hour, a solution of methanesulfonic acid (3.85 g, 40.0 mmol) in acetonitrile (10 mL) was added slowly in a dropwise manner. It took 12 minutes to finish the addition in order to keep the temperature <30 °C. The mixture was stirred for 1 hour, and then 2-fhioro-4-(l-(4-(trifluoromethoxy)phenyl)-lZ/-

I,2,4-triazol-3-yl)aniline (X2, 6.48 g, 18.2 mmol) was added in one portion. The reaction mixture was stirred at 80 °C for 3 hours and then cooled down to 20 °C. The suspension was filtered and the solid was washed with acetonitrile (2 x 10 mL). The filtrate solution was concentrated to ~ 30 mL, transferred to a RBF, washed with acetonitrile (10 mL) and stirred at 700 rpm. Water (40 mL) was added in a dropwise manner and the resulting mixture was stirred for 4 hours. The mixture was filtered and the solid was washed with water (3 : 1 water-MeCN, 2 x 20 mL). UPLC analysis showed the solid had X2 left (12%). The solid was put back into the filtrate, and more acetonitrile was added (40 mL) to give a ratio of MeCN-water (90:70). The mixture was stirred 4 days at room temperature. The product was isolated by vacuum filtration, washed with water and dried to give the title compound (Zl) as a light tan solid (11.61 g, 85% yield, 92% purity): Analytical data matched that from above.

[00101] Example 4n: A reactor was charged with toluene (257 g) and 15 wt% phosgene in toluene (43.4 g, 65.9 mmol). A solution containing 2-fluoro-4-(l-(4-(trifluoromethoxy)phenyl)- 17/-l,2,4-triazol-3-yl)aniline (X2) in toluene (272 g, 5.5 wt% solution, 43.9 mmol) was added at 25-30 °C to the reactor containing the phosgene solution. This mixture was stirred for 60 minutes. Triethylamine (11.1 g, 110 mmol) was added, and the mixture was stirred at 25-30 °C. Upon complete consumption of starting material, the reactor was heated to 40-45 °C and phosgene/toluene were removed by distillation. A solution of Y2b-Form A in toluene (126 g,

I I.6 wt%) was added at 40-45 °C. This reaction mixture was stirred for 120 minutes. The reaction mixture was quenched with water (206 g). The mixture was heated to 65-70 °C and agitated for 1 hour. The mixture was filtered and the layers were separated. The organic layer was washed with water (206 g) and the resulting biphasic mixture was separated. The organic layer was seeded with Z1 (0.3 g) and concentrated in-vacuo and cooled to 40-45 °C. The mixture was crystallized by adding cyclohexane (162 g) and cooling to 0 °C. The mixture was filtered and washed with cyclohexane (52 g). The isolated solid was dried in a vacuum oven to afford the title compound (Zl) as a tan solid (25.9 g, 98 wt% purity, 84% yield): Analytical data matched that from above.

[00102] Example 4o: A 500-mL jacket reactor was purged with N?. X2 (10.0 g, 29.6 mmol) was added to the reactor in one portion at ambient temperature (19-22 °C). Toluene (190.5 g, 220 ml, 69.9 eq, 2.068 mol) was added to the reactor. Anhydrous pyridine (2.81 g, 2.87 mL, 35.5 mmol) was added via syringe. Methyl chloroformate (3.07 g, 2.52 mL, 32.5 mmol) was added to the reactor over 5 minutes by syringe. The mixture was stirred at 15 °C for 10 minutes then warmed to 40 °C for 1 hour. Hydrochloric acid (0.30 M, 100 ml, 30 mmol) was added to the reactor. The mixture was stirred for 10 minutes the allowed to settle. The aqueous layer was separated. The organic layer was washed with water (120 ml, 120 g, 6.66 mol). The aqueous layer was separated. The organic layer was distilled. The remaining mixture in the reactor was held at 45 °C overnight.

[00103] Toluene (81.0 g, 93.6 ml, 879 mmol) was added to the reactor. The mixture was warmed to 55 °C and held for 30 minutes. The mixture was then cooled to 25 °C. A solution of boron trichloride in toluene (IM, 13.7 ml, 13.7 mmol) was added to the reactor over 4 minutes. Tri ethylamine (4.94 mL, 35.4 mmol) was added by syringe over 2 minutes. The temperature was increased to 40 °C and the reaction was held for 3 hours. A solution of Y2b-Form A (10.4 g, 95% Wt, 31.0 mmol) in toluene (23.9 g, 27.6 mL) was added over 2 minutes. The mixture was held at 40 °C overnight. The mixture was warmed to 70 °C and water (23 °C) was added. The mixture was warmed to 65 °C and held for 1 hour. The slurry mixture was cooled to 20 °C and held for 30 minutes. Solids were collected by filtration to afford a wet cake. The wet cake was washed with water and cyclohexane. The wet cake was dried in a vacuum oven to afford Zl (14.83 g, 73.6% yield). Analytical data matched that from above.

Claims

1. A process for preparation of a compound of formula Z:

Z comprising the steps of: la. reaction of a compound of formula Y, a base, a thiocyanate salt, mixed in a solvent to form a compound of formula Yl;

Y Yl lb. combining a) a crystalline-form of compound of formula Yl or b) Yl formed in situ, with a compound of formula XI, and a CO derivative compound to form Z;

Yl XI wherein

L is a leaving group selected from the group consisting of -Cl, -Br, -I, OSO2CeH4Me, OSO₂Ph, and -OSO₂Me;

Ri is selected from the group consisting of -OCF3, -OCHF₂, -OCH₂F, and OCF2CF3;

A is selected from the group consisting of F, Cl, -(Ci-C4)alkyl;

R₂ is selected from the group consisting of -CH2OCH2CH3, -CH2OCH2CF3, - CH2OCH2CHF2, -CH2OCH2CH2F, -OCF3, -OCH2CH2CH3, -OCH2CH2CF3 , -(Cl- C4)alkyl and -OCH₂CF3_; and R3 is selected from the group consisting of -(Ci-C4)alkyl, -(Ci-C4)alkoxy, -(Ci- C₄)haloalkyl, -CH₃, -CH2CH3, and -OCH2CH3.

2. The process according to claim 1, wherein in step la: the thiocyanate salt is a thiocyanate salt selected from the group consisting of sodium thiocyanate and potassium thiocyanate; the base is a base that consists of an anion and cation, where the anion is carboxylate, carbonate, or bicarbonate and the cation is lithium, sodium, potassium or cesium ; and the solvent is selected from the group consisting of ketones, esters, ethers, halogenated C1-C4 solvents, , aprotic polar solvents, aliphatic hydrocarbons and mixtures thereof.

3. The process according to claim 1, wherein in step lb an optional acid, base or acid and base is present; and wherein the base is selected from the group consisting of organic and inorganic bases; the acid is selected from the group consisting of Lewis acids and Brpnsted acids.

4. The process according to claim 1, wherein in step lb: the solvent is an aprotic solvent selected from the group consisting of ethyl acetate, tetrahydrofuran, acetonitrile, acetone, toluene, xylenes, dichloromethane and mixtures thereof.

5. The process according to claim 1, wherein in step lb: the CO derivative is selected from the group consisting of phosgene, phosgene derivatives, carbonates, chloroformates, carbonyl derivatives and ureas.

6. The process according to claim 5, wherein the CO derivative is selected from the group consisting of dimethyl carbonate, diethyl carbonate, bis(2,5-dioxopyrrolidin-l-yl)carbonate, methyl chloroformate, ethyl chloroformate, phenyl chloroformate, /%/ra-nitrophenyl chloroformate, carbonyl diimidazole, carbonyl ditriazole, oxalyl chloride, phosgene, diphosgene and triphosgene.

7. The process according to claim 1, wherein in step lb, the combining of Y1 and XI is carried out by: a. adding the compound of formula Y1 to a mixture of a compound of formula XI, and a CO derivative; b. adding a mixture of a compound of formula Yl, and a CO derivative compound to the compound of formula XI, or c. adding a compound of formula Yl and a compound of formula XI, simultaneously or sequentially in any order to a CO derivative.

8. The process according to claim 1, wherein combining a) the compound of formula Yl, b) the compound of formula XI, and c) the CO derivative comprises mixing a), b) and c) components together in any order.

9. The process according to claim 1, wherein step la is carried out in a solvent selected from the group consisting of ethyl acetate, /.w-propyl acetate, //-propyl acetate, zso-butyl acetate, //-butyl acetate, sec-butyl acetate, acetonitrile, tetrahydrofuran, acetone, dichloromethane and mixtures thereof.

10. The process according to claim 1, wherein the step lb further comprising a solvent exchange step which comprises: a. removing the solvent of step la; and b. adding the solvent used in step lb.

11. The process according to claim 10, further comprising an aqueous wash prior to removing the solvent of step la.

12. The process according to any of the claims 1-11, wherein Yl is isolated by crystallization.

13. The process according to claim 1 for the preparation of a compound of formula Zl:

Zl comprising the steps of: a. reaction of a compound of formula Y2, a thiocyanate salt in a polar, aprotic solvent to form a compound of formula Y2b b. combining a) a crystalline-form of the compound of Formula Y2b or b) compound of formula Y2b formed in situ, with mixture of a compound of formula X2, and a CO derivative to form Zl;

X2.

14. The process according to claim 13, wherein combining the compound of formula Y2b with the compound of formula X2 and a CO derivative comprises any of a) adding the compound of formula Y2b to a mixture of the compound of formula X2 and a CO derivative; or b) adding the compound of formula X2 to a mixture of the compound of formula Y2b and a CO derivative; or c) adding a CO derivative to a mixture of the compound of formula Y2b and the compound of formula X2; or d) adding CO derivative, the compound of formula Y2b and the compound of formula X2 sequentially or simultaneously in any order.

15. The process according to claims 13-14, wherein the compound of formula Y2b is a crystalline form of the compound of Formula Y2b, or a crystalline form of acceptable salts, solvates, isotopes or tautomers of Y2b.

16. A compound of formula Zl, prepared according to any of the claims 1-15.