Process for the formation of N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide

Abstract

The present disclosure relates to N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a) or its hydrochloride salt (S6a-HCl), a molecule having insecticidal activity against pests of the phyla Arthropoda, Mollusca, and Nematoda, as well as methods for preparing S6a, S6a-HCl, and N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (S7a).

Description

[Background technology]

[0001] The formation of 2-(pyridin-3-yl)thiazoles is disclosed in WO 2010 / 129497, WO 2013 / 184475, WO 2013 / 184476, WO 2013 / 184480, and PCT / US2022 / 074322. DETAILED DESCRIPTION OF THE INVENTION

[0002] Provided is a molecule, N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (also referred to herein as "S6a"), having the formula: or an agriculturally acceptable acid addition salt. Molecule S6a has demonstrated activity against the green peach aphid (Myzus persicae) (i.e., 71% control at 200 parts per million (ppm)). [ka]

[0003] An example of an agriculturally acceptable acid addition salt is the hydrochloride salt (also referred to herein as "S6a-HCl").

[0004] Additionally, methods for making and using molecules S6a or S6a-HCl are provided. Molecules S6a or S6a-HCl are believed to be useful in methods for making N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (S7a).

[0005] Following are methods for the formation of N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (also referred to herein as "S7a"), which are shown below. [ka]

[0006] One embodiment of Scheme 1 Scheme 1 [ka] The reaction of Scheme 1 is carried out in the presence of an oxidizing agent that oxidizes 3-(methylthio)propanoic acid (also referred to herein as "S1a") to 3-(methylsulfonyl)propanoic acid (also referred to herein as "S1b"). In other words, functionally, the oxidizing agent oxidizes a thioether (-SCH) to a sulfone (-S(=O)CH). Examples of oxidizing agents are oxygen (O), sodium hypochlorite (NaOCl), ozone (O), hydrogen peroxide (HO), organic peracids (-OOH), and other inorganic oxidizing agents, such as potassium peroxymonosulfate, potassium persulfate, and potassium hydrogen peroxymonosulfate sulfate (a triple double salt having the formula 2KHSO·KHSO·KSO, available from EI du Pont de Nemours and Company or its affiliates as OXONE® (a registered trademark of EI du Pont de Nemours and Company or its affiliates) [CAS 70693-62-8]). Typically, about 2 to about 4 moles of oxidizing agent per mole of S1a can be used, preferably about 2.0 to about 3.0 moles of oxidizing agent per mole of S1a. Mixtures of oxidizing agents may also be used.

[0007] The reaction of Scheme 1 is carried out in the presence of a polar solvent. Examples of polar solvents are polar aprotic solvents and polar protic solvents. Examples of polar aprotic solvents are ethyl acetate ("EtOAc"), tetrahydrofuran ("THF"), dichloromethane ("DCM"), acetone, acetonitrile ("ACN"), N,N-dimethylformamide ("DMF"), and dimethyl sulfoxide ("DMSO"). Examples of polar protic solvents are acetic acid ("AcOH"), n-butanol ("n-BuOH"), isopropanol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), formic acid ("HCOOH"), tert-butyl alcohol ("t-BuOH"), and water ("HO"). Optionally, a mixture of such polar solvents may be used.

[0008] The reaction of Scheme 1 can be carried out at ambient temperature (about 15° C. to about 25° C.) and ambient pressure of about 95 kilopascals (kPa) to about 105 kPa (typically about 101 kPa), however, higher and lower temperatures and pressures may be used.

[0009] One embodiment of Scheme 2 Scheme 2 [ka] (In the above scheme, A is Cl, O(C=O)R1, or OR1, where R1 is (C1-C4) alkyl).

[0010] The reaction in Scheme 2 is carried out in the presence of a carboxylic acid activating agent. Activated carboxylic acids S2a include acid chlorides, mixed anhydrides, and esters. Acid chlorides can be prepared from the corresponding carboxylic acids by treatment with a dehydrating chlorination reagent such as oxalyl chloride or thionyl chloride. Mixed anhydrides can be prepared from carboxylic acids and chloroformate esters (RO(C=O)Cl) (e.g., ethyl chloroformate, methyl chloroformate, and isobutyl chloroformate) or other acid chlorides (e.g., pivaloyl chloride). Esters can be generated from the reaction of S1b with an alcohol (e.g., methanol or ethanol) under acidic conditions. Typically, about 1.0 to about 5 moles of activating agent per mole of S1b, more preferably about 1.0 to about 1.5 moles of activating agent per mole of S1b, can be used.

[0011] Optionally, a catalyst may be used to promote the reaction from S1b to activated S2a. Examples of catalysts include N,N-dimethylformamide, N-formylpyrrolidine, and N-formylpiperidine. Typically, about 0.01 to about 0.5 moles of catalyst per mole of S1b, more preferably about 0.05 to about 0.1 moles of catalyst per mole of S1b, may be used.

[0012] The reaction of Scheme 2 is carried out in the presence of an aprotic solvent. Examples of aprotic solvents are polar aprotic solvents and non-polar aprotic solvents. Examples of polar aprotic solvents are ethyl acetate ("EtOAc"), tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), dichloromethane ("DCM"), chloroform ("CHCl"), acetonitrile ("ACN"), and benzonitrile ("PhCN"). An example of a non-polar aprotic solvent is toluene ("PhCH"). Optionally, a mixture of such solvents may be used.

[0013] The reaction of Scheme 2 can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures can be used. Generally, temperatures of about 0°C to about 100°C can be used, with temperatures of about 50°C to about 80°C being used, and preferably temperatures of about 20°C to about 60°C being used.

[0014] Compound S2a may be isolated and used, or may be used directly in the subsequent reaction without isolation.

[0015] One embodiment of Scheme 3 Scheme 3 [ka] The reaction in Scheme 3 can provide either the amine (S4a) or the amine hydrochloride (S4a-HCl).

[0016] Alternatively, the product of Scheme 3 can be prepared in one step as the free amine (S4a) from glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride (also referred to herein as "S3 / 3a") by the reaction shown in Scheme 3 in the presence of ethylamine and a second base. Examples of the second base are organic and inorganic bases. Examples of organic bases are N,N-diisopropylethylamine ("DIPEA") and triethylamine ("TEA"). Examples of inorganic bases are potassium carbonate ("K2CO3"), potassium bicarbonate ("KHCO3"), potassium hydroxide ("KOH"), sodium carbonate ("Na2CO3"), sodium bicarbonate ("NaHCO3"), and sodium hydroxide ("NaOH"). Optionally, the second base may be added after the reaction is complete. Typically, about 1 to about 15 moles of ethylamine can be used per mole of S3 / 3a, more preferably about 5 to about 12 moles of ethylamine can be used per mole of S3 / 3a. Typically, about 0.8 to about 2 moles of the second base can be used per mole of S3 / 3a, more preferably about 0.8 to about 1.2 moles of the second base can be used per mole of S3 / 3a.

[0017] Optionally, the reaction of Scheme 3 is carried out in the presence of a polar solvent or a non-polar solvent. Examples of polar solvents are polar aprotic solvents and polar protic solvents. Examples of polar aprotic solvents are tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), anisole, and acetonitrile ("ACN"). Examples of polar protic solvents are n-butanol ("n-BuOH"), sec-butanol ("s-BuOH"), 4-methyl-2-pentanol ("MIBC"), isopropanol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), and water ("HO"). An example of a non-polar solvent is toluene ("PhCH3"). Optionally, a mixture of such solvents may be used. Water is preferred.

[0018] The reaction of Scheme 3 can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures can be used. Generally, temperatures of about -20°C to about 50°C can be used, and preferably, temperatures of about -10°C to about 10°C can be used. Generally, pressures from ambient pressure to 1000 kilopascals (kPa) can be used, and preferably, pressures from ambient pressure to about 200 kPa can be used.

[0019] Optionally, the amine S4a may be isolated as a solution in the reaction solvent. Preferably, S4a can be isolated as a 5 to 40 weight percent (wt %) solution in acetonitrile, water, or sec-butanol.

[0020] Optionally, the reaction of Scheme 3 to produce amine S4a can be carried out under flow conditions. Flow conditions are known in the art. See, for example, Luis, Santiago V., and Eduardo Garcia-Verdugo, eds. Chemical reactions and processes under flow conditions. No. 5. Royal Society of Chemistry, 2010.

[0021] Optionally, S4a can be converted to the hydrochloric acid (HCl) salt (S4a-HCl) by reaction with ethylamine followed by treatment with anhydrous or aqueous HCl. Typically, about 1 mole to about 10 moles of HCl can be used per mole of S4a, and more preferably, about 1 mole to about 3 moles of HCl can be used per mole of S4a. The formation of the HCl salt form is carried out in the presence of a polar solvent. Examples of polar solvents are polar aprotic solvents and polar protic solvents. Examples of polar aprotic solvents are 1,4-dioxane, ethyl acetate ("EtOAc"), methyl tert-butyl ether ("MTBE"), and cyclopentyl methyl ether ("CPME"). Examples of polar protic solvents are sec-butanol ("s-BuOH"), 4-methyl-2-pentanol ("MIBC"), isopropanol ("i-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), and water ("HO"). Optionally, mixtures of such polar solvents with each other or with a non-polar solvent such as toluene may be used.

[0022] One embodiment of Scheme 4 Scheme 4 [ka] The reaction of Scheme 4 converts S4a or S4a-HCl to pyridylthioamide S4A-a using 3-pyridinecarboxaldehyde (nicotinaldehyde) in the presence of sulfur and a base in a solvent.

[0023] The reaction of Scheme 4 is carried out in the presence of 3-pyridinecarboxaldehyde (also known as nicotinaldehyde), a Bronsted base, and sulfur. Typically, about 0.5 to about 5 moles of 3-pyridinecarboxaldehyde can be used per mole of S4a or S4a-HCl, and more preferably, about 0.7 to about 1.3 moles of 3-pyridinecarboxaldehyde can be used per mole of S4a or S4a-HCl. Commercially available forms of 3-pyridinecarboxaldehyde include neat and aqueous solutions, both of which can be used. Typically, about 1 to about 5 moles of sulfur can be used per mole of S4a or S4a-HCl, and more preferably, about 1.0 to about 3.5 moles of sulfur can be used per mole of S4a or S4a-HCl. Typically, about 0.05 to about 5 moles of Bronsted base can be used per mole of S4a or S4a-HCl, and more preferably, about 0.1 to about 1.2 moles of Bronsted base can be used per mole of S4a or S4a-HCl. Examples of Bronsted bases are potassium carbonate ("K2CO3"), potassium phosphate ("K3PO4"), triethylamine ("TEA"), pyridine, sodium acetate ("NaOAc"), sodium bicarbonate ("NaHCO3"), sodium hydrosulfide ("NaSH"), sodium sulfide ("Na2S"), imidazole, potassium tert-butoxide ("KOtBu"), and N,N-diisopropylethylamine ("DIPEA"). Sodium sulfide and triethylamine are preferred.

[0024] The reaction of Scheme 4 can be carried out in the presence of a polar aprotic solvent, a polar protic solvent, or a non-polar aprotic solvent. Examples of polar aprotic solvents are tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), benzonitrile ("PhCN"), butyronitrile, cyclopentyl methyl ether ("CPME"), dimethyl carbonate ("DMC"), ethyl acetate ("EtOAc"), isopropyl acetate ("i-PrOAc"), N,N-dimethylformamide ("DMF"), N,N-dimethylacetamide ("DMAC"), isobutyl acetate ("i-BuOAc"), methyl ethyl ketone ("MEK"), dichloromethane ("DCM"), chlorobenzene ("PhCl"), and acetone. Examples of polar protic solvents are n-butanol ("n-BuOH"), sec-butanol ("s-BuOH"), 4-methyl-2-pentanol ("MIBC"), isopropanol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), and water ("HO"). An example of a non-polar aprotic solvent is toluene ("PhCH"). Optionally, mixtures of such solvents may be used. Water and toluene are preferred.

[0025] The reaction of Scheme 4 can be carried out at ambient temperature, pressure, and pH. However, higher or lower temperatures, pressures, and pHs can be used. Generally, temperatures from about -10°C to about 100°C can be used, with temperatures from about 35°C to about 70°C being preferred. Generally, pressures from ambient to 1000 kilopascals (kPa) can be used, with pressures from ambient to about 200 kPa being preferred. Generally, a pH of 6 to 13 can be used, with a pH of about 8 to 10 being preferred.

[0026] One embodiment of Scheme 4-A Scheme 4-A [ka] The reaction of Scheme 4-A converts S4A-a to pyridylthiazole S5a in the presence of a Lewis or Bronsted acid. In some cases, the reaction may yield intermediate S5A-a, which requires further processing to yield S5a.

[0027] Examples of Lewis or Bronsted acids are phosphorus oxychloride ("POCl"), phosphorus trichloride ("PCl"), phosphorus pentachloride ("PCl"), trifluoromethanesulfonic anhydride ("TfO"), trifluoroacetic anhydride ("TFAA"), boron trifluoride diethyl etherate ("BF·OEt"), trimethylsilyl trifluoromethanesulfonate ("TMSOTf"), trifluoromethanesulfonic acid ("TfOH"), methanesulfonic acid ("MSOH"), Eaton's reagent ("PO-MSOH"), hydrogen bromide ("HBr"), aqueous hydrobromic acid ("aqueous HBr"), hydrogen bromide in acetic acid ("HBr in AcOH"), trifluoroacetic acid ("TFA"), p-toluenesulfonic acid ("p-TSA"), sulfuric acid ("HSO"), and solid supported acidic resins. Phosphorus oxychloride and phosphorus trichloride are preferred. Other Lewis or Bronsted acids may be used, resulting in intermediates that require further processing to obtain S5a. Typically, about 0.5 to about 50 moles of Lewis or Bronsted acid can be used per mole of S4A-a, and more preferably, about 1 to about 5 moles of Lewis or Bronsted acid can be used per mole of S4A-a.

[0028] In one embodiment of Scheme 4-A, the reaction can be carried out in the presence of a polar aprotic solvent or a non-polar aprotic solvent. Examples of polar aprotic solvents are tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), benzonitrile ("PhCN"), cyclopentyl methyl ether ("CPME"), dimethyl carbonate ("DMC"), chlorobenzene ("PhCl"), and ethyl acetate ("EtOAc"). An example of a non-polar aprotic solvent is toluene ("PhCH3"). Optionally, a mixture of such solvents can be used. Acetonitrile is preferred.

[0029] The reaction of Scheme 4-A can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures can be used. Generally, temperatures from about -10°C to about 80°C can be used, and preferably, temperatures from about 45°C to about 75°C can be used. Generally, pressures from ambient pressure to 1000 kilopascals (kPa) can be used, and preferably, pressures from ambient pressure to about 200 kPa can be used.

[0030] Optionally, the reaction of Scheme 4-A to produce amine S5A-a can be carried out under flow conditions.

[0031] One embodiment of Scheme 5 Scheme 5 [ka] The reaction of Scheme 5 is carried out in the presence of 3-pyridinecarboxaldehyde, also known as nicotinaldehyde, a Brønsted base, sulfur, and a Lewis or Brønsted acid that promotes the formation of S5a from S4a or S4a-HCl. Typically, about 0.5 to about 5 moles of 3-pyridinecarboxaldehyde can be used per mole of S4a or S4a-HCl, and more preferably, about 0.7 to about 1.3 moles of 3-pyridinecarboxaldehyde can be used per mole of S4a or S4a-HCl. Commercially available forms of 3-pyridinecarboxaldehyde include neat or aqueous acid solutions, both of which can be used. Typically, about 1 to about 5 moles of sulfur can be used per mole of S4a or S4a-HCl, and more preferably, about 1.0 to about 3.5 moles of sulfur can be used per mole of S4a or S4a-HCl. Typically, about 0.05 to about 5 moles of Bronsted base can be used per mole of S4a or S4a-HCl, more preferably about 0.1 to about 1.2 moles of Bronsted base can be used per mole of S4a or S4a-HCl. Typically, about 0.5 to about 50 moles of Lewis acid or Bronsted acid can be used per mole of S4a or S4a-HCl, more preferably about 1 to about 5 moles of Lewis acid or Bronsted acid can be used per mole of S4a or S4a-HCl. Examples of Bronsted bases are potassium carbonate ("K2CO3"), potassium phosphate ("K3PO4"), triethylamine ("TEA"), pyridine, sodium acetate ("NaOAc"), sodium bicarbonate ("NaHCO3"), sodium hydrosulfide ("NaSH"), sodium sulfide ("Na2S"), imidazole, potassium tert-butoxide ("KOtBu"), and N,N-diisopropylethylamine ("DIPEA"). Sodium sulfide and triethylamine are preferred.Examples of Lewis or Bronsted acids are phosphorus oxychloride ("POCl"), phosphorus trichloride ("PCl"), phosphorus pentachloride ("PCl"), trifluoromethanesulfonic anhydride ("TfO"), boron trifluoride diethyl etherate ("BF·OEt"), trimethylsilyl trifluoromethanesulfonate ("TMSOTf"), trifluoromethanesulfonic acid ("TfOH"), methanesulfonic acid ("MsOH"), Eaton's reagent ("PO-MsOH"), hydrogen bromide ("HBr"), aqueous hydrobromic acid ("aqueous HBr"), hydrogen bromide in acetic acid ("HBr in AcOH"), trifluoroacetic acid ("TFA"), p-toluenesulfonic acid ("p-TSA"), sulfuric acid ("HSO"), and solid-supported acidic resins. Phosphorus oxychloride and phosphorus trichloride are preferred. In some cases, the reaction may yield intermediates that require further processing to afford S5a.

[0032] The reaction of Scheme 5 can be carried out in the presence of a polar aprotic solvent or a non-polar aprotic solvent. Examples of polar aprotic solvents are tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), benzonitrile ("PhCN"), cyclopentyl methyl ether ("CPME"), dimethyl carbonate ("DMC"), chlorobenzene ("PhCl"), and ethyl acetate ("EtOAc"). An example of a non-polar aprotic solvent is toluene ("PhCH3"). Optionally, a mixture of such solvents can be used. Acetonitrile is preferred.

[0033] The reaction of Scheme 5 can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures can be used. Generally, temperatures from about -10°C to about 80°C can be used, preferably from about 35°C to about 70°C. Generally, pressures from ambient pressure to 1000 kilopascals (kPa) can be used, preferably from ambient pressure to about 200 kPa.

[0034] Optionally, the reactions of Scheme 5 to produce amines S5A (Scheme 4-a) and S5a can be carried out under flow conditions.

[0035] One embodiment of Scheme 6 Scheme 6 [ka] The reaction in Scheme 6 is carried out in the presence of a base. Treating S5a with a base first generates the free base form of S5a (S5A-a shown in Example 12), which reacts with S2a to form S6a or S6a-HCl. Examples of bases are organic and inorganic bases. Examples of organic bases are pyridine, lutidine (e.g., 2,6-lutidine and 3,5-lutidine), picoline (e.g., 2-picoline and 3-picoline), N,N-diisopropylethylamine ("DIPEA"), and triethylamine ("TEA"). Examples of inorganic bases are potassium carbonate ("K2CO3"), potassium bicarbonate ("KHCO3"), potassium hydroxide ("KOH"), sodium carbonate ("Na2CO3"), sodium bicarbonate ("NaHCO3"), and sodium hydroxide ("NaOH"). Typically, about 1 mole to about 5 moles of base can be used per mole of S5a, and more preferably about 2.0 moles to about 3.5 moles of base can be used per mole of S5a. The coupling reaction with S2a can also be catalyzed by reagents such as N,N-dimethylpyridin-4-amine ("DMAP") or N-methylimidazole ("NMI").

[0036] The reaction of Scheme 6 is carried out in the presence of a polar aprotic solvent or a non-polar aprotic solvent. Examples of polar aprotic solvents are ethyl acetate ("EtOAc"), isobutyl acetate ("i-BuOAc"), tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), dichloromethane ("DCM"), chloroform ("CHCl"), acetonitrile ("ACN"), and benzonitrile ("PhCN"). An example of a non-polar aprotic solvent is toluene ("PhCH"). Optionally, a mixture of such solvents may be used.

[0037] The reaction of Scheme 6 can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures can be used. Generally, temperatures from about -10°C to about 80°C can be used, preferably from about 0°C to about 60°C. Generally, pressures from ambient pressure to about 1000 kilopascals (kPa) can be used, preferably from ambient pressure to 200 kPa.

[0038] The product of Scheme 6 can be isolated as the free base form S6a or as an agriculturally acceptable acid addition salt form of S6a. Examples of agriculturally acceptable acid addition salts include hydrochloride salts ("HCl salts", S6a-HCl) and hydrobromide salts ("HBr salts"), with hydrochloride salts being preferred. S6a can be isolated from a polar protic solvent (e.g., water and alcohols, such as methanol), a polar aprotic solvent, or a non-polar solvent, or a mixture thereof. Optionally, a base may be used.

[0039] One embodiment of Scheme 7 Scheme 7 [ka] The reaction of Scheme 7 is carried out in the presence of a chlorinating agent. N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a) or N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (S6a-HCl) is chlorinated to form N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)propanamide (S7a). Typically, about 1 mole to about 5 moles of the chlorinating agent can be used per mole of S6a or S6a-HCl, and more preferably, about 1.0 mole to about 3.5 moles of the chlorinating agent can be used per mole of S6a or S6a-HCl. Examples of chloro agents include chlorine, N-chlorosuccinimide ("NCS"), 1,1,3,3-dichlorodimethylhydantoin ("DCDMH"), N-chlorophthalimide ("NCP"), N-chlorosaccharin ("NCSH"), tert-butyl hypochlorite, chloramine-T, N-chlorobenzotriazole ("NCBT"), trichloroisocyanuric acid ("TCCA"), and sodium hypochlorite. Chlorine or sodium hypochlorite is preferred.

[0040] The reaction of Scheme 7 is carried out in the presence of a polar solvent. Examples of polar aprotic solvents are 1,4-dioxane, tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), dichloromethane ("DCM"), ethyl acetate ("EtOAc"), and isobutyl acetate ("i-BuOAc"). Examples of polar protic solvents are n-butanol ("n-BuOH"), isopropanol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), water ("HO"), acetic acid ("AcOH"), formic acid ("HCOOH"), and aqueous hydrochloric acid ("HCl"). Aqueous HCl is preferred. Optionally, mixtures of such solvents may be used.

[0041] The reaction of Scheme 7 can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures can be used. Generally, temperatures from about -10°C to about 80°C can be used, preferably from about 0°C to about 50°C. Generally, pressures from ambient pressure to 1000 kilopascals (kPa) can be used, preferably from ambient pressure to about 200 kPa.

[0042] In another embodiment of Scheme 1, when the oxidizing agent used is hydrogen peroxide (HO), a catalyst may be used in the process to promote the reaction of S1a to S1b. An example of a catalyst is sodium tungstate.

[0043] In another embodiment of Scheme 2, a catalyst may optionally be used to promote the reaction of S1b to the activated form S2a. Examples of bases include lutidine (e.g., 2,6-lutidine and 3,5-lutidine), picolines (e.g., 2-picoline and 3-picoline), N-methylmorpholine, triethylamine ("TEA"), and N,N-diisopropylethylamine ("DIPEA"). Typically, about 0.1 mole to about 1.5 moles of base per mole of S1b can be used, more preferably about 0.5 mole to about 1.2 moles of base per mole of S1b.

[0044] The reaction of Scheme 2 can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures can be used. Generally, temperatures from about 0°C to about 100°C can be used, preferably from about 20°C to about 49°C.

[0045] In another embodiment of Scheme 3, amine S4a may optionally be isolated as a solution by extraction from the reaction solvent with a polar or nonpolar solvent. Examples of polar solvents are polar aprotic solvents and polar protic solvents. Examples of polar aprotic solvents are tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), dichloromethane ("DCM"), ethyl acetate ("EtOAc"), 2-butanone, 4-methylpentan-2-one ("MIBK"), isopropyl acetate ("i-PrOAc"), n-butyl acetate ("n-BuOAc"), dimethyl carbonate ("DMC"), methyl tert-butyl ether ("MTBE"), anisole, butyronitrile, and acetonitrile ("ACN"). Examples of polar protic solvents are sec-butanol ("s-BuOH") and 4-methyl-2-pentanol ("MIBC"). An example of a non-polar solvent is toluene. Optionally, mixtures of such solvents may be used.

[0046] In another embodiment of Scheme 4, 3-pyridinecarboxaldehyde (nicotinaldehyde) from an aqueous solution can be extracted using a polar aprotic solvent or a non-polar aprotic solvent, which can then be used in the reaction. Examples of polar aprotic solvents are tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), dichloromethane ("DCM"), ethyl acetate ("EtOAc"), n-butyl acetate ("nBuOAc"), 2-butanone, and dimethyl carbonate ("DMC"). Examples of non-polar aprotic solvents are toluene and xylene. Optionally, a mixture of such solvents can be used. Toluene and ethyl acetate are preferred.

[0047] In another embodiment of Scheme 4-A, sulfuric acid ("H2SO4") is the preferred Lewis or Bronsted acid. In another embodiment of Scheme 4-A, temperatures of about 10°C to 44°C can be preferably used. In another embodiment of Scheme 4-A, the free amine S5A-a can be isolated.

[0048] In another embodiment of Scheme 4-A, the free base S5A-a may be converted to the HCl salt form of S5a by treatment with anhydrous or aqueous HCl.

[0049] In another embodiment of Scheme 6, S5a can be utilized in the reaction without first generating the free base form of S5a, S5A-a.

[0050] In another embodiment of Scheme 7, N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (S6a-HCl) is chlorinated in the presence of a chlorinating agent to form N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (S7a), where the chlorinating agent comprises an oxidizing agent. An example of an oxidizing agent is potassium hydrogen peroxymonosulfate sulfate (a triple salt of formula 2KHSO KHSO KSO [CAS 70693-62-8] available from EI du Pont de Nemours and Company or its affiliates as OXONE® (a registered trademark of EI du Pont de Nemours and Company or its affiliates)). The reaction proceeds in the presence of a chloride source (eg, the hydrochloride salt of S6a-HCl) or by addition of, for example, a chloride salt (eg, sodium chloride) and / or hydrochloric acid. [Example]

[0051] Example 1: Synthesis of 3-(methylsulfonyl)propanoic acid (S1b) [ka] A 5-liter (L) jacketed reactor equipped with a mechanical stirrer and nitrogen inlet was charged with 3-(methylthio)propanoic acid (S1a; 152.2 grams (g), 131 milliliters (mL), 1.267 moles (mol)), acetonitrile (3 L), and water (70 mL). The jacket was cooled to 20°C, and Oxone® (1191 g, 3.89 mol) was added in small portions to the clear, homogeneous solution to control the internal temperature below 30°C. After the addition was complete, the white slurry was stirred until the internal temperature returned to 20°C (approximately 1 hour). The jacket was heated to 40°C. 1 After confirming the completion of the reaction by H NMR spectroscopy, the jacket was cooled to 20 °C and sodium bisulfite was added to quench the peroxide. After 60 min, the peroxide was quenched and the solution was concentrated to a solid. The resulting white solid was dissolved in acetonitrile (1 L) to give a slurry containing residual salts. The mixture was filtered to remove the salts, and the filtrate was concentrated to give a white solid. This was dried in a vacuum oven at 40 °C to give 3-(methylsulfonyl)propanoic acid (167 g, 88%), which was used directly in the next step: mp 94.0-99.2 °C; 1 H NMR(500MHz,DMSO-d6)δ 12.54(s,1H),3.33(t,J=7.5Hz,2H),3.00(s,3H),2.68(t,J=7.5Hz,2H); 13 C NMR(126MHz,DMSO-d6)δ 171.12,48.74,39.62,26.50.

[0052] Example 2: Synthesis of 3-(methylsulfonyl)propanoyl chloride (S2a-1) [ka] A 500 mL three-necked round-bottom flask equipped with a nitrogen inlet, a reflux condenser, a vent to a 1N sodium hydroxide (NaOH) base scrubber, and a stir bar was charged with 3-(methylsulfonyl)propanoic acid (S1b; 50 g, 329 mmol) and toluene (299 mL), resulting in a heterogeneous solution. To this was added thionyl chloride (493.5 mmol), and the solution was heated until the internal temperature reached 70-75 °C. The reaction mixture was stirred at this temperature while monitoring for completion. The reaction mixture was cooled to room temperature, at which point significant solid formation was observed. Heptane (250 mL) was added to the slurry, and the mixture was stirred for 10 minutes. The white solid was isolated by filtration under nitrogen (to prevent decomposition) and washed with heptane to yield a white solid (52.14 g, 93%): 1 H NMR(500MHz,CDCl3)δ 3.51-3.46(m,2H),3.43-3.38(m,2H),3.00(s,3H); 13 C NMR(126MHz,CDCl3)δ 171.8,49.5,41.6,39.3.

[0053] Example 3: Synthesis of 3-(methylsulfonyl)propanoyl chloride (S2a-1) [ka] A 100 mL three-necked round-bottom flask equipped with a condenser, an overhead stirrer with a pitched blade impeller, a thermocouple, and an outlet for nitrogen with a NaOH scrubber was charged with 3-(methylsulfonyl)propanoic acid (S1b; 2.04 g, 13.5 mmol). Acetonitrile (31.8 g) was added to the flask, which was then heated to 40 °C. Thionyl chloride (1.86 g, 15.6 mmol) was added dropwise to the flask over 10 minutes. The clear solution was held at 40 °C for 1 hour and 40 minutes (until proton NMR spectroscopy indicated a conversion of greater than 98%). The acid chloride solution could be used directly in the amide coupling (Example 12). 1 H NMR(500MHz,CDCl3)δ 3.51-3.46(m,2H),3.43-3.38(m,2H),3.00(s,3H);13 C NMR(126MHz,CDCl3)δ 171.8,49.5,41.6,39.3.

[0054] Example 4: Synthesis of 2-amino-N-ethylacetamide (S4a) [ka] Ethylamine (70 wt% aqueous solution, 152 mL, 1912 mmol) was added to a 250 mL jacketed reactor, and the solution was cooled to -5 °C. Glycine methyl ester hydrochloride S3 (20 g, 159 mmol) in water (40 mL) was added to the ethylamine via syringe pump over 2 h. The solution was stirred at -5 °C. After 45 min, 50 wt% aqueous sodium hydroxide (12.7 g, 159 mmol) was added, and the reaction mixture was warmed to 25 °C. The solution was concentrated under reduced pressure at 0.9 kPa and a jacket temperature of 50 °C to give an oil containing a white solid. ACN (125 mL) was added, and the resulting slurry was concentrated to 50% of its volume under reduced pressure at 6.7 kPa and a jacket temperature of 50 °C. The slurry was filtered and washed with ACN (50 mL). The filtrate was concentrated under reduced pressure of 0.9 kPa and a jacket temperature of 50° C. to give 2-amino-N-ethylacetamide as a clear, colorless oil (15.83 g): 1 H NMR(500MHz,DMSO-d6)δ 7.78(s,1H),3.14-3.06(m,2H),3.04(s,2H),1.02(t,J=7.2Hz,3H); 13 C NMR(126MHz,DMSO-d6)δ 173.04,45.27,33.50,15.34.

[0055] Example 5: Synthesis of 2-amino-N-ethylacetamide (S4a) [ka] A 250 mL jacketed reactor equipped with a mechanical stirrer and thermocouple and a nitrogen atmosphere was charged with an aqueous ethylamine solution (66-72 wt%, 128.26 g, 1991.24 mmol) and cooled to an internal temperature of -4 °C. A 40 wt% solution of glycine methyl ester hydrochloride S3 (50.0 g, 398.25 mmol) in water (75 g) was slowly added to the reactor over 2 h, maintaining the temperature below 3 °C. Sodium hydroxide (50%, 15.93 g, 398.25 mmol) was added over 10 min. The reaction was then fitted with a vacuum distillation apparatus, the bath heated to 95 °C, and methanol and ethylamine were distilled off until the bottoms volume stabilized. The bath temperature was then reduced to 65 °C, and distillation continued at a reduced pressure of 10 kPa until no ethylamine was detected in the bottoms. S4a was isolated as a 25 wt % aqueous solution (149.72 g, 90% yield).

[0056] Example 6: Synthesis of 2-amino-N-ethylacetamide (S4a) [ka] A 250 mL jacketed reactor equipped with a mechanical stirrer and thermocouple and under a nitrogen atmosphere was charged with aqueous ethylamine (66-72 wt%, 127.45 g, 1978.60 mmol) and cooled to an internal temperature of -4 °C. A solution of glycine methyl ester hydrochloride S3 (50.49 g, 398.13 mmol) in water (75 g) was slowly added to the ethylamine reactor over 2 h. The temperature was raised to 0 °C, and the reaction mixture was stirred for 1 h. 43 wt% aqueous sodium hydroxide (37.05 g, 398.82 mmol) was added over 10 min. The reaction was then fitted with a vacuum distillation apparatus, the bath heated to 95 °C, and methanol and ethylamine were distilled off until the bottoms volume stabilized. The bath temperature was lowered to 65 °C, and distillation continued at a reduced pressure of 10 kPa until no ethylamine was detected in the bottoms. The contents were filtered and transferred over 1 hour to a nitrogen-atmosphered 1 L jacketed reactor equipped with a mechanical stirrer, a thermocouple, and a condenser already containing acetonitrile (388.76 g, 494.61 mL). The temperature was increased to 91 °C to azeotropically distill water and acetonitrile. The temperature was reduced to 25 °C, and the reactor contents were filtered to remove salts and washed with acetonitrile (86.3 g, 109.80 mL) to give S4a as a 12 wt % solution in acetonitrile (245.06 g, 94% yield).

[0057] Example 7: Synthesis of 2-amino-N-ethylacetamide (S4a) [ka] A 250 mL jacketed reactor under nitrogen was charged with ethylamine (70 wt % in water) (159 mL, 2000 mmol) and cooled to -5°C. Glycine ethyl ester hydrochloride S3a (55.8 g, 400 mmol) in water (75 mL) was added to the ethylamine via syringe over 2 h. The solution was stirred at -5°C. After 45 min, 45 wt % aqueous potassium hydroxide solution (49.9 g, 400 mmol) was added, and the reaction mixture was warmed to 25°C. During this time, a white slurry formed. Excess ethylamine was removed by distillation at 95°C under ambient conditions. The system was then slowly evacuated to 10 kPa to remove residual water to approximately 30 wt %. The mixture was cooled to 5°C and filtered to give 2-amino-N-ethylacetamide S4a as a 32 wt % aqueous solution (109.5 g, 86% yield): 1 H NMR(500MHz,DMSO-d6)δ 7.78(s,1H),3.14-3.06(m,2H),3.04(s,2H),1.02(t,J=7.2Hz,3H); 13 C NMR(126MHz,DMSO-d6)δ 173.04,45.27,33.50,15.34.

[0058] Example 8: Synthesis of N-ethyl-2-(pyridine-3-carbothioamido)acetamide (S4A-a) [ka] A 1 L jacketed reactor equipped with a mechanical stirrer, reflux condenser, a scrubber containing bleach and sodium hydroxide, and a thermocouple under a nitrogen atmosphere was charged with sulfur (8.30 g, 258.81 mmol), potassium carbonate (2.82 g, 20.4 mmol), acetonitrile (365.84 g, 465.45 mL), 25.9 wt% aqueous S4a solution (101.39 g, 257.1 mmol), and 98 wt% nicotinaldehyde (22.85 g, 209.1 mmol). The suspension was stirred, and the mixture was heated to an internal temperature of 67 °C. The reaction was maintained at these conditions and monitored by HPLC analysis until completion (18 h). The reaction was then cooled to 50 °C. HCl (16 wt%, 94.7 g, 415.6 mmol) was then added over 10 minutes, and the reaction mixture was held for 15 minutes and scavenged to remove any H2S gas that may have formed. Toluene (287 g, 331.03 mL) was added over 5 minutes, and the solution was stirred for 30 minutes and then allowed to settle for 30 minutes. The organic and aqueous layers were collected separately, and the aqueous layer was returned to the reactor. The aqueous layer was heated to 55°C, and 345 g of 1 M NaOH was added in portions until the pH reached approximately 6. The resulting slurry was cooled to 20°C over 5 hours. The mixture was filtered, and the wet cake was washed twice with water. The wet cake was collected and dried in a vacuum oven at 50°C and 4 kPa to give the title compound S4A-a (24.5 g) as a yellow solid: mp = 145°C; 1 H NMR(400MHz,CDCl3)δ 9.02(dd,J=2.4,0.8Hz,1H),8.70(dd,J=4.9,1.7Hz,2H),8.15(ddd,J=8.0,2.4,1.6Hz,1H),7.35(ddd,J=8 .0,4.8,0.9Hz,1H),5.86(s,1H),4.42(d,J=4.4Hz,2H),3.40(qd,J=7.3,5.6Hz,2H),1.21(t,J=7.3Hz,3H); 13 C NMR(101MHz,CDCl3)δ 195.58,166.76,152.01,147.13,136.34,134.85,123.19,49.35,34.91,14.74;ESIMS m / z 224.2([M+H] + )

[0059] Example 9: Synthesis of N-ethyl-2-(pyridine-3-carbothioamido)acetamide (S4A-a) [ka] A 15 wt% aqueous solution of nicotinaldehyde (26.4 g, 36.97 mmol) was placed in a 100 mL jacketed reactor equipped with a mechanical stirrer, thermocouple, and pH meter under a nitrogen atmosphere. 25 wt% aqueous NaOH (17.55 mL) was added until the pH reached 10. This solution was transferred to a 250 mL jacketed reactor equipped with a mechanical stirrer, a reflux condenser, a scrubber containing bleach and sodium hydroxide, and a thermocouple, flushed with nitrogen, and already containing sulfur (1.51 g, 47.1 mmol). Acetonitrile (96.17 g, 122.34 mL) and a 30.0 wt% aqueous solution of S4a (15.6 g, 45.82 mmol) were then added. The suspension was stirred, and the mixture was heated to an internal temperature of 67 °C. The reaction was maintained under these conditions and monitored by HPLC analysis until completion (18 h). The reaction was then cooled to 50 °C. HCl (16 wt %, 17.11 g, 75.30 mmol) was then added over 5 min, and the reaction was held for 15 min, scavenging to remove any H2S gas that may have formed. Toluene (73.6 g, 84.89 mL) was added over 5 min, and the solution was stirred for 10 min and then allowed to settle for 5 min. The aqueous layer was removed. The organic layer was concentrated under vacuum. The resulting solid was resuspended in acetonitrile (50 mL) and filtered. The wet cake was washed with acetonitrile (2 x 50 mL) and dried in a vacuum oven at 50 °C under a reduced pressure of 4 kPa to afford the title compound S4A-a as a yellow solid (2.39 g, 29% yield), mp 145 °C; 1H NMR(400MHz,CDCl3)δ 9.02(dd,J=2.4,0.8Hz,1H),8.70(dd,J=4.9,1.7Hz,2H),8.15(ddd,J=8.0,2.4,1.6Hz,1H),7.35(ddd,J=8 .0,4.8,0.9Hz,1H),5.86(s,1H),4.42(d,J=4.4Hz,2H),3.40(qd,J=7.3,5.6Hz,2H),1.21(t,J=7.3Hz,3H); 13 C NMR(101MHz,CDCl3)δ 195.58,166.76,152.01,147.13,136.34,134.85,123.19,49.35,34.91,14.74.ESIMS m / z 224.2([M+H] + ).

[0060] Example 10: Synthesis of N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine dihydrochloride (S5a) [ka] N-ethyl-2-(pyridine-3-carbothioamido)acetamide S4A-a (33.3 g, 148 mmol) was placed in a 1 L jacketed reactor equipped with a mechanical stirrer, a reflux condenser with a vacuum distillation apparatus, a peristaltic pump, and a thermocouple under a nitrogen atmosphere. To this was added acetonitrile (132 g, 168 mL), and the mixture was stirred at 70 °C. POCl3 (47.6 g, 310 mmol) was added dropwise over 1 h while maintaining the internal temperature below 80 °C. The reaction was maintained under these conditions and followed to completion by HPLC analysis. After 1 h, the reaction mixture visibly darkened as the reaction progressed. After complete consumption of S4A-a was confirmed, the mixture was cooled to 50 °C and concentrated under vacuum to 30 wt% product. The mixture was cooled to 0 °C and held for 12 h, after which it was filtered through a sintered frit under a slight vacuum and nitrogen backfill. The solid was dried in a vacuum oven at 40° C. under a reduced pressure of 4 kPa for 16 hours to give N-ethyl-2-(pyridin-3-yl)thiazol-5-amine dihydrochloride (30.3 g, 98% by weight, 81% yield, 108.8 mmol):1 H NMR(400MHz,DMSO-d6)δ 9.07(d,J=2.1Hz,1H),8.71(dd,J=5.6,1.3Hz,1H),8.66(ddd,J=8.3,2.2,1.3Hz,1H),7.97(ddd,J= 8.3,5.5,0.7Hz,1H),7.54-7.19(m,1H),7.02(s,1H),3.15(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ 155.15,140.81,139.39,139.16,136.62,133.13,127.52,120.35,41.56,13.89;ESIMS m / z 206([M+H-2HCl] + )

[0061] Example 11: Synthesis of N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine dihydrochloride (S5a) [ka] A 250 mL jacketed reactor equipped with an overhead stirrer, nitrogen inlet, reflux condenser, and thermocouple under a nitrogen atmosphere was charged with 2-amino-N-ethylacetamide hydrochloride (4.99 g, 36.0 mmol) and anhydrous ACN (48 mL). Triethylamine (5.60 mL, 39.7 mmol) was added, and the mixture was stirred for 1 hour, resulting in a thick white slurry. Nicotinaldehyde (3.08 g, 28.8 mmol) was added, resulting in a thin slurry. Solid sulfur powder (1.20 g, 37.4 mmol) was added. The mixture was stirred at 70°C and gradually became a dark red-orange solution. The reaction was monitored by high-performance liquid chromatography (HPLC) for the disappearance of nicotinaldehyde (which took approximately 5 hours). The reaction mixture was cooled to 50°C. Phosphorus oxychloride (POCl3, 99%, 6.70 mL, 77.8 mmol) was added dropwise to the reaction mixture while maintaining the internal temperature below 60°C. The thin, dark brown slurry / oil was stirred at 50°C for 7 hours, during which time a yellow slurry formed (as observed by HPLC). The yellow-orange slurry was cooled to 15°C and toluene (20 mL) was added. The mixture was filtered and the yellow wet cake was dried under vacuum at 40°C for 16 hours to give the title compound S5a (4.73 g, 58%): 1 H NMR(400MHz,DMSO-d6)δ 9.07(d,J=2.1Hz,1H),8.71(dd,J=5.6,1.3Hz,1H),8.66(ddd,J=8.3,2.2,1.3Hz,1H),7.97(ddd,J= 8.3,5.5,0.7Hz,1H),7.54-7.19(m,1H),7.02(s,1H),3.15(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ 155.15,140.81,139.39,139.16,136.62,133.13,127.52,120.35,41.56,13.89;ESIMS m / z 206([M+H-2HCl] + )

[0062] Example 12: Synthesis and isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (S6a-HCl) [ka] 3-(Methylsulfonyl)propanoic acid (11.1 g, 1.5 equiv., 73.1 mmol) was placed in a 250 mL jacketed reactor set at a bath temperature of 25 °C, followed by the addition of ACN (32.0 g, 779 mmol) and subsequent stirring (internal temperature 23–24 °C). Thionyl chloride (8.69 g, 73.1 mmol) was added dropwise over 1 h, maintaining the internal temperature below 30 °C. After the addition was complete, the solution was held at 25 °C for 2 h (total 3 h) to convert the acid to the acid chloride, 3-(methylsulfonyl)propanoyl chloride.

[0063] N-ethyl-2-(pyridin-3-yl)thiazol-5-amine dihydrochloride (13.5 g, 48.7 mmol) and DCM (33.1 g, 390 mmol) were placed in a separate 250 mL reactor with a bath temperature set at 25 °C. Aqueous potassium carbonate solution (20 wt%, 70.7 g, 102 mmol) was added over 15 min via a peristaltic pump. The mixture was stirred at 25 °C for 30 min. Stirring was stopped and the layers were allowed to separate. The organic layer was returned to the 250 mL reactor, and the DCM was solvent exchanged with acetonitrile by distillation to give a solution of S5A-a.

[0064] The solution of 3-(methylsulfonyl)propanoyl chloride S2a was transferred to the solution of S5A-a via peristaltic pump over 15 minutes, maintaining the internal temperature below 30°C. The reaction was stirred at 25°C for 12 hours, then cooled to 0°C for an additional 12 hours, and then filtered. The wet cake was washed with ACN (50 g), and the solid was dried in a vacuum oven for 18 hours (<50 mmHg) to give N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride as a mixture of rotamers (12.1 g, 66% yield): 1H NMR(400MHz,D2O)δ 9.07(m,1H),8.90-8.53(m,2H),8.16-7.91(m,1H),7.69(m,1H),4.00-3.56(m,2H),3.52(m,2H),3.24-2.62(m,5H),1.10(m,3H); 13 C NMR(101MHz,D2O)δ 171.63,169.14,160.98,153.15,143.54,142.70,142.17,141.06,140.03,138.90,137.78,132.55,132. 38,130.11,128.00,127.95,49.63,49.29,45.99,44.15,40.55,40.36,27.01,26.33,12.05,11.84;ESIMS m / z 340([M+H-HCl] + )

[0065] Example 13: Synthesis and isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a) [ka] A 250 mL jacketed reactor set at a bath temperature of 25 °C was charged with 3-(methylsulfonyl)propanoic acid (10.5 g, 68.7 mmol), followed by ACN (30.1 g, mmol), followed by stirring (internal temperature 23-24 °C). Thionyl chloride (7.91 g, 66.5 mmol) was added dropwise over 1 h, maintaining the internal temperature below 30 °C. The solution was held at 25 °C for 2 h to allow complete conversion to 3-(methylsulfonyl)propanoyl chloride.

[0066] N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine dihydrochloride S5a (13.4 g, 5.8 mmol) was added to a separate 250 mL reactor set at a bath temperature of 25 °C, followed by acetonitrile (60.2 g, 1.47 mol) (internal temperature 24 °C). Triethylamine (9.74 g, 96.2 mmol) was added dropwise via syringe over 5 min, and the mixture was aged at 25 °C for 15 min. To this was added a solution of 3-(methylsulfonyl)propanoyl chloride dropwise over 30 min, maintaining the internal temperature below 45 °C.

[0067] After 1.5 hours, 20 wt % aqueous potassium carbonate (87.1 g, 126 mmol) was added, and the mixture was stirred for 30 minutes. Acetonitrile was removed under vacuum until no distillation overhead was collected. The resulting mixture was cooled to 0° C. over 1 hour and then filtered. The wet cake was washed with water and acetonitrile. The solid was dried in a vacuum oven for 18 hours to give N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide S6a as a mixture of rotamers (13.2 g, 81% yield): 1 H NMR(400MHz,CDCl3)δ 9.16-9.12(m,1H),8.75-8.59(m,1H),8.25-8.15(m,1H),7.70-7.61(m,1H),7.47-7.3 4(m,1H),4.09-3.69(m,2H),3.63-3.33(m,2H),3.26-2.76(m,5H),1.52-1.17(m,3H); 13 C NMR(101MHz,CDCl3)δ 169.50,167.11,164.92,158.79,151.53,150.36,147.62,147.22,141.95,139.86,137.90,133.56,133.02,130. 14,129.88,129.28,123.87,123.75,50.37,50.15,45.77,44.18,42.08,41.81,27.43,26.55,13.10,12.83;ESIMS m / z 340([M+H] + ])

[0068] Example 14: Synthesis and isolation of N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (S7a) [ka] A 250 mL jacketed reactor equipped with a pH probe, overhead stirrer, nitrogen inlet, caustic soda scrubber, temperature probe, and metering unit inlet was charged with N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide S6a (29.73 g, 55.5 wt%, 1 equiv., 48.61 mmol), followed by ethyl acetate (23.56 g, 267.4 mmol). The mixture was stirred to give a white slurry. 30 wt% aqueous sodium acetate (19.94 g, 72.92 mmol) was added in one portion, followed by acetic acid (4.38 g, 72.92 mmol). 10 wt% aqueous sodium hypochlorite (45.23 g, 60.76 mmol) was added dropwise over 1 h. Two hours after the addition was complete, the mixture was quenched with 32 wt % aqueous sodium thiosulfate (7.205 g, 14.58 mmol). 25 wt % aqueous sodium hydroxide (3.111 g, 19.44 mmol) was added dropwise until the pH reached >8. The stirring was stopped, and the organic layer was transferred to a 1 L round-bottom flask. The water content of the organic layer was reduced to less than 1 wt % by azeotropic distillation with dry EtOAc at a bath temperature of 50 °C under a vacuum of 20 kPa. The mixture after distillation was approximately 30 wt %. The mixture was heated to 70 °C, held for 30 minutes, and then cooled to 35 °C, at which point spontaneous nucleation occurred. The mixture was aged for 4 hours, after which heptane (26.79 g, 267.4 mmol) was added dropwise. The mixture was finally cooled to 0 °C and held at that temperature for 6 hours. The slurry was filtered, the wet cake was washed with heptane, and the resulting solid was dried in a vacuum oven at 50°C for 18 hours (<50 mmHg) to give N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide S7a as a beige solid (16.2 g, 84% yield): mp 101-104°C; 1H NMR(400MHz,CDCl3)δ 9.12(d,J=2.3Hz,1H),8.77-8.71(m,1H),8.22(dt,J=8.1,2.0Hz,1H),7.45(dd,J=8.1,4.8Hz,1H), 3.79(q,J=7.2Hz,2H),3.43(s,2H),2.96(s,3H),2.80(t,J=7.1Hz,2H),1.23(t,J=7.2Hz,3H);ESIMS m / z 374([M+H] + ).

[0069] Example 15: Synthesis and isolation of N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (S7a) [ka] A 250 mL round-bottom flask equipped with a stir bar was charged with N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride S6a-HCl (15.0 g, 85 wt%, 33.9 mmol), followed by water (38.5 g, 38.5 mL, 2.14 mol) (pH 4). The solution was cooled to 0 °C, and 10 wt% sodium hypochlorite (53.0 g, 71.2 mmol) was added dropwise over 30–45 min. UPLC monitoring of the reaction after 45 and 75 min indicated that approximately 35% starting material remained by LC area. Additional 10 wt% aqueous sodium hypochlorite (53.0 g, 71.2 mmol) was added dropwise at 0 °C, and the mixture was stirred for an additional 1 h. After the reaction was complete, 40 wt% aqueous sodium bisulfite solution (13.2 g, 50.9 mmol) was added dropwise over 30 minutes. 40 wt% aqueous potassium carbonate solution (29.3 g, 84.8 mmol) was added to adjust the pH to 10, and the mixture was extracted twice with isopropyl acetate (34.6 g, 339 mmol). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The mixture was redissolved in isopropyl acetate (34.6 g, 39.8 mL, 339 mmol) and heated to 70 °C to dissolve, then cooled to room temperature overnight to induce crystallization. The resulting slurry was filtered and washed with cyclohexane (40 mL). The solid was dried in a vacuum oven overnight to give N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (9.5 g, 25 mmol, 75% yield): mp 101-104 °C; 1 H NMR(400MHz,CDCl3)δ 9.12(d,J=2.3Hz,1H),8.77-8.71(m,1H),8.22(dt,J=8.1,2.0Hz,1H),7.45(dd,J=8.1,4.8Hz,1H), 3.79(q,J=7.2Hz,2H),3.43(s,2H),2.96(s,3H),2.80(t,J=7.1Hz,2H),1.23(t,J=7.2Hz,3H);ESIMS m / z 374([M+H] + )

[0070] Example 16: Synthesis of 2-amino-N-ethylacetamide (S4a) [ka] A nitrogen-environmented jacketed reactor equipped with a mechanical stirrer and thermocouple was charged with aqueous ethylamine (70 wt %, 512 g, 7.95 mol) and cooled to an internal temperature of -4 °C. A solution of glycine methyl ester hydrochloride S3 (200 g, 1.58 mol) in water (307 g) was slowly added to the ethylamine reactor. The temperature was maintained at -3 °C, and the reaction mixture was stirred for 1 to 3 h. After the reaction was complete, the temperature was increased to 0 °C. 50 wt % aqueous sodium hydroxide (130 g, 1.63 mol) was added over 10 min, and the reaction mixture was stirred for 30 min. The reactor was heated to 95 °C, and methanol and ethylamine were distilled off until the bottom volume stabilized. The reactor temperature was reduced to 40 °C, the pressure was reduced to 10 kPa, and distillation was continued by increasing the temperature to 65 °C until no ethylamine was detected in the bottoms. The reactor contents were extracted twice with s-BuOH (231 g, 3.12 mol). Water was added to the aqueous layer (50 g, 2.77 mol) to dissolve the precipitated salts, and the aqueous layer was extracted again with s-BuOH (231 g, 3.12 mol). Additional water (50 g, 2.77 mol) was added to the aqueous layer, and this layer was extracted with additional s-BuOH (231 g, 3.12 mol). Additional water (20 g, 1.11 mol) was added to the aqueous layer, and this layer was extracted with additional s-BuOH (231 g, 3.12 mol). The organic extracts were combined (1450 g total) to give a 9.4 wt% solution of S4a in s-BuOH (84% yield).

[0071] Example 17: Synthesis of 2-amino-N-ethylacetamide hydrochloride (S4a-HCl) [ka] A 5 L jacketed reactor equipped with a mechanical stirrer and thermocouple and under a nitrogen atmosphere was charged with aqueous ethylamine (67 wt %, 1040 g, 15.5 mol) and additional water (600 g, 33.3 mol) and cooled to an internal temperature of -4 °C. Solid glycine methyl ester hydrochloride S3 (50.49 g, 398.13 mmol) was slowly added to the ethylamine reactor over 4 h. The temperature was raised to 0 °C, and the reaction mixture was stirred for 2 h. 48 wt % aqueous sodium hydroxide (258 g, 3.1 mol) was added over 20 min. The reactor was warmed to 80 °C, and methanol and ethylamine were distilled off until the bottoms volume stabilized. The reactor temperature was reduced to 60 °C, the pressure was reduced to 10 kPa, and distillation was continued by increasing the temperature to 75 °C until no ethylamine was detected in the bottoms. MIBC (1600 g, 15.5 mol) was added, and the contents were further distilled at 75 °C and 8.5-10 kPa to remove water. The slurry was filtered, and the solid was washed with MIBC (200 g, 1.94 mol). The filtrates were combined, and aqueous HCl (35%, 355 g, 3.41 mol) was added. Further distillation at 75 °C and 10 kPa removed additional water. The slurry was cooled to 50 °C, and MTBE (1600 g, 18.0 mol) was added. The slurry was stirred for 30 minutes and cooled to 5-10 °C over 90 minutes. The wet cake was filtered and washed twice with MTBE (400 g, 4.49 mol). The wet cake was dried in an oven at 70 °C for 8 hours to give S4a-HCl as a white solid (389 g, 87.8% yield): mp 136 °C; 1 H NMR(500MHz,D2O)δ 3.71,(s,2H),3.19(q,J=7.4Hz,2H),1.06(t,J=7.4Hz,3H); 13 C NMR(126MHz,D2O)δ 166.46,40.48,34.64,13.44.

[0072] Example 18: Extraction of nicotinaldehyde [ka] Ethyl acetate (102 g) was added to a 250 mL jacketed glass reactor via a dropping funnel with stirring. Nicotinaldehyde aqueous solution (16.76 wt. % nicotinaldehyde, 102 g) was added to the reactor. Sodium sulfate (NaSO, 20 g) was added to the reactor, followed by a commercially available 2.5 M NaOH solution (20 mL). The reactor was heated until the temperature of the reaction mixture reached 41 °C. The contents were stirred at 270 rpm for 10 minutes. The stirring was stopped, and the two layers were allowed to separate and settle. The aqueous and organic layers were collected separately and weighed (organic layer: 125.72 g, aqueous layer: 117.93 g). The organic layer was concentrated using a rotary evaporator to yield a viscous liquid. GC analysis indicated that the viscous layer contained 62.36 wt. % nicotinaldehyde.

[0073] Example 19: Extraction of nicotinaldehyde [ka] Toluene (60 g) was added to a 500 mL jacketed glass reactor via a dropping funnel with stirring. Nicotinaldehyde aqueous solution (18.49 wt % nicotinaldehyde, 108.5 g) was added to the reactor. Na2SO4 (24 g) was added to the reactor, followed by a commercially available 10% NaOH solution (0.32 mol equivalents). The reactor was heated until the temperature of the reaction mixture reached 40 °C. The contents were stirred at 270 rpm for 10 minutes. The stirring was stopped, and the two layers were allowed to separate and settle. The aqueous and organic layers were collected separately, and the aqueous layer was returned to the reactor. Toluene (60 g) was added to the reactor, and the two phases were stirred at 40 °C. The stirring was stopped, and the layers were allowed to settle. The aqueous and organic layers were collected separately, and the two organic layers were combined. Analysis of the organic layer using GC revealed a nicotinaldehyde content of 13.66 wt % in solution.

[0074] Example 20: Synthesis of N-ethyl-2-(pyridine-3-carbothioamido)acetamide (S4A-a) [ka] A 250 mL jacketed reactor equipped with a mechanical stirrer and thermocouple and under a nitrogen atmosphere was charged with sulfur (1.32 g, 41.1 mmol) and S4a-HCl (5.82 g, 41.1 mmol). Ethyl acetate (38.4 g, 42.6 mL) was added, followed by triethylamine (4.53 g, 44.8 mmol) and a 14 wt% solution of nicotinaldehyde in ethyl acetate (28.8 g). The suspension was stirred at 350 rpm, and the mixture was heated to an internal temperature of 67 °C. The reaction was maintained at these conditions and monitored by HPLC analysis until completion (18 h). The reaction mixture was cooled to 50 °C. 70% saturated Na2SO4 solution (53.8 g, 50.0 mL) was added. The reaction mixture was thoroughly stirred at 450 rpm for 10 minutes and then allowed to settle for 5 minutes. The aqueous layer was removed. The organic layer was diluted with hot ethyl acetate (31.5 g, 30.0 mL). The resulting solution was heated to 65°C and stirred at 300 rpm for 1 hour. The solution was slowly cooled to 40°C over 14 hours. A seed slurry of S4A-a (0.104 g) in ethyl acetate (2.82 g) was added, and the reaction mixture was cooled nonlinearly to 0°C over 6 hours. The resulting slurry was filtered. The wet cake was washed with ethyl acetate (2 x 50.0 mL) and dried in a vacuum oven at 40°C under a reduced pressure of 4 kPa to give the title compound S4A-a as a yellow solid (4.36 g, 49% yield): mp 145°C; 1 H NMR(400MHz,CDCl3)δ 9.02(dd,J=2.4,0.8Hz,1H),8.70(dd,J=4.9,1.7Hz,2H),8.15(ddd,J=8.0,2.4,1.6Hz,1H),7.35(ddd,J=8 .0,4.8,0.9Hz,1H),5.86(s,1H),4.42(d,J=4.4Hz,2H),3.40(qd,J=7.3,5.6Hz,2H),1.21(t,J=7.3Hz,3H); 13 C NMR(101MHz,CDCl3)δ 195.58,166.76,152.01,147.13,136.34,134.85,123.19,49.35,34.91,14.74;ESIMS m / z 224.2([M+H] + )

[0075] Example 21: Synthesis of N-ethyl-2-(pyridine-3-carbothioamido)acetamide (S4A-a) [ka] A 250 mL jacketed reactor equipped with a mechanical stirrer and thermocouple and under a nitrogen atmosphere was charged with sulfur (1.50 g, 46.7 mmol) and S4a-HCl (6.60 g, 46.7 mmol). Ethyl acetate (62.7 g, 69.5 mL) was added, followed by triethylamine (5.10 g, 50.4 mmol) and nicotinaldehyde (4.00 g). The suspension was stirred at 300 rpm, and the mixture was heated to an internal temperature of 67 °C. The reaction was maintained at these conditions and monitored by HPLC analysis until completion (18 h). The reaction mixture was cooled to 50 °C. 18 wt% brine solution (53.2 g, 50.0 mL) was added. The reaction mixture was thoroughly stirred at 450 rpm for 10 min and then allowed to settle for 5 min. The aqueous layer was removed. The organic layer was heated to 60 °C and stirred at 300 rpm for 1 h. The solution was slowly cooled to 40°C over 3 hours. A seed slurry of S4A-a (0.090 g) in ethyl acetate (1.20 g) was added. The reaction mixture was held at 40°C for 1 hour and cooled to 0°C over 7 hours. The resulting slurry was stirred overnight and then filtered. The wet cake was washed with ethyl acetate (3 x 45.0 mL) and dried in a vacuum oven at 40°C under a reduced pressure of 4 kPa to give the title compound S4A-a as a yellow solid (5.15 g, 58% yield): mp 145°C; 1 H NMR(400MHz,CDCl3)δ 9.02(dd,J=2.4,0.8Hz,1H),8.70(dd,J=4.9,1.7Hz,2H),8.15(ddd,J=8.0,2.4,1.6Hz,1H),7.35(ddd,J=8 .0,4.8,0.9Hz,1H),5.86(s,1H),4.42(d,J=4.4Hz,2H),3.40(qd,J=7.3,5.6Hz,2H),1.21(t,J=7.3Hz,3H); 13C NMR(101MHz,CDCl3)δ 195.58,166.76,152.01,147.13,136.34,134.85,123.19,49.35,34.91,14.74;ESIMS m / z 224.2([M+H] + ).

[0076] Example 22: Synthesis of N-ethyl-2-(pyridine-3-carbothioamido)acetamide (S4A-a) [ka] A 500 mL jacketed reactor equipped with a mechanical stirrer and thermocouple under a nitrogen atmosphere was charged with 25 wt% aqueous S4a solution (104 g, 189 mmol) and Na2S·9H2O (5.4 g, 22.5 mmol). The pH of the resulting solution was adjusted to 8.79 using 32% HCl solution (10.1 g). Sulfur (5.93 g, 185 mmol) was added, followed by nicotinaldehyde (16.4 g, 153 mmol) and toluene (128 g, 148 mL). The reaction mixture was stirred at 400 rpm and heated to an internal temperature of 68 °C. The reaction was maintained at these conditions and monitored by HPLC analysis until completion (19 h). The reaction mixture was stirred at 85 °C, and water (55 g, 55 mL) was added. The solution was then gradually cooled to 10 °C over 4 h. The slurry was filtered, and the cake was washed with water (55 mL) and toluene (2×70 mL). The wet cake was dried overnight in a vacuum oven at 90° C. under a reduced pressure of 4 kPa to give the title compound S4A-a as a yellow solid (23.3 g, 69% yield): mp 145° C.; 1 H NMR(400MHz,CDCl3)δ 9.02(dd,J=2.4,0.8Hz,1H),8.70(dd,J=4.9,1.7Hz,2H),8.15(ddd,J=8.0,2.4,1.6Hz,1H),7.35(ddd,J=8 .0,4.8,0.9Hz,1H),5.86(s,1H),4.42(d,J=4.4Hz,2H),3.40(qd,J=7.3,5.6Hz,2H),1.21(t,J=7.3Hz,3H); 13C NMR(101MHz,CDCl3)δ 195.58,166.76,152.01,147.13,136.34,134.85,123.19,49.35,34.91,14.74.ESIMS m / z 224.2([M+H] + ).

[0077] Example 23: Synthesis of N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine (S5A-a) [ka] A 250 mL jacketed reactor was charged with concentrated sulfuric acid (69.3 g, 37.7 mL, 95 wt%, 10 equiv., 672 mmol). The reactor was cooled to 15 °C, and N-ethyl-2-(pyridine-3-carbothioamido)acetamide S4A-a (15.0 g, 1 equiv., 67.2 mmol) was added portionwise over 30 min with the overhead stirrer set to 650 rpm. The internal temperature was maintained below 26 °C throughout the addition. The jacket temperature was set to 40 °C, and the mixture was vigorously stirred (650 rpm) for 4 h. The reaction mixture was cooled to room temperature and stirred overnight. The reaction mixture was cooled to 10 °C, and water (80 mL) was added dropwise over 30 min, ensuring the temperature did not exceed 25 °C. To the resulting aqueous solution, 10 M aqueous KOH was then added dropwise over 30 min until the reaction mixture became thick and heterogeneous and measured a pH of 7–8. The slurry was drained into a filter funnel and washed with water (2 x 50 mL). The filter cake was dried in a vacuum oven at 50 °C to give N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine S5A-a (11.72 g, 83% yield): mp 93.67 °C (DSC); 1 H NMR(500MHz,CDCl3)δ 8.99(d,J=2.4Hz,1H),8.55(d,J=4.5Hz,1H),8.08(dt,J=8.1,1.9Hz,1H),7.33(dd,J=8 .1,4.8Hz,1H),6.99(s,1H),4.00(s,1H),3.25(q,J=7.2Hz,2H),1.33(t,J=7.1Hz,3H); 13C NMR(126MHz,CDCl3)δ 152.04,149.18,149.13,146.55,132.20,130.47,123.62,121.81,43.06,14.77;ESIMS m / z 206([M+H] + )

[0078] Example 24: Synthesis of N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine dihydrochloride (S5a) [ka] Acetonitrile (805.4 g, 19.619 mol) and S4A-a (145 g, 0.6364 mol) were placed in a jacketed reactor at 25–30°C. The mixture was stirred at 500 rpm, and the reactor was heated to 55–60°C. Phosphorus trichloride (PCl3; 218.49 g, 2.50 equiv., 1.591 mol) was added over 2 h. The temperature was maintained at 60°C with stirring for 4–6 h. The reaction mixture was cooled to 50°C. Under a vacuum of approximately 20 kPa, acetonitrile and PCl3 were removed by solvent-swap distillation with toluene (1172.7 g, 12.728 mol) at 50°C. The vacuum was released, and the mixture was cooled to 25°C. Water (229.10 g, 12.728 mol) was added, and the pH was adjusted to 8.0-8.5 with 50% potassium carbonate solution (508.7 g, 1.840 mol) at 25°C. The mixture was heated to 50-55°C, stirred for 30 minutes, and then allowed to stand for 30 minutes. The aqueous layer was separated, and the organic layer was set aside. Toluene (234.5 g, 2.546 mol) was added to the aqueous layer, and the mixture was stirred for 30 minutes and then allowed to stand for 30 minutes. The organic layer was separated. The organic layers were combined, and water (229.1 g, 12.728 mol) was added at 50-55°C. The mixture was stirred for 30 minutes and then allowed to stand for 30 minutes. The organic layer was separated, and toluene and water were azeotropically distilled at 50-55°C under a vacuum of approximately 31 kPa. The vacuum was released, and fresh toluene (284.2 g, 3.084 mol) was added at 50-55°C. The mixture was cooled to 25-30°C with stirring. Dry HCl gas (58.1 g, 1.591 mol) was passed through the mixture at 25-30°C for 1 hour. The mixture was held at 25-30°C for 1 hour. The solid was filtered, and the mother liquor was separated. The wet cake was washed with acetonitrile (260.8 g, 6.353 mol) and dried under nitrogen for 15 minutes. Acetonitrile (260.8 g, 6.353 mol) was added to the wet cake, and the mixture was slurried and dried under nitrogen for 15 minutes. The wet cake was dried at 40°C under a vacuum of approximately 6.7 kPa. N-ethyl-2-(pyridin-3-yl)-1,3-thiazol-5-amine dihydrochloride (152.4 g, 84% yield) was isolated: 1H NMR(400MHz,DMSO-d6)δ 9.07(d,J=2.1Hz,1H),8.71(dd,J=5.6,1.3Hz,1H),8.66(ddd,J=8.3,2.2,1.3Hz,1H),7.97(ddd,J= 8.3,5.5,0.7Hz,1H),7.54-7.19(m,1H),7.02(s,1H),3.15(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ 155.15,140.81,139.39,139.16,136.62,133.13,127.52,120.35,41.56,13.89;ESIMS m / z 206([M+H-2HCl] + )

[0079] Example 25: Synthesis and isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a) [ka] 3-(Methylsulfonyl)propanoic acid (3.56 g, 1.2 equiv., 23.4 mmol) was placed in a 250 mL jacketed reactor with the bath temperature set at 25 °C. ACN (24.6 g, 600 mmol) and 3,5-dimethylpyridine (1.24 g, 0.59 equiv., 11.6 mmol) were added. The mixture was stirred. The bath temperature was raised to 35 °C. Pivaloyl chloride (3.05 g, 1.3 equiv., 25.3 mmol) was added. After the addition was complete, the solution was held at 35 °C for 2 hours to convert the acid to pivalic anhydride, 3-(methylsulfonyl)propanoic acid pivalic anhydride.

[0080] S5A-a was prepared in solution from S5a according to the procedure of Example 12. Dichloromethane was removed by distillation, and the solid was dried under vacuum at 40°C for 16 hours to give S5A-a as a yellow solid (95%). S5A-a (4.01 g, 1 equiv., 19.5 mmol) was placed in a 100 mL glass reactor at ambient conditions. DCM (80.9 g, 953 mmol) and 3,5-dimethylpyridine (2.99 g, 1.4 equiv., 27.9 mmol) were added, and the solution was stirred. The solution of S5A-a was transferred to the 3-(methylsulfonyl)propanoic acid pivalic anhydride solution at 33°C. The reaction mixture was stirred at 29-34°C for 19 hours. The mixture was concentrated to 24 mL by vacuum distillation at 50-55°C. ACN (31.0 g, 755 mmol) was added, and the mixture was concentrated to 24 mL by vacuum distillation at 55-60 °C. Water (24.1 g, 1340 mol) and ACN (6.3 g, 153 mmol) were added to the mixture at 55 °C, and the mixture was concentrated to 24 mL by vacuum distillation at 55-66 °C. The slurry was cooled to 10 °C over 4 h, held at 10 °C for 1 h, and filtered. The wet cake was washed with a 90 / 10 (v / v) mixture of water / ACN (20 mL), and the solid was dried in a vacuum oven at 50 °C for 16 h to give N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide S6a as a rotamer mixture (4.59 g, 68% yield): 1 H NMR(400MHz,CDCl3)δ 9.16-9.12(m,1H),8.75-8.59(m,1H),8.25-8.15(m,1H),7.70-7.61(m,1H),7.47-7.34( m,1H),4.09-3.69(m,2H),3.63-3.33(m,2H),3.26-2.76(m,5H),1.52-1.17(m,3H);ESIMS m / z 340([M+H] + ])

[0081] Example 26: Synthesis and isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a) [ka] A 250 mL jacketed reactor with a bath temperature set to 25 °C was charged with 3-(methylsulfonyl)propanoic acid (3.55 g, 1.2 equiv., 23.3 mmol). DCM (42.2 g, 497 mmol) and 3,5-dimethylpyridine (1.25 g, 0.60 equiv., 11.7 mmol) were added. The mixture was stirred. The bath temperature was raised to 35 °C. Pivaloyl chloride (3.11 g, 1.3 equiv., 25.8 mmol) was added. After the addition was complete, the solution was held at 35 °C for 2 h to convert the acid to pivalic anhydride, 3-(methylsulfonyl)propanoic acid pivalic anhydride (S2a-2).

[0082] S5A-a was prepared in solution from S5a according to the procedure of Example 12. Dichloromethane was removed by distillation, and the solid was dried under vacuum at 40 °C for 16 hours to give S5A-a as a yellow solid (95%). S5A-a (4.00 g, 1 equiv., 19.5 mmol) was placed in a 100 mL glass reactor at ambient conditions. DCM (42.2 g, 497 mmol) and 3,5-dimethylpyridine (3.22 g, 1.5 equiv., 30.0 mmol) were added, and the solution was stirred. The solution of S5A-a was transferred to the 3-(methylsulfonyl)propanoic acid pivalic anhydride solution at 35 °C. The reaction mixture was stirred at 29–34 °C for 20 hours. Methanol (31.6 g, 989 mmol) was added to the mixture, and the mixture was concentrated by vacuum distillation to 20 mL. Methanol (31.6 g, 989 mmol) was added, and the mixture was concentrated by vacuum distillation to 20 mL. At 50° C., methanol (15.8 g, 494 mmol) was added to the mixture. The slurry was cooled to 10° C. over 3 hours, maintained at 10° C. for 1 hour, and then filtered. The wet cake was washed twice with methanol (15.8 g, 494 mmol), and the solid was dried in a vacuum oven at 50° C. for 16 hours to give N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide S6a (5.74 g, 87% yield). 1 H NMR data is consistent with S6a.

[0083] Example 27: Synthesis and isolation of N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a) [ka] 3-(Methylsulfonyl)propanoic acid (913 mg, 1.2 equiv., 6.00 mmol), acetonitrile (7.86 g, 10.0 mL, 38.3 equiv., 191 mmol), and pivaloyl chloride (754 mg, 1.25 equiv., 6.25 mmol) were placed in a 30 mL vial at 25 °C. 3-Methylpyridine (698 mg, 1.5 equiv., 7.50 mmol) was added dropwise to prepare a mixed anhydride solution. The solution was stirred at room temperature for 10–15 min. S5a (1.39 g, 1 equiv., 5.00 mmol) was placed in a 40 mL vial at ambient conditions as a yellow solid. Acetonitrile (7.86 g, 10.0 mL, 38.3 equiv., 191 mmol) and 3-methylpyridine (1.40 g, 3 equiv., 15.0 mmol) were slowly added. The suspension was stirred, and the mixed anhydride solution prepared above was added to the suspension at 25 °C. The reaction was stirred at 50–55 °C for 10 h. The mixture was concentrated to half its volume by vacuum distillation, and methanol (7.92 g, 10.0 mL, 49.4 equiv., 247 mmol) was added. The mixture was again concentrated to a reaction volume of 20 mL by vacuum distillation. Methanol (7.92 g, 10.0 mL, 49.4 equiv., 247 mmol) was added to the mixture at 25 °C. The slurry was cooled to 5 °C, held for 1 h, and then filtered. The wet cake was washed with 5 mL of methanol-water (1:1), followed by water (5 mL). The resulting solid was dried in a vacuum oven at 50 °C for 16 h to give N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (1.53 g, 90.2% yield). 1 H NMR data is consistent with S6a.

[0084] Example 28: Synthesis and isolation of N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (S7a) [ka] A 1 L jacketed reactor equipped with an overhead stirrer was charged with N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide S6a (30.1 g, 100 wt %, 89 mmol). Water (157.8 g, 8.8 mol) was added to form a slurry. Aqueous HCl (32 wt %, 13.1 g, 122 mmol) was added to the reactor to form a brown solution. The jacket was set to 25 °C. Chlorine gas (9.1 g, 128 mmol) was added slowly over 50 minutes through a glass tube submerged in the liquid. After the reaction was complete, 36 wt % aqueous sodium bisulfite solution (12.4 g, 48 mmol) was added, and the mixture was stirred for 60 minutes. Ethyl acetate (131.4 g, 1.49 mol) was added to the reactor. Aqueous sodium hydroxide (50 wt%, 25.5 g, 319 mmol) was added to raise the pH to 7. The reactor was warmed to 35°C. The phases were allowed to settle and separate. The organic layer was washed with water (69.8 g, 3.87 mol) and cooled to 30°C. S7a (0.15 g, 4.0 mmol) was added as seed crystals. The seeded mixture was held at 30°C for 2 hours. Heptane (147.1 g, 1.47 mol) was added dropwise over 2 hours. The slurry was cooled to -10°C over 1 hour, held for an additional 1 hour, and then filtered. The wet cake was washed once with heptane (44.8 g, 447 mmol). The solid was dried in a vacuum oven overnight to give N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (25.4 g, 76% yield).

[0085] Example 29: Synthesis of N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (S7a) [ka] To a 250 mL jacketed reactor was added N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (12.50 g, 85 wt%, 1 eq, 28.27 mmol), followed by water (37.69 g, 37.69 mL, 74 eq, 2.092 mol). The mixture was stirred at 23° C. Separately, a solution of Oxone® (20.85 g, 1.2 eq, 33.92 mmol) in water (63.67 g, 63.67 mL, 125 eq, 3.533 mol), pH ∼2.5, was prepared in a stirred round-bottom flask. The Oxone® solution was added dropwise to the jacketed reactor over 1 h, and the mixture was stirred. After complete conversion was confirmed, sodium bisulfite (8.823 g, 40 wt%, 1.2 equiv, 33.92 mmol) was added dropwise over 15 min. Potassium carbonate (23.44 g, 20 wt%, 1.2 equiv, 33.92 mmol) was added dropwise to bring the pH to 10. Isobutyl acetate (32.83 g, 41.8 mL, 10 equiv, 282.7 mmol) was added in one portion, and the mixture was heated to 50° C. The phases were separated, and the organic layer was set aside. Additional isobutyl acetate (32.83 g, 41.8 mL, 10 equiv, 282.7 mmol) was added in one portion to the aqueous layer, and the mixture was heated to 50° C. The phases were separated, and the organic layer was set aside. The combined organic layers were placed under vacuum at 50° C. and the mixture was concentrated azeotropically to less than 1.0 wt% water. After reaching the target moisture level, the mixture was heated to 65-70 °C to dissolve all material and then cooled to 0 °C over 12 hours. The mixture was held for 4 hours and then filtered. The wet cake was washed with 50 mL of heptane and dried in a vacuum oven (50 °C, <50 mmHg) to give N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (8.5 g, 71% yield).

[0086] Accordingly, in view of the above, the following further non-exhaustive disclosure details (d) are provided. 1d. [ka] A process comprising oxidizing 3-(methylthio)propanoic acid to 3-(methylsulfonyl)propanoic acid in the presence of an oxidizing agent and a polar solvent. 2d. The method of detail 1d, wherein the oxidizing agent is oxygen (O2), sodium hypochlorite (NaOCl), ozone (O3), hydrogen peroxide (H2O2), an organic peroxide, an organic peracid (-OOH), potassium peroxymonosulfate, potassium persulfate, potassium hydrogen peroxymonosulfate sulfate (triple salt having the formula 2KHSO5·KHSO4·K2SO4 [CAS 70693-62-8]), or a mixture thereof. 3d. The method of detail 1d, wherein the oxidizing agent, hydrogen peroxide (H2O2), further comprises the catalyst, sodium tungstate. 4d. The method of details 1d, 2d, and 3d, wherein about 2 moles to about 4 moles of oxidizing agent per mole of S1a are used. 5d. The method described in detail in 1d, 2d, and 3d, wherein about 2.0 moles to about 3.0 moles of oxidizing agent per mole of S1a are used. 6d. The method of Details 1d, 2d, 3d, 4d, and 5d, wherein the polar solvent is a polar aprotic solvent, a polar protic solvent, or a mixture thereof. 7d. The method of detail 6d, wherein the solvent is ethyl acetate ("EtOAc"), tetrahydrofuran ("THF"), dichloromethane ("DCM"), acetone, acetonitrile ("ACN"), N,N-dimethylformamide ("DMF"), dimethyl sulfoxide ("DMSO"), acetic acid ("AcOH"), n-butanol ("n-BuOH"), isopropanol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), formic acid ("HCOOH"), tert-butyl alcohol ("t-BuOH"), water ("HO"), or a mixture thereof. 8d. The method of details 1d, 2d, 3d, 4d, 5d, 6d, and 7d, wherein the oxidation is carried out at a temperature of about 15°C to about 25°C and a pressure of about 95 kPa to about 105 kPa. 9d. A method comprising reacting S1b in the presence of a carboxylic acid activator and an aprotic solvent to produce S2a. [ka] (wherein A is Cl, O(C=O)R1, or OR1, where R1 is (C1-C4) alkyl, and the reaction is optionally carried out using a catalyst or base to facilitate the reaction of S1b to S2a). 10d. The method of detail 9d, wherein about 1.0 mole to about 5 moles of carboxylic acid activating agent are used per mole of S1b. 11d. The method of detail 9d, wherein about 1.0 mole to about 1.5 moles of carboxylic acid activating agent are used per mole of S1b. 12d. The method of details 9d, 10d, and 11d, wherein a catalyst is used to promote the reaction of S1b to S2a. 13d. The method of detail 12d, wherein the catalyst is N,N-dimethylformamide, N-formylpyrrolidine, N-formylpiperidine, or a mixture thereof. 14d. The process of details 12d and 13d, wherein about 0.01 mole to about 0.5 moles of catalyst are used per mole of S1b. 15d. The process of details 12d and 13d, wherein about 0.05 moles to about 0.1 moles of catalyst are used per mole of S1b. 16d. The methods described in 9d, 10d, and 11d, wherein a base is used to promote the reaction of S1b to S2a. 17d. The method of detail 16d, wherein the base is lutidine (e.g., 2,6-lutidine and 3,5-lutidine), picoline (e.g., 2-picoline and 3-picoline), N-methylmorpholine, triethylamine ("TEA"), N,N-diisopropylethylamine ("DIPEA"), or a mixture thereof. 18d. The process of details 16d and 17d, wherein about 0.1 to about 1.5 moles of base are used per mole of S1b. 19d. A method as described in detail in 16d and 17d, wherein about 0.5 moles to about 1.2 moles of base are used per mole of S1b. 20d. The method of details 9d, 10d, 11d, 12d, 13d, 14d, 15d, 16d, 17d, 18d, and 19d, wherein the aprotic solvent is a polar aprotic solvent, a non-polar aprotic solvent, or a mixture thereof. 21d. The method of detail 20d, wherein the solvent is ethyl acetate ("EtOAc"), tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), dichloromethane ("DCM"), acetonitrile ("ACN"), benzonitrile ("PhCN"), chloroform ("CHCl3"), toluene ("PhCH3"), or a mixture thereof. 22d. The method described in Details 9d, 10d, 11d, 12d, 13d, 14d, 15d, 16d, 17d, 18d, 19d, 20d, and 21d, wherein the reaction temperature is from about 0°C to about 100°C. 23d. The method according to details 9d, 10d, 11d, 12d, 13d, 14d, 15d, 20d, and 21d, wherein the reaction temperature is about 20°C to about 60°C. 24d. The method described in details 9d, 10d, 11d, 16d, 17d, 18d, 19d, 20d, and 21d, wherein the reaction temperature is about 20°C to about 49°C. 25d. The method as detailed in 9d, 10d, 11d, 12d, 13d, 14d, 15d, 16d, 17d, 18d, 19d, 20d, 21d, 22d, 23d, and 24d, wherein S2a is isolated or used directly without isolation under flow conditions. 26d. A method comprising aminating S3 / 3a to S4a or S4a-HCl with ethylamine in the presence of a second base and optionally a polar or non-polar solvent. [ka] 27d. The method of detail 26d, wherein the amount of ethylamine used is from about 1 mole to about 15 moles of ethylamine per mole of S3 / 3a. 28d. The method of detail 26d, wherein the amount of ethylamine used is from about 5 moles to about 12 moles of ethylamine per mole of S3 / 3a. 29d. The method of any one of details 26d to 28d above, wherein the second base is an organic base. 30d. The method of any one of details 26d to 28d above, wherein the second base is an inorganic base. 31d. The method described in any one of Details 26d to 28d above, wherein the second base is N,N-diisopropylethylamine or triethylamine. 32d. The method of any one of Details 26d-28d above, wherein the second base is potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, or a mixture thereof. 33d. The method of any one of details 26d to 32d above, wherein the amount used is about 0.8 moles to about 2 moles of the second base per mole of S3 / 3a. 34d. The method of any one of details 26d to 32d above, wherein the amount used is about 0.8 moles to about 1.2 moles of the second base per mole of S3 / 3a. 35d. The method of any one of details 26d to 34d above, wherein the polar solvent is a polar aprotic solvent. 36d. The method of any one of details 26d to 34d above, wherein the polar solvent is a polar protic solvent. 37d. The method of any one of Details 26d to 34d above, wherein the polar solvent is tetrahydrofuran, 2-methyltetrahydrofuran, anisole, acetonitrile, or a mixture thereof. 38d. The method described in any one of Details 26d to 34d above, wherein the polar solvent is n-butanol, sec-butanol, 4-methyl-2-pentanol, isopropanol, n-propanol, ethanol, methanol, water, or a mixture thereof. 39d. The method according to any one of the preceding details 26d to 34d, wherein the non-polar solvent is toluene. 40d. The method according to any one of the preceding details 26d to 39d, carried out at a temperature of about -20°C to about 50°C. 41d. The method according to any one of the preceding details 26d to 39d, carried out at a temperature of about -10°C to about 10°C. 42d. The method of any one of details 26d-41d above, carried out at a pressure of about 10 kPa to about 1000 kPa, or from about ambient pressure to about 1000 kPa. 43d. The method of any one of details 26d-41d above, carried out at a pressure of about 50 kPa to about 200 kPa, or from about ambient pressure to about 200 kPa. 44d. The method according to any one of details 26d to 43d above, carried out under flow conditions. 45d.S4a is (a) isolated as a free base form, or (b) used as the free base form in solution; or (c) isolated as the hydrochloride salt form; A method according to any one of details 26d to 44d above. 46d. A process comprising reacting S4a or S4a-HCl with 3-pyridinecarboxaldehyde in the presence of sulfur, a Bronsted base, and a solvent to produce S4A-a. [ka] 47d. A method according to detail 46d, wherein 3-pyridinecarboxaldehyde is used in neat form, as an aqueous solution, or as a solution in an organic solvent. 48d. A method as described in detail in 46d and 47d, wherein about 0.5 moles to about 5 moles of 3-pyridinecarboxaldehyde are used per mole of S4a or S4a-HCl. 49d. The process of details 46d and 47d, wherein about 0.7 moles to about 1.3 moles of 3-pyridinecarboxaldehyde are used per mole of S4a or S4a-HCl. 50d. The process of details 46d, 47d, 48d, and 49d, wherein about 1 mole to about 5 moles of sulfur are used per mole of S4a or S4a-HCl. 51d. The process of details 46d, 47d, 48d, and 49d, wherein about 1.0 mole to about 3.5 moles of sulfur are used per mole of S4a or S4a-HCl. 52d. The process of details 46d, 47d, 48d, 49d, 50d, and 51d, wherein 0.05 moles to about 5 moles of Bronsted base are used per mole of S4a or S4a-HCl. 53d. The process of Details 46d, 47d, 48d, 49d, 50d, and 51d, wherein about 0.1 mole to about 1.2 moles of Bronsted base are used per mole of S4a or S4a-HCl. 54d. The method of Details 46d, 47d, 48d, 49d, 50d, 51d, 52d, and 53d, wherein the Bronsted base is potassium carbonate ("K2CO3"), potassium phosphate ("K3PO4"), triethylamine ("TEA"), pyridine, sodium acetate ("NaOAc"), sodium bicarbonate ("NaHCO3"), sodium hydrosulfide ("NaSH"), sodium sulfide ("Na2S"), imidazole, potassium tert-butoxide ("KOtBu"), N,N-diisopropylethylamine ("DIPEA"), or a mixture thereof. 55d. The method of details 46d, 47d, 48d, 49d, 50d, 51d, 52d, and 53d, wherein the Bronsted base is sodium sulfide ("Na2S") or triethylamine ("TEA"). 56d. The method of Details 46d, 47d, 48d, 49d, 50d, 51d, 52d, 53d, 54d, and 55d, wherein the solvent is a polar aprotic solvent, a polar protic solvent, a non-polar aprotic solvent, or a mixture thereof. 57d. The solvent is tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), benzonitrile ("PhCN"), butyronitrile, cyclopentyl methyl ether ("CPME"), dimethyl carbonate ("DMC"), ethyl acetate ("EtOAc"), isopropyl acetate ("i-PrOAc"), N,N-dimethylformamide ("DMF"), N,N-dimethylacetamide ("DMAC"), isobutyl acetate ("i-BuOAc") , methyl ethyl ketone ("MEK"), dichloromethane ("DCM"), chlorobenzene ("PhCl"), acetone, n-butanol ("n-BuOH"), sec-butanol ("s-BuOH"), 4-methyl-2-pentanol ("MIBC"), isopropanol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), water ("H2O"), toluene ("PhCH3"), or a mixture thereof. 58d. The method according to any one of details 46d to 57d above, wherein the temperature at which the reaction is carried out is from about -10°C to about 100°C. 59d. The method described in any one of Details 46d to 57d above, wherein the temperature at which the reaction is carried out is from about 35°C to about 70°C. 60d. The method of any one of details 46d-59d above, wherein the pressure at which the reaction is carried out is from ambient pressure to 1000 kilopascals (kPa). 61d. The method of any one of details 46d to 59d above, wherein the pressure at which the reaction is carried out is from ambient pressure to about 200 kPa. 62d. A method according to any one of the preceding details 46d to 61d, wherein the pH at which the reaction is carried out is between 6 and 13. 63d. A method according to any one of the preceding details 46d to 61d, wherein the pH at which the reaction is carried out is 8 to 10. 64d. A method comprising converting S4A-a to S5a in the presence of a Lewis acid or a Bronsted acid. [ka] Optionally, the conversion is carried out in the presence of a solvent. 65d. Lewis acids or Bronsted acids include phosphorus oxychloride ("POCl3"), phosphorus trichloride ("PCl3"), phosphorus pentachloride ("PCl5"), trifluoromethanesulfonic anhydride ("Tf2O"), trifluoroacetic anhydride ("TFAA"), boron trifluoride diethyl etherate ("BF3·OEt2"), trimethylsilyl trifluoromethanesulfonate ("TMSOTf"), ... 64d. The method of claim 64d, wherein the acid is selected from the group consisting of toluenesulfonic acid ("TfOH"), methanesulfonic acid ("MSOH"), Eaton's reagent ("PO-MSOH"), hydrogen bromide ("HBr"), aqueous hydrobromic acid ("aqueous HBr"), hydrogen bromide in acetic acid ("HBr in AcOH"), trifluoroacetic acid ("TFA"), p-toluenesulfonic acid ("p-TSA"), sulfuric acid ("HSO"), a solid supported acidic resin, or a mixture thereof. 66d. The method of detail 65d, wherein the Lewis acid or Bronsted acid is phosphorus oxychloride ("POCl3") or phosphorus trichloride ("PCl3"). 67d. The method of detail 65d, wherein the Lewis acid or Bronsted acid is sulfuric acid. 68d. The process of details 64d, 65d, 66d, and 67d, wherein about 0.5 moles to about 50 moles of Lewis acid or Bronsted acid are used per mole of S4a. 69d. The process of details 64d, 65d, 66d, and 67d, wherein about 1 mole to about 5 moles of Lewis acid or Bronsted acid are used per mole of S4a. 70d. The method of details 64d, 65d, 66d, 67d, 68d, and 69d, wherein the solvent is a polar aprotic solvent, a non-polar aprotic solvent, or a mixture thereof. 71d. The method of detail 70d, wherein the solvent is tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), benzonitrile ("PhCN"), cyclopentyl methyl ether ("CPME"), dimethyl carbonate ("DMC"), ethyl acetate ("EtOAc"), toluene ("PhCH3"), chlorobenzene ("PhCl"), or a mixture thereof. 72d. The method of detail 71d, wherein the solvent is acetonitrile. 73d. The process of details 64d, 65d, 66d, 67d, 68d, 69d, 70d, 71d, and 72d, wherein the temperature at which the conversion is carried out is from about -10°C to about 80°C. 74d. The method of detail 73d, wherein the temperature is about 45°C to about 75°C. 75d. The method according to detail 73d, wherein the temperature is about 10°C to about 44°C. 76d. The method of details 64d, 65d, 66d, 67d, 68d, 69d, 70d, 72d, 72d, 74d, 74d, and 75d, wherein the pressure at which the conversion is carried out is from ambient pressure to about 1000 kilopascals (kPa). 77d. The method of detail 76d, wherein the pressure is from ambient pressure to about 200 kPa. 78d. The method of details 64d, 65d, 66d, 67d, 68d, 69d, 70d, 71d, 72d, 73d, 74d, 75d, 76d, and 77d, wherein the conversion is performed under flow conditions. 79d. The method as described in detail in 64d, 65d, 66d, 67d, 68d, 69d, 70d, 71d, 72d, 73d, 74d, 75d, 76d, 77, and 78d, wherein S5a is isolated as the free amine S5A-a. 80d. The method as detailed in 64d, 65d, 66d, 67d, 68d, 69d, 70d, 71d, 72d, 73d, 74d, 75d, 76d, 77, and 78d, wherein the free amine S5A-a can be converted into salt form S5a. 81d. A process comprising reacting S4a or S4a-HCl to produce S5a, wherein the reaction is carried out in the presence of 3-pyridinecarboxaldehyde, a Bronsted base, sulfur, and a Lewis acid or Bronsted acid; [ka] Optionally, the reaction is carried out in a solvent. 82d. A method according to detail 81d, in which 3-pyridinecarboxaldehyde is used in neat form, as an aqueous solution, or as a solution in an organic solvent. 83d. The process of details 81d and 82d, wherein about 0.5 moles to about 5 moles of 3-pyridinecarboxaldehyde are used per mole of S4a or S4a-HCl. 84d. The process of details 81d and 82d, wherein about 0.7 moles to about 1.3 moles of 3-pyridinecarboxaldehyde are used per mole of S4a or S4a-HCl. 85d. The process of details 81d, 82d, 83d, and 84d, wherein about 1 mole to about 5 moles of sulfur are used per mole of S4a or S4a-HCl. 86d. The process of details 81d, 82d, 83d, and 84d, wherein about 1.0 mole to about 3.5 moles of sulfur are used per mole of S4a or S4a-HCl. 87d. The process of details 81d, 82d, 83d, 84d, 85d, and 86d, wherein about 0.05 moles to about 5 moles of Bronsted base are used per mole of S4a or S4a-HCl. 88d. The process of details 81d, 82d, 83d, 84d, 85d, and 86d, wherein about 0.1 mole to about 1.2 moles of Bronsted base are used per mole of S4a or S4a-HCl. 89d. The process of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, and 88d, wherein about 0.5 moles to about 50 moles of Lewis acid or Bronsted acid are used per mole of S4a or S4a-HCl. 90d. The process of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, and 88d, wherein about 1 mole to about 5 moles of Lewis acid or Bronsted acid are used per mole of S4a or S4a-HCl. 91d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, and 90d, wherein the Bronsted base is potassium carbonate ("K2CO3"), potassium phosphate ("K3PO4"), triethylamine ("TEA"), pyridine, sodium acetate ("NaOAc"), sodium bicarbonate ("NaHCO3"), sodium hydrosulfide ("NaSH"), sodium sulfide ("Na2S"), imidazole, potassium tert-butoxide ("KOtBu"), and N,N-diisopropylethylamine ("DIPEA"), or a mixture thereof. 92d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, and 90d, wherein the Bronsted base is sodium sulfide ("Na2S") or triethylamine ("TEA"). 93d. Lewis or Bronsted acids include phosphorus oxychloride ("POCl3"), phosphorus trichloride ("PCl3"), phosphorus pentachloride ("PCl5"), trifluoromethanesulfonic anhydride ("Tf2O"), boron trifluoride diethyl etherate ("BF3·OEt2"), trimethylsilyl trifluoromethanesulfonate ("TMSOTf"), trifluoromethanesulfonic acid ("TfOH"), methanesulfonate ("TfOH"). 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91d, and 92d, wherein the acid used is toluenesulfonic acid ("MsOH"), Eaton's reagent ("PO-MsOH"), hydrogen bromide in acetic acid ("HBr in AcOH"), trifluoroacetic acid ("TFA"), p-toluenesulfonic acid ("p-TSA"), sulfuric acid ("HSO"), a solid supported acidic resin, or a mixture thereof. 94d. The method of detail 93d, wherein the Lewis acid or Bronsted acid is phosphorus oxychloride or phosphorus trichloride. 95d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91d, 92d, 93d, and 94d, wherein a solvent is used, and the solvent is a polar aprotic solvent, a non-polar aprotic solvent, or a mixture thereof. 96d. The method of detail 95d, wherein the solvent is tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), benzonitrile ("PhCN"), cyclopentyl methyl ether ("CPME"), dimethyl carbonate ("DMC"), chlorobenzene ("PhCl"), ethyl acetate ("EtOAc"), toluene ("PhCH3"), or a mixture thereof. 97d. The method of detail 96d, wherein the solvent is acetonitrile. 98d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91d, 92d, 93d, 94d, 95d, 96d, and 97d, wherein the temperature at which the reaction is carried out is from about -10°C to about 80°C. 99d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91d, 92d, 93d, 94d, 95d, 96d, and 97d, wherein the temperature at which the reaction is carried out is from about 35°C to about 70°C. 100d. The method of details 81d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91d, 92d, 93d, 94d, 95d, 96d, 97d, 98d, and 99d, wherein the pressure at which the reaction is carried out is from about ambient pressure to 1000 kilopascals (kPa). 101d. The method of detail 100d, wherein the pressure is from ambient pressure to about 200 kPa. 102d. The method according to any one of 81d to 101d, wherein the reaction is carried out under flow conditions. 103d. A process comprising coupling S5a with S2a to produce S6a or S6a-HCl, wherein the coupling is carried out in the presence of a base, a solvent, and optionally a catalyst. [ka] 104d. The method of detail 103d, wherein the base is an organic base, an inorganic base, or a mixture thereof. 105d. The method of detail 103d, wherein the base is an organic base. 106d. The method of detail 103d, wherein the base is an inorganic base. 107d. The method of Details 103d, 104d, 105d, and 106d, wherein the base is pyridine, lutidine (e.g., 2,6-lutidine and 3,5-lutidine), picoline (e.g., 2-picoline and 3-picoline), N,N-diisopropylethylamine ("DIPEA"), triethylamine ("TEA"), potassium carbonate ("K2CO3"), potassium bicarbonate ("KHCO3"), potassium hydroxide ("KOH"), sodium carbonate ("Na2CO3"), sodium bicarbonate ("NaHCO3"), sodium hydroxide ("NaOH"), or a mixture thereof. 108d. The method of details 103d, 104d, 105d, 106d, and 107d, wherein about 1 mole to about 5 moles of base are used per mole of S5a. 109d. The method of detail 108d, wherein about 2.0 moles to about 3.5 moles of base are used per mole of S5a. 110d. The method of Details 103d, 104d, 105d, 106d, 107d, 108d, and 109d, wherein the catalyst is N,N-dimethylpyridin-4-amine ("DMAP"), N-methylimidazole ("NMI"), or a mixture thereof. 111d. The method of Details 103d, 104d, 105d, 106d, 107d, 108d, 109d, and 110d, wherein the solvent is a polar aprotic solvent, a non-polar aprotic solvent, or a mixture thereof. 112d. The method of detail 111d, wherein the solvent is ethyl acetate ("EtOAc"), isobutyl acetate ("i-BuOAc"), tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), dichloromethane ("DCM"), chloroform ("CHCl3"), acetonitrile ("ACN"), benzonitrile ("PhCN"), toluene ("PhCH3"), or a mixture thereof. 113d. The method of details 103d, 104d, 105d, 106d, 107d, 108d, 109d, 110d, 111d, and 112d, wherein the coupling is carried out at a temperature of from about -10°C to about 80°C. 114d. The method of detail 113d, wherein the temperature is about 0°C to 60°C. 115d. The method of details 103d, 104d, 105d, 106d, 107d, 108d, 109d, 110d, 111d, 112d, 113d, and 114d, wherein the coupling is performed at a pressure from ambient pressure to 1000 kilopascals (kPa). 116d. The method of detail 115d, wherein pressures from ambient pressure up to about 200 kPa may be used. 117d.S6a, (a) isolated as a free base form, or (b) used in the hydrochloride salt form (S6a-HCl) or hydrobromide salt form in solution, or (c) isolated in hydrochloride (S6a-HCl) or hydrobromide form; A method according to any one of details 103d to 116d above. 118d. Using a chlorinating agent in the presence of a polar solvent, (a) N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a) and / or (b) N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (S6a-HCl)); to produce N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (S7a). [ka] 119d. The method of detail 118d, wherein about 1 mole to about 5 moles of chlorinating agent are used per mole of S6a or S6a-HCl. 120d. The method of detail 118d, wherein about 1.0 mole to about 3.5 moles of chlorinating agent are used per mole of S6a or S6a-HCl. 121d. The method of details 118d, 119d, and 120d, wherein the chlorinating agent is chlorine, N-chlorosuccinimide ("NCS"), 1,1,3,3-dichlorodimethylhydantoin ("DCDMH"), N-chlorophthalimide ("NCP"), N-chlorosaccharin ("NCSH"), tert-butyl hypochlorite, chloramine-T, N-chlorobenzotriazole ("NCBT"), trichloroisocyanuric acid ("TCCA"), sodium hypochlorite, or a mixture thereof. 122d. The method of detail 121d, wherein the chlorinating agent is sodium hypochlorite. 123d. The method of detail 121d, wherein the chlorinating agent is chlorine. 124d. The method of details 118d, 119d, and 120d, wherein chlorination comprises contacting S6a-HCl with an oxidizing agent, preferably potassium hydrogen peroxymonosulfate sulfate (triple salt of formula 2KHSO5·KHSO4·K2SO4 [CAS 70693-62-8]). 125d. The method of detail 124d, wherein chlorinating further comprises adding a chloride salt or hydrochloric acid. 126d. The method of Details 118d, 119d, 120d, 121d, 122d, 123d, 124d, and 125d, wherein the polar solvent is a polar aprotic solvent, a polar protic solvent, or a mixture thereof. 127d. The method of detail 126d, wherein the solvent is 1,4-dioxane, tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), dichloromethane ("DCM"), ethyl acetate ("EtOAc"), isobutyl acetate ("i-BuOAc"), n-butanol ("n-BuOH"), isopropanol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), water ("HO"), acetic acid ("AcOH"), formic acid ("HCOOH"), aqueous hydrochloric acid ("HCl"), or a mixture thereof. 128d. The method of detail 127d, wherein the solvent is ethyl acetate. 129d. The method of detail 127d, wherein the solvent is acetic acid. 130d. The method of detail 1273d, wherein the solvent is aqueous hydrochloric acid. 131d. The method of details 118d, 119d, 120d, 121d, 122d, 123d, 124d, 125d, 126d, 127d, 128d, 129d, and 130d, wherein the chlorination is carried out at a temperature of from about -10°C to about 80°C. 132d. The method of detail 131d, wherein the temperature is about 0°C to about 50°C. 133d. The method of details 118d, 119d, 120d, 121d, 122d, 123d, 124d, 125d, 126d, 127d, 128d, 129d, 130d, 131d, and 132d, wherein the chlorination is carried out at a pressure from ambient pressure to about 1000 kilopascals (kPa). 134d. The method of detail 133d, wherein the chlorination is carried out at a pressure from ambient pressure to about 200 kPa. 135d. N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide molecule. [ka] 136d. A composition comprising a molecule as described in detail in 135d and HCl.

Claims

1. The following formula 【Chemistry 1】 or an agriculturally acceptable acid addition salt thereof.

2. The agriculturally acceptable acid addition salt is a hydrochloride salt (S6a-HCl), and is represented by the following formula: 【Chemistry 2】 2. The molecule of claim 1, having the formula:

3. (a) coupling S5a with S2a to produce a molecule (S6a) according to claim 1 or a molecule (S6a-HCl) according to claim 2, wherein the coupling is carried out in the presence of a base, a solvent, and optionally a catalyst. 【Transformation 3】 ;and (b) using a chlorinating agent in the presence of a polar solvent, (a) the molecule (S6a) according to claim 1 and / or (b) The molecule (S6a-HCl) according to claim 2 to produce N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (S7a). 【Chemistry 4】 A method comprising:

4. 4. The method of claim 3, wherein about 1 mole to about 5 moles of chlorinating agent are used per mole of S6a or S6a-HCl.

5. 4. The method of claim 3, wherein about 1.0 mole to about 3.5 moles of chlorinating agent are used per mole of S6a or S6a-HCl.

6. 6. The method of claim 3, 4, or 5, wherein the chlorinating agent is chlorine, N-chlorosuccinimide ("NCS"), 1,1,3,3-dichlorodimethylhydantoin ("DCDMH"), N-chlorophthalimide ("NCP"), N-chlorosaccharin ("NCSH"), tert-butyl hypochlorite, chloramine-T, N-chlorobenzotriazole ("NCBT"), trichloroisocyanuric acid ("TCCA"), sodium hypochlorite, or a mixture thereof.

7. 7. The method of claim 6, wherein the chlorinating agent is sodium hypochlorite.

8. 7. The method of claim 6 wherein the chlorinating agent is chlorine.

9. The chlorination is carried out by reacting the molecule (S6a-HCl) according to claim 2 with an oxidizing agent, preferably potassium hydrogen peroxymonosulfate sulfate (formula 2KHSO ５ ・KHSO ４ ・K ２ SO ４ 6. The method of claim 3, 4, or 5, comprising contacting a compound of formula (I) with a triple salt of formula (II) [CAS 70693-62-8].

10. 10. The method of claim 9, wherein the chlorinating further comprises adding a chloride salt or hydrochloric acid.

11. 11. The method of claim 3, 4, 5, 6, 7, 8, 9, or 10, wherein the polar solvent is a polar aprotic solvent, a polar protic solvent, or a mixture thereof.

12. The solvent may be 1,4-dioxane, tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("2-MeTHF"), acetonitrile ("ACN"), dichloromethane ("DCM"), ethyl acetate ("EtOAc"), isobutyl acetate ("i-BuOAc"), n-butanol ("n-BuOH"), isopropanol ("i-PrOH"), n-propanol ("n-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), water ("H ２ 12. The method of claim 11 , wherein the aqueous solution is acetic acid ("AcOH"), aqueous hydrochloric acid, or a mixture thereof.

13. 11. The method of claim 10, wherein the solvent is ethyl acetate, aqueous hydrochloric acid, or acetic acid.

14. 14. The method of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the chlorination is carried out at a temperature of from about -10°C to about 80°C, or from about 0°C to 50°C.

15. 15. The method of claim 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein the chlorination is carried out at a pressure from ambient pressure to about 1000 kilopascals (kPa), or from ambient pressure to about 200 kPa.

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