WO2024168001A1

WO2024168001A1 - Processes related to formation of n-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)- n-ethyl-3-(methylsulfonyl)propanamide

Info

Publication number: WO2024168001A1
Application number: PCT/US2024/014736
Authority: WO
Inventors: Nakyen Choy; Megan CISMESIA; David J. COULING; Taxiarchis Minas GEORGIADIS; Kaitlyn C. Gray; Janelle K. KIRSCH; Daniel Kohlman; Kumar ITYALAM; Jeffrey Scott Nissen; Aditya N. PATIL; Brandon REIZMAN; Neeraj Sane; Zican SHEN; Tony K. Trullinger; Qiang Yang; Gary Alan Roth
Original assignee: Corteva Agriscience LLC
Current assignee: Corteva Agriscience LLC
Priority date: 2023-02-07
Filing date: 2024-02-07
Publication date: 2024-08-15
Anticipated expiration: 2025-08-07
Also published as: EP4661672A1; AR131810A1; CN120659539A

Abstract

This disclosure relates to a molecule, N-ethyl-3-(methylsulfonyl)-N-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a) or its hydrochloride salt (S6a-HCl), and processes to prepare S6a, S6a-HCl, and N-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-N-ethyl-3-(methylsulfonyl)propanamide (S7a), having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda.

Description

PROCESSES RELATED TO FORMATION OF N-(4-CHLORO-2-(PYRIDIN-3- YL)THIAZOL-5-YL)-/V-ETHYL-3-(METHYLSULFONYL)PROPAN AMIDE

BACKGROUND OF THIS DISCLOSURE

Formation of 2-(pyridin-3-yl)thiazoles has been disclosed in applications WO 2010/129497; WO 2013/184475; WO 2013/184476; WO 2013/184480; and PCT/US2022/074322.

DETAILED DESCRIPTION OF THIS DISCLOSURE

A molecule, Y-ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (also known as “S6a” herein), or agriculturally acceptable acid addition salts having the following formula is provided. Molecule S6a has shown activity against green peach aphid (Myzus persicae i.e., 71% control at 200 parts per million (ppm)).

An example of an agriculturally acceptable acid addition salt is the hydrochloride salt (also known as “S6a-HCl” herein).

Additionally, processes to make and use a molecule of S6a or S6a-HCl are provided. The molecule S6a or S6a-HCl may be useful in the process to prepare /V-(4-chloro-2-(pyridin-3- yl )thiazol-5-yl )-/V-ethyl-3-(methyl sulfonyl )propanamide (S7a).

The following are processes related to the formation of /V-(4-chloro-2-(pyridin-3- yl)thiazol-5-yl)-7V-ethyl-3-(methylsulfonyl)propanamide (also known as “S7a” herein) and shown below.

In embodiment one of Scheme One

Scheme One

Sla Sib

The reaction in Scheme One is conducted in the presence of an oxidizing agent that oxidizes 3-(methylthio)propanoic acid (also known as “Sla” herein) to 3- (methylsulfonyl)propanoic acid (also known as “Sib” herein). In other words, functionally the oxidizing agent oxidizes the thioether (-SCH3) to the sulfone (-S(=O)2CH ). Examples of oxidizing agents are oxygen (O2), sodium hypochlorite (NaOCl), ozone (O3), hydrogen peroxide (H2O2), organic peroxides, organic peracids (-OOH), and other inorganic oxidants, such as, potassium peroxymonosulfate, potassium persulfate, potassium hydrogen peroxymonosulfate sulfate (a triple salt with the formula 2KHSOs KHSO4 K2SO4 [CAS 70693-62-8] available from E.I. du Pont de Nemours and Company or its affiliates as OXONE®, a registered trademark of E.I. du Pont de Nemours and Company or its affiliates). In general, about 2 moles to about 4 moles of oxidizing agent per mole of Sla, preferably, about 2.0 moles to about 3.0 moles of oxidizing agent per mole of Sla may be used. Mixtures of oxidizing agents may also be used.

The reaction in Scheme One is conducted 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”), AfA-dimethylformamidc (“DMF”), and dimethyl sulfoxide (“DMSO”). Examples of polar protic solvents are acetic acid (“AcOH”), //-butanol (“n-BuOH”), isopropanol (“z-PrOH”), zz-propanol (“zz-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), formic acid (“HCOOH”), Zc/7-butyl alcohol (“Z-BuOH”), and water (“H2O”). Optionally, mixtures of such polar solvents may be used.

The reaction in Scheme One may be conducted at ambient temperatures (about 15 °C to about 25 °C) and ambient pressures from about 95 kilopascal (kPa) to about 105 kPA (usually about 101 kPa). However, higher and lower temperatures and pressures may be used. In embodiment one of Scheme Two

Scheme Two

Sib S2a wherein

A is Cl, O(C=O)Ri, or ORi, wherein Ri is (Ci-C4)alkyl.

The reaction in Scheme Two is conducted in the presence of a carboxylic acid activator.

Activated carboxylic acids S2a may include acid chlorides, mixed anhydrides and esters. Acid chlorides may be prepared from the corresponding carboxylic acid by treatment with a dehydrating chlorinating reagent, such as oxalyl chloride or thionyl chloride. Mixed anhydrides may be prepared from carboxylic acids with chloroformates (RiO(C=O)Cl) such as ethyl, methyl, and isobutyl chloroformate or other acid chlorides such as pivaloyl chloride. Esters can be generated from the reaction of Sib with alcohols such as methanol or ethanol under acidic conditions. In general, about 1.0 moles to about 5 moles of activator per mole of Sib, more preferably, about 1.0 moles to about 1.5 moles of activator per mole of Sib may be used.

Optionally, a catalyst may be used to promote the reaction of Sib to the activated form S2a. Examples of catalysts include A^f, A-dimethylformamide, A -formyl pyrrolidine, and A- formylpiperidine. In general, about 0.01 to 0.5 moles of catalyst per mole of Sib, more preferably, about 0.05 moles to about 0.1 moles of catalyst per mole of Sib may be used.

The reaction in Scheme Two is conducted in the presence of an aprotic solvent. Examples of aprotic solvents are polar aprotic solvents and nonpolar aprotic solvents. Examples of polar aprotic solvents are ethyl acetate (“EtOAc”), tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), dichloromethane ("DCM”), chloroform (“CHCI3”), acetonitrile (“ACN”), and benzonitrile (“PhCN”). An example of a nonpolar aprotic solvent is and toluene (“PI1CH3”). Optionally, mixtures of such solvents may be used.

The reaction in Scheme Two may be conducted at ambient temperatures and ambient pressures. However, higher or lower temperatures and pressures may be used. Currently, temperatures from about 0 °C to about 100 °C may be used, temperatures from about 50 °C to about 80 °C may be used, preferably temperatures from about 20 °C to about 60 °C may be used. The compound S2a may be isolated and used or used directly without isolation in the subsequent reaction.

In one embodiment of Scheme Three

Scheme Three

= CH

S4a, amine

^S3' ^R2 - Cfi S3a, R₂ 2^CH3 S4a-HCI, amine hydrochloride

The reaction in Scheme Three may provide either the amine (S4a) or the amine hydrochloride (S4a-HCl).

Alternatively, the product of Scheme Three may be prepared as the free amine (S4a) in one step from methyl or ethyl glycinate hydrochloride (also known as “S3/3a” herein) by the reaction shown in Scheme Three in the presence of ethylamine and a secondary base. Examples of secondary bases are organic bases 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 (“NaHCCh”), and sodium hydroxide (“NaOH”). Optionally, the secondary base can be added after the reaction is complete. In general, about 1 mole to about 15 moles of ethylamine per mole of S3/3a may be used; more preferably, about 5 moles to about 12 moles of ethylamine per mole of S3/3a may be used. In general, about 0.8 moles to about 2 moles of secondary base per mole of S3/3a may be used; more preferably, about 0.8 to about 1.2 moles of secondary base per mole of S3/3a may be used.

Optionally, the reaction in Scheme Three is conducted in the presence of a polar or a 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”), anisole, and acetonitrile (“ACN”). Examples of polar protic solvents are //-butanol (“n-BuOH”), sec-butanol (“s-BuOH”), 4-methyl-2-pentanol (“MIBC”), isopropanol (“z-PrOH”), zz-propanol (“zz-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), and water (“H2O”). An example of a nonpolar solvent is toluene (“PhCHs”). Optionally, mixtures of such solvents may be used. Water is preferred.

The reaction in Scheme Three may be conducted at ambient temperatures and pressures. However, higher or lower temperatures and pressures may be used. Currently, temperatures from about -20 °C to about 50 °C may be used; preferably temperatures from about -10 °C to 10 °C may be used. Currently, pressures from ambient to 1000 kilopascal (kPa) may be used; preferably pressures from ambient to about 200 kPa may be used.

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

Optionally, the reaction in Scheme Three to produce amine S4a may be conducted under flow conditions. Flow conditions are known in the art. See for example Luis, Santiago V., and Eduardo Gar ci a- Verdugo, eds. Chemical reactions and processes underflow conditions. No. 5. Royal Society of Chemistry, 2010.

Optionally, S4a may be converted to the hydrochloride (HC1) salt (S4a-HCl) by treatment with anhydrous HC1 or aqueous HC1, subsequent to the reaction with ethylamine. In general, about 1 mole to about 10 moles of HC1 per mole S4a may be used; more preferably, 1 mole to about 3 moles of HC1 per mole of S4a may be used. The formation of the HC1 salt form is conducted 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-di oxane, ethyl acetate (“EtOAc”), methyl Ze/7-butyl ether (“MTBE”), and cyclopentyl methyl ether (“CPME”). Examples of polar protic solvents are ec-butanol (“s-BuOH”), 4-methyl-2-pentanol (“MIBC”), isopropanol (“z-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), and water (“H2O”). Optionally, mixtures of such polar solvents with each other or with nonpolar solvents such as toluene may be used.

In one embodiment of Scheme Four

Scheme Four

S4a-HCI

The reaction in Scheme Four converts S4a or S4a-HCl to the pyridylthioamide S4A-a using 3-pyridinecarboxaldehyde (nicotinaldehyde) in the presence of sulfur and a base in solvents.

The reaction in Scheme Four is conducted in the presence of 3-pyridinecarboxaldehyde, also known as nicotinaldehyde, a Bronsted base, and sulfur. In general, about 0.5 mole to about 5 moles of 3-pyridinecarboxaldehyde per mole of S4a or S4a-HCl can be used; more preferably, about 0.7 mole to about 1.3 moles of 3-pyridinecarboxaldehyde per mole of S4a or S4a-HCl can be used. Commercially available forms of 3-pyridinecarboxaldehyde include the neat form or as an aqueous solution, both of which can be used. In general, about 1 mole to about 5 moles of sulfur per mole of S4a or S4a-HCl can be used; more preferably, about 1.0 mole to about 3.5 moles of sulfur per mole of S4a or S4a-HCl can be used. In general, about 0.05 mole to about 5 moles of Bronsted base per mole of S4a or S4a-HCl can be used; more preferably, about 0.1 mole to about 1.2 moles of Bronsted base per mole of S4a or S4a-HCl can be used. Examples of Bronsted bases are potassium carbonate (“K2CO3”), potassium phosphate (“K3PO4”), triethylamine (“TEA”), pyridine, sodium acetate (“NaOAc”), sodium bicarbonate (“NaHCCh”), sodium hydrosulfide (“NaSH”), sodium sulfide (“NazS”), imidazole, potassium /c/7-butoxide (“KO/Bu”), and .V,A'-diisopropylethylamine (“DIPEA”). Sodium sulfide and triethylamine are preferred.

The reaction in Scheme Four can be conducted in the presence of a polar aprotic or a polar protic solvent or a nonpolar aprotic solvent. Examples of polar aprotic solvents are tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), benzonitrile (“PhCN”), butyronitrile, cyclopentylmethyl ether (“CPME”), dimethyl carbonate (“DMC”), ethyl acetate (“EtOAc”), isopropyl acetate (“z-PrOAc”), A'-di methyl form am ide (“DMF”), A, V-dimethylacetamide (“DMAC”), isobutyl acetate (“/-BuOAc”), methyl ethyl ketone (“MEK”), dichloromethane (“DCM”), chlorobenzene (“PhQ”), and acetone. Examples of polar protic solvents are //-butanol (“n-BuOH”), ec-butanol (“s-BuOH”), 4-methyl-2-pentanol (“MIBC"), isopropanol (“z'-PrOH”), //-propanol (“//-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), and water (“H2O”). An example of a nonpolar aprotic solvent is toluene (“PI1CH3”). Optionally, mixtures of such solvents may be used. Water and toluene are preferred.

The reaction in Scheme Four may be conducted at ambient temperatures, pressures and pH. However, higher or lower temperatures, pressures and pH may be used. Currently, temperatures from about -10 °C to about 100 °C may be used; preferably temperatures from about 35 °C to 70 °C may be used. Currently, pressures from ambient to 1000 kilopascal (kPa) may be used; preferably pressures from ambient to about 200 kPa may be used. Currently, a pH from 6 to 13 may be used; preferably a pH from about 8 to 10 may be used.

In one embodiment of Scheme Four-A

Scheme Four-A

The reaction in Scheme Four-A converts S4A-a to the pyridylthi azole S5a in the presence of a Lewis or Bronsted acid. In some cases the reaction may result in an intermediate S5A-a requiring further manipulation to arrive at S5a.

Examples of Lewis acids or Bronsted acids are phosphorus oxychloride (“POCI3”), phosphorus trichloride (“PCI3”), phosphorus pentachloride (“PCI5”), trifluoromethanesulfonic anhydride (“TfzO”), trifluoroacetic anhydride (“TFAA”), boron trifluoride diethyl etherate (“BF3*OEt2”), trimethylsilyl trifluoromethanesulfonate (“TMSOTf’), trifluoromethanesulfonic acid (“TfOH”), methanesulfonic acid (“MsOH”), Eaton’s reagent (“P2O5-MSOH”), hydrogen bromide (“HBr”), aqueous hydrobromic acid (“aqueous HBr”), hydrogen bromide in acetic acid (“HBr in AcOH”), trifluoroacetic acid (“TFA”), >-toluenesulfonic acid (“ -TSA”), sulfuric acid (“H2SO4”), and solid supported acidic resins. Phosphorus oxychloride and phosphorus trichloride are preferred. Other Lewis acids or Bronsted acids may be used resulting in an intermediate requiring further manipulation to arrive at S5a. In general, about 0.5 mole to about 50 moles of Lewis acid or Bronsted acid per mol of S4A-a can be used; more preferably, about 1 mole to about 5 moles of Lewis acid or Bronsted acid per mole of S4A-a can be used.

In one embodiment of Scheme Four- A, the reaction can be conducted in the presence of a presence of a polar aprotic or a nonpolar aprotic solvent. Examples of polar aprotic solvents are tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), benzonitrile (“PhCN”), cyclopentylmethyl ether (“CPME”), dimethyl carbonate (“DMC”), chlorobenzene (“PhQ”), and ethyl acetate (“EtOAc”). An example of a nonpolar aprotic solvent is toluene (“PhCFL”). Optionally, mixtures of such solvents may be used. Acetonitrile is preferred.

The reaction in Scheme Four-A may be conducted at ambient temperatures and pressures. However, higher or lower temperatures and pressures may be used. Currently, temperatures from about -10 °C to about 80 °C may be used; preferably temperatures from about 45 °C to 75 °C may be used. Currently, pressures from ambient to 1000 kilopascal (kPa) may be used; preferably pressures from ambient to about 200 kPa may be used.

Optionally, the reaction in Scheme Four-A to produce amine S5A-a may be conducted under flow conditions.

In one embodiment of Scheme Five

Scheme Five

S4a-HCI

The reaction in Scheme Five is conducted in the presence of 3-pyridinecarboxaldehyde, also known as ni cotinaldehyde, a Bronsted base, sulfur, and a Lewis acid or Bronsted acid which promotes the formation of S5a from S4a or S4a-HCl. In general, about 0.5 mole to about 5 moles of 3-pyridinecarboxaldehyde per mol of S4a or S4a-HCl can be used; more preferably, about 0.7 mole to about 1.3 moles of 3-pyridinecarboxaldehyde per mole of S4a or S4a-HCl can be used. Commercially available forms of 3-pyridinecarboxaldehyde include the neat form or as an aqueous acidic solution both of which can be used. In general, about 1 mole to about 5 moles of sulfur per mole of S4a or S4a-HCl can be used; more preferably, about 1.0 mole to about 3.5 moles of sulfur per mole of S4a or S4a-HCl can be used. In general, about 0.05 mole to about 5 moles of Bronsted base per mol of S4a or S4a-HCl can be used; more preferably, about 0.1 mole to about 1.2 moles of Bronsted base per mole of S4a or S4a-HCl can be used. In general, about 0.5 mole to about 50 moles of Lewis acid or Bronsted acid per mol of S4a or S4a-HCl can be used; more preferably, about 1 mole to about 5 moles of Lewis acid or Bronsted acid per mole of S4a or S4a-HCI can be used. Examples of Bronsted bases are potassium carbonate (“K2CO3”), potassium phosphate (“K3PO4”), triethylamine (“TEA”), pyridine, sodium acetate (“NaOAc”), sodium bicarbonate (“NaHCCh”), sodium hydrosulfide (“NaSH”), sodium sulfide (“Na2S”), imidazole, potassium tert-butoxide (“KO/Bu”), and A,A-diisopropylethylamine (“DIPEA”). Sodium sulfide and triethylamine are preferred. Examples of Lewis acids or Bronsted acids are phosphorus oxychloride (“POCI3”), phosphorus trichloride (“PCI3”), phosphorus pentachloride (“PCh”), trifluoromethanesulfonic anhydride (“TfzO”), boron trifluoride diethyl etherate (“BF3*OEt2”), trimethyl silyl trifluoromethanesulfonate (“TMSOTf’), trifluoromethanesulfonic acid (“TfOH”), methanesulfonic acid (“MsOH”), Eaton’s reagent (“P2O5-MSOH”), hydrogen bromide (“HBr”), aqueous hydrobromic acid (“aqueous HBr”), hydrogen bromide in acetic acid (“HBr in AcOH”), trifluoroacetic acid (“TFA”),/?-toluenesulfonic acid (“ -TSA”), sulfuric acid (“H2SO4”), and solid supported acidic resins. Phosphorus oxychloride and phosphorus trichloride are preferred. In some cases, the reaction may result in an intermediate requiring further manipulation to arrive at S5a.

The reaction in Scheme Five can be conducted in the presence of a polar aprotic or a nonpolar aprotic solvent. Examples of polar aprotic solvents are tetrahydrofuran (“THF”), 2- methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), benzonitrile (“PhCN”), cyclopentylmethyl ether (“CPME”), dimethyl carbonate (“DMC”), chlorobenzene (“PhCl”), and ethyl acetate (“EtOAc”). An example of a nonpolar aprotic solvent is toluene (“PhCEL”). Optionally, mixtures of such solvents may be used. Acetonitrile is preferred. The reaction in Scheme Five may be conducted at ambient temperatures and pressures.

However, higher or lower temperatures and pressures may be used. Currently, temperatures from about -10 °C to about 80 °C may be used; preferably temperatures from about 35 °C to 70 °C may be used. Currently, pressures from ambient to 1000 kilopascal (kPa) may be used; preferably pressures from ambient to about 200 kPa may be used.

Optionally, the reaction in Scheme Five to produce amine S5A-a (Scheme Four-A) and S5a may be conducted under flow conditions.

In one embodiment of Scheme Six

The reaction in Scheme Six is conducted in the presence of a base. The treatment of S5a with a base initially produces 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 bases 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), /V,,V-di isopropyl ethyl amine (“DIPEA”), and triethylamine (“TEA”). Examples of inorganic bases are potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), potassium hydroxide (“KOH”), sodium carbonate (“Na2CO3”), sodium bicarbonate (“NaHCOs”), and sodium hydroxide (“NaOH”). In general, about 1 mole to about 5 moles of base per mole of S5a can be used; more preferably, about 2.0 moles to about 3.5 moles of base per mole of S5a may be used. The coupling reaction with S2a can also be catalyzed by a reagent such as N, A-dimethylpyridin-4-amine (“DMAP”) or A-m ethyl imidazole (“NMI”).

The reaction in Scheme Six is conducted in the presence of a polar aprotic solvent or nonpolar aprotic solvents. Examples of polar aprotic solvents are ethyl acetate (“EtOAc”), isobutyl acetate (“/-BuOAc”), tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), dichloromethane ("DCM”), chloroform (“CHCh”), acetonitrile (“ACN”), and benzonitrile (“PhCN”). An example of a nonpolar aprotic solvent is toluene (“PhCHs”). Optionally, mixtures of such solvents may be used.

The reaction in Scheme Six may be conducted at ambient temperatures and pressures. However, higher or lower temperatures and pressures may be used. Currently, temperatures from about -10 °C to about 80 °C may be used; preferably temperatures from about 0 °C to 60 °C may be used. Currently, pressures from ambient to 1000 kilopascal (kPa) may be used; preferably pressures from ambient to about 200 kPa may be used.

The product of Scheme Six may 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 the hydrochloride (“HC1 salt”, S6a-HCl) and the hydrobromide (“HBr salt”), of which the hydrochloride salt is preferred. S6a may be isolated from polar protic (e.g., water and alcohols such as methanol), polar aprotic, or nonpolar solvents or mixtures thereof. Optionally a base may be used.

In one embodiment of Scheme Seven

Scheme Seven

S6a-HCI

The reaction in Scheme Seven is conducted in the presence of a chlorinating agent. N- Ethyl-3-(methylsulfonyl)-7V-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a) or /V-ethyl-3- (methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl )propanamide hydrochloride (S6a-HCl) is chlorinated to form A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A-ethyl-3- (methylsulfonyl)propanamide (S7a). In general, about 1 mole to about 5 moles of chlorinating agent per mole of S6a or S6a-HCl can be used; more preferably, about 1.0 mole to about 3.5 moles of chlorinating agent per mole of S6a or S6a-HCl can be used. Examples of chlorinating agents include chlorine, A-chlorosuccinimide (“NCS”), 1,1,3,3-dichlorodimethylhydantoin (“DCDMH”), A-chlorophthalimide (“NCP”), /V-chlorosaccharin (“NCSH”), tert- butylhypochlorite, chloramine-T, A-chlorobenzotri azole (“NCBT”), trichloroisocyanuric acid (“TCCA”), and sodium hypochlorite. Chlorine or sodium hypochlorite are preferred.

The reaction in Scheme Seven is conducted in the presence of a polar solvent. Examples of polar aprotic solvents are 1,4-di oxane, tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2- MeTHF”), acetonitrile (“ACN”), dichloromethane (“DCM”), ethyl acetate (“EtOAc”) and isobutyl acetate (“/-BuOAc”). Examples of polar protic solvents are //-butanol (“//-BuOH”), isopropanol (“z-PrOH”), //-propanol (“n-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), water (“H2O”), acetic acid (“AcOH”), formic acid (“HCOOH”), and aqueous hydrochloric acid (“HC1”). Aqueous HC1 is preferred. Optionally, mixtures of such solvents may be used.

The reaction in Scheme Seven may be conducted at ambient temperatures and pressures. However, higher or lower temperatures and pressures may be used. Currently, temperatures from about -10 °C to about 80 °C may be used, preferably temperatures from about 0 °C to 50 °C may be used. Currently, pressures from ambient to 1000 kilopascal (kPa) may be used; preferably pressures from ambient to about 200 kPa may be used.

In another embodiment of Scheme One, a catalyst may be used in the process to promote the reaction from Sla to Sib when the oxidizing agent used is hydrogen peroxide (H2O2). An example of a catalyst is sodium tungstate.

In another embodiment of Scheme Two, optionally, a base may be used to promote the reaction of Sib to the activated form S2a. Examples of bases include lutidine (e.g., 2,6-lutidine and 3,5-lutidine), picoline (e.g., 2-picoline and 3-picoline), A-methylmorpholine, tri ethylamine (“TEA”), and MA'-diisopropylethylamine (“DIPEA”). In general, about 0.1 to 1.5 moles of base per mole of Sib, more preferably, about 0.5 moles to about 1.2 moles of base per mole of Sib may be used.

The reaction in Scheme Two may be conducted at ambient temperatures and ambient pressures. However, higher or lower temperatures and pressures may be used. Currently, temperatures from about 0 °C to about 100 °C may be used, preferably temperatures from about 20 °C to about 49 °C may be used. In another embodiment of Scheme Three, optionally, amine S4a maybe isolated as a solution by extraction from the reaction solvent with a polar or a 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 (“z-PrOAc”), //-butyl acetate, (“//-BuOAc”), dimethylcarbonate (“DMC”), methyl tert- butyl ether, (“MTBE”), anisole, butyronitrile, and acetonitrile (“ACN”). Examples of polar protic solvents are ec-butanol (“s-BuOH”) and 4-methyl-2-pentanol (“MIBC”). An example of a nonpolar solvent is toluene. Optionally, mixtures of such solvents may be used.

In another embodiment of Scheme Four, the 3-pyridinecarboxaldehyde (nicotinaldehyde) from the aqueous solution can be extracted using a polar aprotic or a nonpolar aprotic solvent and 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 dimethylcarbonate (“DMC”). Examples of nonpolar aprotic solvents are toluene and xylene. Optionally, mixtures of such solvents may be used. Toluene and ethyl acetate are preferred.

In another embodiment of Scheme Four-A, sulfuric acid (“H2SO4”) is the preferred Lewis or Bronsted acid. In another embodiment of Scheme Four-A, preferably temperatures from about 10 °C to 44 °C may be used. In another embodiment of Scheme Four-A, the free amine S5A-a may be isolated.

In another embodiment of Scheme Four-A, the free-base S5A-a may be converted to the HC1 salt form, S5a, by treatment with anhydrous HC1 or aqueous HC1.

In another embodiment of Scheme Six, S5a may be utilized in the reaction without first producing the free-base form of S5a, S5A-a.

In another embodiment of Scheme Seven, A-ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3- yl)thiazol-5-yl)propanamide hydrochloride (S6a-HCl) is chlorinated to form A’-(4-chl oro-2- (pyndin-3-yl)thiazol-5-yl)-A-ethyl-3-(methylsulfonyl)propanamide (S7a) in the presence of a chlorinating agent, wherein the chlorinating agent includes an oxidizing agent. An example of an oxidizing agent is potassium hydrogen peroxymonosulfate sulfate (a triple salt with the formula 2KHSO5 KHSO4 K2SO4 [CAS 70693-62-8] available from E.I. du Pont de Nemours and Company or its affiliates as OXONE®, a registered trademark of E.I. du Pont de Nemours and Company or its affiliates). The reaction proceeds in the presence of a chloride source (e.g., the hydrogen chloride salt of S6a-HCl), or, for example, by the addition of chloride salt (e.g., sodium chloride) and/or or hydrochloric acid.

EXAMPLES

Example

To a 5-liter (L) jacketed reactor equipped with a mechanical stirrer and nitrogen inlet were added 3-(methylthio)propanoic acid (Sla; 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 to the homogeneous clear solution was added Oxone® (1191 g, 3.89 mol) in portions to control the internal temperature to below 30 °C. After addition was complete the white slurry was stirred until the internal temperature returned to 20 °C (~1 hour). The jacket was heated to 40 °C. Once the reaction was complete as monitored by ¹ H NMR spectroscopy, the jacket was cooled to 20 °C, and sodium bisulfite was added to quench the peroxide. After 60 minutes and confirmation of a peroxide quench, the solution was concentrated to a solid. The resulting white solid was dissolved in acetonitrile (1 L) giving a slurry with residual salts. The mixture was filtered to remove the salts, and the filtrate was concentrated to provide a white solid which was dried in a vacuum oven at 40 °C giving 3-(methylsulfonyl)propanoic acid (167 g, 88%) which was used as is in the next step: mp 94.0-99.2 °C; ^rH NMR (500 MHz, DMSO-tifc) 5 12.54 (s, 1H), 3.33 (t, J = 7.5 Hz, 2H), 3.00 (s, 3H), 2.68 (t, J= 7.5 Hz, 2H); ¹³C NMR (126 MHz, DMSO- e) 5 171.12, 48.74, 39.62, 26.50. Example

Sib S2a-1

A 500 mL three-neck round bottomed flask equipped with a nitrogen inlet, reflux condenser, vent tube to a 1 Normal (N) sodium hydroxide (NaOH) base scrubber, and a stir bar was charged with 3 -(methyl sulfonyl)propanoic acid (Sib; 50 g, 329 mmol) and toluene (299 mL) to give a heterogeneous solution. To this was added thionyl chloride (493.5 mmol), and the solution was heated to an internal temperature of 70-75 °C. The reaction mixture was stirred at this temperature with monitoring for reaction completion. The reaction mixture was cooled to room temperature at which time significant solid formation was observed. Heptane (250 mL) was added to the slurry, and the mixture was stirred for 10 minutes. The white solids were isolated by filtration under nitrogen (to avoid degradation) and washed with heptane to yield a white solid (52.14 g, 93%): 'H NMR (500 MHz, CDCh) 8 3.51 - 3.46 (m, 2H), 3.43 - 3.38 (m, 2H), 3.00 (s, 3H); ¹³C NMR (126 MHz, CDCh) 8 171.8, 49.5, 41.6, 39.3.

Example

Sib S2a-1

3-(Methylsulfonyl)propanoic acid (Sib; 2.04 g, 13.5 mmol) was charged into a three- neck 100 mL round bottom flask fitted with a condenser, overhead stirrer with a pitch blade impeller, a thermocouple, and an outlet to nitrogen with a NaOH scrubber. Acetonitrile (31 .8 g) was added to the flask which was heated to 40 °C. Thionyl chloride (1.86 g, 15.6 mmol) was added to the flask dropwise over ten minutes. The clear solution was held at 40 °C for 1 hour 40 minutes (until proton NMR spectroscopy indicated >98% conversion). The solution of acid chloride can be used directly in the amide coupling (Example 12). 'l l NMR (500 MHz, CDCh) 8 3.51 - 3.46 (m, 2H), 3.43 - 3.38 (m, 2H), 3.00 (s, 3H); ¹³C NMR (126 MHz, CDC1₃) 8 171.8, 49.5, 41.6, 39.3.

Example 4: Synthesis of 2-amino-2V-ethylacetamide (S4a)

To a 250-mL jacketed reactor was added ethylamine (70 wt% in water; 152 mL, 1912 mmol), and the solution was cooled to -5 °C. Methyl glycinate hydrochloride S3 (20 g, 159 mmol) in water (40 mL) was added to the ethylamine by syringe pump over 2 hours. The solution was stirred at -5 °C. After 45 minutes, a 50 wt% aqueous solution of sodium hydroxide (12.7 g, 159 mmol) was added, and the reaction mixture was warmed to 25 °C. The solution was concentrated at a reduced pressure of 0.9 kPa and a jacket temperature of 50 °C to provide an oil with white solid. ACN (125 mL) was added, and the resulting slurry was concentrated to 50% of the volume, at a reduced pressure of 6.7 kPa and a jacket temperature of 50 °C. The slurry was fdtered and washed with ACN (50 mL). The fdtrate was concentrated at a reduced pressure of 0.9 kPa and a jacket temperature of 50 °C to provide 2-amino-A-ethylacetamide as a clear, colorless oil (15.83 g): *HNMR (500 MHz, DMSO-t7₆) 8 7.78 (s, 1H), 3.14 - 3.06 (m, 2H), 3.04 (s, 2H), 1.02 (t, J= 7.2 Hz, 3H); ¹³C NMR (126 MHz, DMSO-tfc) 8 173.04, 45.27, 33.50, 15.34.

S4a

A 250-mL jacketed reactor under nitrogen equipped with a mechanical stirrer and thermocouple was charged with a solution of ethylamine in water (66-72 wt%, 128.26 g, 1991.24 mmol) and cooled to an internal temperature of -4 °C. A 40 wt% solution of methyl glycinate hydrochloride S3 (50.0 g, 398.25 mmol) in water (75 g) was gradually added to the reactor over 2 hours, maintaining the temperature below 3 °C. Sodium hydroxide (50%, 15.93 g, 398.25 mmol) was added over 10 minutes. The reaction was then equipped with a vacuum distillation apparatus and the bath was warmed to 95 °C to distill out the methanol and ethylamine until the volume of the bottoms stabilized. The bath temperature was decreased to 65 °C and the distillation was continued at a reduced pressure of 10 kPa until ethylamine was undetected in the bottoms. S4a was isolated as a 25 wt% aqueous solution (149.72 g, 90% yield).

Example 6: Synthesis of 2-amino-JV-ethylacetamide (S4a)

A 250-mL jacketed reactor under nitrogen equipped with a mechanical stirrer and thermocouple was charged with a solution of ethylamine in water (66-72 wt%, 127.45 g, 1978.60 mmol) and cooled to an internal temperature of -4 °C. A solution of methyl glycinate hydrochloride S3 (50.49 g, 398. 13 mmol) in water (75 g) was gradually added to the ethylamine reactor over 2 hours. The temperature was increased to 0 °C and the reaction mixture was stirred for 1 hour. A 43 wt% aqueous solution of sodium hydroxide (37.05 g, 398.82 mmol) was added over 10 minutes. The reaction was then equipped with a vacuum distillation apparatus and the bath was warmed to 95 °C to distill out the methanol and ethylamine until the volume of the bottoms stabilized. The bath temperature was decreased to 65 °C and the distillation was continued at a reduced pressure of 10 kPa until ethylamine was undetected in the bottoms. The contents were filtered and transferred to a 1-L jacketed reactor under nitrogen equipped with a mechanical stirrer, thermocouple, and condenser already containing acetonitrile (388.76 g, 494.61 m ) over 1 hour. The temperature was increased to 91 °C to azeotropically distill out water and acetonitrile. The temperature was decreased to 25 °C and the reactor contents were filtered to remove the salts and washed with acetonitrile (86.3 g, 109.80 mb) to provide S4a as a 12 wt% solution in acetonitrile (245.06 g, 94% yield).

Example 7: Synthesis of 2-amino-/V-ethylacetamide (S4a)

S3a S4a A 250 mL jacketed reactor under nitrogen was charged with ethylamine (70 wt% in water) (159 mL, 2000 mmol) and the solution was cooled to -5 °C. Ethyl glycinate hydrochloride S3a (55.8 g, 400 mmol) in water (75 mL) was added to the ethylamine by syringe pump over 2 hours. The solution was stirred at -5 °C. After 45 minutes, 45 wt% aqueous potassium hydroxide (49.9 g, 400 mmol) was added, and the reaction mixture was warmed to 25 °C during which time a white slurry formed. The excess ethylamine was removed by distillation at 95 °C at ambient atmosphere. Subsequently, the system was slowly placed under vacuum at 10 kPa to remove residual water until ~30 wt%. The mixture was cooled to 5 °C and filtered to provide 2-amino-A- ethylacetamide S4a as a 32 wt% aqueous solution (109.5 g, 86% yield): 'H NMR (500 MHz, DMSO-tA) 8 7.78 (s, 1H), 3.14 - 3.06 (m, 2H), 3.04 (s, 2H), 1.02 (t, J= 7.2 Hz, 3H); ¹³C NMR (126 MHz, DMSO-tL) 6 173.04, 45.27, 33.50, 15.34.

Example 8: Synthesis of A-ethyl-2-(pyridine-3-carbothioamido)acetamide (S4A-a)

S4a S4A-a

A 1-L jacketed reactor under nitrogen and equipped with a mechanical stirrer, reflux condenser, scrubber containing bleach and sodium hydroxide, and thermocouple 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 (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 held under these conditions and monitored by HPLC analysis until complete (18 hours). The reaction was then cooled to 50 °C. Then, HC1 (16 wt% 94.7 g, 415.6 mmol) was added over 10 minutes and the reaction mixture was held for 15 minutes to allow the sweep to remove any potential H2S gas that is formed. Toluene (287 g, 331 .03 mL) was added over 5 minutes, and the solution was agitated 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 portion-wise until pH ~ 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 at 4 kPa to provide the title compound S4A-a as a yellow solid (24.5 g): mp = 145 °C; 'H NMR (400 MHz, CDCI3) 8 9.02 (dd, J= 2.4, 0.8 Hz, 1H), 8.70 (dd, J= 4.9, 1.7 Hz, 2H), 8.15 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.35 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 5.86 (s, 1H), 4.42 (d, J= 4.4 Hz, 2H), 3.40 (qd, J= 13, 5.6 Hz, 2H), 1.21 (t, .7= 7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 8 195.58, 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]⁺).

Example 9: Synthesis of A-ethyl-2-(pyridine-3-carbothioamido)acetamide (S4A-a)

S4a S4A-a

A 100-mL jacketed reactor under nitrogen equipped with a mechanical stirrer, thermocouple, and pH meter was charged with 15 wt% aqueous nicotinaldehyde (26.4 g, 36.97 mmol). 25 wt% Aqueous NaOH (17.55 mL) was added until pH 10. The solution was transferred to a 250-mL jacketed reactor equipped with a mechanical stirrer, reflux condenser, scrubber containing bleach and sodium hydroxide, and thermocouple flushed with nitrogen and already containing sulfur (1.51 g, 47.1 mmol). Acetonitrile (96.17, 122.34 mL) and 30.0 wt% aqueous solution of S4a (15.6, 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 held under these conditions and monitored by HPLC analysis until complete (18 hours). The reaction was then cooled to 50 °C. Then, HC1 (16 wt% 17.11 g, 75.30 mmol) was added over 5 minutes and the reaction was held for 15 minutes to allow the sweep to remove any potential H2S gas that is formed. Toluene (73.6 g, 84.89 mL) was added over 5 minutes and the solution was agitated for 10 minutes and then allowed to settle for 5 minutes. The aqueous layer was removed. The organic layer was concentrated under vacuum. The resulting solids were resuspended in acetonitrile (50 mL) and fdtered. The wet cake was washed with acetonitrile (2 x 50 mL) and dried in a vacuum oven at 50 °C at a reduced pressure of 4 kPa to provide the title compound S4A-a as a yellow solid (2.39 g, 29% yield): mp 145 °C; 'H NMR (400 MHz, CDCI3) 59.02 (dd, J= 2.4, 0.8 Hz, 1H), 8.70 (dd, J = 4.9, 1.7 Hz, 2H), 8.15 (ddd, J= 8.0, 2.4, 1.6 Hz, 1H), 7.35

(ddd, J= 8.0, 4.8, 0.9 Hz, 1H), 5.86 (s, 1H), 4.42 (d, J= 4.4 Hz, 2H), 3.40 (qd, J= 13, 5.6 Hz, 2H), 1.21 (t, J = 7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 8 195.58, 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]⁺).

Example 10: Synthesis of JV-ethyl-2-(pyridin-3-yl)-l,3-thiazol-5-amine dihydrochloride

(S5a)

S4A-a S5a

A 1 -L jacketed reactor under nitrogen equipped with a mechanical stirrer, reflux condenser with a vacuum distillation apparatus, peristaltic pump and thermocouple was charged withA-ethyl-2-(pyridine-3-carbothioamido)acetamide S4A-a (33.3 g, 148 mmol). To this was added acetonitrile (132 g, 168 mL) and the mixture was agitated at 70 °C. POCh (47.6 g, 310 mmol) was added dropwise over 1 hour, maintaining an internal temperature below 80 °C. The reaction was held under these conditions and monitored by HPLC analysis until complete. After 1 hour, the reaction mixture darkened significantly during the course of the reaction. When complete consumption of S4A-a was observed, the mixture was cooled to 50 °C and vacuum was applied to concentrate to 30 wt% product. The mixture was cooled to 0 °C and held for 12 hours, then filtered onto a sintered frit under a light vacuum and a pad of nitrogen. The solids were dried in a vacuum oven at a reduced pressure of 4 kPa at 40 °C for 16 hours to provide V-ethyl-2-(pyridin-3-yl)thiazol-5-amine dihydrochloride (30.3 g, 98 wt%, 81% yield, 108.8 mmol):

NMR (400 MHz, DMSO-t/e) 8 9.07 (d, J= 2.1 Hz, 1H), 8.71 (dd, J= 5.6, 1.3 Hz, 1H), 8.66 (ddd, J= 8.3, 2.2, 1.3 Hz, 1H), 7.97 (ddd, J= 8.3, 5.5, 0.7 Hz, 1H), 7.54 - 7.19 (m, 1H), 7.02 (s, 1H), 3.15 (q, J= 7.2 Hz, 2H), 1.21 (t, J= 7.2 Hz, 3H); ¹³C NMR (101 MHz, DMSO-t/r,) 8 155.15, 140.81, 139.39, 139.16, 136.62, 133.13, 127.52, 120.35, 41.56, 13.89; ESIMS m/z 206 ([M+H-2 HC1]⁺). Example 11: Synthesis of /V-ethyl-2-(pyridin-3-yl)-l,3-thiazol-5-amine dihydrochloride (S5a)

S4a-HCI S5a

To a 250-mL jacketed reactor under nitrogen equipped with an overhead stirrer, nitrogen inlet, reflux condenser and thermocouple were added 2-amino-A-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, leading to a white, thick slurry. Nicotinaldehyde (3.08 g, 28.8 mmol) was added leading to a thinner slurry. Sulfur solid 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 disappearance of nicotinaldehyde (which took ~5 hours). The reaction mixture was cooled to 50 °C. Phosphorus oxychloride (POCI3, 99%; 6.70 mL, 77.8 mmol) was added dropwise to the reaction mixture while keeping the internal temperature below 60 °C. The dark brown thin slurry/oil was stirred at 50 °C for 7 hours over which time a yellow slurry formed (monitored 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 afford the title compound S5a (4.73 g, 58%): ¹H NMR (400 MHz, DMSO-fifc) 5 9.07 (d, J= 2.1 Hz, 1H), 8.71 (dd, J= 5.6, 1.3 Hz, 1H), 8.66 (ddd, J= 8.3, 2.2, 1.3 Hz, 1H), 7.97 (ddd, J= 8.3, 5.5, 0.7 Hz, 1H), 7.54 - 7.19 (m, 1H), 7.02 (s, 1H), 3.15 (q, J= 7.2 Hz, 2H), 1.21 (t, J= 7.2 Hz, 3H); ¹³C NMR (101 MHZ, DMSO-t/e) 8 155.15, 140.81, 139.39, 139.16, 136.62, 133.13, 127.52, 120.35, 41.56, 13.89; ESIMS m/z 206 ([M+H-2 HC1]⁺). Example 12: Synthesis of and Isolation of V-ethyl-3-(niethylsulfonyl)- V-(2-(pyridin-3-

S5a S5A-a S6a-HCI

3-(Methylsulfonyl)propanoic acid (11.1 g, 1.5 equiv, 73.1 mmol) was charged into a 250 mL jacketed reactor with a bath temperature set to 25 °C followed by ACN (32.0 g, 779 mmol) and then agitated (internal temperature 23-24 °C). Thionyl chloride (8.69 g, 73.1 mmol) was added dropwise over 1 hour, maintaining an internal temperature < 30 °C. The solution was held at 25 °C for 2 hours after addition completion (3 hours total) to allow the acid to convert to the acid chloride, 3-(methylsulfonyl)propanoyl chloride.

In a separate 250 mL reactor with a bath temperature set to 25 °C, A-ethyl-2-(pyri din-3 - yl)thiazol-5-amine dihydrochloride (13.5 g, 48.7 mmol) and DCM (33.1 g, 390 mmol) were charged. Aqueous potassium carbonate (20 wt%, 70.7 g, 102 mmol) was added by peristaltic pump over 15 minutes. The mixture was agitated for 30 minutes at 25 °C. The agitation was stopped, and the phases were separated. The organic layer was re-loaded into the 250 mL reactor and the DCM was solvent swapped with acetonitrile via distillation to produce a solution of S5A-a

The solution of 3 -(methyl sulfonyl)propanoyl chloride S2a was transferred into the solution of S5A-a over 15 minutes via a peristaltic pump, maintaining an internal temperature < 30 °C. The reaction was stirred 12 hours at 25 °C then cooled to 0 °C for an additional 12 hours then filtered. The wet cake was washed with ACN (50 g), and the solids were dried in a vacuum oven for 18 hours (<50 mm Hg) to afford A-ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol- 5-yl)propanamide hydrochloride (12.1 g, 66% yield) as a mixture of rotamers: 'H NMR (400 MHz, D₂O) 5 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); ¹³C NMR (101 MHz, D2O) 8 171.63, 169.14, 160.98, 153.15, 143.54, 142.70, 142.17, 141.06, 140.03, 138.90, 137.78, 132.55, 132.38, 130.1 1, 128.00, 127.95, 49.63, 49.29, 45.99, 44.15, 40.55, 40.36, 27.01 , 26.33, 12.05, 1 1.84;

ESIMS m'z 340 ([M+H-HC1]⁺).

Example 13: Synthesis of and Isolation of 7V-ethyl-3-(methylsulfonyl)-7V-(2-(pyridin-3- yl)thiazol-5-yl)propanamide (S6a)

3-(Methylsulfonyl)propanoic acid (10.5 g, 68.7 mmol) was charged into a 250-mL jacketed reactor with a bath temperature set to 25 °C followed by ACN (30.1 g, mmol) and then agitated (internal temperature 23-24 °C). Thionyl chloride (7.91 g, 66.5 mmol) was added dropwise over 1 hour, maintaining an internal temperature < 30 °C. The solution was held at 25 °C for 2 hours to allow complete conversion to 3-(methylsulfonyl)propanoyl chloride.

In a separate 250 m reactor with a bath temperature set to 25 °C, /V-ethyl-2-(pyri din-3 - yl)-l,3-thiazol-5-amine dihydrochloride S5a (13.4 g, 5.8 mmol) was charged followed by acetonitrile (60.2 g, 1.47 mol) (internal temperature 24 °C). Triethylamine (9.74 g, 96.2 mmol) was added dropwise by syringe over 5 minutes, and the mixture aged for 15 minutes at 25 °C. To this was added the solution of 3 -(methyl sulfonyl)propanoyl chloride dropwise over 30 minutes maintaining an internal temperature < 45 °C.

After 1.5 hours, 20 wt% aqueous potassium carbonate solution (87.1 g, 126 mmol) was added, and the mixture was stirred for 30 minutes. Acetonitrile was removed under vacuum until distillate overheads were no longer 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 solids were dried in a vacuum oven for 18 hours to afford A-ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3- yl)thiazol-5-yl)propanamide S6a (13.2 g, 81% yield) as a mixture of rotamers: 'H NMR (400 MHz, CDCh) 5 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); ¹³C NMR (101 MHz, CDCh) 8 169.50, 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]⁺]).

Example 14: Synthesis and Isolation of JV-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-JV-ethyl-3-

(methylsulfonyl)propanamide (S7a)

A-Ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl)propanamide S6a (29.73 g, 55.5 wt%, 1 equiv, 48.61 mmol) was added to a 250 mL jacketed reactor equipped with a pH probe, overhead stirrer, nitrogen inlet, caustic scrubber, temperature probe and dosing unit inlet, followed by ethyl acetate (23.56 g, 267.4 mmol) and the mixture was stirred to provide a white slurry. 30 wt% Aqueous sodium acetate (19.94 g, 72.92 mmol) was added in a single 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 hour. 2 Hours after 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 pH > 8. Agitation was stopped and the organic layer was transferred to a 1 L round bottom flask. Water content in the organic layer was brought to <1 wt% via azeotropic distillation using dry EtOAc at 20 kPa vacuum at 50 °C bath temperature. The mixture post distillation was approximately 30 wt% by mass. The mixture was heated to 70 °C and held for 30 minutes 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 solids were dried in a vacuum oven for 18 hours (<50 mm Hg) at 50 °C to give A- (4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A-ethyl-3-(methylsulfonyl)propanamide S7a as a beige solid (16.2 g, 84% yield): mp 101-104 °C; ’HNMR (400 MHz, CDC1₃) 8 9.12 (d, J = 2.3 Hz, 1H), 8.77 - 8.71 (m, 1H), 8.22 (dt, J = 8.1, 2.0 Hz, 1H), 7.45 (dd, J = 8.1 , 4.8 Hz, 1H), 3.79 (q, J = 7.2 Hz, 2H), 3.43 (s, 2H), 2.96 (s, 3H), 2.80 (t, J= 7.1 Hz, 2H), 1.23 (t, J= 7.2 Hz, 3H); ESIMS m/z 374 ([M+H]⁺).

Example 15: Synthesis and Isolation of 7V-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-7V-ethyl-3-

(methylsulfonyl)propanamide (S7a)

A-Ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride S6a-HCl (15.0 g, 85 wt%, 33.9 mmol) was added to a 250 mL round bottom flask with a stir bar, 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 minutes. The reaction was checked at 45 minutes and at 75 minutes by UPLC, showing that there was about 35% by LC area of starting material remaining. An additional lot of 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 hour. Upon reaction completion, 40 wt% aqueous sodium bisulfite (13.2 g, 50.9 mmol) was added dropwise over 30 minutes. 40 wt% Aqueous potassium carbonate (29.3 g, 84.8 mmol) was added to bring 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 re-constituted in isopropyl acetate (34.6 g, 39.8 mL, 339 mmol), heated to 70 °C to solubilize, and then allowed to cool to room temperature overnight to induce crystallization. The resulting slurry was filtered and washed with cyclohexane (40 mL). The solid was dried in the vacuum oven overnight to afford A-(4-chloro-2- (pyridin-3-yl)thiazol-5-yl)-A-ethyl-3-(methylsulfonyl)propanamide (9.5 g, 25 mmol, 75% yield): mp 101-104 °C; ^LH NMR (400 MHz, CDCL) 8 9.12 (d, J= 2.3 Hz, 1H), 8.77 - 8.71 (m, 1H), 8.22 (dt, J= 8.1, 2.0 Hz, 1H), 7.45 (dd, J= 8.1, 4.8 Hz, 1H), 3.79 (q, J= 7.2 Hz, 2H), 3.43 (s, 2H), 2.96 (s, 3H), 2.80 (t, J= 7.1 Hz, 2H), 1.23 (t, J= 7.2 Hz, 3H); ESIMS m/z 374 ([M+H] ). Example 16: Synthesis of 2-amino-A-ethylacetamide (S4a)

S3 S4a

A jacketed reactor under nitrogen equipped with a mechanical stirrer and thermocouple was charged with a solution of ethylamine in water (70 wt%, 512 g, 7.95 mol) and was cooled to an internal temperature of -4 °C. A solution of methyl glycinate hydrochloride S3 (200 g, 1 .58 mol) in water (307 g) was gradually added to the ethylamine reactor. The temperature was held at -3 °C, and the reaction mixture was stirred for 1-3 hours. After the reaction was complete, the temperature was increased to 0 °C. A 50 wt% aqueous solution of sodium hydroxide (130 g, 1.63 mol) was added over 10 minutes, and the reaction mixture was stirred for 30 minutes. The reactor was warmed to 95 °C to distill out the methanol and ethylamine until the volume of the bottoms stabilized. The reactor temperature was decreased to 40 °C, the pressure was reduced to 10 kPa, and the distillation was continued by increasing the temperature to 65 °C until ethylamine was undetected 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). More water was added to the aqueous layer (50 g, 2.77 mol) and the layer was extracted with more s-BuOH (231 g, 3.12 mol). More water was added to the aqueous layer (20 g, 1.11 mol) and the layer was extracted with more s-BuOH (231 g, 3.12 mol). The organic extracts were combined (1450 g in total) to give a 9.4 wt% solution of S4a in s-BuOH (84% yield).

Example 17: Synthesis of 2-amino-2V-ethylacetamide hydrochloride (S4a-HCl)

S3 S4a-HCI

A 5-L jacketed reactor under nitrogen equipped with a mechanical stirrer and thermocouple was charged with a solution of ethylamine in water (67 wt%, 1040 g, 15.5 mol) and extra water (600 g, 33.3 mol) and was cooled to an internal temperature of -4 °C. Solid methyl glycinate hydrochloride S3 (50.49 g, 398.13 mmol) was gradually added to the ethylamine reactor over 4 hours. The temperature was increased to 0 °C, and the reaction mixture was stirred for 2 hours. A 48 wt% aqueous solution of sodium hydroxide (258 g, 3.1 mol) was added over 20 minutes. The reactor was warmed to 80 °C to distill out the methanol and ethylamine until the volume of the bottoms stabilized. The reactor temperature was decreased to 60 °C, the pressure was reduced to 10 kPa, and the distillation was continued by increasing the temperature to 75 °C until ethylamine was undetected in the bottoms. MIBC (1600 g, 15.5 mol) was added, and the contents were distilled further at 75 °C and 8.5-10 kPa to remove water. The slurry was filtered, and the solids were washed with MIBC (200 g, 1.94 mol). The filtrates were combined and aqueous HC1 (35%, 355 g, 3.41 mol) was added. Another distillation at 75 °C and 10 kPa was performed to remove more 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 was 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 h to give S4a-HCl (389 g, 87.8% yield) as a white solid: mp 136 °C; 'H NMR (500 MHz, D₂O) 8 3.71, (s, 2H), 3.19 (q, J= 7.4 Hz, 2H), 1.06 (t, J= 7.4 Hz, 3H); ^,3C NMR (126 MHz, D2O) 8 166.46, 40.48, 34.64, 13.44.

Example 18: Extraction of nicotinaldehyde

To a 250-mL jacketed glass reactor, ethyl acetate (102 g) was added via an addition funnel, under agitation. To the reactor an aqueous solution of nicotinaldehyde (16.76% nicotinaldehyde by weight, 102 g) was added. Sodium sulfate (Na2SC>4, 20 g) was added to the reactor, followed by addition of commercially obtained 2.5 M NaOH solution (20 m ). 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 layer and organic layer were collected separately and weighed. (Organic layer - 125.72 g, Aqueous layer - 117.93 g) The organic layer was concentrated by rotary evaporator to obtain a viscous liquid. Upon analysis with GC, it was found that the viscous layer contained 62.36% of nicotinaldehyde by weight. Example 19: Extraction of nicotinaldehyde

To a 500 mL jacketed glass reactor, toluene (60 g) was added via an addition funnel, under agitation. To the reactor an aqueous solution of nicotinaldehyde (18.49 wt% nicotinaldehyde, 108.5 g) solution was added. Na2SC>4 (24 g) was added to the reactor, followed by addition of commercially obtained 10% NaOH solution (0.32 mol equiv). 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 layer and organic layer were collected separately, and the aqueous layer was recharged to the reactor. Toluene (60 g) was charged to the reactor, and the two phases were agitated at 40 °C. Stirring was stopped and the layers were allowed to settle. The aqueous layer and organic layer were collected separately, and the two organic layers were combined. The organic layer was analyzed using GC, and the nicotinaldehyde content in the solution was found to be 13.66 wt%.

Example 20: Synthesis of 7V-ethyl-2-(pyridine-3-carbothioamido)acetamide (S4A-a)

S4a-HCI S4A-a

A 250-mL jacketed reactor under nitrogen equipped with a mechanical stirrer, and thermocouple 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 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 held under these conditions and monitored by HPLC analysis until complete (18 hours). The reaction mixture was cooled to 50 °C. A 70% saturated Na2SCU solution (53.8 g, 50.0 mL) was added. The reaction mixture was thoroughly mixed for 10 minutes at 450 rpm and 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. The seed slurry of S4A-a (0.104 g) in ethyl acetate (2.82 g) was added, and the reaction mixture was non-linearly cooled to 0 °C over 6 hours. The resulting slurry was fdtered. The wet cake was washed with ethyl acetate (2 x 50.0 mL) and dried in a vacuum oven at 40 °C at a reduced pressure of 4 kPa to provide the title compound S4A-a as a yellow solid (4.36 g, 49% yield): mp 145 °C; ^JH NMR (400 MHz, CDCh) 8 9.02 (dd, J = 2.4, 0.8 Hz, 1H), 8.70 (dd, J = 4.9, 1.7 Hz, 2H), 8.15 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.35 (ddd, J= 8.0, 4.8, 0.9 Hz, 1H), 5.86 (s, 1H), 4.42 (d, J= 4.4 Hz, 2H), 3.40 (qd, J= 7.3, 5.6 Hz, 2H), 1.21 (t, .7= 7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCh) 8 195.58, 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]⁺).

Example 21: Synthesis of JV-ethyl-2-(pyridine-3-carbothioamido)acetamide (S4A-a)

S4a-HCI S4A-a

A 250-mL jacketed reactor under nitrogen equipped with a mechanical stirrer and thermocouple 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 held under these conditions and monitored by HPLC analysis until complete (18 hours). The reaction mixture was cooled to 50 °C. An 18 wt% brine solution (53.2 g, 50.0 mL) was added. The reaction mixture was thoroughly mixed for 10 minutes at 450 rpm and then allowed to settle for 5 minutes. The aqueous layer was removed. The organic layer was heated to 60 °C and stirred at 300 rpm for 1 hour. The solution was slowly cooled to 40 °C over 3 hours. The 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 was 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 at a reduced pressure of 4 kPa to provide the title compound S4A-a as a yellow solid (5.15 g, 58% yield): mp 145 °C; ’HNMR (400 MHz, CDCI3) 8 9.02 (dd, J= 2.4, 0.8 Hz, 1H), 8.70 (dd, J= 4.9, 1 .7 Hz, 2H), 8.15 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.35 (ddd, J= 8.0, 4.8, 0.9 Hz, 1H), 5.86 (s, 1H), 4.42 (d, J= 4.4 Hz, 2H), 3.40 (qd, J= 13, 5.6 Hz, 2H), 1.21 (t, J= 13 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 8 195.58, 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]⁺).

Example 22: Synthesis of JV-ethyl-2-(pyridine-3-carbothioamido)acetamide (S4A-a)

S4a S4A-a

A 500-mL jacketed reactor under nitrogen equipped with a mechanical stirrer and thermocouple was charged with a 25 wt% S4a aqueous 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 with 32% HC1 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 held under these conditions and monitored by HPLC analysis until complete (19 hours). The reaction mixture was stirred at 85 °C, and water (55 g, 55 mL) was added. The solution was then cooled gradually to 10 °C over 4 hours. The slurry was filtered, and the cake was washed with water (55 mL) and toluene (2 x 70 mL). The wet cake was dried in a vacuum oven at 90 °C at reduced pressure of 4 kPa overnight to provide the title compound S4A-a as a yellow solid (23.3 g, 69% yield): mp 145 °C; H NMR (400 MHz, CDCI3) 8 9.02 (dd, J = 2.4, 0.8 Hz, 1H), 8.70 (dd, J = 4.9, 1.7 Hz, 2H), 8.15 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.35 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 5.86 (s, 1H), 4.42 (d, J = 4.4 Hz, 2H), 3.40 (qd, J = 13, 5.6 Hz, 2H), 1.21 (t, J = 13 Hz, 3H); ¹³C NMR (101 MHz, CDCI3) 8 195.58, 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] J. Example 23: Synthesis of \-elhyl-2-(pyridin-3-yl)-l ,3-thiazol-5-amine (S5A-a)

S4A-a S5A-a

To a 250-mL jacketed reactor was added cone sulfuric acid (69.3 g, 37.7 mL, 95 wt%, 10 equiv, 672 mmol). The reactor was cooled to 15 °C, and V-ethyl-2-(pyridine-3- carbothioamido)acetamide S4A-a (15.0 g, 1 equiv, 67.2 mmol) was added portion-wise over 30 minutes with overhead stirring set at 650 rpm and maintaining the internal temperature below 26 °C during the complete addition. The jacket temperature was set at 40 °C, and the mixture was stirred vigorously (650 rpm) for 4 hours. The reaction mixture was cooled to ambient temperature and stirred overnight. The reaction mixture was cooled to 10 °C, and water (80 mL) was added dropwise over 30 minutes with temperature never exceeding 25 °C. The resulting aqueous solution was then treated dropwise with 10 M KOH in water over 30 minutes until the reaction mixture became thick and heterogeneous and the pH was measured as 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 until dry to provide 2V-ethyl-2-(pyridin-3-yl)-l,3-thiazol-5-amine S5A-a

(11.72 g, 83% yield): mp 93.67 °C (DSC); 'H NMR (500 MHz, CDCb) 5 8.99 (d, J= 2.4 Hz, 1H), 8.55 (d, .7= 4.5 Hz, 1H), 8.08 (dt, .7= 8.1, 1.9 Hz, 1H), 7.33 (dd, ,7 = 8.1, 4.8 Hz, 1H), 6.99 (s, 1H), 4.00 (s, 1H), 3.25 (q, .7= 7.2 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCh) 5 152.04, 149.18, 149.13, 146.55, 132.20, 130.47, 123.62, 121.81, 43.06, 14.77; ESIMS m z 206 ([M+H]-).

Example 24: Synthesis of JV-ethyl-2-(pyridin-3-yl)-l,3-thiazol-5-amine dihydrochloride

(S5a)

S4A-a S5A-a S5a Acetonitrile (805.4 g, 19.619 mol) and S4A-a (145 g, 0.6364 mol) were added to 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 (PCh; 218.49 g, 2.50 equiv, 1.591 mol) was added over 2 hours. The temperature was maintained at 60 °C for 4-6 hours with stirring. The reaction mixture was cooled to 50 °C. The acetonitrile and PCh were removed by solvent exchange distillation with toluene (1172.7 g, 12.728 mol) at 50 °C under vacuum of ~20 kPa. The vacuum was removed, 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, and the mixture was stirred for 30 minutes and allowed to settle 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 allowed to settle 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 allowed to settle for 30 minutes. The organic layer was separated, and the toluene and water were distilled azeotropically at 50-55 °C under vacuum of ~31 kPa. The vacuum was removed, fresh toluene (284.2 g, 3.084 mol) was added at 50-55°C, and the mixture was cooled to 25-30 °C with stirring. Dry HC1 gas (58.1 g, 1.591 mol) was passed through the mixture at 25-30 °C over 1 hour. The mixture was maintained 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 allowed to dry for 15 minutes under nitrogen atmosphere. Acetonitrile (260.8 g, 6.353 mol) was added to the wet cake, and the mixture was slurried and allowed to dry for 15 minutes under nitrogen atmosphere. The wet cake was dried at 40 °C under vacuum of ~6.7 kPa. A-Ethyl-2-(pyridin-3-yl)-l,3-thiazol-5-amine dihydrochloride (152.4 g, 84% yield) was isolated: 'l l NMR (400 MHz, DMSO- e) 8 9.07 (d, J= 2.1 Hz, 1H), 8.71 (dd, J= 5.6, 1.3 Hz, 1H), 8.66 (ddd, J= 8.3, 2.2, 1.3 Hz, 1H), 7.97 (ddd, J= 8.3, 5.5, 0.7 Hz, 1H), 7.54 - 7.19 (m, 1H), 7.02 (s, 1H), 3.15 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, DMSO-t/₆) 8 155.15, 140.81, 139.39, 139.16, 136.62, 133.13, 127.52, 120.35, 41.56, 13.89; ESIMS m/z 206 ([M+H-2 HC1]⁺).

Example 25: Synthesis of and Isolation of A-etliyl-3-(methylsulfonyl)-A-(2-(pyridin-3- yl)thiazol-5-yl)propanamide (S6a)

S5a S5A-a S6a

3-(Methylsulfonyl)propanoic acid (3.56 g, 1.2 equiv, 23.4 mmol) was charged into a 250- mL jacketed reactor with a bath temperature set to 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 agitated. The bath temperature was increased to 35 °C. Pivaloyl chloride (3.05 g, 1.3 equiv, 25.3 mmol) was added. The solution was held at 35 °C for 2 hours after addition completion to allow conversion of the acid to the pivalic anhydride, 3-(methylsulfonyl)propanoic pivalic anhydride.

S5A-a was prepared in solution from S5a according to the procedure in Example 12. Dichloromethane was removed by distillation, and the solids were dried under vacuum at 40 °C for 16 hours to afford S5A-a as a yellow solid (95%). S5A-a (4.01 g, 1 equiv, 19.5 mmol) was charged into 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 agitated. The solution of S5A-a was transferred into the solution of 3-(methylsulfonyl)propanoic pivalic anhydride at 33 °C. The reaction mixture was stirred for 19 hours at 29-34 °C. The mixture was concentrated by vacuum distillation at 50-55 °C to 24 mL. ACN (31.0 g, 755 mmol) was added, and the mixture was concentrated by vacuum distillation at 55-60 °C to 24 mL. 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 by vacuum distillation at 55-66 °C to 24 mL. The slurry was cooled to 10 °C over 4 hours, maintained at 10 °C for 1 hour, and fdtered. The wet cake was washed with a 90/10 (v/v) mixture of water/ ACN (20 mL), and the solids were dried in a vacuum oven at 50 °C for 16 hours to afford A-ethyl-3-(methylsulfonyl)- V-(2-(pyridin-3-yl)thiazol-5-yl)propanamide S6a (4.59 g, 68% yield) as a mixture of rotamers: ^!H NMR (400 MHz, CDCh) 5 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]⁺]). Example 26: Synthesis of and Isolation of 2V-ethyl-3-(methylsulfonyl)-2V-(2-(pyridin-3- yl)thiazol-5-yl)propanamide (S6a)

S5a S5A-a S6a

3-(Methylsulfonyl)propanoic acid (3.55 g, 1.2 equiv, 23.3 mmol) was charged into a 250- mL jacketed reactor with a bath temperature set to 25 °C. DCM (42.2 g, 497 mmol) and 3,5- dimethylpyridine (1.25 g, 0.60 equiv, 11.7 mmol) were added. The mixture was agitated. The bath temperature was increased to 35 °C. Pivaloyl chloride (3.11 g, 1.3 equiv, 25.8 mmol) was added. The solution was held at 35 °C for 2 hours after addition completion to allow conversion of the acid to the pivalic anhydride, 3-(methylsulfonyl)propanoic pivalic anhydride (S2a-2).

S5A-a was prepared in solution from S5a according to the procedure in Example 12. Dichloromethane was removed by distillation and the solids were dried under vacuum at 40 °C for 16 hours to afford S5A-a as a yellow solid (95%). S5A-a (4.00 g, 1 equiv, 19.5 mmol) was charged into 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 agitated. The solution of S5A-a was transferred into the solution of 3-(methylsulfonyl)propanoic pivalic anhydride at 35 °C. The reaction mixture was stirred for 20 hours at 29-34 °C. 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. Methanol (15.8 g, 494 mmol) was added to the mixture at 50 °C. The slurry was cooled to 10 °C over 3 hours, maintained at 10 °C for 1 hour, and filtered. The wet cake was washed two times with methanol (15.8 g, 494 mmol), and the solids were dried in a vacuum oven at 50 °C for 16 hours to afford A-ethyl-3-(methylsulfonyl)-V-(2-(pyridin-3- yl)thiazol-5-yl)propanamide S6a (5.74 g, 87 % yield).

data are consistent with S6a.

Example 27: Synthesis of and Isolation of7V-ethyl-3-(methylsulfonyl)-JV-(2-(pyridin-3- yl)thiazol-5-yl)propanamide (S6a)

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 charged into a 30 mL vial at 25 °C . 3 -Methylpyridine (698 mg, 1.5 equiv, 7.50 mmol) was added dropwise to prepare a solution of the mixed anhydride. The solution was stirred for 10-15 minutes at room temperature. S5a (1.39 g, 1 equiv, 5.00 mmol) as a yellow solid was charged to a 40 mL vial at ambient conditions. Acetonitrile (7.86 g, 10.0 mL, 38.3 equiv, 191 mmol) and 3- m ethylpyridine (1.40 g, 3 equiv, 15.0 mmol) were added slowly. The suspension was agitated, and the solution of the mixed anhydride prepared above was added into the suspension at 25 °C. The reaction was stirred for 10 hours at 50-55 °C. The mixture was concentrated by vacuum distillation to half the volume, methanol (7.92 g, 10.0 mL, 49.4 equiv, 247 mmol) was added, and the mixture was re-concentrated by vacuum distillation to 20 mL reaction volume. 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 hour, and then filtered. The wet cake was washed with 5 mL of methanol -water (1 : 1), followed by water (5 mL), and the resulting solids were dried in a vacuum oven at 50 °C for 16 hours to afford A-ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (1.53 g, 90.2% yield). ^XH NMR data are consistent with S6a.

Example 28: Synthesis and Isolation of JV-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-JV-ethyl-3- (methylsulfonyl)propanamide (S7a)

S6a S7a .V-F.thyl-3-(methylsulfonyl)-/ -(2-(pyridin-3-yl)thiazol-5-yl)propanamide S6a (30.1 g, 100 wt%, 89 mmol) was added to a 1-L jacketed reactor with overhead agitator. Water (157.8 g, 8.8 mol) was added, forming a slurry. Aqueous HC1 (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 through a glass tube submerged under the liquid surface over 50 minutes. Upon reaction completion, 36 wt% aqueous sodium bisulfite (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 bring the pH up 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 was cooled to 30 °C. S7a (0.15 g, 4.0 mmol) was added as seed. 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 and held for an additional 1 hour before filtration. The wet cake was washed once with heptane (44.8 g, 447 mmol). The solid was dried in the vacuum oven overnight to afford A-(4-chloro-2-(pyridin-3- yl)thiazol-5-yl)-A-ethyl-3-(methylsulfonyl)propanamide (25.4 g, 76% yield).

Example 29: Synthesis of A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A-ethyl-3- (methylsulfonyl)propanamide (S7a)

A-Ethyl-3-(methylsulfonyl)-A-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (12.50 g, 85 wt%, 1 equiv, 28.27 mmol) was added to a 250 mL jacketed reactor, followed by water (37.69 g, 37.69 mL, 74 equiv, 2.092 mol). The mixture was stirred at 23 °C. A solution of Oxone® (20.85 g, 1.2 equiv, 33.92 mmol) in water (63.67 g, 63.67 mL, 125 Eq, 3.533 mol) (pH of —2.5) was prepared separately in a round bottom flask with agitation. The solution of Oxone® was added drop wise to the jacketed reactor over 1 hour, and the mixture was stirred. After complete conversion was observed, sodium bisulfite (8.823 g, 40 wt%, 1 .2 equiv, 33.92 mmol) was added dropwise over 15 minutes. 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 a single 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 a single 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 put under vacuum at 50 °C to concentrate the mixture via azeotrope down to <1.0 wt% water. After reaching the desired water level, the mixture was heated to 65-70 °C to solubilize all of the material, and then allowed to cool to 0 °C over 12 hours. The mixture was maintained for 4 hours and then filtered. The wet cake was washed with 50 mL of heptane, and the wet cake was dried in a vacuum oven (50 °C, < 50 mm Hg) to afford A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A-ethyl-3-(methylsulfonyl)propanamide (8.5 g, 71% yield).

Consequently, in light of the above the following additional, non-exhaustive, disclosure details (d) are provided.

Id. A process comprising

Sla Sib oxidizing 3-(methylthio)propanoic acid to 3-(methylsulfonyl)propanoic acid in the presence of an oxidizing agent and a polar solvent.

2d. A process according to detail Id wherein the oxidizing agent is oxygen (O2), sodium hypochlorite (NaOCl), ozone (O3), hydrogen peroxide (H2O2), organic peroxides, organic peracids (-OOH), potassium peroxymonosulfate, potassium persulfate, potassium hydrogen peroxymonosulfate sulfate (a triple salt with the formula 2KHSO5 KHSO4 K2SO4 [CAS 70693-62-8]), or mixtures thereof. 3d. A process according to detail Id wherein the oxidizing agent, hydrogen peroxide (H2O2), further comprises the catalyst, sodium tungstate.

4d. A process according to details Id, 2d, and 3d wherein from about 2 moles to about 4 moles of oxidizing agent per mole of Sla is used.

5d. A process according to details Id, 2d, and 3d wherein from about 2.0 moles to about 3.0 moles of oxidizing agent per mole of Sla is used.

6d. A process according to details Id, 2d, 3d, 4d, and 5d wherein the polar solvent is a polar aprotic solvent, a polar protic solvent, or mixtures thereof.

7d. A process according to 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”), //-butanol (“H-BUOH”), isopropanol (“z-PrOH”), zz-propanol (“rz-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), formic acid (“HCOOH”), ze/7-butyl alcohol (“/-BuOH”), water (“H2O”), or mixtures thereof.

8d. A process according to details Id, 2d, 3d, 4d, 5d, 6d, and 7d wherein the oxidation is conducted at temperatures from about 15 °C to about 25 °C and pressures from about 95 kPa to about 105 kPA.

9d. A process comprising reacting Sib in the presence of a carboxylic acid activator and an aprotic solvent to produce S2a

Sib S2a wherein A is Cl, O(C=O)Ri, or ORi, wherein Ri is (Ci-C4)alkyl, and wherein the reaction is optionally conducted with a catalyst or a base to promote the reaction of Sib to S2a. lOd. A process according to detail 9d wherein from about 1.0 moles to about 5 moles of carboxylic acid activator per mole of Sib is used. l id. A process according to detail 9d wherein from about 1.0 moles to about 1.5 moles of carboxylic acid activator per mole of Sib is used.

12d. A process according to details 9d, lOd, and l id wherein a catalyst is used to promote the reaction of Sib to S2a.

13d. A process according to detail 12d wherein the catalyst is A,A-dimethylformamide, /V-formylpyrrolidine, A-formylpiperidine, or mixtures thereof.

14d. A process according to details 12d and 13d wherein from about 0.01 to about 0.5 moles of catalyst per mole of Sib is used.

15d. A process according to details 12d and 13d wherein from about 0.05 moles to about 0.1 moles of catalyst per mole of Sib is used.

16d. A process according to details 9d, lOd, and l id wherein a base is used to promote the reaction of Sib to S2a.

17d. A process according to detail 16d wherein the base is lutidine (e.g., 2,6-lutidine and 3,5-lutidine), picoline (e.g., 2-picoline and 3-picoline), A-methylmorpholine, tri ethylamine (“TEA”), A^r,A-di isopropyl ethyl amine (“DIPEA”), or mixtures thereof.

18d. A process according to details 16d and 17d wherein from about 0.1 to about 1.5 moles of base per mole of Sib is used.

19d. A process according to details 16d and 17d wherein from about 0.5 moles to about 1.2 moles of base per mole of Sib is used. 20d. A process according to details 9d, lOd, l id, 12d, 13d, 14d, 15d, 16d, 17d, 18d, and 19d wherein the aprotic solvent is a polar aprotic solvent, a nonpolar aprotic solvent, or a mixture thereof.

2 Id. A process according to detail 20d wherein the solvent is ethyl acetate (“EtOAc”), tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), dichloromethane ("DCM”), acetonitrile (“ACN”), benzonitrile (“PhCN”), chloroform (“CHCh”), toluene (“PhCHj”), or mixtures thereof.

22d. A process according to details 9d, lOd, l id, 12d, 13d, 14d, 15d, 16d, 17d, 18d, 19d, 20d, and 21 d wherein the temperatures of the reaction are from about 0 °C to about 100 °C.

23d. A process according to details 9d, lOd, 1 Id, 12d, 13d, 14d, 15d, 20d, and 21d wherein the temperatures of the reaction are from about 20 °C to about 60 °C.

24d. A process according to details 9d, lOd, l id, 16d, 17d, 18d, 19d, 20d, and 2 Id, wherein the temperatures of the reaction are from about 20 °C to about 49 °C.

25d. A process according to details 9d, lOd, l id, 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 process comprising aminating S3/3a to S4a or S4a-HCl with ethylamine in the presence of a secondary base and optionally a polar or a nonpolar solvent,

S3 a, R₂ _;CH₃ S4a-HCI, amine hydrochloride 27d. A process according to 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. A process according to 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. A process according to any of the previous details 26d through 28d wherein the secondary base is an organic base.

30d. A process according to any of the previous details 26d through 28d wherein the secondary base is an inorganic base.

3 Id. A process according to any of the previous details 26d through 28d wherein the secondary base is /V,A'-di isopropyl ethyl amine or triethylamine.

32d. A process according to any of the previous details 26d through 28d wherein the secondary base is potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, or mixtures thereof.

33d. A process according to any of the previous details 26d through 32d wherein the amount used is from about 0.8 mole to about 2 moles of the secondary base per mole of S3/3a.

34d. A process according to any of the previous details 26d through 32d wherein the amount used is from about 0.8 mole to about 1.2 moles of the secondary base per mole of S3/3a.

35d. A process according to any of the previous details 26d through 34d wherein the polar solvent is a polar aprotic solvent.

36d. A process according to any of the previous details 26d through 34d wherein the polar solvent is a polar protic solvent. 37d. A process according to any of the previous details 26d through 34d wherein the polar solvent is tetrahydrofuran, 2-methyltetrahydrofuran, anisole, acetonitrile, or mixtures thereof.

38d. A process according to any of the previous details 26d through 34d wherein the polar solvent is n-butanol, sec-butanol, 4-methyl-2-pentanol, isopropanol, n-propanol, ethanol, methanol, water, or mixtures thereof.

39d. A process according to any of the previous details 26d through 34d wherein the nonpolar solvent is toluene.

40d. A process according to any of previous details 26d through 39d wherein the process is conducted at temperatures from about -20 °C to about 50 °C.

4 Id. A process according to any of previous details 26d through 39d wherein the process is conducted at temperatures from about -10 °C to about 10 °C.

42d. A process according to any of the previous details 26d through 41d wherein the process is conducted at a pressure from about 10 kPa to about 1000 kPa or from about ambient to about 1000 kPa.

43d. A process according to any of the previous details 26d through 41d wherein the process is conducted at a pressure from about 50 kPa to about 200 kPa or from about ambient to about 200 kPa.

44d. A process according to any of the previous details 26d through 43d wherein the process is conducted under flow conditions.

45d. A process according to any of the previous details 26d through 44d, wherein S4a is

(a) isolated as a free base form; (b) used as a free base form in solution; or

(c) isolated as a hydrochloride salt form.

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

S4a S4a-HCI S4A-a

47d. A process according to detail 46d wherein the 3-pyridinecarboxaldehyde is used in a neat form, as a solution in water, or as a solution in an organic solvent.

48d. A process according to details 46d and 47d wherein from about 0.5 mole to about 5 moles of 3-pyridinecarboxaldehyde per mole of S4a or S4a-HCl is used.

49d. A process according to details 46d and 47d wherein from about 0.7 mole to about 1.3 moles of 3-pyridinecarboxaldehyde per mole of S4a or S4a-HCl is used.

50d. A process according to details 46d, 47d, 48d, and 49d wherein from about 1 mole to about 5 moles of sulfur per mole of S4a or S4a-HCl is used.

5 Id. A process according to details 46d, 47d, 48d, and 49d wherein from about 1.0 mole to about 3.5 moles of sulfur per mole of S4a or S4a-HCl is used.

52d. A process according to details 46d, 47d, 48d, 49d, 50d, and 5 Id wherein from 0.05 mole to about 5 moles of Bronsted base per mole of S4a or S4a-HCl is used.

53d. A process according to details 46d, 47d, 48d, 49d, 50d, and 5 Id wherein from about 0.1 mole to about 1.2 moles of Bronsted base per mole of S4a or S4a-HCl is used. 54d. A process according to details 46d, 47d, 48d, 49d, 50d, 5 I d, 52d, and 53d wherein the Bronsted base is potassium carbonate (“K2CO3”), potassium phosphate (“K3PO4”), triethylamine (“TEA”), pyridine, sodium acetate (“NaOAc”), sodium bicarbonate (“NaHCCh”), sodium hydrosulfide (“NaSH”), sodium sulfide (“NazS”), imidazole, potassium zczv-butoxide (“KO/Bu”), A^f,;V-di isopropyl ethyl amine (“DIPEA”), or mixtures thereof.

55d. A process according to details 46d, 47d, 48d, 49d, 50d, 5 Id, 52d, and 53d wherein the Bronsted base is sodium sulfide (“Na2S”) or triethylamine (“TEA”).

56d. A process according to details 46d, 47d, 48d, 49d, 50d, 5 Id, 52d, 53d, 54d, and 55d wherein the solvent is a polar aprotic solvent, a polar protic solvent, a nonpolar aprotic solvent, or a mixture thereof.

57d. A process according to detail 56d wherein the solvent is tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), benzonitrile (“PhCN”), butyronitrile, cyclopentylmethyl ether (“CPME”), dimethyl carbonate (“DMC”), ethyl acetate (“EtOAc”), isopropyl acetate (“z-PrOAc”), N, A'-dimethylform amide (“DMF”), N,N- dimethylacetamide (“DMAC”), isobutyl acetate (“z-BuOAc”), methyl ethyl ketone (“MEK”), dichloromethane (“DCM”), chlorobenzene (“PhQ”), acetone, zz-butanol (“zz-BuOH”), sec- butanol (“ -BuOH”), 4-methyl-2-pentanol (“MIBC”), isopropanol (“z-PrOH”), zz-propanol (“zz- PrOH”), ethanol (“EtOH”), methanol (“MeOH”), water (“H2O”), toluene (“PI1CH3”), or a mixture thereof.

58d. A process according to any of the previous details 46d through 57d wherein the temperature at which this reaction is conducted is from about -10 °C to about 100 °C.

59d. A process according to any of the previous details 46d through 57d wherein the temperature at which this reaction is conducted is from about 35 °C to 70 °C.

60d. A process according to any of the previous details 46d through 59d wherein the pressure at which this reaction is conducted is from ambient to 1000 kilopascal (kPa). 6 Id. A process according to any of the previous details 46d through 59d wherein the pressure at which this reaction is conducted is from ambient to about 200 kPa.

62d. A process according to any of the previous details 46d through 61d wherein the pH at which this reaction is conducted is from 6 to 13.

63d. A process according to any of the previous details 46d through 61d wherein the pH at which this reaction is conducted is from 8 to 10.

64d. A process comprising converting S4A-a in the presence of a Lewis or Bronsted acid to S5a

optionally, the converting is conducted in the presence of a solvent.

65d. A process according to detail 64d wherein the Lewis or Bronsted acid is phosphorus oxychloride (“POCI3”), phosphorus trichloride (“PCI3”), phosphorus pentachloride (“PCI5”), trifluoromethanesulfonic anhydride (“TfzO”), tri fluoroacetic anhydride (“TFAA”), boron trifluoride diethyl etherate (“BF.3*OEt2”), trimethyl silyl trifluoromethanesulfonate (“TMSOTf’), trifluoromethanesulfonic acid (“TfOH”), methanesulfonic acid (“MsOH”), Eaton’s reagent (“P2O5-MSOH”), hydrogen bromide (“HBr”), aqueous hydrobromic acid (“aqueous HBr”), hydrogen bromide in acetic acid (“HBr in AcOH”), trifluoroacetic acid (“TFA”), >- toluenesulfonic acid (“ -TSA”), sulfuric acid (“H2SO4”), solid supported acidic resins, or mixtures thereof.

66d. A process according to detail 65d wherein the Lewis or Bronsted acid is phosphorus oxychloride (“POCI3”) or phosphorus trichloride (“PCI3”).

67d. A process according to detail 65d wherein the Lewis or Bronsted acid is sulfuric acid.

68d. A process according to details 64d, 65d, 66d, and 67d wherein from about 0.5 mole to about 50 moles of Lewis acid or Bronsted acid per mole of S4a is used.

69d. A process according to details 64d, 65d, 66d, and 67d wherein from about 1 mole to about 5 moles of Lewis acid or Bronsted acid per mole of S4a is used.

70d. A process according to details 64d, 65d, 66d, 67d, 68d, and 69d wherein the solvent is a polar aprotic solvent, a nonpolar aprotic solvent, or a mixture thereof.

7 Id. A process according to detail 70d wherein the solvent is tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), benzonitrile (“PhCN”), cyclopentylmethyl ether (“CPME”), dimethyl carbonate (“DMC”), and ethyl acetate (“EtOAc”), toluene (“PI1CH3”), chlorobenzene (“PhQ”) or mixtures thereof.

72d. A process according to detail 71 d wherein the solvent is acetonitrile.

73d. A process according to details 64d, 65d, 66d, 67d, 68d, 69d, 70d, 71d, and 72d wherein the temperature at which the converting is done is from about -10 °C to about 80 °C.

74d. A process according to detail 73d wherein the temperature is from about 45 °C to

75 °C. 75d. A process according to detail 73d wherein the temperature is from about 10 °C to

44 °C.

76d. A process according to details 64d, 65d, 66d, 67d, 68d, 69d, 70d, 72d, 72d, 74d, 74d, and 75d wherein the pressure at which the converting is done is from ambient to about 1000 kilopascal (kPa).

77d. A process according to detail 76d wherein the pressure is from ambient to about 200 kPa.

78d. A process according to details 64d, 65d, 66d, 67d, 68d, 69d, 70d, 71d, 72d, 73d, 74d, 75d, 76d, and 77d wherein the converting is conducted under flow conditions.

79d. A process according to details 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. A process according to details 64d, 65d, 66d, 67d, 68d, 69d, 70d, 71 d, 72d, 73d, 74d, 75d, 76d, 77, and 78d wherein the free amine S5A-a can be converted to the salt form S5a.

8 Id. A process comprising reacting S4a or S4a-HCl to produce S5a wherein the reacting is conducted in the presence of 3-pyridinecarboxaldehyde, a Bronsted base, sulfur, and a Lewis acid or Bronsted acid

S4a S5a S4a-HCI optionally, this reaction is conducted in a solvent. 82d. A process according to detail 81 d wherein the 3-pyridinecarboxaldehyde is used in a neat form, as a solution in water, or as a solution in an organic solvent.

83d. A process according to details 81 d and 82d wherein from about 0.5 mole to about 5 moles of 3-pyridinecarboxaldehyde per mol of S4a or S4a-HCl is used.

84d. A process according to details 8 Id and 82d wherein from about 0.7 mole to about 1.3 moles of 3-pyridinecarboxaldehyde per mol of S4a or S4a-HCl is used.

85d. A process according to details 81 d, 82d, 83d, and 84d wherein from about 1 mole to about 5 moles of sulfur per mole of S4a or S4a-HCl is used.

86d. A process according to details 81 d, 82d, 83d, and 84d wherein from about 1.0 mole to about 3.5 moles of sulfur per mole of S4a or S4a-HCl is used.

87d. A process according to details 81 d, 82d, 83d, 84d, 85d, and 86d wherein from about 0.05 mole to about 5 moles of Bronsted base per mole of S4a or S4a-HCl is used.

88d. A process according to details 81 d, 82d, 83d, 84d, 85d, and 86d wherein from about 0.1 mole to about 1.2 moles of Bronsted base per mole of S4a or S4a-HCl is used.

89d. A process according to details 81 d, 82d, 83d, 84d, 85d, 86d, 87d, and 88d wherein from about 0.5 mole to about 50 moles of Lewis acid or Bronsted acid per mole of S4a or S4a- HC1 is used.

90d A process according to details 8 Id, 82d, 83d, 84d, 85d, 86d, 87d, and 88d wherein from about 1 mole to about 5 moles of Lewis acid or Bronsted acid per mole of S4a or S4a-HCl is used.

91 d. A process according to details 81 d, 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 (“NaHCCh”), sodium hydrosulfide (“NaSH”), sodium sulfide (“Na2S”), imidazole, potassium /c/7-butoxide (“KO/Bu”), and A'A'-diisopropylethylamine (“DIPEA”), or mixtures thereof.

92d. A process according to details 8 Id, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, and 90d wherein the Bronsted base is sodium sulfide (“Na2S”) or triethylamine (“TEA”).

93d. A process according to details 81 d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91 d and 92d wherein the Lewis acid or Bronsted acid is phosphorus oxychloride (“POCI3”), phosphorus trichloride (“PCI3”), phosphorus pentachloride (“PCls”), trifluoromethanesulfonic anhydride (“TfzO”), boron trifluoride diethyl etherate (“BF3*OEt2”), trimethyl silyl trifluoromethanesulfonate (“TMSOTf ’), trifluoromethanesulfonic acid (“TfOH”), methanesulfonic acid (“MsOH”), Eaton’s reagent (“P2O5-MSOH”), hydrogen bromide in acetic acid (“HBr in AcOH”), trifluoroacetic acid (“TFA”), p-toluenesulfonic acid (“ -TSA”), sulfuric acid (“H2SO4”) solid supported acidic resins, or mixtures thereof.

94d. A process according to detail 93d wherein the Lewis acid or Bronsted acid is phosphorus oxychloride or phosphorus trichloride.

95d. A process according to details 81 d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91 d, 92d, 93d, and 94d wherein a solvent is used and the solvent is a polar aprotic solvent, a nonpolar aprotic solvent, or mixtures thereof.

96d. A process according to detail 95d wherein the solvent is tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), benzonitrile (“PhCN”), cyclopentylmethyl ether (“CPME”), dimethyl carbonate (“DMC”), chlorobenzene (“PhCl”), ethyl acetate (“EtOAc”), toluene (“PhCFL”), or mixtures thereof.

97d. A process according to detail 96d wherein the solvent is acetonitrile. 98d. A process according to details 8 Id, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91 d, 92d, 93d, 94d, 95d, 96d, and 97d wherein the temperature at which the reaction is conducted is from about -10 °C to about 80 °C.

99d. A process according to details 8 Id, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91 d, 92d, 93d, 94d, 95d, 96d, and 97d wherein the temperature at which the reaction is conducted is from about 35 °C to about 70 °C. lOOd. A process according to details 81 d, 82d, 83d, 84d, 85d, 86d, 87d, 88d, 89d, 90d, 91 d, 92d, 93d, 94d, 95d, 96d, 97d, 98d, and 99d wherein the pressure at which the reaction is conducted is from about ambient to 1000 kilopascal (kPa). lOld. A process according to detail lOOd wherein the pressure is from ambient to about 200 kPa.

102d. A process according to any of the previous details 81 d through 101 d wherein the reacting is conducted under flow conditions.

103d. A process comprising coupling S5a with S2a to produce S6a or S6a-HCl wherein the coupling is conducted in the presence of a base, a solvent, and optionally a catalyst

104d. A process according to detail 103d wherein the base is an organic base, an inorganic base, or mixtures thereof. 105d. A process according to detail 103d wherein the base is an organic base.

106d. A process according to detail 103d wherein the base is an inorganic base.

107d. A process according to 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), A'A'-di isopropyl ethyl amine (“DIPEA”), triethylamine (“TEA”), potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), potassium hydroxide (“KOH”), sodium carbonate (“Na2CO3”), sodium bicarbonate (“NaHCO3”), sodium hydroxide (“NaOH”), or mixtures thereof.

108d. A process according to details 103d, 104d, 105d, 106d, and 107d wherein from about 1 mole to about 5 moles of base per mole of S5a is used.

109d. A process according to detail 108d wherein from about 2.0 moles to about 3.5 moles of base per mole of S5a is used.

I lOd. A process according to details 103d, 104d, 105d, 106d, 107d, 108d, and 109d wherein the catalyst is A( A-dimethylpyridin-4-amine (“DMAP”), .V- methyl imidazole (“NMI”), or a mixture thereof.

I I Id. A process according to details 103d, 104d, 105d, 106d, 107d, 108d, 109d, and 1 lOd wherein the solvent is a polar aprotic solvent, a nonpolar aprotic solvent, or mixtures thereof.

112d. A process according to detail 11 Id wherein the solvent is ethyl acetate (“EtOAc”), isobutyl acetate (“z-BuOAc”), tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), dichloromethane ("DCM”), chloroform (“CHCI3”), acetonitrile (“ACN”), benzonitrile (“PhCN”), toluene (“PhCH?”), or mixtures thereof. 113d A process according to details 103d, 104d, 105d, 106d, 107d, 108d, 109d, l lOd,

I l id, and 112d wherein the coupling is conducted at temperatures from about -10 °C to about 80 °C.

114d A process according to detail 113d wherein the temperature is from about from about 0 °C to 60 °C.

115d. A process according to details 103d, 104d, 105d, 106d, 107d, 108d, 109d, HOd,

I I Id, 112d, 113d, and 114d wherein the coupling is conducted at pressures from ambient to 1000 kilopascal (kPa)

116d. A process according to detail 115d wherein the pressure is from ambient to about 200 kPa may be used.

117d. A process according to any of the previous details 103d through 116d, wherein S6a is

(a) isolated as a free-base form;

(b) used as a hydrochloride form (S6a-HCl) or hydrobromide form in solution; or

(c) isolated in a hydrochloride form (S6a-HCl) or hydrobromide form.

118d. A process comprising chlorinating

(a) A-ethyl-3-(methylsulfonyl)- V-(2-(pyridin-3-yl)thiazol-5-yl)propanamide (S6a) and/or

(b) A-ethyl-3-(methylsulfonyl)-/V-(2-(pyridin-3-yl)thiazol-5-yl)propanamide hydrochloride (S6a-HCl); with a chlorinating agent to produce A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A- ethyl-3-(methylsulfonyl)propanamide (S7a), in the presence of a polar solvent

S6a-HCI

119d. A process according to detail 118d wherein about 1 mole to about 5 moles of chlorinating agent per mole of S6a or S6a-HCl is used.

120d. A process according to detail 118d wherein about 1.0 mole to about 3.5 moles of chlorinating agent per mole of S6a or S6a-HCl is used.

121 d. A process according to details 118d, 119d, and 120d, wherein the chlorinating agent is chlorine, A-chlorosuccinimide (“NCS”), 1,1,3,3-dichlorodimethylhydantoin (“DCDMH”), A-chlorophthalimide (“NCP”), A-chlorosaccharin (“NCSH”), tert- butylhypochlorite, chloramine-T, A -chlorobenzotri azole (“NCBT”), trichloroisocyanuric acid (“TCCA”), sodium hypochlorite, or mixtures thereof.

122d. A process according to detail 121 d wherein the chlorinating agent is sodium hypochlorite.

123d. A process according to detail 121 d wherein the chlorinating agent is chlorine.

124d. A process according to details 118d, 119d, and 120d wherein the chlorinating comprises contacting S6a-HCl and an oxidizing agent, preferably potassium hydrogen peroxymonosulfate sulfate (a triple salt with the formula 2KHSO.5 KHSCh K2SO4 [CAS 70693- 62-8]).

125d. A process according to detail 124d wherein the chlorinating further comprises adding chloride salt or hydrochloric acid. 126d. A process according to details 118d, 119d, 120d, 121d, 122d, 123d, 124d, and 125d, wherein the polar solvent is a polar aprotic solvent, a polar protic solvent, or mixtures thereof.

127d. A process according to detail 126d wherein the solvent is 1,4-dioxane, tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), dichloromethane (“DCM”), ethyl acetate (“EtOAc”) isobutyl acetate (“z-BuOAc”), //-butanol (“n-BuOH”), isopropanol (“z-PrOH”), //-propanol (“//-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), water (“H2O”), acetic acid (“AcOH”), formic acid (“HCOOH”), aqueous hydrochloric acid (“HQ”), or mixtures thereof.

128d. A process according to detail 127d wherein the solvent is ethyl acetate.

129d. A process according to detail 127d wherein the solvent is acetic acid.

130d. A process according to detail 1273d wherein the solvent is aqueous hydrochloric acid.

13 Id. A process according to details 118d, 119d, 120d, 121d, 122d, 123d, 124d, 125d, 126d, 127d, 128d, 129d, and 130d wherein the chlorinating is conducted at a temperature from about -10 °C to about 80 °C.

132d. A process according to detail 13 Id wherein the temperature is from about 0 °C to 50 °C.

133d. A process according to details 118d, 119d, 120d, 121d, 122d, 123d, 124d, 125d, 126d, 127d, 128d, 129d, 130d, 131d, and 132d wherein the chlorinating is conducted at pressures from ambient to about 1000 kilopascal (kPa) 134d. A process according to details 133d wherein the chlorinating is conducted at pressures from ambient to about 200 kPa.

135d. The molecule jV-ethyl-3-(methylsulfonyl)-A^r-(2-(pyridin-3-yl)thiazol-5- yl)propanamide

136d. A composition comprising the molecule according to detail 135d and HC1.

THE CLAIMS FOLLOW.

Claims

WE CLAIM

1. A molecule, _JV-ethyl-3-(methylsulfonyl)-JV-(2-(pyridin-3-yl)thiazol-5- yl)propanamide (S6a), or agriculturally acceptable acid addition salts having the following formula

S6a

2. The molecule according to claim 1, wherein the agriculturally acceptable acid addition salt is the hydrochloride (S6a-HCl) and having the following formula

S6a-HCI

3. A process comprising:

(a) coupling S5a with S2a to produce the molecule according to claim 1 (S6a) or the molecule according to claim 2 (S6a-HCl) wherein the coupling is conducted in the presence of a base, a solvent, and optionally a catalyst

(b) chlorinating

(a) the molecule according to claim 1 (S6a) and/or

(b) the molecule according to claim 2 (S6a-HCl), with a chlorinating agent to produce A-(4-chloro-2-(pyridin-3-yl)thiazol-5-yl)-A- ethyl-3-(methylsulfonyl)propanamide (S7a), in the presence of a polar solvent

4. A process according to claim 3, wherein about 1 mole to about 5 moles of chlorinating agent per mole of S6a or S6a-HCl is used.

5. A process according to claim 3, wherein about 1.0 mole to about 3.5 moles of chlorinating agent per mole of S6a or S6a-HCl is used.

6. A process according to claims 3, 4, or 5, wherein the chlorinating agent is chlorine, A-chlorosuccinimide (“NCS”), 1,1,3,3-dichlorodimethylhydantoin (“DCDMH”), N- chlorophthalimide (“NCP”), A-chlorosaccharin (“NCSH”), ter -butylhypochlorite, chloramine-T, /V-chlorobenzotri azole (“NCBT”), trichloroisocyanuric acid (“TCCA”), sodium hypochlorite, or mixtures thereof.

7. A process according to claim 6, wherein the chlorinating agent is sodium hypochlorite.

8. A process according to claim 6, wherein the chlorinating agent is chlorine.

9. A process according to claims 3, 4, or 5, wherein the chlorinating comprises contacting the molecule according to claim 2 (S6a-HCl) and an oxidizing agent, preferably potassium hydrogen peroxymonosulfate sulfate (a triple salt with the formula

2KHSO5 KHSO4 K2SO4 [CAS 70693-62-8]).

10. A process according to claim 9, wherein the chlorinating further comprises adding chloride salt or hydrochloric acid.

11. A process according to claims 3, 4, 5, 6, 7, 8, 9, or 10, wherein the polar solvent is a polar aprotic solvent, a polar protic solvent, or mixtures thereof.

12. A process according to claim 11 wherein the solvent is 1,4-di oxane, tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), acetonitrile (“ACN”), dichloromethane (“DCM”), ethyl acetate (“EtOAc”) isobutyl acetate (“z-BuOAc”), //-butanol (“n-BuOH”), isopropanol (“z-PrOH”), //-propanol (“//-PrOH”), ethanol (“EtOH”), methanol (“MeOH”), water (“H2O”), acetic acid ("AcOH”), aqueous hydrochloric acid or mixtures thereof.

13. A process according to claim 10 wherein the solvent is ethyl acetate, aqueous hydrochloric acid, or acetic acid.

14. A process according to claims 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the chlorinating is conducted at a temperature from about -10 °C to about 80 °C or from about 0 °C to 50 °C.

15. A process according to claims 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14, wherein the chlorinating is conducted at pressures from ambient to about 1000 kilopascal (kPa) or from ambient to about 200 kPa.