Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH2:11]([CH:13]([NH2:16])[CH2:14][CH3:15])[CH3:12].Cl>O>[CH2:11]([CH:13]([NH:16][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:14][CH3:15])[CH3:12]
Reactant: CCC(N)CC
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: Cl
Solvent: O
Product: CCC(CC)Nc1ccccc1[N+](=O)[O-]
Yield: 91 %

Procedure:
A solution of 158 grams of o-nitrochlorobenzene and 260 grams of 1-ethylpropylamine are refluxed together for 5 days. The solution is cooled and 500 ml. of water is added. Concentrated hydrochloric acid (10 milliliters) is added and the product separates out as an oil. The product is extracted with chloroform (2×200 milliliters), the extractions dried over MgSO4 and evaporated to yield 190 grams (91%) of product as an oil. The analytical sample is prepared by distillation of the crude oil, b.p. 1.8 mm Hg=148° C.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)=[O:15])[CH2:10][C@H:9]1[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=[O:7].O.NN>C(O)C>[NH2:17][CH2:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:46])([F:1])[F:45])[CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=2)[C@H:9]([CH2:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)[CH2:10]1)=[O:15]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Yield: 55.2 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-yl-methyl)-4-(phthalimidomethyl-carbonyl)piperazine (250 mg), hydrazine hydrate (50 mg) in ethanol (5 ml) was heated under reflux for 2 hours. The resulting precipitate was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was washed with aqueous 1N sodium hydroxide solution and then purified by column chromatography on a silica gel eluting with a mixture of ethyl acetate and methanol (4:1) to afford (2R)-4-(2-aminoacetyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (110 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([CH:14](Cl)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8].[C:30]1([P:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C(C)=CC=CC=1C>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([C:14](=[P:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COCCOCC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: COCCOCC(=O)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 43.2 %

Procedure:
A mixture of p-nitrobenzyl 2-[4-(2-methoxyethoxyacetylthio)-2-oxo-1-azetidinyl]-2-chloroacetate (761 mg.), triphenylphosphine (524 mg.; 2.00 mmoles) and 2,6-lutidine (0.235 ml.; 214 mg.; 2.00 mmoles) in tetrahydrofuran (7 ml.) was stirred under N2 atmosphere at room temperature for 50 hours. After filtration of the precipitate, the filtrate was evaporated to yield 1.39 g. of a crude oil. This oil was purified by columm chromatography (SiO2 ; 30 g.; eluant-ethyl acetate) yielding title product (494 mg.; 0.736 mmole; yield 42.3% based on starting ester) as a brownish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18]OS(C)(=O)=O)[CH2:13]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][N:35]4[CH2:34][CH2:33][N:32]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][CH3:24])[CH2:37][CH2:36]4)[CH2:13]3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)OCC1CCCN(CC2(c3ccc(Cl)cc3)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1N1CCN(CC2CCCN(CC3(c4ccc(Cl)cc4)CC3)C2)CC1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
To a solution of methanesulfonic acid 1-[1-(4-chloro-phenyl)-cyclopropylmethyl]-piperidin-3-ylmethyl ester (2.94 g, 8.20 mmol) in acetonitrile (40.0 mL) at room temperature was added 1-(2-methoxy-phenyl)-piperazine (1.58 g, 8.20 mmol) followed by potassium carbonate (13.35 g, 41.0 mmol). The reaction mixture was refluxed overnight. After cooling down to room temperature the reaction mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield a crude oil. The resulting residue was purified by silica gel chromatography (96:4 DCM: 2M NH3 in EtOH) to obtain the desired compound as an oil (2.04 g). 13C NMR (100 MHz, CDCl3) δ 152.5, 143.9, 141.8, 131.5, 130.4, 128.2, 123.1, 121.3, 118.4, 111.5, 67.8, 63.0, 59.5, 55.6, 55.2, 54.2, 51.0, 33.5, 29.8, 25.2, 23.1, 13.4, 13.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37]([OH:39])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:23]2[N:22]=[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]3[CH2:11][C@@H:10]([C:37]([N:62]4[CH2:67][CH2:66][O:65][CH2:64][CH2:63]4)=[O:39])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13]3)=[O:20])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]=2[CH:32]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (1.05 g), HOBt (361 mg) and WSC.HCl (549 mg) were dissolved in DMF (50 ml), morpholine (332 μl) and diisopropylethylamine (780 μl) were added, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (1.14 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:24])=[N:4][C:5]([C:8]2[N:9]=[C:10]([CH:21]3[CH2:23][CH2:22]3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:6][CH:7]=1.[N:25]([C@@H:28]([CH3:33])[CH2:29][CH2:30][O:31][CH3:32])=[C:26]=S.C1(N=C=NC2CCCCC2)CCCCC1>C(O)C>[CH:21]1([C:10]2[NH:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[C:8]([C:5]3[N:4]=[C:3]4[O:24][C:26]([NH:25][C@@H:28]([CH3:33])[CH2:29][CH2:30][O:31][CH3:32])=[N:1][C:2]4=[CH:7][CH:6]=3)[N:9]=2)[CH2:22][CH2:23]1
Reactant: Nc1ccc(-c2nc(C3CC3)[nH]c2-c2ccc(F)cc2F)nc1O
Reactant: COCC[C@H](C)N=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Product: COCC[C@H](C)Nc1nc2ccc(-c3nc(C4CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 85 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
A KIMAX® tube is charged with 3-amino-6-[2-cyclopropyl-5-(2,4-difluorophenyl)-1H-imidazol-4-yl]pyridin-2-ol (0.7 g, 2.13 mmol) and ethanol (7 mL). (3S)-3-isothiocyanato-1-methoxy-butane (0.46 g, 3.2 mmol) is added, the flask sealed, and the mixture is heated to 85° C. After 16 h, N,N′-dicyclohexylcarbodiimide (0.88 g, 4.26 mmol) is added and the mixture is stirred for 4 h at 85° C. in the sealed tube. After this time, additional N,N′-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) is added to the mixture. Heating is continued at 85° C. overnight. After this time, additional N,N′-dicyclohexyl-carbodiimide (0.88 g, 4.26 mmol) is added to the mixture, and heating is continued at 85° C. for 4 h. The crude reaction is concentrated under reduced pressure, and the residue is purified by normal phase chromatography (120 g silica-gel cartridge, dichloromethane-ethanol gradient). The fractions containing the desired compound are further purified by semi-preparative reverse phase high performance (LC/MS) using an XBRIDGE™ column (5 μm, 19×100 mm) and an isocratic program of 36% of acetonitrile in NH4HCO3 20 mM (pH 9), in 5 min at flow 25 mL/min to afford the title compound (0.15 g, 16%). LCES/MS m/z 440 (M+1); [α]D22+58.60°, (c=0.50, methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[S:13]([CH2:16][CH2:17][OH:18])(=[O:15])=[O:14])([O-:3])=[O:2].O.[S:20](=O)(=[O:23])([OH:22])[OH:21].[Cl-].[Na+]>>[S:20]([OH:23])([O:18][CH2:17][CH2:16][S:13]([C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:15])=[O:14])(=[O:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)CCO)c([N+](=O)[O-])c1
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)CCOS(=O)(=O)O)c([N+](=O)[O-])c1
Reaction time: 14 h

Procedure:
105 parts of 2-[2,4-dinitrophenylsulfonyl]ethanol are slowly introduced, at from 0 to 5° C., into 380 parts of sulfuric acid monohydrate and stirring is carried out for 14 hours at that temperature. The brown solution obtained is then slowly discharged onto a mixture of ice and 20% sodium chloride solution, whereupon a yellowish suspension is formed. The precipitate is filtered off and washed first with 1000 parts of cold 20% sodium chloride solution and then with 200 parts of ice-water. After drying, 2-[2,4-dinitrophenylsulfonyl]ethyl hydrogen sulfate is obtained in a very good yield and very good purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[CH:18]=O.O>N1CCCCC1.CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:18]\[C:17]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:12]
Reactant: Cc1nc[nH]c1C=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(Br)cc21
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-1,3-dihydro-2H-indol-2-one (0.3 g, 1.41 mmol) (Starting Material 6), and excess 4-methyl-5-imidazolecarboxaldehyde (0.25 g, 2.27 mmol) (Aldrich) in 1% piperidine in 2-propanol (6 mL) was heated at 90° C. for 4 h. Hot water (6 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.44 g, 100%)
Reaction SMILES: C(OP([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][NH:13][C:12]2[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:11]1=2)(=O)OCC)C.[H-].[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH:28]=O>O1CCCC1>[ClH:21].[ClH:24].[Cl:21][C:17]1[C:12]2[NH:13][CH2:14][CH2:15][N:16]=[C:10]([CH:9]=[CH:28][C:27]3[CH:30]=[CH:31][C:32]([Cl:33])=[C:25]([Cl:24])[CH:26]=3)[C:11]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CCOP(=O)(C=C1NCCNc2c(Cl)cccc21)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: Clc1ccc(C=CC2=NCCNc3c(Cl)cccc32)cc1Cl
Reaction time: 18 h
Yield: 154.2 %

Procedure:
To a solution of 91 mg (0.275 mmol) of (9-chloro-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester in 2 ml of tetrahydrofuran was added 19 mg (0.48 mmol) of sodium hydride (60% dispersion in mineral oil). After 10 minutes 50 mg (0.29 mmol) of 3,4-dichlorobenzaldehyde was added and the mixture was stirred for 18 hours. The product was purified by column chromatography (20 g IST pre-packed column) eluting with 1% methanol/dichloromethane and treated with 0.10 ml of 4M hydrogen chloride in dioxan. The solvent was evaporated to give 90 mg of (E)-9-chloro-5-(3,4-dichlorostyryl)-2,3-dihydro-1H-1,4-benzodiazepine dihydrochloride as an orange solid; MS: m/e 352.7 [M+H]+.
Reaction SMILES: C(OC([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:11]=32)[CH2:7]1)=O)C.[OH-].[K+]>CCO.C(Cl)Cl>[Cl:17][C:16]1[C:10]2[CH2:9][CH:8]3[CH:12]([C:11]=2[S:14][C:15]=1[CH3:18])[CH2:13][NH:6][CH2:7]3
Reactant: CCOC(=O)N1CC2Cc3c(sc(C)c3Cl)C2C1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1sc2c(c1Cl)CC1CNCC21

Procedure:
The product of step d) was treated with 40% aqueous KOH in EtOH at 105° C. for 16 hours. The reaction was cooled, diluted with CH2Cl2 and passed through an extrelut column to remove the water. The organic layer was concentrated and the residue purified by preparative LC/MS to give the title compound. MS calculated for C10H12ClNS+H 214, observed 214.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:33][CH2:34][CH2:35][C:36]#[N:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:34][CH2:35][C:36]#[N:37])[C:23](=[O:25])[CH2:22][N:14]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: N#CCCNCc1ccccc1
Product: Cc1ccc(N(CC(=O)N(CCC#N)Cc2ccccc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3-benzylamino-propionitrile
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17](O)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[NH:24]1[CH2:34][CH2:33][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:25]1.Cl>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([N:24]4[CH2:25][CH2:26][CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:33][CH2:34]4)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(C(=O)C23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
A suspension of (9RS,10RS)-2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (7.50 g, 27.7 mmol), prepared as described in Example 1j, in toluene (75 mL) was treated with thionyl chloride (4.12 g, 34.6 mmol) and N,N-dimethylformamide (2 drops). The mixture was heated to reflux for 3 h, then was cooled to room temperature and treated with ethyl isonipecotate (10.88 g, 69.25 mmol). The resulting thick slurry was stirred at room temperature for 16 h, then was poured into 1N hydrochloric acid (100 mL) and extracted with ethyl acetate (3×100 mL). The organic extracts were washed sequentially with 1N hydrochloric acid (100 mL), 10% aqueous sodium bicarbonate (100 mL) and brine (100 ml), combined, dried (MgSO4), filtered and evaporated to leave an amber oil which solidified on standing. The crystalline product was triturated with hexane (300 mL) and ether (25 mL), isolated by filtration, washed with hexane/ether (10:1, 50 mL) and air dried to afford the title compound (9.83 g, 23.9 mmol, 87%) as a white solid. 1H NMR (d6-DMSO): δ7.5 (br, 1H, H--C(1)), 7.35 (m, 3H), 7.01 (m, 3H), 4.5 (br, 1H), 4.43 (s, 1H, H--C(10)), 4.08 (q, J=7.0 Hz, 2H, CH2CH3), 3.6 (br, 1H), 3.2-2.55 (brm, 6H), 2.05-1.45 (brm, 5H), 1.19 (t, J=7.0 Hz, 3H, CH2CH3).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([Br:10])[S:8][CH:9]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:1]([N:4]([C:17](=[O:19])[CH3:18])[C:5]1[N:6]=[C:7]([Br:10])[S:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1csc(Br)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(C(C)=O)c1csc(Br)n1
Yield: 10.7 %

Procedure:
A solution of 4-acetylamino-2-bromothiazole 10g, prepared as described in Example 1, in acetic anhydride (100 ml) and pyridine (35 ml) was stirred at 100° C. for 24 hours. The reaction mixture was cooled and the excess acetic anhydride and pyridine removed in vacuo, and the residue was re-evaporated three times with toluene. The residue was purified by column chromatography using silica gel and eluting with chloroform, and recrystallised from hexane to give the title compound (1.2 g) m.p. 63°-65° C. (Found: C, 32.1; H, 2.8; H, 10.6 C7H7BrN2O2S requires C, 32.0; H, 2.7; N, 10.7%)
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH:15]([CH2:25][CH:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([CH:15]([CH2:25][CH:26]2[CH2:31][CH2:30][C:29](=[N:2][OH:3])[CH2:28][CH2:27]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnccn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)CC2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of hydroxylamine hydrochloride (19 mg, 0.27 mmol) in methanol (0.5 mL) and pyridine (0.5 mL) was treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 58, 80 mg, 0.18 mmol). The reaction mixture was heated under reflux for 2 h, cooled to 25° C., and concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 35/65 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-N-pyrazin-2-yl-propionamide (65 mg, 80%) was a white foam: EI-HRMS m/e calcd for C20H23ClN4O4S (M+H)+ 451.1202, found 451.1206.
Reaction SMILES: [F:1][C:2]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]2)[CH2:27][O:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH:36][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:32]2)[CH2:27][O:26]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 50.6 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.254 g, 0.79 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.187 g, 0.95 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.795 g, 1.80 mmol). The mixture was stirred at 0° C. and triethylamine (0.194 g, 1.90 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 10% to 70% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-fluoro-3-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.200 g, 51%) as a tan solid: HR-ES-MS m/z calculated for C26H33FN4O5 [M+H]+ 501.2508, observed 501.2511, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.36-1.49 (m, 1H), 1.49-1.64 (m, 1H), 1.68-1.83 (m, 1H), 2.29 (s, 3H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.04-4.16 (m, 2H), 4.21 (d, J=18.7 Hz, 1H), 4.35 (quin, J=5.8 Hz, 1H), 4.59 (d, J=18.7 Hz, 1H), 4.85 (s, 1H), 4.85-4.92 (m, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.13-7.34 (m, 3H), 7.60 (d, J=2.1 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H]2CC[C@H](C=O)CC2)=[C:6]([F:18])[C:5]=1[F:19])[CH3:2].C[C:21](C)=[O:22].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.C1(C)C=CC=CC=1>O>[CH2:1]([O:3][C:4]1([C:21]([OH:22])=[O:26])[CH2:9][CH2:8][CH2:7][C@@H:6]([F:18])[C@@H:5]1[F:19])[CH3:2]
Reactant: CCOc1ccc([C@H]2CC[C@H](C=O)CC2)c(F)c1F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC1(C(=O)O)CCC[C@@H](F)[C@@H]1F
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
The compound (16) (10.0 g) and acetone (50 ml) were mixed and the mixture was stirred at 35° C. for 30 minutes. Jones reagent (8N) (4.7 ml) was added to the mixture in the temperature range of 30 to 40° C. and the mixture was stirred at 35° C. for 2 hours. After the reaction mixture had been cooled to 30° C., toluene (200 ml) and water (200 ml) were added to the mixture and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, an aqueous solution of sodium thiosulfate and water, and then dried over anhydrous magnesium sulfate, giving 4-ethoxy-2,3-difluoro-(trans-4-cyclohexyl)-carboxylic acid (31) (8.8 g). The yield based on the compound (16) was 83.1%.