Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:10]([CH2:23][C:24](OC)=[O:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO.[Pt](=O)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[NH:20][C:24](=[O:25])[CH2:23][CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1c1ncccc1[N+](=O)[O-]
Agent: O=[Pt]=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CC2CN(Cc3ccccc3)CCN2c2ncccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Platinum(IV) oxide (35 mg, 0.154 mmol) was added to a solution of the product of Example 51A (1.20 g, 2.92 mmol) in methanol (150 mL), and the suspension was stirred under hydrogen (1 atm) for 1 hour. The reaction flask was evacuated and purged with nitrogen (4 cycles), and the mixture was filtered through a pad of diatomaceous earth with a methanol (30 mL) rinse. A solution of 25% sodium methoxide in methanol (Aldrich, 1.83 g, 8.47 mmol) was added to the filtrate, and the solution was stirred at reflux under nitrogen for 41 hours and then cooled to room temperature. The reaction mixture was concentrated under vacuum, and the residue was purified by chromatography (SiO2, eluted with CH2Cl2—CH3OH, 95:5), followed by crystallization from ethanol (2 mL) to provide the title compound: 1H NMR (300 MHz, CD3OD) δ ppm 2.15 (dd, J=13.7, 3.0 Hz, 1H), 2.22-2.32 (m, 1H), 2.31 (t, J=10.7 Hz, 1H), 2.75 (dd, J=13.7, 6.5 Hz, 1H), 2.83-2.96 (m, 2H), 3.23 (td, J=12.7, 2.8 Hz, 1H), 3.51-3.59 (m, 1H), 3.60 (s, 2H), 3.64-3.74 (m, 1H), 6.99 (dd, J=7.7, 5.0 Hz, 1H), 7.22-7.40 (m, 6H), 8.08 (dd, J=4.8, 1.6 Hz, 1H); MS (DCI) m/z 309 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:10][CH2:1][C:2]([CH3:9])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(C)CBr
Yield: 106.5 %

Procedure:
The olefins 66 can also be prepared by reacting the corresponding substitued phenols with ethyl 4-bromo-3-methyl-2-butenate in the presence of potassium carbonate and small amount of 18-crown-ether in methylene chloride. The starting material ethyl 4-bromo-3-methylbutenate has been obtained from the reaction of ethyl 3,3-dimethylacrylate with N-bromosuccinimide (NBS) as follows: to 20 g of ethyl 3,3-dimethylacrylate in 250 ml of carbon tetrachloride, 30 g of N-bromosuccinimide (NBS) and 0.01 g of azobisisobutyronitrile were added. The mixture was refluxed for 3 hours. Succinimide was removed by filtration and the filtrate was washed with chloroform. The combined organic layers were washed sequentially with saturated sodium sulfite, saturated sodium chloride and then dried over anhydrous magnesium sulfate. Evaporation of the solvent afforded 34.4 g ethyl 4-bromo-3-methyl-2-butenate (Safaryn, J. E.; Chiarello, J.; Chen, K. M.; Joullie, M. M.; Tetrahedron, 1986, 42, 2635). The product can be further purified by silica gel flash column chromatography using ether/hexane (e.g. 1:50) as eluent, and hydrolyzed to the corresponding carboxylic acid with aqueous methanolic NaOH.
Reaction SMILES: [N+]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl[C:12]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:5]1([NH:6][C:20]2([Cl:21])[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=[O:15])[CH2:12]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:4]=1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)C1=CC=CC(Cl)(Nc2ccccc2)C1
Temperature: 110 °C
Yield: 55.2 %

Procedure:
To a stirred solution of 20.0 g (0.145 mole) of 2-nitroaniline 1, 28.0 g (0.146 mole) of 2,3-dichlorobenzoic acid in 200 mL dry dimethyl sulfoxide, 20.0 g (0.19 mole) of anhydrous sodium carbonate is added. The reaction mixture is heated at 110° C. for 5 hours under nitrogen atmosphere. The dimethyl sulfoxide solvent from the reaction mixture is removed under high vacuum and dried. The crude product is extracted three times each time with 100 mL methylene chloride by partitioning into water. The combined methylene chloride layer is dried over anhydrous sodium sulfate and filtered. Solvent from the filtrate is removed under reduced pressure and dried. The crude residue is chromatographed on a silica gel 60 column (230-400 mesh) using 25% ethyl acetate in hexane as an elution solvent. The fractions containing the desired product are combined and the solvent removed under reduced pressure to yield 20.0 g (47%) of N-phenyl N-(1-chloro 3-carboxyphenyl) amine 9.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[NH4+:22].[OH-]>>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:22])=[O:7])([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Product: NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 89 %

Procedure:
2,4-Dinitrobenzoic acid (8.17 g, 38.5 mmol) was treated with oxalyl chloride (3.90 mL, 44.7 mmol). The resulting acid chloride was treated with saturated NH4OH solution (200 mL) to yield the title compound (7.25 g, 89%). m.p. 202°-204° C. 1H NMR (300 MHz, DMSO) δ8.75 (d, 1H), 8.58 (dd, 1H), 8.48 (br s, 1H), 7.99 (br s, 1H), 7.91 (d, 1H), 5.50-6.20 (br s, 2H). MS (DCI/NH3) m/e 229 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[O:11]([CH2:19][C:20]([NH2:23])([CH3:22])[CH3:21])[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:23][C:20]([CH3:22])([CH3:21])[CH2:19][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(N)CO[Si](C)(C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NCc1ccc(F)cc1F
Temperature: 0 °C
Yield: 88.6 %

Procedure:
To a solution of 2,4-difluorobenzaldehyde (1.42 g, 10.0 mmol) in toluene (30 ml) was added 1-t-butyldimethylsiloxy-2-methyl-2-propylamine (2.03 g, 10.0 mmol) and stirred under reflux using a Dean-Stark trap to remove water for 6 hours. The solvent was evaporated and the residue was dissolved in methanol (10 ml). The solution was cooled to 0° C. in ice-water bath and an excess amount of NaBH4 was added. The mixture was gradually warmed to room temperature and stirring was continued until the Schiff base disappeared. The mixture was added to 1N NaOH aqueous solution, extracted with toluene, washed with sat. NaCl aqueous solution and dried over MgSO4. The solvent was evaporated to give the crude title compound (2.92 g; 92% in 2 steps).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]
Reactant: COc1n[nH]c2cc(Br)ccc12
Reactant: CCOC(=O)C=Cc1cccnc1
Product: CCOC(=O)C=C(c1cccnc1)c1ccc2c(OC)n[nH]c2c1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-3-pyridin-3yl-acrylic acid ethyl ester was prepared from 6-bromo-3-methoxy-1H-indazole and 3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl esterLVIII (Example 14).
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH2:17]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:21])=[CH:5][N:6]=2)=[CH:16][O:15][N:14]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCc1nocc1COc1ccc(C(=O)OC)cn1
Reactant: NC1CCOCC1
Product: CCCCc1nocc1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 73 %

Procedure:
As described for example 25e, 6-(3-butyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (200 mg, 0.69 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (180 mg, 73%) which was obtained as a white solid after purification by chromatography (silica, 40 to 60% ethyl acetate in heptane). MS: m/e=360.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[CH:5]=[C:4]([F:20])[C:3]=1[S:21]([NH2:24])(=[O:23])=[O:22].[F:25][C:26]1[N:31]=[C:30](F)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:20][C:4]1[CH:5]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[CH:7]=[C:2]([F:1])[C:3]=1[S:21]([NH:24][C:28]1[CH:29]=[CH:30][N:31]=[C:26]([F:25])[N:27]=1)(=[O:23])=[O:22]
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(N)(=O)=O)c(F)c1
Reactant: Fc1ccnc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccnc(F)n2)c(F)c1
Yield: 50.9 %

Procedure:
A solution of the 2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide (0.23 g, 0.65 mmol) prepared in Example 111c, 2,4-difluoropyrimidine (0.23 g, 1.96 mmol) and potassium carbonate (0.36 g, 2.61 mmol) in DMF (6.5 mL) was stirred at 120° C. for 3 hours. After allowing to cool, water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed twice with water (50 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (ethyl acetate/methanol=6:1) to yield the title compound (150 mg, 51%) as a colorless amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:13]1([NH:1][C:2]2[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1cccc(N)c1C
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(NC2CCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a stirred solution of methyl 3-amino-2-methylbenzoate (2 g, 12.1 mmol) and cyclopentanone (5 g, 60.6 mmol) in methanol (20 mL) was added acetic acid (0.72 g, 12.12 mmol) and the reaction stirred at room temperature for 3 h. Sodium cyanoborohydride (1.13 g, 18.2 mmol) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the product was purified by column chromatography to afford methyl 3-(cyclopentylamino)-2-methylbenzoate (2.2 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([NH2:16])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)c1n[nH]cc1NC1CCCCC1
Temperature: 25 °C
Yield: 15.9 %

Procedure:
To a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (200 mg; 1 mmol) and cyclohexanone (107 mg; 1.1 mmol) in dichloromethane (10 ml) were added 3 Å molecular sieves (1 g) and sodium triacetoxyborohydride (315 mg; 1.5 mmol), and the mixture was then stirred at room temperature over the weekend. The reaction mixture was filtered through Celite®, diluted with ethyl acetate, washed with brine, dried (MgSO4) and evaporated to give the 48 mg of the product as a grey gum. (LC/MS: Rt 2.95, [M+H]+ 285).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[Na+].[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][C@H:17]1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CN(C)C=O>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@@H:19]([S:3][C:1](=[O:4])[CH3:2])[CH2:18][C@H:17]1[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc3ccccc3)C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)S[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
29.34 g (257 mmol) of sodium thioacetate were added to a solution of 127.17 g (245 mmol) of (2S,4R)-1-benzyloxycarbonyl-2-(t-butyldimethylsilyloxy)methyl-4-(p-toluenesulfonyloxy)pyrrolidine [obtained as described in step (a) above] in 245 ml of dimethylformamide, and the resulting mixture was stirred for 1.5 hours at 60° C. After it was cooled to room temperature, water was added and it was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel using an 8:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 91.67 g (yield: 88%) of the title compound as an orange oil.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[CH2:34][CH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([CH:48]=O)[CH2:44][CH2:43]2)[CH2:38][CH2:37]1.C(OCC)C>COC(C)(C)C>[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[CH2:34][CH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([CH:48]=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=3)[CH2:44][CH2:43]2)[CH2:38][CH2:37]1
Reactant: O=C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Fc1ccc(C=C[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Reaction time: 1.5 h

Procedure:
3 g of p-fluorobenzyl-triphenylphosphonium bromide (preparable from p-fluorobenzyl bromide and triphenylphosphine) are suspended in 50 ml of tert.butyl methyl ether. The suspension is treated at room temperature with 0.75 g of potassium tert.butylate and stirred for 1.5 hours. Subsequently, the mixture is treated dropwise at 0° C. within 5 minutes with a solution of 1.40 g of trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxaldehyde in 25 ml of tert.butyl methyl ether and stirred at room temperature for a further 24 hours. Thereafter, the reaction mixture is taken up diethyl ether, washed several times with water, dried over magensium sulfate, filtered and concentrated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gives β-[trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]-4-fluorostyrene.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36]>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: ClCCCCBr
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Temperature: 50 °C
Reaction time: 20 h
Yield: 109.4 %

Procedure:
N2-Butyl-8-(methyloxy)-9H-purine-2,6-diamine trifluoroacetate (5 g, 14.27 mmol) and potassium carbonate (4.93 g, 35.7 mmol) were suspended in DMF (40 ml) and heated to 50° C. under nitrogen for 30 mins. The mixture was cooled to room temperature, 1-bromo-4-chlorobutane (1.645 ml, 14.27 mmol) was added and stirring was continued at room temperature for 20 hours. The solvent was concentrated under vacuum and the residue was partitioned between DCM (100 ml) and water (100 ml). The layers were separated using a hydrophobic frit and the aqueous phase was re-extracted with DCM (100 ml). The combined organics extracts were concentrated in vacuo and the residue purified by chromatography using a FlashMaster apparatus (100 g silica cartridge) and using a DCM:methanol 0-25% gradient over 40 mins. The desired fractions were combined and concentrated under vacuum to give the impure title compound as a yellow oil (5.1 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)=[N:5][NH:6]S(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:25])[C:4](=[N+:5]=[N-:6])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1
Reactant: COC(=O)C(=NNS(=O)(=O)c1ccc(C)cc1)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
In a dry flask under argon was placed a solution of (3,4-dichloro-phenyl)-(4-toluenesulfonylhydrazono)-acetic acid methyl ester (1.45 g, 3.61 mmol) in dichloromethane (20 mL) containing triethylamine (0.55 mL, 3.97 mmol) at 25° C. The bright yellow solution was then stirred at 25° C. for 1 h, then the solvent was removed in vacuo to yield a bright yellow solid. The product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 7/1/0.5 hexanes/dichloromethane/methanol) to furnish diazo-(3,4-dichloro-phenyl)-acetic acid methyl ester (814 mg, 92% yield) as a bright yellowish orange solid: EI-HRMS m/e calcd for C9H6Cl2N2O2 (M+) 243.9806, found 243.9800.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[NH2:25][CH2:26][CH2:27][CH2:28][OH:29]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][CH2:26][CH2:27][CH2:28][OH:29])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NCCCO
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCO)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-aminopropan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (quin, J=6.69 Hz, 2H) 2.44 (s, 3H) 3.32-3.39 (m, 2H) 3.49 (br. s., 2H) 4.51 (br. s., 1H) 7.66 (dd, J=7.83, 1.52 Hz, 1H) 7.73 (s, 1H) 7.78 (d, J=6.82 Hz, 1H) 8.17 (br. s., 1H) 8.41 (d, J=6.32 Hz, 2H) 8.69 (t, J=5.43 Hz, 1H) 8.88-8.95 (m, 1H) 12.93-13.41 (m, 1H). MS m/z [M+H]+ 378.1.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:22]([CH3:23])=[CH:21][C:15]2[N:16]=[C:17]([CH:19]=C)[S:18][C:14]=2[C:13]=1[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[O:35]=O>CO>[C:1]([O:5][C@@H:6]([C:12]1[C:22]([CH3:23])=[CH:21][C:15]2[N:16]=[C:17]([CH:19]=[O:35])[S:18][C:14]=2[C:13]=1[O:24][S:25]([C:28]([F:29])([F:31])[F:30])(=[O:26])=[O:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=Cc1nc2cc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(OS(=O)(=O)C(F)(F)F)c2s1
Reactant: O=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C=O)sc2c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A solution of 91A (170 mg, 0.353 mmol), DCM (5.0 mL), and MeOH (5.0 mL) was cooled to 78° C. and perfused with oxygen gas for 3 min. Then using an ozonator, a stream of O3 in oxygen gas was bubbled through the solution for 5 min. After this, the reaction was stirred for 10 min, then sparged with oxygen gas for 2 min to drive out unreacted ozone in solution. While the reaction was still at 78° C., dimethylsulfide (200 μL) was added and the reaction allowed to warm to 0° C. After 30 min, 10% w/v aq Na2S2O3 (5 mL) was added and the reaction was warmed to 23° C. and stirred for 10 min. The reaction was diluted with H2O (20 mL) and extracted with DCM (3×15 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated. More DCM was added and the reaction was concentrated once more to remove residual methanol, giving 91B (165 mg, 97% yield). 1H-NMR: 400 MHz, (CDCl3) δ: 10.04 (s, 1H), 8.00 (s, 1H), 5.60 (s, 1H), 4.22-4.00 (m, 2H), 2.51 (s, 3H), 1.16 (s, 9H), 1.14 (t, J=6.8 Hz, 3H). 19F-NMR: 376 MHz, (CDCl3) δ: −73.6.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:7])[C:4](O)=[O:5].[C:8]([O:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1)([CH3:11])([CH3:10])[CH3:9].C1(N=C=NC2CCCCC2)CCCCC1>C(O)(=O)C.ClCCl>[C:8]([O:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:4](=[O:5])[CH:3]([CH3:7])[CH2:2][SH:1])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(CS)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To the cold (5°) solution of 1.2 g. (10 mMol.) of 3-mercapto-2-methylpropanoic acid and 1.7 g. (10 mMol.) of L-proline tert. butyl ester in 25 ml. dichloromethane 2.26 g. of dicyclohexylcarbodiimide in 5 ml. dichloromethane is added in portions. After 2 hours at room temperature, 5 drops of acetic acid are added, the mixture is filtered and the filtrate evaporated to an oily residue. This residue is taken up in 20 ml. of petroleum ether-ethyl acetate (3:1) and applied to a 150 ml. silica gel column prepared in petroleum ether. The fraction eluted with petroleum ether-ethyl acetate (1:1) contains the product, 1-(3-mercapto-2-methylpropanoyl)-L-proline tert.butyl ester. This fraction (0.6 g.) is dried over P2O5 in vacuo for 12 hours. Rf 0.6 (Silica gel, Benzene/Acetic acid 3:1), Rf 0.8 (Silica gel, Methyl-ethylketone/acetic acid/pyridine/water 14:1:2:1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[C:3]1=[O:24].C(N(CC)CC)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CCO>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=4)[N:36]=[CH:35][N:34]=3)[C:3]2=[O:24])[C@H:8]([CH2:18][S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:9]1)([CH3:17])[CH3:16]
Reactant: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 80 °C
Yield: 63 %

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (50 mg, 0.1 mmol) in EtOH (2 mL) was added triethylamine (0.1 mL, 0.6 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (27 mg, 0.11 mmol). The mixture was heated at 80° C. for 14 h and then concentrated in vacuo. The residue was pjurified by HPLC to provide the title compound, (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one (35 mg). MS found: (M+H)+=556.