Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:16])=O.[BH4-].[Na+].S(=O)(=O)(O)O>O1CCCC1.C(O)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:15]([N:6]2[CH2:7][C@H:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[CH2:9][C@H:5]2[CH2:3][OH:2])=[O:16])=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylic acid methyl ester (79.4 g: 205 mmole) in a mixture of tetrahydrofuran (200 ml) and ethanol (300 ml), sodium borohydride (14 g) is added in several portions under ice cooling. The mixture is stirred at room temperature for 4 hours. The reaction mixture is neutralized with conc. sulfuric acid, concentrated in vacuo to approximately a half volume, diluted with water, and extracted with ethyl acetate. The extract is successively washed with aqueous sodium hydrogen carbonate, water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate=1:2) to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (58.7 g). Yield: 81.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(C#N)ccc1-c1ccc(NS(C)(=O)=O)cc1
Reaction time: 4 h
Yield: 66.1 %

Procedure:
5-(4-Aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.5 g, 2.3 mmol) was dissolved in pyridine (5 mL), methane sulfonyl chloride (0.16 mL, 2.1 mmol) was added, the mixture was stirred for 4 hours, and then water was added. The mixture diluted with ethyl acetate and the mixture was washed with water, saturated CuSO4, 2N HCl, brine, dried over MgSO4, and concentrated. Flash chromatography (5%-50% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]methanesulfonamide (0.382 g).
Reaction SMILES: C([NH:8][CH2:9][CH:10]([OH:23])[CH2:11][O:12][C:13]1[C:21]2[C:17](=[N:18][C:19](=[O:22])[N:20]=2)[CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH2:8][CH2:9][CH:10]([OH:23])[CH2:11][O:12][C:13]1[C:21]2[C:17](=[N:18][C:19](=[O:22])[N:20]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C1N=c2cccc(OCC(O)CNCc3ccccc3)c2=N1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCC(O)COc1cccc2c1=NC(=O)N=2

Procedure:
1.6 g of palladium-on-charcoal catalyst are added to a solution of 15.5 g of 4-(3-benzylamino-2-hydroxypropoxy)benzimidazol-2-one in 160 ml of methanol, and the mixture is hydrogenated until the calculated amount of hydrogen has been absorbed. The catalyst is filtered off and the solvent distilled off to leave 4-(3-amino-2-hydroxypropoxy)-benzimidazol-2-one, which melts at 188°-190° after recrystallization from ethanol.
Reaction SMILES: C(=O)([O-])O.[K+].[C:6]1([S:12]([NH:15][C:16]2[CH:17]=[C:18]([C@@H:22]([OH:42])[CH2:23][NH:24][C:25]([CH3:41])([CH3:40])[CH2:26][CH2:27][N:28]3[C:36]4[C:31](=[CH:32][C:33]([C:37]([OH:39])=[O:38])=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[CH2:44][C:45]([N:47]([CH3:49])[CH3:48])=[O:46]>CN(C=O)C.O>[C:6]1([S:12]([NH:15][C:16]2[CH:17]=[C:18]([C@@H:22]([OH:42])[CH2:23][NH:24][C:25]([CH3:40])([CH3:41])[CH2:26][CH2:27][N:28]3[C:36]4[C:31](=[CH:32][C:33]([C:37]([O:39][CH2:44][C:45](=[O:46])[N:47]([CH3:49])[CH3:48])=[O:38])=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)(CCn1ccc2cc(C(=O)O)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Potassium hydrogen carbonate (141 mg, 1.4 mmol) is added to a solution of 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylic acid-hydrotrifluoroacetate (Example 6; 300 mg, 0.47 mmol) in 2 ml DMF. Then the reaction mixture is stirred for 20 minutes at RT and 2-chloro-N,N-dimethylacetamide (143 mg, 1.18 mmol) is added. After 90 hours stirring at RT the reaction mixture is diluted with 50 ml of water and extracted with ethyl acetate. The organic phase is dried on magnesium sulphate and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel (DCM/methanol=100:0→95:5).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[Si:11]([O:18][CH2:19][CH2:20][CH2:21]Br)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:21][CH2:20][CH2:19][O:18][Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:12])[CH3:13])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Cc1cc(O)cc(C)c1Br
Product: Cc1cc(OCCCO[Si](C)(C)C(C)(C)C)cc(C)c1Br
Yield: 102.3 %

Procedure:
According to the method of (Example 17) <Step 1>, from 4-bromo-3,5-dimethylphenol (4.00 g) and 3-((tert-butyldimethylsilyl)oxy)propyl bromide (5.55 g), the subject compound (7.60 g) was obtained as a colorless oil.
Reaction SMILES: [Cl-].[Li+].COP([CH2:9][CH2:10][CH:11]=[O:12])(=O)OC.[CH:13](N(C(C)C)CC)(C)C.[CH3:22][C:23]1([C:28]2(C=O)[CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25][O:24]1.[Cl-].[Na+]>C(#N)C>[CH3:22][C:23]1([C:28]2(/[CH:9]=[CH:10]/[C:11](=[O:12])[CH3:13])[CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25][O:24]1
Reactant: CC1(C2(C=O)CC2)OCCO1
Reactant: COP(=O)(CCC=O)OC
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)/C=C/C1(C2(C)OCCO2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
13.8 g of lithium chloride (anhydrous) is introduced into 120 ml of acetonitrile under nitrogen, and 49.8 ml of oxopropylphosphonic acid dimethyl ester, 51.3 ml of diisopropylethylamine and 5.4 g of aldehyde 7 are added in succession. It is stirred for 18 hours at room temperature, and then sodium chloride solution is added. It is extracted with ethyl acetate, washed with sodium chloride solution and dried on sodium sulfate. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 5.3 g of the title compound accumulates as a colorless oil.
Reaction SMILES: C(C1SC2C(=O)N(C3C=CC=C([B:20]4[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]4)C=3C)CC=2C=1)(C)(C)C.[C:30]([O:33][CH2:34][C:35]1[C:40]([N:41]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[C:46]([N:50]([CH3:52])[CH3:51])[CH:47]=3)[C:42]2=[O:53])=[CH:39][CH:38]=[CH:37][C:36]=1Br)(=[O:32])[CH3:31].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1>>[C:30]([O:33][CH2:34][C:35]1[C:36]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[CH:37][CH:38]=[CH:39][C:40]=1[N:41]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46]([N:50]([CH3:52])[CH3:51])[CH:47]=2)[C:42]1=[O:53])(=[O:32])[CH3:31]
Reactant: CC(=O)OCc1c(Br)cccc1N1Cc2cc(N(C)C)ccc2C1=O
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(N(C)C)ccc2C1=O
Yield: 100 %

Procedure:
Using the same general procedure as described for the preparation of 102g reaction of 123d (2.65 g, 6.59 mmol) with bis(pinacolato)diboron (5.02 g, 19.8 mmol) gave a 100% yield (3.00 g) of 123e as a brown solid: mp 75-76° C.; 1H NMR (300 MHz, CDCl3) δ 7.85 (dd, 1H, J=4.2, 1.8 Hz), 7.76 (d, 1H, J=8.7 Hz), 7.45 (m, 2H), 6.80 (dd, 1H, J=8.7, 2.1 Hz), 6.69 (s, 1H), 5.13 (s, 2H), 4.69 (s, 2H), 3.08 (s, 6H), 1.93 (s, 3H), 1.34 (s, 12H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([OH:7])=O)[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:21][CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[C:25](=[O:42])[N:26]([CH:34]1[CH2:39][CH2:38][C:37](=[O:40])[NH:36][C:35]1=[O:41])[C:27]([CH3:33])=[N:28]2>CN(C=O)C>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]([NH:21][CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[C:25](=[O:42])[N:26]([CH:34]1[CH2:39][CH2:38][C:37](=[O:40])[NH:36][C:35]1=[O:41])[C:27]([CH3:33])=[N:28]2)=[O:7]
Reactant: CN(C)CC(=O)O
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)CN(C)C)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a stirred solution of dimethylamino-acetic acid (0.27 g, 1.9 mmol) in DMF in a 40° C. oil bath (8 mL), was added 1.1′carbonyldiimidazole (0.35 g, 2.1 mmol) and stirred for one hour. Then 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.65 g, 1.9 mmol) was added and stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-dimethylamino-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamide as a light yellow solid (340 mg, 46% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 05/95 CH3CN/0.1% H3PO4, 7.29 min (99.8%); mp, 275° C. (decomposed); 1HNMR (DMSO-d6)2.16-2.19 (m, 7H, CHH and NMe2), 2.63-2.91 (m, 8H, CHCH2, CH3 and NCH2), 4.74-4.76 (m, 2H, CH2NH), 5.25 (dd, J=6, 12 Hz, 1H, CH), 7.31-7.76 (m, 3H, Ar), 8.26 (t, J=6 Hz, 1H, CH2NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.68, 23.31, 30.59, 41.62, 45.54, 56.51, 62.81, 117.69, 125.53, 125.74, 133.96, 140.54, 148.52, 154.82, 161.03, 169.42, 169.63, 172.63. LCMS MH=386; Anal Calcd For C19H23N5O4: C, 59.21; H, 6.01; N, 18.17. Found: C, 58.95; H, 6.05; N, 17.79.
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH2:20][CH3:21])[C:3]1=[O:22].C(N(S(F)(F)[F:29])CC)C.O>C(Cl)Cl>[F:29][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH2:20][CH3:21])[C:3]1=[O:22]
Reactant: CCN1C(=O)C(O)N=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCN1C(=O)C(F)N=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Yield: 57.1 %

Procedure:
A solution of 3.5 g (0.01 mol) of 3-hydroxy-1,3-dihydro-1-ethyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one in 7 ml of anhydrous methylene chloride was added dropwise to a stirred solution of 3.53 ml (0.028 mol) of diethylaminosulfur trifluoride in 84 ml of anhydrous methylene chloride cooled to -70°. The reaction mixture was allowed to warm slowly to 5° and then poured into 150 ml of ice and water. The lower organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give 2.84 g (90% yield) of crude product as light yellow crystals. Recrystallization from 200 ml of heptane gave 1.81 g (57% yield) of 3-fluoro-1,3-dihydro-1-ethyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one: mp 156°-158°; 1H nmr (DMSO-d6) δ 7.2-7.8 ppm (m, 8H), δ 5.85 ppm (d, 1H, J=57 Hz), δ 3.5-4.38 (m, 2H, methylene protons on nitrogen), δ 1.02 (t, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:15][C:16]1([F:42])[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([S:30]([C:33]3[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:22]=2)[CH2:17]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(Cl)Cl>[F:42][C:16]1([F:15])[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([C:37]([NH:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[O:38])=[CH:40][CH:41]=3)(=[O:32])=[O:31])[CH:22]=2)[CH2:17]1
Reactant: NC1CCOCC1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCOCC1)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Yield: 89 %

Procedure:
Add a 2 ml CH2Cl2 solution of Tetrahydro-pyran-4-ylamine (62 mg, 0.0610 mmol, 1.1 eq) and triethylamine (365 mg, 3.6 mmol, 6.5 eq) to a 2 ml CH2Cl2 solution of 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid. Add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (245 mg, 0.555 mmol, 1.0 eq) and stir reaction at room temperature for 18 hours. Remove volatiles on rotovap and purify by silica gel chromatography, followed by SCX ionic chromatography to give 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-yl)-benzamide (240 mg, 89% yield). Mass Spectrum (m/e): 489.71 (MH+).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1)#[CH:2].C(N(CC)CC)C.[CH3:16][CH:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18]>ClCCl>[C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([S:19]([CH:17]([CH3:18])[CH3:16])(=[O:21])=[O:20])[CH2:4]1)#[CH:2]
Reactant: C#CC1CCCNC1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC1CCCN(S(=O)(=O)C(C)C)C1
Reaction time: 3 h

Procedure:
To a solution of Example 10A (500 mg, 4.58 mmol) in dichloromethane (10 mL) was added triethylamine (2.55 mL, 18.32 mmol) followed by propane-2-sulfonyl chloride (1.306 g, 9.16 mmol) and the mixture was stirred for 3 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 30% ethyl acetate in hexane) afforded the title compound. LCMS: 216.2 (M+H-Boc)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.C(=O)=O.C[Li].C([Li])CCC.CON(C)[C:41](=[O:43])[CH3:42]>O.C1COCC1>[C:41]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2)(=[O:43])[CH3:42]
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Reactant: CON(C)C(C)=O
Agent: O=C=O
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C

Procedure:
A mixture of N-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (1.0 g) and THF (10 ml) was cooled to −78° C. (dry ice bath), and a solution of methyllithium (2.0 ml; 1.6 M in diethyl ether) was added dropwise. One minute after the addition had ended, a solution of butyllithium (1.4 ml; 2.5 M in toluene) was added dropwise. One minute after the addition had ended, N-methoxy-N-methylacetamide (0.24 g) was added. After warming to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (eluent: 1:1 heptane/ethyl acetate). The product was thus obtained with the molecular weight of 393.49 (C24H27NO4); MS (ESI): 394 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:9]([C:19]#[N:20])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23]CC)=[O:22].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[C:9]([C:19]#[N:20])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C)C)c(C#N)c2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)COc1ccc(-n2ncc(C(=O)O)c2Cl)cc1C#N
Temperature: 60 °C
Yield: 49.4 %

Procedure:
To a solution (10 ml) of ethyl 5-chloro-1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylate (1.01 g) in ethanol was added 1 N aqueous sodium hydroxide solution (3.4 ml) with stirring, and the mixture was heated at 60° C. for 1 hour. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from ethyl acetate to give 0.46 g of 5-chloro-1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylic acid, melting point 212° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[O:22][CH3:23])(=[O:13])=[O:12])=[C:4]([N+:24]([O-])=O)[CH:3]=1.C(O)(=O)C.Cl.N>O1CCCC1.[Zn]>[NH2:24][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[O:22][CH3:23])(=[O:13])=[O:12]
Reactant: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: N
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(Br)cc1N
Temperature: 25 °C
Yield: 101.5 %

Procedure:
To a stirred solution of 5.9 g of N-[2-(4-bromo-2-nitrophenyl)ethyl]-5-cyano-2-methoxybenzenesulfonamide and 46 mL of acetic acid in 67 mL of tetrahydrofuran were added successively 2.23 mL of concentrated hydrochloric acid and 8.76 g of zinc under ice-cooling. After the mixture was stirred at room temperature for an hour, and to the reaction mixture was added 25% aqueous ammonia solution to alkalify. After the mixture was extracted with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 5.58 g of N-[2-(2-amino-4-bromophenyl)ethyl]-5-cyano-2-methoxybenzenesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1[S:42]([Cl:45])(=[O:44])=[O:43]>>[ClH:45].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:42]([C:35]3[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:34]=3[O:33][CH3:32])(=[O:44])=[O:43])=[C:3]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Product: COc1ccc(OC)c(S(=O)(=O)Nc2ccc(N3CCCNCC3)cc2NS(=O)(=O)c2ccccc2)c1
Product: Cl

Procedure:
The compound was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and 2,5-dimethoxybenzenesulfonylchloride (64 mg, 0.27 mmol) to give 14 mg as purple solid. M+ 1 547.3 Calcd 547.16; 1HNMR δ 7.71-7.00 (m, 9H), 6.48 (dd, 1H), 6.16 (d, 1H), 4.04 (s, 3H), 3.68 (s, 3H), 3.56 (app t, 2H), 3.33 (app t, 2H), 3.17 (app t, 2H), 3.11 (app t, 2H), 2.03-1.95 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]3[CH2:25][CH2:24][CH:23]=[CH:22]3)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH2:32].CC([OH:37])(C)C.C[N+]1([O-])CCOCC1>C1COCC1.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]3[CH2:25][CH2:24][C@@H:23]([OH:32])[C@H:22]3[OH:37])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: C[C@]1(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C2C=CCC2)C1=O
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: C1CCOC1
Product: C[C@]1(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H]2CC[C@@H](O)[C@H]2O)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 102, Step F) (94 mg, 0.205 mmol) in THF (1.0 mL) was added water (0.25 mL) and tBuOH (0.2 mL) at room temperature. NMO (36.0 mg, 0.308 mmol) was added followed by osmium tetroxide (4% aq) (1.303 μL, 0.205 mmol). The reaction mixture was stirred at room temperature for 24 h. Water (10 mL) was added and the mixture was extracted with DCM twice. The organic layers were combined and dried over Na2SO4 and concentrated under reduced pressure. The residue, containing a mixture of three stereoisomers, was purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 30 to 50% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to provide the title compound as the first eluting isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26]([N:17]2[C:14]3=[N:15][CH:16]=[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:12]=[C:13]3[CH:19]=[CH:18]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(-c2cnc3[nH]ccc3c2)cc1OC
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COc1ccc(-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)cc1OC

Procedure:
1-Benzenesulfonyl-5-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine 132 was prepared using the same protocol as described in Example 9, substituting 3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo-[2,3-b]pyridine and quioline-8-sulfonyl chloride with 5-(3,4-Dimethoxy-phenyl)-1H-pyrrolo-[2,3-b]pyridine and benzene sulfonyl chloride respectively. MS(ESI) [M+H+]+=395.20
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:30]=[C:29]([F:31])[C:28]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:27][C:11]=1[O:12][C:13]1[C:14]([O:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[CH3:22])=[N:15][C:16]([CH3:19])=[N:17][CH:18]=1.[ClH:45]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:45][C:10]1[CH:30]=[C:29]([F:31])[C:28]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:27][C:11]=1[O:12][C:13]1[C:14]([O:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[CH3:22])=[N:15][C:16]([CH3:19])=[N:17][CH:18]=1
Reactant: COC(=O)C(C)Oc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)C(C)Oc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
Isoamyl nitrite is added to a mixture of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine, copper(I) chloride, copper(II) chloride and acetonitrile dropwise at room temperature, and the mixture is stirred for 1 hour. This reaction solution is poured into 2% hydrochloric acid, and extracted with ethylacetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-{1-(methoxycarbonyl)ethoxy}-2-methylpyrimidine [present compound4-76].