Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([NH2:8])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[O:38][C:39](=O)[C:40]1[CH:45]=[CH:44][C:43]([C:46]2[NH:50][N:49]=[N:48][N:47]=2)=[CH:42][C:41]=1[F:51]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([NH:8][C:39](=[O:38])[C:40]2[CH:45]=[CH:44][C:43]([C:46]3[NH:50][N:49]=[N:48][N:47]=3)=[CH:42][C:41]=2[F:51])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: COC(=O)c1ccc(-c2nnn[nH]2)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1)c1ccc(-c2nnn[nH]2)cc1F
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a stirred solution of 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenylamine (60 mg, 0.16 mmol) in dry tetrahydrofuran (15 ml) was added lithium bis(trimethylsilyl)amide at −30° C. and stirring continued for 30 minutes at that temperature. To this was added a solution of 2-fluoro-4-(1H-tetrazol-5-yl)-benzoic acid methyl ester (42 mg, 0.19 mmol) in tetrahydrofuran (5 ml) at −30° C. The temperature was then allowed to slowly rise to 25° C., and the reaction mixture was allowed to stir for 13 h. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride, extracted with ethyl acetate (3×5 ml). Combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel (ethyl acetate to 4% methanol/ethyl acetate) gave the desired final compound as light yellow powder (30%). MS (Turbo Spray): m/z=566.4 (M+H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([N:13]([CH3:25])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To a solution of the compound (12.1 g) obtained in step 1 in DMF (55 mL) was added sodium hydride (1.82 g) at 0° C. The reaction mixture was stirred at 0° C. for 5 min, methyl iodide (11.4 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The extract was washed with saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (10% ethyl acetate/hexane) to give tert-butyl [3,5-bis(trifluoromethyl)phenyl](methyl)carbamate (12.5 g, 99%) as a colorless oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:24][CH2:25][C@@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[OH:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>CN(C)C=O>[OH:27][C@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[CH2:25][NH:24][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3cccnc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NS(=O)(=O)c4cccnc4)cc3)CC2)ccc1O
Reaction time: 18 h
Yield: 14.6 %

Procedure:
To a stirred mixture of pyridine-3-sulfonic acid-[4-(4-oxo piperidin-1-yl)-phenyl]amide (which was obtained in Example 237) (0.94 g, 2.8 mmol), N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) (0.70 g, 2.8 mmol) in dimethylformamide (10 mL) at room temperature was added sodium triacetoxyborohydride (0.72 g, 3.4 mmol) and glacial acid (0.18 mL, 3.1 mmol). The reaction was stirred under N2 atmosphere for 18 hours. The reaction mixture was poured onto 1:1 water/saturated sodium bicarbonate, extracted with ethyl acetate three times, dried over sodium sulfate and concentrated. The product was purified by flash silica gel chromatography eluting with 10% methanol in methylene chloride and finally with 20% methanol in methylene chloride to give the titled compound as a yellow solid (0.23 g, 15%); 1H NMR (300 MHz, DMSO-d6) δ 1.25–1.45 (m, 2 H), 1.80–1.95(m, 2 H), 2.50–2.80(m, 5 H), 2.92(s, 3 H), 3.40–3.55(m, 2), 4.45–4.60(m, 1 H), 6.85–6.90(m, 5 H), 7.02(dd, J=8.3, 2.0 Hz, 1 H), 7.18(d, J=2.0 Hz, 1 H), 7.59(dd, J=7.4, 4.4 Hz, 1 H), 7.95–8.05(m, 2 H), 8.70–8.80(m, 2 H); MS (ES) m/z: 561.95 (MH+, 100%); HRMS Calcd. for C25H32N5O6S2(MH+): 562.1788. Found: 562.1774.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1.[Cl:16][C:17]1[C:18]([Cl:30])=[C:19]([Cl:29])[C:20]([Cl:28])=[C:21]2[C:26](=[O:27])[O:25][C:23](=[O:24])[C:22]=12>C(OC(=O)C)(=O)C>[CH3:12][C:10]1([CH3:13])[CH2:11][CH:6]([NH:5][C:26](=[O:27])[C:21]2[C:22](=[C:17]([Cl:16])[C:18]([Cl:30])=[C:19]([Cl:29])[C:20]=2[Cl:28])[C:23]([OH:25])=[O:24])[CH2:7][C:8]([CH3:15])([CH3:14])[NH:9]1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC(NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)CC(C)(C)N1

Procedure:
The acetic acid salt of N-(2,2,6,6-tetramethyl-4-piperidinyl)tetrachlorophthalamic acid was prepared by refluxing 7.8 grams (0.05 mole) of 4-amino-2,2,6,6-tetramethylpiperidine, 14.3 grams (0.05 mole) of tetrachlorophthalic anhydride in 100 ml of acetic anhydride for 4 hours. The acetic anhydride was stripped off on a rotary evaporator under reduced pressure. The light yellow residue was slurried in 300 ml hexane and filtered. The filter cake was reslurried in fresh hexane and refiltered. The filter cake was air dried for 3 days on a watch glass. The dried product weighed 26.5 grams.
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[CH:11][CH:10]=2)[N:5]1C(OCC1C=CC=CC=1)=O)=[O:3]>CO.[Pd]>[CH3:42][C:39]([Si:36]([CH3:38])([CH3:37])[O:35][CH2:34][C@@:4]1([C:2]([NH2:1])=[O:3])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[CH:11][CH:10]=2)[NH:5]1)([CH3:40])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C(N)=O)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@]1(C(N)=O)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a solution of phenylmethyl (2R,5R)-2-(aminocarbonyl)-2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1-pyrrolidinecarboxylate (D74, 85 mg, 0.14 mmol) in methanol (2 ml) was added palladium (10 mg, 10 wt. % dry basis on activated carbon) and the mixture was stirred under hydrogen atmosphere (1 atm) for 30 min. The catalyst was filtered off, the solvent removed under reduced pressure and the crude material purified by chromatography on silica gel using cyclohexane and ethyl acetate (9:1 to 75:25) to afford the title compound (50 mg, 79%) as a colourless oil; Rt (HPLC): 5.00 min; MS: (ES/+) m/z: 459 [MH]+ C25H35FN2O3Si requires 458.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=2[CH3:27])=[N:14]1>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])=[N:14]2)=[O:9])[N:6]=1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: O=C(O)c1csc(Br)n1
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(Br)n3)n2)ccc(C#N)c1Cl
Yield: 45 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-bromo-1,3-thiazole-4-carboxylic acid (0.909 g, 4.37 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (1 g, 3.64 mmol). The product was purified by Flash-chromatography. Yield 45.0%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.61 (s, 3H), 4.29 (dd, 1H), 4.45 (dd, 1H), 4.60 (m, 1H), 6.46 (d, 1H), 7.51 (d, 1H), 7.57 (dd, 1H), 7.61 (dd, 1H), 7.98 (d, 1H), 8.04 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:13])=O.CN(C)C=O>ClCCl>[Cl:13][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: CSc1nccc(CO)n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1nccc(CCl)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 13.69 g of [2-(methylthio)pyrimidin-4-yl]methanol obtained in stage a) in 250 mL of dichloromethane are added dropwise 7.67 mL of thionyl chloride, followed by 3.91 mL of N,N-dimethylformamide. The reaction mixture is stirred at room temperature for 15 hours and concentrated under reduced pressure. The residue is taken up in diisopropyl ether and the solid formed is filtered off and dried to give 10.28 g of 4-(chloromethyl)-2-(methylthio)pyrimidine, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([OH:17])[N:11]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([OH:17])[C:13]([N+:18]([O-:20])=[O:19])=[C:14]([OH:16])[N:15]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(F)c(-c2nc(O)cc(O)n2)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(F)c(-c2nc(O)c([N+](=O)[O-])c(O)n2)c1
Temperature: 50 °C

Procedure:
To a suspension of 2-(2-Fluoro-5-methoxyphenyl)-4,6-dihydroxypyrimidine (12 g) in 35 mL of acetic acid is added 12 mL of 90% nitric acid and the mixture is heated at 50° C. for 45 min. The reaction mixture is diluted with 150 mL of water and the product is collected, washed with water and ethanol and oven dried to afford 2-(2-Fluoro-5-methoxyphenyl)-5 -nitro-4,6-dihydroxy-pyrimidine as a pink solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[OH:12].B1([O-])O[O:14]1.O.O.O.O.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Zn]>[NH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2]([CH3:1])=[O:14])[C:4]=1[OH:12]
Reactant: CSc1cccc([N+](=O)[O-])c1O
Reactant: [O-]B1OO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1cccc(N)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a solution of 2-methylthio-6-nitrophenol (410 mg, 2.21 mmol) in acetic acid (15 ml) was added sodium perborate tetrahydrate (1.00 g, 6.50 mmol) and the mixture was stirred at room temperature for 2 hours. To the reaction solution was then added zinc powder (7 g, 0.107 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with a saturated sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 50 g, developing solvent; chloroform) to provide 234 mg (yield 62%) of 2-amino-6-methanesulfinylphenol as colorless amorphous.
Reaction SMILES: C([NH:11][C@H:12]([C:21]([OH:23])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)(OCC1C=CC=CC=1)=O.CN1CCOCC1.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[NH:32][NH2:33]>O1CCCC1>[C:31]([NH:32][NH:33][C:21](=[O:23])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[NH2:11])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NNC(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of CBZ-L-tyrosine (3.00 gm, 9.11 mmoles), N-methylmorpholine (0.92 gm, 1.00 ml, 9.11 mmoles) in 100 ml dry tetrahydrofuran (THF) was cooled to 0° C. under nitrogen. 2,2,2-Trichloro-1,1-dimethylethylchloroformate (2.18 gm, 9.11 mmoles) was added to the cold solution. After 5 minutes stirring, a solution of t-butyl carbazate (1.20 gm, 9.11 mmoles) in 20 ml dry THF was cooled to 0° C. and added to the reaction mixture. The mixture was allowed to warm slowly to room temperature and was stirred for about 18 hours. The solvent was removed by rotary evaporation and the residue was partitioned between chloroform and water and the layers separated. The organic layer was washed with saturated NaCl dried over Na2SO4, filtered, and solvent evaporated to yield the crude protected product. The CBZ-protected product, CBZ-tyrosine N'-Boc-hydrazide, was purified on silica gel via flash chromatography using a mixture of petroleum ether and ethyl acetate (1:1).
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:31])=O>ClCCl>[CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([Cl:31])=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-chlorobenzoic acid (936.1 mg, 2.7 mmol) obtained from Example 27-(4) in dichloromethane (15 ml) was cooled to 0° C., and then N,N-dimethylformamide (15 μl) and oxalyl chloride (1.71 g, 13.5 mmol) were added thereto. After the mixture was stirred at room temperature for 30 minutes, it was worked up according to a similar procedure to that described in Example 1-(12) to afford crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-chlorobenzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH:12]=[O:13])=[CH:6]2.[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])=[CH:6]2
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc2[nH]c(C=O)cc2c1
Product: COc1ccc2[nH]c(C(=O)c3ccccc3)cc2c1
Yield: 91 %

Procedure:
Reaction of 5-methoxy-1H-indole-2-carbaldehyde with phenylmagnesium bromide using the procedure described in example 404 gave (805) (91%), mp 159–161° C. 1H NMR δ [(CD3)2SO] 11.86 (s, 1H), 7.94–7.91 (m, 2H), 7.71–7.66 (m, 1H), 7.61–7.57 (m, 2H), 7.42 (d, J=8.9 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.03 (s, 1H), 6.99 (dd, J=8.9, 2.4 Hz, 1H), 3.77 (s, 3H). Found: C, 76.28; H, 5.21; N, 5.42. C16H13NO2 requires: C, 76.48; H, 5.21; N, 5.57.
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].[C:17]1([CH3:25])[CH:22]=[CH:21][CH:20]=[C:19]([Mg]Br)[CH:18]=1.C1COCC1>>[OH:15][C@H:4]([C:19]1[CH:18]=[C:17]([CH3:25])[CH:22]=[CH:21][CH:20]=1)[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6]
Reactant: Cc1cccc([Mg]Br)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cccc([C@@H](O)[C@H](C)NC(=O)OC(C)(C)C)c1

Procedure:
The subtitle compound was prepared in two steps analogous to the methods described in Example 19 (step 19c+19d). Starting from (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (2.323 g, 10 mmol), and m-tolylmagnesium bromide 1.0M solution in THF (12.00 mL, 12.00 mmol). Yield 2.33 g (88%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[N:6][CH:5]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24](=[O:27])[CH2:25][SH:26]>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([S:26][CH2:25][C:24]([O:23][CH3:22])=[O:27])=[N:6][CH:5]=1
Reactant: COC(=O)CS
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CSc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-chloro-5-nitro-nicotinic acid methyl ester (1.0 g) [prepared as described by A. H. Berrie et al. J. Chem. Soc. 2590-2594 (1951)] in dichloromethane (10 mL) containing triethylamine (0.76 mL) was treated with mercapto-acetic acid methyl ester (0.44 mL) and the solution was stirred at room temperature for 1 hour and evaporated to dryness. Sodium bicarbonate solution was added and the mixture was extracted with dichloromethane, dried (anhydrous sodium sulfate) and evaporated to afford a solid (11.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]2[NH:11][CH2:12][CH2:13][N:14]([S:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH2:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ncccc1CC1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncccc1CC1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a 100-mL round-bottomed flask was added 2-((2-methoxy-3-pyridinyl)methyl)piperazine (350 mg, 1.69 mmol), triethylamine (0.353 mL, 2.54 mmol), and 2-thiophenesulfonyl chloride (0.34 mL, 1.86 mmol, Aldrich, St. Louis, Mo.) in DCM (5 mL). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow glass. The crude product was purified by silica gel chromatography, eluting with 10% MeOH/EtOAc to give 3-((2-methoxy-3-pyridinyl)methyl)-1-(2-thiophenylsulfonyl)piperazine (202 mg) as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[S:16][CH:15]=[C:14]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:13]=2)=[O:11])=[CH:8][CH:7]=1)(=O)C.C([O-])([O-])=O.[K+].[K+].CO>C(OCC)(=O)C>[OH:4][CH2:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[S:16][CH:15]=[C:14]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:13]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: CC(=O)OCc1ccc(C(=O)c2cc(S(N)(=O)=O)cs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1csc(C(=O)c2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 0.1 %

Procedure:
14 mg (41.3 mmol) of 5-(4-acetoxymethylbenzoyl)-3-thiophene sulfonamide and 9 mg (61.8 mmol) of K2CO3 were added to 3 mL of methanol. After stirring at rt for 11 h the solution was diluted with ethyl acetate and washed with 1N HCl followed with water (2×) and brine. The solvent was removed under vacuum to afford 12.5 mg of 5-(4-hydroxymethylbenzoyl)-3-thiophene sulfonamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=O)[C:9]2[CH2:8][CH2:7][CH2:6][C:5]([CH2:16][CH2:17][CH3:18])([CH2:13][CH2:14][CH3:15])[C:4]=2[N:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5]([CH2:16][CH2:17][CH3:18])([CH2:13][CH2:14][CH3:15])[C:4]=2[N:3]=[C:2]([CH3:1])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC1(CCC)CCCc2c1nc(C)[nH]c2=O
Product: CCCC1(CCC)CCCc2c(Cl)nc(C)nc21
Yield: 87 %

Procedure:
2-Methyl-8,8-dipropyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (180 mg, 0.72 mmol) and POCl3 (3 mL) were combined and heated under reflux for 6 hrs. The excess POCl3 was evaporated under reduced pressure. The residue was taken up in CH2Cl2 (25 mL), washed with cold water, sat. NaHCO3 solution., brine and dried over MgSO4. The CH2Cl2 solution was passed through a short (22 mm×20 cm) SiO2 column, eluting with CH2Cl2. Evaporation afforded 169 mg (87%) of 4-chloro-2-methyl-8,8-dipropyl-5,6,7,8-tetrahydroquinazoline as a pale yellow viscous liquid. MS (ES+) 267 (M+H).
Reaction SMILES: [F:1][CH:2]([F:20])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:5]1.[H-].[Na+].[CH3:23][N:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]=[C:25]1S(C)(=O)=O.O>CN(C=O)C>[F:20][CH:2]([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:25]3[N:24]([CH3:23])[C:28]4=[N:29][CH:30]=[CH:31][CH:32]=[C:27]4[N:26]=3)=[CH:15][CH:14]=2)=[N:5]1
Reactant: Oc1ccc(-c2nn(CC(F)F)c3cccnc23)cc1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(-c3nn(CC(F)F)c4cccnc34)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a stirred solution of 4-[1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl]phenol (142 mg) in DMF (4 mL) was added NaH (60% in oil, 20.63 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (109 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (90 mg)
Reaction SMILES: [Cl:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[CH:29]([NH:31][C@H:32]([C:37](O)=[O:38])[CH2:33][CH2:34][S:35][CH3:36])=[O:30]>>[Cl:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][S:18][C:37](=[O:38])[CH:32]([NH:31][CH:29]=[O:30])[CH2:33][CH2:34][S:35][CH3:36])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Reactant: CSCC[C@H](NC=O)C(=O)O
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@@]21C
Yield: 43.6 %

Procedure:
The title compound (0.51 gm) was prepared from 9-chloro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol (0.85 gm) and N-formyl-L-methionine (1.15 gm) in the same manner as in Synthetic Example 1.