Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C@H:27]([OH:29])[CH3:28])[C:11]([NH:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[O:12])=[CH:5][C:4]=1[C:30]([F:33])([F:32])[F:31])#[N:2].N1C=CN=C1.[CH3:39][C:40]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])[CH3:41]>CN(C=O)C>[Si:43]([O:29][C@H:27]([CH3:28])[C@@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:5]=1)[C:11]([NH:13][NH:14][C:15](=[O:26])[C:16]1[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1)=[O:12])([C:40]([CH3:42])([CH3:41])[CH3:39])([CH3:45])[CH3:44]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.6 %

Procedure:
To a pre-cooled (0° C.) solution of N′-((2R,3R)-2-(4-cyano-3-(trifluoromethyl)phenylamino)-3-hydroxybutanoyl)-4-(methylsulfonyl)benzohydrazide (5.16 g, 10.7 mmol) in DMF (150 mL) was added imidazole (4.36 g, 64.0 mmol) then TBSCl (4.81 g, 32.0 mmol). The reaction was warmed slowly to room temperature, stirred for 17 h, cooled to 0° C. and quenched with H2O (300 mL). The solution was extracted with EtOAc (250 mL). The organic extract was washed with brine (2×200 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (50% EtOAc in hexanes) to provide the title compound (5.29 g, 83%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 10.06 (s, 2H), 8.10 (dm, J=8.6 Hz, 2H), 8.03 (dm, J=8.6 Hz, 2H), 7.70 (d, J=8.6 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 7.14 (dd, J=2.4, 8.6 Hz, 1H), 6.57 (d, J=7.4 Hz, 1H), 4.50-4.41 (m, 2H), 3.17 (s, 3H), 1.36 (d, J=5.9 Hz, 3H), 0.85 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:24][CH:23]=[CH2:22])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2[nH]c(C(=O)OCC)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a solution of 5-hydroxyindole-2-carboxylic acid ethyl ester (14.2 g, 68.5 mmol) in DMF (150 mL) was added cesium carbonate (26.8 g, 82.3 mmol). The resulting mixture was stirred at room temperature for 20 min followed by the addition of allyl bromide (5.94 mL, 68.5 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction was diluted with ethyl acetate, washed with H2O, brine and dried (Na2SO4). The solvent was removed in vacua and the resulting crude product was purified by flash column chromatography on silica gel (0-20% EtOAc/hexanes) to give the desired material as solid (8.9 g, 52%). LC/MS (ES+) m/e 248 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH:11]S(C(C)(C)C)=O)[CH2:9][CH3:10])[CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[BH4-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]([NH2:11])[CH2:9][CH3:10])[CH:3]=1
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1cc(Br)ccn1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](N)c1cc(Br)ccn1
Reaction time: 3 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(4-bromo-pyridin-2-yl)-propyl]amide (985 mg, 3.10 mmol) in THF (25 mL) was added a 1 M solution of L-Selectride (3.2 mL, 3.2 mmol) in THF. The reaction was monitored by TLC (ethyl acetate-ether 3:7) indicating a single diastereomer when compared to a mixture of diastereomers prepared by reduction of 2-methyl-propane-2-sulfinic acid [(S)-1-(4-bromo-pyridin-2-yl)-propyl]amide with lithium borohydride in THF. After 3 hours, the mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (3×30 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in dichloromethane. The material from the column was crystallized from hexanes to afford (S)-1-(4-bromo-pyridin-2-yl)-propylamine.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[C:10](Cl)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Yield: 93.9 %

Procedure:
Following the procedure described in Referential Example 3, but using 4-(S)-isopropyl-2-oxazolidinone (5.06 g) and octanoyl chloride (6.67 g), the desired compound (9.39 g) was obtained.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10](O)([CH3:13])([CH3:12])[CH3:11].ClCCl.[Br:18][CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22]>[Cu]Cl.C(O)(=O)C>[C:10]([CH:19]([Br:18])[C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(CBr)C(=O)O
Reactant: CC(C)(C)O
Agent: Cl[Cu]
Agent: CC(C)N=C=NC(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)C(Br)C(C)(C)C(=O)O
Reaction time: 96 h

Procedure:
At room temperature under shielded light, to N,N′-diisopropylcarbodiimide (99.75 g) was added copper(I) chloride (1.57 g), and then tert-butanol (83 ml) was added dropwise over 20 minutes, followed by stirring for 4 days. The supernatant (78 ml) was added dropwise to a dichloromethane suspension (270 ml) of 3-bromo-2,2-dimethylpropanoic acid (49.4 g) at room temperature over 30 minutes, followed by stirring for 18 hours. Acetic acid (18.8 ml) was added, and stirred for 1 hour. The reaction suspension was filtered, and ice water and sodium hydrogen carbonate were added to the filtrate for neutralization. After the precipitate was filtered off, the organic layer separated from the filtrate was washed with saturated sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After pentane was added to the residue, insolubles were filtered off, and the filtrate was concentrated under reduced pressure to afford tert-butyl 3-bromo-2,2-dimethylpropanoic acid (18.81 g).
Reaction SMILES: [CH3:1][S:2][CH3:3].[Na].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=C(F)[CH:17]=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])=[N:10][CH:11]=1>CN(C)C=O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[C:1]([S:2][CH3:3])[CH:17]=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])=[N:10][CH:11]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CSC
Agent: [Na]
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a stirring solution of sodium methylsulfide (0.13 g, 2 mmol) in N,N-dimethylformamide (20 mL) was added N-(5-chloropyridin-2-yl)-5-fluoro-2-nitrobenzamide (0.48 g, 1.6 mmol) and additional N,N-dimethylformamide (5 mL). The reaction solution was stirred overnight at room temperature and concentrated in vacuo. The resulting residue was partitioned between dichloromethane and water and the layers separated. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was slurried in diethyl ether and filtered to give 0.33 g (63%) of a yellow solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([CH2:19][O:20][P:21]([CH2:36][C:37]([OH:39])=O)([CH:23]([NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(#N)C.[NH:43]1[CH2:57][CH2:56][CH2:55][C@H:44]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]>C(OCC)(=O)C>[C:13]1([CH2:19][O:20][P:21]([CH2:36][C:37]([N:43]2[CH2:57][CH2:56][CH2:55][C@H:44]2[C:45]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:46])=[O:39])([CH:23]([NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(NC(=O)OCc1ccccc1)P(=O)(CC(=O)O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(NC(=O)OCc1ccccc1)P(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
1,1'-Carbonyldiimidazole (1 g. 0.066 mole) is added to a chilled (0°) solution of the product from part (c) (2.5 g., 0.063 mole) in 40 ml. of acetonitrile. The mixture is stirred for one hour at 0°. A solution of L-proline, benzyl ester (1.3 g., 0.066 mole) in 20 ml. of acetonitrile is added. The mixture is stirred at ambient temperature for 16 hours. The solvent is removed in vacuo. The residue is dissolved in dichloromethane (125 ml.), washed with 5% potassium bisulfate, saturated sodium bicarbonate solution, brine, and dried (MgSO4). The solution is concentrated in vacuo to give an oil residue of 3.3 g. Tlc, silica gel, ethyl acetate shows a major spot at Rf 0.10. A portion (2.2 g.) is chromatographed on silica gel, eluting with ethyl acetate to give 1.7 g. of (±)-1-[(phenylmethoxy)[1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]acetyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[O:24]1[CH2:29][CH2:28][CH:27]([C:30]2([NH2:33])[CH2:32][CH2:31]2)[CH2:26][CH2:25]1>>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:33][C:30]3([CH:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)[CH2:32][CH2:31]3)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: NC1(C2CCOCC2)CC1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NC4(C5CCOCC5)CC4)cn3)c2O)ccn1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 1-(tetrahydro-2H-pyran-4-yl)cyclopropanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-1.03 (m, 5 H) 1.25 (s, 1 H) 1.45-1.67 (m, 3 H) 1.74 (d, J=12.4 Hz, 2 H) 3.37 (t, J=11.6 Hz, 2 H) 4.03 (dd, J=11.4, 3.5 Hz, 2 H) 4.09 (s, 3 H) 7.22 (s, 1 H) 7.31 (d, J=6.1 Hz, 1 H) 7.41 (s, 1 H) 7.83 (d, J=8.6 Hz, 1 H) 7.90 (s, 1 H) 8.13 (d, J=6.1 Hz, 1 H) 8.37 (dd, J=8.7, 2.1 Hz, 1 H) 8.83 (d, J=1.8 Hz, 1 H). MS m/z [M+H]+ 436.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:17]=[CH:16][N:15]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:36][CH:37]([Cl:41])[C:38](Cl)=[O:39]>ClCCl>[Cl:36][CH:37]([Cl:41])[C:38]([N:20]([CH2:21][CH2:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH:19]=1)=[O:39]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)OC(=O)CCNc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropyl 3-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-ylamino)propanoate (520 mg, 1.23 mmol) was dissolved in anhydrous dichloromethane (25 mL) with triethylamine (270 mg, 2.7 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (320 mg, 2.17 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 95:5 hexanes:ethyl acetate to yield isopropyl 3-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)propanoate (Cpd. No. 57). 1H NMR (CDCl3): 8.38 (m, 1H), 8.01 (s, 1H), 7.80 (m, 1H), 7.50-7.41 (m, 4H), 7.18 (s, 1H), 6.86 (s, 1H), 6.32 (s, 2H), 5.08 (m, 1H), 1.38 ppm (s, 6H).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:10]2[C:27]([F:30])([F:29])[F:28].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[N:44]([CH3:45])[CH:43]=[N:42][CH:41]=2)=[O:39])=[CH:34][CH:33]=1>C1COCC1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([C:40]2[N:44]([CH3:45])[CH:43]=[N:42][CH:41]=2)([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]3[C:27]([F:28])([F:30])[F:29])[OH:39])=[CH:36][CH:37]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Reactant: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(C(F)(F)F)c2c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Isopropylmagnesium chloride (2.0 M in THF, 0.532 mL, 1.06 mmol) was added dropwise to a solution of 6-iodo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (474 mg, 1.01 mmol, Intermediate 8, step d) in THF (1 mL) at −78° C. under an argon atmosphere. The mixture was stirred at −78° C. for 5 min, then was removed from the cold bath and was stirred for 15 min. Neat (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (246 mg, 1.12 mmol, Intermediate 18, step b) was added followed by 1 mL THF to aid stirring of the thick mixture. The mixture was stirred at room temperature overnight. The reaction was quenched by addition of saturated aqueous NH4Cl and extracted with EtOAc (three times). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, gradient 0-3% MeOH-DCM) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=1.71 Hz, 1H), 8.29 (d, J=8.80 Hz, 1H), 7.89 (dd, J=1.59, 8.93 Hz, 1H), 7.41-7.52 (m, 3H), 7.38 (s, 1H), 7.32-7.37 (m, 4H), 7.28-7.31 (m, 2H), 6.43 (s, 1H), 3.40 (s, 3H); MS m/e 562.0 [M+H]+.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=O)[CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][CH2:8]\1.[NH2:12][NH2:13]>CO>[CH3:9][C:6]1([CH3:10])[CH2:5][C:4]2[NH:13][N:12]=[CH:2][C:3]=2[CH2:8][CH2:7]1
Reactant: NN
Reactant: CC1(C)CC/C(=C/O)C(=O)C1
Solvent: CO
Product: CC1(C)CCc2cn[nH]c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of 2-[1-hydroxy-meth-(Z)-ylidene]-5,5-dimethyl-cyclohexanone (1.64 g, 10.6 mmol) in MeOH (10 mL) was added hydrazine (0.33 mL, 10.6 mmol) dropwise. The exothermic reaction was controlled by intermitant use of an ice bath. The yellow reaction mixture was stirred at room temperature for 30 min then concentrated. The residue was dissolved in CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated to afford 1.53 g (96%) of 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.32 (s, 1H), 2.55 (t, J=6.4 Hz, 2H), 2.44 (s, 2H), 1.53 (t, J=6.4 Hz, 2H), 1.01 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH2:21][OH:22])=[CH:3]1.N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>CN(C=O)C>[O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[CH2:21][O:22][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.1 %

Procedure:
To a solution of 3-oxo-17β-(hydroxymethyl)-4-androstene (15 g, 0.05 mol) in 200 ml DMF was added 5.8 g (0.085 mol) imidazole followed by 9.7 g (0.065 mol) t-butyldimethylsilyl chloride. The reaction mixture was stirred at room temperature under argon, for 2.5 hours. The reaction mixture was then poured into 250 ml ice water and washed 3 times with ethyl acetate. The combined organic layers were washed twice with cold 5% hydrochloric acid and once each with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated. Recrystallization from methanol afforded 16.9 g (82%) of 3-oxo-17β-(t-butyldimethylsilyloxymethyl)-4-androstene as a white crystalline solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[N:14]=[C:13]([S:15][CH3:16])[N:12]=[C:11]([NH2:17])[CH:10]=1>C(=O)(O)[O-].[Na+]>[Cl:8][C:9]1[N:14]=[C:13]([S:15][CH3:16])[N:12]=[C:11]([NH:17][C:5](=[O:7])[CH3:6])[CH:10]=1
Reactant: CSc1nc(N)cc(Cl)n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CSc1nc(Cl)cc(NC(C)=O)n1
Temperature: 135 °C
Yield: 120.4 %

Procedure:
Acetic anhydride (10.4 ml, 0.11 mol) was added to 6-chloro-2-(methylthio)pyrimidin-4-amine (2.5 g, 0.01 mol) and the reaction mixture was refluxed at 135° C. for 5 hr. The reaction mixture was cooled to room temperature and basified to pH 7 with saturated sodium bicarbonate solution (20 ml). The mixture was partitioned between EtOAc and water, the organic layer was washed with water and brine, dried over MgSO4 and concentrated to give the title compound (2.62 g).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].[F:12][C:13]1[CH:14]=[C:15]([C:20](=O)/[CH:21]=[CH:22]/N(C)C)[CH:16]=[CH:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([C:20]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1ccc(F)c(F)c1
Agent: Cl
Product: N#Cc1ccnc(-n2nccc2-c2ccc(F)c(F)c2)c1
Yield: 83 %

Procedure:
The title compound was prepared in 83% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-1-(3,4-difluorophenyl)-3-(dimethylamino)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 6.50 (1H, d, J=1.6 Hz), 7.01-7.04 (1H, m), 7.11-7.18 (2H, m), 7.38-7.40 (1H, m), 7.77 (1H, d, J=2.0 Hz), 8.12 (1H, s), 8.36 (1H, d, J=4.8 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30]>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH:1][C@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](NS(=O)(=O)c3ccccc3Cl)CN12
Yield: 27 %

Procedure:
In analogy to the procedure described for the synthesis of 2-Chloro-N-[(6R,7aS)-3-oxo-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-6-yl]-benzamide (example 1, step i) the title compound was prepared from (6R,7aS)-6-Amino-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step h) and 2-chlorobenzene-1-sulfonyl chloride to yield 27% the title compound. 1H NMR (300 MHz, CDCl3): δ 8.13 (d, 1H, J=7.2 Hz), 7.58-7.45 (m, 6H), 7.19 (d, 2H, J=9.0 Hz), 5.33 (d, 1H, J=6.3 Hz), 4.06-3.98 (m, 3H), 3.94-3.85 (m, 1H), 3.66 (d, 1H, J=6.9 Hz), 2.94 (dd, 1H, J1=12.9 Hz, J2=3.6 Hz), 2.19-2.12 (m, 1H), 1.74-1.64 (m, 1H); LC-MS: 476.0 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:26])=O)(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:25](=[O:26])[CH2:24][CH2:23][C@@H:9]2[CH2:10][C@@H:11]([S:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][NH:8]2)=[CH:32][CH:31]=1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CCC(=O)c3ccc(F)cc3)N(C(=O)OC(C)(C)C)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CS[C@H]2CN[C@H](CCC(=O)c3ccc(F)cc3)C2)cc1
Temperature: 25 °C

Procedure:
A solution of 0.539 g (1.14 mmol) (2R,4R)-2-[3-(4-Fluoro-phenyl)-3-oxo-propyl]4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 10 ml CH2Cl2 was treated at 0° C. with 0.43 ml TFA. After 30 min the reaction was warmed up to room temperature (2 h) and evaporated to give (2R,4R)-1-(4-fluoro-phenyl)-3-[4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-yl]-propan-1-one; compound with trifluoro-acetic acid, MS: 374 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Cu+2].CN(C=O)C>[C:14]1([N:11]2[CH:12]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:8]=[CH:9][C:10]2=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1ccc(-c2ccccn2)c[nH]1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=c1ccc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
While stirring 5-Pyridin-2-yl-2(1H)-pyridone (185 g), PhB(OH)2(261 g), Cu(OAc)2(19.4 g), pyridine (173 ml) and DMF (1480 ml) at room temperature, air was blown at 2.0 L/minute therein, to initiate the reactions. Since 26% of the reactant remained unreacted 7 hours after the initiation of the reaction, flow of air was stopped to suspend the reactions. On the next day, air was blown into the solution to restart the reactions, and the reactant was consumed to 0.57% of the initial weight in 5.5 hours. The reaction solution was poured into ice-cooled 10% aqueous ammonia (7.5 L), to give MA045. The resulting precipitates were collected by filtration under reduced pressure, and washed with water (3 L). The resulting crystals were suspended into 10% aqueous ammonia (3.6 L) under stirring at room temperature for 1 hour. Then the crystals were collected by filtration under reduced pressure, and washed with water (2 L). The resulting crystals were air-dried overnight, to give 187 g (68%) of the title compound as brown crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(O)(=O)C>[C:8]([NH:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(S)n[nH]1
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(S)n[nH]1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a 2 L, 3-necked flask equipped with an efficient stirrer, reflux condenser, and thermometer was added 116 g (1.0 mole) of 5-amino-3-mercapto-1,2,4-triazole, 1 L of glacial acetic acid and 153 g (1.5 moles) of acetic anhydride. The mixture was heated to reflux (118°-120° C.) with stirring for 2 hr and then cooled to about 10° C. Recovery of the solids present by filtration and drying resulted in about 102 g (65 percent of theory) of the title compound, m.p. 326°-328° C. (dec.), a white, crystalline solid. A sample purified by washing with 2-propanol and drying melted at 336° C. (dec.). The carbon nmr spectrum of this compound was consistent with the assigned structure, having absorptions at 169.29, 164.99, 144.77, and 22.73 ppm as were the proton nmr spectrum, having an absorption at -2.00 ppm, and the elemental (C, H, and N) analysis.