Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]([F:40])([F:39])[S:28]([C:31]1[CH:32]=[C:33]([NH:37][NH2:38])[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[F:40][C:27]([F:39])([F:26])[S:28]([C:31]1[CH:32]=[C:33]([N:37]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:38]2)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]
Reactant: NNc1cccc(S(=O)(=O)C(F)(F)F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(S(=O)(=O)C(F)(F)F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and (3-trifluoromethanesulfonyl-phenyl)-hydrazine according to the method described for example 91. MS: M=531.1 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]([O:17][C@H:18]4[C@H:22]5[O:23][CH2:24][C@@H:25]([OH:26])[C@H:21]5[O:20][CH2:19]4)=[N:16][C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:46])[O:44][CH3:45])[CH2:38][CH2:37]1>>[Cl:35][C:9]1[CH:10]=[C:11]2[N:16]=[C:15]([O:17][C@@H:18]3[CH2:19][O:20][C@@H:21]4[C@H:25]([OH:26])[CH2:24][O:23][C@H:22]34)[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:12]2=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([N:36]2[CH2:37][CH2:38][CH:39]([NH:42][C:43](=[O:46])[O:44][CH3:45])[CH2:40][CH2:41]2)=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(Br)cc3)nc21
Reactant: COC(=O)NC1CCNCC1
Product: COC(=O)NC1CCN(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)CC1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(5-(4-bromophenyl)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and methyl piperidin-4-ylcarbamate following a procedure analogous to that described for Intermediate 23. LC (method 1): tR=0.97 min; Mass spectrum (ESI+): m/z=660 [M+H]+.
Reaction SMILES: O.[CH2:2]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)[CH2:11][C:12]([O:14]C)=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:2]([NH:9][C@H:10]([C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)[CH2:11][C:12]([OH:14])=[O:13])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC(NCc1ccccc1)c1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)C[C@H](NCc1ccccc1)c1ccc2c(c1)OCO2
Temperature: 30 °C
Reaction time: 20 h

Procedure:
To 4 mL of water were added 400 mg (1.28 mmol) of methyl (±)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate and 107 mg (1.28 mmol) of sodium hydrogen carbonate, and the mixture was maintained to 30° C. To the resulting mixture was added 2 mg of lipase (CAL; available from Roche, CHIRAZYME L-2 (trade name)) originated from Candida antarctica at the same temperature, and the mixture was reacted at 30° C. while stirring. After 20 hours, at the time when the conversion rate of the starting materials reached 46.2%, 8 ml of ethyl acetate and 112 mg of sodium hydrogen carbonate were added to the reaction mixture and the aqueous layer was extracted. The resulting aqueous layer was adjusted to an inner pH of 2.0 with 2 mol/L of hydrochloric acid aqueous solution, and 8 ml of ethyl acetate and 500 mg of sodium chloride were added to the mixture to extract the organic layer. The resulting organic layer was dried over magnesium sulfate, filtered and concentrated to obtain 135 mg (Isolated yield based on methyl (±)-3-benzylamino-3-(4-fluorophenyl)propionate=35.3%) of (R) or (S)-3-benzylamino-3-(3,4-methylenedioxyphenyl)propionic acid as white crystal.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][OH:26])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].Br[CH2:29][C:30]1[O:31][C:32](=[O:36])[O:33][C:34]=1[CH3:35].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][OH:26])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH2:29][C:30]4[O:31][C:32](=[O:36])[O:33][C:34]=4[CH3:35])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Reactant: Cc1oc(=O)oc1CBr
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C=CC1=C(C(=O)OCc2oc(=O)oc2C)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Yield: 26.5 %

Procedure:
To a solution of potassium 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g) in N,N-dimethylacetamide (30 ml) was added 4-bromomethyl-5-methyl-1,3-dioxol-2-one (1.0 g) under ice-cooling with stirring. The reaction mixture was stirred at the same temperature for 30 minutes. The resulting mixture was poured into ethyl acetate (200 ml) and the organic solution was washed with water three times. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (50 g) to give (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (0.62 g).
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:3]1[O:4][C:5]2[C:10]([C:11](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=c1c(I)coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2cc3ccccc3[nH]2)oc2ccccc12
Temperature: 0 °C
Yield: 32.2 %

Procedure:
To an eggplant type flask (25 ml), 3-iodochromone (136 prepared in Example 1, indole (234 mg), potassium carbonate (1382 mg), and dimethylformamide (15 mg) were added and the mixture was reacted at 80° C. for 30 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column ghromatography, and the purified product was recrystallized from benzene/hexane to give the titled compound (42.3 mg; yield=32.2%) as crystals. Melting point: 157°-158° C. 1H-NMR(CDCl3, δ ppm): 6.46 (s, H3), 8.26 (dd, H5), 7.47 (t, H6), 7.72 (t, H7), 7.58 (d, H8), 7.55 (d, H2'), 6.80 (d, H3'), 7.66 (d, H4'), 7.28-7.42 (m, H5'), 7.28-7.42 (m, H6'), 7.99 (m, H7').
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24].O>O1CCCC1>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:9][C:10]1[N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc2nccn12
Reactant: ClCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: ClCCCCCc1cccc2nccn12
Reaction time: 0.25 h

Procedure:
In an argon atmosphere, 51.5 ml (103 mmol) of a 2M lithium diisopropylamide solution (produced by Aldrich Company) was added to a solution of 13.6 g (103 mmol) of 5-metylimidazo[1,2-a]pyridine in 100 ml of tetrahydrofuran at -78° C. After stirring at constant temperature for 15 minutes, 17.64 g (103 mmol) of 1-bromo-4-chlorobutane was added, followed by stirring for 1 more hour. After stirring at 0° C. for 1 hour, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent; ethyl acetate) to yield 18.74 g (81.7%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+]>CN(C=O)C.C(O)C>[CH2:15]([N:12]1[CH2:11][CH:10]=[C:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(CCc2ccncc2)cc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C1=C(CCc2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
To a stirred solution of 120b (500 mg, 2.73 mmol) in DMF (5 ml) was added benzyl bromide (810 mg, 4.05 mmol) at 20-35° C. and the reaction mixture was stirred at 100° C. for 3 h. After 3 h, the reaction mixture was cooled to 20-35° C., diluted with ethanol (10 ml) and NaBH4 (110 mg, 2.97 mmol) was added slowly portion wise at 0° C., then heated at 100° C. for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with NaOH solution at 20-35° C., excess ethanol was removed under vacuum and resultant residue was diluted with ethyl acetate (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and evaporated. The crude compound was triturated with pet ether to get the desired compound as a yellow sticky solid (440 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 7.56-7.43 (m, 5H), 7.38-7.7.28 (m, 2H), 7.27-7.20 (m, 2H), 7.19-7.12 (m, 1H), 5.44 (s, 1H), 4.61 (d, J=12.7 Hz, 1H), 4.41 (d, J=12.7 Hz, 1H), 3.62-3.56 (m, 2H), 3.39 (t, J=6.1 Hz, 2H), 2.79 (t, J=7.6 Hz, 2H), 2.62-2.52 (m, 2H), 2.41 (t, J=7.6 Hz, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([N:18]3[CH2:23][CH2:22][N:21](C(=O)C)[CH2:20][CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:27][CH2:28][Cl:29])[CH:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>C(O)C>[ClH:29].[CH:27]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([F:17])=[C:11]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1)=[CH2:28]
Reactant: CCOC(=O)c1cn(CCCl)c2cc(N3CCN(C(C)=O)CC3)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Yield: 88.7 %

Procedure:
A mixture of the 1-(2-chloroethyl)-6-fluoro-7-(4-acetyl-1-piperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (65 mg) (0.153 millimole), NaOH (0.10 g), H2O (1 ml), and ethanol (1 ml) was heated at 95°-100° C. for 4 hours under stirring. After cooling, the reaction mixture was acidified with hydrochloric acid, and evaporated under vacuum. The residue was recrystallized from a mixture of water and ethanol to obtain 48 mg of 1-vinyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].Cl[CH2:11][CH2:12][OH:13].[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][CH2:11][CH2:12][OH:13]
Reactant: OCCCl
Reactant: NCc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCNCc1cccc(F)c1

Procedure:
Combine 3-fluorobenzylamine (31.1 g, 0.248 mol), 2-chloroethanol (10 g, 0.124 mol) and water (30 g, 1.66 mol) and heat on a steam-bath for ˜5 hours. Add sodium hydroxide (15 g, 0.373 mol) to the cooled solution and heat the resulting mixture on a steam-bath for ˜30 minutes. Add water (˜50 mL) to dissolve the inorganic salts and extract the two-phase mixture twice with 25 mL and 13 mL portions of benzene. Combine the extracts and remove the water by co-distillation with benzene through a modified Claisen flask. The final desired compound may be purified with further distillation.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][N:8]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([F:27])=[CH:29][CH:30]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1=CNCC(Cc2ccccc2)c2c1[nH]c1ccccc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(Cc2ccccc2)c2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using 1-benzyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester and 4-fluorobenzoyl chloride; 1H NMR (CDCl3) δ 10.58 (1H, s), 8.07 (1H, s), 7.62-7.66 (2H, m), 7.36 (1H, d), 7.13-7.23 (9H, m), 6.99 (1H, t), 5.25 (1H, dd), 4.26 (2H, m), 3.94 (1H, d), 2.99 (1H, dd), 2.83 (1H, dd), 1.22 (3H, t); MS (ESI): 469 (MH+).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[OH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:27])=[C:17]2[C:25]=1[C:24](=[O:26])[CH:23]1[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]1>C(O)(=O)C>[OH:12][C:13]1[C:14]([N+:8]([O-:11])=[O:9])=[CH:15][C:16]([CH3:27])=[C:17]2[C:25]=1[C:24](=[O:26])[CH:23]1[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Cc1ccc(O)c2c1C1CCCCC1C2=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(O)c2c1C1CCCCC1C2=O
Temperature: 15 °C
Reaction time: 1 h

Procedure:
A mixture of 15 ml of acetic anhydride and 50 ml of acetic acid was ice-cooled and thereto was added dropwise 10 ml of nitric acid (d=1.38). After stirring for 1 hour, thereto was added dropwise an acetic acid solution containing 10 g of 8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 100 ml of acetic acid. After stirring for 30 minutes, the ice bath was removed and the solution was warmed to an inner temperature of 15° C. To this solution was added 150 ml of diethyl ether, followed by stirring under ice-cooling. The resulting precipitate was collected by filtration to obtain 8 g of 8-hydroxy-5-methyl-7-nitro-1,2,3,4,4a,9a-hexahydro-9-fluorenone of yellowish green powdery crystal.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35](F)[CH:36]=1)[C:32]#[N:33]>CN1C(=O)CCC1>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:35]1[CH:34]=[C:31]([CH:30]=[C:29]([Br:28])[CH:36]=1)[C:32]#[N:33])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(Cl)cccc23)c1
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Br)cc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(Cl)cccc34)c2)c1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 18.4 %

Procedure:
3-(3-benzyl-8-chloroquinolin-4-yl)phenol (0.100 g, 0.289 mmol) was taken into NMP (1 mL) and to this was added NaH (0.0127 g, 0.318 mmol, 60% dispersion in oil) and stirred for 15 minutes. 3-Bromo-5-fluorobenzonitrile (0.116 g, 0.578 mmol) was added and the reaction was heated at 160° C. overnight. The reaction was cooled and quenched with water followed by extraction with ether. After drying and concentration the product was purified via Prep HPLC using 10-100% v acetonitrile in water as the eluent to yield 0.028 g of product. MS (ESI) m/z 526 ([M+H])+.
Reaction SMILES: C([O-])(=O)C.[Na+].C(OC[O:10][CH2:11][CH3:12])C.P(Cl)(Cl)(Cl)=O.[CH3:18][C@H:19]1[C@@:36]2([CH3:37])[C:23]([CH2:24][C@@H:25](C)[C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][C@@H:29]([F:39])[C:30]2=[O:38])=[CH:22][C:21](=O)[CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:20][C@H:19]1[C@@:36]2([CH3:37])[C:23]([C:22](=[CH2:21])[C@@H:25]([CH3:24])[C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][C@@H:29]([F:39])[C:30]2=[O:38])=[CH:12][C:11](=[O:10])[CH2:18]1
Reactant: C[C@@H]1CC2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Reactant: CCOCOCC
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=C1C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@@H]2[C@@H]1C
Yield: 60 %

Procedure:
A mixture of sodium acetate (1 g), absolute chloroform (30 ml), formaldehyde diethyl acetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and 1β,7α-dimethyl-16α-fluoroandrost-4-ene-3,17-dione (0.896 g, 2.7 mmol) is stirred at reflux for about 5 hrs, i.e. until the starting material has disappeared. The suspension is allowed to cool and under vigorous stirring a saturated sodium carbonate solution is added dropwise until the pH of the aqueous layer becomes alkaline. The organic layer is separated, washed to neutrality with water, and dried with sodium sulfate. After concentration under reduced pressure the oily residue is purified by chromatography on silica gel using hexane/ethyl acetate as eluant. Thus the pure 1β,7α-dimethyl-16α-fluoro-6-methylenandrost-4-ene-3,17-dione is obtained in 60% yield (0.56 g).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:28]([O:32][C:33](=[O:39])[C@@H:34]([CH:36]([CH3:38])[CH3:37])[NH2:35])([CH3:31])([CH3:30])[CH3:29]>ClCCl>[C:28]([O:32][C:33](=[O:39])[C@@H:34]([CH:36]([CH3:37])[CH3:38])[NH:35][S:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)(=[O:15])=[O:14])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Br)cc2)cc1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a 0° C. suspension of 4-(4-bromophenoxy)benzene sulfonyl chloride (1.10 g, 3.16 mmol) in 20 mL of dichloromethane was added a solution of diisoproylethylamine (1.10 mL, 6.3 mmol) and D-valine tert-butyl ester (660 mg, 3.8 mol) in 11 mL of dichloromethane. The ice bath was removed, and the reaction was stirred for 3 h, diluted with 30 mL dichloromethane, and 30 ml of 1 M HCl was added. The layers were separated, and the aqueous layer was washed with 30 mL of dichloromethane. The combined dichloromethane fractions were washed with brine, dried over MgSO4, and concentrated. The residue was chromatographed on silica, eluting with 25% ethyl acetate in hexane, to give 980 mg (64%) of N-[4-(4-bromophenoxy)benzenesulfonyl]-D-valine t-butyl ester as a white foam.
Reaction SMILES: [Mg].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6](Cl)[CH2:5][CH2:4]1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:19]=1[CH:20]=[O:21].[Cl-].[NH4+]>O1CCCC1>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([CH:20]([OH:21])[C:19]2[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=2[S:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[F:10])[CH2:5][CH2:4]1
Reactant: CN1CCC(Cl)CC1
Reactant: COc1ccc(Sc2ccccc2F)c(C=O)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Sc2ccccc2F)c(C(O)C2CCN(C)CC2)c1
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
A solution of the Grignard reagent is prepared by reaction of 2.5 g of magnesium with 13.35 g of 1-methyl-4-chloropiperidine (reference above) in 80 ml of tetrahydrofuran in the usual manner. Over 15 minutes with stirring, a solution of 18.2 g of 2-(2-fluorophenylthio)-5-methoxybenzaldehyde in 40 ml tetrahydrofuran is added dropwise and the mixture refluxed for 4 hours. After cooling, it is decomposed with 20% ammonium chloride solution and extracted with benzene. The extract is dried with potassium carbonate and evaporated. There are obtained 23.7 g (100%) crude oily α-(1-methyl-4-piperidyl)-2-(2-fluorophenylthio)-5-methoxybenzyl alcohol which is used for further work without purification.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[Cl:27][C:28]1[S:32][C:31]([S:33]([N:36]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37]2)(=[O:35])=[O:34])=[CH:30][C:29]=1[N+:42]([O-])=O>>[Cl:27][C:28]1[S:32][C:31]([S:33]([N:36]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37]2)(=[O:35])=[O:34])=[CH:30][C:29]=1[NH:42][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)N2CCC(O)C2)sc1Cl
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cc(S(=O)(=O)N2CCC(O)C2)sc1Cl)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and (RS)-1-(4-amino-5-chloro-thiophene-2-sulfonyl)-pyrrolidin-3-ol-(example B.18) according to general procedure II. Yellow solid. MS (ISP) 640.2 [(M+H)+]; mp 270° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14]>C(OCC)C>[CH2:21]([CH:18]1[CH2:17][CH2:16][N:15]([C:13](=[O:14])[CH2:12][NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCOCC
Product: O=C(CNc1ccc2cn[nH]c2c1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 6-aminoindazol and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 142b. Melting Point: 179-182° C. (diethylether)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH:8]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:7]2=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>CN(C)C=O>[C:27]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH:8]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([CH3:3])[CH:5]=2)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(C(=O)OCc1ccccc1)CCC3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2C(=O)c2ccccc2)CCCC1C(=O)OCc1ccccc1

Procedure:
Following a procedure similar to that of Example 35B but using 0.84 g. sodium hydride, 50 ml. of dry dimethylformamide, 9.1 g. of benzyl 6-methyl-1,2,3,4-tetrahydrocarbazole-4-carboxylate, and 4.4 g. of benzoyl chloride, but eliminating the 1% aqueous hydrochloric acid wash subsequent to the bicarbonate wash, there was obtained 8.5 g. of the title compound which was purified by suspension in hot isopropyl alcohol, filtration, followed by suspension in, and filtration from, ether; m.p. 119°-121°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:12]2[S:16]N=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[O:26][CH2:27][C:28](=[O:35])[C:29]1C=CC=CC=1.Cl[CH2:37]C(=O)C>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:12]2[S:16][CH:37]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[O:26][CH2:27][C:28](=[O:35])[CH3:29]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(N)c(OCC(=O)c3ccccc3)c2)cc1
Reactant: CC(=O)CCl
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(N)c(OCC(C)=O)c2)cc1

Procedure:
4-Amino-N-(4-methoxybenzyl)-3-(2-oxopropoxy)-1N-(thiazol-2-yl)benzenesulfonamide was prepared from INTERMEDIATE AD in the same manner as described for INTERMEDIATE Q, using 1-chloropropan-2-one instead of 2-bromo-1-phenylethanone.