Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][C:12]2[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=2)[C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Solvent: CO
Product: COc1ccc(CNc2cccc(C(=O)OC(C)(C)C)c2)cc1

Procedure:
253A was prepared from 4-methoxybenzaldehyde and tert-butyl 3-aminobenzoate following the procedure as described in 4A. HPLC: Rt=3.82 min. (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=314.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH2:7][CH:8]3[CH:14]([NH2:15])[C:13]([CH3:16])([C:5]=2[CH:4]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3.[CH2:19](C12C(=O)C(CC3C=CC(OC)=CC=31)CCCC2)C>>[CH2:16]([C:13]12[C:14](=[NH:15])[CH:8]([CH2:7][C:6]3[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][C:5]=31)[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH3:19]
Reactant: COc1ccc2c(c1)C1(C)CCCCC(C2)C1N
Reactant: CCC12CCCCC(Cc3ccc(OC)cc31)C2=O
Product: CCC12CCCCC(Cc3ccc(OC)cc31)C2=N

Procedure:
Using a procedure analogous to that described in Example XXVIIA for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine there is obtained from 3.5 g. of 5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one, oxime 1.6 g. of the title product, b.p. 150°-160° C. (0.5 mm.). I.R. Analysis: 6.1 μ. Addition of ethereal hydrogen chloride to the title product in ether gives the hydrochloride salt, m.p. 252°-255° C. (dec).
Reaction SMILES: [NH4+:1].[OH-].[C:3]([C:5]1[CH:6]=[C:7]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)#[N:4]>C(#N)C>[C:3]([C:5]1[CH:6]=[C:7]([S:11]([NH2:1])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NH4OH (22 mL, excess) can be added to a solution of 3-cyanobenzene-1-sulfonyl chloride (1.0 g, 4.97 mmol) in acetonitrile (22 mL) and the reaction stirred overnight at r.t. The reaction can be concentrated and the solid obtained washed with water to give 500 mg of product. The water phase can be extracted with AcOEt, dried with MgSO4 anh, filtered and evaporated to give 400 mg of product that can be combined with the solid obtained before (0.90 g, 99%).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([O:31]CC)=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:16]1.[OH-].[Na+]>C(O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([OH:31])=[O:30])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][S:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3cccnc32)CCN(CCSc2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(CCCn2c(=O)ccc3cccnc32)CCN(CCSc2cccs2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 77.8 %

Procedure:
To a solution of 0.30 g of ethyl 4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate in 5 mL of ethanol, 1.7 mL of a 20% aqueous sodium hydroxide solution was added at room temperature, and the mixture was heated under reflux while stirring for 7 hours. Thereto was further added 0.3 mL of a 20% aqueous sodium hydroxide solution, and mixture was stirred for 1 hour, and then cooled to room temperature, and the solvent was distilled off under reduced pressure. The resultant residue was charged with water and adjusted to pH 6.5 with 1 mol/L hydrochloric acid. The solid was filtered off to obtain 0.22 g of 4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl) propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([CH:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:18](OC)=[O:19])(=O)[CH3:15]>CC1C=CC=CC=1C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]3[N:13]=[C:14]([CH3:15])[C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:18]([OH:19])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: Nc1cc(-c2cccc(Cl)c2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1O
Yield: 98.8 %

Procedure:
To a solution of 3-(3-chlorophenyl)-1H-pyrazol-5-amine (23 g, 119 mmol), dimethyl 2-acetylsuccinate (22.35 g, 119 mmol) in o-Xylene (200 mL) was added p-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 2 h. The solid was filtered and washed with hexanes to afford (39 g, 99%) of the title compound. 1H NMR (500 MHz, METHANOL-d4) δ 8.14-7.95 (m, 1H), 7.93-7.79 (m, 1H), 7.51-7.27 (m, 2H), 6.62-6.35 (m, 1H), 3.72 (s, 3H), 3.67 (s, 2H), 2.39 (s, 3H).
Reaction SMILES: C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](Cl)([O-])(=O)=O.[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:30]([OH:35])[C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Cl:23][C:24]1[CH:25]=[C:26]([C:30](=[O:35])[C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)[C@H](O)c1cccc(Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Product: COC(=O)C(=O)c1cccc(Cl)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Pyridium chlorochromate (32.4 g, 150.00 mmol, 2.01 equiv.) was added to a solution of (R)-Methyl 2-(3-chlorophenyl)-2-hydroxyacetate (15 g, 74.77 mmol, 1.00 equiv) in dichloromethane (500 mL). The resulting solution was stirred at about 30° C. for about 2 hours, and then fresh pyridinium chlorochromate (16.4 g, 75.93 mmol, 1.02 equiv.) was added. The resulting solution was stirred at about 30° C. for about 16 hours, and then fresh pyridinium chlorochromate (16.4 g, 75.93 mmol, 1.02 equiv) was added. The resulting solution was stirred at about 30° C. for about 16 hours, and then concentrated in vacuo. The resulting crude residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:20)) to give the title product as a yellow solid (13.8 g; yield=91%). 1H NMR (300 MHz, DMSO-d6) δ: 8.02 (t, J=1.8 Hz, 1H), 7.98 (m, 1H) 7.95 (m, 1H), 7.64 (d, J=7.8 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4]([Cl:22])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Reaction time: 1 h

Procedure:
A solution of 2-methyl-4,6-bis(trifluoromethyl)benzoic acid D52 alternative method (400 mg, approximately 1.47 mmol) in DCM (5 ml), containing DMF (1 drop), was treated with oxalyl chloride (166 ul, 1.91 mmol) and stirred under argon for 1 hour. The solvent was carefully removed under reduced pressure and the residue re-evaporated from further DCM. The mixture of acid chlorides was then treated with methanol (3 ml) and kept at room temperature for 2 hours after which time the solvent was again carefully removed under reduced pressure. NMR data indicated this to be a mixture of the title product 2-methyl-4,6-bis(trifluoromethyl)benzoyl chloride and methyl 2,4-bis(trifluoromethyl)benzoate. The mixture was used without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:4]=[C:5]2[C:10]([C:11](OCC)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]2[CH:16]=1.[K+].[Br-]>>[OH:12][CH2:11][C:10]1[C:5]2[N:6]([CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cccn2cc(C(F)(F)F)nc12
Agent: [Br-]
Agent: [K+]
Product: OCc1cccn2cc(C(F)(F)F)nc12

Procedure:
From 2e (yield: 54%); mp 118-120° C.; IR (KBr) 3400-3100, 1225, 1163 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.06 (s, 2H), 6.95 (t, 1H, J=7 Hz), 7.31 (d, 1H, J=7 Hz), 7.92 (s, 1H), 8.11 (d, 1H, J=7 Hz); 13C NMR (100 MHz, CDCl3) δ 61.7, 111.9, 114.0, 121.5 (d, 1JF-C=267 Hz), 123.3, 125.2, 131.0, 135.4 (q, 2JF-C=39 Hz), 144.4; MS m/z 216 (M+, 50), 215 (100), 195 (25), 187 (20), 167 (29).
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.S(=O)(=O)(O)O.C(OCC)(=O)C>CCCCCC>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 0 °C

Procedure:
9α-Hydroxyandrostenedione (9.07 g.) is added to aqueous sulfuric acid (22.5 ml. of 70%; 3 parts water and 7 parts sulfuric acid). The resulting slurry is stirred at 23°-25° until the reaction is complete as measured by TLC(ethyl acetate:hexane, 60:40). When complete the reaction mixture is cooled (10°) and added dropwise to ice-water (800 ml.) with rapid stirring. The resulting slurry is stirred overnight, filtered and the solids washed with water (500 ml.), sodium bicarbonate solution (10%, 500 ml.) and water (500 ml.). The solids are air-dried to give androsta-4,9(11)-diene-3,17-dione, 8.31 g. (97.4% chemical yield); m.p. 196°201°; [α]D +219° (chloroform); UV (methanol)λmax =240 nm (ε=16,500). GC (Example 1) shows an androsta-4,9(11)-diene-3,17-dione/androsta-4,8-diene-3,17-dione ratio of greater than 99 to 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11]>CO.O>[N+:10]([C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1)([O-:12])=[O:11]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1cccc(Nc2ncc(F)c(Nc3cccc([N+](=O)[O-])c3)n2)c1
Temperature: 100 °C
Yield: 75.8 %

Procedure:
2,4-Dichloro-5-fluoropyrimidine (4.7 g, 28.1 mmol) was dissolved in a mixture of MeOH (150 ml) and H2O (15 ml). 3-nitroaniline (15.5 g, 112 mmol) was added and the mixture was refluxed for 20 hours (100° C. oil-bath temperature). The mixture was cooled to 22° C. and filtered. The residue was washed carefully with 200 ml MeOH—H2O (1:1; v/v) and dried under vacuum to give 7.89 g (76%) of N2,N4-bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine as yellow crystals. 1H NMR (DMSO-d6+D2O): δ 8.63 (m, 2H), 8.21 (m, 1H), 8.08 (d, 1H, J=8.41 Hz), 7.88 (d, 1H, J=8.4 Hz), 7.79 (d, 1H, J=8.4 Hz), 7.70 (d, 1H, J=8.4 Hz), 7.57 (d, 1H, J=8.4 Hz), 7.45 (t, 1H, J=8.4 Hz); LCMS: purity: 100%; MS (m/e): 371.30 (M+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]2[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(C(=O)O)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(CO)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 62.6 %

Procedure:
To a stirring slurry of 2-[(1-tert-butoxycarbonylpiperidin-4-ylcarbonyl)amino]-5-carboxy-N-(5-chloropyridin-2-yl)benzamide (0.25 g, 0.49 mmol) in tetrahydrofuran (5 mL) under argon was added N-methylmorpholine (0.055 mL, 0.5 mmol) followed by ethyl chloroformate (0.05 mL, 0.5 mmol) After 20 min. the reaction slurry was cooled in an ice bath and treated with sodium borohydride (61 mg, 1.6 mmol) followed by dropwise addition of methanol (10 mL). After 30 min the resulting reaction solution was treated with saturated aqueous ammonium chloride. The mixture was partitioned between dichloromethane and saturated aqueous ammonium chloride. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with 20–50% ethyl acetate in hexane and then 5% methanol in ethyl acetate, to give 0.15 g (63%) of a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH3:19])[C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:20].[CH2:21]([NH:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24]>CS(C)=O>[CH2:21]([N:25]([CH2:26][CH3:27])[C:2]1[C:3]([CH3:20])=[C:4]([N:9]([CH3:19])[C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:6]([CH3:8])[N:7]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Cc1cc(C)c(N(C)c2nc(C)nc(Cl)c2C)c(C)c1
Reactant: CCCCNCC
Solvent: CS(C)=O
Product: CCCCN(CC)c1nc(C)nc(N(C)c2c(C)cc(C)cc2C)c1C
Temperature: 160 °C

Procedure:
A mixture of (6-chloro-2,5-dimethyl-pyrimidin-4-yl)-methyl-(2,4,6-trimethylphenyl)-amine (200 mg) and N-butyl-ethylamine (0.3 ml) in 1 ml of DMSO was heated in oil bath of 160° C. for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give the crude material. After silica gel column purification using chloroform as eluent, the title compound was obtained as an oil. 1H NMR (CDCl3) δ 6.83 (s, 2H), 3.22 (s, 3H), 3.12 (m, 4H), 2.44 (s, 3H), 2.26 (s, 3H), 2.01 (s, 6H), 1.35–1.42 (m, 2H), 1.1–1.25(m, 2H), 1.00 (t, 3H), 0.90 (t, 3H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][C:5]#[C:6][CH:7]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][CH2:8]1>CCO.O=[Pt]=O.O>[CH3:1][N:2]([CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][CH2:8]1
Reactant: CCCN(C)CCC#CC1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: O=[Pt]=O
Solvent: O
Solvent: CCO
Product: CCCN(C)CCCCC1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Yield: 93.7 %

Procedure:
A suspension of 83 mg (0.198 mmol) of Methyl-propyl-{4-[1-(4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-but-3-ynyl}-amine in 4 ml EtOH and 8 mg of PtO2.H2O was hydrogenated (1 atm) for 7 h. The reaction was filtered and evaporated. Flash column chromatography on silica gel (CH2Cl2/MeOH 19:1 to 9:1) gave 78 mg (93%) of Methyl-propyl-{4-[1-(4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-butyl}-amine, mp: 73.0-74.8° C., MS: 421 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH:15]=[C:14]3[C:9]([NH:10][C:11](=O)[N:12]([CH3:17])[C:13]3=[O:16])=[N:8]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:11]1[N:12]([CH3:17])[C:13](=[O:16])[C:14]2[C:9](=[N:8][N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([Br:1])=[CH:3][CH:4]=3)[CH:15]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(Br)cc3)cc2c1=O
Product: Cn1c(Cl)nc2nn(Cc3ccc(Br)cc3)cc2c1=O
Temperature: 0 °C
Yield: 94 %

Procedure:
2-(4-Bromobenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (159 g, 475 mmol) is suspended in POCl3 (300 mL), and then slowly heated to reflux. After the mixture is refluxed for 60 h, POCl3 is removed under reduced pressure. The obtained residue is dissolved in methylene chloride (5 L), cooled to 0° C., and then adjusted to pH 8-9 with saturated sodium bicarbonate. After filtration, the obtained solids are washed with water twice, and then dried under vacuum to give 157 g of product (yield: 94%). MS (ESI) m/z 353.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[C:5]1([CH:3]([CH3:4])[CH2:2][NH:1][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(CN)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(CNC(=O)c1ccccc1)c1ccccc1
Yield: 94.9 %

Procedure:
To a solution of 1-amino-2-phenylpropane (25.0 g, 0.185 mol) and triethylamine (18.2 g, 0.185 mol) in 150 mL of chloroform was added dropwise, a solution of benzoyl chloride (26.0 g, 0.185 mol) in 150 mL of chloroform under nitrogen. After completion of the addition, the reaction mixture was heated at reflux for 1 hour. The solution was then washed with water and the organic layer dried over magnesium sulfate. Removal of the solvent yielded 42.0 g (95%) of N-(2-phenylpropyl)benzamide as a white powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19](CC[Si](C)(C)C)[C:18](=[O:29])[CH2:17]1)C1C=CC=CC=1.I[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][C:13]2[CH:12]=[CH:11][C:10]([N:16]3[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:29])[CH2:17]3)=[C:9]([OH:8])[CH:14]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: ICC1CCCCC1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: O=C1CN(c2ccc(CC3CCCCC3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and iodomethylcyclohexane analogous to Example 57, steps B, C and D: (M−1)−=323. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (d, J=11.37 Hz, 2 H) 1.09-1.19 (m, 2 H) 1.14 (d, J=9.60 Hz, 1 H) 1.44 (dd, J=14.78, 3.66 Hz, 1 H) 1.62 (d, J=10.86 Hz, 5 H) 2.34 (d, J=7.07 Hz, 2 H) 4.00 (s, 2 H) 6.54 (dd, J=7.96, 1.89 Hz, 1 H) 6.61 (d, J=1.77 Hz, 1 H) 7.25 (d, J=8.08 Hz, 1 H) 8.85 (s, 1 H)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: NC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CCCC1NC1CCCCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (2.01 g, 12.9 mmol) in ethanol (20 mL) was treated with cyclohexylamine (1.75 mL, 12.1 mmol), sodium cyanoborohydride (1.39 g, 22.2 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product 2-cyclohexylamino-cyclopentanecarboxylic acid ethyl ester (2.10 g, 8.77 mmol, 86.9%), as a light yellow oil. LC-MS (ESI) calcd for C14H25NO2239.19, found 240.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Br:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[K+].O1CCCC1.Cl.[CH3:29][N:30]([CH2:32][CH2:33]Cl)[CH3:31]>[Cl-].[Na+]>[CH3:29][N:30]([CH3:31])[CH2:32][CH2:33][S:20][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:14]2[CH:15]=[C:16]([Br:19])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: Fc1ccccc1C1=NCC(=S)Nc2ccc(Br)cc21
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCSC1=Nc2ccc(Br)cc2C(c2ccccc2F)=NC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of 4.4 g of 1,3-dihydro-5-(2-fluorophenyl)-7-bromo-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 21.5 ml of a 10% aqueous potassium hydroxide solution and 1.4 ml of tetrahydrofuran is added at room temperature with stirring 2.74 g of N,N-dimethyl-2-chloroethylamine hydrochloride, and the resulting mixture is then stirred at room temperature for 2 hours. The reaction mixture is diluted with an aqueous sodium chloride solution and then extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is removed by distillation under reduced pressure, whereby crude crystalline 2-(2-dimethylaminoethylthio)-5-(2-fluorophenyl)-7-bromo-3H-1,4-benzodiazepine is obtained. Recrystallization from an ether-n-hexane mixture gives 4.05 g of 2-(2-dimethylaminoethylthio)-5-(2-fluorophenyl)-7-bromo-3H-1,4-benzodiazepine, m.p. 105°-107.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[F:42])[C:12]2[C:13]([C:30]([O:32]CC)=[O:31])=[N:14][N:15]([C:20]3[C:21]([O:28][CH3:29])=[N:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[C:16]=2[CH:17]([CH3:19])[CH3:18])[CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[F:42])[C:12]2[C:13]([C:30]([OH:32])=[O:31])=[N:14][N:15]([C:20]3[C:21]([O:28][CH3:29])=[N:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[C:16]=2[CH:17]([CH3:18])[CH3:19])[CH:3]=1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ncc(-n2nc(C(=O)O)c(C(Nc3cc(Cl)c(=O)n(C)c3)c3ccc(Cl)cc3F)c2C(C)C)c(OC)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
A solution of 465 mg (0.743 mmol) ethyl 4-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)(4-chloro-2-fluorophenyl)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (product from step 184.2) in 7.42 ml THF/MeOH (1:1) under N2 atmosphere was cooled down to 0° C. After that 2.60 ml (5.20 mmol) of a 2M NaOH solution was added drop wise and the solution was stirred at 0° C. for 10 min and at RT for 1.5 hour. The solvent was evaporated, diluted in 50 ml CH2Cl2 and washed with 1M citric acid aqueous solution (30 ml). The water phase was extracted twice with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and evaporated to give 461 mg (0.741 mmol, 100% yield) of the title compound as a foam, which was used in the next step without purification. LCMS: (M+H)=591/593; tR=0.97 min (LC-MS 4). HPLC: tR=4.69 min (HPLC 7). TLC: R=0.14 (CH2Cl2/MeOH 20:1).
Reaction SMILES: [CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][C:10](=[CH2:23])[C:9]1=[CH:8][C:7](=[O:24])[CH2:6][CH2:5]2)[C:2]#[CH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][C:10](=[CH2:23])[C:9]1=[CH:8][C:7](=[O:24])[CH:6]=[CH:5]2)[C:2]#[CH:3]
Reactant: C#CC[C@]12CCC(=O)C=C1C(=C)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: C#CC[C@]12C=CC(=O)C=C1C(=C)C[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]12

Procedure:
To a solution of 480 mg of 10β-(2-propynyl)-6-methylenestr-4-ene-3,17-dione in 15 ml of dioxane are added 511 mg of dichlorodicyanoquinone (DDQ) and 571 mg of p-toluenesulfonic acid, and the mixture is refluxed for half an hour.