Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:26]=[C:27]([C:42]([F:45])([F:44])[F:43])[CH:28]=[C:29]2[C:33]=1[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[N:31]=[CH:30]2.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH2:24][C:25]3[CH:26]=[C:27]([C:42]([F:45])([F:43])[F:44])[CH:28]=[C:29]4[C:33]=3[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:40])[CH3:41])[N:31]=[CH:30]4)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(C(F)(F)F)cc(CBr)c21
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cnn(COCC[Si](C)(C)C)c23)(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.16 g, 0.517 mmol) and 7-(bromomethyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.212 g, 0.517 mmol) in dimethylformamide (6 mL) at 0° C. was added sodium hydride (60% in mineral oil, 0.027 g, 0.672 mmol). The resulting solution was stirred at 0° C. for 30 min. The reaction was quenched by the cautious addition of saturated ammonium chloride and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12% EtOAc/Hex) gave 280 mg (85%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 8.16 (s, 1H), 8.10 (s, 1H), 7.51 (s, 1H), 7.24 (m, 2H), 6.98 (m, 2H), 5.58 (s, 2H), 4.86 (s, 2H), 3.78 (m, 2H), 3.55 (s, 2H), 3.52 (m, 2H), 3.11 (m, 2H), 2.19 (m, 2H), 1.87 (m, 2H), 1.53 (s, 9H), 0.89 (m, 2H), 0.00 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 162.3, 160.3, 155.0, 139.2, 138.4, 134.8, 128.63, 128.57, 125.7, 124.8, 124.6 (q, J=272 Hz), 123.5 (q, J=32 Hz), 121.9, 119.3 (q, J=3.8 Hz), 115.2, 115.0, 79.5, 79.2, 78.7, 70.5, 66.2, 41.1, 40.0 (br), 32.3, 28.5, 17.8, −1.4. Mass spec.: 638.12 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br>C(Cl)(Cl)Cl.CC(O)=O>[Br:15][CH2:13][C:12]([C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][O:9][CH:10]=1)=[O:14]
Reactant: CC(=O)c1conc1-c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)c1conc1-c1ccccc1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
To a solution of 1-(3-phenyl-isoxazoi-4-yl)-ethanone (6.35 g, 34 mmol) in chloroform (50 mL) and AcOH (1 mL) at 48° C. was added a solution of bromine (1.83 mL, 36 mmol) in chloroform (15 mL) over 10 min keeping the temperature below 50° C. After addition the reaction mixture was allowed to cool down to room temperature and poured into ice-water (200 mL). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate: 100:0 to 7:3) afforded the title compound (3.72 g, 41%) which was obtained as a light yellow solid. MS m/e (EI): 265.0/267.0 [M].
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.C1(C)C=CC=CC=1.[CH2:15]=[CH:16][C:17]([Cl:19])=[CH2:18]>C1(C)C(C)=CC=CC=1>[Cl:19][CH:17]1[CH:16]=[CH:15][CH:2]2[C:1]([O:6][C:4](=[O:5])[CH:3]2[CH2:18]1)=[O:7]
Reactant: C=CC(=C)Cl
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2CC(Cl)C=CC12
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
156.9 g (1.6 mole) of maleic anhydride and 250 ml toluene were added to a flask. 25 ml of toluene was removed by distillation to dry the solution. 150 g (1.69 mole) of chloroprene dissolved in 250 ml of xylene was slowly added to the flask. The entire addition took 30 minutes. The resulting solution was then heated at 55° C. for three hours. The solution was then distilled to remove solvents. The remaining material was distilled at 160-165° C. (1 to 2 mm pressure) to afford 4-chlorotetrahydrophthalic anhydride in 85% yield (253 grams).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: NCc1cccnc1
Product: c1cncc(CNc2cccnc2)c1
Yield: 82.6 %

Procedure:
Using the general procedure, 3-bromopyridine (96 μL, 1.0 mmol) was coupled with 3-(aminomethyl)pyridine (153 μL, 1.5 mmol) at 90° C. for 20 h. Purification of the crude product by column chromatography on silica gel using dichloromethane (saturated with ammonia)/methanol (15:1) as eluent afforded the desired product as a light yellow liquid (153 mg, 83% yield). Rf=0.4 (dichloromethane (saturated with ammonia)/methanol=10:1).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19](C(C)=C)[C:18]3=[O:29])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[ClH:39]>O>[ClH:39].[ClH:39].[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:29])[CH2:10][CH2:9]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 76 parts of 1-{-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one in 280 parts of ethanol are added 120 parts of a hydrochloric acid solution and 250 parts of water. The whole is stirred for 30 minutes at room temperature. Upon cooling in an ice-bath, the product is precipitated. It is filtered off, washed with 2-propanone and with 2,2'-oxybispropane, and dried, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride, hydrate; mp. 237.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>[Zn].C(O)(=O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An acetic acid (3 ml) solution of the 4-nitrobenzylpiperidine compound (25) (65.8 mg, 0.2 mmol) obtained in the process 2 was added with zinc (300 mg) little by little at 0° C. After having been stirred at the room temperature for 2 hours, this was filtered to be taken out, had the solvent distilled out and neutralized with 2M aqueous sodium hydroxide, and then was extracted with ethylacetate. The resultant was washed with water and the saturated saline solution, dried and then vacuum concentrated, thus obtained a 4-aminobenzylpiperidine compound (26:R=2,2-dimethylcyclopropane) in the form of a yellow oily matter (50 mg, 85%).
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][C:16]=2[C:21]2[CH:22]=[C:23]3[C:32](=[CH:33][CH:34]=2)[C:31]2[N:27]([CH:28]=[C:29]([C:35]4[N:39]([CH:40]([CH3:42])[CH3:41])[N:38]=[C:37]([CH3:43])[N:36]=4)[N:30]=2)[CH2:26][CH2:25][O:24]3)[CH2:10]1)([CH3:8])[C:3](OCC)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH:40]([N:39]1[C:35]([C:29]2[N:30]=[C:31]3[C:32]4[CH:33]=[CH:34][C:21]([C:16]5[CH:17]=[N:18][N:19]([CH3:20])[C:15]=5[CH:11]5[CH2:12][CH2:13][CH2:14][N:9]([C:2]([CH3:1])([CH3:8])[CH2:3][OH:4])[CH2:10]5)=[CH:22][C:23]=4[O:24][CH2:25][CH2:26][N:27]3[CH:28]=2)=[N:36][C:37]([CH3:43])=[N:38]1)([CH3:42])[CH3:41]
Reactant: CCOC(=O)C(C)(C)N1CCCC(c2c(-c3ccc4c(c3)OCCn3cc(-c5nc(C)nn5C(C)C)nc3-4)cnn2C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCN(C(C)(C)CO)C4)cc2OCC3)n(C(C)C)n1
Yield: 30.6 %

Procedure:
To a solution of ethyl 2-methyl-2-[3-(1-methyl-4-{4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}-1H-pyrazol-5-yl)piperidin-1-yl]propanoate (35 mg, 0.060 mmol) in dry THF (2 ml), was added LiAlH4 (11.4 mg, 0.300 mmol) in small portions at room temperature. The resulting mixture was heated to reflux for 1 h. Water (1 mL) was added to quench the reaction. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 248 (10 mg, 31% yield). LCMS (ESI): RT=4.72 min, m/z: 545.4 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.39 (d, J=8.5 Hz, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 7.09-7.08 (m, 1H), 6.93 (d, J=1.5 Hz, 1H), 5.86-5.83 (m, 1H), 4.53 (d, J=6.0 Hz, 4H), 4.27-4.25 (m, 1H), 3.89 (s, 3H), 3.28-3.25 (m, 2H), 2.99-2.96 (m, 3H), 2.44-2.40 (m, 2H), 2.26 (s, 3H), 2.08-2.06 (m, 1H), 1.58-1.70 (m, 3H), 1.47-1.45 (m, 6H), 0.93-0.91 (m, 6H)
Reaction SMILES: [CH:1]1([N:4]([CH3:29])[C:5]2[C:6]([C:19]3[O:20][C:21]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:22]=4[CH:23]=3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[CH:1]1([N:4]([CH3:29])[C:5]2[C:6]([C:19]3[O:20][C:21]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:22]=4[CH:23]=3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N(C)C3CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of methyl 3-[cyclopropyl(methyl)amino]-2-(5-fluoro-1-benzofuran-2-yl)quinoxaline-6-carboxylate (79 mg, 0.20 mmol) in methanol (15 mL) and water (1 mL) was added sodium hydroxide (24 mg, 0.60 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (20 mL), adjusted the pH value to 5 with 3N HCl and filtered to give 3-[cyclopropyl(methyl)amino]-2-(5-fluoro-1-benzofuran-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid (60 mg, 79%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].C(NC(C)C)(C)C.[C:14]([C:18]1[CH:23]=[CH:22][C:21](/[C:24](/[C:41]2[CH:46]=[CH:45][C:44](I)=[CH:43][CH:42]=2)=[CH:25]/[CH2:26][O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[C:30]([CH3:40])[CH:29]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]([C:18]1[CH:19]=[CH:20][C:21](/[C:24](/[C:41]2[CH:46]=[CH:45][C:44]([C:6]#[C:5][CH2:4][N:2]([CH3:3])[CH3:1])=[CH:43][CH:42]=2)=[CH:25]/[CH2:26][O:27][C:28]2[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[C:30]([CH3:40])[CH:29]=2)=[CH:22][CH:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: C#CCN(C)C
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 25 °C

Procedure:
1-(N,N-Dimethylamino)prop-2-yne (0.131 mL, 1.23 mmol) and diisopropylamine (0.40 mL, 2.85 mmol) were added to a solution of the methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (350 mg, 0.614 mmol; prepared as described in example 30) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride (22 mg, 0.031 mmol) were added. The reaction mixture was stirred at ambient temperature over night, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 98:2) yielding methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as oil.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]([Cl:23])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:13]=2)[N:8]=1>C1COCC1>[CH:1]1([C:24]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([Cl:6])[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:15]3[Cl:23])([C:26]2[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=2)[OH:25])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: Cn1cncc1C(=O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Cyclopropylmagnesium bromide (0.5 M in THF, 0.6 mL, 0.3 mmol) was added dropwise to a solution of (2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (57.3 mg, 0.15 mmol, Intermediate 2: step b) in THF (1 mL) at 0° C. The mixture was stirred at 0° C. for 5 minutes, then the ice bath was removed and the mixture was stirred for 3 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl and was diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-4% MeOH-DCM) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J=1.71 Hz, 1H), 8.03 (d, J=8.80 Hz, 1H), 7.66 (dd, J=1.96, 8.80 Hz, 1H), 7.46-7.61 (m, 4H), 7.39-7.46 (m, 2H), 7.30 (d, J=0.98 Hz, 1H), 5.82 (s, 1H), 3.14 (s, 3H), 1.63-1.74 (m, 1H), 0.53-0.71 (m, 2H), 0.19-0.42 (m, 2H); MS m/e 424.0 (M+H)+.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[F:8][C:9]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21]>>[F:8][C:9]1[CH:27]=[C:26]([CH:28]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=C1CSC(=S)N1
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2F)c(C(F)(F)F)c1
Product: N#Cc1ccc(Oc2ccc(C=C3SC(=S)NC3=O)cc2F)c(C(F)(F)F)c1

Procedure:
4-[2-Fluoro-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile was prepared using rhodanine and 4-(2-Fluoro-4-formyl-phenoxy)-3-trifluoromethyl-benzonitrile according the General Procedure B. 1H NMR (400 Hz, DMSO-d6) δ 8.41 (d, 1H), 8.11 (dd, 1H), 7.76 (d, 1H), 7.67 (s, 1H), 7.51 (m, 2H), 7.23 (d, 1H).
Reaction SMILES: [NH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][CH2:5][C:4]=2[CH:3]=[N:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[NH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[CH2:6][CH2:5][C:4]=2[CH:3]=[N:2]1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1ccc2c(c1)NCCc1cn[nH]c1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ccccc32)cn1
Reaction time: 16 h

Procedure:
To a solution of 0.20 mol of 1,4,5,6-tetrahydropyrazolo[4,3-d][1]benzazepine, 0.80 mol of triethylamine is added 0.42 mol of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride in 15 ml of dichloromethane. The mixture is stirred under argon for 16 hours and diluted with dichloromethane (25 ml). The mixture is washed with H2 O), 1MNaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue in methanol-tetrahydrofurane(1:1) stirred with 1NNaOH for 5 hours. The mixture is neutralized with acetic acid and the solvent removed. To the residue is added H2O and the mixture extracted with ethyl acetate. The extract is washed with H2O, 1NHCl, 1MNaHCO3 and dried (Na2SO4). The solvent removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=O)[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1.Cl.[OH:25][NH2:26].C([O-])(=O)C.[K+]>CO>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[N:26][OH:25])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:6]=1
Reactant: NO
Reactant: COC(=O)c1c(C=O)cccc1Oc1nc(OC)cc(OC)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(C=NO)cccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
2.0 g of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-formylbenzoate, 0.8 g of hydroxyamine hydrochloride, 1.1 g of potassium acetate and 10 ml of methanol were placed in a 50 ml eggplant type flask, and were stirred for 10 minutes at room temperature. Methanol was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with water, 5% hydrochloric acid and a saturated salt aqueous solution, and was dried with magnesium sulfate anhydride. After filtering, a small amount of Florisil was added to the resultant product, and was stirred for 5 minutes. The Florisil was filtered out, and ethyl acetate was distilled off under reduced pressure to obtain 1.5 g of the aimed compound (refractive index=1.5558) at a yield of 72%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)c(O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-4-methoxybenzoic acid (20 g, 118.9 mmol) in 500 mL CH2Cl2 was added thionyl chloride (21.2 g, 178.4 mmol), followed by 0.4 mL DMF. After stirring at rt for 8 h, the reaction mixture was concentrated to a white solid (azeotroped twice from benzene). This material was used as is in the next step.
Reaction SMILES: [C:1]1([C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH:10]([N:12]=[N+]=[N-])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:26]=CC=C[CH:22]=1>CC(C)=O>[CH:21]([NH:12][CH:10]1[CH2:11][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9]1)([CH3:26])[CH3:22]
Reactant: [N-]=[N+]=NC1C=CC(c2ccccc2)(c2ccccc2)C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Product: CC(C)NC1C=CC(c2ccccc2)(c2ccccc2)C1
Reaction time: 0.33 h
Yield: 81.6 %

Procedure:
To a solution of 4,4-diphenyl-2-cyclopentenyl azide (0.30 g) in acetone (3 ml) was added triphenylphosphine (0.33 g) at room temperature and refluxed for 21 hours. After being cooled, the solvent was removed under reduced pressure and a solution of sodium borohydride (0.22 g), in methanol (3 ml) was added thereto. After being stirred for 20 minutes, brine and ethyl acetate were added. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-isopropyl-4,4-diphenyl-2-cyclopentenylamine (0.26 g).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:12]3[CH2:11][N:10]([CH3:22])[C:9](=[O:23])[C:8]=2[CH:24]=1>C(O)C.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:12]3[CH2:11][N:10]([CH3:22])[C:9](=[O:23])[C:8]=2[CH:24]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(Cl)ccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)O)ncn2-c2ccc(Cl)cc2C1=O
Yield: 74.6 %

Procedure:
5.4 ml of 5N sodium hydroxide solution were added dropwise to a suspension of 6.9 g (21.6 mmol) of ethyl 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate in 5 ml of ethanol and 7 ml of water and the mixture was heated to reflux for 30 minutes. The solution was filtered while hot, concentrated to about 6 ml and acidified with 5.5 ml 5N hydrochloric acid. The product was filtered off under suction. There were obtained 4.7 g (75%) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo [1,5-a][1,4]benzodiazepine-3-carboxylic acid as colourless crystals of m.p. 263°-267° (dec.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[O:5][N:4]=1.C(N(C(C)C)C(C)C)C.Br[CH2:35][C:36]1[C:37]([CH2:42]Br)=[CH:38][CH:39]=[CH:40][CH:41]=1>CN(C)C=O>[CH2:42]1[C:37]2[C:36](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:35][N:1]1[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[O:5][N:4]=1
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)n1
Reactant: BrCc1ccccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2cnc(-c3nc(CN4Cc5ccccc5C4)no3)c2[C@@H]2CCN12
Yield: 60.8 %

Procedure:
1.5 g (4.65 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 20 ml of N,N-dimethylformamide, 4 ml (13.9 mmol) of N-ethyldiisopropylamine and 1.3 g (4.9 mmol) of α,α'-dibromo-o-xylene were stirred at room temperature for 1 hour. The reaction solution was evaporated, the residue was dissolved in methylene chloride and chromatographed on 50 g of silica gel while eluting with methylene chloride/ethyl acetate 1/1. There were obtained 1.2 g (61%) of (S)-12,12a-dihydro-1-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 210°-213°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([C:33](=[O:34])[NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)C1

Procedure:
3-[(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared starting from intermediate D and 1-(tert-butoxycarbonyl)-pyrrolidine-3-carboxylic acid. MS calcd. for C26H29ClN3O4 [(M+H)+] 481.3, obsd. 482.0.