Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH:3]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)(O)[O-].[K+]>CN(C)C=O>[CH2:21]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CCCc1cccc(O)c1)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCc1cccc(OCc2ccccc2)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-hydroxy-3-(3-benzyloxycarbonylpropyl)benzene (2.0 g), benzylbromide (1.14 ml), potassium bicabonate (1.53 g) and dimethylformamide (20 ml) was stirred for 3 h at room temperature. The mixture was quenched by addition of water and extracted with a mixture of n-hexane:ethyl acetate (3:1). The extract was washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to give the title compound (2.55 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:52])[C:41]5[C:46]([O:47][CH2:48][CH2:49][CH3:50])=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:51])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:52])[C:41]5[C:46]([O:47][CH2:48][CH2:49][CH3:50])=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:51])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4c(OCCC)ccc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4c(OCCC)ccc[n+]4[O-])cc2)CCN3)cc1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-N-[4-[hydroxy(1-oxido-3-propoxypyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (330 mg) in ethanol (20 ml) was added sodium borohydride (85 mg) at room temperature and the mixture was stirred for 2 hours. To the reaction solution was further added sodium borohydride (85 mg), and the mixture was stirred for 2 hours. To the reaction solution was further added sodium borohydride (85 mg), and the mixture was stirred for 2 hours. To the reaction solution was further added sodium borohydride (85 mg), and the mixture was stirred for 14 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxido-3-propoxypyridine-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 113) (230.7 mg) as yellow crystals.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[C:4]([CH3:17])[CH:3]=1.[C:18]([Cu])#[N:19]>CN(C=O)C.O.C(OCC)(=O)C>[C:18]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[C:4]([CH3:17])[CH:3]=1)#[N:19]
Reactant: N#C[Cu]
Reactant: Cc1cc(Br)c([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)c([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Temperature: 115 °C
Reaction time: 4 h
Yield: 65.1 %

Procedure:
To a solution of 4-bromo-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide (450 mg, 1.42 mmol) in dry DMF (14 mL) under argon was added CuCN (178 mg, 1.99 mmol). The resulting mixture was heated to 115° C. and stirred for 4 h. The reaction was cooled and diluted with water and ethyl acetate. The layers were separated, and the organics were washed once with water. The organics were then dried, concentrated, and purified by flash chromatography (35% ethyl acetate/hexanes) to provide 4-cyano-2-methyl-5-nitro-(N,N-dimethyl)benzenesulfonamide (249 mg, 65%) as pale yellow crystals. IR (thin film): 2240 cm−1. 1H NMR (400 MHz, CDCl3): δ2.78 (s, 3), 2.94 (s, 6), 7.87 (s, 1), 8.74 (s, 1).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C:4]([N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:8]2=[O:17])=[CH:3]1.[CH3:18][C:19]1[C:27]2[CH2:26][O:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[C@@H:29]1[CH2:31][O:30]1>C(O)C>[OH:30][C@H:29]([C:20]1[CH:21]=[CH:22][C:23]2[C:24](=[O:28])[O:25][CH2:26][C:27]=2[C:19]=1[CH3:18])[CH2:31][N:14]1[CH2:13][CH2:12][C:9]2([C:8](=[O:17])[N:7]([C:4]3[CH2:5][O:6][C:2](=[O:1])[CH:3]=3)[CH2:11][CH2:10]2)[CH2:16][CH2:15]1
Reactant: O=C1C=C(N2CCC3(CCNCC3)C2=O)CO1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCC3(CC2)CCN(C2=CC(=O)OC2)C3=O)ccc2c1COC2=O
Temperature: 145 °C

Procedure:
2-(5-Oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-16, 200 mg, 0.846 mmol) was combined with 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (I-4B) (177 mg, 0.931 mmol) in ethanol (5 mL) and heated in a microwave apparatus at 145° C. for 3 hours. The solvent was removed and the residue was purified by preparative TLC, eluting with 25% methanol/EtOAc to afford the title compound. LC-MS (IE, m/z): 427 (M+1)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][N:10]=[C:11]([C:35]1[N:36]=[C:37]([NH:40]C(OC(CC)(C)C)=O)[S:38][CH:39]=1)[C:12]([NH:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[S:25][C:26]([CH3:29])=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:13]>CCOCC>[CH3:8][O:9][N:10]=[C:11]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)[C:12]([NH:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[S:25][C:26]([CH3:29])=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:13]
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
Trifluoroacetic acid (3 ml) was added under ice-cooling to 7-[2-methoxyimino-2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.5 g) and the mixture was stirred for 30 minutes at ambient temperature. To the mixture was added ether and precipitating powder was collected by filtration and dissolved in a mixture of water (20 ml) and an 1N aqueous solution of sodium hydroxide to adjust to pH 12 to 13. The solution was adjusted to pH 4.6 with 10% hydrochloric acid, washed with ethyl acetate and methylene chloride. Excess methylene chloride in the aqueous layer was thoroughly removed by bubbling of nitrogen gas. The aqueous layer was adjusted to pH 2 with stirring and ice-cooling to precipitate powder. The powder was collected by filtration and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.128 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Cl)[CH:9]=1)[C:5]#[N:6].[CH3:11][O-:12].[Na+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:11])[CH:9]=1)[C:5]#[N:6]
Reactant: C[O-]
Reactant: N#Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C#N)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 71.8 %

Procedure:
To a 250 mL round bottom flask charged with 3,5-dichlorobenzonitrile (130a, 7.31 g; 34.90 mmol) and maintained under an argon atmosphere was added DMF (70 mL). The flask was cooled to 0° C. and powdered sodium methoxide (1.88 g; 34.90 mmol) was added in two portions 15 m apart. The homogeneous mixture was allowed to warm to room temperature and stirred for 24 h. The solution was cooled to 0° C. and aqueous 10% HCl (20 mL) was added dropwise via an addition funnel after which the reaction was warmed to RT. The mixture was extracted with EtOAc and the combined extracts washed sequentially with water and brine. The organic phase was dried (Na2SO4), filtered, and volatile solvents were removed in vacuo. The resulting solid was recrystallized from hexanes to afford 3-chloro-5-methoxybenzonitrile (130b, 4.2 g; 72%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:22]([F:25])([F:24])[F:23])[N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH:10]([CH3:21])[C:9]=12)=[O:4].[ClH:26]>C(OCC)(=O)C>[ClH:26].[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:22]([F:25])([F:24])[F:23])[N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH3:21])[C:9]=12)=[O:4]
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1C(C)N(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C(F)(F)F)n2c1C(C)NCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-Methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 1-methyl ester 39b (0.35 g, 0.96 mmol) was added into the reaction flask. A solution of 2.3 N hydrochloric acid in 10 mL of ethyl acetate was then added to the flask. The reaction mixture was stirred at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound 8-methyl-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride 39c crude product (0.4 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([C:11]#[C:12][Si](C)(C)C)[CH2:10][C:6]2[CH:7]=[N:8][O:9][C:5]=2[CH:4]=[CH:3]1.C[O-].[Na+]>CCOCC.CO.C(Cl)Cl.CCOCC>[C:11]([C:2]1([CH3:1])[CH2:10][CH:6]([C:7]#[N:8])[C:5](=[O:9])[CH:4]=[CH:3]1)#[CH:12]
Reactant: CC1(C#C[Si](C)(C)C)C=Cc2oncc2C1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: C#CC1(C)C=CC(=O)C(C#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 9 (75 mg, 0.32 mmol) in dry ether (7.4 mL) was added a solution of sodium methoxide (565 mg) in dry methanol (6 mL). The mixture was stirred at room temperature for 1 h. The mixture was diluted with methylene chloride/ether (1:2, 40 mL). The mixture was washed with 5% aqueous HCl solution (10 mL×2). The acidic washings were extracted with methylene chloride/ether (1:2, 10 mL×1). The original organic solution and the extract were combined. The combined solution was washed with water (15 mL×2) and brine (15 mL×1), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give MCE-4 as a crystalline solid (51 mg, quantitative yield). This material was used without further purification for the next step.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[F:15][C:16]1[C:17](C)=[C:18](C2C=CC(C(O)=O)=CC=2COC)[CH:19]=[CH:20][CH:21]=1.FC1C=CC=CC=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: COCc1cc(C(=O)O)ccc1-c1cccc(F)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1F
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCc1cc(C(=O)OC)ccc1-c1ccccc1F
Reaction time: 3 h

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate (Intermediate 1 Step 2, 10 g, 38.6 mmol) in toluene (80 mL) and water (20 mL) under nitrogen was added 2-fluorophenylboronic acid (7.0 g, 50.2 mmol), followed by potassium carbonate (16 g, 115.8 mmol) and Pd(PPh3)4 (2.23 g, 1.9 mmol). After 3 hours at 100° C., the reaction mixture was diluted with EtOAc (200 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL), water (2×100 mL) and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (silica, pet ether/EtOAc) to afford of the title compound as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.26 (1H, s), 8.04 (1H, d), 7.42 (1H, m), 7.35 (1H, d), 7.14-7.27 (3H, m), 4.34 (2H, s), 3.95 (3H, s), 3.30 (3H, s).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1.Cl([O-])(=O)(=O)=O.CS[C:24]1[S:28][CH:27]=[CH:26][S+:25]=1.O>O1CCCC1>[S:25]1[CH:26]=[CH:27][S:28][C:24]1=[C:10]([C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)OC(=O)Cc1ccc(F)cc1
Reactant: CSc1scc[s+]1
Agent: [H-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)C(=C1SC=CS1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (2.2 g, 55 % dispersion in mineral oil) is added to a solution of isopropyl 4-fluorophenylacetate (3.9 g) in dry tetrahydrofuran (50 ml). The mixture is stirred for two hours at room temperature. 2-Methylthio-1,3-dithiolium perchlorate (5.5 g) is then added and the mixture is heated under reflux for seven hours. After cooling to room temperature, water (300 ml) is slowly added. The solution is extracted with ether (3×200 ml). The combined organic solutions are washed with water (100 ml), dried over magnesium sulphate and the solvents are evaporated in vacuo. The residue is purified by column chromatography on silica gel using hexane/toluene 1:9 as eluant. The product is recrystallized from ligroin and dried -in vacuo to constant weight to yield isopropyl (1,3-dithiol-2-ylidene)-(4-fluorophenyl)-acetate, m.p. 86° (as Example 8).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]([C@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]([O:19]C)=[O:18])[NH:12][C:11]1=[O:21])=[N+:8]=[N-:9].Cl>O.O1CCCC1>[N:7]([C@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]([OH:19])=[O:18])[NH:12][C:11]1=[O:21])=[N+:8]=[N-:9]
Reactant: COC(=O)COC[C@H]1NC(=O)[C@H]1N=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H]1C(=O)N[C@@H]1COCC(=O)O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of potassium carbonate (7.335 g, 53.08 mmole) in water (80 ml) was cooled to 0° C. and deoxygenated with argon. A solution of (±)-(cis)-[(3-azido-2-oxo-4-azetidinyl)methoxy]acetic acid, methyl ester (2.261 g, 10.62 mmole) in tetrahydrofuran (60 ml) was added and the mixture stirred at 0° C. for five minutes and then at room temperature for 5.5 hours. The reaction was cooled and acidified with 6N hydrochloric acid to pH 7. The tetrahydrofuran was mostly removed in vacuo, and the aqueous residue (pH ca. 8) was extracted with ethyl acetate. The aqueous layer was cooled to 0° C., acidified with 6N hydrochloric acid to pH 2, saturated with sodium chloride, and extracted with ethyl acetate (fifteen 80 ml portions). The organic extracts were dried (sodium sulfate), filtered, and concentrated in vacuo. The yield of crude acid was 1.503 g.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[I-].[K+].[CH2:26]([NH2:29])[CH:27]=[CH2:28]>O1CCCC1>[CH2:26]([NH:29][CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1)[CH:27]=[CH2:28]
Reactant: C=CCN
Reactant: ClCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 31, 1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide and allylamine in tetrahydrofuran are reacted to give 1-[(allylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.[NH4+].[Cl-].C(O)(=O)C>CO.O.[Fe]>[Cl:1][C:2]1[CH:15]=[C:14]([CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1)[NH2:16]
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CN1CCN(Cc2ccc(N)cc2Cl)CC1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of 1-(2-chloro-4-nitrobenzyl)-4-methylpiperazine (0.96 g, 3.6 mmol) in MeOH/water (4:1, 50 mL) was added 1.80 g (33.7 mmol) of NH4Cl and 1.47 g (26.3 mmol) of Fe dust and the mixture heated at reflux under an atmosphere of N2 for 2 h (HPLC indicated no progress). To this was added 4 mL of glacial acetic acid and the mixture heated at reflux for an additional 2 h. The reaction mixture was cooled to ambient temperature, filtered, and the filtrate concentrated. The residue was partitioned between EtOAc and saturated aq. NaHCO3, the separated aqueous layer was extracted with EtOAc, and the combined organics washed with brine and dried over Na2SO4. Upon concentration, the crude product was purified by silica gel chromatography (eluted with 5-7% MeOH/DCM; silica gel deactivated with 1% triethylamine/DCM) to provide 0.53 g of product.
Reaction SMILES: [CH:1]1[C:6]([C:7]#[N:8])=[CH:5][N:4]=[C:3](Cl)[CH:2]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12]>>[NH2:12][CH2:11][CH2:10][NH:13][C:3]1[N:4]=[CH:5][C:6]([C:7]#[N:8])=[CH:1][CH:2]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NCCN
Product: N#Cc1ccc(NCCN)nc1
Temperature: 50 °C

Procedure:
6-Chloronicotinitrile (2.0 g) was treated with ethylenediamine (5 ml). The mixture was then heated at 50° C. for 22 hours. Excess ethylenediamine was removed by rotary evaporation. The residue was partitioned between 2.5 M aqueous sodium hydroxide and dichloromethane. The aqueous layer was extracted 4× more with dichloromethane. The combined organic layers were washed with a saturated sodium chloride solution, dried and then concentrated in vacuo to give 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile as an amber liquid which solidified upon standing. The amine (0.97 g, 6 mmol) was shaken overnight with benzotriazole carboxamidinium 4-methylbenzenesulfonate (2.0 g, 6 mmol) and DIEA (1.05 ml, 6 mmol) in acetonitrile (10 ml). Addition of ether gave amino{2-[(5-cyano(2-pyridyl)amino]ethyl}carboxamidinium 4-methylbenzenesulfonate as a white solid.
Reaction SMILES: C(O[CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][N:7]=1)(=O)C.S(Cl)(Cl)=O.[SH:19][C:20]1[NH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C[O-].[Na+]>C(Cl)(Cl)Cl.CO>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][S:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=2)[C:11]=1[CH3:12]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COc1ccnc(COC(C)=O)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 85.2 %

Procedure:
5.7 g of 2-acetoxymethyl-3-methyl-4-methoxy-pyridine was dissolved in chloroform, and 18 g (4 eq.) of thionyl chloride was added. The mixture was heated to reflux for one hour and then concentrated, and a residue resulting therefrom was dissolved in methanol. The solution was added in advance to 5.3 g (1 eq.) of 2-mercaptobenzimidazole, 45 mL of a 28% sodium methoxide solution, and 100 mL of methanol, and the mixture was heated to reflux for one hour. Methanol was distilled off, and ice and ethyl acetate were added to the residue, to wash the residue by suspending. Produced crystals were collected by filtration, and then were washed by suspending in water, to obtain 7.1 g of colorless crystals. Total yield 20.9% (purity by HPLC: 98.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14]1(=O)[O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15]1.S(=O)(=O)(O)O>>[C:14]1(=[O:20])[N:1]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=2)[C:5]([OH:7])=[O:6])[C:18](=[O:19])[CH2:17][CH2:16][CH2:15]1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=C1CCCC(=O)O1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(N2C(=O)CCCC2=O)cc([N+](=O)[O-])c1

Procedure:
3-Glutarimido-5-nitrobenzoic Acid [D; Y is CH2CH2CH2, Z is OH] was prepared by heating a mixture of 18.2 g. of 3-amino-5-nitrobenzoic acid, 45.6 g. of glutaric anhydride and 0.5 ml. of concentrated sulfuric acid on a steam bath for 2 hours. The product was isolated and recrystallized from aqueous dimethylformamide to give 3-glutarimido-5-nitrobenzoic acid, pale yellow prisms, m.p. above 300° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2O)=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1CCc2ccc(Br)cc21
Reactant: C1CCNC1
Product: Brc1ccc2c(c1)C(N1CCCC1)CC2
Yield: 52.7 %

Procedure:
6-bromoindanol (0.3 g, 1.39 mmol) was subjected to the same conditions as 104, part A by substituting methylamine with pyrrolidine (1.16 mL, 14 mmol) to yield the title compound (0.195 g, 52%). 1H NMR (CDCl3): 7.4 (s, 1H), 7.25 (d, 1H), 7.0 (d, 1H), 4.1 (t, 1H), 2.9 (m, 1H), 2.6 (m, 1H), 2.55 (m, 4H), 2.1 (m, 2H), 1.7 (brs, 4H).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][C:6]([F:9])([F:8])[CH2:5][N:4]1[C:10](=[O:20])[CH2:11][NH:12]C(=O)OC(C)(C)C)#[N:2].[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(#N)C>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:12][CH2:11][C:10]([N:4]1[CH2:5][C:6]([F:8])([F:9])[CH2:7][C@H:3]1[C:1]#[N:2])=[O:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CC(F)(F)C[C@H]1C#N
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@@H]1CC(F)(F)CN1C(=O)CN
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of (S)-tert-butyl 2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamate (7.3 g, 25.2 mmol), obtained from step 7, in 150 mL of ACN was added trifluoroacetic acid (38.9 mL, 0.505 mol) dropwise. The mixture was stirred overnight and the volatiles were evaporated. The residue was washed with ether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=3)([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1c1ccc2ccccc2c1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)c1ccc2ccccc2c1
Temperature: 65 °C

Procedure:
A mixture of rac-6-chloro-3-naphthalen-2-yl-1,3-dihydro-indol-2-one (0.07 g, 0.24 mmol) (from Example 47b supra), 3-chlorobenzyl bromide (0.053 g, 0.28 mmol) (Aldrich), potassium iodide (0.047 g, 0.28 mmol) and potassium carbonate (0.071 g, 0.52 mmol) in acetone (3 mL) was heated at 65° C. for 2 hours. After cooling, mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate three times. The combined organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated. Residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-naphthalen-2-yl-1,3-dihydro-indol-2-one as a brown solid. (Yield 0.02 g, 20.2%).