Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:21]([N:4]1[C:3](=[O:9])[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[N:5]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
To a round bottom flask was added 4,5-dichloropyridazin-3(2H)-one (50 gm, 303.03 mmol), DMF (150 ml), K2CO3 (46 gm, 333.33) and benzyl bromide (51.83 gm, 303.03 mmol). The reaction was stirred at rt for 16 hrs. After this time, the reaction mixture was slowly poured into water (500 ml) and a solid precipitate formed. The slurry was stirred at rt for 1 hr. After this time, the reaction mixture was filtered and the solid was collected. The solid was dried under vacuum to give product 2-benzyl-4,5-dichloropyridazin-3(2H)-one as tan-colored solid (74 gm, 97% yield). HPLC retention time (method A)2.788 min; LCMS (M+1)=255.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:18][OH:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]([C:30]1([O:33][C:34]2[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=2)[CH2:32][CH2:31]1)=[O:29].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>C1COCC1>[CH3:26][O:27][C:28]([C:30]1([O:33][C:34]2[CH:39]=[CH:38][C:37]([O:19][CH2:18][CH:17]([C:16]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[C:10]4[C:15]=3[CH2:14][CH2:13][CH2:12][CH2:11]4)[CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:36][CH:35]=2)[CH2:32][CH2:31]1)=[O:29]
Reactant: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: COC(=O)C1(Oc2ccc(O)cc2)CC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(Oc2ccc(OCC(c3c4c(nn3-c3ccc(Cl)cc3)CCCC4)C3CCCCC3)cc2)CC1

Procedure:
In analogy to the procedure described in example 29.2, [rac]-2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethanol (example 37.1) was reacted with 1-(4-hydroxy-phenoxy)-cyclopropanecarboxylic acid methyl ester (Hazeldine, Stuart T.; Polin, Lisa; Kushner, Juiwanna; White, Kathryn; Corbett, Thomas H.; Horwitz, Jerome P. Bioorganic & Medicinal Chemistry (2005), 13(12), 3910-3920) in the presence of tri-n-butylphosphine and N,N,N′,N′-tetramethylazodicarboxamide in THF at ambient temperature to give the title compound as white solid. MS: m/e=549.3 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH3:14])[C:7](=O)[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:5])[CH3:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23](Cl)(=[O:25])[CH3:24]>CO>[C:23]([C:8](=[C:7]([NH:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:6]([CH3:14])[C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:9]([O:11][CH3:12])=[O:10])(=[O:25])[CH3:24]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(C)C(=O)CC(=O)OC
Reactant: CC(=O)Cl
Solvent: CO
Product: CCOC(=O)C(C)C(NCc1ccccc1)=C(C(C)=O)C(=O)OC
Reaction time: 16 h

Procedure:
Methyl 4-ethoxycarbonyl-3-oxopentanoate (200 ml; 1.06 mmole) was dissolved in dry methanol (2.5 ml), and benzylamine (386 mg; 3.6 mmole) and molecular sieve 3A (0.3 g) were added thereto. A solution of acetyl chloride (170 mg; 2.17 mmole) in dry methanol (0.9 ml) was added to the resultant mixture, followed by allowing to stand at room temperature for 16 hours. Molecular sieve was removed by filtraton, and the filtrate was diluted with ethyl acetate, washed successively with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (2.5 ml). Gaseous ketene was introduced therein at room temperature. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl ethyl 2-acetyl-3-benzylamino-4-methyl-2-pentenedioate.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C[O:25][C:26](=[O:35])[CH:27](Br)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([CH2:28][CH:27]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:23][C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=3)[CH:6]=[N:5]2)[C:26]([OH:25])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1cccc(F)c1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(F)c2)cc1=O
Yield: 71 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 3-fluoro-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(3-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (10.5 g, 71%); ESI-MS 347 [M+H+] HPLC: >96% (purity). 1H-NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.40-7.48 (m, 1H), 7.02-7.07 (t, 1H), 6.87-6.96 (m, 2H), 6.05 (s, 1H), 5.51-5.56 (m, 1H), 2.32-2.41 (m, 1H), 2.12-2.14 (m, 1H), 1.50-1.80 (m, 7H), 1.15-1.17 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3]#[C:4][CH2:5][OH:6]>C(O)C.[Pd]>[CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH:5]=[O:6]
Reactant: CC(C)(C)C#CCO
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)CCC=O
Product: CC(C)(C)CCCO
Reaction time: 16 h

Procedure:
To a stirred solution of 4,4-dimethyl-pent-2-yn-1-ol (3.1 g, 27.6 mmol) in ethanol (30 ml) is added 10% palladium on carbon (0.3 g). The mixture is stirred under an atmosphere of hydrogen for 16 h. The reaction mixture is filtered through a pad of celite and the celite bed is washed with methanol (10 ml). The filtrate thus obtained is concentrated and the crude product is purified by column chromatography (5-10% ethyl acetate/hexane) to afford 4,4-dimethyl-pentan-1-ol and 4,4-dimethyl-pentan-1-al. To a stirred solution of 4,4-dimethyl-pentan-1-al (0.85 g, 7.45 mmol) in methanol (12 ml) is added sodium borohydride (0.56 g, 14.9 mmol) at 0° C. The reaction mixture is stirred at RT for 1.5 h. On completion, the solvent is evaporated and then diluted with ethyl acetate (30 ml). The organic layer is washed with water (2×20 ml), brine (20 ml), dried over sodium sulfate and concentrated affording 4,4-dimethyl-pentan-1-ol (1.52 g, 13.1 mmol, 48%).
Reaction SMILES: OO.NC(N)=[O:5].C1(=O)OC(=O)C2=CC=CC=C12.[C:18]([Si:22]([CH3:56])([CH3:55])[O:23][CH2:24][CH2:25][N:26]([CH2:53][CH3:54])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH3:52])[S:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:34][CH2:33]1)([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([Si:22]([CH3:55])([CH3:56])[O:23][CH2:24][CH2:25][N:26]([CH2:53][CH3:54])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]1[CH2:33][CH2:34][C@H:35]([N+:38]([O-:5])([CH3:52])[S:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:50])([F:51])[F:49])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:36][CH2:37]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: CCN(CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)CCO[Si](C)(C)C(C)(C)C
Reactant: NC(N)=O
Agent: O=C1OC(=O)c2ccccc21
Agent: OO
Solvent: ClCCl
Product: CCN(CCCCC[C@H]1CC[C@H]([N+](C)([O-])S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
175 mg (1.86 mmol) H2O2-Urea adduct suspended in 2 ml CH2Cl2 were treated with 137 mg (0.9 mmol) phthalic anhydride. After stirring at RT for 15 min to this mixture was added 500 mg (8.4 mmol) crude trans-N-[4-(5-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-pentyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 3 ml CH2Cl2 and the solution was stirred at RT. The mixture was washed with an aqueous solution of NaHCO3, the organic phase was washed with brine and dried over Na2SO4.348 mg crude trans-N-[4-(5-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-pentyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide N-oxide were isolated as colorless oil.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[I:12][C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.CCN(CC)CC>C1(C)C=CC=CC=1>[CH2:4]([O:3][C:1]([N:15]1[CH:14]=[C:13]([I:12])[CH:17]=[N:16]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Ic1cn[nH]c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)n1cc(I)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
CbzCl (95% grade, 2.9 mL, 20 mmol) is added to a solution of 4-iodo-1H-pyrazole (2.97 g, 15.3 mmol) and Et3N (3.2 mL, 23 mmol) in toluene (30 mL) at 0° C. The mixture is stirred at 0° C. for 1 h and partitioned between EtOAc and aq. NaHCO3. The organic layer is dried over MgSO4, concentrated and chromatographed to afford the title compound as a white solid: 1H NMR (CDCl3) δ 8.20 (s, 1H), 7.72 (s, 1H), 7.50-7.31 (m, 5H), 5.46 (s, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[F:12][C:13]([F:17])([F:16])[CH2:14]I.O>CS(C)=O>[F:12][C:13]([F:17])([F:16])[CH2:14][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: FC(F)(F)CI
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
To sodium hydride (60% in oil, 240 mg, 6.0 mmol) 0° C. was added 2 mL anhydrous dimethylsulfoxide. The resulting suspension was stirred for 15 minutes at 0° C. 4-Hydroxybenzaldehyde (610 mg, 5.0 mmol) was added dropwise as a solution in 2 mL dimethylsulfoxide and the resulting mixture stirred for 30 minutes at 0° C. Trifluoroethyl iodide (1.5 mL, 15.24 mmol) was added and the reaction mixture was heated to 55° C. for 24 h. The reaction mixture was cooled to room temperature and poured into water. Organics were extracted with ether (3×50 mL), dried with magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel (20% ethyl acetate in hexanes) to give 4-(2,2,2-trifluoroethoxyl)benzaldehyde (250 mg, 24%) as an oil. Used without further characterization.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[S:10][C:5]2=[N:4][CH:3]=1.[OH-].[Na+].C1C[O:20][CH2:19][CH2:18]1>C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:19]([O:20][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[S:10][C:5]2=[N:4][CH:3]=1)[CH3:18]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc2nc(Cl)cnc2s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cnc2sc(C(=O)O)cc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of methyl 2-chlorothieno[3,2-b]pyrazine-6-carboxylate 22 (100 mg, 0.437 mmol) in THF (1.8 mL) and ethanol (1.2 mL) was added 2N sodium hydroxide (1.09 mL, 2.19 mmol). The reaction was stirred overnight at 50° C. The reaction mixture was poured in citric acid solution and the resulting precipitate was collected, washed with water and dried to give crude 2-ethoxythieno[2,3-b]pyrazine-6-carboxylic acid (60 mg, 61%). (m/z)=225 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f18) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=1.CC1C=CC=C(C)C=1C1C=CC(C([N:38]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[CH2:42][N:41]3[C:49]([C:52]([NH:54][CH2:55][C:56]4[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=4)=[O:53])=[CH:50][CH:51]=[C:40]3[CH2:39]2)=O)=CC=1>N1C=CC=CC=1>[CH3:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]([N:38]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[CH2:42][N:41]3[C:49]([C:52]([NH:54][CH2:55][C:56]4[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=4)=[O:53])=[CH:50][CH:51]=[C:40]3[CH2:39]2)=[O:21])=[CH:17][CH:18]=1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: CSc1ccccc1-c1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CSc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reaction time: 1 h

Procedure:
To 20 mL of thionyl chloride was added 0.244 g (0.001 mol) of 2′-(methylthio)-1,1′-biphenyl-4-carboxylic acid of Step A. The solution was heated under reflux for 1 hour. The excess thionyl chloride was removed in a vacuo. To the residue was added 25 mL of dry pyridine and 0.318 g (0.001 mol) of N-(pyridyl-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 12. The reaction was allowed to stand at room temperature for 1 hour and the pyridine was removed in vacuo. The residue was collected and washed with water giving a tan solid (0.62 g), m.p. 172-175° C.
Reaction SMILES: C(Cl)(Cl)(Cl)[Cl:2].[C:6]([CH2:8][NH:9][C:10](=O)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)=[C:15]([O:25][CH3:26])[CH:14]=1)#[N:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Cl:2][C:6]1[N:7]=[C:10](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:15]([O:25][CH3:26])[CH:14]=2)[NH:9][CH:8]=1
Reactant: COc1cc(/C=C/C(=O)NCC#N)ccc1-n1cnc(C)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc(/C=C/c2nc(Cl)c[nH]2)ccc1-n1cnc(C)c1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
Carbon tetrachloride (0.326 mL) was added to a solution of (E)-N-cyanomethyl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (400 mg) and triphenylphosphine (888 mg) in acetonitrile (20 mL), and the reaction solution was stirred at 45° C. for 12 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate) to obtain 76 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([O:12][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:8]=[CH:7]2
Reactant: Nc1cccc2ccc(O)cc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2cccc(N)c2c1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 360.5 %

Procedure:
To a solution of 8-amino-2-naphthol (5.0 g, 31.4 mmol) in 200 mL of dimethylformamide was added imidazole (2.4 g, 34 mmol) and tert-butyldiphenylsilyl chloride (8.6 mL, 33 mmol). After 48 hours, water was added and the reaction was stirred overnight. The solution was partitioned between EtOAc and water, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to provide the titled product (45.0 g). The crude product was purified by silica gel chromatography (10% EtOAc/hexane) to provide the pure titled product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=S.IC>C(O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2ccccc2N)CC1
Solvent: CI
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Yield: 28 %

Procedure:
A mixture of 28 parts of ethyl 4-[[(2-aminophenyl)aminothioxomethyl]amino]-1-piperidinecarboxylate, 112 parts of iodomethane and 240 parts of ethanol was stirred and refluxed for 8 hours. The reaction mixture was evaporated and the residue was taken up in water. The whole was alkalized with ammonium hydroxide and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 7 parts (28%) of ethyl 4-(1H-benzimidazol-2-yl-amino)-1-piperidinecarboxylate (41).
Reaction SMILES: [CH:1]1([CH:4]([OH:20])[C:5]2([C:18]#[N:19])[CH2:10][CH2:9][CH:8]([S:11]([CH2:14][CH:15]3[CH2:17][CH2:16]3)(=[O:13])=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.O>N.CO.[Ni].CCO>[NH2:19][CH2:18][C:5]1([CH:4]([CH:1]2[CH2:2][CH2:3]2)[OH:20])[CH2:10][CH2:9][CH:8]([S:11]([CH2:14][CH:15]2[CH2:17][CH2:16]2)(=[O:12])=[O:13])[CH2:7][CH2:6]1
Reactant: N#CC1(C(O)C2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCO
Solvent: O
Product: NCC1(C(O)C2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Reaction time: 40 h

Procedure:
To 1-(cyclopropyl-hydroxy-methyl)-4-cyclopropylmethanesulfonyl-cyclohexanecarbonitrile (1.90 g; 6.39 mmol) in 2 M ammonia in methanol solution (20 ml) (nitrile did not dissolve) under a nitrogen atmosphere was added Raney Nickel (approx. 1 ml of 50% aqueous slurry). The resulting mixture was agitated under an atmosphere of hydrogen (50 psi) on a Parr apparatus for 40 hours. MS indicated that very little reduction of the nitrile had taken place. The mixture was filtered through a catalyst filter and the catalyst washed extensively with MeOH (300 ml, added in portions). The filtrate was evaporated in vacuo to give a greeny-white solid, which was transferred to the Parr flask as a suspension in EtOH (20 ml). Aqueous ammonia solution (1.5 ml) was added followed by Raney Nickel (approx. 1 ml of 50% aqueous slurry). The resulting mixture was agitated under an atmosphere of hydrogen (50 psi) on a Parr apparatus for 24 hours. MS indicated the presence of starting material (m/z=320, [M+Na]+), a small amount of product (m/z=302) and product with water eliminated (m/z=284). The mixture was filtered and the catalyst washed as before. The filtrate was evaporated in vacuo to give a greeny-white solid, which was triturated with MeOH and collected by filtration as a white solid (775 mg). NMR indicated that this was recovered starting material. The trituration filtrate was evaporated in vacuo and the residue was loaded in MeOH on to a SCX cartridge. The cartridge was washed with several column lengths of MeOH followed by 2M ammonia in methanol solution to elute the amine. The desired product was obtained as a green oil upon evaporation of the appropriate fractions (229 mg). m/z=302 (M+H+).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].[OH2:21].CCCCCC>C(O)(=O)C>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:21])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18]
Reactant: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C2
Reactant: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 30 %

Procedure:
1.10 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is refluxed for 2 hours in 10 ml. of acetic acid and 7.5 ml. of water containing 2.24 gm. of ceric ammonium nitrate. The solution is poured into water and extracted with ethyl acetate. The extract is washed, dried and evaporated and the residue chromatographed on silica gel, eluting with 40:60:1 ethyl acetate:hexane:acetic acid, so as to isolate a 30% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:11][C@@H:12]([CH3:15])[CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccncc1F
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](CO)Nc1cnccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of 3-fluoro-4-nitropyridine (0.400 mL, 4.05 mmol), (S)-2-aminopropane-1-ol (0.347 mL, 4.46 mmol) and potassium carbonate (0.616 g, 4.46 mmol) in DMF (5.0 mL) was stirred at 60° C. for 2 h. Water was added and the mixture stirred at room temperature to afford a precipitate. The mixture was filtered to afford an orange solid. The filtrate was extracted with dichloromethane. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtrate, and concentrated to afford an orange solid. The solids were combined and purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 0-10% methanol-dichloromethane) to afford (S)-2-(4-nitropyridin-3-ylamino)propane-1-ol (0.668 g, 84%) as an orange solid. MS (ESI, pos. ion) m/z 198.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:34]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:35])=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)N4CCCCC4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which has been described in example 16) with commercially available piperidine-1-carbonyl chloride as electrophile, the title compound was obtained as a white powder.