Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[O:27][C:28]5[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc2ccccc2o1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5ccccc5o4)cc3CC[C@@H]12
Yield: 45.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chlorobenzoxazole (71 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 65 mg (45%) of the title compound as an amorphous foam. FDMS: m/e=378.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][CH2:18][CH2:17]2)[CH:3]=1.[NH3:27]>O1CCCC1.CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:27])=[O:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][CH2:18][CH2:17]2)[CH:3]=1
Reactant: COC(=O)c1ccc2nc(N3CCSc4ccccc4C3)cc(Cl)c2c1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1ccc2nc(N3CCSc4ccccc4C3)cc(Cl)c2c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a mixture of methyl 4-chloro-2-(2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate (400 mg, 1.04 mmol, prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-1) in tetrahydrofuran (5 mL) and a saturated solution of ammonia in methanol (30 mL) was heated with stirring for 16 hours at 120° C. in a sealed tube. The reaction mixture was concentrated in vacuo to afford 300 mg of the product (yield was 78%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][NH:8][C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[CH2:5]2.[C:15]1([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:21]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:22]=[CH:23][C:24]([C:25]([N:8]2[CH2:9][C:10]3[N:4]([CH:3]=[CH:2][CH:1]=3)[CH2:5][C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]2=3)=[O:26])=[CH:28][CH:29]=1
Reactant: c1cnc2c(c1)NCc1cccn1C2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccn2Cc2ncccc21

Procedure:
A stirred mixture of 9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene of Step D (0.54 mmol), 4-phenylbenzoylchloride (1.08 mmol) and triethylamine (1.08 mmol) in toluene was refluxed under nitrogen for 72 hours. The reaction was cooled and the solvent removed in vacuo. Chromatography of the residue over silica gel Merck-60 with a solvent gradient from 5 to 20% ethyl acetate in hexane provided the title compound as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])C.[Mg].ClCCl>CO>[CH3:1][O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=2)[NH:7]1)=[O:5]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [Mg]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1Cc2cc(OCc3ccccc3)ccc2N1
Temperature: 7.5 °C
Reaction time: 3 h

Procedure:
5-Benzyloxyindole-2-carboxylic acid ethylester (3 g, 10.1 mmol) and magnesium turnings (1.2 g, 50 mmol) were suspended in dried methanol (180 mL). This mixture was stirred at 5-10° C. under nitrogen for 3 hours, then poured into dichloromethane, and washed with saturated ammonium chloride solution. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated to leave a brown solid which was further purified by column chromatography (silica gel, dichloromethane) to afford a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](Cl)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][CH2:12][OH:13].CN1C(=O)CCC1.[H-].[Na+]>CCOC(C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([O:13][CH2:12][CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CCO
Reactant: N#Cc1cnc(N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOc1cc(N)ncc1C#N
Temperature: 70 °C

Procedure:
6-Amino-4-chloronicotinonitrile (intermediate 16, 40 mg, 0.260 mmol) and EtOH (0.076 ml, 1.302 mmol) were charged into a sealed vial. NMP (1.5 ml) was added to the mixture at room temperature followed by NaH (60% dispersion in mineral oil, 62.5 mg, 1.56 mmol). The mixture was then heated at 70° C. for 2.5 days. The reaction mixture was diluted in EtOAc and washed with water (2×) and brine. The org. layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a beige solid. (UPLC-MS 1) tR 0.50 min; ESI-MS 164.0 [M+H]+.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:40])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][C:26]([N:28]2[CH2:32][CH2:31][CH2:30][C@@H:29]2[C:33]([O:35]C(C)(C)C)=[O:34])=[O:27])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:33]([C@H:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26](=[O:27])[CH2:25][O:24][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([O:22][CH3:23])[CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:40])([OH:35])=[O:34]
Reactant: COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A solution of 370 mg (0.66 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 287 mg (97%) of the title compound as a white powder.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>N1C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:21][C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1I
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(OS(=O)(=O)c2ccccc2I)cc1
Yield: 70.6 %

Procedure:
A solution of 2-iodobenzenesulphonyl chloride (obtained as described in J. Org. Chem. 1977, 42, 3265) (8.28 g) and 4-nitrophenol (3.81 g) in pyridine (50 ml) was heated at 100° C. for 3 hours. Volatile material was removed by evaporation and water (200 ml) was added to the residue. The mixture was extracted with ethyl acetate (2×200 ml) and the combined extracts were washed with 1M hydrochloric acid (2×200 ml) and dried (MgSO4). Solvent was removed by evaporation and the residue was recrystallised from a mixture of ethyl acetate and hexane to give 4-nitrophenyl 2-iodobenzenesulphonate (7.83 g), m.p. 131-133° C.; mass spectrum (+ve CI): 405 (M+).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([OH:19])=O)=[C:15]([CH3:20])[N:14]=[C:13]3[CH2:21][CH2:22][CH3:23])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32].[CH3:38][NH2:39]>>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][N:12]3[C:16]([C:17]([NH:39][CH3:38])=[O:19])=[C:15]([CH3:20])[N:14]=[C:13]3[CH2:21][CH2:22][CH3:23])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32]
Reactant: CN
Reactant: CCCc1nc(C)c(C(=O)O)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Product: CCCc1nc(C)c(C(=O)NC)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1

Procedure:
From the product of Example 91 and methylamine according to the method of Example 103.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[OH:17][NH3+:18]>C(O)C>[C:1]1([C:7](=[N:18][OH:17])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH3+]O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCO
Product: ON=C(Cc1ccccc1)c1ccccc1
Yield: 24.1 %

Procedure:
A mixture of 1,2-diphenylethanone (19.6 g, 100 mmol) and hydroxyl ammonium chloride (13.9 g, 200 mmol) in absolute ethanol (200 ml) was heated at reflux for 4 h. The solvent was evaporated in vacuo and the residue extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (2×50 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue left for crystallisation. The crystallised product was suspended in n-heptane/diethylether 20/1 and the precipitate collected to give 5.1 g of 1,2-diphenylethanone oxime.
Reaction SMILES: [C:1]1([SH+]C2C=CC=CC=2)C=CC=C[CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[CH:19]=[O:20]>O1CCCC1>[CH3:25][O:24][C:22]1[CH:21]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[CH:23]=1)[CH:19]1[O:20][CH:1]1[CH3:2]
Reactant: c1ccc([SH+]c2ccccc2)cc1
Reactant: COc1cc(C=O)cc(OC)c1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C2OC2C)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a -78° C. solution of diphenylsulfonium ethylide (1.0 mole) in tetrahydrofuran (one liter) is slowly added 3,5-dimethoxybenzaldehyde (1.0 mole). The reaction mixture is stirred at -78° C. for 3 hours and then allowed to warm to room temperature. It is then added to ether-water and the ether phase separated. The ether phase is washed with water, dried (MgSO4) and evaporated. Fractional distillation of the residue gives the title product.
Reaction SMILES: [OH-].[K+].Cl[CH2:4][C:5]1[O:6][CH:7]=[CH:8][CH:9]=1.[F:10][C:11]1[C:12](=[O:45])[NH:13][C:14](=[O:44])[N:15]([CH:43]=1)[C@@H:16]1[O:42][C@H:20]([CH2:21][O:22]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:18]([OH:19])[CH2:17]1>O1CCOCC1>[F:10][C:11]1[C:12](=[O:45])[NH:13][C:14](=[O:44])[N:15]([CH:43]=1)[C@@H:16]1[O:42][C@H:20]([CH2:21][OH:22])[C@@H:18]([O:19][CH2:4][C:5]2[O:6][CH:7]=[CH:8][CH:9]=2)[CH2:17]1
Reactant: ClCc1ccco1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccco3)[C@@H](CO)O2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A 0.35 g quantity of particulate potassium hydroxide and 0.29 g of 2-chloromethylfuran were added to a solution of 1.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 30 ml of dioxane. The mixture was stirred at 80° C. for 2 hours. The solvent was distilled off and the residue was dissolved in 30 ml of ethyl acetate. The solution was washed with water and dried. The residue was dissolved in 15 ml of 80% acetic acid and the solution was left to stand at 80° C. for 2 hours. The solvent was distilled off and the residue was dissolved in ml of ethyl acetate. The solution was washed with water and dried. The residue was treated with chloroform, the insolubles were filtered and recrystallized from ethanol, giving 0.37 g of 2'-deoxy-5-fluoro-3'-O-(2-furanylmethyl)uridine in a yield of 55%.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].O.[S:17](=[O:21])(=[O:20])([OH:19])[OH:18]>CO>[S:17]([OH:21])([OH:20])(=[O:19])=[O:18].[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: NNCCO
Reactant: COC(OC)C(C#N)=NO
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Nc1c(N=O)cnn1CCO
Temperature: 66.5 °C
Yield: 88.1 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 1.47 g (10.0 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 98.1% by weight synthesized in the same manner as in Example 1, 0.84 g (10.5 mmol) of 2-hydroxyethylhydrazine with a purity of 95% by weight, 0.54 ml of water, 10 ml of methanol and 1.18 g (12.0 mmol) of conc. sulfuric acid, and the mixture was reacted under reflux (66 to 67° C.) for 3 hours. After completion of the reaction, when the reaction mixture was analyzed by high performance liquid chromatography (absolute calibration curve method), it was found that 2.24 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole hydrogen sulfate (Reaction yield: 88.2%) had been formed.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][N:27]3[CH:35]=[CH:36][CH:37]=[C:26]3[CH2:25]2)=[O:23])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:35]1[N:27]2[C:26]([CH2:25][N:24]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][CH3:8])=[CH:17][CH:18]=3)=[O:23])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28]2)=[CH:37][CH:36]=1)=[O:4]
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Trichloroacetyl chloride (2.63 mL, 23.6 mmol) was added dropwise over five minutes to a solution of (2′-methoxy-biphenyl-4-yl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (3.0 g, 7.60 mmol) and N,N-diisopropylethyl amine (2.65 mL, 15.2 mmol) in dichloromethane (60 mL). The reaction was stirred under nitrogen at room temperature overnight and then quenched with water. The organic layer was washed with 0.1N hydrochloric acid and water, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was purified by flash chromatography over silica gel Merck-60 using a 0-5% gradient of ethyl acetate in dichloromethane to give the title compound (2.34 g) as a yellow foam.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)[CH2:3][CH2:2]1.[Br:9]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)Cl>[Br:9][C:8]1[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=[N:6][CH:7]=1
Reactant: c1cn(C2CC2)cn1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: ClCCl
Product: Brc1cncn1C1CC1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
Cyclopropyl-1H-imidazole (1.18 g, 10.9 mmol) was dissolved in methylene chloride (0.1 M), cooled to 5-10° C., and 1,3-dibromo-5,5-dimethylhydantoin (1.59 g, 5.57 mmol) was added. The temperature was maintained between 5-10° C. and the reaction was stirred for 2 hours. Solvent was removed from the reaction mixture under reduced pressure, and the residue was purified by column chromatography (eluting with 1%-7% methanol in methylene chloride, 5% methanol/methylene chloride) to afford 620 mg (37% yield) of 5-bromo-1-cyclopropyl-1H-imidazole.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1)(=O)=O.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>>[CH2:17]([O:16][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCCCc1cccc(OCc2ccccc2)c1
Product: c1ccc(COc2cccc(CCCCn3ccnc3)c2)cc1
Yield: 61 %

Procedure:
In substantially the same manner as in Reference Example 88, 4-(3-benzyloxyphenyl)butyl methanesulfonate was allowed to react with imidazole to give 1-[4-(3-benzyloxyphenyl)butyl]imidazole. The yield was 61%. Oily substance.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[NH2:1][C:2]1[N:3]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1nc2cc(Cl)c(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
2-Amino-5,6-dichlorobenzimidazole (4) (1 g, 4.95 mmole) was dissolved in acetonitrile (200 ml) and NaOH (198 mg, 4.95 mmole) was added. After stirring for 1 hr at room temperature, benzyl bromide (0.589 ml, 4.95 mmole) was added and the mixture was allowed to stir overnight. The mixture was concentrated under reduced pressure and purified on a silica gel column (3.5×5 cm) using 5% MeOH/CHCl3 to give 1.23 g (85%) of 2-amino-1-benzyl-5,6-dichlorobenzimidazole (182). The compound was then recrystallized from EtOH/H2O to give a white powder. 1H NMR (DMSO-d6): d 5.28 ppm (s, 2H), 6.95 (s, 2H), 7.16 (d, 2H), 7.25 (d, 1H), 7.31 (m, 4H). 13C NMR (DMSO-d6); d 44.74 ppm, 109.15, 115.37, 119.62, 122.66, 125.82, 127.37, 128.55, 134.10, 136.46, 143.13, 156.91. MS (Electron Impact): m/e 291, 200, 158, 91, 65. MP: 245°-246° C. Elemental Analysis: (C14H11Cl2N3'): Calculated: C, 57.55; H, 3.79; N, 14.58. Found: C, 57.66; H, 3.83; N, 13.98. UV Imax nm (e×104): (pH 7) 230 (0.761), 260 (0.324), 302 (0.452); (pH 1) 238 (0.306), 294 (0.383), 299 (0.359); (pH 11) 229 (0.869), 257 (0.316) 301 (0.443).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][C:14]=2[N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>>[N:20]1([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]3[S:11][CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[CH:18][CH:17]=[CH:16]3)[N:3]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: Clc1cncc(OCc2sccc2-n2cccc2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccn(-c2ccsc2COc2cncc(N3CCNCC3)n2)c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from the product obtained in step 1 above (1.78 g, 6.10 mmol), piperazine (1.58 g, 18.3 mmol) and K2CO3 (0.86 g, 6.2 mmol). The yield of the title compound was 1.43 g (69%) and was obtained as a beige solid. HRMS m/z calcd for C17H19N5OS (M)+ 341.1310, found 341.1301.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:18]1[CH:19]=[C:20]([CH3:26])[C:21]([Cl:25])=[C:22]([CH3:24])[CH:23]=1>>[Cl:25][C:21]1[C:22]([CH3:24])=[CH:23][C:18]([C:6]2[CH:7]=[C:2]([CH3:1])[N:3]=[N:4][CH:5]=2)=[CH:19][C:20]=1[CH3:26]
Reactant: Cc1cc(Br)cc(C)c1Cl
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnn1
Product: Cc1cc(-c2cc(C)c(Cl)c(C)c2)cnn1

Procedure:
The title compound is prepared from 3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridazine and 5-bromo-2-chloro-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 11): tR=0.91 min; Mass spectrum (ESI+): m/z=233/235 (Cl) [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:26]=[C:25]([CH:32]=O)[CH:24]=2)=[CH:19][CH:18]=1>>[C:28]([N:27]1[C:23]([C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=2)=[CH:24][C:25]([CH2:32][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[N:26]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Product: CC(C)(C)n1nc(CNCCN2CCN(c3ccccc3)CC2)cc1-c1ccc(Cl)cc1
Yield: 69.1 %

Procedure:
Compound 11 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: N1C=CN=C1.[CH3:6][O:7][C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([OH:17])[CH:11]=1.ClCCl.[C:22]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[CH3:6][O:7][C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([O:17][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:11]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)Cc1cc(O)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
Imidazole (230 mg, 3.38 mmol) was added to a solution of 3,5-dihydroxyphenylacetic acid methyl ester (530 mg, 2.91 mmol) in tetrahydrofuran (6.7 mL)-dichloromethane (6.7 mL) at room temperature. t-Butylchlorodiphenylsilane (0.75 mL, 2.9 mmol) was added under cooling with ice. Then, the ice bath was removed, and the mixture was stirred at room temperature for three hours. The reaction mixture was diluted with diethyl ether. 50% saturated aqueous ammonium chloride was added, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (470 mg, 33%).
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][N:11]2[C:14](=[O:16])[CH3:15])=[CH:7][CH:6]=1.CCOCC>CN1C(=O)CCC1>[C:14]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:1]#[N:2])[CH:13]=2)[C:9]([CH3:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)(=[O:16])[CH3:15]
Reactant: N#C[Cu]
Reactant: CC(=O)N1CC(C)(c2ccccc2)c2ccc(Br)cc21
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CC(=O)N1CC(C)(c2ccccc2)c2ccc(C#N)cc21
Temperature: 175 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
CuCN (179 mg, 2 mmol) was added to a solution of 1-(6-bromo-3-methyl-3-phenyl-2,3-dihydro-indol-1-yl)-ethanone (330 mg, 1 mmol) in NMP (5 mL). The reaction was stirred at 175° C. for 16 h. Et2O was added to the mixture and the solid was filtered off. The filtrate was washed with 2 M aqueous HCl and saturated aqueous NaHCO3. The solvent was removed in vacuo to give the title compound (250 mg) as a brown solid. MS: [M+H]+=277.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:10]2[C:11]3[C:16]([NH:17][C:18](=[O:19])[C:9]2=[CH:8][N:7]=1)=[CH:15][C:14]([C:20]([OH:22])=O)=[CH:13][CH:12]=3)[CH2:4][CH3:5])[CH3:2].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.N.O>CN(C)C=O>[CH2:4]([CH:3]([C:6]1[N:10]2[C:11]3[C:16]([NH:17][C:18](=[O:19])[C:9]2=[CH:8][N:7]=1)=[CH:15][C:14]([C:20]([NH2:25])=[O:22])=[CH:13][CH:12]=3)[CH2:1][CH3:2])[CH3:5]
Reactant: CCC(CC)c1ncc2c(=O)[nH]c3cc(C(=O)O)ccc3n12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)c1ncc2c(=O)[nH]c3cc(C(N)=O)ccc3n12

Procedure:
1-(1-Ethylpropyl)-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylic acid as synthesized in above Example 13, 300 mg was dissolved in 10 mL of N,N-dimethylformamide, and to the solution 1,1′-carbonyldiimidazole 275 mg was added little by little in nitrogen atmosphere. After another hour's stirring, ammonia gas was injected into the reaction liquid for 30 minutes, followed by an hour's stirring. Water 30 mL was added and the formed precipitate was recovered by filtration. The crystals were washed with water and dried by heating under reduced pressure to provide 250 mg of the title compound.