Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:19](=[O:20])[CH2:18][CH2:17][CH:16]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:23][N:24]1[CH2:31][C@@H:30]2[C@@H:26]([NH:27][CH2:28][CH2:29]2)[CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[O-]S(C(F)(F)F)(=O)=O.[Ag+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:23][N:24]1[CH2:31][C@@H:30]2[C@@H:26]([N:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([N:14]5[C:19](=[O:20])[CH2:18][CH2:17][CH:16]=[N:15]5)=[CH:10][CH:9]=4)=[CH:4][CH:3]=3)[CH2:28][CH2:29]2)[CH2:25]1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Reactant: O=C1CCC=NN1c1ccc(-c2ccc(Br)cc2)cc1
Agent: [Ag+]
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CN1C[C@H]2CCN(c3ccc(-c4ccc(N5N=CCCC5=O)cc4)cc3)[C@H]2C1
Temperature: 100 °C
Yield: 15.6 %

Procedure:
A small pressure tube equipped with a magnetic stir bar was charged with 100 mg of 2-(4′-bromobiphenyl-4-yl)-4,5-dihydropyridazin-3(2H)-one, 58 mg of (3aR,6aR)-5-methylhexahydropyrrolo[3,4-b]pyrrole dihydrochloride, 350 mg of cesium carbonate, 15 mg of silver triflate, 4.2 mg of tris(dibenzylideneacetone)dipalladium, and 7.2 mg of 2-dicyclohexylphosphino-2′(N,N-dimethylamino)biphenyl and 2 ml of toluene. After sealing and purging with argon the tube was heated at 100° C. for 20 hours. Crude product was purified by flash chromatography (silica gel, gradient 2 to 10% methanol in dichloromethane), which yielded 17 mg of the title compound as a dark yellow oil. Mass spectroscopy gave (M+H)+ m/z 375.2, consistent with assigned structure.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1B(O)O)=[O:26]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:28]4[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=4[CH:25]=[O:26])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: Cc1ccc(C=O)c(B(O)O)c1
Product: Cc1ccc(C=O)c(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1
Yield: 19.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-formyl-5-methylphenylboronic acid (available from Frontier Scientific, Inc.; 66 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-formyl-5′-methyl-biphenyl-2-carboxylic acid (18 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 13.10 (br s, 1H), 9.72 (s, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.49 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.26 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.17 (s, 1H), 2.43 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:10][NH2:11])[N:3]=1
Reactant: NN
Reactant: Brc1ccc(Br)nc1
Solvent: O
Solvent: C1COCCO1
Product: NNc1cccc(Br)n1
Temperature: 80 °C

Procedure:
2,5-Dibromopyridine (2.0 g, 8.4 mmol) was dissolved in 1,4-dioxane (2 mL) and a solution of hydrazine hydrate (500 mg, 8.4 mmol) in 1,4-dioxane (15 mL) was added dropwise by syringe pump. The reaction was heated to 80° C. for 16 h. The solvents were removed in vaccuo and the residue was chromatographed on silica gel eluting with hexanes:EtOAc (1:1) to afford 2-bromo-6-hydrazinopyridine as a brown solid. MS (ESI) 187.0 (M++H), 189.0 (M+H+2).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([O:22][CH3:23])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[C:30]1([NH2:37])[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][O:22][C:19]([CH:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:3]=[C:2]([NH:36][C:31]2[C:30]([NH2:37])=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:10]=3)[CH2:14][CH2:15]1)([CH3:21])[CH3:20]
Reactant: Nc1ccccc1N
Reactant: COC(C)(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COC(C)(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Nc4ccccc4N)nc3n2C)CC1
Temperature: 95 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A mixture of 4-(2-chloro-8-((4-(2-methoxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-9H-purin-6-yl)morpholine (1.21 g, 2.96 mmol), benzene-1,2-diamine (520 mg, 4.8 mmol), palladium acetate (66 mg, 0.29 mmol), bist(tri-t-butylphosphine)palladium (150 mg, 0.29 mmol) and sodium t-butoxide (620 mg, 6.4 mmol) in toluene (30 mL) was stirred at 95° C. for 18 hours. The reaction mixture was then filtered through paper and then concentrated. The crude product was then purified by flash chromatography using a Biotage KP—NH column (0-10% gradient MeOH in DCM) to give N1-(8-((4-(2-methoxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-6-morpholino-9H-purin-2-yl)benzene-1,2-diamine (1.2 g, 84%). LCMS: M+H+=481.2.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[C:11][CH3:12])[CH2:8][CH2:7][C@H:6]1[C:13]#[N:14])=[O:4].[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(#N)C>[CH:15]1([NH:20][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]#[C:11][CH3:12])[CH2:8][CH2:7][C@H:6]2[C:13]#[N:14])=[O:4])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCC1
Reactant: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: CC#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.018 g, 0.086 mmol) in acetonitrile (1 mL) at room temperature was added cyclopentyl amine (0.017 mL, 0.17 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/97% dichloromethane to provide the titled compound. MS (ESI) m/z 260 (M+H)+; 1H NMR (DMSO) δ ppm 4.89 (m, 1H), 4.84 (m, 1H), 4.07-4.13 (m, 2H), 3.52 (m, 1H), 2.05-2.42 (m, 4H), 1.96 (m, 2H), 1.87 (d, 3H), 1.70 (m, 4H), 1.52 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[ClH:18].Cl.[NH2:20][CH2:21][CH2:22][O:23][NH2:24].N1C=CC=CC=1>C(O)C>[ClH:18].[ClH:18].[NH2:20][CH2:21][CH2:22][O:23][N:24]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C(CCCn1ccnc1)c1ccc(F)cc1
Reactant: NCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCCn1ccnc1)c1ccc(F)cc1
Reaction time: 4 h
Yield: 113.7 %

Procedure:
A mixture of 1-(4-fluorophenyl)-4-(1-(1H)-imidazolyl)-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.31 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for four hrs. The reaction mixture was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol to give 3.2 g (68%) of product, mp 237°-238° C. (dec).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:16][CH3:17])[C:14]=1[OH:15])[O:11][C:10](=[O:18])[CH:9]=[CH:8]2)=O.C(=O)([O-])[O-].[Na+].[Na+].[BH4-].[Na+]>CC(C)=O.S(=O)(=O)(O)O>[CH3:17][O:16][C:13]1[C:12]2[O:11][C:10]([CH:9]=[CH:8][C:7]=2[CH:6]=[C:5]2[CH:3]=[CH:2][O:15][C:14]=12)=[O:18]
Reactant: COc1c(O)c(C(=O)CCl)cc2ccc(=O)oc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: CC(C)=O
Product: COc1c2occc2cc2ccc(=O)oc12
Yield: 80 %

Procedure:
1.5 g of 6-(2′-chloroacetyl)-7-hydroxy-8-methoxycoumarin (0.006 mole) is cyclized by heating in 20 ml of acetone in the presence of 0.5 g sodium carbonate (0.007 mole), reducing using 1.4 mg of sodium borohydride (0.03 mole) and neutralizing in sulfuric acid medium. After vacuum filtration and evaporation and trituration in ethanol, 8-MOP is obtained (yield 80%). Lastly, the 8-MOP is recrystallized in ethanol.
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([OH:3])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.C(Cl)(Cl)Cl>[CH3:15][C:10]1[C:9]2[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:6]3[C:14]=2[C:13]([C:1](=[O:3])[CH2:4][CH2:5]3)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2c(C)cccc2n1CCC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3=O
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A mixture of ethyl 1-(2-carboxyethyl)-4-methyl-1H-indole-2-carboxylate (1.00 g, 3.63 mmol), thionyl chloride (1.35 g, 11.4 mmol) and chloroform (16 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and dichloromethane (80 ml) was added to the residue, followed by stirring at room temperature. Subsequently, aluminum chloride (2.02 g, 15.1 mmol) was added and the resulting mixture was stirred at room temperature for 1.5 hours and then heated under reflux for 0.5 hour. The reaction mixture was added to a mixture of water (300 ml) and 35% hydrochloric acid (1.5 ml), followed by extraction with chloroform (three times). The extract solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography graphy (eluent: ethyl acetate/n-hexane=3/97) to obtain ethyl 5,6-dihydro-9-methyl-6-oxo-4H-pyrrolo-[3,2,1-ij]quinoline-2-carboxylate (0.53 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[CH:9]1[C:19]2[CH:18]([C:20](Cl)=[O:21])[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=3[CH2:15][O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:20]([CH:18]2[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=3[CH2:15][O:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:19]2=3)=[O:21])=[N:6]1)[CH3:8]
Reactant: O=C(Cl)C1c2ccccc2COc2ccccc21
Reactant: CCn1nnc(N)n1
Product: CCn1nnc(NC(=O)C2c3ccccc3COc3ccccc32)n1

Procedure:
The title compound, yellow solid, m.p. 158-159° and MS: (neg. ions): m/e=334.1 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and 6,11 -dihydro-dibenzo[b,e]oxepine-11-carbonyl chloride.
Reaction SMILES: I[C:2]1[N:6]2[C:7]([O:17][CH3:18])=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[S:30][CH:31]=2)O1.C(=O)(O)[O-].[Na+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:18][O:17][C:7]1[N:6]2[C:2]([C:27]3[CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[S:30][CH:31]=3)=[CH:3][N:4]=[C:5]2[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=1
Reactant: COc1cc(-c2ccccc2)cc2ncc(I)n12
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnc3cc(-c4ccccc4)cc(OC)n23)cs1
Temperature: 90 °C

Procedure:
3-iodo-5-methoxy-7-phenylimidazo[1,2-a]pyridine (166 mg, 0.474 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (254 mg, 0.948 mmol), tetrakis(triphenylphosphine)palladium (0) (55.0 mg, 0.047 mmol), and sodium bicarbonate (150 mg, 1.42 mmol) were added to a dry flask. Dioxane (5 ml) and water (0.5 ml) were added and the reaction mixture was sparged with argon for 3 minutes. The reaction mixture was heated to 90° C. After 6 h the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, washed with water, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/dichloromethane gradient) to give methyl 4-(5-methoxy-7-phenylimidazo[1,2-a]pyridin-3-yl)thiophene-2-carboxylate. LRMS (ESI) calculated for C20H17N2O3S [M+H]+, 365.1 found 365.0.
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[NH:3][C:4]([N:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[OH:7])=[O:5].[OH-].[Na+].Cl[C:21](OCC)=[O:22]>O1CCOCC1>[Cl:15][C:10]1[CH:9]=[C:8]([N:6]2[C:4](=[O:5])[N:3]([C:2]([Cl:1])([Cl:16])[Cl:17])[C:21](=[O:22])[O:7]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: O=C(NC(Cl)(Cl)Cl)N(O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1on(-c2ccc(Cl)c(Cl)c2)c(=O)n1C(Cl)(Cl)Cl

Procedure:
1-Trichloromethyl-3-(3',4'-dichlorophenyl)-3-hydroxyurea (16.9 grams; 0.05 mol) is dissolved in dioxane (75 ml) and mixed with 2N aqueous sodium hydroxide (30 ml). Ethyl chloroformate (5.7 ml; 0.06 mol) is then added dropwise to the mixture with stirring, resulting in the formation of a precipitate. The precipitate is recovered by filtration, washed with water and dried to yield 2-(3', 4'-dichlorophenyl)-4-trichloromethyl-1,2,4-oxadiazolidine-3,5-dione.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[F:28][C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:8][C:9]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:10]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: Fc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 7.5 mL solution of tert-butyl 2-amino-4-phenylbenzoate 0.50 g were added 1-fluoro-4-iodobenzene 0.22 mL, cesium carbonate 1.3 g, palladium acetate 4.3 mg and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 12 mg at room temperature, and it was heated and refluxed for 4 hours. After the reaction mixture was cooled to room temperature, palladium acetate 4.3 mg and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 12 mg were added to it, and it was heated and refluxed for 13 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-fluoroanilino)-4-phenylbenzoate 0.44 g of brown oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][C@H:2]1[CH2:7][N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Brc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccccn2)CCN1C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 48 h
Yield: 46.9 %

Procedure:
To a solution of tert-butyl (2S)-2-methylpiperazine-1-carboxylate (8 g, 39.94 mmol) in DMSO (25 ml) was added 2-bromopyridine (6.594 g, 41.74 mmol), and DIEA (15.48 g, 119.78 mmol). After stirring 2 days at 120° C., the resulting solution was quenched by the addition of DCM (200 ml), washed with water (3×300 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified via silica gel chromatography (3% ethyl acetate in petroleum ether) to afford (S)-tert-butyl 2-methyl-4-(pyridin-2-yl)piperazine-1-carboxylate as a red oil (5.2 g, 47%).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=C[N:52]([C:54]([C:67]2[CH:72]=[CH:71]C=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.N1CCCC1>>[NH:9]1[CH:10]=[C:6]([C:2]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:40]([N:52]4[CH2:54][CH2:67][CH2:72][CH2:71]4)=[O:41])[CH:36]=3)[CH:31]=2)([OH:1])[CH:3]([CH3:4])[CH3:5])[N:7]=[CH:8]1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: C1CCNC1
Product: CC(C)C(O)(c1ccc2cc(C(=O)N3CCCC3)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.83 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with pyrrolidine (0.13 mL) in a similar manner as described in Example 24-(i) to give the titled compound (550 mg) as a colorless powder.
Reaction SMILES: [CH:1]1([C:7]2([CH2:22]OS(C)(=O)=O)[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][S-:29].[Na+].C(OCC)C>CN(C=O)C>[CH:1]1([C:7]2([CH2:22][S:29][CH3:28])[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(COS(C)(=O)=O)(C1CCCCC1)C2
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSCC1(C2CCCCC2)CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 3-cyclohexyl-3-{[(methylsulfonyl)oxy]methyl}-8-azabicyclo[3.2.1]octane-8-carboxylate (3-4) (1.01 g, 2.69 mmol) in 50 mL of DMF was added sodium thiomethoxide (0.943 g, 13.5 mmol). The mixture was stirred at 60° C. for 3 days. After cooling to room temperature, 200 mL of diethyl ether was added. The solid was filtered and the filtrates were washed with water three times. The organics were dried over anhydrous MgSO4, filtered, and concentrated to give (3-5) as a clear yellow oil.
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:13]1)=[O:11])=O)(C)(C)C.[ClH:27]>>[ClH:27].[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:10]([NH:9][NH2:8])=[O:11])[CH2:13]2)=[O:26])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Agent: Cl
Product: NNC(=O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
N′-[1-(4-Fluoro-benzoyl)-piperidine-3-carbonyl]-hydrazinecarboxylic acid tert-butyl ester was dissolved in 8 ml of 4N HCl (dioxane solution). The resulting reaction mixture was stirred at R.T. for 1 h and concentrated to afford 0.88 g (100%) of 1-(4-Fluoro-benzoyl)-piperidine-3-carboxylic acid hydrazide hydrochloride as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(N(CC)CC)C.[N:23]1[C:30]([Cl:31])=[N:29][C:27](Cl)=[N:26][C:24]=1[Cl:25]>CO>[Cl:25][C:24]1[N:23]=[C:30]([Cl:31])[N:29]=[C:27]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:26]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(Nc2nc(Cl)nc(Cl)n2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
A solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (1.0 g, 4.92 mmol) and triethylamine (0.75 ml, 5.42 mmol) in 15 ml of methanol was cooled in an ice-bath and cyanuric chloride (889 mg, 4.82 mmol) added portionwise. The mixture was stirred for 1 hour at 0° C. Filtration of the precipitate gave the title compound (1.115 g, 65%) as a slightly brownish solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([NH2:21])=[N:17][N+:18]([O-:20])=[O:19])[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N+:18]([N:17]=[C:16]([NH2:21])[NH:15][C:11]1[CH:10]=[C:9]([CH2:8][NH2:7])[CH:14]=[CH:13][CH:12]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)NCc1cccc(NC(N)=N[N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(NC(N)=N[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
A mixture of the compound (230 mg) obtained in Example 33, methylene chloride (3 ml) and trifluoroacetic acid (1.15 ml) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and 25% aqueous ammonia solution was added to the resulting residue, and the reaction mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; methanol) to give 117 mg of the titled compound (yield, 75%).