Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C(#N)C>[F:12][C:11]1[C:2]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:3]2[C:8]3=[C:9]([C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[N:6]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:5][CH2:4]2)[CH:10]=1
Reactant: O=C(O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2Cc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)c1cn2c3c(c(N4CCCC4)c(F)cc3c1=O)CCN2Cc1ccccc1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
50 mg of compound (182) obtained in Example 59, 26 mg of pyrrolidine and 10 mg of triethylamine were added to 3 ml of acetonitrile, and the solution was heated at 80° C. for 3 hours. The solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and washed with ethanol and ether in this order to obtain 33 mg of the subject compound (183).
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[C:23]([F:24])=[CH:22][C:21]([NH:25][C:26]([C:28]3([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])[CH2:30][CH2:29]3)=[O:27])=[C:20]([F:41])[CH:19]=2)[CH:14]=[CH:13][N:12]=1)=[O:9])C1C=CC=CC=1.Cl.[OH:43][CH:44]1[CH2:47][NH:46][CH2:45]1.C(=O)([O-])O.[Na+]>CCCCCC.C(N(CC)CC)C.CN(C)C=O>[F:41][C:20]1[CH:19]=[C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([N:46]3[CH2:47][CH:44]([OH:43])[CH2:45]3)=[O:9])[CH:16]=2)[C:23]([F:24])=[CH:22][C:21]=1[NH:25][C:26]([C:28]1([C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])[CH2:29][CH2:30]1)=[O:27]
Reactant: OC1CNC1
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)N1CC(O)C1
Reaction time: 0.17 h
Yield: 45.1 %

Procedure:
Triethylamine (0.100 ml) was added to a mixture of benzyl 1-({[4-({2-[(phenoxycarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]amino}carbonyl)cyclopropanecarboxylate (200 mg), 3-hydroxyazetidine hydrochloride (39.1 mg) and N,N-dimethylformamide (4.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 6 hours and 10 minutes. 3-Hydroxyazetidine hydrochloride (10.0 mg) and triethylamine (0.025 ml) were added at room temperature, and the mixture was stirred for 1 hour and 20 minutes. A saturated aqueous solution of sodium hydrogencarbonate (16 ml) and hexane (5 ml) were added to the mixture, and the precipitated solid was collected by filtration. The solid was washed with water (2 ml, three times), and dried under aeration. The resultant solid was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). The fractions containing the target compound was concentrated under reduced pressure to give the title compound (86.7 mg, 45%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:26]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27]1.CCN=C=NCCCN(C)C>>[O:26]1[CH2:30][CH2:29][CH:28]([C:31]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:32])[CH2:27]1
Reactant: O=C(O)C1CCOC1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)C4CCOC4)c3)c2c1
Yield: 15.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (250 mg, 0.74 mmol) with tetrahydro-3-furoic acid (0.10 g, 0.89 mmol) and EDCI (0.21 g, 1.11 mmol) furnished 40 mg (15% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (s, 1H), 7.7 (t, 1H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4 (s, 1H), 3.9 (m, 1H), 3.82-3.68 (m, 2H), 3.3-3.1 (m, 2H), 2.2-2.0 (m, 2H); ES-MS (m/z) 351 [M+H]+.
Reaction SMILES: O.N.N.[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)#[N:5]>[Co]>[NH2:5][CH2:4][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][CH2:11]1
Reactant: N#C[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Co]
Agent: N
Solvent: O
Product: NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
In 75 ml of ammonia water containing 0.033 mole of ammonia, 5 g. of trans-4-cyanocyclohexane-1-carboxylic acid was dissolved. To this solution, 0.5 g of Raney cobalt developed by a known method was added. The mixture was subjected to the same reaction and treatment as described in Example 1, and 4 g. of trans-4-aminomethylcyclohexane-1-carboxylic acid was obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH2:12])=[N:7]2.Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>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].O1CCOCC1>[CH3:2][C:3]1[N:4]=[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)=[N:7]2
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: Cc1nc(-c2ccccc2)n2nc(N)ncc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(-c2ccccc2)n2nc(Nc3ccc(S(N)(=O)=O)cc3)ncc12
Temperature: 160 °C
Yield: 3.9 %

Procedure:
To a mixture of 5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine hydrochloride (0.026 g, 0.10 mmol), 4-bromobenzenesulfonamide (0.026 g, 0.11 mmol), tris(dibenzylideneacetone)dipalladium (2.7 mg, 0.0030 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (5.6 mg, 0.0090 mmol) and sodium t-butoxide (0.025 g, 0.23 mmol) was added dioxane (1 mL). The solution was heated with microwave radiation to 160° C. for 15 minutes. After cooling to room temperature, the solution was filtered, and silica gel (1 g) was added, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (50:50) to ethyl acetate:hexanes (100:0) using a RediSep silica gel cartridge (4 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 4-[(5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-yl)amino]benzenesulfonamide (0.0015 g) as a yellow solid. MS m/z 381 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]2)=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1.[OH-].[K+]>CN(C)C=O>[Cl:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:17])[N:9]=[CH:10][C:11]=1[O:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1-c1ccc(Cl)cc1F
Yield: 68.4 %

Procedure:
In 30 m, of N,N-dimethylformamide were dissolved 1.0 g (3.4 m mol) of 2-(4-chloro-2-fluorophenyl)-4,5-dichloro-3(2H)-pyridazinone and 0.48 g (3.4 m mol) of p-chlorobenzyl alcohol, and thereto was added 0.22 g of powdery potassium hydroxide. Then, the procedures in Synthesis Example 2 were repeated to give 920 mg of the intended compound.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>N1C=CC=CC=1>[CH3:2][S:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:6][CH:5]=1
Reactant: CSc1ccc2c(c1)C(CCN)CCC2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CSc1ccc2c(c1)C(CCNC(C)=O)CCC2
Reaction time: 5 h

Procedure:
In a 50 ml round-bottomed flask, 0.0025 mol of the compound obtained in Step E is dissolved in 5 ml of pyridine. The solution is cooled with the aid of an ice bath and 5 ml of acetic anhydride are added dropwise. Stirring is carried out for 5 hours at ambient temperature. The reaction mixture is poured into aqueous 3M hydrochloric acid solution and is then extracted with ethyl ether. The organic phase is washed with aqueous 10% potassium carbonate solution and then with water, is dried over magnesium sulphate and is evaporated under reduced pressure. The residue obtained is recrystallised.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[C:13](Cl)(=[O:15])[CH3:14]>>[C:13]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:12])([CH3:1])[CH2:3][CH2:4]1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CC1(C)CCNc2ccccc21
Product: CC(=O)N1CCC(C)(C)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a stirred solution of 15 g (0.93 mol) of 4,4-dimethyl-1,2,3,4-tetrahydroquinoline in 50 ml of pryidine, at 0° C., was added, dropwise, 14.5 g (0.185 mol) of acetyl chloride over a 30 minute period. Stirring was continued at 0° C. for 1 hour, and then the reaction mixture was poured onto 200 g of ice. The resulting mixture was extracted with ether. The combined organic extracts were washed successively with 1N hydrochloric acid and saturated sodium bicarbonate and then they were dried using magnesium sulfate. Evaporation of the ether solution in vacuo afforded 18.8 g (99% yield) of the title compound as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([O:35]C)=[O:34])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=4)[CH2:21][CH2:22]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([OH:35])=[O:34])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)nc2c1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-phenyl-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (210.8 mg, 0.43 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (85.5 mg, 2.14 mmol, 5.00 equiv) in water (1.5 mL), which was added dropwise with stirring. The suiting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrochloric acid. The mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 78 mg (38%) of 2-phenyl-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)C.C[O-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1>C(OCC)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH2:24][C:4]([C:5]2[CH:6]=[CH:7][C:8]([Br:11])=[CH:9][CH:10]=2)=[O:12])=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
A mixture of ethyl-4-bromobenzoate and sodium methoxide in dry diethyl ether was stirred under an argon atmosphere After 30 min, a solution of 4′-bromoacetophenone in dry diethyl ether was then added drop-wise under stirring. The reaction mixture was stirred for 48 h under argon at room temperature. The muddy mixture was acidified and filtered under reduced pressure. The filtrate was washed with water until pH reaches about 7. The crude product was decolourized with activated charcoal and further purified by recrystallization from ethyl acetate. The white needle crystals obtained was dried in a vacuum oven at 40° C. for 24 h. Yield: 5.40 g (28.3%). M.P.: 193.2-195.4° C. The structure was confirmed by EI-MS, 1H NMR, 13C NMR, FT-IR, UV-Vis spectroscopy, and elemental analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25](Br)=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[NH:49][C:48]2[CH:50]=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:52]=[CH:53][C:47]=2[N:46]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C([O-])(=O)C.[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25]([C:51]5[CH:52]=[CH:53][C:47]6[N:46]=[C:45]([CH:41]7[CH2:42][CH2:43][CH2:44][N:40]7[C:38]([O:37][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:39])[NH:49][C:48]=6[CH:50]=5)=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(Br)ccc2-3)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(-c4ccc5nc(C6CCCN6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1
Temperature: 80 °C
Yield: 63.2 %

Procedure:
A mixture of 2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (246 mg, 0.497 mmol), 2-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1 eq., 206 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5%, 20 mg), tetrakis(triphenylphosphine)palladium (5%, 29 mg) and potassium acetate (2 eq., 137 mg) in 5 mL DME and 1 mL water was heated to 80° C. for 100 minutes. The reaction mixture was cooled and diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(5-{7-[2-(1-Boc-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-9,10-dihydro-phenanthren-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (220 mg, yield 63%). LCMS-ESI−: calc'd for C42H48N6O4: 700.87. Found: 701.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1Br.Cl[Si:11]([CH2:19][Cl:20])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([Li])CCC.C(OCC)(=O)C>O1CCCC1.CCCCCC>[Cl:20][CH2:19][Si:11]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](Cl)(CCl)c1ccccc1
Reactant: Clc1ccc(Br)c(Cl)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](CCl)(c1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of 13.6 g (0.060 mol) of 2,4-dichlorobromobenzene and 12.3 g (0.060 mol) of chloro(chloromethyl)methyl(phenyl)silane (prepared as in Example 14) in 85 ml of dry tetrahydrofuran was chilled to -60° under nitrogen and stirred while 38 ml (0.060 mol) of 1.6 molar n-butyllithium in hexane was added dropwise at a rate that held the mixture below -55°. The resulting red solution was allowed to warm to room temperature, treated with 5 ml of ethyl acetate to quench any unreacted organolithium reagent, and poured into 170 ml of water. The organic layer was separated, the aqueous phase was washed with 50 ml of hexanes, and the combined organic phases were washed three times with water and once with brine, dried over magnesium sulfate, and evaporated to leave 19.0 g of bright yellow oil. Distillation gave 8.6 g (45%) of the title compound as a colorless liquid: b.p. 125°-130° (0.05 mm); nD21 1.5978; ir (neat) 3080, 3060, 2960, 2930, 1570, 1540, 1460, 1430, 1365, 1260, 1120, 1100, 1040, 820, 745, 735, 705 cm-1 ; nmr (CDCl3) 0.8 (3H, s), 3.4 (2H, s), 7.2-7.9 (8H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21]([N:28]1[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:21]([N:28]1[CH2:32][CH2:31][C@@H:30]([NH:33][C:2]2[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CCOC(=O)/C=C/c1ccc(Cl)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)nc1
Temperature: 95 °C
Yield: 45.1 %

Procedure:
To a solution of ethyl (2E)-3-(6-chloro-3-pyridyl)acrylate (14.3 g) in dioxane (140 mL) was added palladium(II) acetate (1.52 g), 2′-(dicyclohexylphosphino)-N,N-dimethyl-2-diphenylamine (3.99 g), cesium carbonate (30.2 g), and (3R)-(−)-1-benzyl-3-aminopyrrolidine (13.1 g), and the mixture was heated at 95° C. for 2.5 days. The resulting mixture was poured into sat.NH4Cl aqueous solution and extracted with AcOEt. The organic layer was washed with sat. NH4Cl aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo and residual brown oil was purified by silica gel column chromatography eluted with AcOEt to give ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-3-pyridyl)acrylate as pale yellow oil (10.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=3)[CH2:33][CH2:32]1)=[O:20])=[N:5]2
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Product: COc1nc2cc(F)c(F)cc2nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 58 %

Procedure:
Ethyl N-(6,7-di fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-bromo phenyl)piperazine were reacted by the same way with the example 169 to obtain the titled compound (yield, 58%). 1H NMR (300 MHz, CDCl3) δ 3.30 (m, 4H), 3.76 (m, 4H), 4.15 (s, 3H), 6.85-6.87 (m, 1H), 7.02-7.03 (m, 2H), 7.06-7.07 (m, 1H), 7.13-7.16 (m, 1H), 7.30 (br s, 1H), 7.51-7.53 (m, 1H), 7.60 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: ClCCN1CCCCC1
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCCN2CCCCC2)cc1
Temperature: 100 °C
Yield: 78.6 %

Procedure:
4-bromophenol (5.2 g, 30 mmol), K2CO3 (10.4 g, 75 mmol) and anhydrous DMF (50 ml) were mixed together under Ar and heated at 100° C. 1-(2-chloroethyl)-piperidine hydrochloride (5.5 g, 30 mmol) was added in portions over 10 min and the reaction maintained at 100° C. for 1.5 h. After cooling the reaction, the solid was filtered off and the solvent removed under vacuum. The crude product was chromatographed on silica gel with methanol/ethyl acetate (3:1) to yield 6.7 g (78%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 1.44 (2H, m, NCH2CH2CH2), 1.59, (4H, m, NCH2CH2), 2.48 (4H, m, NCH2CH2), 2.73 (2H, t, NCH2CH2O), 4.03 (2H, t, NCH2CH2O), 6.76 (2H, d, ArH), 7.33 (2H, d, ArH).
Reaction SMILES: [N:1]([C@H:4]1[C@H:9]2[CH2:10][C@H:6]([C@@H:7]([C:18]([O:20][CH3:21])=[O:19])[N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C@H:4]1[C@H:9]2[CH2:10][C@H:6]([C@@H:7]([C:18]([O:20][CH3:21])=[O:19])[N:8]2[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:5]1
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](N=[N+]=[N-])C2)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1[C@@H]2C[C@@H](N)[C@@H](C2)N1C(=O)OC(C)(C)C
Yield: 99.9 %

Procedure:
To a solution of 2-tert-butyl 3-methyl (1R,3S,4S,6R)-6-azido-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 29-2 (170 mg) in methanol (4 mL), was added 10% palladium on carbon (30 mg). The mixture was stirred under 1 atm of hydrogen for 1.5 hrs at room temperature. The resulting mixture was filtered through celite and washed with methanol. The filtrate and washings were evaporated in vacuo to give the target compound (155 mg).
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][S:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[F:22][C:23]([F:34])([F:33])[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25]>O.C(OCC)(=O)C>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[S:9][CH2:8][CH2:7][NH:32][CH:29]1[CH2:28][CH2:27][N:26]([C:24](=[O:25])[C:23]([F:22])([F:33])[F:34])[CH2:31][CH2:30]1
Reactant: BrCCSc1cccs1
Reactant: NC1CCN(C(=O)C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N1CCC(NCCSc2cccs2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 0.14 g of 2-(2-bromoethylthio)thiophene, 95 mg of potassium carbonate and 0.16 g of 1-(trifluoroacetyl)piperidine-4-amine hydrochloride were added under cooling with ice, and the mixture was stirred at room temperature for 40 minutes. Thereto was added 95 mg of potassium carbonate under cooling with ice, and the mixture was stirred for 45 minutes, and stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added thereto. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=50:1] to obtain 62 mg of a yellow oily substance, N-(2-(2-thienylthio)ethyl)-1-(trifluoroacetyl)piperidine-4-amine.