Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH3:6]>C(N(CC)CC)C.ClCCl>[C:5]([NH:8][N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([NH:2][CH3:1])=[O:4])(=[O:7])[CH3:6]
Reactant: CN=C=O
Reactant: CC(=O)NNc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N(NC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 5.7-g (0.1-mol) sample of methyl isocyanate was added dropwise to a solution of 15.0 g (0.1 mol) 1-acetyl-2-phenyl-hydrazine and 2 drops triethylamine in 200 ml dichloromethane. The resulting reaction mixture was stirred for 2 hours at about 25° C., refluxed for about 16 hours and evaporated under reduced pressure to give 21 g of crude 1-acetyl-2-phenyl-4-methyl semicarbazide, as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:16]=[CH:17][C:18]2[N:40]([CH:41]=1)[C:21]1[N:22]([C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)[C:23](=[O:30])[C:24]3[C:29]([C:20]=1[N:19]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3>CN(C=O)C>[N+:37]([C:34]1[CH:33]=[CH:32][C:31]([N:22]2[C:21]3[N:40]4[CH:41]=[C:15]([O:14][CH2:6][C:5]([O:4][CH2:3][CH3:2])=[O:7])[CH:16]=[CH:17][C:18]4=[N:19][C:20]=3[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:30])=[CH:36][CH:35]=1)([O-:39])=[O:38]
Reactant: O=c1c2ccccc2c2nc3ccc(O)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Yield: 94.9 %

Procedure:
Bromoethylacetate (1.2 equiv., 1.128 mmol, 0.188 g) and potassium carbonate (3.0 equiv., 2.820 mmol, 0.390 g) were added to a solution of 10 (1.0 equiv., 0.940 mmol, 0.350 g) in DMF (10 ml). The mixture was heated at reflux for 2 h. The reaction product was precipitated by the addition of water, filtered off and washed with isopropanol and isopropyl ether successively to give ethyl 2-[[5,6-dihydro-6-(4-nitrophenyl)-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-yl]oxy]-acetate (13) (0.409 g, yield=95%, purity (LC)=92%) as a light red powder.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:12]([CH:21]=1)[C:13]([CH2:15][CH2:16][C:17](OC)=[O:18])=O)(=[O:6])[CH3:5]>C(O)(=O)C>[C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:12]([C:13]2[CH2:15][CH2:16][C:17](=[O:18])[NH:2][N:3]=2)[CH:21]=1)(=[O:6])[CH3:5]
Reactant: NN
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1

Procedure:
Hydrazine hydrate (0.0785 ml, 0.00157 mole) was added to a stirred solution of methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate (0.21 g, 0.0005 mole) in glacial acetic acid (2 ml) and the solution was heated under reflux for 90 minutes. The residue after evaporation was treated with an excess of sodium bicarbonate solution and the solution evaporated to dryness under reduced pressure. The residue was extracted with dichloromethane and the dried extract evaporated to dryness. An aqueous solution of the residue was washed with two small portions of dichloromethane and then evaporated to an oily residue, which with ethyl acetate gave 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone
Reaction SMILES: [N:1]1[N:2]2[CH:10]=[CH:9][CH:8]=[C:3]2[C:4]([NH2:7])=[N:5][CH:6]=1.P(Cl)(Cl)(Cl)=O.[C:16](=O)(O)[O-:17].[Na+].C(OCC)(=O)C>CN(C=O)C>[NH2:7][C:4]1[C:3]2=[CH:8][CH:9]=[C:10]([CH:16]=[O:17])[N:2]2[N:1]=[CH:6][N:5]=1
Reactant: Nc1ncnn2cccc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Nc1ncnn2c(C=O)ccc12
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Pyrrolo[2,1-f][1,2,4]triazin-4-amine (20.5 g, 152 mmol) was dissolved in 150 mL DMF. Under ice cooling, phosphoryl chloride (31.3 mL, 336 mmol) was added dropwise at such a rate that the internal temperature did not rise above 30° C. The mixture was then heated for 2 days at 50° C. After cooling, another portion of phosphoryl chloride (14.2 mL, 152 mmol) was added, and stirring was continued for another 24 h at 50° C. After cooling, the reaction batch was slowly poured into a mixture of 2.0 L saturated aqueous sodium bicarbonate solution and 2.0 L ethyl acetate. Solid sodium bicarbonate was added until gas evolution stopped. The layers were separated, the aqueous layer was extracted with 0.5 L ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated. The residue was suspended in 100 mL diisopropyl ether, stirred at room temperature for 10 min and then filtered. The dried residue was stirred in 6 N hydrochloric acid (500 mL) for 1 h at 50° C. and then poured into an ice/water mixture (1000 mL). The mixture was carefully neutralized with solid sodium bicarbonate, stirred for 30 min at room temperature and then filtered again. The residue was washed with water and ligroin to yield 20.6 g (83% of th.) of white crystals which were used in the next step without further purification.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11](=[O:12])/[CH:16]=[CH:1]/[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:15]
Reactant: O=CCCc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/CCc1ccccc1

Procedure:
A solution of dihydrocinnamaldehyde (6.73 g, 50.2 mmol) and (carboethoxymethylene)triphenylphosphorane (17.84 g, 50.2 mmol) in toluene (250 mL) was refluxed for 18 h. It was then cooled to r.t and concentrated in vacuo. The residue was taken up in ether (250 mL) and the triphenylphosphine oxide was filtered off. The filtrate was concentrated to afford the intermediate trans-ethyl-(5-phenyl)-2-pentenoate (32.1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][OH:15].CC([O-])(C)C.[K+]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:15][CH2:14][CH2:13][O:12][CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: COCCO
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COCCOc1ccnc(Cl)c1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
A mixture of 2-chloro-4-nitropyridine (43.6 g, 275.0 mmol) and 2-methoxyethanol (325.6 ml, 425 mmol) was cooled to 0° C. Potassium 2-methylpropan-2-olate (35.73 g, 302.5 mmol) was added and the resulting mixture was stirred while warming to ambient temp over 2 hours. The reaction mixture was concentrated under reduced pressure followed by dilution with 500 ml of water. The resulting mixture was extracted twice with 250 ml of dichloromethane. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to produce the desired compound as a golden oil (50.2 g, 97% yield) MS APCI (+) m/z 188 and 189.9 (M+1 of each isotope) detected.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[C:11](C(O)=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCOC(C)=O.CCCCCC>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)Nc1c(C(=O)O)cnn1-c1ccc(Br)cc1
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: CC(C)S(=O)(=O)Nc1ccnn1-c1ccc(Br)cc1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
Dissolve 1-(4-Bromo-phenyl)-5-(propane-2-sulfonylamino)-1H-pyrazole-4-carboxylic acid (1.952 g, 5.03 mmol) in quinoline (2.79 mL) in a sealed tube. Add copper (0.16 g, 2.51 mmol) and immerse into a pre-heated (180° C.) oil bath and stir for 15 min. Cool to room temperature and remove the solvent under reduced pressure. Dilute with dichloromethane, wash with 1.0M HCl (2×50 mL), dry over sodium sulfate, filter, and concentrate to yield a residue. Subject to silica gel flash column chromatography (15-55% EtOAc/n-hexane) to yield the title compound (1.323 g, 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[C:14]([NH2:16])[CH:15]=1)[C:7]([NH:9][CH2:10][CH2:11][OH:12])=[O:8])([O-:3])=[O:2].[CH:17]([CH:20]1[O:25][CH2:24][CH:23]([C:26](Cl)=[O:27])[CH2:22][O:21]1)([CH3:19])[CH3:18].C(N(CC)CC)C>CC(N(C)C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[C:14]([NH:16][C:26]([CH:23]2[CH2:22][O:21][CH:20]([CH:17]([CH3:19])[CH3:18])[O:25][CH2:24]2)=[O:27])[CH:15]=1)[C:7]([NH:9][CH2:10][CH2:11][OH:12])=[O:8])([O-:3])=[O:2]
Reactant: CC(C)C1OCC(C(=O)Cl)CO1
Reactant: Nc1cc(C(=O)NCCO)cc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)C1OCC(C(=O)Nc2cc(C(=O)NCCO)cc([N+](=O)[O-])c2)CO1

Procedure:
40 g (0.177 mole) of 3-nitro-5-amino-N-(2-hydroxyethyl)benzamide are dissolved in 400 cm3 of DMAC. The addition of 74.9 g (0.389 mole) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride in the presence of triethylamine (54.6 cm3) gives rise to an exothermic reaction.
Reaction SMILES: C([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([CH2:28][S:29][CH:30]([F:32])[F:31])[CH2:11]1)(=O)C1C=CC=CC=1.C[O-].[Na+].CO.C(O)(=O)C>CO.O1CCCC1>[F:32][CH:30]([F:31])[S:29][CH2:28][C@@H:12]1[CH2:11][C@H:10]([SH:9])[CH2:14][N:13]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C(S[C@H]1C[C@@H](CSC(F)F)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CSC(F)F
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of (2S,4S)-4-benzoylthio-2-(difluoromethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.0 g) in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml) was added 28% sodium methoxide-methanol solution (0.52 ml) under an atmosphere of nitrogen at 2°-5° C. The mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added glacial acetic acid (1 ml) and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (50 ml). The solution was washed twice with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (80 g) eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V). The fractions containing the desired compound were collected and concentrated under reduced pressure to give (2S, 4S)-2-(difluoromethyl)thiomethyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.58 g).
Reaction SMILES: C(OCl)(C)(C)C.FC(F)(F)[C:9]1[CH:10]=[C:11]([CH:13]=[C:14](C(F)(F)F)[CH:15]=1)[NH2:12].[CH3:22][S:23][CH2:24][C:25](OCC)=[O:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:22][S:23][C:24]1[C:25](=[O:26])[N:12]=[C:11]2[C:10]=1[CH:9]=[CH:15][CH:14]=[CH:13]2
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CSC
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1=c2ccccc2=NC1=O
Temperature: -65 °C
Reaction time: 0.17 h
Yield: 103.5 %

Procedure:
Freshly prepared tBuOCl (2.2 g, 20 mmol) was added dropwise to a stirred cold (-65° C.) solution of 3,5-bis-(trifluoromethyl)aniline (4.58 g, 20 mmol) in anhydrous CH2Cl2 (25 mL). After 10 minutes, neat ethyl (methylthio)acetate (2.68 g, 20 mmol) was added and the mixture stirred at -65° C. for 1 hr. Triethylamine (2.68 g, 20 mmol) was added and then the mixture was allowed to warm to room temperature. The reaction mixture was quenched with water, the organic layer was separated and then rotary evaporated. The oily residue (6.35 g) was dissolved in hexanes and boiled for several hours and then allowed to cool. The precipitated beige solid was filtered and washed with hexanes to afford 3.67 g of pure (methylthio) indolone intermediate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Na].[H][H].Br[CH2:10][C:11]1[C:23]2[CH:22]=[CH:21][S:20][C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1>O1CCCC1>[S:20]1[CH:21]=[CH:22][C:23]2[C:11]([CH2:10][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:12][C:13]3[C:18]([C:19]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: [H][H]
Reactant: BrCc1cc2ccccc2c2sccc12
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: C1CCOC1
Product: c1ccc2c(c1)cc(Cn1ccnc1)c1ccsc12
Reaction time: 2 h

Procedure:
13.6 g (0.2 mole) of 1H-imidazole is dissolved in 200 ml of absolute tetrahydrofuran, and to the solution is added portionwise with stirring, in a nitrogen atmosphere, 2.3 g (0.1 gram atom) of sodium, with slight self-heating occurring accompanied by the evolution of hydrogen. The reaction mixture is heated at 45°-50° until the sodium has been completely absorbed. There is subsequently added dropwise at the same temperature, within 60 minutes, a solution of 27.7 g (0.1 mole) of 4-(bromomethyl)-naphtho[1,2-b]thiophene in 50 ml of tetrahydrofuran, and stirring is continued at 45°-50° for a further two hours. After cooling, the sodium bromide which has precipitated is filtered off, and the filtrate is concentrated in a water-jet vacuum. The residue is taken up in 400 ml of ether and 200 ml of water. The organic phase is separated in a separating funnel from the aqueous phase, washed repeatedly with water, dried over sodium sulphate and concentrated in a water-jet vacuum to leave as residue 1-[(naphtho[1,2-b]thiophen-4-yl)-methyl]-1H-imidazole, m.p. 109°-111°.
Reaction SMILES: Br.[NH2:2][CH2:3][C:4](=O)[C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)([CH3:7])[CH3:6].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.CCN(CC)CC>C1C=CC=CC=1>[Cl:15][C:10]1[CH:9]=[C:8]([C:5]([C:4]2[N:24]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)[C:25]([SH:26])=[N:2][CH:3]=2)([CH3:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CC(C)(C(=O)CN)c1ccc(Cl)c(Cl)c1
Reactant: Fc1ccc(N=C=S)cc1
Agent: Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(S)n1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A mixture of 1-amino-3-(3,4-dichlorophenyl)-3-methylbutan-2-one hydrobromide (900 mg, 2.75 mmol), 4-fluorophenyl isothiocyanate (464 mg, 3.029 mmol), and Et3N (570 uL, 4.13 mmol) in dry benzene (20 mL) was heated at reflux 6 h. The reaction mixture was concentrated under reduced pressure, diluted with acetic acid (9 mL) and then heated at reflux 5 h. After cooling to room temperature and concentrating, the crude product was purified by flash column chromatography to afford 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (370 mg). 1H NMR (400 MHz, CDCl3) δ 7.15 (m, 2H), 6.91 (m, 2H), 6.80 (m, 2H), 6.62 (m, 2H), 1.61 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C.Cl>O1CCCC1.O>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([N:22]1[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]1)=[O:8]
Reactant: OC1CCNCC1
Reactant: COc1cc2sc(C(=O)Cl)c(Cl)c2cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2sc(C(=O)N3CCC(O)CC3)c(Cl)c2cc1OC
Reaction time: 2 h

Procedure:
3-Chloro-5,6-dimethoxy-benzo[b]thiophene-2-carbonyl chloride (2.0 g) and 4-hydroxy-piperidine (1.60 g) was suspended in tetrahydrofuran (15 ml) and triethylamine (0.96 ml) was added and stirring continued at room temperature for two hours. Water was added, pH adjusted to 3 by HCl and the precipitate filtered.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:52]([N:59]1[CH2:64][CH2:63][O:62][CH:61]([C:65]([NH2:68])=[N:66]O)[CH2:60]1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C)C=O.O>[CH2:52]([N:59]1[CH2:64][CH2:63][O:62][CH:61]([C:65]2[N:68]=[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:9][N:66]=2)[CH2:60]1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: O=C(O)c1ccccc1
Reactant: NC(=NO)C1CN(Cc2ccccc2)CCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CN2CCOC(c3noc(-c4ccccc4)n3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a stirred solution of benzoic acid (2.30 g, 19.1 mmol) in N,N-dimethylformamide (20 ml) was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (6.15 g, 19.1 mmol), 1-hydroxybenzotriazole hydrate (518 mg, 3.83 mmol) and N,N-diisopropylethylamine (11.0 ml, 63.8 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. After addition of 4-benzyl-N′-hydroxymorpholine-2-carboxamidine (intermediate 26, 3.0 g, 12.8 mmol), the reaction mixture was stirred at room temperature for one hour, and then heated to 110° C. When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by addition of water and the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluent: 30% ethyl acetate in hexane) to afford 4-benzyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)morpholine (intermediate 27, 3.08 g, 75%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)[CH2:17][CH2:16]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].CC(C)([O-])C.[K+].[CH2:37]([O:39][CH2:40][CH2:41]CS([O-])(=O)=O)[CH3:38].CN(C=O)C>C(OC(=O)C)C.O>[CH3:1][O:2][C:3](=[O:30])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([C:21]3[N:22]([CH2:38][CH2:37][O:39][CH2:40][CH3:41])[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)[CH2:19][CH2:20]2)=[CH:9][CH:8]=1)([CH3:5])[CH3:6]
Reactant: COC(=O)C(C)(C)c1ccc(CCN2CCC(c3nc4ccccc4[nH]3)CC2)cc1
Reactant: CCOCCCS(=O)(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C(=O)OC)cc3)CC2)nc2ccccc21
Yield: 84.9 %

Procedure:
In a reaction vessel, 2-(4-{2-[4-(1H-benzoimidazol-2-yl)-piperidin-1-yl]-ethyl}-phenyl)-2-methyl-propionic acid methylester (0.5 g) prepared in the Example 13, potassium-t-butoxide (0.14 g), ethoxyethylmesylate (0.25 g) and DMF (20 mL) were introduced, and the mixture was reacted at 50° C. for 3 hours. Distilled water (50 mL) and ethylacetate (50 mL) were added thereto, and the mixture was stirred to separate a layer. Separated organic layer was washed with distilled water (50 mL), dehydrated, and condensed under reduced pressure to obtain 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid methylester (0.5 g, yield 85%, HPLC purity 98.5% or more).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:11])[CH3:10])=[C:3]([CH3:12])[C:2]=1[Cl:1]
Reactant: CC(=O)Nc1cccc(Cl)c1C
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c(Cl)c1C
Temperature: 0 °C
Reaction time: 17 h
Yield: 93.6 %

Procedure:
Dissolve N-(3-chloro-2-methyl-phenyl)-acetamide (120.0 g, 0.653 mol) in acetic acid and cool to 0° C. Add bromine (313.3 g, 1.96 mol) dropwise over 30 min via an addition funnel. Stir for 17 h while allowing the reaction to warm to room temperature. Pour the reaction into 1 L of ice, and filter. Rinse the filter cake with 4 L of water. The title product is isolated in 93.6% yield (160.6 g) as a white solid. MS: MS (ESI−): 262 (M−1)−. MS (ESI+): 263 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]=[O:19])=[CH:16][C:15]3[C:10](=[C:11]([O:20][CH3:21])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCCC1.[BH4-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18][OH:19])=[CH:16][C:15]3[C:10](=[C:11]([O:20][CH3:21])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc2cc(C=O)c(-c3cccc(F)c3)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2cc(CO)c(-c3cccc(F)c3)nc12
Temperature: 0 °C

Procedure:
To a solution of 2-(3-fluorophenyl)-8-methoxyquinoline-3-carbaldehyde (2.2967 g, 8.165 mmol) in tetrahydrofuran (40.83 mL, 8.165 mmol) at 0° C. was added sodium borohydride (0.4634 g, 12.25 mmol) and the mixture was stirred at 0° C. After 1 h of stirring at 0° C., the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL), and the organic layer was washed with brine (100 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (2-(3-fluorophenyl)-8-methoxyquinolin-3-yl)methanol as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (1 H, s), 7.46-7.60 (5 H, m), 7.29-7.36 (1 H, m), 7.19 (1 H, dd, J=7.4, 1.6 Hz), 5.50 (1 H, t, J=5.3 Hz), 4.61 (2 H, dd, J=5.5, 0.8 Hz), 3.96 (3 H, s); LC-MS (ESI) m/z 284.0 [M+H]+. The brown solid was carried on crude without purification for the next step.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([OH:13])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[CH2:26]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][S:33][CH2:32][NH:31]1)[CH3:27]>C(Cl)Cl>[CH2:26]([O:28][C:29](=[O:35])[C@@H:30]1[CH:34]([C:11](=[O:13])[CH2:10][CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[S:33][CH2:32][NH:31]1)[CH3:27]
Reactant: CCOC(=O)[C@@H]1CSCN1
Reactant: O=C(O)CC1CCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H]1NCSC1C(=O)CC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
1.4 g of 2-indanylacetic acid and 1.9 g of WSC.HCl were added to 15 ml of methylene chloride under ice-cooling. The mixture was stirred for 5 minutes at room temperature. After an addition of 1.3 g of L-thioproline ethyl ester dissolved in 10 ml of methylene chloride, the mixture was stirred for 5 hours. The reaction mixture was washed with water, diluted hydrochloric acid, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to produce 1.45 g of 3-(2-indanylacetyl)-L-thioproline ethyl ester as a colorless oil (yield: 57%).