Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH3:17])[S:4]([C:7]1[CH:8]=[N:9][C:10]([Sn](C)(C)C)=[CH:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2].[NH2:18][C:19]1[C:24]([C:25]2[S:34][C:28]3[C:29](=[O:33])[NH:30][CH2:31][CH2:32][C:27]=3[CH:26]=2)=[CH:23][C:22](Br)=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([N:3]([CH2:1][CH3:2])[CH3:17])(=[O:6])=[O:5])=[CH:8][N:9]=2)=[CH:23][C:24]=1[C:25]1[S:34][C:28]2[C:29](=[O:33])[NH:30][CH2:31][CH2:32][C:27]=2[CH:26]=1
Reactant: CCN(C)S(=O)(=O)c1ccc([Sn](C)(C)C)nc1
Reactant: Nc1ncc(Br)cc1-c1cc2c(s1)C(=O)NCC2
Product: CCN(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cc4c(s3)C(=O)NCC4)c2)nc1
Yield: 51.7 %

Procedure:
The final step of general method D was applied to N-ethyl-N-methyl-6-(trimethylstannyl)pyridine-3-sulfonamide (233 mg, 0.6 mmol) and 2-(2-amino-5-bromopyridin-3-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (194 mg, 0.6 mmol) to give 6′-amino-N-ethyl-N-methyl-5′-(7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-[2,3′-bipyridine]-5-sulfonamide as a yellow solid (140 mg, 0.31 mmol, 53% yield) after purification by reverse phase preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (d, J=2.0 Hz, 1H), 8.85 (d, J=2.3 Hz, 1H), 8.26 (d, J=2.3 Hz, 1H), 8.10-8.19 (m, 2H), 7.73 (br. s, 1H), 7.33 (s, 1H), 6.62 (s, 2H), 3.44-3.50 (m, 2H), 3.09 (s, 2H), 2.86 (t, J=1.0 Hz, 1H), 2.72 (s, 3H), 1.01-1.09 (m, 3H); MS (EI) m/z=444.5 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7]=1[N+:8]([O-:10])=[O:9].[OH:15]O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7]=1[N+:8]([O-:10])=[O:9])=[O:15]
Reactant: OO
Reactant: CCCCc1c[nH]c(SC)c1[N+](=O)[O-]
Solvent: CC(=O)O
Product: CCCCc1c[nH]c(S(C)=O)c1[N+](=O)[O-]
Yield: 40.2 %

Procedure:
2-Methylthio-3-nitro-4-n-butylpyrrole (3.7 g) was suspended in glacial acetic acid (50 ml) and 30% hydrogen peroxide (1.62 g) was added. The mixture was heated to 80° for 7 hours, and it was then evaporated to a brown oil. The crude product was purified by column chromatography using silica gel, eluted with benzene and chloroform, to give an oil which crystallized on standing. This was recrystallised from 2-propanol to give 2-methylsulphinyl-3-nitro-4-n-butylpyrrole (1.6 g), m.p. 133°-4°.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[F:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][CH:2]([CH2:3][OH:20])[CH2:1][C:4]=2[CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc(F)ccc1O
Solvent: ClC(Cl)Cl
Product: OCC1Cc2cc(F)ccc2O1
Temperature: 60 °C
Yield: 79 %

Procedure:
Into a 500 ml round-bottomed flask that contained a solution of 2-allyl-4-fluoro-phenol (10.0 g, 65.7 mmol) in 300 ml of chloroform was added m-CPBA (11 g, 64 mmol, ˜0.96 eq). The mixture was heated at 60° C. (oil bath) for 6 hours. The contents were cooled to room temperature and the solids were filtered off and washed with 3×20 ml of chloroform The filtrate was washed with saturated aqueous NaHCO3 (2×100 mL) to remove traces of m-CPBA, dried over magnesium sulfate, filtered, and then concentrated under vacuum. The crude residue was then chromatographed on silica gel using petroleum ether/ethyl acetate to elute. The product-containing fractions were combined and concentrated under vacuum to afford 8.5 grams of the alcohol as a yellow oil (77%); 1H NMR (300 MHz, CDCl3): δ 6.91-6.88 (m, 1H), 6.84-6.78 (m, 1H), 6.72-6.68 (m, 1H), 4.99-4.90 (m, 1H), 3.90-3.85 (dd, J=3.3 Hz, 12 Hz, 1H), 3.78-3.70 (dd, J=3.3 Hz, 12 Hz, 1H), 3.29-3.21 (dd, J=9.3 Hz, 15.9 Hz, 1H), 3.01-3.08 (dd, J=7.5 Hz, 15.9 Hz, 1H).
Reaction SMILES: [C:1]1([C:11](C2N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2)([OH:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>>[C:1]1([CH:11]([OH:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1nccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(O)c1nccc2ccccc12

Procedure:
1-Isoquinolin-1-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate H3) was subjected to TFA: trifluoroacetic acid, Pd/C under hydrogen similar to the catalytic reduction procedure of Method D to remove the trityl group and produced 1-1H-imidazol-4-yl)-isoquinolin-1-yl ethanol (Intermediate H4).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9]C23C=CC=CC2C(NC3=O)=O)[C:4](=[O:21])[C:3]1=[O:22].O.[NH2:24]N.O.[ClH:27]>C(O)C>[ClH:27].[NH2:24][CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:22])[C:4]1=[O:21]
Reactant: NN
Reactant: CN1CCN(CCC23C=CC=CC2C(=O)NC3=O)C(=O)C1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1CCN(CCN)C(=O)C1=O
Temperature: 40 °C
Yield: 85 %

Procedure:
To a solution of 3.60 g (11.95 mmol) of 2-[2-(4-methyl-2,3-dioxo-1-piperazinyl)ethyl]phthalimide in 30 mL of ethanol was added 695 μL (14.34 mmol) of hydrazine monohydrate and the mixture was stirred at 40° C. for over night. The reaction mixture was cooled to room temperature, then, 25 mL of water and 6 mL of 6N—HCl were added to this mixture and the mixture was stirred for 5 hours at room temperature. After removed off the insoluble substances by filtration, the filtrate was concentrated and the residue was re-crystallized by 2% water-ethanol solution to give 2.12 g (85%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[C:23]([CH2:24][N:25]3C(=O)C4=CC=CC=C4C3=O)=[N:22][N:21]=[C:20]2[CH2:36][N:37]2C(=O)C3=CC=CC=C3C2=O)=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=O)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:19]3[C:20]([CH2:36][NH2:37])=[N:21][N:22]=[C:23]3[CH2:24][N:25]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:8]=2[CH:18]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 22, 5-nitro-2'-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-nitro-1-(aminomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]enzodiazepine.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([N:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH:17]=[O:18])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:8]([N:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[C:17]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: Cl[Mg]C1CCCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C1CCCC1

Procedure:
22.5 ml (45 mmol) 2 M cyclopentylmagnesium chloride (diethyl ether) and 3.0 g (15 mmol) BOC-L-prolinal were allowed to react at −80° C. for 30 min according to procedure F. Yield of crude product 3.37 g. The product was purified with a silica column using 0–4% methanol in dichloromethane as eluent. Yield 3.10 g (11.5 mmol, 77%). The product was oxidized to the corresponding ketone according to procedure G. Yield of crude product 3.12 g. The product was purified with a silica column using 16% ethyl acetate in petroleum ether as eluent. Yield 1.3 g (4.9 mmol, 42%).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].Cl>C(OCC)(=O)C>[CH3:1][C:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)O
Reaction time: 4 h
Yield: 90.9 %

Procedure:
6.68 g (0.0305 mol) of methyl 2-methyl-6-trifluoromethyinicotinate (prepared as described in Heterocycles, 46, 129 (1997)) are dissolved in 250 ml of methanovwater (3:1 mixture), and 1.92 g (0.046 mol) of lithium hydroxide hydrate are added a little at a time at 22° C. After 4 hours at 22° C, the reaction mixture is poured into ethyl acetate and 2N hydrochloric acid, the organic phase is washed three times with water, dried with sodium sulfate and evaporated and the residue is triturated with a little hexane. Filtration gives 5.69 g (90% of theory) of the expected 2-methyl-6-trifluoromethyinicotinic acid of m.p. 147-149° C. The 2-methyl6trifluoromethyinicotinic acid obtained (2.0 g, 0.0098 mol) is dissolved in 20 ml of oxalyl chloride. Three drops of dimethylformamide are added, and the mixture is heated under reflux for 1 hour. The mixture is then concentrated using a rotary evaporator, and the residue (2-methyl-6-trifluoromethyinicotinoyl chloride) is taken up in 30 ml of methylene chloride. At 0° C., 2.7 ml (0.0196 mol) of triethylamine and 0.12 g (0.00098 mol) of dimethylaminopyridine are added. 1.49 g (0.0108 mol) of bicyclo[3.2.1]octane-2,4-dione, dissolved in 20 ml of methylene chloride, are then added dropwise. After 3 hours at 22° C., the reaction mixture is extracted with 2 N hydrochloric acid. The methylene chloride phase is separated off, washed with water and subsequently extracted with 10% aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated. This gives 3.18 g (100% of theory) of 4-oxobicyclo[3.2.1]oct-2-en-2-yl 2-methyl-6-trifluoromethyinicotinate as an oil, which can be processed further without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:28]=[C:29]([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[S:37])=[O:34]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (80 mg, yield 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](OCC)=[O:16])[CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1
Reactant: CCOC(=O)c1cccc(-c2ccc(C)cc2C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(CO)c2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of ethyl 2′,4′-dimethylbiphenyl-3-carboxylate (5.0 g, 19.7 mmol) in anhydrous tetrahydrofuran (50 mL) was added lithium aluminum hydride (0.91 g, 24.0 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction solution was ice-cooled, and sodium sulfate decahydrate (8.0 g, 24.8 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The precipitated insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil. yield 96%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-bromobenzoic acid (3.30 g, 16.4 mmol) in anhydrous DCM (120 mL) was added oxalyl chloride (6.26 g, 49.3 mmol) dropwise at 0° C. followed by 3 drops of DMF. The resulting mixture was stirred at room temperature for 2 h. The mixture was then concentrated in vacuo to give 4-bromobenzoyl chloride as a yellow solid. The solid was dissolved in anhydrous THF (40 mL) and a solution of Preparation 3 tert-butyl (3R)-3-(isoquinolin-1-ylamino)piperidine-1-carboxylate (4.89 g, 14.9 mmol) in anhydrous THF (50 mL) was added. The resulting solution was treated with lithium bis(trimethylsilyl)amide (44.8 mL, 44.8 mmol, 1 M) dropwise at 0° C. The reaction mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc (4×100 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with a gradient of (0-25%) EtOAc/petroleum ether to afford the title compound (4.80 g, 63%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:27]1[CH:28]=[CH:29][C:24]([CH:22]=[CH:23][C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]3[CH2:14][CH2:13][N:12]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][C:7]=2[Cl:8])=[CH:25][CH:26]=1
Reactant: C=Cc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 66a (470 mg, 1.25 mmol) in acetonitrile (6.2 mL) was added 4-vinylpyridine (0.17 mL, 1.57 mmol), palladium acetate (26.0 mg, 0.11 mmol), tri-o-tolylphosphine (130 mg, 0.1 mmol) and triethylamine (2.6 mL). The reaction mixture was heated at reflux overnight, then cooled to room temperature. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with ethyl acetate:hexane 1:1 to 3:1 to afford the title compound (176 mg, 35% yield). MS (CI/NH3) m/z 402 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.27-2.43 (m, 2H), 3.86-3.95 (m, 2H), 4.27-4.24 (m, 1H), 4.36-4.67 (m, 1H), 4.50-4.60 (m, 1H), 7.07 (d, J=11, 1H), 7.41-7.47 (m, 4H), 7.57 (d, J=11, 1H), 7.58-7.65 (m, 1H), 8.09 (d, J=2, 1H), 8.61-8.68 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([SH:22])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[C:29]=1[CH2:38][CH2:39][CH3:40].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([S:22][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[C:29]=2[CH2:38][CH2:39][CH3:40])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(S)ccc(C(C)=O)c1OCCCC(=O)OCC
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCCc1c(OCCCSc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 7.5 h
Yield: 71 %

Procedure:
A mixture of ethyl 4-(6-acetyl-3-mercapto-2-propylphenoxy)-butyrate (1.7 g), (4-(3-bromopropoxy)-2-hydroxy-3-propylphenyl)ethanone (1.7 g), potassium iodide (0.5 g) and potassium carbonate (1.45 g) in acetone (40 ml) was heated with refluxing and stirring for 7.5 hours. Ice-water and conc. hydrochloric acid were added thereto, and the mixture was subjected to extraction with ethyl acetate. After washed with water, the extract was dried over sodium sulfate and concentrated under a reduced pressure. The resultant residue was separated and purified through silica-gel column chromatography (eluting with benzene:ethyl acetate=9:1) to give the title compound (2.08 g, 71.0%) as light yellow crystal, mp 87-88° C.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.[C:18]([O:21][C@@H:22]1[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:43]([O:49][C:50](=[O:52])[CH3:51])[C@@H:42]([CH2:53][O:54][C:55](=[O:57])[CH3:56])[O:41][C@H:23]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]#[N:40])=[CH:34][CH:33]=1)(=[O:20])[CH3:19]>>[C:18]([O:21][C@@H:22]1[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:43]([O:49][C:50](=[O:52])[CH3:51])[C@@H:42]([CH2:53][O:54][C:55](=[O:57])[CH3:56])[O:41][C@H:23]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]#[N:40])=[CH:36][CH:37]=1)(=[O:20])[CH3:19].[O:1]([C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)[C@@H:23]1[O:41][C@H:42]([CH2:53][OH:54])[C@@H:43]([OH:49])[C@H:44]([OH:45])[C@H:22]1[OH:21]
Reactant: N#CCc1ccc(Cc2ccccc2O)cc1
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(CC#N)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: N#CCc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1

Procedure:
2-(4-Cyanomethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside was prepared in a similar manner to that described in Reference Example 25 using 4-(2-hydroxybenzyl)phenylacetonitrile instead of methyl 4-(2-hydroxybenzyl)benzoate. Then, the title compound was prepared in a similar manner to that described in Reference Example 50 using 2-(4-cyanomethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside instead of 2-(4-methoxycarbonylbenzyl)-phenyl 2,3,4,6-tetra-O-acetyl-BD-glucopyranoside.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:16][CH:15]([Cl:17])[CH:14]([CH2:18][NH:19]C(=O)C)[CH2:13]1)[N:8]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:6]([C:28]([OH:30])=[O:29])[C:5]2=[O:31].Cl.C(=O)([O-])O.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:16][CH:15]([Cl:17])[CH:14]([CH2:18][NH2:19])[CH2:13]1)[N:8]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:6]([C:28]([OH:30])=[O:29])[C:5]2=[O:31]
Reactant: CC(=O)NCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2cccs2)CC1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: NCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2cccs2)CC1Cl
Yield: 89.5 %

Procedure:
To 6-fluoro-1-(2-thienyl)-7-(3-acetylaminomethyl-4-chloro-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.43 g) is added 20% hydrochloric acid (8 ml), and the mixture is refluxed for 5 hours. After cooling, the mixture is neutralized with saturated aqueous sodium hydrogen carbonate, the precipitated crystals are separated by filtration and dried. The product is converted into its hydrochloride by treating it with a hydrochloric acid-saturated ethanol, and the resulting crude crystals are recrystallized from ethanol-ether to give 6-fluoro-1-(2-thienyl)-7-(3-aminomethyl-4-chloro-1-pyrrolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.35 g).
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O>>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:40]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:26]=3)[N:20]=2)[CH:42]=[CH:43][CH:44]=1
Reactant: COc1cccc(C=O)c1
Reactant: NC(=O)c1cc(N2CCCC2)ccc1N
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(N4CCCC4)cc3c(=O)[nH]2)c1
Yield: 38.1 %

Procedure:
According to the preparation of 42, 26 (1.0 g, 4.9 mmol) and 3-methoxybenzaldehyde (34) (0.7 g, 4.9 mmol) were used to afford 56 (0.6 g, 40.0%) as pale yellow prism crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH:16]([CH3:19])[C:17]#[N:18])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.Cl>C(O)C.[Pt]=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH2:15][CH:16]([CH3:19])[CH2:17][NH2:18]
Reactant: COc1ccc(CCN(C)CC(C)C#N)cc1OC
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: COc1ccc(CCN(C)CC(C)CN)cc1OC
Yield: 92.9 %

Procedure:
2.1 g of the above nitrile and 0.2 ml of concentrated hydrochloric acid were dissolved in 30 ml of ethanol, followed by the addition of 0.2 g of platinum oxide to carry out hydrogenation under a hydrogen pressure of 2.1 kg/cm2. The reaction mixture was filtered to remove the catalyst. The filtrate was distilled under a reduced pressure to remove the ethanol. The residue was made alkaline with a dilute solution of caustic soda. The aqueous layer was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and distilled under a reduced pressure to obtain 1.98 g of the title compound as a pale yellow oil (yield: 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CC[N:25]([CH:29]([CH3:31])C)[CH:26]([CH3:28])C.CO.C(Cl)Cl>C(OCCO)C>[C:19]([O:18][C:16]([NH:15][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]2[C:28]3[C:31](=[CH:29][N:25]=[CH:26][CH:28]=3)[CH:31]=[CH:29][N:25]=2)=[CH:7][CH:6]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOCCO
Solvent: CO
Product: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3cnccc23)cc1)NC(=O)OC(C)(C)C
Yield: 77.4 %

Procedure:
Ethyl (S)-3-(4-aminophenyl)-2-[N-(t-butyloxycarbonyl)amino]propanoate (600 mg, 1.95 mmol), Intermediate 21 (350 mg, 2.13 mmol) and DIPEA (276 mg, 372 μl, 2.13 mmol) in 2-ethoxyethanol (0.5 ml) were stirred at 130° under N2 for several hours. The reaction was partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (30 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic extracts were washed with brine (10 ml), dried (MgSO4) and evaporated in vacuo to afford a dark oil. Chromatography (SiO2; 3% MeOH/DCM) gave the title compound as a dull orange foam (360 mg, 42%). δH (CDCl3) 9.19 (1H, s), 8.67 (1H, d, J 5.9 Hz), 8.24 (1H, d, J 5.8 Hz), 7.66 (1H, d, J 5.9 Hz), 7.65 (2H, d, J 8.5 Hz), 7.21 (1H, d, J 5.8 Hz), 7.16 (2H, d, J 8.5 Hz), 7.15 (1H, obscured s), 5.05-4.97 (1H, m), 4.60-4.51 (1H, m), 4.19 (2H, q, J 7.1 Hz), 3.17-3.04 (2H, m), 1.44 (9H, s), 1.27 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 459 (MNa+), 437 (MH+).