Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][CH:31]([CH2:33][NH:34]C(C3C=CC=CC=3)C)[O:30][C:29]2=[O:43])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][C@H:31]([CH2:33][NH2:34])[O:30][C:29]2=[O:43])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1.[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][C@@H:31]([CH2:33][NH2:34])[O:30][C:29]2=[O:43])[CH:19]=[CH:20][C:21]=1[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CC(NCC1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1)c1ccccc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: NC[C@@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Product: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1

Procedure:
The procedure is the same as in Example 41 except that the dihydrochloride of 3-(3-fluoro-4-morpholinylphenyl)-5-[(1-phenylethyl)aminomethyl]-1,3-oxazolidin-2-one (4a) was replaced by the corresponding 3-(3-fluoro-4-morpholinylphenyl)-5-[(1-phenylethyl)aminomethyl]-1,3-oxazolidin-2-one (4c-4h) to give 3-(3-fluoro-4-morpholinylphenyl)-5(S)-aminomethyl-1,3-oxazolidin-2-one ((S)-5b) or 3-(3-fluoro-4-morpholinylphenyl)-5(R)-aminomethyl-1,3-oxazolidin-2-one ((R)-5b).
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])(=O)C.[NH4+:17]>C(O)C>[NH2:17][C:2]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: [NH4+]
Reactant: CCCCC(=O)CC(=O)OCC
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCCCC(N)=CC(=O)OCC
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Ethyl 3-oxoheptanoate (8.28 g, 48.13 mmol) and ammonium acetate (18.55 g, 240 mmol) were stirred in ethanol (80 ml) at room temperature for 96 hours. The solvent was evaporated and the residue stirred in dichloromethane (100 ml) for 30 minutes. The solid formed was filtered and the filtrate was washed with water (50 ml), saturated brine (50 ml) and dried over MgSO4 filtered and evaporated to give ethyl 3-aminohept-2-enoate (7.8 g, 94%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:10]=[C:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].C(Cl)(=O)C1C=CC=C(C(Cl)=O)C=1.[CH2:25]([OH:30])[C:26]([F:29])([F:28])[F:27]>>[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:10][C:11](=[O:12])[O:30][CH2:25][C:26]([F:29])([F:28])[F:27])=[C:8]=[O:9]
Reactant: OCC(F)(F)F
Reactant: O=C=NCCCCCCN=C=O
Agent: O=C(Cl)c1cccc(C(=O)Cl)c1
Product: O=C=NCCCCCCNC(=O)OCC(F)(F)F

Procedure:
684 g of hexamethylene diisocyanate (HDI) were initially introduced at 80° C. in a 1 l round-bottomed flask and 0.002 g of isophthaloyl dichloride was added. 54.4 g of trifluoroethanol were slowly added dropwise and stirring was effected until the NCO value was 43.2% by weight. The mixture was separated by distillation on a thin-film evaporator and 47 g (=47% of theory) of the title compound having an NCO content of 22.7% by weight were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[F:12][C:13]([F:35])([F:34])[C:14]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][C:26]2=[O:31])=[CH:22][CH:21]=1)([OH:19])[C:15]([F:18])([F:17])[F:16].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:23]3[CH:32]=[CH:33][C:20]([C:14]([OH:19])([C:13]([F:12])([F:34])[F:35])[C:15]([F:18])([F:16])[F:17])=[CH:21][CH:22]=3)[C:26](=[O:31])[CH2:27]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: O=C1CNCCN1Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)C(=O)C2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a stirring solution of 4-amino-3-fluorobenzoic acid (1.965 mmol, 305 mg), 1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-2-one (1.965 mmol, 700 mg) and triethylamine (5.89 mmol, 596 mg) in dichloromethane (10 mL) was added 1-propanephosphonic acid cyclic anhydride (2.95 mmol, 1876 mg; 50% solution in ethyl acetate). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (30 mL). The organic phase was concentrated and the resulting residue was purified by column chromatography on silica gel (eluting with 50% ethyl acetate/50% dichloromethane—100% ethyl acetate gradient) to afford the title compound (550 mg). MS (ESI) m/z 492.3 [M−H]−
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Br:17]Br>CO.O>[Br:17][C:8]1[C:7]([Cl:12])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([Cl:1])=[N:3]2
Reactant: BrBr
Reactant: Clc1ccc2nc(Cl)ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Clc1ccc2c(Br)c(Cl)ccc2n1
Temperature: 120 °C
Yield: 81 %

Procedure:
A mixture of 2,6-dichloroquinoline (5.0 g, 25.4 mmol) and aluminium trichloride (10.0 g, 76.1 mmol) was heated to 120° C. with stirring under a nitrogen atmosphere. Bromine (4.81 g, 30.48 mmol, 1.54 mL) was added dropwise over 0.5 h, and the mixture was then stirred at 120° C. for 1 hour before being cooled to room temperature. A MeOH/water mixture (50 mL, 1:1) was then slowly added and the mixture was concentrated in vacuum. Dichloromethane (500 mL) and water (250 mL) were added, the organic layers were separated and the aqueous fraction was extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (150 mL) before being dried, filtered and concentrated. Purification by column chromatography on silica gel (petroleum ether: EtOAc=10:1) gave 5-bromo-2,6-dichloroquinoline (5.7 g, 82%) as a solid. m/z: 275.2 [M+H]+
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][O:13]C(=O)C)[CH:9]=[CH:8][C:7]=1[Br:17])(=O)C.C(OCC1C=CC=C(COC(=O)C)C=1Br)(=O)C.[OH-].[Na+]>CO>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:7]=1[Br:17]
Reactant: CC(=O)OCc1ccc(Br)c(COC(C)=O)c1
Agent: CC(=O)OCc1cccc(COC(C)=O)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1ccc(Br)c(CO)c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
An about 93:7 mixture (36.7 g) of 2,4-bis(acetoxymethyl)bromobenzene and 2,6-bis(acetoxymethyl)bromobenzene was dissolved in methanol (183 ml) and cooled to 10° C. To this solution was added dropwise 10% aqueous sodium hydroxide solution (133 g). The reaction mixture was stirred at room temperature for 1 hr, and the solvent (about 200 ml) was evaporated. The residue was neutralized with dilute hydrochloric acid (about 200 ml). To the neutralized solution was added toluene (150 ml) and the mixture was stirred at 80-85° C. for 1 hr and cooled. The resulting crystals were collected by filtration and dried under reduced pressure to give an about 93:7 mixture (22.2 g, 83.7%) of 2,4-bis(hydroxymethyl)bromobenzene and 2,6-bis(hydroxymethyl)bromobenzene as almost white crystals. 2,4-bis(Hydroxymethyl)bromobenzene was isolated by preparative HPLC and used in the measurement. mixture:
Reaction SMILES: B(F)(F)F.CCOCC.[N:10]([CH2:13][C@H:14]1[O:23][CH:18]([O:19][C:20](=O)[CH3:21])[C@H:17]([O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:28][C:29](=[O:31])[CH3:30])[C@H:15]1[O:32][C:33](=[O:35])[CH3:34])=[N+:11]=[N-:12].[CH:36]1[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=C(O)C=1.CCOCC>C(Cl)Cl>[C:25]([O:24][C@@H:17]1[C@@H:16]([O:28][C:29](=[O:31])[CH3:30])[C@@H:15]([O:32][C:33](=[O:35])[CH3:34])[C@@H:14]([CH2:13][N:10]=[N+:11]=[N-:12])[O:23][C@@H:18]1[O:19][C:20]1[CH:39]=[CH:40][C:41]([N+:42]([O-:44])=[O:43])=[CH:36][CH:21]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC1O[C@H](CN=[N+]=[N-])[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CN=[N+]=[N-])O[C@H](Oc2ccc([N+](=O)[O-])cc2)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 15.4 %

Procedure:
Boron trifluoride diethyl etherate (80 μl, 0.70 mmol) was added to a stirred solution of 6-azido-6-deoxy-1,2,3,4-tetra-O-acetyl-D-galactopyranose 36 (α:β, 1:1) (52 mg, 0.139 mmol) in DCM (5 mL). The solution was stirred under argon at RT. After 20 min a solution of p-nitrophenol (19 mg, 0.14 mmol) in DCM (5 mL) was added to the reaction mixture and stirring under argon maintained. After 65 min, t.1.c. (DCM:ether, 60:1) indicated formation of two products (Rf 0.1, 0.4) with some remaining starting material (Rf 0.3). The DCM was removed in vacuo. The residue was diluted with chloroform (30 mL), washed with brine (3×30 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (DCM:ether, 60:1) to afford p-nitrophenyl 2,3,4-tri-β-acetyl-6-azido-6-deoxy-α-D-galactopyranoside 40 (9.7 mg, 14%) as a colourless oil; partial data [α]D25 +18.3 (c, 0.5 in CHCl3); νmax (thin film) 3430 (br, OH), 2101 (sh, N3), 1637 (st, C═O)cm−1; δH (500 Mz, CDCl3) 2.05, 2.09, 2.21 (9H, 3 x s, 3 x CH3), 3.13 (1H, dd, J5,6 4.2 Hz, J6,6′ 13.1 Hz, H-6), 3.46 (1H, dd, J5,6′ 8.2 Hz, H-6′), 4.18 (1H, dd, H-5), 5.34 (1H, dd, J2,3 3.7 Hz, J2,3 10.9 Hz, H-2), 5.49 (1H, d, J3,4 3.0 Hz, H-4), 5.57 (1H, dd, H-3), 5.94 (1H, d, H-1) 7.21 (2H, J=9.3 Hz, 2 x CHCHCNO2), 8.26 (2H, 2 x CHCNO2); 5c (125.7 MHz, CDCl3) 19.9, 20.0, 21.0 (3 x q, 3 x CH3), 51.9 (t, C-6), 53.3 (d, C-2), 66.6 (d, C-3), 67.6 (d, C-4), 69.0 (d, C-5), 95.2 (d, C-1), 115.6, 115.7, 125.3 (3 x s, 3 x C═O), 116.9, 117.0 (2 x d, CHCHCNO2), 126.5, 126.6 (2 x d, CHCNO2), 140.8 (s, CNO2), 167.2, 169.9, 170.2, 171.8 (4 x s, 3 x C═O, 1x CCHCHCNO2); m/z (CI+) 470 (M+NH4+, 10%).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:23]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([NH2:32])[C:26]=2[CH:25]=[CH:24]1.Cl>CCO.C(Cl)Cl.N.CO>[N:16]1[C:8]([C:7]2[C:2]([NH:32][C:27]3[C:26]4[CH:25]=[CH:24][NH:23][C:31]=4[CH:30]=[CH:29][CH:28]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[C:9]2[C:13]([NH:12][CH:11]=[N:10]2)=[N:14][CH:15]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: c1cnc(Nc2cccc3[nH]ccc23)c(-c2ncnc3[nH]cnc23)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 5.5 %

Procedure:
6-(2-Fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (115.0 mg, 0.3842 mmol) and 1H-indol-4-amine (Aldrich, St. Louis, Mo., 70.7 mg, 0.535 mmol) were suspended in EtOH (1.8 mL) and aqueous hydrochoric acid (5.0 M, 0.090 ml, 0.45 mmol) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (100° C.), and the reaction was stirred for 3 hours. Then, the reaction was cooled to room temperature and diluted with DCM, 2 N ammonia in MeOH, EtOH, and MeOH and concentrated. The residue was treated with MeOH and filtered. Neither the filtrate nor the solid contained pure material, so they were combined, concentrated, treated with DMF, and filtered. The filtrate was concentrated and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min). The fractions with product were collected, concentrated, and filtered through a silica gel plug (about 1 inch, 50:1 DCM/2 N ammonia in MeOH to 20:1 DCM/2 N ammonia in MeOH to 5:1 DCM/2 N ammonia in MeOH) to afford N-(3-(9H-purin-6-yl)pyridin-2-yl)-1H-indol-4-amine (6.9 mg, 5% yield). MS (ESI pos. ion) m/z: 328, (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 12.90 (s, 1H), 11.16 (s, 1H), 9.87 (d, J=7.82 Hz, 1H), 9.24 (s, 1H), 8.73 (s, 1H), 8.43 (dd, J=4.69 Hz, 1.96 Hz, 1H), 8.28 (dd, J=4.6 Hz, 3.81 Hz, 1H), 7.38-7.35 (m, 1H), 7.09 (s, 1H), 7.08-7.06 (m, 1H), 7.04 (dd, J=7.82 Hz, 4.69 Hz, 1H), 6.79-6.76 (m, 1H).
Reaction SMILES: [H-].[Na+].C(=O)=O.CC(C)=O.[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14]CC)=O.[N+:21]([C:24]1C=CC=[C:26]([CH:27](Cl)Cl)[C:25]=1O)([O-:23])=[O:22]>C(COC)OC.C(Cl)Cl>[OH:14][C:12]1[C:20]2[C:19](=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=[CH:26][CH:27]=2)[O:18][C:10](=[O:17])[CH:11]=1
Reactant: O=[N+]([O-])c1cccc(C(Cl)Cl)c1O
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=c1cc(O)c2cccc([N+](=O)[O-])c2o1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of NaH (6.94 g, 0.291 mole) in dimethoxyethane is cooled using dry ice/acetone cooling, treated dropwise with diethyl malonate (46.6 g, 0.29 mole), allowed to warm to 0° C., treated dropwise with a solution of 3-nitrosalicylyl chloride (19.5 g, 0.10 mole) in dimethoxyethane, allowed to warm to room temperature, stirred for 3 hours at room temperature, heated at 60° C. until reaction is complete by HPLC analysis, cooled to room temperature, poured onto a mixture of ice water and methylene chloride and stirred for about 0.5 hour. The phases are separated, the aqueous phase is acidified with 50% HCl to pH 5 and filtered. The filtercake is dispersed in acetic acid, heated and filtered. This filtercake is air-dried and 8.6 g is dispersed in dimethyl sulfoxide, heated at 100° C. for about 2 hours, cooled to room temperature, poured onto ice water and filtered. The solid is taken up in acetonitrile, filtered hot, cooled and filtered to give the title product, mp 242°-245° C., identified by IR, 1HNMR and mass spectral analyses.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1OC1C.CCN(CC)CC.C1OC1C>C(Cl)(Cl)Cl.CCN(CC)CC.CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: BrCCCCCCc1ccccc1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: ClC(Cl)Cl
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCc1ccccc1
Reaction time: 24 h
Yield: 58.3 %

Procedure:
To a stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (2.3 g, 0.01 mole), 1-bromo-6-phenylhexane (2.4 g, 0.01 mole) and HMPA (25 ml), at 130° C., was added dropwise, during 2 h, a mixture of Et3N (1 ml) and propylene oxide (9 ml). After four more hours, an additional 10 ml of the Et3N-propylene oxide mixture was introduced. Heating was continued for 24 h and 1.2 g (0.005 mole) of 1-bromo-6-phenylhexane was added followed by another 10 ml of Et3N-propylene oxide. This final mixture was heated for 6 h, allowed to cool, diluted with CHCl3 (50 ml), placed on a silica gel column and eluted with CHCl3. Concentration of the yellow eluate gave 2.3 g of 6-methoxy-4-methyl-8-nitro-5-(6-phenylhexoxy) quinoline as an oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:17])=[CH:4][CH:3]=1.C([N:20]([CH2:23]C)[CH2:21][CH3:22])C.ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[CH3:23][N:20]([C:21]1[CH:22]=[CH:3][CH:4]=[C:5]([CH3:8])[CH:6]=1)[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:17])=[CH:6][CH:7]=1)=[O:35]
Reactant: CCN(CC)CC
Reactant: Nc1ccc(-c2cccc3c2CNC3=O)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cccc(N(C)C(=O)Nc2ccc(-c3cccc4c3CNC4=O)cc2)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 55.3 %

Procedure:
A suspension of Example 1D (0.25 g, 1.1 mmol) in dioxane (3 mL) was sequentially treated with triethylamine (0.17 mL, 1.2 mmol) and triphosgene (0.11 g, 0.37 mmol), heated to 70° C. for 2 hours, and concentrated. The concentrate was resuspended in THF (3 mL), treated with N-methyltoluidine, stirred at room temperature for 18 hours, and partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography with 2% methanol/dichloromethane to give 76 mg (20% yield) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.34 (s, 3H); 3.27 (s, 3H); 4.50 (s, 2H); 7.08 (d, J=7.46 Hz, 1H); 7.12 (d, J=8.48 Hz, 1H); 7.17 (s, 1H); 7.31 (t, J=7.80 Hz, 1H); 7.48 (d, J=8.82 Hz, 2H); 7.57 (d, J=8.82 Hz, 3H); 7.62 (d, J=3.39 Hz, 1H); 7.65 (d, J=5.76 Hz, 1H); 8.24 (s, 1H); 8.64 (s, 1H). MS (ESI(+)) m/e 372 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([O:5][C:6]([CH:9]=[CH2:10])=[CH:7]2)[CH2:3]1.[CH2:11]([O:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([S:28][CH2:10]/[CH:9]=[C:6]2/[CH2:7][N:8]3[C@H:4]([O:5]/2)[CH2:3][C:2]3=[O:1])=[CH:26][CH:27]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CC1=CN2C(=O)C[C@H]2O1
Reactant: O=C(Nc1ccc(S)cc1)OCc1ccccc1
Product: O=C(Nc1ccc(SC/C=C2/CN3C(=O)C[C@H]3O2)cc1)OCc1ccccc1

Procedure:
(5R)-7-Oxo-3-vinyl-4-oxa-1-azabicyclo[3.2.0]hept-2-ene (2.4 mmole) and p-benzyloxycarbonylaminophenyl mercaptan (0.775 g) were converted into the title compound using the process described in Example 1. The title compound was obtained as a colourless gum (63 mg), [α]D25 =34.6° (c 1.0, CHCl3), (Found: M+, 396.1136; C21H20N2O4S requires 396.1144). νmax (CHCl3): 3370, 3240, 1790, 1735, 1700, 1590, 1515 cm-1. δ(CDCl3): 2.71 (1H, d, J 16 Hz), 3.10-3.60 (4H, complex), 4.22 (1H, d, J 15 Hz), 4.38 (1H, t, J 7 Hz), 5.16 (2H, s), 5.32 (1H, d, J 2 Hz), 6.90 (1H, br.s), 7.10-7.45 (9 H, complex). m/e: 396 (M+, 6%), 138 (41), 108(20), 107(12), 96(46), 91(100).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]3[CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=2[O:2]1.CN(C)C=O.[CH3:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33]Cl)=[O:31]>C(N(CC)CC)C>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:22])[C:7]([C:19]([O:21][CH2:33][O:32][C:30](=[O:31])[C:29]([CH3:36])([CH3:35])[CH3:28])=[O:20])=[CH:8][N:9]3[CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)c1cn(CC(F)(F)F)c2cc3c(cc2c1=O)OCO3
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOC(=O)c1cn(CC(F)(F)F)c2cc3c(cc2c1=O)OCO3
Reaction time: 0.5 h

Procedure:
To a mixture of 2.6 g. 6,7-methylenedioxy-1-(2,2,2-trifluoroethyl)-4(1H)-quinolone-3-carboxylic acid and 35 ml. of dimethyl formamide was added 1.4 g. of triethylamine. The mixture was warmed to 55° and kept there for 1/2 hour. 2.8 g. of chloromethyl trimethylacetate was then added and the resulting mixture was stirred at 55° for 5 hours. The cooled solution was diluted with 150 ml. of ethyl acetate and washed with water. The ethyl acetate solution was dried over magnesium sulfate and concentrated. The solid residue, 6,7-methylenedioxy-1-(2,2,2-trifluoroethyl)-4(1H)-quinolone-3-carboxylic acid, trimethylacetoxymethyl ester, was recrystallized from CH2C12 -ether mixture; m.p. 190°-1° .
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12](=[O:20])[NH:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(OC(=O)C)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12](=[O:20])[NH:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C1Cc2ccccc2C(c2cccc([N+](=O)[O-])c2)N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(C2NC(=O)Cc3ccccc32)c1
Yield: 83.1 %

Procedure:
A mixture of 1-(3-nitrophenyl)-1,4-dihydroisoquinol-3-one (12.2 g) and 5% palladium-carbon (3 g) in ethylacetate (400 ml) was hydrogenated at room temperature and pressure until uptake of hydrogen ceased. The mixture was filtered (celite), and the filtrate evaporated to dryness to give 1-(3-aminophenyl)-1,4-dihydroisoquinol-3-one (9.0 g), m.p. 179°-180° C. which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=O.[F:14][CH2:15][C:16](=O)[CH2:17][C:18]([O:20][CH3:21])=[O:19].[NH2:23][C:24]([CH3:32])=[CH:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>>[F:14][CH2:15][C:16]1[NH:23][C:24]([CH3:32])=[C:25]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH:4]([C:3]2[C:6]([C:10]([F:13])([F:12])[F:11])=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC(N)=CC(=O)OC(C)C
Reactant: COC(=O)CC(=O)CF
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)OC(C)C)C1c1c(F)cccc1C(F)(F)F
Reaction time: 2 h
Yield: 3 %

Procedure:
2-Fluoro-6-(trifluoromethyl)benzaldehyde (1.51 g, 7.8 mmoles), methyl 4-fluoro-3-oxobutanoate (1.06 g, 7.8 mmoles) and 1-methylethyl 3-amino-2-butenoate (1.13 g, 7.8 mmoles) were heated at 90° under nitrogen with stirring for 2 hours. The cooled reaction mixture was chromatographed twice; first eluting with toluene/ethyl acetate mixtures and then with ethyl acetate/petroleum ether (60°-80°) mixtures. The title compound (0.1 g) was obtained on evaporation of the pure fractions mp 82°-4°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[O:14])[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6]2.P([O-])(O)(O)=[O:18].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([OH:18])=[O:14])[N:9]([CH3:15])[C:8](=[O:16])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)CC2
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc2c(cc1C(=O)O)N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
To a mixture of 6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carbaldehyde (2.0 g) synthesized by a known method (WO2001/077100), sodium dihydrogen phosphate (1.63 g) and 2-methyl-2-butene (4.3 ml) in tert-butanol (52 mL) and water (8 mL) was slowly added sodium chlorite (2.89 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. After cooling to 0° C., the reaction was quenched with 6N hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained crystals were collected by filtration, and washed with hexane to give 6-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (0.72 g, 34%) as white crystals.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:18])=[C:13](F)[C:14]=3[F:16])[C:9](=[O:19])[C:8]([C:20]([OH:22])=[O:21])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([NH:25][CH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)[CH3:24]>C(#N)C>[CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:18])=[C:13]([N:29]4[CH2:30][CH2:31][CH:27]([CH2:26][NH:25][CH2:23][CH3:24])[CH2:28]4)[C:14]=3[F:16])[C:9](=[O:19])[C:8]([C:20]([OH:22])=[O:21])=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCNCC1CCNC1
Reactant: O=C(O)c1cn(C2CCCC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CCCC4)c3c2F)C1
Yield: 74.2 %

Procedure:
To 0.86 g (2.7 mmol) of the 1-cyclopentyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.40 g (2.7 mmol) of 1,8-diazobicyclo [5.4.0] undec-7-ene and 0.36 g (2.7 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for seven hours, cooled, filtered, and the solids washed with ether to give 0.84 g of 1-cyclopentyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic-acid, mp 214°-217° C.