Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.[CH:22]([C:24]1[O:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:27]3[O:28][C:24]([CH:22]=[O:23])=[CH:25][CH:26]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)o1
Temperature: 65 °C
Yield: 84.2 %

Procedure:
A stirred suspension of 7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (24) [US 2006/0287343 A1] (5.00 g, 12.01 mmol, scheme 4)], 5-formyl-2-furanboronic acid (2.19 g, 15.19 mmol), Pd(PPh3)2Cl2 (422 mg, 0.6 mmol), Na2CO3 (8.53 g, 80.50 mmol) in a mixture of DME/ethanol/water (60 mL/40 mL/40 mL) was degassed with nitrogen for 15 min, and heated at 65° C. for five hours under nitrogen. The reaction mixture was allowed to cool to room temperature, and filtered. The cake was successively washed with water and AcOEt. The filtrate and washings were combined, extracted with AcOEt. The extract was successively washed with water, saturated solution of ammonium chloride, water and brine, and concentrated. The residue was combined with the cake, absorbed on silica gel and subjected to flash column chromatography on silica gel (eluents AcOEt/DCM: 10/90 to 20/90, then MeOH/DCM: 5/95) followed by trituration with AcOEt, to afford aldehyde 107 (3.886 g, 84% yield) as a pale clay solid. MS (m/z): 385.0 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11](=[O:45])[NH:12][C@H:13]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]2[C:22](=[O:26])[N:23]([CH3:25])[CH2:24][C@:18]2([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[CH2:17]1)=[O:15])([CH3:10])[CH3:9])(C)(C)C.[ClH:47]>CCO>[ClH:47].[NH2:7][C:8]([CH3:10])([CH3:9])[C:11]([NH:12][C@H:13]([CH2:36][O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]2[C:22](=[O:26])[N:23]([CH3:25])[CH2:24][C@:18]2([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[CH2:17]1)=[O:15])=[O:45]
Reactant: CN1C[C@]2(Cc3ccc(F)cc3F)CN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CCN2C1=O
Agent: Cl
Solvent: CCO
Product: CN1C[C@]2(Cc3ccc(F)cc3F)CN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)CCN2C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of Example 198, Step D (12 mg) in EtOH (2 mL, 0° C.) was added conc. HCl (0.2 mL). The solution was stirred at 0° C. for 1 h and concentrated down to deliver 10 mg of Example 198, Step E: +APcI MS (M+1)+ 544; 1H NMR=400 MHz (CD3OD) δ: 7.31 (br m, 6H), 6.83 (m, 2H), 2.59 (br s, 3H), 1.56 (br s, 6H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:13]([O-])=O.[Na+].O.O.Cl[Sn]Cl.Cl.[F:23][C:24]([F:36])([F:35])[C:25](=O)[CH2:26][C:27]([C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)=O>O>[F:23][C:24]([F:36])([F:35])[C:25]1[CH:26]=[C:27]([C:29]2[O:30][CH:31]=[CH:32][CH:33]=2)[N:12]([C:3]2[C:2]([F:1])=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)[N:13]=1
Reactant: Nc1cc2ccccc2cc1F
Reactant: O=N[O-]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Fc1cc2ccccc2cc1-n1nc(C(F)(F)F)cc1-c1ccco1
Yield: 60 %

Procedure:
3-fluoro-2-naphthylamine (1.38 g, 8.57 mmol, see Step 2, Example 3) was placed in 20 mL concentrate HCl. The slurry was stirred in ice bath. To it was added dropwise a chilled solution of sodium nitrite (0.71 g, 10.3 mmol) in 4 mL water. After completion, the mixture was stirred for 30 min in ice bath. A chilled solution of SnCl2.2H2O (4.9 g, 21.6 mmol) in 4 mL concentrate HCl was added dropwise. The mixture was stirred for 30 min. It was chilled and filtered with a Buchner funnel to collect the solid hydrazine. The solid was dried in vacuuo. It was then dissolved in 50 mL glacial acetic acid. To it was added 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (2.18 g, 10.6 mmol). The mixture was refluxed for 2 hrs. The solvent was removed in vacuuo. The residue was taken into DCM. It was washed with water ×2, dried, concentrated and subjected to flash column to isolate 3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-5-(2-furyl)-1H-pyrazole (60%). Rf 0.52 (1:4 EtOAc:hexane). ES-MS: (M+H)+347.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C@:13]([C:18]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=2[F:25])([CH:15]([F:17])[F:16])[N:14]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]([C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=[O:36])=[N:33][CH:34]=1)#[N:28].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C@:13]([C:18]2[CH:23]=[C:22]([NH:24][C:35]([C:32]3[CH:31]=[CH:30][C:29]([C:27]#[N:28])=[CH:34][N:33]=3)=[O:36])[CH:21]=[CH:20][C:19]=2[F:25])([CH:15]([F:17])[F:16])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)CCOC1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)(C(F)F)CCOC1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
A solution of [(S)-5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamic acid tert-butyl ester (51.2 mg, 0.137 mmol), 5-cyano-2-pyridinecarboxylic acid (30.5 mg, 0.206 mmol) and HOAT (33.6 mg, 0.247 mmol) in 0.6 mL DMF was cooled to 0-5° C. EDC (39.4 mg, 0.206 mmol) and DIPEA (35.4 mg, 0.274 mmol) were added. The resulting solution was allowed to warm up to rt over night. The reaction mixture was then partitioned between saturated aqueous NaHCO3 solution and EtOAc. The layers were separated, washed with saturated aqueous NaHCO3 solution, brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 3/1→1.5/1 to give 67.7 mg of the title compound as a colorless resin.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:13]1[C:25]2[NH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1.C1O[CH2:42][CH2:41]OCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1Cl>[CH:22]1[C:23]2[N:24]([C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([N:24]4[C:42]5[CH:41]=[CH:14][CH:15]=[CH:16][C:17]=5[C:18]5[C:23]4=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])[C:25]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: COC(=O)c1cc(I)cc(I)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Reaction time: 10.5 h

Procedure:
To a solution of methyl 3,5-diiodobenzoate (3.0 g, 7.73 mmol), carbazole (3.0 g, 17.94 mmol), Cu (6.4 g, 100.71 mmol) and 18-crown-6 (65 mg, 0.25 mmol) in 1,2-dichlorobenzene (30.0 ml) was added potassium carbonate (12.6 g, 91.17 mmol) under nitrogen and stirring. The reaction was carried out at 180° C. for 10.5 hours. After cooling, the reaction mixture was filtrated. Then, the solid residues were carefully washed with THF. The THF and 1,2-dichlorobenzene were evaporated from the combined filtration solution. The product was purified by silica gel column chromatography using toluene as eluent. The final pure white product was obtained in 2.6 g (71.7%) by recrystallization from acetone/methanol.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].[C:16]([CH2:20]OS(C(F)(F)F)(=O)=O)([F:19])([F:18])[F:17]>CN(C=O)C>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[N:7]2[CH2:20][C:16]([F:19])([F:18])[F:17]
Reactant: Cc1ccc2[nH]c(=O)ccc2c1Br
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(ccc(=O)n2CC(F)(F)F)c1Br
Reaction time: 2 h

Procedure:
5-Bromo-6-methylquinolin-2(1H)-one (103.5 mg, 0.435 mmol) was suspended into DMF (3 mL). To the suspension, was added NaH (17.4 mg 60% in mineral oil) at room temperature. After 2 h stirring, CF3CH2OTf (201.8 mg, 0.869 mmol) was added into the mixture at room temperature. The reaction mixture was stirred for 2 h at the same temperature. The reaction mixture was quenched with water (30 mL). The whole was extracted with AcOEt (30 mL×3). Organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give the crude product. Gilson PHPLC purification gave 5-bromo-6-methyl-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:3]=1.[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=1.[OH-].[Na+]>ClCCl>[Cl:8][C:6]1[N:7]=[C:2]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=2)[N:3]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=1
Reactant: C=Cc1ccc(O)cc1
Reactant: Cc1cc(C)c(Oc2nc(Cl)nc(Cl)n2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=Cc1ccc(Oc2nc(Cl)nc(Oc3c(C)cc(C)cc3C)n2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 25.57 g (0.09 moles) 2,4-dichloro-6-(2,4,6-trimethylphenoxy)-1,3,5-triazine in 300 ml of dichloromethane was treated with 11.8 g (0.098 moles) p-hydroxystyrene (prepared by hydrolysis of p-acetoxystyiene) dissolved in about 40 ml dichloromethane. The mixture was cooled in an ice-water bath and 36.8 g of 10% aqueous sodium hydroxide solution was added with stirring over about 5 minutes. Stirring was continued for 30 minutes after which time the ice-water bath was removed and stirring was continued for about 2 hours. The mixture was treated with brine, the layers were separated, and after standing, the organic layer was washed twice with brine, and once with water, and dried over magnesium sulfate. Filtration and evaporation gave a white solid with proton NMR spectrum consistent with the desired product, 2-chloro-4-(4-ethenylphenoxy)-6-(2,4,6-trimethylphenoxy)-1,3,5-triazine.
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4](=[O:18])[CH:3]=1.[Cl:19]N1C(=O)CCC1=O>C(#N)C>[Cl:19][C:3]1[C:4](=[O:18])[N:5]([CH2:10][CH:11]([CH2:16][CH3:17])[CH2:12][CH2:13][CH2:14][CH3:15])[C:6](=[O:9])[N:7]([CH3:8])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCC(CC)Cn1c(=O)cc(Cl)n(C)c1=O
Solvent: CC#N
Product: CCCCC(CC)Cn1c(=O)c(Cl)c(Cl)n(C)c1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 111.2 %

Procedure:
To a solution containing 20 g of 6-chloro-3-(2-ethylhexyl)-1-methyluracil thus obtained in 50 ml of acetonitrile was added 8.6 g of N-chlorosuccinimide, and the mixture was heated to 40° C. and stirred for 2 hours. After allowing the mixture to cool, the acetonitrile was distilled off under reduced pressure, to the residue was added water and it was extracted with 100 ml of chloroform. The organic phase was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The chloroform was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 22 g of 5,6-dichloro-3-(2-ethylhexyl)-1-methyluracil as an oily product.
Reaction SMILES: [OH:1][CH:2]([CH3:38])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19]Br)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[SH:39][C:40]1[NH:41][CH:42]=[CH:43][N:44]=1.[H-].[Na+].O>CN(C=O)C.C(OCC)C>[OH:1][CH:2]([CH3:38])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][S:39][C:40]2[NH:41][CH:42]=[CH:43][N:44]=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]
Reactant: CCCOc1c(OCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Reactant: Sc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(OCCSc2ncc[nH]2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trans-2-[3-(2-hydroxy-n-propylsulfonyl)-4-n-propoxy-5-(2-bromoethoxy)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (47 mg, 0.07 mmol)(Example 19A) in DMF (250 mL) was added to a mixture of 2-mercaptoimidazole (25 mg, 0.25 mmol) and NaH (56%; 10 mg, 0.25 mmol) in DMF (0.5 mL) under nitrogen, and the mixture was stirred at room temperature for 30 min. Water (5 mL) and ethyl ether (5 mL) were added, and the mixture was stirred for another 5 min. The ethereal layer was separated, dried over MgSO4, and filtered. The filtrate was evaporated to a residue, which was purified by preparative TLC (EtOAc) to give the title compound: Rf 0.5; MS, m/z 636 M+. ; NMR (CDCl3) δ 1.02 (t, CH2CH2CH3), 1.24 (d, CH2CHOHCH3), 1.85 (m, CH2CH2CH3), 2.0 and 2.49 (2 m, H-3 and H-4), 3.42 (m, CH2S), 3.54 (m, CH2CHOH) 3.84 and 3.88 (2 s, 3 OCH3), 4.18 (m, CH2CH2S), 4.3 (m, CH2CHOH), 4.38 (t, CH2CH2CH3), 5.22 (m, H-2 and H-5), 6.62 (s, C5ArH), 6.96 (s, NH), 7.1 (s, imidazole), 7.32 and 7.50 (2 d, J=1.5 Hz, C2ArH).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:28])[C:13]2[O:19][C:18]3[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:17]=3[CH2:16][S:15](=[O:26])(=[O:25])[C:14]=2[CH:27]=1)=[O:9].[N+:29]([O-])([OH:31])=[O:30]>>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:28])[C:13]2[O:19][C:18]3[C:20]([Cl:24])=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[CH:23][C:17]=3[CH2:16][S:15](=[O:25])(=[O:26])[C:14]=2[CH:27]=1)=[O:9]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cccc(Cl)c1O2
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc([N+](=O)[O-])cc(Cl)c1O2
Temperature: 5 °C
Reaction time: 0.42 h

Procedure:
Concentrated sulfuric acid (240 mL, 4.2 mol) was added to a solution of compound of Example 1i (37 g, 0.105 mol) in concentrated nitric acid (1100 mL, 17.34 mol) at 5° C. The reaction mixture was stirred at 5° C. for 25 min, and then at 40° C. for 4.5 h. Reaction mixture was quenched into ice water (2500 mL), the solid precipitated was filtered, washed with water till filtrate was neutral to pH and dried to obtain the title compound. Yield: 38 g (90.91%); 1H NMR (CDCl3, 300 MHz): δ 2.7 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 4.79 (s, 2H, CH2), 8.10 (s, 1H, Ar), 8.22 (s, 1H, Ar), 8.38 (s, 1H, Ar), 8.48 (s, 1H, Ar); MS: m/e (ES−) 396 (M−1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.[C:30]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31]1.Cl>N1C=CC=CC=1>[O:8]=[C:6]1[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:27])[F:29])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4][C@H:3]([CH2:2][O:1][C:30]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:36])[O:7]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 50 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
The 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (50 mg, 0.12 mmol) obtained in step B of Example 1-14 was dissolved in pyridine (3 ml). Thereafter, succinic anhydride (14 mg, 0.14 mmol) was added to the solution, and the obtained mixture was then stirred at 50° C. for 6 hours. Thereafter, succinic anhydride (24 mg, 0.25 mmol) was further added to the reaction solution, and the obtained mixture was then stirred at 50° C. for 15 hours. Thereafter, 1 N hydrochloric acid was added to the reaction mixture, and precipitated powders were collected by filtration. The obtained filtrate was washed with water. The resultant was subjected to air-drying, and was then dried under reduced pressure, so as to obtain 3-{(R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethoxycarbonyl}propionic acid (46 mg, 74%) in the form of white powders.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]2=[O:17])=[C:5]1[C:27]([O:29]C)=[O:28])[CH:2]=[CH2:3].C[N+]1([O-])CC[O:35]CC1.O>CC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13](=[O:14])[N:4]3[CH2:1][CH:2]([CH2:3][OH:35])[O:29][C:27](=[O:28])[C:5]3=2)[C:10]1=[O:17]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCn1c(C(=O)OC)c2c(c(OC)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)=O
Product: COc1c2c(c3n(c1=O)CC(CO)OC3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.20 g, 0.46 mmol), N-methylmorpholine N-oxide (67 mg, 0.58 mmol), water (0.2 mL), and osmium tetroxide (0.75 mL, 0.08 M in t-butanol) in acetone (1 mL) was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the title compound. (ES MS M+1=437.2)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]3[CH:21]=[C:22]([F:26])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[CH2:6][CH3:7].[C:27](Cl)(=[O:29])[CH3:28].Cl>[N+](C1C=CC=CC=1)([O-])=O.C1(C)C=CC=CC=1>[C:27]([C:23]1[CH:24]=[CH:25][C:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([C@H:11]3[CH2:10][CH2:9][C@H:8]([CH2:5][CH2:6][CH3:7])[CH2:13][CH2:12]3)[CH2:15][CH2:16]2)=[CH:21][C:22]=1[F:26])(=[O:29])[CH3:28]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cccc(F)c3)CC2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(C)=O)c(F)c3)CC2)CC1
Temperature: 0 °C

Procedure:
Successively, anhydrous aluminum chloride (30.8 g, 0.23 mol) was dissolved in nitrobenzene (150 ml), followed by adding to the solution, the total quantity of the above compound 3-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (38.7 g) at room temperature, dissolving the mixture together with stirring, adding acetyl chloride (27.3 g, 0.348 mol) over 15 minutes, reacting the mixture on heating at a reaction temperature of 35°-40° C. for 2 hours, adding the reaction solution after completion of the reaction to a mixture of 6N hydrochloric acid (50 ml) with ice water (500 g) to subject them to decomposition reaction, adding toluene (500 ml) to extract the resulting oily layer, washing the extract solution with an aqueous solution of sodium hydrogen carbonate, further washing it with water until the washing water became neutral, distilling off toluene and nitrobenzene and recrystallizing the residue from ethyl acetate to obtain 2-acetyl-5-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (a compound of the formula (VII) wherein R1 =C3H7 and R"=CH3) (23.8 g). This product exhibited liquid crystal phases and had a crystal-nematic phase transition point (C-N point) of 90.5° C. and a nematic phase-isotropic liquid phase transition point (N-I point) of 204.7° C. (iii) Successively, the compound 2-acetyl-5-[trans-4-(trans-4-propylcyclohexyl) cyclohexyl]fluorobenzene (23.8 g) was added to diethylene glycol (100 ml), followed by agitating the mixture, adding hydrazine hydrate (17.9 g) and potassium hydroxide (20.1 g), gradually raising the temperature with stirring to react the mixture at 180° C. for 3 hours, allowing the resulting material to cool down to room temperature, adding water (500 ml), extracting the deposited crystals with toluene (100 ml), washing the extract solution with water, drying it over anhydrous sodium sulfate, distilling off toluene and recrystallizing from ethyl acetate to obtain 2-ethyl-5-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (15.2 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[Si](C)(C)CC[Si]2(C)C)=[N:6][CH:7]=1.C([Li])CCC.[CH2:22]([S:24]SCC)[CH3:23]>O1CCCC1>[CH2:22]([S:24][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)[CH3:23]
Reactant: CCSSCC
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCSc1ccc(N)nc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a solution of 5-bromo-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)pyridine (4 g, 12.7 mmol, J. Am. Chem. Soc. 1997, 119, 5499-5511) in tetrahydrofuran (40 mL) was added n-butyllithium at −78° C. under nitrogen. After 2 h, diethyl disulfide (1.7 mL, 12.7 mmol) was added and the mixture was stirred at −78° C. for 3 h. The temperature was gradually raised to room temperature over 2 h. The mixture was poured into ice aqueous sodium hydrogencarbonate. The organic layer was separated and extracted with 2 N hydrochloric acid. The aqueous layer was separated and basified and the mixture was extracted with ethyl acetate (50 mL×4). The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 as eluent) to afford the title compound (1.23 g, 63%) as a pale brown solid.
Reaction SMILES: C1(O[C:8](=[O:42])[O:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([C:32]5[C:40]6[CH:39]=[CH:38][S:37][C:36]=6[CH:35]=[CH:34][CH:33]=5)[CH2:28][CH2:27]4)[CH:19]=3)[CH2:14][CH2:13][C:12]2=[O:41])C=CC=CC=1.[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.N12CCCN=C1CCCCC2.O>C1COCC1>[S:37]1[CH:38]=[CH:39][C:40]2[C:32]([N:29]3[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18]4[CH:19]=[C:20]5[C:15]([CH2:14][CH2:13][C:12](=[O:41])[N:11]5[CH2:10][O:9][C:8]([N:43]5[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]5)=[O:42])=[CH:16][CH:17]=4)[CH2:31][CH2:30]3)=[CH:33][CH:34]=[CH:35][C:36]1=2
Reactant: C1CCNCC1
Reactant: O=C(OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)Oc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C(OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution (3 ml) of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester phenyl ester (0.29 g) synthesized in the same manner as in Example 5 in THF were added piperidine (0.5 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.05 ml), and the mixture was stirred at room temperature for 16 hr. Water was added and the reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:1) to remove phenol, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) to give the title compound (yield 0.21 g, 74%) as a colorless oil.