Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[Cl:28][C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:28][C:29]1[N:34]=[C:33]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)CCN(c1ccnc(Cl)n1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Yield: 79.3 %

Procedure:
A mixture of 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.72 g, 2.0 mmol), 2,4-dichloropyrimidine (0.298 g, 2.0 mmol), and sodium bicarbonate (0.2 g, 2.4 mmol) in ethanol (10 mL) was heated at 80° C. for 3 hours. It was quenched with water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (SiO2, 30-6-% ethyl acetate/hexane) to provide the title compound (0.749 g, 79% yield): 1H NMR (CDCl3) 7.95 (d, 1H), 7.32-7.41 (m, 4H), 6.94 (d, 2H), 6.83 (d, 2H), 6.69 (m, 3H), 6.37 (m, 1H), 5.9 (d, 1H), 5.03 (s, 2H), 4.97 (m, 1H), 3.80 (s, 3H), 3.25-3.62 (m, 2H), 3.13 (m, 1H), 2.86 (m, 3H); ES-MS (m/z) 472 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[CH:24]#[C:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.CN(C)C=O>[Cl:1][C:2]1[CH:22]=[C:21]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(I)cc3Cl)c2n1
Reactant: C#CCCCC
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCCC#Cc1ccc(Cn2c(C)nc3ccc(C(=O)OC)nc32)c(Cl)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
A mixture of methyl 3-(2-chloro-4-iodobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (2.31 g), 1-hexyne (2.00 g), palladium(II) acetate (235 mg), triphenylphosphine (549 mg), copper(I) iodide (297 mg), tributylamine (2.91 g) and dimethylformamide (23 ml) was stirred under an nitrogen atmosphere at 60° C. for 1.5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-1:2) to give the objective compound (1.44 g) as a gray powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:14])([CH3:13])[C:11](=[O:15])[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)[C:9]2=[S:28])=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].N1C=CC=CC=1>ClCCl>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:10]2[C:11](=[O:15])[C:12]([CH3:14])([CH3:13])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:7][CH:6]=3)[C:9]2=[S:28])=[CH:17][C:18]=1[C:24]([F:26])([F:27])[F:25])#[N:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 36 %

Procedure:
A mixture of 4-[3-(4-aminophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile (2d) (0.02 g, 0.05 mmol), methanesulfonyl chloride (0.009 g, 0.075 mmol) and pyridine (0.006 g, 0.075 mmol) in dichloromethane (1 ml) was stirred at room temperature for 15 hours. The medium was washed with water (2 ml) and extracted with ethyl acetate (5 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (HPLC, alumina column) to yield N-{4-[3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]phenyl}methanesulfonamide (47a) [RD150] (0.009 g, 0.018 mmol, 36%), the structure of which is illustrated in Formula 2, as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][CH:10]([O:12][Si](C)(C)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)OC1CN(Cc2ccccc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC1CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
1-Benzyl-3-trimethylsilyloxy-azetidine (1.8 g, 7.65 mmol) prepared in preparation example 25 was dissolved in methanol (9 ml), sodium methoxide (826 mg, 15.29 mmol) was added thereto, and stirred at room temperature for 30 min. The solvent was removed by evaporation under a reduced pressure, and the residue was extracted using ethyl acetate. The organic extract layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure, to obtain 0.964 g (yield: 77%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[CH:4][C:3]=1[CH3:12].[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](Cl)=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:13]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:11][C:5]3[CH:4]=[C:3]([CH3:12])[C:2]([CH3:1])=[CH:7][C:6]=3[C:8](=[O:9])[CH3:10])=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:32][CH3:33])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: CC(=O)c1cc(C)c(C)cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
2-Hydroxy-4,5-dimethylacetophenone (3.63 g), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.50 g), and 4-dimethylaminopyridine (2.71 g) were suspended in o-dichlorobenzene (15 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (1.10 g, yield 37%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:11]2=[O:12])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:11]2=[O:12])=[CH:8][CH:9]=1
Reactant: O=c1ccc2ccccc2n1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(-n2c(=O)ccc3ccccc32)cc1
Yield: 82.6 %

Procedure:
To 10 % Pd-C (0.1 g) is added acetic acid (20 ml) and then 1-(4-nitrophenyl)carbostyril (0.9 g) and the mixture is subjected to catalytic reduction at 80° C. under normal pressure. After completion of the reaction, 10 % Pd--C is removed by filtration and the resulting solution is concentrated under reduced pressure. To the concentrate is added water and the solution is made alkaline with an aqueous sodium hydroxide solution and then extracted with dichloromethane. The extract is washed with water and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is purified by silica gel column chromatography and recrystallized from ethanol to give 1-(4-aminophenyl)carbostyril (0.66 g) as brown powders, m.p. 225°-230° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:4][NH:3]1>C(O)C.[Pd]>[C:24]1([C:5]2[CH:6]=[C:7]([CH:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[C:2](=[O:1])[NH:3][N:4]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2cc(-c3ccccc3)n[nH]c2=O)CC1
Agent: [Pd]
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)cc1C1CCNCC1
Reaction time: 24 h
Yield: 98.5 %

Procedure:
Palladium (10% on carbon; 0.50 g) was added to a solution of benzyl 4-(3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)piperidine-1-carboxylate (1.10 g, 2.82 mmol) in ethanol (50 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 24 h, the mixture was filtered through celite and concentrated to give the title compound (709 mg). MS 256.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([C:12]3([CH2:15][OH:16])[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[I:17]N1C(=O)CCC1=O.B(F)(F)F.O.O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>>[I:17][C:6]1[N:5]2[N:9]=[C:10]([C:12]3([CH2:15][OH:16])[CH2:14][CH2:13]3)[N:11]=[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1cccn2nc(C3(CO)CC3)nc12
Reactant: O=C1CCC(=O)N1I
Agent: FB(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Product: COc1ccc(I)n2nc(C3(CO)CC3)nc12
Reaction time: 24 h
Yield: 52.3 %

Procedure:
A mixture of (1-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropyl)methanol (1.7 g, 7.76 mmol) and N-iodosuccinimide (1.7 g, 7.76 mmol) was treated with BF3.2H2O (8.5 g, 77.6 mmol, 5.3 ml) at RT. After 24 h, the reaction mixture was poured into a 1:1 mixture of the aq. solutions of NaHCO3 (1 M) and Na2S2O3 (1 M) and extracted with DCM. The combined organic phase was washed with H2O, over anhyd. Na2SO4 and concentrated under reduced pressure. The residue obtained was purified by column chromatography to afford (1-(5-iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropyl)methanol (1.4 g, 52%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O-])([O-])=[O:14].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:14][CH3:13])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 50 °C
Yield: 95 %

Procedure:
To a solution of 2.45 g (14.0 mmol) of 1,3,5-trifluoro-2-nitrobenzene in acetone are successively added 2.9 g (21.0 mmol) of K2CO3 powder and 3.5 mL (56.0 mmol) of methyl iodide. The reaction mixture is heated at 50°C. for 2 hours and then filtered and evaporated to dryness. The residue is taken up in ethyl acetate and washed with water and with saturated aqueous NaCl solution. The organic phase is dried over Na2SO4, filtered and concentrated under vacuum. 2.52 g of the expected product are recovered in the form of a yellow solid, which is used as obtained in the following step. Yield=95%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(O)C>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Br)c1
Temperature: 0 °C
Yield: 87 %

Procedure:
To 1.9 g of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile in 30 mL of absolute ethanol was added 1.6 mL of 3-bromoaniline. After refluxing the reaction under an inert atmosphere for 8 hours, the reaction mixture was cooled to 0° C. and the product was filtered and washed with cold ethanol. Drying in vacuo yielded 2.7 g (87%) of 4-(3-bromo-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile as an off-white solid: melting point 185-195° C.; mass spectrum (m/e): M+H 343.0, 345.1.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: Cc1ncccc1N
Product: CCOC(=O)c1cnn2c(Nc3cccnc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 64.5 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.20 g, 0.48 mmol) obtained in Example 19, step 4 and 3-amino-2-methylpyridine (0.105 g, 0.97 mmol), the title compound (0.150 g, 64%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:14][CH:13]=1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)(=[O:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(F)cc3)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OC(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(F)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 545.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[N:29][C:5]2[O:6][CH2:7][CH2:8][C@@H:9]3[C@@:14]([CH3:15])([C:4]=2[CH:3]=1)[N:13]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]1([CH2:26][CH2:25][CH2:24]1)[S:10]3(=[O:28])=[O:27].[C:31]([C:33]1[CH:34]=[CH:35][C:36]([C:39](O)=[O:40])=[N:37][CH:38]=1)#[N:32].O.[Cl-].C[NH+]1CCOCC1>C1COCC1.CO>[C:31]([C:33]1[CH:34]=[CH:35][C:36]([C:39]([NH:1][C:2]2[CH:30]=[N:29][C:5]3[O:6][CH2:7][CH2:8][C@@H:9]4[C@@:14]([CH3:15])([C:4]=3[CH:3]=2)[N:13]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])[C:11]2([CH2:26][CH2:25][CH2:24]2)[S:10]4(=[O:27])=[O:28])=[O:40])=[N:37][CH:38]=1)#[N:32]
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)cnc3OCC[C@H]2S(=O)(=O)C12CCC2
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: C[NH+]1CCOCC1
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(NC(=O)c4ccc(C#N)cn4)cnc3OCC[C@H]2S(=O)(=O)C12CCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl ((4a′R,11b′R)-10′-amino-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate (0.086 g, 0.197 mmol) in THF/MeOH (3/0.9 mL) was added 5-cyano-2-pyridinecarboxylic acid (0.035 g, 0.236 mmol) and 4-(4,)dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate, 99+% (0.070 g, 0.236 mmol) and the resulting mixture was stirred at rt for 1.5 h. The reaction was quenched with sat. NaHCO3 and extracted with DCM. The combined organics were dried over Na2SO4, filtered, concentrated. The residue was purified by silica gel chromatography using a gradient 0-3% MeOH/DCM solvent system to afford a white solid as tert-butyl ((4a′R,11b′R)-10′-(5-cyanopicolinamido)-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate as a white solid. MS m/z=588.9 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl.[CH2:17]([O:19][C:20]([NH:22][C:23]1([CH2:29][N:30]2[CH2:35][CH2:34][N:33]([S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH:45]=[CH2:46])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH2:32][C:31]2=[O:47])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:21])[CH3:18]>C(O)C>[NH2:1][C:2]1[CH:7]=[C:6]([N:26]2[CH2:27][CH2:28][C:23]([CH2:29][N:30]3[CH2:35][CH2:34][N:33]([S:36]([C:39]4[CH:40]=[CH:41][C:42]([CH:45]=[CH2:46])=[CH:43][CH:44]=4)(=[O:38])=[O:37])[CH2:32][C:31]3=[O:47])([NH:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])[CH2:24][CH2:25]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCNCC3)C(=O)C2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=Cc1ccc(S(=O)(=O)N2CCN(CC3(NC(=O)OCC)CCN(c4ccnc(N)c4)CC3)C(=O)C2)cc1
Yield: 20.8 %

Procedure:
2-Amino-4-chloropyridine (132 mg), triethylamine (700 mg) and ethanol (15 ml) were added to 1-{[4-ethoxycarbonylamino-4-piperidinyl]methyl}-4-(4-vinylbenzensulfonyl)-2-piperazinone hydrochloride (250 mg), to react at 155° C. for 20 hours in a sealed tube. The reaction solution was concentrated, a 10% aqueous sodium carbonate solution was added to the residue, the material was extracted with dichloromethane, dried, and concentrated. The resulting residue was dried, concentrated, purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1), and crystallized from dichloromethane-hexane to obtain the title compound (58 mg) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:7]2=O)([O-:3])=[O:2].ClS([N:23]=C=O)(=O)=O.CO>C(#N)C>[NH2:23][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=1
Reactant: COC(=O)c1cc(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1cc(N)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C

Procedure:
To a suspension of methyl 1,4-dihydro-6-nitro-4-oxo-2-quinolinecarboxylate (3.72 g, 15 mmol) obtained in Example 131, Step 2 in acetonitrile (50 ml) was added chlorosulfonyl isocyanate (1.30 ml, 15 mol) and the mixture was refluxed under heating for 1 hr. The reaction mixture was cooled to room temperature and methanol was added, which was followed by concentration under reduced pressure. To the residue was added 2 mol/l aqueous sodium carbonate solution to allow suspending and the insoluble matter was collected by filtration. The insoluble matter was dried under reduced pressure at 80° C. to give methyl 4-amino-6-nitro-2-quinolinecarboxylate as crude brown crystals (3.23 g). This compound was used in the next reaction without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:38])=[C:11]([CH2:13][O:14][C:15]3[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]4[C:25]([CH:26]=[O:27])=[CH:24][N:23]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:22]=4)=[CH:17][C:16]=3[O:36][CH3:37])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:40][C:41]([O:43][CH3:44])=[O:42].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:26]([C:25]1[C:21]([O:20][CH2:19][C:18]2[CH:34]=[CH:35][C:15]([O:14][CH2:13][C:11]3[N:12]=[C:8]([C:4]4[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=4)[O:1][CH2:40][C:41]([O:43][CH3:44])=[O:42])[O:9][C:10]=3[CH3:38])=[C:16]([O:36][CH3:37])[CH:17]=2)=[N:22][N:23]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=1)=[O:27]
Reactant: COC(=O)CBr
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(O)c2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
A mixture of 3-[(4-{[2-(3-hydroxyphenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.80 g), methyl bromoacetate (0.37 g), potassium carbonate (0.33 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl (3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenoxy)acetate as colorless crystals (0.38 g, yield 41%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 107-109° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:10])[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[I:19]>O1CCCC1>[I:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][O:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1ccccc1O
Reactant: BrCc1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1OCc1ccccc1I
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 93.4 %

Procedure:
Sodium hydride (60% oil dispersion) (7.8 g) was added portionwise to a ice-water cooled solution of o-cresol (21.1 g) in tetrahydrofuran (500 mL). The mixture was stirred 20 minutes and then 1-(bromomethyl)-2-iodobenzene (58 g) was added. The mixture was warmed to 60° C. for 16 h. Additional sodium hydride (2 g) was added and the reaction mixture heated for an additional 3 h. The reaction mixture was cooled and carefully quenched with water and extracted with ethyl acetate (2×250 mL). The combined organic extracts were dried (Mg SO4), filtered and concentrated under reduced pressure to an oil, which was triturated with cold hexane to provide a solid which was collected by filtration to yield 59.1 g (94%) of the title compound of Step B as a white solid, mp 106°-108° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:29][C@@H:30]1[O:32][CH2:31]1)(=O)=O.CN(C=O)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][CH2:29][C@H:30]1[CH2:31][O:32]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: O=[N+]([O-])c1ccc(O)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
A 500 mL round bottomed flask equipped with a nitrogen inlet and a magnetic stir bar is charged with: 2-(benzyloxy)-4-nitrophenol (10.00 g, 40.8 mmol), potassium carbonate (7.05 g, 51.0 mmol), (R)-(−)-glycidyl tosylate (10.00 g, 43.8 mmol) and DMF (65 mL). The mixture is immersed in an oil bath heated to 60° C. and stirred for 18 h. The solution is allowed to cool to rt, then water (200 mL) is slowly added. The resulting suspension is stirred for 2 h, the precipitate is collected by vacuum filtration and the filter cake is washed with water (25 mL). The cake is dried under suction to yield 10.70 g (87%) of the title compound as a light yellow powder. LCMS (Standard Method): 2.74 min, 302 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J=2.6, 9.0 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.48-7.34 (m, 5H), 6.98 (d, J=8.8 Hz, 1H), 5.19 (s, 2H), 4.43 (dd, J=2.7, 11.5 Hz, 1H), 4.08 (dd, J=5.8, 11.5 Hz, 1H), 3.43-3.39 (m, 1H), 2.95-2.91 (m, 1H), 2.81-2.78 (m, 1H).