Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:17]([NH2:23])=[N:18][CH:19]=[C:20](Br)[CH:21]=1.[CH3:24][N:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[CH3:26].CN(C=O)C>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.C(O)C.O.COCCOC>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:17]([NH2:23])=[N:18][CH:19]=[C:20]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][N:25]([CH3:26])[CH3:24])=[CH:29][CH:30]=2)[CH:21]=1
Reactant: Nc1ncc(Br)cc1-c1nc2ccccc2o1
Reactant: CN(C)Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: COCCOC
Product: CN(C)Cc1ccc(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cc1
Temperature: 160 °C
Yield: 17.7 %

Procedure:
2M Sodium carbonate solution (0.4 ml) was added to a solution of 3-(benzoxazol-2-yl)-5-bromo-pyridin-2-amine (0.10 g), [4-(dimethylaminomethyl)phenyl]boronic acid (0.075 g) and dichlorobis(triphenylphosphine)palladium (II) (0.003 g) in a mixture of 2:7:3:2 DMF:DME:water:ethanol (3 ml). The reaction mixture was heated at 160° C. for 7 mins in a 100 W microwave oven. The solvent was evaporated in a Genevac and NMP (1.8 ml) was added. The mixture was filtered and purified by X bridge preparative HPLC. There was thus obtained the title compound (0.021 g); Mass Spectrum: M+H+ 344, RT 2.82 min.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClCCl.CO>[Cl:1][C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)c(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(CN2CCCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 3.1.b. from 1-(2-chloro-4-nitrobenzyl)piperidine. Yield: 1.88 g (90% of theory); C12H17ClN2 (M=224.73); calc.: molecular ion peak (M+H)+: 225/227 (Cl); found: molecular ion peak (M+H)+: 225/227 (Cl); Rf value: 0.2 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[CH2:27][N:28]=[C:29]=[S:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[N:39]=1>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[CH2:27][NH:28][C:29]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[N:39]=2)=[S:30])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:35][CH:34]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN)n1
Reactant: COc1ccc(C(OCc2cccc(CN=C=S)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(OCc2cccc(CNC(=S)NCc3cccc(CO[Si](C)(C)C(C)(C)C)n3)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 110.4 %

Procedure:
To a solution of 3-(4,4′-dimethoxytrityloxymethyl)benzyl isothiocyanate (21) (332 mg, 0.69 mmol) in CDCl3 (4.6 mL) was added a solution of 2-aminomethyl-6-[(tert-butyldimethylsilyloxy)methyl]pyridine (3) (63.10 mg, 0.39 mmol) in CDCl3 (3 mL). The air was evacuated from the reaction system, and then Ar was charged therein. The reaction mixture was refluxed for 5 hours. TLC was used to confirm there was no starting material in the mixture. Then, the reaction mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=3:1 to 2:1) to give N-[3-(4,4′-dimethoxytrityloxymethyl)benzyl]-N′-{[6-(tert-butyldimethylsilyloxymethyl)pyridin-2-yl]methyl}thiourea (22) (316 mg, 62%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2C=C)=[C:4]([CH:25]=[CH2:26])[N:3]=1>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl>[NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]2[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH:26]=[CH:25][C:4]=2[N:3]=1
Reactant: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(N)nc1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: COc1ccc2c(ccc3nc(N)c(Cc4ccccc4)nc32)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 25.4 %

Procedure:
Under an argon atmosphere, to a solution of Hoveyda-Grubbs second generation catalyst (84.5 mg, 135 μmol) in 1,2-dichloroethane (100 mL) was added 2-amino-3-benzyl-5-(4-methoxy-2-vinylphenyl)-6-vinylpyrazine (9) (585 mg, 1.70 mmol) at room temperature. The mixture was then heated to 90° C. and stirred overnight (17 hours). After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1→2/1) to give 3-amino-2-benzyl-8-methoxybenzo[f]quinoxaline (12) as a white solid (136 mg, 431 μmol, 25.3%). TLC Rf=0.64 (n-hexane/ethyl acetate=1/1); 1H NMR (500 MHz, CDCl3) δ 3.98 (s, 3H), 4.39 (s, 2H), 4.63 (s, 2H), 7.21-7.38 (m, 7H), 7.63 (d, 1H, J=9.0 Hz), 7.85 (d, 1H, J=9.0 Hz), 9.00 (d, 1H, J=9.0 Hz); 13C NMR (126 MHz, CDCl3) δ 41.8, 55.4, 107.5, 118.1, 124.9, 125.5, 125.8, 127.2, 128.7 (2C), 129.1 (2C), 130.1, 132.7, 134.6, 136.6, 138.9, 143.1, 151.2, 158.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].IC.[C:12](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(C)c(Cl)c1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
Heat a solution of 3-chloro-4-methylphenol (15 g, 0.11 mol), iodomethane (9.8 mL, 0.16 mol), and potassium carbonate (22 g, 0.16 mol) in DMF (200 mL) to 50° C. and stir for 2 hr. Cool the reaction to room temperature and quench with 1N aqueous HCl. Extract the aqueous with diethyl ether (Et2O). Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 16.4 g (100%) of the desired product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH3:15])=[CH:21][CH:20]=1
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: Nc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Yield: 79.2 %

Procedure:
A mixture of 1-(4-methylsulfonylphenyl)-1,4-pentanedione (580 mg, 2.28 mmol) of Step 2, 4-fluoroaniline (0.24 ml, 2.5 mmol) and p-toluenesulfonic acid (30 mg) in toluene (50 ml) was heated to reflux for 20 hours. The reaction mixture was cooled, filtered and concentrated. The crude mixture (820 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl)-1H-pyrrole (595 mg, 79%) as a white solid: mp (DSC) 157° C. Anal Calc'd. for C18H16NSO2F: C, 65.64; H, 4.90; N, 4.25; S, 9.73. Found: C, 65.44; H, 5.05; N, 4.16; S, 9.90.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:28]1([CH:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN(CC)CC>CN(C=O)C.O>[CH:34]([NH:35][C:8]([C:7]1[C:2]([OH:1])=[N:3][C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[N:5][CH:6]=1)=[O:10])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(c1ccccc1)c1ccccc1)c1cnc(-n2cccn2)nc1O
Temperature: 105 °C
Reaction time: 0.75 h

Procedure:
4-Hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid (1-1-a, 8 g, 38.8 mmol) and CDI (7.24 g, 44.6 mmol) was dissolved in DMF (80 mL), stirred for 45 min at 105° C., then cooled to 77° C. Diphenylmethanamine (9.2 g, 50.4 mmol) and Et3N (5.41 ml, 38.8 mmol) were then added to the solution at 77° C. and the reaction mixture was stirred for 5 h. The resulting mixture was cooled to ambient temperature, diluted with 150 ml of water, extracted with ethyl acetate (3 times 150 ml). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4, purified by recrystillized in EtOH/Et2O (1/10). A yellow solid was obtained as product, 1-1-b, (6.4 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ 6.32-6.34 (d, J=8.4, 1H), 6.50-6.51 (m, 1H), 7.29-7.43 (m, 11H), 7.74 (s, 1H), 8.55-8.58 (m, 2H), 11.77 (s, 1H). LC-MS 372 [MH]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[CH3:31][CH:32]([NH2:34])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:32]([NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1)([CH3:33])[CH3:31]
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (87.0 mg, 0.213 mmol) and propan-2-amine (18.89 mg, 0.319 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.065 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture was stirred at room temperature for 3 h and purified using HPLC (10-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-isopropyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide (62.1 mg, 0.138 mmol, 64.9% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.13 (d, J=6.57 Hz, 6 H) 1.84-2.01 (m, 3 H) 2.12-2.22 (m, 1 H) 2.41 (d, J=4.29 Hz, 4H) 3.36-3.47 (m, 1H) 3.49-3.64 (m, 5 H) 3.95-4.10 (m, 2 H) 6.81 (d, J=8.84 Hz, 1 H) 6.99 (d, J=2.02 Hz, 1 H) 7.61 (d, J=1.77 Hz, 1 H) 7.94 (dd, J=9.09, 2.53 Hz, 1H) 7.97 (d, J=7.83 Hz, 1 H) 8.57 (d, J=2.53 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C24H31N7O2, 450; found, 450.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:20][OH:21])=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH:20]=[O:21])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(CO)n2Cc1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(c1)cc(C=O)n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a solution of lithium aluminum hydride (366 mg) in tetrahydrofuran (20 ml), a solution of 1-(4-fluorobenzyl)-5-methanesulfonylindole-2-carboxylic acid methyl ester obtained in Example 27 (3) (1.86 g) in tetrahydrofuran (20 ml) was added dropwise at 0° C. under nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into water, filtered through Celite and extracted with chloroform. The organic layer was washed with water and dried. The solvent was distilled off under reduced pressure to obtain (1-(4-fluorobenzyl)-5-methanesulfonylindol-2-yl)-methanol (1.8 g). To a solution of the resulting alcohol (1.8 g) in dichloromethane (100 ml) was added manganese dioxide (15.3 g) at 15 to 30° C. and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was filtered through Celite. The solvent was distilled off under reduced pressure to obtain 1.5 g (88.4%) of the desired product as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12](O)=[O:13])=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[CH2:12][OH:13])=[CH:7][CH:8]=1
Reactant: O=C(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
The carboxylic acid 2.1 (13.3 g, 50 mmol) in anhydrous THF (100 mL) was added dropwise to LiAlH4 (2.9 g, 75 mmol) in anhydrous THF (150 mL) at 0° C. over 30 minutes. The resulting mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction was slowly quenched with water (2.9 mL) at 0° C., 15% NaOH aqueous solution (2.9 mL) and another portion of water (8.7 mL). The mixture was dried over Na2SO4 and concentrated to give a white solid (11.9 g). The crude product (2.2) was used in the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17]([O:20][C:21](=O)[CH3:22])(=O)[CH3:18]>CCOC(OCC)(OCC)C1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([O:20][CH2:21][CH3:22])[C:18]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Agent: CCOC(OCC)(OCC)c1ccccc1
Product: CCOC(=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21)c1ccccc1
Reaction time: 24 h

Procedure:
32.6 g (150 mmol) 1,5-diacetyl-2-indolinone are suspended in 100 ml triethyl orthobenzoate and stirred overnight with 150 ml acetic anhydride at 110° C. Then a further 50 ml triethyl orthobenzoate are added and the mixture is stirred for a further 24 h. Then it is evaporated down and the resulting precipitate is suction filtered, washed and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:17][CH:16]2[C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[Cl:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](C1COC(=O)N1)C1C=CC=CC=1>>[CH3:22][O:19][C:18]([CH:16]1[CH2:17][CH:15]1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([Cl:21])[CH:11]=1)=[O:20]
Reactant: O=C(O)C1CC1c1ccc(OCc2ccccc2)c(Cl)c1
Reactant: O=C1NC(Cc2ccccc2)CO1
Product: COC(=O)C1CC1c1ccc(OCc2ccccc2)c(Cl)c1
Yield: 38 %

Procedure:
The mixture (650 mg) of 2-(4-benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid and 4-benzyloxazolidin-2-on obtained in Step D was reacted in the same manner as in Step B of Preparation Example 59 to obtain the title compound (379 mg, two-step yield 38%).
Reaction SMILES: [CH2:1]1[CH:3]2[CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([O:11][C:12]4[N:13]=[N:14][C:15]([Cl:19])=[CH:16][C:17]=4[OH:18])[C:10]=3[CH:2]12.[OH-].[Na+]>CS(C)=O>[CH2:1]1[CH:3]2[CH2:2][C:10]3[C:9]([O:11][C:12]4[N:13]=[N:14][C:15]([Cl:19])=[CH:16][C:17]=4[OH:18])=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]12
Reactant: Oc1cc(Cl)nnc1Oc1cccc2c1C1CC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Oc1cc(Cl)nnc1Oc1cccc2c1CC1CC21
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
In dimethylsulfoxide (3 mL) was dissolved 32.6 mg (0.111 mmol) of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yloxy)-4,6-dichloropyridazine obtained in Example 14 (8), and 0.1 mL (0.2 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to the solution and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice-cold 1 mol/L aqueous sodium hydroxide solution, and washed with ethyl acetate. The aqueous layer was separated, conc. hydrochloric acid was added thereto to adjust pH to 4 in an ice bath, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, dried over sodium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, 1 plate was used, developed by chloroform:methanol=10:1) to obtain 13.4 mg (0.0487 mmol, Yield: 43.9%) of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yloxy)-6-chloro-4-pyridazinol (Compound No. 516).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[N+:4]([O-])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16]>ClCCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:12][OH:16])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1c(C)c[n+]([O-])c(C)c1Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)cnc(CO)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above 3-chloro-4-methoxy-2,5-dimethylpyridine 1-oxide (530 mg) was suspended in 15 ml of dichloromethane, and trifluoroacetic anhydride (0.39 ml) was then added to the suspension under cooling on ice. The resulting mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with chloroform, and was then washed with a saturated sodium bicarbonate solution. The water layer was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away, so as to obtain the title compound (521 mg) as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][N:4]=1)[CH:9]=[O:10]
Reactant: COc1cc(CO)ccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cc(C=O)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a solution of (2-methoxypyridin-4-yl)methanol (6.74 g) and triethylamine (67.5 mL) in DMSO (200 mL) was added sulfur trioxide pyridine complex (30.8 g), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give a crude product of the title compound (4.33 g) as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(Cl)s1
Temperature: 77.5 °C
Reaction time: 0.5 h

Procedure:
3.00 kg of 5-chlorothiophene-2-carboxylic acid (commercially available) are suspended in 8.48 kg of toluene and heated to 75 to 80° C. At this temperature, 2.63 kg of thionyl chloride are added dropwise over a period of 85 minutes, followed by stirring at 75 to 80° C. for 30 minutes and then at the reflux temperature until gas evolution ceases. After cooling, the reaction mixture is distilled under reduced pressure with gradually increasing internal temperature (up to a maximum of 60° C.) to remove excess thionyl chloride and toluene until an approximately 30% strength solution of the acid chloride in toluene is produced.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[S:22](Cl)(=O)=O>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[SH:22]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S(=O)(=O)Cl)c(Cl)cc2F)c1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S)c(Cl)cc2F)c1=O
Temperature: 0 °C
Yield: 97.1 %

Procedure:
1.65 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]benzenesulfonyl chloride was dissolved in 16 ml of acetic acid, to this was added 4.4 g of zinc, then, they were reacted while heating under reflux. After completion of the reaction, the reaction solution was cooled, then, this was poured into ice water, extracted with ethyl acetate, and filtrated. The filtrate was separated, then, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain 1.35 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenyl mercaptan.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N+:13]([O-:15])=[O:14])[C:7]2[O:11][CH2:10][CH2:9][C:8]=2[CH:12]=1)([O-:3])=[O:2].[NH3:16]>C(N)=O>[NH2:16][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=1[CH2:9][CH2:10][OH:11]
Reactant: O=[N+]([O-])c1cc2c(c([N+](=O)[O-])c1)OCC2
Reactant: N
Solvent: NC=O
Product: Nc1c(CCO)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
0.17 Mole (35.7 g) of 2,3-dihydro-5,7-dinitrobenzofuran, prepared according to Chatelus Ann. Chim. [12], 4, 505-547 (1949), is suspended in 350 ml of 20% strength ammonia solution and 220 ml of formamide. After 8 hours' heating at 110° C., a further 100 ml of 20% strength ammonia solution are added. Heating is maintained for 4 hours. When the reaction medium is cooled, the expected product precipitates.
Reaction SMILES: [Na:1].[CH2:2]1[O:4][CH2:3]1.[C:5]([OH:10])(=[O:9])[C:6]([CH3:8])=[CH2:7].[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=[CH2:21].[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])[CH:26]=[CH2:27].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O>[CH:11]([CH2:7][C:6](=[CH2:8])[C:5]([OH:10])=[O:9])=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])[CH:26]=[CH2:27].[Na:1].[CH2:3]1[O:4][CH2:2]1.[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)O
Agent: C=CC(=O)OCCCC
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: C1CO1
Solvent: O
Product: C=C(CC=Cc1ccccc1)C(=O)O
Temperature: 75 °C
Reaction time: 0.33 h

Procedure:
To a reaction vessel provided with a stirrer and a thermometer, 683 parts of water, 11 parts of sodium salt of the sulfuric acid ester of methacrylic acid ethylene oxide adduct (ELEMINOL RS-30, manufactured by Sanyo Chemical Industries, Ltd.), 78 parts of styrene, 83 parts of methacrylic acid, 115 parts of butyl acrylate, 2 parts of butyl thioglycollate and 1 part of ammonium persulphate were poured, and stirred at 400 rpm for 20 minutes to obtain a white emulsion. The white emulsion was heated, the temperature in the system was raised to 75° C. and the reaction was performed for 6 hours. Next, 30 parts of an aqueous solution of 1% ammonium persulphate was added, and the reaction mixture was matured at 75° C. for 5 hours to obtain an aqueous dispersion liquid of a vinyl resin or copolymer of styrene-methacrylic acid-butyl acrylate-sodium salt of the sulfuric acid ester of methacrylic acid ethylene oxide adduct. This aqueous solution was taken as “particulate dispersion liquid 4”.