Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[CH2:11]([S:14][C:15]1([C:18]([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=O)[CH2:17][CH2:16]1)[CH2:12][CH3:13].[OH-].[K+]>C(O)(C)(C)C>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:21]=[CH:20][C:18]1([C:15]2([S:14][CH2:11][CH2:12][CH3:13])[CH2:16][CH2:17]2)[CH2:10][O:9]1
Reactant: CCCSC1(C(=O)C=Cc2ccc(Cl)cc2Cl)CC1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CSC
Product: CCCSC1(C2(C=Cc3ccc(Cl)cc3Cl)CO2)CC1
Reaction time: 14 h
Yield: 89.2 %

Procedure:
30 ml (0.41 mol) of dimethyl sulphide and 43.5 g (0.35 mol) of dimethyl sulphate are added to 60 ml of tert.-butanol and allowed to stand at room temperature for 14 hours. A solution of 40 g (0.13 mol) of 2,4-dichlorophenylethenyl 1-propylmercaptocyclopropyl ketone in 120 ml of tert.-butanol is first added to the reaction mixture with stirring and 39.1 g of potassium hydroxide powder are then introduced, while keeping the temperature of the reaction mixture at 20° to 30° C. The mixture is stirred at 30 C. for 3 hours more, then the dimethyl sulphide is removed under reduced pressure and the reaction mixture is then poured into 70 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed with water and concentrated by removing the solvent under reduced pressure after drying over sodium sulphate. In this manner, 38.2 g (91% of theory) of 2-(2,4-dichlorophenylethenyl)-2-(1-propylmercaptocyclopropyl)-oxirane are obtained in the form of an oily product, which is reacted further without additional purification. ##STR73##
Reaction SMILES: ClS(O)(=O)=O.S(=O)(=O)(O)O.C(O)(=O)/C=C/C(O)=O.C(O)(=O)/C=C\C(O)=O.[N+:27]([C:30]1[CH:46]=[CH:45][CH:44]=[CH:43][C:31]=1[O:32]/[C:33](=[CH:38]\[C:39]([O:41]C)=O)/[C:34]([O:36][CH3:37])=[O:35])([O-:29])=[O:28].[N+](C1C=CC=CC=1O/C(=C/C(OC)=O)/C(OC)=O)([O-])=O>>[N+:27]([C:30]1[C:31]2[O:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][C:39](=[O:41])[C:43]=2[CH:44]=[CH:45][CH:46]=1)([O-:29])=[O:28]
Reactant: COC(=O)/C=C(\Oc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: COC(=O)/C=C(/Oc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C(O)/C=C\C(=O)O
Product: COC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Temperature: 60 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A reaction container equipped with a stirrer, a cooling tube and a thermometer was charged with 50.2 parts by weight of chlorosulfonic acid. Thereto, 25.0 parts by weight of 98% sulfuric acid was added dropwise over 1 hour and the mixture was then warmed to 60° C. Thereto, 25.3 parts by weight of the mixture (content: 89.6% by weight, fumaric acid/maleic acid ratio=54/46) containing dimethyl 2-(2-nitrophenoxy)fumarate and dimethyl 2-(2-nitrophenoxy)maleate obtained in Example 10 was added dropwise at an inner temperature of 60° C. over 4 hours. After completion of addition, the inner temperature was raised to 95° C. and the mixture was stirred and kept at the same temperature for 4 hours to obtain a reaction solution containing 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield: 88%). The reaction solution was poured gradually into 113 parts by weight of water at 85° C. or below. The mixture was kept at an inner temperature of 85° C. for 6 hours and then cooled gradually to an inner temperature of 25° C. Precipitated crystals were filtered and dried to obtain 16.3 parts by weight of a crystalline mixture of 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran and 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran: 13.8% by weight; the content of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 84.6% by weight). The yield of 8-nitro-2-methoxycarbonyl-4-oxo-4H-1-benzopyran was 11.5% and the yield of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 74.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH2:24].[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:16]=[C:17]([Cl:22])[CH:18]=[C:19]([Cl:21])[CH:20]=2)[C:11]([F:13])([F:14])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:23][NH:24][C:28]([NH:27][CH2:25][CH3:26])=[O:29]
Reactant: CCN=C=O
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Solvent: ClCCl
Product: CCNC(=O)NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and ethylisocyanate (0.053 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.141 g, 60%): mp 177-178° C.; 1H NMR (400 MHz, CDCl3) δ 7.58 (m, 2H), 7.41 (m, 3H), 7.24 (m, 1H), 6.53 (d, J=16.0 Hz, 1H), 6.35 (dd, J=16.0, 8.0 Hz, 1H), 4.70 (br s, 1H), 4.43 (s, 2H), 4.08 (m, 1H), 3.21 (m, 2H), 1.25 (m, 3H); ESIMS m/z 463 ([M−H]−).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:15]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25]I>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:15]2[CH3:25])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C
Reaction time: 2 h

Procedure:
To a stirred suspension of sodium hydride (0.27 g, 60% dispersion in mineral oil) in DMF (50 mL) under nitrogen at room temperature was added ethyl 4-benzyloxyindole-2-carboxylate (1.59 gm). Methyl iodide (0.5 mL) was added 10 min. later. After 2 hr. excess sodium hydride was quenched with acetic acid (0.4 mL) and the solvent evaporated under reduced pressure. The residue was taken into EtOAc, washed with water and brine, dried over MgSO4, and evaporated to dryness to give an oil which was triturated with hexane to precipitate 1.45 g of the title compound. Mp 89-90.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:31][C:32](=[O:34])[CH3:33].FC(F)(F)C(O)=O.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][NH:19]4)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:31][C:32](=[O:34])[CH3:33]
Reactant: CC(=O)Nc1ccc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Nc2ncccc2-c2nc(C)nc3[nH]cnc23)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A mixture of N-(2-chloro-4-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)acetamide (100 mg, 0.209 mmol) in DCM (3 mL) was cooled to 0° C., treated with trifluoroacetic acid (3 mL, 40.4 mmol), and the yellow solution was stirred at 0° C. for 1 h. The mixture was concentrated in vacuo, the residue was treated with 2 M NH3 in MeOH and concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 2% to 10% 2M NH3.MeOH in DCM, to give N-(2-chloro-4-(3-(2-methyl-9H-purin-6-yl)pyridin-2-ylamino)phenyl)acetamide (70 mg, 0.178 mmol, 58.3% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.62 (s, 1H); 13.01 (s, 1H); 9.80 (s, 1H); 9.47 (s, 1H); 8.38-8.43 (m, 1H); 8.31 (d, J=1.57 Hz, 1H); 7.54-7.60 (m, 1H); 7.47-7.52 (m, 1H); 7.07 (dd, J=7.82, 4.69 Hz, 1H); 2.88 (s, 3H); 2.07 (s, 3H). m/z (ESI, +ve ion) 394 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH:19]([O-])=[O:20].[Na+].[C]=O>CN(C)C=O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:19]([C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:20]
Reactant: O=C[O-]
Reactant: COc1ccc(Br)cc1CNC(=O)OC(C)(C)C
Agent: [C]=O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1CNC(=O)OC(C)(C)C
Yield: 75.1 %

Procedure:
1.015 g of tertiary butyl N-(5-bromo-2-methoxybenzyl)carbamate, 45 mg of dichlorobis(triphenylphosphine) palladium (II), 330 mg of sodium formate and 17 mg of triphenyl phosphine were dissolved in anhydrous N,N-dimethylformamide and stirred at 110° C. for 2 hours in a carbon monoxide atmosphere. The reaction mixture was diluted with ethyl acetate, and successively washed with water and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 640 mg of tertiary butyl N-(5-formyl-2-methoxybenzyl)carbamate was obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)[N:12]=[CH:11][N:10]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(-n2ccnc2)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of sodium hydride (0.65 g, 55% dispersion in oil, pre-washed with petrol) in dry DMF (5 ml) at 10°-15° C. under nitrogen, was added a solution of imidazole (1.02 g, 15 mmol) over five minutes. The reaction mixture effervesced and an exotherm took place. After stirring for 11/2 hours at room temperature, the cloudy solution was added drop-wise over one hour to a solution of 4,6-dichloropyrimidine in dry DMF (10 ml) at 0° C. for one hour, added to water and then extracted with ether (×3). The combined ether extracts were washed with dilute sodium hydroxide solution and water (×3) and then dried. Concentration under reduced pressure gave 4-chloro-6-(imidazol-1-yl)pyrimidine as a pale yellow solid (1.00 g); m.p. 122°-4° C., which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[N:3]=[CH:4][N:5]=1
Reactant: c1c[nH]cn1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(-n2ccnc2)ncn1
Yield: 63.1 %

Procedure:
A mixture of 4,6-dichloropyrimidine (5.96 g, 40 mmol), imidazole (2.72 g, 40.0 mmol), and potassium carbonate (5.53 g, 40.0 mmol) was stirred in DMF (50 mL) at room temperature for 18 h. The reaction was diluted into 500 mL water and extracted five times with 150 mL EtOAc. The combined organic layers were concentrated and purified by flash chromatography on a 240 g silica gel cartridge with 0 to 10% methanol in ethyl acetate to yield 4-chloro-6-(1H-imidazol-1-yl)pyrimidine (4.56 g, 63% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.85 (1H, d, J=0.76 Hz), 8.45 (1H, s), 7.62 (1H, t, J=1.51 Hz), 7.34 (1H, d, J=0.76 Hz), 7.23 (1H, dd, J=1.38, 0.88 Hz). LCMS: RT=0.47 min, MH+=181.1.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[OH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:10](=[O:12])[CH3:11])[CH2:3][CH2:2]1
Reactant: OCCN1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCN(CCO)CC1
Yield: 65 %

Procedure:
A solution of 2-(1-piperazinyl)-1-ethanol (6.5 g, 0.05 mol) in DCM (5 mL) was treated with acetic acid anhydride (5.1 g, 0.05 mol), added dropwise. During addition, the reaction temperature rose from 22 to 60° C. The reaction mixture was evaporated several times with toluene to yield 5.6 g (65%) of the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(C=C(C(=O)O)c2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(CC(C(=O)O)c2ccccc2)cc1

Procedure:
Palladium on activated carbon (10% wt., 2.77 g) was added to a solution of 3-(4-methoxyphenyl)-2-phenylacrylic acid (27.7 g, 0.11 mol) in acetic acid (1000 ml). The mixture was hydrogenated at ambient temperature. The mixture was filtered through Celite, and the solvent was evaporated. The product was recrystallized from a small amount of ethyl acetate. Melting point 220-221° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(OCC)(=O)C>C(Cl)(Cl)Cl.O>[CH3:21][S:22]([O:13][CH:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Boc-3-pyrrolidinol (1000 mg) was dissolved in chloroform (20 ml). Triethylamine (1.15 ml) and methanesulfonyl chloride (498 μl) were added thereto at 0° C. After stirring at room temperature for 1.0 hour, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.2 g). Physical properties: m/z [M+H]+ 266.1
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>ClCCl>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[N+:3]([O-:18])[CH:4]=1)#[N:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C#N)cn1
Solvent: ClCCl
Product: Cc1ccc(C#N)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 6-methylnicotinonitrile (4.15 g) and 3-chloroperbenzoic acid (8.3 g) in dichloromethane (200 ml) was stirred under an argon atmosphere at room temperature for 16 h. The dichloromethane was evaporated under reduced pressure and the residue purified by flash column chromatography on silica (K60), using ethyl acetate and then methanol: dichloromethane (1:9 by volume) as eluting solvent to give 5-cyano-2-methylpyridine-1-oxide, mp 133.5°.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH3:10]O.OS(O)(=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:10][O:8][C:7]([CH:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1)=[O:9]
Reactant: CO
Reactant: O=C1CCC(C(=O)O)N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(=O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of DL-pyroglutamic acid (50 g, 0.387 mol) in 157 mL CH3OH (3.87 mol) and 100 mL toluene was added concentrated H2SO4 (2.5 mL). This mixture was warmed to reflux and allowed to stir for 16 h. Since starting material remained, another 4 mL concentrated H2SO4 was added and the mixture stirred at reflux for an additional 24 h then was cooled to ambient temperature and 20% aqueous NaOH was added to bring the solution to pH ˜6. The mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2, filtered through Celite® diatomaceous earth, concentrated and purified via Kugelrohr distillation. The resulting material was carried on directly to the next reaction.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1>C(O)C>[CH3:1][C@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][C@@H:4]([CH3:9])[O:3]1
Reactant: Cc1cc(=O)cc(C)o1
Solvent: CCO
Product: C[C@@H]1CC(=O)C[C@H](C)O1
Reaction time: 24 h

Procedure:
2,6-Dimethyl-4H-pyran-4-one (2.0 g, 16 mmol) was dissolved in ethanol (10 mL) and purged under nitrogen. Palladium on carbon (5%, 200 mg) was then added and the reaction mixture stirred under hydrogen gas (40 psi) for 24 hours. The reaction mixture was filtered over CELITE, rinsed with ethanol, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5 to 30% EtOAc/hexanes) to afford cis-2,6-dimethyltetrahydro-4H-pyran-4-one as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 3.77-3.70 (m, 2H), 2.38-2.32 (m, 2H), 2.25-2.20 (m, 2H), 1.32 (d, J=6.1 Hz, 6H).
Reaction SMILES: [CH3:1][CH:2]([N:11]([CH3:13])[CH3:12])[CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.FC(F)(F)C(O)=O>CS(C)=O.C([O-])(O)=O.[Na+]>[CH3:12][N:11]([CH3:13])[CH:2]([CH3:1])[C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:10]
Reactant: CC(C(O)c1ccccc1)N(C)C
Agent: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)c1ccccc1)N(C)C
Yield: 90.7 %

Procedure:
N-Methylephedrine (200 mg; 1.12 mmol) was added to a solution of o-iodoxybenzoic acid I (1.56 g, 5.59 mmol) and trifluoroacetic acid (0.13 ml) in DMSO (12 ml). After 8 hours the solution was diluted with NaHCO3 (2.5%, 30 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (2×5 ml), dried over sodium sulfate and evaporated to dryness under vacuum to give 180 mg (90%) of 2-dimethylamino-1-phenyl-propan-1-one identical to the sample obtained in Example 31.
Reaction SMILES: [CH2:1](OCC)[CH3:2].C([Mg]Br)C.[C:10]([C:14]1[CH2:18][CH2:17][C:16](=O)[CH:15]=1)([CH3:13])([CH3:12])[CH3:11].Cl>O>[CH2:1]([C:17]1[CH2:16][CH:15]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:18]=1)[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)CC1
Reactant: CCOCC
Agent: CC[Mg]Br
Agent: Cl
Solvent: O
Product: CCC1=CC(C(C)(C)C)=CC1
Temperature: 0 °C
Yield: 78 %

Procedure:
To a 300 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock, 200 ml of dehydrated diethyl ether and 52 ml (154 mmol) of diethyl ether solution of 3.0 M ethyl magnesium bromide were charged under a nitrogen atmosphere. In the ice and water bath, 17.8 g (129 mmol) of 3-tert-butylcyclopentenone was added dropwise over 1 hour. The resultant solution was stirred at room temperature for 20 hours, and then the reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with 50 ml of ether. The obtained organic layers were combined, washed twice with a saturated aqueous solution of sodium hydrogencarbonate, twice with water, and twice with saturated brine, and dried over magnesium sulfate and distilled off the solvent under reduced pressure. Thereafter, the resulting product was purified by column chromatography to obtain 20.2 g (GC purity 75%) of a pale yellowy transparent solution. The yield was 78%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].C[O:15]C(OC)N(C)C>CN(C=O)C.O.CN(C=O)C>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:11]=[O:15])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: COc1cc(C)c([N+](=O)[O-])cc1Br
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c([N+](=O)[O-])cc1Br
Temperature: 140 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a stirred solution of compound 12 (2.3 g, 9.4 mmol) in dry DMF (15 mL) was added N,N-dimethylformamide dimethyl acetal (DMF·DMA) (6.0 g, 24.5 mmol). After the reaction mixture was heated at 140° C. for 16 h, the dark red solution was cooled to 0° C. and added rapidly to a stirred solution of NaIO4 (10.5 g, 49 mmol) in H2O/DMF (4:1, 25 mL) at 0° C. After 8 h of stirring, the brown solution was filtered, and the reaction flask was rinsed with toluene/EtOAc (1:1, 30 mL) and again filtered. The filtrate was washed with saturated aqueous NaCl solution (45 mL) and extracted with EtOAc (2×45 mL). The organic phase was dried (Na2SO4) and concentrated, and the residue was purified by flash chromatography (hexane/EtOAc 3:1) to afford aldehyde 13 (1.3 g, 54%): Rf0.22 (hexane/EtOAc 3:1); 1H NMR (CDCl3) δ 4.09 (s, 3H), 7.38 (s, 1H), 8.43 (s, 1H), 10.50 (s, 1H); 13C NMR (CDCl3) δ 57.4, 110.5, 116.8, 130.3, 132.6, 142.3, 160.5, 187.7; ESI-HRMS [M-H]−C8H579BrNO4 calcd for m/z 257.9402, found 257.9407.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1>C(O)C>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:31]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)CC(=O)c2ccc(OC)cc2)cc1
Reactant: COc1ccc(NN)cc1
Solvent: CCO
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)n(-c3ccc(OC)cc3)n2)cc1
Temperature: 25 °C

Procedure:
A mixture of the 1,3-diketone obtained in step 1 (1.0 equiv.), 4-methoxyphenyl hydrazine (1.5 equiv.) conc. HCl aq. (catalytic amount) and ethanol was heated to reflux overnight. Cooled to rt and removed solvent in vacuo. Water and ethyl acetate were added. The organic layer was separated, washed with dil. HCl, brine, dried, filtered and the solvent was concentrated in vacuo to give the product 1-[1,5-bis(4-methoxyphenyl)pyrazol-3-yl]-4-methoxybenzene.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])[C:5]=1[F:17].[AlH4-].[Li+].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:17][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12]
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)OC)c1F
Agent: O=S(=O)([O-])[O-]
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(CO)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid methyl ester (20, 3.80 g, 13.8 mmol) in 133 mL of tetrahydrofuran, lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 20.0 mL, 20.0 mmol) was added under an atmosphere of nitrogen at room temperature. The reaction was stirred at room temperature for 8 hours, followed by addition of 10 g of sodium sulfate decahydrate. After 12 hours, the reaction was filtered, the filtrate concentrated under vacuum and purified with silica gel column chromatography eluting with 5% methanol in dichloromethane to give the desired compound as a white solid (21, 3.0 g, 87.9%).