Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCI
Reactant: Cc1ncccc1O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1OCCCCl
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxy-2-methylpyridine (2.00 g, 18.3 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.576 g of an 80% dispersion in mineral oil, 19.2 mmol) in DMF (40 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The slurry was cooled to 0-5° C., and 1-chloro-3-iodopropane (4.49 g, 22.0 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 2 h. Cold water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×100 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 3.25 g (96.2%) of an oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:27]I.Cl>CN(C)C=O>[CH2:3]([O:10][C:11]([N:13]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)[CH3:27])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(C)C(=O)OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 44.2 %

Procedure:
0.29 g (6.83 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil) was added, whilst ice-cooling, to a solution of 1.50 g (4.55 mmol) of ethyl 4-(benzyloxycarbonylamino)phenoxyacetate (prepared as described in Preparation 14) in 9 ml of dimethylformamide, and the mixture was stirred for 20 minutes, after which 0.57 ml (9.10 mmol) of methyl iodide was added to the reaction mixture. The mixture was then stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was neutralized with 1N aqueous hydrochloric acid, and the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with ethyl acetate, and the resulting organic solution was washed with 1N aqueous hydrochloric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate, with a 5% w/v aqueous solution of sodium thiosulfate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparative thin layer chromatography, using a 3:2 by volume mixture of hexane and ethyl acetate as the developing solvent, to give 0.69 g of the title compound as an oil.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[CH:29]=[N:28][NH:27][C:14]3=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1>C1COCC1>[CH:30]1([CH2:33][NH:34][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]4[CH:29]=[N:28][NH:27][C:14]4=[N:15][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)[CH:8]=[CH:7][N:6]=2)[CH2:32][CH2:31]1
Reactant: NCC1CC1
Reactant: CS(=O)(=O)c1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(-c2nc3[nH]ncc3cc2-c2ccnc(NCC3CC3)n2)c1
Yield: 69.4 %

Procedure:
A solution of 5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (90 mg, 0.2 mmol, obtained in example 127) and (cyclopropylmethyl)amine (75 mg, 1.0 mmol) in THF (2 mL) was heated in a closed vessel at 60° C. overnight. It was allowed to cool and concentrated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 57 mg of the desired compound (yield: 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH:20]([CH3:22])[CH3:21]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:18])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)C[Mg]Br
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-indazole-5-carboxaldehyde (100 mg, 0.416 mmol, from experimental 1(e)) in 5 mL of THF was added a solution of 2.0M isobutylmagnesium bromide in THF (0.5 mmol) dropwise. After 1 hr, the reaction was quenched with sat. NH4Cl and extracted with 2× EtOAc. The EtOAc extracts were dried over MgSO4, filtered, and concentrated by rotary evaporator to give 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol. MS found: (M+H)+=299.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[Cl:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([CH2:20][CH2:21][CH:22]=O)=[CH:15][C:14]=1[F:24]>>[Cl:12][C:13]1[C:14]([F:24])=[CH:15][C:16]([CH2:20][CH2:21][CH:22]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)=[CH:17][C:18]=1[F:19]
Reactant: O=CCCc1cc(F)c(Cl)c(F)c1
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)c(Cl)c(F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (4.012 mmol) and 3-(4-chloro-3,5-difluoro-phenyl)-propionaldehyde (1.030 g; 5.034 mmol) afforded 8-[2-(4-chloro-3,5-difluoro-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.78 min.; [M+H]+=451.76 g/mol.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:8]=2[CH:21]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:24](=O)([O:27]C)[O:25][CH3:26]>O1CCCC1>[CH3:26][O:25][C:24](=[O:27])[CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:8]=2[CH:21]=1)=[O:3]
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
A solution of 1,1-dimethylethyl 7-acetyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.34 g, 4.60 mmol) in tetrahydrofuran (5 mL) was added to a suspension of sodium hydride (60% oil suspension, 0.80 g, 13.3 mmol) in tetrahydrofuran (20 mL) and the resulting mixture was stirred at room temperature for 5 minutes. Dimethyl carbonate (5 mL) was added and the resulting mixture was stirred at 65° C. for twenty minutes. Then the reaction mixture was cooled, quenched with ice (20 g) and aqueous ammonium chloride (20 mL) then extracted with ethyl acetate (3×40 mL). The combined organic extract was washed with water, then brine solution (80 mL each), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (25% ethyl acetate in hexanes) to give 1,1-dimethylethyl 7-[3-(methyloxy)-3-oxopropanoyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.94 g, 59% yield). MS (EI) for C18H23NO6: 350 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][C:15]([OH:17])=O.[CH2:36]([N:38]1CCOCC1)[CH3:37].ClC(OCC)=O.C(N)C>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)(=[O:19])=[O:20])[CH2:14][C:15]([NH:38][CH2:36][CH3:37])=[O:17]
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)c2c(Cc3c(F)cccc3F)cccc2OC)cc1OC
Reactant: CCN1CCOCC1
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)CN(c1c(Cc2c(F)cccc2F)cccc1OC)S(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 0.25 h

Procedure:
To 1.8 g of N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl]glycine dissolved in 30 ml of tetrahydrofuran at 0° C. are introduced 0.5 ml of N-ethylmorpholine and 0.38 ml of ethyl chloroformate. After 15 minutes at 10° C., 0.8 g of ethylamine dissolved in tetrahydrofuran is added and the mixture is left at room temperature for 30 minutes. The medium is taken up in ethyl acetate and washed with water, and the organic phase is dried over anhydrous sodium sulfate and concentrated to give 1.4 g of the expected product.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CCOC(=O)Cc1ccc(-n2cnnn2)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-n2cnnn2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture ethyl [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetate (0.42 g, 1.8 mmol) in THF (3 mL) was added 1.4 M LiOH (aq.) (5 mL) at room temperature. The mixture was stirred 3 hours at room temperature. The reaction was acidified with citric acid until Ph about 3˜4. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid. 1H-NMR (400 MHz, DMSO) δ 12.62 (s, 1H), 10.16 (s, 1H), 8.54 (s, 1H), 8.01-8.09 (m, 2H), 3.80 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[N:7]=1.[CH2:24]([NH2:35])[C:25]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[C:27]([O:28][CH3:29])[CH:26]=1>CN1CCCC1=O>[CH3:29][O:28][C:27]1[CH:26]=[C:25]([CH:34]=[CH:33][C:30]=1[O:31][CH3:32])[CH2:24][NH:35][C:2]1[N:3]=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[N:7]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: Fc1ccccc1Cn1ccc2c(-c3ccco3)nc(Cl)nc21
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(-c3ccco3)c3ccn(Cc4ccccc4F)c3n2)cc1OC
Temperature: 100 °C
Yield: 88.4 %

Procedure:
A solution of 2-chloro-7-(2-fluorobenzyl)-4-(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine (254 mg, 0.78 mmol) in N-methylpyrrolidone (2 mL) was treated with veratrylamine (0.25 mL, 1.66 mmol), heated to 100° C. for 16 h and purified by chromatography (Heptane:EtOAc, 4:1) to give the title compound (316 mg, 88%) as a cream solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([I:19])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:20][N:21]=[CH:22][C:11]=2[N:10]=1.[H-].[Na+].[CH3:25][N:26]([CH3:31])[S:27](Cl)(=[O:29])=[O:28].O>C1COCC1.CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([I:19])[CH:15]=[CH:14][C:13]=2[C:12]2[N:20]([S:27]([N:26]([CH3:31])[CH3:25])(=[O:29])=[O:28])[N:21]=[CH:22][C:11]=2[N:10]=1
Reactant: Fc1cccc(F)c1-c1nc2cn[nH]c2c2ccc(I)cc12
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)S(=O)(=O)n1ncc2nc(-c3c(F)cccc3F)c3cc(I)ccc3c21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 250 ml three-necked flask equipped with a magnetic stirrer and an argon intake is charged with 4 g of 5-(2,6-difluorophenyl)-7-iodo-1H-pyrazolo[4,3-c]isoquinoline, prepared in step 6 of example 1, in 120 ml of THF and 3 ml of DMF. The mixture is cooled to 0° C. using an ice bath and then 952 mg of sodium hydride (60%) are added. After 15 min at 0° C., 1.3 ml of dimethylsulphamoyl chloride are added. After 16 h at RT, the mixture is poured into 300 ml of water and extracted with ethyl acetate. The organic phase is dried over MgSO4, filtered and concentrated under RP. The solid obtained is triturated in diisopropyl ether. The insoluble material is filtered off under RP and dried under vacuum to give 2.94 g of 5-(2,6-difluorophenyl)-7-iodo-N,N-dimethyl-1H-pyrazolo[4,3-c]isoquinoline-1-sulphonamide (beige solid). LC-MS-DAD-ELSD: 515(+)=(M+H)(+).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Br)[N:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[Br:1][C:2]1[N:6]=[C:5]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1
Reactant: COc1ccc(Cn2nc(Br)nc2Br)cc1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(Br)nc2N2CCCC2)cc1
Yield: 49.4 %

Procedure:
A mixture of 3,5-dibromo-1-(4-methoxybenzyl)-1H-1,2,4-triazole (1.268 g, 3.65 mmol, Eq: 1.00) and pyrrolidine (273 mg, 317 μl, 3.84 mmol, Eq: 1.05) in dimethyl formamide (12 ml) was heated for 18 hours to 110° C. under argon atmosphere. The crude material was applied on silicagel and purified by flash chromatography over a 50 g silicagel column using heptane/ethyl acetate 30-50% as eluent affording 3-bromo-1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-1H-[1,2,4]triazole (608 mg/49.3%) as a colorless oil. MS: m/e=338339 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1.I[C:30]1[CH:31]=[CH:32][C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:30]2[CH:31]=[CH:32][C:33](=[O:37])[N:34]([CH3:36])[CH:35]=2)=[CH:25][CH:26]=1
Reactant: Cn1cc(I)ccc1=O
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Product: Cn1cc(C#Cc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)ccc1=O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene and 5-iodo-1-methyl-1H-pyridin-2-one.
Reaction SMILES: [C:1]([NH:13][NH2:14])(=O)[C:2]1[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:4](NN)=[O:5].P(Br)(Br)(Br)(Br)[Br:16].O>C(Br)(Br)(Br)Br>[Br:16][C:1]1[C:2]2[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:4](=[O:5])[NH:14][N:13]=1
Reactant: BrP(Br)(Br)(Br)Br
Reactant: NNC(=O)c1ccccc1C(=O)NN
Agent: BrC(Br)(Br)Br
Solvent: O
Product: O=c1[nH]nc(Br)c2ccccc12

Procedure:
A mixture of phthalhydrazide (3.2 g) and phosphorus pentabromide (19.0 g) was heated with stirring in carbon tetrabromide (50 g) at 125° for 16 hours. The cooled mixture was poured into water (50 cm3) and the product collected by filtration. The solid product was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with diethyl ether:dichloromethane, 1:3 by volume. Combination and evaporation of appropriate fractions afforded the title compound, m.p. 268°-271° (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]2[NH:12][C:11](=O)[O:10][C:8](=[O:9])[C:7]=12.C(N(CC)CC)C>CO>[NH2:12][C:6]1[C:5]([CH3:14])=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: Cc1ccc(Cl)c2c(=O)oc(=O)[nH]c12
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1c(Cl)ccc(C)c1N
Temperature: 65 °C
Reaction time: 2 h

Procedure:
At 22° C., 110 g (0.52 mol of 6-chloro-3-methylisatoic anhydride were introduced into a mixture of 750 ml of methanol and 47.6 g (0.47 mol) of triethylamine, and the mixture was then stirred at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was taken up in methylene chloride and extracted 3 times with 0.5 N aqueous sodium hydroxide solution. The mixture was dried over magnesium sulfate, filtered through silica gel and concentrated under reduced pressure, giving 45.5 g (43.8% of theory) of the title compound as a colorless oil with nD23=1.5765.
Reaction SMILES: [Cl:1][CH:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:10][C:9]=1[N+:28]([O-])=O)[C:3]([O:5]C)=O.O>C(O)(=O)C.[Fe]>[Cl:1][CH:2]1[CH2:7][C:8]2[C:9](=[CH:10][C:11]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]3=[O:27])=[C:12]([F:14])[CH:13]=2)[NH:28][C:3]1=[O:5]
Reactant: COC(=O)C(Cl)Cc1cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)CC(Cl)C(=O)N3)c1=O
Yield: 221.3 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of this Example, using 2.9 grams (0.006 mole) of methyl 2-chloro-3-[5-fluoro-2-nitro-4-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl]propanoate, 2.0 grams (0.036 g-atom) of iron powder, and 5 mL of water in 50 mL of acetic acid. The product from this reaction was combined with that from another run (0.014 mole) of this reaction. The combination was subjected to column chromatography on silica gel. Elution was accomplished using heptane, 1:1 heptane-ethyl acetate, and ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 5.2 grams of 3-(3-chloro-6-fluoro-3,4-dihydroquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[C:5]([O:13][CH3:14])[CH:4]=1.[I:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>>[I:15][C:16]1[CH:17]=[C:18]([C:19]([C:3]2[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[C:5]([O:13][CH3:14])[CH:4]=2)=[O:20])[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: O=C(Cl)c1cccc(I)c1
Agent: [Mg]
Product: COc1cc(C(=O)c2cccc(I)c2)cc(OC)c1OC

Procedure:
First, magnesium was added to 1-bromo-3,4,5-trimethoxybenzene as a starting material, as shown in Reaction 6, and then 3-iodobenzoyl chloride was added thereto to obtain a Compound 21 derivative [(3-iodophenyl)(3,4,5-trimethoxyphenyl)methanone]. Thus obtained compound (88 mg, 0.250 mmol) was dissolved in tetrahydrofuran (2.5 ml), and 2-(tributylstannyl)thiazole (135 μl, 0.425 mmol) and Pd(PPh3)2Cl2 (8.79 mg, 0.012 mmol) were slowly added thereto at room temperature. The mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc, and an aqueous sodium bicarbonate solution was added thereto. An organic layer was extracted out from the resulting solution. The organic layer was washed with water, and brine, and dried over anhydrous MgSO4. The solid substance was filtered off, and the filtrate was vacuum concentrated. The resulting residue was purified by column chromatography (SiO2, n-Hex/EA=2/1→1/1) to obtain Compound 581 (20 mg, 22%) in a form of a yellow solid.
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:10][N:9]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:24])[CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:8][C@H:7]([CH2:25][C:26](O)=[O:27])[N:6]1[C:29](=[O:42])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)(O)=[O:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[OH:27][CH2:26][CH2:25][C@H:7]1[CH2:8][N:9]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:24])[CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:10][C@H:5]([CH2:4][CH2:1][OH:2])[N:6]1[C:29](=[O:42])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1
Reactant: O=C(O)C[C@H]1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C[C@H](CC(=O)O)N1C(=O)c1ccc(-c2ccncc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(-c2ccncc2)cc1)N1[C@@H](CCO)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C[C@@H]1CCO
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
In tetrahydrofuran (40 ml), trans-2,6-bis(carboxymethyl)-4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[4-(pyridin-4-yl)benzoyl]piperazine (269 mg) was suspended, followed by the addition of N,N-diisopropylethylamine (480 μl) and 1-benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (672 mg) under ice cooling. The resulting mixture was stirred for 3.5 hours at room temperature. Under ice cooling, sodium borohydride (297 mg) was added and the resulting mixture was stirred for 15 hours at room temperature. The reaction mixture was ice cooled and added with water and ethyl acetate to separate the organic layer. The organic layer thus obtained was washed with aqueous NaCl solution, dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (4% methanol—dichloromethane), followed by dissolution in tetrahydrofuran. Saturated hydrochloride in methanol was added to the resulting solution and the resulting mixture was concentrated to dryness. Ethyl acetate was then added to the residue to crystallize the same, whereby the title compound was obtained.
Reaction SMILES: CC1C=CC(S([N:11]2[C:21]3[C:22]4[N:13]([CH2:14][C:15](=[O:24])[N:16]([CH3:23])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[C:12]2=[O:25])(=O)=O)=CC=1.O>OS(O)(=O)=O>[CH3:23][N:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[NH:11][C:12](=[O:25])[N:13]([C:22]=23)[CH2:14][C:15]1=[O:24]
Reactant: Cc1ccc(S(=O)(=O)n2c(=O)n3c4c(cccc42)N(C)C(=O)C3)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CN1C(=O)Cn2c(=O)[nH]c3cccc1c32

Procedure:
A solution of 1-[(4-methylphenyl)sulfonyl]-6-methyl-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione (600 mg, 1.68 mmol) in conc. H2SO4 (3 mL) was heated at 50° C. for 30 min, then poured into H2O at 0° C. (25 mL). The resulting precipitate was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=204 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]3[CH2:19][O:20][C:21]4[CH:22]=[C:23]([C:27]([OH:29])=[O:28])[CH:24]=[CH:25][C:26]=4[C:11]3=[N:10]2)=[CH:5][C:4]=1[CH3:30])#[N:2].CO.C(=O)=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C@@H:13]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C@H:12]3[CH2:19][O:20][C:21]4[CH:22]=[C:23]([C:27]([OH:29])=[O:28])[CH:24]=[CH:25][C:26]=4[C:11]3=[N:10]2)=[CH:5][C:4]=1[CH3:30])#[N:2]
Reactant: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2CCCC2)ccc1C#N
Agent: O=C=O
Solvent: CO
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4OC[C@@H]3[C@@H]2C2CCCC2)ccc1C#N

Procedure:
The title compound was prepared from the 2-(4-cyano-3-methylphenyl)-3-cyclopentyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid prepared in Example 61 using chiral resolution (e.g., Method G (Chiralcel OJ-H 30×250 mm; 60% methanol/carbon dioxide). First eluting peak: tR=3.29 minutes (Chiralcel OJ-H 4.6×250 mm; 50% methanol/carbon dioxide).