Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]#[C:10][C:11]2[C:12]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=2)=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>C(Cl)Cl>[CH:20]1([NH:19][C:12]2[C:11]([C:10]#[C:9][CH2:8][O:7][C:6]3[CH:26]=[CH:27][C:3]([CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[CH:4][CH:5]=3)=[CH:16][N:15]=[C:14]([C:17]#[N:18])[N:13]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#Cc1ncc(C#CCOc2ccc(CCl)cc2)c(NC2CCCCC2)n1
Reactant: CN1CCNCC1
Solvent: O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(OCC#Cc3cnc(C#N)nc3NC3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
5-[3-(4-Chloromethyl-phenoxy)-prop-1-ynyl]-4-cyclohexylamino-pyrimidine-2-carbonitrile (0.050 mmol) is dissolved in CH2Cl2 (2 ml) and 1-methyl-piperazine (0.10 mmol) is added at room temperature and the mixture is stirred at room temperature for overnight. Water is added and the organic layer is washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give the product in 40% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.Cl[CH:10]([CH:16]=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[OH:8][C:6]1[CH:5]=[CH:4][N:3]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(O)ccn1
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(O)ccn12

Procedure:
2-Aminopyridin-4-ol (3 g, 27 mmol) was dissolved in ethanol (90 mL) in 250 mL round bottom flask. Ethyl 2-chloro-3-oxopropanoate (5% in benzene; 130 mL; Commercial solution from Toronto Research Chemicals Inc.) was added and the mixture refluxed for 10 hours. Reaction was concentrated and triturated with ethyl acetate before drying under high vacuum to give ethyl 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate as a beige solid (829 mg).
Reaction SMILES: C1(S([O:10][C:11]2[CH:22]=[CH:21][C:14]3[S:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:13]=3[CH:12]=2)(=O)=O)C=CC=CC=1.Cl>[OH-].[Na+]>[OH:10][C:11]1[CH:22]=[CH:21][C:14]2[S:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:13]=2[CH:12]=1
Reactant: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1csc2ccc(O)cc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A solution of 100 mg (0.3 mmol) of the above obtained 5-benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (2) in 1.2 ml of 1N sodium hydroxide was stirred at 40° C. for 8 hours. Hydrochloric acid (1N, 1.2 ml) was added thereto and the precipitated crystals were filtered, washed with water and dried to give 58 mg of 5-hydroxybenzo[b]thiophene-3-carboxylic acid (1). Yield 96.6%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:20]([O:22][CH3:23])=[O:21])[S:12][C:11]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=2[O:9][CH2:8][C:7]1=[O:19].[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:10]2[O:9][CH2:8][C:7](=[O:19])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:33]3[CH2:34][CH2:35][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH2:32]3)([C:20]([O:22][CH3:23])=[O:21])[S:12][C:11]=2[CH:13]=1
Reactant: COC(=O)C1(CCCCBr)Sc2cc(OC)ccc2OCC1=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1(CCCCN2CCN(c3ccccc3)CC2)Sc2cc(OC)ccc2OCC1=O

Procedure:
A mixture of methyl 4-(4-bromobutyl)-7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate (1.7 g), N-phenylpiperazine (1.37 g), potassium iodide (0.7 g), anhydrous potassium carbonate (1.2 g) and acetonitrile (30 ml) was refluxed under heating for 1.5 hours. After cooling, inorganic matter was filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and dried. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give 1.0 g of colorless, oily methyl 7-methoxy-3-oxo-4-[4-(4-phenylpiperazin-1-yl)butyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate. When converted to hydrochloride, a white powder was obtained, melting point 155°-165° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11](=O)[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1.O=P(Cl)(Cl)[Cl:21].CN(C)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[Cl:21][C:11]1[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:10]=1
Reactant: COc1ccccc1-c1nc2ccsc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: c1ccccc1
Product: COc1ccccc1-c1nc(Cl)c2sccc2n1
Temperature: 80 °C
Yield: 71.1 %

Procedure:
A solution of 2-(2-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (0.80 g, 3.1 mmol), POCl3 (0.28 mL, 3.1 mmol), and N,N-dimethylaniline (1.6 mL, 4.7 mmol) in benzene (3.5 mL) was heated at 80° C. for 2 h. An additional portion of POCl3 (0.28 mL, 3.1 mmol) was added, and the reaction was heated at 80° C. for 16 h. The reaction was cooled, and saturated aqueous NaHCO3 was slowly added. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under vacuum to give 4-chloro-2-(2-methoxyphenyl)thieno[3,2-d]pyrimidine (0.61 g, 71% yield). LC/MS: m/z 277.1 (M+H)+ at 2.98 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]([OH:13])[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: Nc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(O)C(Nc2ccccc2)C1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
In 20 ml of ethyl alcohol was dissolved 5 g (0.027 mole) of 1-t-butoxycarbonyl-3-epoxypyrrolidine, and 12.6 g (0.135 mole) of aniline was added thereto. The mixture was refluxed by heating for 20 hours. After the mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was applied to silica gel column chromatography (the eluent used was a mixture of ethyl acetate:toluene=1:4) to obtain 4.85 g of 1-t-butoxycarbonyl-3-hydroxy-4-phenylaminopyrrolidine as yellowish brown crystals.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([OH:8])(=[O:7])[CH3:6]>C1COCC1>[C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6]
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CC(=O)OC(C)=O

Procedure:
The particularly preferred PTHF acetate or THF copolymer acetates may be worked up by methods known per se. For example, after distillative removal of unconverted THF and then acetic anhydride, acetic acid and comonomer, the PTHF acetate or THF copolymer acetate obtained may be transesterified using methanol under base catalysis to give PTHF or THF copolymer and methylacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10]C)[CH:3]=1.[C-]#N.[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(O)cc(Br)c1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
1-Bromo-3,5-dimethoxy-benzene (0.217 g, 0.001 mol) and KCN (0.20 g, 0.003 mol) were taken up into DMSO (10 mL) and the resulting mixture stirred at 120° C. for six hours, then at 150° C. overnight. The mixture was maintained at this temperature, with stirring for another day. The reaction was then quenched with water and the resulting mixture extracted with EtOAc. The organic layer was washed with saturated NaHCO3, brine, then dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified on normal phase chromatography (Heptane/EtOAc) to yield 3-bromo-5-methoxyphenol. MH+ 203, 205
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]2[C:12]([C:18]3[CH:35]=[CH:34][C:21]4[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][C:20]=4[CH:19]=3)=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH:4]=1)[CH3:2].Cl>O1CCOCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]2[C:12]([C:18]3[CH:35]=[CH:34][C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=4[CH:19]=3)=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1ccnc(COc2ccc(C)nc2-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1ccnc(COc2ccc(C)nc2-c2ccc3c(c2)CCNCC3)c1

Procedure:
To a stirred solution of 1,1-dimethylethyl 7-(3-{[(4-ethyl-2-pyridinyl)methyl]oxy}-6-methyl-2-pyridinyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate, (4.3 g) in dioxane (30 ml) was passed through HCl (gas) for 30 min at 20° C. After completion of reaction by TLC, the solvent was removed in vacuo. The solid obtained was washed with acetone and dissolved in water. This was neutralised with sodium bicarbonate, extracted with DCM and concentrated in vacuo to give a crude product. This was purified through silica using 6% methanol in DCM. Appropriate fractions were combined and concentrated in vacuo to give a product. This was triturated in diethyl ether to yield the title compound, 1.5 g.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:5]([CH2:12][CH:13]=[CH2:14])=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1.S(C1C=CC(C)=CC=1)(O[CH2:19][C:20]([F:23])([F:22])[F:21])(=O)=O.Cl>CN1CCCC1=O.O>[F:21][C:20]([F:23])([F:22])[CH2:19][O:11][C:6]1[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[C:5]=1[CH2:12][CH:13]=[CH2:14]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: C=CCc1c(C)cc(C)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCc1c(C)cc(C)cc1OCC(F)(F)F
Reaction time: 16 h

Procedure:
17 g of sodium hydroxide were metered into a mixture of 50 g of 3,5-dimethyl-2-(2-propen-1-yl)-phenol (C) and 86 g of 2,2,2-trifluoroethyl tosylate in 450 ml of N-methylpyrrolidone at 120° C. Stirring was continued for 16 hours at 120° C., and the mixture was subsequently poured into 21 of water. The pH was brought to 2 using 6N hydrochloric acid, and the mixture was extracted using dichloromethane. The combined organic phases were dried over sodium sulphate, the solvent was removed in vacuo, and the residue was distilled. This gave 32 g (43% of theory) of 3,5-dimethyl-2-(2-propen-1-yl)phenyl 2,2,2-trifluoroethyl ether of a boiling point of 100° C. at 1 mbar.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][N:11]([C:13]([CH3:20])([CH3:19])[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=1)(C)(C)C.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:20][C:13]([N:11]1[CH:12]=[C:8]([NH2:7])[CH:9]=[N:10]1)([CH3:19])[CH2:14][S:15]([CH3:18])(=[O:16])=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1cnn(C(C)(C)CS(C)(=O)=O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(CS(C)(=O)=O)n1cc(N)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
To tert-butyl(1-(2-methyl-1-(methylsulfonyl)propan-2-yl)-1H-pyrazol-4-yl)carbamate (250 mg) obtained in Step C of Example 114 was added dropwise a solution of 4 M hydrogen chloride in ethyl acetate (4.0 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (23 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([OH:22])=[C:11](C(OCC)=O)C(OCC)=O>CC(O)=O.O.OS(O)(=O)=O>[Br:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:22])[CH3:11]
Reactant: CCOC(=O)C(C(=O)OCC)=C(O)c1ccc(Cl)c(F)c1Br
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccc(Cl)c(F)c1Br
Yield: 84.6 %

Procedure:
A solution of Intermediate 12B (18.6 g, 47 mmol) in AcOH (200 mL), H2O (150 mL) and H2SO4 (2.0 mL) was stirred at 110° C. for 4 h. Most of the solvent was removed and the residue was diluted with EtOAc (400 mL), washed with H2O (5×20 mL), saturated NaHCO3, 1N NaOH, and brine. The solvent was removed to give Intermediate 12C (10 g, 84% yield) as a low melting solid. 1H NMR (400 MHz, DMSO-d6) δ 7.42 (q, J=6.8, 6.4 Hz, 1H), 7.24 (q, J=6.4, 5.2 Hz, 1H), 2.5 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16](=[NH:48])[NH:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:37]C(OCC1C=CC=CC=1)=O)[C:22](=[O:36])[NH:23][CH2:24][CH:25]([OH:35])[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:12]([O:11][C:9]([N:8]([C:16](=[NH:48])[NH:17][CH2:18][CH2:19][CH2:20][C@@H:21]([C:22]([NH:23][CH2:24][CH:25]([OH:35])[CH2:26][NH:27][C:28]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:34])=[O:36])[NH2:37])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@H](CCCNC(=N)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@@H](N)CCCNC(=N)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
28 mg of palladium on activated carbon (10%) are added to a mixture of 0.182 g (0.27 mmol) of the compound from Example 256A in 10 ml of ethanol, and the mixture is then hydrogenated under atmospheric pressure for 12 h. The reaction mixture is filtered through kieselguhr, and the filtrate is concentrated in vacuo and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>C(OCC)(=O)C>[Cl:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[C:15]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1Cl
Solvent: CCOC(C)=O
Product: O=C(c1cccc(S(=O)(=O)Cl)c1)c1cc(Cl)ccc1Cl
Temperature: 0 °C

Procedure:
Into a 3 L three-neck flask equipped with a stirrer, and a cooling tube, chlorosulfonic acid (233.0 g, 2 mol) was added, and then 2,5-dichlorobenzophenone (100.4 g, 400 mmol) was added. The mixture was reacted for 8 hours using an oil bath at 100° C. After a predetermined period of time, the reaction liquid was slowly poured into broken ice (1000 g), and extraction using ethyl acetate was carried out. An organic layer was washed with a saline solution, and was dried with magnesium sulfate. Then, the ethyl acetate was distilled away, thereby obtaining a crude crystal of pale yellow (3-(2,5-dichlorobenzoyl)benzene sulfonic acid chloride). The crude crystal was employed at the subsequent step without purification.
Reaction SMILES: [OH:1][CH:2]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:23](Br)([CH3:26])([CH3:25])[CH3:24]>C1CCCCC1.[Ag-]=O>[C:23]([O:1][CH:2]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)C(O)c1c(-c2ccccc2)sc2ccccc12
Reactant: CC(C)(C)Br
Agent: O=[Ag-]
Solvent: C1CCCCC1
Product: CCOC(=O)C(OC(C)(C)C)c1c(-c2ccccc2)sc2ccccc12
Reaction time: 2 h
Yield: 13.3 %

Procedure:
A mixture of ethyl 2-hydroxy-2-(2-phenyl-1-benzothiophen-3-yl)acetate (2c) (190 mg, 0.6 mmol), silver (I) oxide (417 mg, 1.8 mmol) and tertbutylbromide (360 μL, 3.2 mmol) in cyclohexane (5 mL) was vigorously stirred for 2 hours. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired ether oxide (2d) as a white solid (30 mg, 0.08 mmol, 13%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][CH:14]([C:22]([OH:24])=[O:23])[C:15]([CH2:20][CH3:21])(O)[C:16]([OH:18])=O)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:27]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[C:22]([O:23][C:16](=[O:18])[C:15]=2[CH2:20][CH3:21])=[O:24])=[CH:25][CH:26]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)(C(=O)O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC1=C(Cc2ccc(OC(C)=O)cc2)C(=O)OC1=O
Temperature: 115 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To the crude 3-(4-t-butyldimethylsilyloxybenzyl)-2-ethyl-2-hydroxysuccinic acid thus obtained was added acetic anhydride (5 mL), and the mixture was stirred at 115° C. for 3 h. The acetic anhydride was evaporated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (toluene-ethyl acetate 19:1→16:1) to give the title compound as oil in an amount of 210 mg (2 step yield: 79%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(NC(C)C)(C)C>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]1(/[CH:12]=[CH:11]/[C:2]2[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: O=[N+]([O-])c1cccc(/C=C/c2ccccc2)c1

Procedure:
A mixture of 3-bromonitrobenzene (1 g), styrene (1.7 mL), palladium(II) acetate (95 mg), tris(2-methylphenyl)phosphine (0.3 g) and N,N-diisopropylamine (5 mL) was heated for reflux for 24 hours. The reaction mixture was diluted with diethyl ether, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate =10/1) to give 3-((E)-2-phenylvinyl)nitrobenzene (0.76 g). To the solution of the obtained 3-((E)-2-phenylvinyl)nitrobenzene (0.26 g) in methanol (10 mL) was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.22 g).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH3:29])[CH2:42][CH2:41]1)=[O:16]
Reactant: COc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3ccccc3F)noc2N)CC1
Yield: 9273.9 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (464 mg, 1,170.64 mmol, 77%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=O)[N:7]3[CH2:15][CH2:14][CH2:13][CH:8]3[C:9](=[O:12])[N:10]([CH3:11])[C:4]=2[CH:3]=1.CN1C2C=CC=CC=2C(=O)N2CCCC2C1=O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][N:7]3[CH2:15][CH2:14][CH2:13][CH:8]3[C:9](=[O:12])[N:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CN1C(=O)C2CCCN2C(=O)c2ccc(Cl)cc21
Agent: CN1C(=O)C2CCCN2C(=O)c2ccccc21
Product: CN1C(=O)C2CCCN2Cc2ccc(Cl)cc21

Procedure:
This compound is obtained when (+)-8-chloro-1,2,3,11 a-tetrahydro-10-methyl-5 H-pyrrolo[2,1-c] [1,4] benzodiazepin-5,11(10H)-dione (melting point 191° -194°C. prepared from L-proline and 4-chloro-N-methylisatoic anhydride is described in Example 1) is substituted for (+) 1,2,3,11a-tetrahydro-10 -methyl-5 H-pyrrolo[2,1-c] [1,4] benzodiazepin-5,11(10H)-dione in the process of Example 1.
Reaction SMILES: N#N.C([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[C:8]=1C(N)=O)CCC.[CH2:19]([C:23]1C=CN=C(C(N)=O)C=1C(N)=O)[CH2:20][CH2:21]C.C[N:36](C)[CH:37]=[O:38].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>O>[CH2:23]([N:15]1[C:13](=[O:14])[C:9]2[N:10]=[CH:11][CH:12]=[CH:7][C:8]=2[NH:36][C:37]1=[O:38])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1ccnc(C(N)=O)c1C(N)=O
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: N#N
Agent: [Pb+4]
Solvent: O
Product: CCCCn1c(=O)[nH]c2cccnc2c1=O
Reaction time: 2 h

Procedure:
A 100 ml. flask was charged with 9.0 g. of a mixture of N2 -n-butyl-2,3-pyridine-dicarboxamide and N3 -n-butyl-2,3-pyridine-dicarboxamide suspended in 70 g. dimethylformamide. An 18.0 g. portion of lead tetra-acetate was added, and the reaction mixture stirred at 60° for 2 hours. The reaction mixture was poured into 200 ml. water. The precipitate was filtered from the water, recrystallized from dioxane, and dried at 100°, for about 1 hour. The final yield of 3-n-butyl-pyrido[3,2-d] and 3-n-butyl-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione amounted to 8.4 g., melting point 200°-210°, and represented 93 percent of theory based on the dicarboxamide starting material. The structure was determined by nuclear magnetic resonance spectroscopy to consist of 78 percent of the [3,2-d]isomer and 22 percent of the [2,3-d]isomer.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29](Cl)[CH:28]=2)[N:12]=1)=[O:10].NC1C(C2C=CC([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=CC=2)=NC(Br)=C(C(F)(F)F)N=1>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:14]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:13]([C:27]2[CH:32]=[CH:31][C:30]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])=[CH:29][CH:28]=2)[N:12]=1)=[O:10]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2cccc(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: CS(=O)(=O)Nc1ccc(-c2nc(Br)c(C(F)(F)F)nc2N)cc1
Product: CS(=O)(=O)Nc1ccc(-c2nc(C(=O)N[C@@H]3CCCC[C@H]3O)c(C(F)(F)F)nc2OCC(F)(F)F)cc1

Procedure:
The title compound was prepared in analogy to example 4 (6-(3-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-3-trifluoromethyl-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide) by substituting 5-bromo-3-(3-chloro-phenyl)-6-trifluoromethyl-pyrazin-2-ylamine by N-[4-(3-amino-6-bromo-5-trifluoromethyl-pyrazin-2-yl)-phenyl]-methanesulfonamide.