Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:22]O>>[CH3:22][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[CH:12][CH:11]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(N2CCOCC2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 4-morpholinoacetophenone (4.61 g, 22 mmol), sulfur (2.16 g, 67 mmol), and morpholine (6 mL, 67 mmol) was heated at 80° C. for 1 h then heated under reflux for 18 h. The hot reaction mixture was poured into warm ethanol. Upon cooling to 25° C., a precipitate formed. The precipitate was filtered to provide a tan solid (4.16 g). This crude tan solid was then treated with concentrated acetic acid (16 mL), concentrated sulfuric acid (2.4 mL), and water (3.6 mL). The resulting reaction mixture was heated under reflux for 4 h and then poured into water. The water was removed in vacuo to provide crude (4-morpholin-4-yl-phenyl)-acetic acid as a brown oil (8.20 g). This crude (4-morpholin-4-yl-phenyl)-acetic acid was dissolved in methanol (100 mL) and then slowly treated with concentrated sulfuric acid (1 mL). The reaction mixture was heated under reflux for 66 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with water (200 mL) and then treated with a 10% aqueous sodium hydroxide solution until pH=9. The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 to 1/1 hexanes/ethyl acetate gradient elution) afforded (4-morpholin-4-yl-phenyl)-acetic acid methyl ester (2.22 g, 42% for 3 steps) as a yellow oil: EI-HRMS m/e calcd for C13H17NO3 (M+) 235.1208, found 235.1214.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[C:14]1([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[CH2:23][NH2:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:27]=[CH:26][CH:25]=[C:22]([CH2:23][NH:24][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][N:6]=[C:5]3[Cl:13])[CH:21]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(-c2ccccc2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(-c4ccccc4)c3)ccc12
Yield: 2.3 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (95 mg, 0.366 mmol), 3-phenylbenzylamine (95 mg, 0.518 mmol), Pd2(dba)3 (40 mg, 0.044 mmol), rac-BINAP (76 mg, 0.122 mmol) and NaOtBu (101 mg, 1.05 mmol) in DMA (5 mL) was heated at 80° C. for 1.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 6-[(biphenyl-3-ylmethyl)-amino]-4-chloro-2H-phthalazin-1-one (3 mg) as an off white solid, 1H (400 MHz, CDCl3) δ: 4.49 (s, 2H), 7.00 (m, 2H), 7.50 (m, 9H), 8.05 (d, 1H), 10.87 (s, 1H) ppm; m/z (M+1) 361.95.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][N:4]1[C:37](=[O:38])[N:36]([CH2:39][CH2:40][CH3:41])[C:34](=[O:35])[C:33]2[C:5]1=[N:6]/[C:7](/[N:32]=2)=[C:8]1/[CH:9]=[C:10]([NH:14]C(CC2C=CC(OCC3C=CC=CC=3)=CC=2)=O)[NH:11][N:12]/1[CH3:13].Cl>[OH-].[Na+]>[CH2:39]([N:36]1[C:34](=[O:35])[C:33]2[NH:32][C:7]([C:8]3[N:12]([CH3:13])[N:11]=[C:10]([NH2:14])[CH:9]=3)=[N:6][C:5]=2[N:4]([CH2:3][CH:2]=[CH2:1])[C:37]1=[O:38])[CH:40]=[CH2:41]
Reactant: CCCn1c(=O)c2c(n(CCC)c1=O)=N/C(=C1/C=C(NC(=O)Cc3ccc(OCc4ccccc4)cc3)NN1C)N=2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCn1c(=O)c2[nH]c(-c3cc(N)nn3C)nc2n(CC=C)c1=O
Temperature: 75 °C

Procedure:
A mixture of the amide intermediate and 30 mL of 2.5 N NaOH is warmed to 70-80° C. for three hours. The clear aqueous solution is cooled and acidified to pH 5 with concentrated HCl. The white precipitate that forms is collected by filtration and washed with H2O to afford the desired 1,3-diallyl-8-(3-amino-1-methylpyrazol-5-yl)xanthine, which is recrystallized from CH3OH. A solution of 4-(benzyloxy)phenylacetic acid (0.196 mmol) in 3 mL of thionyl chloride is stirred at 70° C. for four hours, then excess thionyl chloride removed in a nitrogen stream.
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][CH:29]1[CH2:31][CH2:30]1.N([O-])=O.[Na+].CC#N.O.[ClH:40]>O.Cl[Cu]>[Cl:40][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][CH:29]1[CH2:31][CH2:30]1
Reactant: CCOC(=O)C1(c2cc(OCC3CC3)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(c2cc(OCC3CC3)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 70 °C
Reaction time: 0.67 h

Procedure:
Ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.280 g, 0.64 mmol) was dissolved in a mixture of MeCN/H2O/HCl 10 mL/10 mL/4 mL at 0° C. A solution of NaNO2 (0.066 g, 0.96 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (0.32 g, 3.2 mmol) in water (2 mL) was added drop wise at 0° C. The reaction mixture was heated to 70° C. for 1 h and the solvent was evaporated under reduced pressure. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.110 g) as yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)[C:3]=1[CH2:21][CH2:22][CH3:23].[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:2]1[C:3]([CH2:21][CH2:22][CH3:23])=[C:4]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)[N:5]=[CH:6][N:7]=1)[CH3:25]
Reactant: CCCc1c(Cl)ncnc1Cn1ccnc1-c1cccc(F)n1
Reactant: CCN
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1NCC
Temperature: 70 °C

Procedure:
A mixture of 6-chloro-4-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (60 mg, 0.18 mmol) and ethylamine (2M in THF, 2 mL) is heated at 70° C. in a sealed tube overnight. Solvent is removed. Water (10 mL) and ethyl acetate (15 mL) are added. The layers are separated—the aqueous layer is extracted with ethyl acetate (2×20 mL) and the organic layers are combined. On drying, the solvent is removed in vacuo. Preparative TLC separation gives the title compound. LC-MS (M+1) 341.2 (retention time: 1.00 min).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([CH2:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([CH2:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[CH2:2][CH2:3]1
Reactant: O=CC1CCOCC1
Reactant: CCc1nn2c(-c3c(C)cc(C)cc3OC)cccc2c1NCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nn2c(-c3c(C)cc(C)cc3OC)cccc2c1N(CC1CCOCC1)CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
After dissolving N-cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine (255 mg) in tetrahydrofuran (2 mL), tetrahydro-2H-4-pyrancarbaldehyde (173 mg) [CAS No.50675-18-8] and sodium triacetoxyborohydride (241 mg) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (134 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([N+:7]([O-])=O)[S:5][CH:6]=1.C(O)(=O)C>[Fe].O>[Br:1][C:2]1[C:3]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([NH2:7])[S:5][CH:6]=1
Reactant: O=[N+]([O-])c1scc(Br)c1-n1nccn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1scc(Br)c1-n1nccn1
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A mixture of 2-(4-bromo-2-nitrothiophen-3-yl)-2H-1,2,3-triazole (0.59 g, 2.15 mmol), iron powder (0.75 g, 13.38 mmol), glacial acetic acid (8.4 mL) and H2O (1.2 mL) was heated in an oil bath set at 70° C. under condenser with N2 (g) inlet for 1 h. Purification by flash chromatography (silica, 40:60 ethyl acetate/hexane) gave 4-bromo-3-(2H-1,2,3-triazol-2-yl)thiophene-2-amine (0.35 g, 66%). Retention time (min)=1.540, method [4], MS(ESI) 246.9 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C1([N:21]2[C:33]3[CH:32]=[CH:31][C:30](B4OC(C)(C)C(C)(C)O4)=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH:4]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[C:2]([C:25]2[CH:24]=[CH:23][C:22]3[NH:21][C:33]4[C:28]([C:27]=3[CH:26]=2)=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:3]=1
Reactant: CC1(C)OB(c2ccc3c(c2)c2ccccc2n3-c2ccccc2)OC1(C)C
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)[nH]c1ccc(-c3ccc4[nH]c5ccccc5c4c3)cc12
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A mixture solution of 3-bromo-9H-carbazole (6.75 g, 27.4 mmol), 9-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole (12.15 g, 32.9 mmol), Pd2(dba)3 (0.251 g, 0.274 mmol), SPhos (0.450 g, 1.097 mmol) and K3PO4 (25.3 g, 110 mmol) in toluene (500 mL) and water (50 mL) was refluxed under nitrogen for 10 h. After cooling to room temperature, the reaction mixture was extracted with dichloromethane and washed with brine. The combined organic solutions were dried over Na2SO4, filtered, and the solvent was evaporated to yield a crude product, which was recrystallized from DCM/hexane (1/1, v/v, 1200 mL) to yield 9H,9′H-3,3′-bicarbazole (6.66 g, 59%) as a yellow solid.
Reaction SMILES: [C:1]([CH:4]([NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:2][C:1]1[O:21][C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:13][C:4]=1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCCCC(NC(=O)c1ccccc1)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)CCCCc1nc(-c2ccccc2)oc1C
Yield: 83.3 %

Procedure:
Methyl 6-acetyl-6-benzoylaminohexanoate (4.35 g) was dissolved in 87 ml of toluene, and 2.9 ml of phosphorus oxychloride was added and heated to reflux for 50 minutes. The reaction solution was cooled, poured into ice-cold water, neutralized with aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate and washed with brine. The resulting solution was dried over anhydrous magnesium sulfate and concentrated to provide 3.40 g of the objective compound as yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:37])[C:5]2[N:6]=[CH:7][N:8]([C@H:11]3[C@H:15]([OH:16])[C@H:14]([O:17]CC4C=CC=CC=4)[C@:13]([CH2:28][O:29]CC4C=CC=CC=4)([CH:25]([F:27])[F:26])[O:12]3)[C:9]=2[N:10]=1>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[NH:3][C:4](=[O:37])[C:5]2[N:6]=[CH:7][N:8]([C@H:11]3[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@:13]([CH:25]([F:27])[F:26])([CH2:28][OH:29])[O:12]3)[C:9]=2[N:10]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1nc2c(ncn2[C@@H]2O[C@@](CO)(C(F)F)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 15 h
Yield: 32.9 %

Procedure:
To a solution of compound 22 (0.22 g, 0.42 mmol) in methanol (30 mL) was added HCO2NH4 (600 mg, 9.52 mmol), followed by Pd(OH)2/C (500 mg). The reaction mixture was stirred at 80° C. for 15 h, then cooled to 25° C., filtered and then evaporated to dryness under reduced pressure. Purification by silica gel chromatography [dichloromethane:methanol (20:1 to 5:1)] and prep-HPLC provided the product 23 (0.046 g, 33%) as a white solid. LC-MS (M+H)+=334.1
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8].Cl>C1C=CC=CC=1>[CH2:7]([O:9][CH:10]([N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[CH3:11])[CH3:8]
Reactant: Ic1cn[nH]c1
Reactant: C=COCC
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(C)n1cc(I)cn1
Yield: 73 %

Procedure:
4-Iodo-1H-pyrazole (3.0 g) was suspended in benzene (150 mL) and the suspension was heated while stirring. Ethyl vinyl ether (4.4 mL) was added thereto, concentrated HCl was added dropwise thereto, and the resulting mixture was stirred at 60° C. for 3 hours. After completion of the reaction, the resulting mixture was concentrated by evaporation under a reduced pressure, and the residue was neutralized using aqueous saturated sodium hydrogen carbonate (10 mL). The resulting mixture was extracted with ethyl acetate (50 mL) and the extract was washed successively with distilled water (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound as a transparent yellow liquid (3.0 g, yield 73%).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22](O)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([CH:17]2[CH2:18][NH:19][CH2:20][CH2:21][N:16]2[CH2:15][C:2]2([CH3:1])[CH2:6][C:5]3[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=3[O:3]2)=[O:31])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Product: COc1ccc(C(=O)C2CNCCN2CC2(C)Cc3c(C)c(N)c(C)c(C)c3O2)cc1
Yield: 67 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and p-anisic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 67%.
Reaction SMILES: [CH3:1]O.[Cl:3][C:4]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O>C1C=CC=CC=1>[Cl:3][C:4]1[C:12]([CH3:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH3:1])=[O:7]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(Cl)c1C
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(OC)c(C)c1Cl
Reaction time: 18 h
Yield: 76 %

Procedure:
To 150 ml methanol, was dissolved 2-chloro-4-methoxy-3-methylbenzoic acid in an amount of 16.6 g (0.0832 mole), and the resulting solution was stirred for 18 hours under reflux and heating following to the addition of concentrated sulfuric acid in an amount of 1.0 g into the solution. The residue obtained by distillating out the solvent under reduced pressure was dissolved in benzene, washed with 3% aqueous solution of sodium hydrogencarbonate and subsequently with saturated saline solution and dried with anhydrous magnesium sulfate. After distillating out the solvent in the solution under reduced pressure, the crystals remained were washed with methanol to obtain methyl 2-chloro-4-methoxy-3-methylbenzoate in an amount of 13.5 g. The yield was 76.0%.
Reaction SMILES: C[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1C(C)(C(OCCCCCCCCCCCC)=O)[CH:21]=[C:20]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:19]1>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:4]([CH3:5])([C:3]2[CH:2]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:21]=[C:20]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:19]1
Reactant: CCCCCCCCCCCCOC(=O)C1(C)C=C(C(=O)OCC)NN1c1ccc(Cl)cc1Cl
Reactant: C=Cc1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)C1=CC(C)(c2ccccc2)N(c2ccc(Cl)cc2Cl)N1
Yield: 63.5 %

Procedure:
23.7 g of 2-methylstyrene and 14.8 g of compound (IIa) (see Example 1) together with 50 ml saturated aqueous sodium carbonate solution are heated for 4 hours at 80° C. The aqueous phase is subsequently separated off, and the organic phase is dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (eluent n-heptane/ethyl acetate 1:1) over silica gel gives 6.9 g of the above-described pyrazoline as a colorless solid of melting point 87°-89° C.
Reaction SMILES: [CH3:1][C:2]1(C)OC(=O)[CH:5]([CH:9]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:4](=[O:29])[O:3]1>N1C=CC=CC=1.C(O)C.[Cu]>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([CH:9]([C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:29])=[CH:23][CH:24]=1
Reactant: CSCc1cccc2c(C(c3ccc(C)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(C)cc1)c1c[nH]c2c(CSC)cccc12
Yield: 67.7 %

Procedure:
6.5 mg (102 μmol) of copper powder were added to a solution of 4.34 g of the compound from Example 94A in 75 ml of pyridine and 20 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.55 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([N:10]2[C:14]([CH:15]([CH3:17])[CH3:16])=[N:13][N:12]=[N:11]2)[CH:7]=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)[CH:5]=1.[Li+].[OH-]>O.C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([N:10]3[C:14]([CH:15]([CH3:17])[CH3:16])=[N:13][N:12]=[N:11]3)[CH:7]=2)[C:3]([OH:25])=[O:2])=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cn2)cc(-n2nnnc2C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nnnn1-c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid methyl ester (1.84 g, 5.14 mmol) was dissolved in a mixture of MEOH (15 mL), water (2 mL) and THF (2 mL), and LiOH 308 mg, 12.86 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and 1N aqueous HCl. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 1.70 g of 3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid, Mp=179.5-181.2° C., MS (M+H)=344.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.[F:30][C:31]([F:46])([F:45])[C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH:35]=[N:36][OH:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:37]/[N:36]=[CH:35]/[C:34]2[CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=[C:32]([C:31]([F:30])([F:45])[F:46])[CH:33]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1
Reactant: ON=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCO/N=C/c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Yield: 79.2 %

Procedure:
This compound was produced using similar methods as those used in Step 5, example 27, starting with 4-(3-bromo-propoxy)-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (0.56 g, 1.18 mmol), 3,5-bis-trifluoromethyl-benzaldehyde oxime (0.32 g, 1.23 mmol) and cesium carbonate (1.53 g, 4.70 mmol) in acetone (35 mL). The crude material was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 10/90) to give 4-{3-[({(1E)-[3,5-bis(trifluoromethyl)phenyl]methylidene}amino)oxy]propoxy}-2-{[4-(trifluoromethoxy)benzoyl]amino}benzoic acid methyl ester (0.61 g, 94%) as a white solid. 1H NMR (400 MHz, CDCl3); δ 12.26 (s, 1H), 8.56 (d, 1H), 8.13 (s, 1H), 8.06 (d, 2H), 7.98 (d, 1H), 7.97 (s, 2H), 7.80 (s, 1H), 7.33 (d, 2H), 6.64 (dd, 1H), 4.41 (t, 2H), 4.22 (t, 2H), 3.91 (s, 3H), 2.24 (m, 2H).
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[F:17][C:18]([F:34])([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][CH2:30][CH2:31][CH:32]=[O:33])=[CH:25][CH:24]=1)[CH:19]([F:21])[F:20]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:33][CH:32]([CH2:31][CH2:30][S:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:18]([F:17])([F:34])[CH:19]([F:21])[F:20])=[CH:24][CH:25]=1)[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: O=CCCSc1ccc(OC(F)(F)C(F)F)cc1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CC(O)CCSc1ccc(OC(F)(F)C(F)F)cc1
Reaction time: 3 h
Yield: 83.9 %

Procedure:
10.56 Grams of methyl acetoacetate were dissolved in 14 ml of water, and 13.9 g of a 28% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 35° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.5 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.6 g of sodium acetate and 2.3 g of tetrabutylammonium bromide were added thereto and then 43.4 g of a toluene solution containing 34.9% of 3-[4-(1,1,2,2-tetrafluoroethoxy)phenylthio]propanal were added thereto. The mixture was stirred at 45°-50° C. for 6 hours and then at room temperature for 12 hours. After the mixture had been neutralized with a concentrated aqueous hydrochloric acid solution, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 21.88 g of crude 4-hydroxy-6-[4-(1,1,2,2-tetrafluoroethoxy)phenylthio]-2-hexanone (purity: 70.9%, yield: 83.9%).