Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C[C:11]1[CH:12]=[CH:13][C:14](S(O)(=O)=O)=[CH:15][CH:16]=1.O.C(CC(=O)C)C(C)=O.N1C=CC=C1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:15]([CH3:14])=[CH:16][CH:11]=[C:12]1[CH3:13]
Reactant: Nc1ccc(I)cc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)CCC(C)=O
Solvent: c1cc[nH]c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1ccc(I)cc1F
Temperature: 25 °C

Procedure:
A 500 mL round bottom flask was charged with 2-fluoro-4-iodoaniline (53.3 g, 220 mmol), toluene (250 mL), TsOH·H2O (0.43 g, 2.3 mmol, 1 mol %), and acetonylacetone (30.8 g, 270 mmol, 1.2 eq). The solution was warmed to reflux under Dean-Stark conditions for 1 h, at which point GC/MS and TLC analysis indicate complete conversion to the pyrrole. The solution is cooled to room temperature, washed with aqueous NaHCO3, dried over MgSO4, filtered, and concentrated to provide a dark brown oil which crystallized upon standing (crude yield=72.8 g, 103% of theory). This material was homogeneous by HPLC and 1H nmr, and was suitable for use in the next reaction. An analytical sample was prepared by dissolving in 210 mL of hot hexanes, cooling, then concentrating to 50% of the original volume. Cooling in an ice bath with rapid stirring provided 35.5 g (49% recovery) of a brown, granular solid (m.p. 68-70° C.). 1H NMR (CDCl3): d 7.43 (t, J=27 Hz, 2H), 7.13 (t, J=20 Hz, 1H), 5.94 (s, 2H), 2.02 (s, 6H); 13C NMR (CDCl3) d 158.3 (d, J=254 Hz), 131.6, 128.9, 127.8 (d, J=3 Hz), 122.0, 120.3 (d, J=23 Hz), 106.4, 12.4; MS (El): m/z 268 (100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10](=[CH:15][CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10](=[CH:15][CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Product: CC=C1CN(C(=O)OC(C)(C)C)CCC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 1.32 g (5.9 mmol) of 1-(t-butoxycarbonyl)-3-ethylidene-4-piperidone in 10 ml of methanol, 2.19 g (5.9 mmol) of cerium chloride 7 hydrate were added under ice cooling, followed by the addition of 0.22 g (5.9 mmol) of sodium borohydride. The resulting mixture was then stirred at room temperature for 1 hour. After removal of the solvent by distillation under reduced pressure, water was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to chromatography on a silica gel column (eluting solvent: chloroform), whereby 1.33 g of 1-(t-butoxycarbonyl)-3-ethylidene-4-hydroxypiperidine were obtained in a quantitative yield as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]1.C(N(CC)CC)C.[F:34][C:35]1[CH:43]=[CH:42][C:41]([I:44])=[CH:40][C:36]=1[C:37](Cl)=[O:38].CCOC(C)=O>C(Cl)Cl>[F:34][C:35]1[CH:43]=[CH:42][C:41]([I:44])=[CH:40][C:36]=1[C:37]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:13]1)=[O:38]
Reactant: O=C(Cl)c1cc(I)ccc1F
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2N)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(I)ccc2F)C1
Reaction time: 2 h

Procedure:
In a vial, (S)-tert-butyl 1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate (0.500 g, 1.3 mmol) was taken up in CH2Cl2. The solution was cooled to 0 deg. C and Triethylamine (0.24 ml, 1.7 mmol) and 2-fluoro-5-iodobenzoyl chloride (0.42 g, 1.5 mmol) were added. The tube was sealed and the reaction stirred for 2 h. The reaction mixture was poured into EtOAc/1N NaOH. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting off-white foam (S)-tert-butyl 1-(2-(2-fluoro-5-iodobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate was used without further purification. MS m/z=622 [M+H]+. Calc'd for C25H28F4IN3O3: 621.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:33](Cl)(=[O:35])[CH3:34].O>ClCCl>[C:33]([C:8]1[CH:7]=[CH:6][C:5]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a solution of N-(3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (1.0 g, 2.62 mmol) obtained in Example 72 in dichloromethane (20 mL) was added at −50° C. under an argon atmosphere aluminum chloride (769 mg, 5.77 mmol) and the resulting mixture was stirred for 10 minutes. To the reaction solution was added dropwise at the same temperature acetyl chloride (0.62 mL, 8.65 mmol and the resulting mixture was warmed to room temperature. The reaction solution was added to water and the product was extracted with ethyl acetate. The combined organic layers were washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 993 mg (yield: 89%) of the title compound. Melting point: 131-133° C. (ethyl acetate-hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1)([O-])=O.C1COCC1.[H][H]>[Pd].[C].C(O)C>[NH2:1][C:4]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: Cc1ccccc1NC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccccc1NC(=O)c1ccc(Oc2ccc(N)cc2N)cc1
Reaction time: 15 h
Yield: 96.9 %

Procedure:
1.55 g (3.90 mmol) of 4-(2,4-dinitrophenoxy)-2′-methylbenzanilide was dissolved into the solvent mixture with 70 ml THF and 30 ml of ethanol, and 0.166 g of 5% Pd-carbon powder was added into this solution. The solution was thoroughly deaerated under the reduced pressure at −78° C., and then stirred for 15 hours after the system was replaced with hydrogen gas and temperature was brought back to room temperature. The solution was concentrated after removing catalyst with Celite to yield 1.26 g of 4-(2,4-diaminophenoxy)-2′-methylbenzanilide shown in the structural formula (V) above in light brown solid (Yield: 96.7%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:13][C:14]1([CH3:22])[O:21][C:19](=[O:20])[CH2:18][C:16](=[O:17])[O:15]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O.N1CCC[C@H]1C(O)=O>CCO>[CH3:13][C:14]1([CH3:22])[O:21][C:19](=[O:20])[CH:18]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)[C:16](=[O:17])[O:15]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2ccc(C(F)(F)F)cc2)C(=O)O1
Temperature: 25 °C

Procedure:
Similar procedures to those referenced in Tett. Lett. (2006), 651, D. Ramachary; Eur. J. Org. Chem. (2008), 975, D. Ramachary were employed. To a 5 L 3-necked flask fitted with an overhead mechanical stirrer was charged with 4-(trifluoromethyl)benzaldehyde (43.5 g, 250 mmol) followed by the addition of anhydrous EtOH (3,000 mL), Meldrum's acid (37.5 g, 260 mmol), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (67.5 g, 266 mmol) and L-proline (6.0 g, 51 mmol) at room temperature. The yellowish reaction mixture was stirred at room temperature under N2. An aliquot was removed after 4 hours and rinsed with EtOH and then Et2O, and air dried. The 1H NMR of this aliquot showed the reaction to be complete. The full reaction was stopped and the white precipitate from the reaction was collected by filtration and rinsed with EtOH and then Et2O and dried under vacuum to afford the title compound in the first crop as a fine white solid. The yellowish mother liquors were concentrated and allowed to crystallize overnight from EtOH and the solid material was collected as before to provide the title compound.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Mn]([O-])(=O)(=O)=[O:22].[K+]>C1C=CC=CC=1>[C:7]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:22])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=C(c1ccccc1)c1cccc(C(C)C(=O)O)c1
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 18 h

Procedure:
α-(3-(1-Phenylethenyl)phenyl)propionic acid (35 g) obtained in Example 2 was dissolved in 250 ml of benzene and 250 ml of water was further added thereto with vigorous stirring to prepare a suspension. Then, 2 liter of 2% aqueous solution of potassium permanganate was dropped little by little over 1.5 hours. After the dropping, stirring was continued for 18 hours at room temperature. After the reaction, it was acidified by adding concentrated sulfuric acidand was treated by adding 35 g of sodium sulfite. After that, 500 ml of water was added and extraction was carried out three times with 150 ml of ether. The ether solution was washed with water and it was extracted three times with 200 ml of 5% aqueous solution of sodium hydroxide. The aqueous layer was then acidified by adding hydrochloric acid and extracted again three times with 150 ml of ether, which was followed by washing with water, drying with anhydrous magnesium sulfate, and filtration. The ether was then removed by reduced-pressure evaporation. Finally, 20 g of α-(3-benzoylphenyl)propionic acid (ketoprofen) was obtained by re-crystallization from benzene/petroleum ether mixture. The melting point and spectrum were the same as those of an authentic sample.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:36](O)(=[O:39])[CH:37]=[CH2:38]>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][C:36](=[O:39])[CH:37]=[CH2:38]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: C=CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Reaction time: 4 h

Procedure:
2-Methoxy-5-nitroaniline (0.4 g, 2.38 mmol) was dissolved into CH2Cl2 (12 ml). To this solution was added EDC (1.37 g, 7.14 mmol), HOBT (964 mg, 7.14 mmol), DIEA (2.07 ml, 11.9 mmol) and acrylic acid (0.65 ml, 9.51 mmol). The reaction mixture was kept at RT for 4 h. The reaction mixture was diluted with EtOAc, washed with water, 1 N HCl, dilute NaHCO3, then brine. The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography using 2:1 EtOAc/hexanes as the solvent to give N-(2-methoxy-5-nitrophenyl)-acrylamide.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].Cl.[F:23][C:24]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:25]=1[CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:23][C:24]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:25]=1[CH2:26][N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1
Reactant: CCCCCCCCCNCc1ccc(F)cc1F
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.120 g, 0.40 mmol) in methylene chloride (5.0 mL) were added (N-(2,4-difluorobenzyl)-N-nonylamine hydrochloride (0.173 g, 0.57 mmol), DMAP (0.058 g, 0.45 mmol), and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.085 g, 0.45 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (50 mL) and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL), and brine (25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent afforded 0.117 g (53%) of a colourless oil.
Reaction SMILES: C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:30])[CH:27]=2)[NH:22][C:21]1=[O:31].CCN=C=NCCCN(C)C.[Cl:43][C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48]([C:53](O)=[O:54])=[CH:47]2>CN(C=O)C.O>[Cl:43][C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48]([C:53]([NH:19][CH:20]1[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:30])[CH:27]=3)[NH:22][C:21]1=[O:31])=[O:54])=[CH:47]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NC1Cc2cc(F)ccc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1Cc2cc(F)ccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
Triethylamine (184 μL, 1.32 mmol), HOBt (89 mg, 0.66 mmol), 3-amino-6-fluoro-3,4-dihydro-2(1H)-quinolinone monohydrochloride (CAS Reg. No: 82420-54-0) (143 mg, 0.66 mmol), and EDAC (127 mg, 0.66 mmol) were added to a solution of 5-chloroindole-2-carboxylic acid (129 mg, 0.66 mmol) in anhydrous DMF (3.5 mL). The reaction was stirred at ambient temperature for approximately 16 h, and then poured into water (50 mL). This was stirred vigorously for about 10 mins. and filtered. The collected precipitate was washed with water and dried in vacuum at 40° C., to give the title compound (200 mg, 85%) as an amorphous solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[CH2:17][CH2:16]1.O.[OH-].[Na+]>CCOCC>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]2[OH:32])[CH2:17][CH2:16]1
Reactant: COc1ccccc1N1CCN(CC2CCc3ccccc3C2=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1N1CCN(CC2CCc3ccccc3C2O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a slurry of 0.54 g of lithium aluminum hydride in ether is added a solution of 3,4-dihydro-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-1(2H)-naphthalenone (5.0 g, prepared as described in Example 1A) in 150 ml of warm ether. The resulting mixture is refluxed under a nitrogen atmosphere for 3 hours, cooled in ice, and treated (in order) with 0.55 ml of water, 0.55 ml of 15% sodium hydroxide solution and 1.65 ml of water. This mixture is stirred at room temperature for 30 minutes and the inorganic precipitates removed by filtration. The ether solution is dried over anhydrous sodium sulfate, concentrated in vacuo, and triturated with 1:1 hexane-ether to yield 4.8 g of 1,2,3,4-tetrahydro-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-1-naphthalenol. One crystallization of this material from cyclohexane yields the trans isomer in pure form as determined by NMR and thin layer chromatography analysis.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[C-]#N.[Na+].[CH:16](=[CH:23][C:24](=[O:26])[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[O:7]=[C:1]([C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:23][C:24](=[O:26])[CH3:25]
Reactant: OCc1ccco1
Reactant: CC(=O)C=Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CC(C(=O)c1ccco1)c1ccccc1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A solution of 38.4 g (0.4 mol) of freshly distilled furfurol and 125 ml of absolute dimethylformamide is added dropwise to a mixture of 9.8 g (0.2 mol) of NaCN and 125 ml of absolute dimethylformamide at 35° C in the course of 45 minutes in a manner analogous to Example 3. Stirring is then continued for 1/2 hour at 35° C. A solution of 43.8 g (0.3 mol) of benzalacetone and 150 ml of absolute dimethylformamide is then added dropwise in the course of 11/2 hours. Stirring is continued at the same temperature for a further 11/2 hours and the reaction mixture is then treated with twice its quantity of water and worked up as described in Example 5. 32.1 g of 1,4-dioxo-1-furyl-2-phenyl-pentane (44% of theoretical) are isolated from 83.5 g of the crude product by distillation; b.p. 147°-148° C/0.4 torr.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[OH:22][CH2:23][CH:24]1[CH2:29][N:28]([S:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([Br:43])[CH:39]=3)[CH:34]=2)(=[O:32])=[O:31])[CH2:27][CH2:26][NH:25]1.C(N(CC)CC)C>ClCCl.O.CN(C=O)C>[Br:43][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([S:30]([N:28]1[CH2:27][CH2:26][N:25]([C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[CH:15][CH:14]=3)[CH:24]([CH2:23][OH:22])[CH2:29]1)(=[O:32])=[O:31])[CH:42]=[CH:41]2
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1CO
Reaction time: 2 h
Yield: 56.6 %

Procedure:
A stirred suspension of 4-(4-pyridyl)benzoic acid (sodium salt) (190 mg, 0.86 mmol) in dichloromethane (10 ml) was treated with oxalyl chloride (0.2 ml, 2.3 mmol) and DMF (catalytic amount). After stirring for 2 hours, further oxalyl chloride 0.2 ml, 2.3 mmol) and DMF (catalytic amount) was added and the suspension stirred a further 4 hours. The solvent was removed in vacuo and the residue, after drying, was suspended in dichloromethane (20 ml) and treated with 2-(hydroxymethyl)-4-(6-bromonaphth-2-ylsulphonyl)piperazine (300 mg, 0.78 mmol) and triethylamine (0.36 ml, 2.5 mmol). After stirring at room temperature overnight the reaction mixture was diluted with dichloromethane (20 ml) and water (20 ml). A copious precipitate appeared which was filtered off, dried and recrystallised from ethyl acetate (10 ml) to yield 1-(6-bromonaphth-2-ylsulphonyl)-3-(hydroxymethyl)-4-[4-(4-pyridyl)benzoyl] piperazine as a colourless solid (250 mg); 1H NMR (300 MHz, DMSO-d6) δ=3-4 ppm (broad, 9H), δ7.2 ppm (d, 2H), δ=7.7 ppm (d, 2H), δ=7.8 ppm (m, 4H), δ=8.2 ppm (t, 2H), δ8.4 ppm (s,1H), δ=8.45 ppm (s,1H), δ=8.6 ppm (d, 2H); signals due ethyl acetate (1 mol eq) were also present; MS: (M+H)+ 566/568 (1 Br pattern); analysis; found: C, 56.8; H, 4.9; N, 6.3%; C27H24BrN3SO4. C4H8O2 requires: C, 56.9; H, 4.9; H, 4.9; N, 6.4%.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]([F:13])([F:12])[CH2:10][OH:11].[Cl:14][C:15]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3F)[O:21][C:17]=2[CH:16]=1>O>[Cl:14][C:15]1[C:30]([C:31]([F:34])([F:32])[F:33])=[CH:29][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[O:11][CH2:10][C:9]([F:13])([F:12])[F:8])[O:21][C:17]=2[CH:16]=1
Reactant: OCC(F)(F)F
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1cnccc1-c1nc2cc(C(F)(F)F)c(Cl)cc2o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
A mixture of 46 mg of 60% sodium hydride (in oil) and 2 ml of DMF was stirred at room temperature, to which a mixture solution of 0.12 g of 2,2,2-trifluoroethanol and 0.5 ml of DMF was added. After 15 minutes, 0.28 g of 6-chloro-2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole was added and stirred at room temperature for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.26 g of 6-chloro-2-[3-(2,2,2-trifluoroethoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 92”).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:35]O>>[CH3:35][O:2][C:1]([CH2:4][CH2:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)=[O:3]
Reactant: CO
Reactant: O=C(O)CCc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[4-(2-Carboxyethyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2 g) is dissolved in methanol (50 ml) and thereto is added dropwise thionyl chloride (1.1 ml) under ice cooling. After adding, the mixture is stirred at 0°-5° C. for 1 hour and further at room temperature overnight. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) and recrystallized from n-hexane to give 1-{1-[4-(2-methoxycarbonylethyl)benzoyl]-4-piperidinyl)-3,4-dihyrocarbostyril (1.46 g) as white powder, m.p.: 85°-86° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](O)=[CH:10][C:9](=[O:13])[N:8]([CH3:14])[C:7]=1[NH:15][CH3:16])=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:19]>CN(C)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:19])=[CH:10][C:9](=[O:13])[N:8]([CH3:14])[C:7]=1[NH:15][CH3:16])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)cc(=O)n(C)c1NC
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1c(Cl)cc(=O)n(C)c1NC
Temperature: 25 °C
Reaction time: 21 h
Yield: 86.6 %

Procedure:
Dimethylaniline (0.770 mL, 0.61 mmol) was added to a stirring solution of example 31b (15 g, 66.1 mmol) in POCl3 (36 mL, 397 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 21 h. The reaction was concentrated in vacuo, poured onto ice, and the resulting precipitate was collected by filtration to give 14 g (87%) of clean desired product as a beige solid. The filtrate was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give an additional 2 g (12%) of clean desired product. 1H NMR (400 MHz, DMSO-d6): δ 6.99 (q, 1H, J=4.8 Hz), 5.80 (s, 1H), 4.23 (q, 2H, J=7.2 Hz), 3.32 (s, 3H), 2.76 (d, 3H, J=4.8 Hz), 1.27 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C10H13ClN2O3, 245; found 245.