Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[CH2:21]Br)[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH2:10][C:11]2[C:20](=[CH:19][CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1ccc(CBr)c(CBr)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzylamine (3.21 g, 30.0 mmol) in anhydrous tetrahydrofuran (25 ml) was added to a stirred mixture of methyl 3,4-bis-(bromomethyl)benzoate (9.66 g, 30.0 mmol) (obtained from Fluorochem) and triethylamine (9 ml, 64.7 mmol) in anhydrous tetrahydrofuran (50 ml) and the resulting mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo at 40° C. and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with a further portion of water (100 ml), separated and the solvent removed in vacuo at 40° C. to afford methyl 2-benzyl-2,3-dihydro-1H-isoindole-5-carboxylate as a pale orange solid that was used immediately without further purification as described below. 1H NMR (DMSO-d6) 7.82 (2H, m), 7.40-7.25 (6H, m), 3.90 (3H, s), 3.88 (2H, s), 3.84 (4H, s). MS: [M+H]+ 268.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:15][O:1][C:2]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(C)=O)ccc1OC

Procedure:
To a stirred solution of Methyl 2-hydroxy-5-acetylbenzoate (12 g, 61.7 mmol) in DMF (200 ml) was added cesium carbonate (24.15 g, 74.1 mmol) and MeI (9.64 g, 68 mmol).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([Br:7])[N:6]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([Br:7])[N:6]=1
Reactant: O=Cc1sc(Br)nc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
2,4-Dibromo-thiazole-5-carbaldehyde (2.0 g, 7.4 mmol) in methanol (80 mL) was treated with NaBH4 (419 mg, 11.0 mmol). The reaction mixture was stirred at rt overnight, quenched with 10% NaOH, diluted with water and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using hexane/ethyl acetate (3:1) to give the title compound (1.84 g, 91%). MS (DCI/NH3) m/z 274 (M)+. 1H NMR (500 MHz, CDCl3) δ ppm 2.11 (s, 1H) 4.78 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>C1COCC1>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:31])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
To a stirred solution of ethyl 4-aminophenylacetate (1.13 g, 6.31 mmol) and Et3N (965 ml, 6.92 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (953 ml, 6.31 mmol) and the reaction mixture was stirred at room temperature for 2 days. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give ethyl 4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.93 g, 84%) as white needles. mp 137-139° C.; 1H-NMR (CDCl3) δ1.25-1.29 (m, 3 H), 3.59 (s, 2 H), 4.15-4.20 (m, 2 H), 7.05 (br s, 1 H), 7.13-7.23 (m, 6 H), 7.47-7.51 (m, 1 H), 7.54-7.56 (m, 1 H), 8.01-8.03 (m, 1 H).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[CH:14]=[C:15](I)[CH:16]=[CH:17][C:5]=2[O:4]1.[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[F:27][C:23]([F:28])([C:15]1[CH:16]=[CH:17][C:5]2[O:4][C:3]([CH2:19][F:20])([CH2:2][F:1])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]=2[CH:14]=1)[C:22]([F:30])([F:29])[F:21]
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21

Procedure:
In the same manner as described in Example 3 (6) but using ethyl 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylate, potassium pentafluoropropionate, cuprous iodide, toluene and N,N-dimethylformamide, ethyl 6-pentafluoroethyl-2,2-bisfluoromethyl-2H-1-benzopyran-4-carboxylate was obtained as an oily substance.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])([O:3][CH2:4][CH3:5])=[O:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:15]([O:14][C:10]1[CH2:11][CH2:12][CH2:13][C:9]=1[CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)CCCC1=C(OC(C)=O)CCC1

Procedure:
In the manner described in Example 10, treatment of 2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with acetic anhydride and p-toluenesulfonic acid mohohydrate gives a yellow oil, b.p. 98°-103° C. (0.35 mm).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Al]>C(Cl)Cl>[CH2:8]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCCCCO
Reactant: BrCc1ccccc1
Agent: [Al]
Solvent: ClCCl
Product: OCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,5-pentanediol (2.10 mL, 20.0 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (100 mL). Ag2O (6.95 g, 30.0 mmol, 1.5 equiv.) and benzyl bromide (2.62 mL, 22.0 mmol, 1.1 equiv.) were added to the solution sequentially. The flask was wrapped with aluminium foil, and the solution was stirred at room temperature for 18 h. The solution was filtered through a pad of celite, eluting with CH2Cl2, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, Ethyl Acetate (EtOAc): petroleum ether (pet ether)=3:17 to 1:1) to give the alcohol as a colorless oil. 1H NMR (500 MHz, CDCl3) δ=7.37-7.26 (m, 5H), 4.50 (s, 2H), 3.64 (t, J=6.5 Hz, 2H), 3.49 (t, J=6.5 Hz, 2H), 1.70-1.63 (m, 2H), 1.62-1.55 (m, 2H), 1.50-1.42 (m, 2H), 1.34 (br s, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ=138.8, 128.6, 127.8, 127.7, 73.2, 70.5, 63.1, 32.8, 29.7, 22.7 ppm; Low Resolution Mass Spectrometry (LRMS) (ESI+ve) m/z: 217 (M+Na+).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C=O)C>[CH2:10]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCCCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCCOCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
31.5 g of sodium hydride (60%) is introduced at room temperature in portions in 900 ml of absolute DMF. 104.8 ml of 1,5-pentanediol in 450 ml of absolute DMF is added in drops to the suspension that is cooled to −20° C. in such a way that the internal temperature does not exceed −15° C. After the addition has been completed, a solution of 121 ml of benzyl bromide in 870 ml of absolute DMF is quickly added in drops, and then the reaction mixture is stirred for 30 minutes at room temperature. The reaction is completed by careful addition of 315 ml of water. For working-up, the reaction mixture is stirred into 1.5 l of water and extracted 3 times with 1 l of ether in each case. The ethereal phases are combined, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Chromatography on silica gel with a hexane-ethyl acetate gradient yields 85 g of 5-benzyloxy-pentan-1-ol as an oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[CH2:16]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(O)c(Cc2ccccc2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Trifluoromethanesulfonic anhydride (10.0 mL, 60 mmol) was added over 3 min to a solution of 2-benzyl-4-methoxyphenol (10.71 g, 50 mmol; prepared according to J. Am. Chem. Soc. 1949, 71, 64) and anhydrous 2,6-lutidine (12.0 mL, 100 mmol) in anhydrous CH2Cl2 (250 mL) at −78° C. under argon. The reaction was stirred at −78° C. for 0.5 h, then was warmed to RT. After 1 h, the reaction was diluted with hexanes (250 mL) and washed sequentially with 1.0 N HCl (2×100 mL), 1.0 N NaOH (2×50 mL), H2O (100 mL) and brine (50 mL). Drying (Na2SO4), concentration, and silica gel chromatography (10% EtOAc/hexanes) gave the title compound as a light yellow solid (16.65 g, 96%): TLC Rf 0.51 (10% EtOAc/hexanes); 1H NMR (250 MHz, CDCl3) δ 7.10-7.40 (m, 6H), 6.77 (dd, J=9.0, 3.1 Hz, 1H), 6.66 (d, J=3.1 Hz, 1H), 4.03 (s, 2H), 3.73 (s, 3H); FTIR (CCl4) 1492, 1423, 1405, 1249, 1216, 1161, 1144, 1039, 869 cm−1; MS (ES) m/e 369 (M+Na)+, 364.0 (M+NH4)+, 347.0 (M+H)+.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:16]([CH:13]1[CH2:15][CH2:14]1)=[O:17]
Reactant: O=C(Cl)C1CC1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CC1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
N,O-dimethyl-hydroxylamine HCl (40 g, 410 mmol) was suspended under nitrogen in DCM (400 mL) and cooled in ice. Triethylamine (63 mL, 451 mmol) was added slowly, then cyclopropanecarbonyl chloride (41 mL, 451 mmol) was added slowly. Stirring without cooling was continued for 1 h. Extraction: 2×DCM, 1×1 N HCl, 1×NaCl. Distillation: 75° C./20 mbar. One obtained 32.5 g (61%) of a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Cl:7][C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1>C(O)(C)C>[Cl:7][C:8]1[CH:13]=[C:12]([NH:1][CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4])[N:11]=[C:10]([NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1
Reactant: CC(C)(C)CN
Reactant: CC(C)(C)CNc1nc(Cl)cc(Cl)n1
Solvent: CC(C)O
Product: CC(C)(C)CNc1cc(Cl)nc(NCC(C)(C)C)n1

Procedure:
After adding 5 ml of 1-amino-2,2-dimethylpropane to a solution of 5.0 g of 4,6-dichloro-2-(2,2-dimethylpropylamino)pyrimidine in 25 ml of isopropanol the reaction mixture is boiled under reflux for 20 hours, then evaporated. The residue is distributed between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. After recrystallization from hexane the title compound is obtained in a yield of 2.994 g (49.4%), m.p.:95°-98° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>N1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
20.2 g (0.129 mol) of 4-fluoro-3-nitroaniline was dissolved in 120 ml of pyridine, and 17.8 g (0.136 mol) of ethanesulfonyl chloride was added dropwise to the solution at a temperature of not higher than 5° C. Thereafter the temperature was raised to room temperature and the reaction was continued for one night. After the pyridine was distilled off, the thus-obtained product was dissolved in ethyl acetate and washed with diluted hydrochloric acid twice, then with water, and with saturated saline solution. The solution was dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off to obtain the crude product (crystals). The crude product was washed with diisopropyl ether, thereby obtaining 29.7 g of the objective product (yield: 93%) in the form of brown crystals. Melting point: 133° to 136° C.
Reaction SMILES: N1C=CC=CC=1.[C:7]([OH:16])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[C:7]([OH:16])=[O:15])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
Pyridine (64 μl, 0.80 mmol) was added to an ice cooled mixture of salicylic acid (10 mg, 0.72 mmol) and methylene chloride (10 mL). After 5 minutes, acetic anhydride (10 μl, 1.09 mmoles) was added. The resulting mixture was stirred at room temperature for 4 hrs. The product was extracted with methylene chloride and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 2-acetoxybenzoic acid in 76% yield.
Reaction SMILES: [CH2:1]([OH:7])[C@@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:1][C@H:2]2[CH2:3][CH2:4][CH2:5][O:6]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-tetrahydrofurfuryl alcohol (Lancaster, 1.0 g, 9.8 mmol) in 5 mL of CH2Cl2 and 5 mL of pyridine was added p-toluenesulfonyl chloride (2.8 g, 14.7 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 5 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL of portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+, 274 (M+NH4)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+].O.C(Cl)(Cl)(Cl)[Cl:40]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([Cl:40])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Cl[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 20 h
Yield: 72 %

Procedure:
To a stirred solution of (R)-1-benzyl-3-pyrrolidinol (886 mg, 5.0 mmol) in CCl4(20 ml) was added triphenylphosphine(1.574 g, 6.0 mmol) at rt. After 20 h stirring at reflux temperature, the solvent was evapolated. Saturated NaHCO3 aqueous solution and water was added to the residue, and the mixture was extracted with AcOEt. The extract was brine, dried(Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel; 100 g, CH2Cl2/MeOH: 50/1-45/1) to give 706 mg(72%) of pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:4][C:3]=1[O:34][CH3:35].[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([O:1][C:2]1[C:3]([O:34][CH3:35])=[CH:4][C:5](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:6][C:7]=1[O:8][CH3:9])(=[O:38])[CH3:37]
Reactant: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1O
Reactant: CC(=O)Cl
Product: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1OC(C)=O
Temperature: 0 °C

Procedure:
To a mixture of 1-[2-{5-(4-hydroxy-3, 5-dimethoxyphenyl)-(2E, 4E)-2, 4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine (1 g) and pryidine (10 ml) was added slowly acetyl chloride (0.48 ml) at 5° to 10° C. After hour, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was treated with a mixture of fumaric acid (83 mg) and methanol (8 ml) and concentrated under reduced pressure to give white crystals. The crystals were recrystallized from ethanol to give 1-[2-{5-(4-acetoxy-3, 5-dimethoxyphenyl)-(2E, 4E)-2, 4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine 1/2fumarate (0.25 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N1C=CC=CC=1.[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[OH:25])([O-:15])=[O:14].Cl>O>[OH:25][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[N:21]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:20]=1
Reactant: CCOC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2[nH]nc(O)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl chloroformate (5 ml) was added to a pyridine (30 ml) solution containing 5-nitro-1H-indazol-3-ol (5.42 g) obtained in the 1st step, followed by stirring at room temperature for 1.5 hours. Water and concentrated hydrochloric acid (32 ml) were added dropwise to the reaction solution and a solid precipitate was collected by filtration. The obtained residue was washed with water. A brown solid of ethyl 3-hydroxy-5-nitro-1H-indazol-1-carboxylate (7.5 g) was thus obtained.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1)#[N:2].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:10])[C:12]([F:14])([F:13])[F:11])=[CH:7][N:8]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)C(F)(F)F)cn1
Yield: 81.6 %

Procedure:
According to Reference Example 8-12, by use of 6-cyano-3-pyridinecarboxaldehyde (364 mg, 2.76 mmol), (trifluoromethyl)trimethylsilane (490 μL, 3.31 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 276 μL, 0.276 mmol) and tetrahydrofuran (7.0 mL), the mixture was stirred and reacted at room temperature for 5 hours. Then, purification by column chromatography (hexane/ethyl acetate=7/3) was performed to give 2-cyano-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound ES) (455 mg, yield: 82%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.[CH3:24]I>CN(C)C=O.C(OCC)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[N:14]=[CH:13][N:12]([CH3:24])[C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:17][CH:18]=1
Reactant: CI
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ncn(C)c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
1.8 g of sodium hydride (50% in white oil) is added in incremental portions to a solution of 10.5 g of 4,5-bis(4-methoxyphenyl)imidazole in 50 ml of absolute dimethylformamide. The mixture is agitated for another 30 minutes and then 5.35 g of methyl iodide in 50 ml of dimethylformamide is dropped thereto. After 60 minutes, the mixture is poured into ice water, the product taken up in ethyl acetate, the organic solution dried over sodium sulfate and concentrated under vacuum. The residue is recrystallized from benzene, thus obtaining 9.59 g of 4,5-bis(4-methoxyphenyl)-1-methylimidazole, mp 122°-123°.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[H-].[Na+]>>[O:1]=[C:2]1[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 2-hydroxybenzimidazole (4.00 g, 29.8 mmol) and tert-butyl bromoacetate (5.53 g, 28.3 mmol) in DM (50 mL) at 0° C. was added sodium hydride (1.31 g of a 60% dispersion in mineral oil, 32.8 mmol). The mixture was stirred at 0° C. for 1 h, then quenched with saturated aqueous NaHCO3 and concentrated in vacuo. The residue was partitioned between EtOAc (500 mL) and H2O (300 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].C([Li])CCC.[C:14](Cl)(=[O:18])/[CH:15]=[CH:16]/[CH3:17].C([O-])(O)=O.[Na+]>O1CCCC1>[C:14]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:18])/[CH:15]=[CH:16]/[CH3:17]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)(C)OC(N)=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C/C=C/C(=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 27.9 %

Procedure:
1,1-Dimethylethyl carbamate (5 g, 42.7 mmol) was dissolved in tetrahydrofuran (THF) (100 mL) in a 500 mL 3 necks round bottom flask and cooled at −78° C. under nitrogen. n-Butyl lithium (1.6 M in THF, 26.7 mL, 42.7 mmol) and (2E)-2-butenoyl chloride (4.55 mL, 42.7 mmol) were added in slow successive additions as follow: 1) n-Butyl lithium: 13.4 mL and (2E)-2-butenoyl chloride 2.28 mL; 2) n-Butyl lithium:6.8 mL and (2E)-2-butenoyl chloride 1.14 mL; 3) n-Butyl lithium:3.34 mL and (2E)-2-butenoyl chloride 0.57 mL; 4) n-Butyl lithium: 1.67 mL and (2E)-2-butenoyl chloride 0.28 mL (2×). A five to ten minutes waiting time was observed between each double addition, and the final mixture was stirred for an extra 30 minutes period at −78° C. The temperature was kept below −60° C. during the additions. The reaction mixture was then slowly poured into a stirred saturated NaHCO3 aqueous solution (250 mL). The aqueous layer was extracted with AcOEt (2×250 mL). The combined organic phases were washed with brine (150 mL), dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue by flash chromatography on silica gel (gradient:50 to 100% AcOEt in Hexanes) gave 1,1-dimethylethyl (2E)-2-butenoylcarbamate (2.21 g, 11.93 mmol, 28%) as a white solid.