Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(I)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Ic1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a solution of 4-iodobenzyl alcohol (2.0 g, 8.54 mmol) in dry dichloromethane (15 mL) was added 3,4-dihydro-2H-pyran (0.92 mL, 10.25 mmol) followed by p-toluenesulfonic acid (147 mg, 0.85 mmol). The reaction mixture was stirred at ambient temperature for 2 h under a nitrogen atmosphere before partitioning between water and dichloromethane. The organic layer was washed with water followed by brine solution then dried over Na2SO4. After concentration in vacuo the residue was purified by flash column chromatography (SiO2, 9:1 hexanes/ethyl acetate) to give 2-(4-iodobenzyloxy)tetrahydro-2H-pyran (2.0 g, 74%) as a colorless liquid: 1H NMR (CDCl3, 400 MHz) δ 8.12 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 4.76-4.65 (m, 2H), 4.46 (d, J=12.0 Hz, 1H), 3.94-3.84 (m, 1H), 3.59-3.49 (m, 1H), 1.91-1.49 (m, 6H).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([OH:11])=O)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>ClCCl>[CH:1]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([Cl:15])=[O:11])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)N1CCC[C@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)N1CCC[C@H]1C(=O)Cl
Reaction time: 0.08 h

Procedure:
To a solution of (S)-1-isopropylpyrrolidine-2-carboxylic acid (4 g, 23.4 mmol) in dry dichloromethane (40 mL) was added oxalyl chloride (4.4 mL, 46.8 mmol) drop wise under nitrogen at ice bath temperature (0-10° C.). After stirring for 5 min, a drop of dry DMF was added to the reaction mixture and was allowed to stir for 2 h at the same temperature. The volatiles were removed on a rotavapor at reduced pressure and the residue was allowed to stay at high vacuum pump for 1 h to afford (S)-1-isopropylpyrrolidine-2-carbonyl chloride.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([O:23][C:18]1[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]2[O:14][C:13]([CH3:26])([CH3:25])[CH:12]([C:9]3[CH:10]=[CH:11][C:6]([CH:3]([CH3:5])[CH3:4])=[CH:7][CH:8]=3)[C:16]=2[C:17]=1[CH3:24])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 68 mg, 1.70 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol (0.5 g, 1.54 mmol) in N,N-dimethylformamide (20 mL) at 0° C., and the mixture was stirred for 10 minutes at the same temperature. To the reaction mixture was added benzyl bromide (290 mg, 1.70 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured Into water (30 mL), and extracted twice with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from methanol to obtain the title compound (380 mg, yield 60%).
Reaction SMILES: [C:1]([C:3]1([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][NH:24][CH2:25]3)=[CH:20][CH:19]=2)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)#[N:2].C(N(C(C)C)CC)(C)C.[ClH:37].[N:38]1([C:43](N)=[NH:44])C=CC=N1>CN(C)C=O>[ClH:37].[ClH:37].[C:1]([C:3]1([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][N:24]([C:43]([NH2:44])=[NH:38])[CH2:25]3)=[CH:20][CH:19]=2)[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)#[N:2]
Reactant: N=C(N)n1cccn1
Reactant: N#CC1(CCOc2ccc3c(c2)CNCC3)CCN(c2ccncc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(CCOc2ccc3c(c2)CN(C(=N)N)CC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.7 %

Procedure:
To a solution of 7-[2-[4-cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline (70 mg) in dimethylformamide (5 ml)solution were added diisopropylethylamine (0.1 ml) and 1H-pyrazole-1-carboxamidine hydrochloride (85 mg), and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by HPLC (0.05% aquesous trifluoroacetic acid:methanol=1:1). The obtained residue was treated with dil. hydrochloric acid and dried under reduced pressure to give the title compound (67 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9](OCC)=[O:10])[C:4]=1[CH3:14].[BH4-].[Na+]>CO>[CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[C:4]=1[CH3:14]
Reactant: CCOC(=O)c1ncnc(N(C)C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(CO)ncnc1N(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl 6-(dimethylamino)-5-methylpyrimidine-4-carboxylate (23) (0.4 g, 1.91 mmol) in MeOH (10 mL) was added in portionwise NaBH4 (0.14 g, 3.82 mmol) at 0° C. and the mixture was stirred for 16 h at RT. The solvent was evaporated under the reduced pressure and the reaction mixture was poured in to water (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated at reduced pressure to yield (6-(dimethylamino)-5-methylpyrimidin-4-yl)methanol (24); 0.1 g, (31.3%).
Reaction SMILES: Br[C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:3]([OH:5])(=[O:4])[CH:2]=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)[C@H](Br)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)C=Cc1ccccc1

Procedure:
5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were treated at room temperature with 2.7 ml of triethylamine in 20 ml of toluene. After a stirring time of about 150 minutes, no precipitation of the product was to be observed. An HPLC analysis of the solution showed that the (2R)-2-bromo-3-phenylpropionic acid had reacted completely to give cinnamic acid.
Reaction SMILES: FC1C=C(C=CC([C:12]2[N:19]3[C:15]([S:16][C:17]4CCCC[CH2:20][C:18]=43)=[N:14][CH:13]=2)=O)C=CC=1.[BH4-].[Na+].C([OH:29])C>>[S:16]1[CH:17]=[C:18]([CH2:20][OH:29])[N:19]2[CH:12]=[CH:13][N:14]=[C:15]12
Reactant: O=C(C=Cc1cccc(F)c1)c1cnc2sc3c(n12)CCCCC3
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: OCc1csc2nccn12

Procedure:
3-(3-Fluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula N-5, X=3-fluoro), 0.34 g, in ethanol (35 mL) was treated with NaBH4 (0.11 g), reacted for 3 hours, and solvent removed in vacuo. The residue was suspended in water, filtered and the filter cake was crystallized from acetonitrile to provide pure α-[2-(3-fluorophenyl) ethenyl]-6,7,8,9-tetrahydro-5H, imidazo[2,1-b]thiazole-3-methanol, 0.30 g, m.p. 175-176° (Formula N-8, X=3-fluoro).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([N+:17]([O-])=O)=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].O.NN>CO.[Ni]>[NH2:1][C:2]1[CH:15]=[C:14]([Cl:16])[C:13]([NH2:17])=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C(=O)NCc1cc([N+](=O)[O-])c(Cl)cc1N
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)C(=O)NCc1cc(N)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of N-(2-amino-4-chloro-5-nitrobenzyl)pivalamide (2.0 g, 6.9 mmol) in methanol (20 mL), Raney Ni (2.0 g) and hydrazine hydrate (5.0 mL) were added and the reaction mass was stirred at RT for 3 h. After the completion of the reaction, the reaction mass was filtered through celite pad and obtained filtrated was concentrated to afford 1.5 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.11 (s, 9H), 3.97 (br d, 2H), 4.52 (br d, 2H), 5.44 (br s, 2H), 6.50 (d, J=11.4 Hz, 2H), 7.88 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([CH3:11])=[O:10])[CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:12]([C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:10])[CH3:11])=[CH:3][C:2]=1[CH3:1])(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1cccc(C)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1ccc(C(C)=O)c(C)c1
Reaction time: 1 h

Procedure:
The reaction was run in a 500 mL 3 neck round bottom (RB) fitted with a mechanical stirrer and reflux condenser. To 45 g (301.6 mmol) of 3-methylacetanilide in 240 mL of carbon disulfide under argon at RT was added 38.6 mL (542.8 mmol) of acetyl chloride with stirring. To the solution was then added 145 g (1.09 mol) of aluminum chloride in small portions over a 1 h period. After addition was complete the mixture was refluxed for 1 h and then allowed to cool and stand for 1 h. The supernatant carbon disulfide layer was decanted off and the very dark viscous lower layer was poured into a mixture of cracked ice and hydrochloric acid. The precipitate was collected and washed with 1 L of water. The solid was dried under high vacuum for 30 h at RT no provide 52.17 g (90%) of title amide in the form of a light tan solid which is used as the crude material in the following reaction.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([S:16](=[O:21])(=[O:20])[N:17]([CH3:19])[CH3:18])=[CH:12][C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[Cl:30]>Cl.CO.C(O)C>[Cl:30][C:24]1[CH:25]=[C:26]([I:29])[CH:27]=[CH:28][C:23]=1[NH:22][C:11]1[CH:12]=[C:13]([S:16](=[O:21])(=[O:20])[N:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:9]([NH:8][OH:7])=[O:31]
Reactant: CN(C)S(=O)(=O)c1ccc(C(=O)NOC2CCCCO2)c(Nc2ccc(I)cc2Cl)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc(C(=O)NO)c(Nc2ccc(I)cc2Cl)c1

Procedure:
The compound 2-(2-chloro-4-iodo-phenylamino)-4-dimethylsulfamoyl-benzoic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide is dissolved in an appropriate hydrogen chloride-saturated solvent like methanol or ethanol. Once homogeneous, the solution is concentrated in vacuo to give the desired product. The product may be triturated with an appropriate solvent like chloroform or dichloromethane if further purification is necessary.
Reaction SMILES: C([C:5]1[CH:33]=[CH:32][C:8]([N:9](O[SiH](C)C)[C:10]2[CH:15]=[C:14]([N:16]([CH2:25][C:26]#[N:27])[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[Br:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1)(C)(C)C.[F-].[O:35]1CCCC1>>[OH:35][C:5]1[CH:33]=[CH:32][C:8]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:25][C:26]#[N:27])[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[Br:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(N(CC#N)c2cc(N(O[SiH](C)C)c3ccc(C(C)(C)C)cc3)ncn2)c(Br)c1
Agent: [F-]
Product: Cc1ccc(N(CC#N)c2cc(Nc3ccc(O)cc3)ncn2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 4-(4-tertbutyldimethylsilyloxyanilino)-6-(N-cyanomethyl-2-bromo-4-methylanilino)pyrimidine (Reference Example 2, 890 mg) in tetrahydrofuran (1 ml) was added N,N,N,N-tetraburylammonium fluoride (1M solution in tetrahydrofuran, 2 ml). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was evaporated and the residue partitioned between EtOAc and water. The organic layer was separated and dried (MgSO4), evaporated and purified by column chromatography eluting with DCM:MeOH:concentrated ammonia; 95:4:1 to give the title compound (510 mg, 73%) as a solid. M/z 410 (MH+).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8]I)=[O:2].[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>CN(C=O)C>[CH:1]([NH:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8][N:26]1[C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]2[C:22]1=[O:32])=[O:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=CNCC(CCCI)(c1ccccc1)c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=CNCC(CCCN1C(=O)c2ccccc2C1=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
A mixture of 5-formylamino-1-iodo-4,4-diphenylpentane (7 g) and potassium phthalimide (3.63 g) was stirred in DMF (40 ml) at room temperature for 3 hours. The reaction mixture was poured in ice-water and the syrup which separated out was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was washed with isopropyl ether to provide the title compound (5.2 g) as colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][OH:22])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[CH:23]1([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34](O)[CH:33]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:24]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:23]1([CH:26]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:22][CH2:21][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:15]([CH2:16][C:17]([CH3:19])([CH3:18])[CH3:20])[N:14]=3)[CH:37]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:25]1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CC(c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67.2 %

Procedure:
Under a nitrogen atmosphere, to a solution of (5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methanol (100 mg) and methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (73 mg) in toluene (4.7 mL) were added 1,1′-(azodicarbonyl)dipiperidine (133 mg) and tributylphosphine (131 μL) at room temperature, and the mixture was stirred at room temperature for 14 hr. Hexane/ethyl acetate (1:1) was added to the reaction mixture, and the resulting precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (112 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][NH:17][CH3:18].[BH4-].[Na+]>CO>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:17]([CH3:18])[CH3:16])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CNC
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)c1ccc(CN(C)C)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75.8 %

Procedure:
A mixture of 1-(4-(diethoxymethyl)benzaldehyde (2.08 g, 10 mmol) and dimethylamine (33% aqueous solution, 2.74 g, 20 mmol) in methanol (20 mL) was stirred at room temperature for 40 mins. The mixture was cooled to 0° C., sodium borohydride (0.57 g, 15 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature for 4 hr. Methanol was removed under reduced pressure. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 1-(4-(diethoxymethyl)phenyl)-N,N,-dimethylmethanamine (1.8 g) as a light yellow oil which was used in the next step without further purification. MS (ESI) m/z: 237 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C@@:17]1([CH2:21][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[C@H:19]([CH3:20])[O:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C@:17]([OH:18])([C@H:19]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:20])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](n1cc([N+](=O)[O-])cn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 180 °C
Yield: 74.6 %

Procedure:
4-Nitropyrazole (0.5 g, 4.42 mmol) and 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazol (0.93 g, 3.68 mmol) were suspended in N,N-dimethylformamide (20 mL), and anhydrous potassium carbonate (0.61 g, 4.44 mmol) was added thereto, followed by heating at 180° C. for 5 minutes by microwave irradiation while stirring. After completion of the reaction, the resulting mixture was extracted with ethyl acetate (200 mL), and the extract was washed successively with saturated ammonium chloride (200 mL) and brine (200 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 (1.0 g, yield 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C2(C#N)CCOCC2)c1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
3-Methoxyphenylacetonitrile (10 g, 67.9 mmol) in DMF (50 ml) was added slowly to a suspension of NaH (5.04 g, 150 mmol) in DMF (50 ml) at 0° C. under N2. The reaction was allowed to warm to room temperature and stirred for 30 nms. The reaction was cooled to 0° C. and bis(2-chloroethyl)ether (10.7 g, 74.7 mmol) in DMF (100 ml) was added dropwise over 80 min. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with water (500 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (3×50 ml), dried over MgSO4, filtered, washed with ethyl acetate and concentrated in vacuo. The crude mixture was purified by column chromatography, eluting with heptane increasing the polarity to heptane:ethyl acetate (90:10), to give 4-(3-methoxyphenyl)tetrahydro-pyran-4-carbonitrile (4.1 g, 28%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18]>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28][CH2:29]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18].[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5]
Reactant: O=C(O)/C=C/C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 25 °C

Procedure:
Fumaric acid (1.16 g, dissolved in 35 ml of absolute ethanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 167.7° C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[CH3:15][O:16][C:17](=[O:22])[CH2:18][C:19]([CH3:21])=O.C[O-].[Na+]>CO>[CH3:15][O:16][C:17]([C:18]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=2)=[N:2][O:1][C:19]=1[CH3:21])=[O:22]
Reactant: ON=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(C(F)(F)F)c2)noc1C
Yield: 57 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-3-(trifluoromethyl)benzimidoylchloride (8.0 g, 35.78 mmol), methylacetoacetate (8.30 g, 71.56 mmol) and sodium methoxide (5.80 g, 107.34 mmol), a white solid required compound (5.82 g, 20.41 mmol, 57%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].I[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].BrCC>CS(C)=O.C(OCC)(=O)C.[Cu]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Ic1cccs1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCBr
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2cccs2)c1
Temperature: 150 °C
Reaction time: 6 h
Yield: 20.1 %

Procedure:
1H-Pyrazole-4-carboxylic acid ethyl ester (7.0 g) and 2-iodothiophene (10.5 g) were dissolved in DMSO (50 mL), potassium carbonate (6.91 g) and copper powder (31.7 mg) were added, and the mixture was stirred at 150° C. for 6 hr. The reaction mixture was cooled to 80° C., bromoethane (2 mL) was added, and the mixture was stirred for 2 hr and cooled to room temperature. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=9:1) to give 1-(2-thienyl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.23 g) as a white solid. The obtained compound was subjected to reactions in the same manner as in Reference Examples 17 to 18 to give the title compound.
Reaction SMILES: [ClH:1].[Cl:2]C1C=C(C#N)C=CC=1[N:11]([CH2:19][C:20]1[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:21]=1[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)C(=O)OC(C)(C)C>O1CCOCC1>[ClH:2].[NH2:11][CH:19]([C:20]1[C:25](=[O:26])[CH2:24][CH2:23][CH2:22][C:21]=1[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=1)[C:23]1[CH:24]=[CH:25][C:20]([C:19]#[N:11])=[CH:21][C:22]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)c1ccc(C#N)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCCC2=O)c(Cl)c1
Temperature: 25 °C

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane, 4.0 mL, 16.2 mmol) is added to a solution of tert-butyl (2-chloro-4-cyanophenyl)(6-oxo-2-(3-(trifluoromethyl)phenylamino)cyclohex-1-enyl)methylcarbamate (intermediate 53, 1.05 g, 2.02 mmol) in 1,4-dioxane (5 mL), and the mixture is stirred at room temperature over night. All volatiles are removed under reduced pressure, and the residue is treated with tert-butyl methyl ether. The precipitate is filtered and dried. Yield: 690 mg; ESI mass spectrum [M+H]+=420; Retention time HPLC: 0.57 min (X012_S01).