Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:29](=[O:30])[CH2:28][C:27](=[O:31])[NH:26][C:25]3[C:32]4[C:37]([CH:38]=[CH:39][C:24]2=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:19][CH:18]=1>>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:29](=[O:30])[CH2:28][C:27](=[O:31])[NH:26][C:25]3[C:32]4[C:37]([CH:38]=[CH:39][C:24]2=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:19][CH:18]=1)=[O:7])[CH3:2]
Reactant: CCc1ccccc1C(=O)O
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: O=S(Cl)Cl
Product: CCc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 57.8 %

Procedure:
2-Ethylbenzoic acid (23 mg, 0.15 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (26 mg, yield 58%) was obtained as slightly brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:2]1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3]2[N:4]=[CH:5][N:1]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=3)[N:2]=2)[CH:7]=1
Reactant: c1cncc(-c2nc[nH]n2)c1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-n2cnc(-c3cccnc3)n2)n1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
100 mg (684 μmol) of 3-(1H-1,2,4-triazol-3-yl)pyridine (preparation cf. J. Org. Chem. 1979, 44, 4160-4164), 124 mg (683 μmol) of 2-chloro-6-(trifluoromethyl)pyridine and 142 mg (1.03 mmol) of potassium carbonate were initially charged in 5 ml of N,N-dimethylformamide, and the mixture was stirred at 120° C. for about 18 hours. After cooling, water was added and the mixture was extracted three times with ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. This gave 180 mg (90% of theory) of 2-[3-(pyridin-3-yl)-1H-1,2,4-triazol-1-yl]-6-(trifluoromethyl)pyridine as a white solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[Br:16][C:17]1[C:18](=O)[NH:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(=O)(O)[O-].[Na+]>O>[Br:16][C:17]1[C:18]([Cl:3])=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1
Reactant: O=c1[nH]cc(C(F)(F)F)cc1Br
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: FC(F)(F)c1cnc(Cl)c(Br)c1
Temperature: 120 °C
Yield: 77.2 %

Procedure:
To phosphorous oxychloride (2.02 mL, 21.6 mmol) was added quinoline (1.34 mL, 11.2 mmol) followed by 3-bromo-5-trifluoromethyl-2(1H)-pyridone (5.0 g, 20.07 mmol). The mixture was heated at 120° C. for 3 hrs, then cooled to 100° C., whn water (10 mL) was carefully added. After cooling to room temperature, saturated sodium bicarbonate was added (100 mL) and the mixture extracted with ethyl acetate (2×100 mL). The extracts were dried (MgSO4) and concentrated, and the residue purified by silica chromatography to give the product as a liquid (4.05 g, 15.5 mmol, 75% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(O)(=O)C.[CH2:22]([CH2:24][NH2:25])[OH:23]>CC(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[C:11](/[NH:25][CH2:24][CH2:22][OH:23])=[CH:12]/[C:13]([O:15][CH3:16])=[O:14]
Reactant: NCCO
Reactant: COC(=O)CC(=O)c1ccc(OC)cc1OC
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)/C=C(\NCCO)c1ccc(OC)cc1OC
Temperature: 83 °C
Reaction time: 48 h
Yield: 65.8 %

Procedure:
To a mixture of methyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (3.50 g, 14.69 mmol) and acetic acid (0.17 mL, 2.94 mmol) in i-PrOH (70 mL) was added ethanolamine (0.88 mL, 14.69 mmol) and the reaction mixture was heated to 83° C. Additional ethanolamine (0.88 mL, 14.69 mmol) was added to the reaction mixture at two, four and six hours. After stirring at 80° C. for 48 hours, the reaction mixture was cooled and concentrated under reduced pressure before the residue was suspended in equal parts of a saturated sodium bicarbonate solution and water under N2. After stirring overnight, the solids were collected by vacuum filtration and dried in a vacuum oven at 30° C. overnight to afford the title compound (2.72 g, 63%) as a beige colored power.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:22])[NH:12][C:13]1[S:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][N:17]=1)(=O)C.Cl>C1COCC1>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:12][C:13]1[S:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][N:17]=1)=[O:22]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ncc(S(C)(=O)=O)s1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cnc(NC(=O)c2ccccc2O)s1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A solution of 7 (1.0 g, 2.94 mmol, 1.0 eq) dissolved in THF (20 mL) was added under stirring to 2M HCl (100 mL). The reaction was refluxed for one hour and allowed to cool under stirring over one hour. The product was filtered using a sintered glass funnel, washed with distilled water and THF and dried in high vacuum ato afford 834 mg (95%) of 6 as a colorless solid.
Reaction SMILES: C[N:2](CC1SC=C(CSCCN)N=1)C.[N+:15]([CH:18]=[C:19]1[NH:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28]C=C[CH:25]=2)O1)([O-:17])=[O:16].[CH2:30]([OH:32])[CH3:31]>>[OH:32][C:30]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:31]=1)[CH2:21][CH2:22][NH:23][C:19]([NH2:2])=[CH:18][N+:15]([O-:17])=[O:16]
Reactant: CCO
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: O=[N+]([O-])C=C1NCC(c2ccccc2)O1
Product: NC(=C[N+](=O)[O-])NCCc1cccc(O)c1

Procedure:
With 2 ml of ethanol was mixed 1 g of 2-{[2-(dimethylamino)methyl-4-thiazolyl]methylthio}ethylamine and 1.1 g of 2-nitromethylene-5-phenyl-oxazolidine, and the resulting mixture was subjected to reaction under reflux for 1 hour. After completion of the reaction, the reaction mixture was filtered with cooling, and the solvent was removed by distillation under reduced pressure, after which the resulting residue was purified by a column chromatography (Wako Silica Gel C-200, eluent: chloroform:ethanol=20:1 by volume) to obtain 1.3 g (yield 68%) of N-{2-[[2-(dimethylamino)methyl-4-thiazolyl]methylthio]ethyl}-(dimethylamino)methyl-4-thiazolyl]methylthio]ethyl}-N'-(3-hydroxyphenethyl)-2-nitro-1,1-ethenediamine having a melting point of 100°-101° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[F:22][C:23]([F:36])([F:35])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:32]2[CH2:33][CH2:34][CH:30]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:35])[F:36])=[CH:25][CH:26]=3)[CH2:31]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: FC(F)(F)c1ccc(C2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccc(C(F)(F)F)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-[4-(trifluoromethyl)phenyl]pyrrolidine oxalate (15.1 mg, 0.050 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.3 mg). Calcd for C22H19F3N2O2: 400.1399, found 400.1403.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(NC(C)C)(C)C>CS(C)=O>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[NH:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:17][CH2:18]3)[C:8]2=[O:19])[CH2:4]1
Reactant: Clc1nc2ccccc2o1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CS(C)=O
Product: O=c1n(C2CC2)c2nccnc2n1[C@H]1C[C@H](Nc2nc3ccccc3o2)C1

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.1099 g, 0.390 mmol), 2-chlorobenzoxazole (0.088 ml, 0.768 mmol, Sigma-Aldrich Chemical Company, Inc.), and diisopropylamine (0.204 ml, 1.170 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO. The reaction was heated to 90° C. for 24 h The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 909% over 15 min. LCMS showed product was not isolated at ≧95% purity. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (25 g), eluting with a gradient of % to 5% MeOH in CH2Cl2, to provide the title compound (0.0590 g, 0.163 mmol, 42.4% yield). LCMS showed product peak at 1.604 min (m+1=362.9). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.02 (m, 2 H) 1.02-1.09 (m, 2 H) 2.52-2.58 (m, 1 H) 2.91-3.01 (m, 1 H) 3.18-3.30 (m, 2 H) 4.46-4.59 (m, 1 H) 5.11-5.23 (m, 1 H) 6.99 (td, J=7.73, 1.37 Hz, 1 H) 7.12 (td, J=7.63, 1.17 Hz, 1 H) 7.27 (dd, J=7.73, 0.68 Hz, 1 H) 7.36 (dd, J=7.82, 0.59 Hz, 1 H) 7.94-7.98 (m, 1 H) 7.99-8.02 (m, 1 H) 8.42 (d, J=6.46 Hz, 1 H)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:25](CC)CC)C.ClC(OCC)=O.N[C@@H:37]1[C:43](=[O:44])[N:42]2[C@@H:38]1[O:39][CH2:40][CH2:41]2>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([C@H:37]1[C:43](=[O:44])[N:42]2[C@@H:38]1[O:39][CH2:40][CH:41]2[NH2:25])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N[C@@H]1C(=O)N2CCO[C@H]12
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC1CO[C@@H]2[C@@H](C(=O)[C@H](Cc3ccccc3)NC(=O)OCc3ccccc3)C(=O)N12
Temperature: -2.5 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-phenylalanine (867 mg, 2.90 mmole) and triethylamine (323 mg, 3.2 mmole) in dichloromethane (20 ml), ethyl chloroformate (315 mg, 2.90 mmole) was added at -15° C. The reaction mixture was stirred at -10 to 5° C. for 1.5 hrs. Then a precooled (~-15° C.) solution of (5R,6S)-6-amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one in ethyl acetate (see above) was added at -15° C. and the resulting mixture was stirred at room temperature for 10 hrs. After removal of solvent, the residue was dissolved in ethyl acetate, washed with water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (55:45) as eluent and 205 mg of the title compound was obtained as white solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]=[CH:3][CH2:4][C:5]([OH:7])=[O:6].[H-].[Na+].I[CH3:13]>CN(C=O)C>[CH3:13][O:6][C:5](=[O:7])/[CH:4]=[CH:3]/[CH2:2][C:1]([OH:9])=[O:8]
Reactant: O=C(O)C=CCC(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/CC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of glutaconic acid in DMF (0.1 M) at 0° C. was added NaH (1 eq). After 15 min, iodomethane (1.2 eq) was added, and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with saturated ammonium chloride, and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (silica; 10% MeOH/CHCl3) to afford a colorless viscous oil. EI-MS m/z 143 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:43]([F:46])([F:45])[F:44])=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12]C(=O)OC(C)(C)C)[CH3:11])[N:7]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][C:29]([NH:31][S:32]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)(=[O:34])=[O:33])=[O:30])=[CH:22][CH:21]=3)[C:6]=2[CH:42]=1.FC(F)(F)C(O)=O.O>C(Cl)Cl>[NH2:12][CH:10]([C:8]1[N:7]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][C:29]([NH:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])=[O:30])=[CH:22][CH:21]=2)[C:6]2[CH:42]=[C:2]([Cl:1])[C:3]([C:43]([F:45])([F:44])[F:46])=[CH:4][C:5]=2[N:9]=1)[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(C(C)NC(=O)OC(C)(C)C)nc4cc(C(F)(F)F)c(Cl)cc43)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(C(C)N)nc4cc(C(F)(F)F)c(Cl)cc43)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of 1,1-dimethylethyl 1-[6-chloro-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5-(trifluoromethyl)-1H-benzimidazol-2-yl]ethylcarbamate (step 2, 190 mg, 0.28 mmol) in CH2Cl2 (2 ml) was added trifluoroacetic acid (1 ml) and stirred at room temperature for 2 h. The mixture was added water (10 ml) and extracted with CH2Cl2 (20 ml). The organic layer was washed with brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with CH2Cl2/MeOH (10:1/5:1) to afford 160 mg (99%) of the title compound as white solids.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])[CH3:15]>Cl.C(Cl)Cl>[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13])[CH3:15]
Reactant: CCOc1ccccc1O
Reactant: c1ccc(CN2CC3OC3C2)cc1
Agent: Cl
Solvent: ClCCl
Product: CCOc1ccccc1O[C@@H]1CN(Cc2ccccc2)C[C@H]1O

Procedure:
A mixture of 45.5 g. (0.26 mole) of 1-benzyl-3,4-epoxypyrrolidine (60 g. of 76% epoxide), 48 g. (0.35 mole) of o-ethoxyphenol and 8 drops of concentrated hydrochloric acid was heated at 145° C. for 16 hr. The mixture was cooled, dissolved in methylene chloride and washed with dilute sodium hydroxide solution. The methylene chloride layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on 1 kg. of silica gel using 20% acetone in benzene as the eluent. Two recrystallizations from cyclohexane gave 8.0 g. (10%) of tan needles, m.p. 88.5°-90.0° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH:11]=[C:12](O)[CH3:13])=[CH:5][CH:4]=1)[CH3:2].O.[NH2:17][NH2:18]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[C:12]([CH3:13])[NH:18][N:17]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NN
Reactant: CCc1ccc(CC(=O)C=C(C)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2cc(C)[nH]n2)cc1
Temperature: 100 °C

Procedure:
4-Ethylphenylacetic acid (3.0 g) (see Japanese Unexamined Patent Publication 63-233975) was dissolved in dichloromethane (15 ml), and thereto were added oxalyl chloride (6.0 ml) and N,N-dimethylformamide (one drop). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure, and the residue was subjected to azeotropic distillation with toluene to give a crude 4-ethylphenylacetyl chloride, which was used in the subsequent step without further purification. (2) A suspension of magnesium chloride (1.74 g) in dichloromethane (30 ml) was cooled to 0° C., and thereto were added t-butyl acetoacetate (3.03 ml) and pyridine (2.96 ml), and successively was added a solution of the above 4-ethylphenylacetyl chloride in dichloromethane (30 ml). The mixture was stirred at the same temperature for 2.5 hours, and an aqueous citric acid solution was added thereto. The mixture was extracted with chloroform. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give t-butyl 2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate (4.75 g) as pale yellow oil. APCI-Mass m/Z 322 (M+NH4). (3) A solution of the above t-butyl 2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate in trifluoroacetic acid (60 ml) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, and the mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (4.00 g) as yellow oil. APCI-Mass m/Z 205 (M+H). (4) A solution of the above 1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (3.98 g) and hydrazine hydrate (4.0 ml) in toluene (20 ml) was stirred under heating at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=2:1) to give 3-(4-ethylphenylmethyl)-5-methyl-1H-pyrazole (3.12 g) as yellow oil. APCI-Mass m/Z 201 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl.CCOCC>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CCCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1CCCC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A solution of tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}propyl)piperidine-1-carboxylate (0.0313 g, 0.0605 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with ether, and the precipitated solid was collected by filtration, and washed with ether. The resulting solid was dissolved in a small volume of water, and the solution was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate. The solution was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[3-(piperidin-4-yl)propyl]benzofuran-3(2H)-one (0.0223 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:15])[CH2:13]Br)=[CH:10][CH:9]=1>C(OCC)(=O)C.O>[F:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:15])[CH2:13][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:10][CH:9]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nccn1CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A mixture of 2-methylimidazole (8.0 g, 97.5 mmol) and 4-fluorophenacyl bromide (21.16 g, 97.5 mmol) dissolved in ethyl acetate (40 ml) at ambient temperature was treated with tiethylamine (16.4 ml, 117 mmol) and the cloudy mixture heated at reflux for 16 hours. The mixture was cooled to ambient temperature and diluted with ethyl acetate and water, washed with water and brine, dried and evaporated to dryness. The residue was recrystallised (3×) from dichloromethane/methanol/isohexane to give 1-(4-fluorophenyl)-2-(2-methylimidazol-1-yl)ethanone (1, 9.0 g, 42%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3][CH:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>O1CCCC1>[N:1]1[CH:6]=[C:5]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])[CH:4]=[N:3][CH:2]=1
Reactant: Nc1cncnc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cncnc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a solution of pyrimidine-5-amine (100 mg, 1.05 mmol) and pyridine (0.255 ml, 3.15 mmol) in tetrahydrofuran (3 ml) was added 2,2,2-trichloroethyl chloroformate (0.217 ml, 1.58 mmol) with ice-cooling, the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to obtain the desired product (100 mg, 35.2%) as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH2:23]>>[CH3:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH:23][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Reactant: Cc1ccc(C)c(N)c1
Product: Cc1ccc(C)c(Nc2cc(-c3ccccn3)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 2,5-dimethylaniline (17 μl, 0.140 mmol) similar to Example 111 and isolated as a yellow oil (7 mg, 21%). 1H NMR (CDCl3): 8.88–8.86 (m, 1H), 8.71–8.68 (m, 1H), 8.64–8.58 (m, 2H), 7.92–7.82 (m, 2H), 7.50 (s, 1H), 7.43–7.32 (m, 2H), 7.23 (s, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.09 (s, 1H), 7.04 (dd, J=1.8, 7.8 Hz, 1H), 2.36 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [C:1]1(=N)[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.Cl.[C:16]([O:20][C:21](=[O:24])[CH2:22][NH2:23])([CH3:19])([CH3:18])[CH3:17].C(Cl)Cl>C(OCC)C.CCCCCC>[C:16]([O:20][C:21](=[O:24])[CH2:22][N:23]=[C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)([CH3:19])([CH3:18])[CH3:17]
Reactant: N=C1C=CC=C2C1=Cc1ccccc12
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN=C1c2ccccc2-c2ccccc21
Yield: 47.4 %

Procedure:
The fluorenone imine (1.52 g, 8.48 mmol) and the glycine tert-butylester hydrochloride (1.42 g, 8.48 mmol) were stirred in the methylene chloride for five hours at room temperature. The reaction solution was filtered with celite, and the solvent was removed by the distillation under reduced pressure. The obtained residual was allowed to dissolve in the diethyl ether. And, it was filtered with the celite. The obtained ether solution was cleaned with water and a saturated sodium chloride aqueous solution. And, it was dried over sodium sulfate. After the filtering and the concentration under reduced pressure were conducted, the obtained crude product was refined with the diethyl ether/hexane (recrystallization). And, (Fluoren-9-ylideneamino)-acetic acid tert-butyl ester (1.18 g, 66%) was obtained.