Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH2:24]([O:26][C:27]([CH:29]1[CH:33]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:32][N:31]([C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:30]1)=[O:28])[CH3:25].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>O1CCCC1.CN(C)C=O>[CH2:24]([O:26][C:27]([CH:29]1[CH:33]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:21](=[O:23])[CH2:20][C:5]3[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:36][CH:35]=2)[CH2:32][N:31]([C:41](=[O:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:30]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1c1ccc(N)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A stirred solution of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (5.1 g) in anhydrous tetrahydrofuran (140 ml), at 23° C. and under an atmosphere of argon, was treated with benzotriazol-lyloxytris(dimethylamino)phosphonium hexafluorophosphate (8.61 g). After stirring for 1 hour the mixture was treated with 1-benzoyl-4-(4-amino-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (5.48 g, Reference Example 8) then with triethylamine (9.1 ml), dimethylaminopyridine (0.2 g) and dimethylformamide (5 ml). The resulting mixture was stirred at 23° C. for 2 days then evaporated (40° C. and 2.7 kPa). The residue was treated with ethyl acetate (300 ml) and the resulting solution was washed twice with water (200 ml), twice with hydrochloric acid (200 ml, 1N), then twice with aqueous sodium bicarbonate solution (200 ml, 10%), then with brine (100 ml), then with water (100 ml), then dried over magnesium sulphate and then evaporated (40° C. and 2.7 kPa). The resulting white meringue was triturated with diethyl ether (50 ml) for 20 hours affording the title compound (9.6 g) as a white powder, m.p. 130° C. 1H-NMR [500 MHz, (CD3)2SO at 383° K.]: δ 1.15 (t, J=7 Hz, 3H); 2.30 (s, 3H); 3.33 (m, 1H); 3.50 to 3.70 (m, 2H); 3.62 (s, 2H); 3.77 (m, 1H); 3.85 to 4.00 (m, 2H); 3.91 (s, 3H); 4.10 (q, J=7 Hz, 2H); 6.89 (bd, J=8 Hz, 1H); 6.95 to 7.05 (m, 1H); 7.04 (d, J=2 Hz, 1H); 7.15 (t, J=8 Hz, 1H); 7.20 (d, J=7.5 Hz, 1H); 7.25 (d, J=8 Hz, 2H); 7.45 (m, 3H); 7.54 (m, 4H); 7.69 (d, J=8 Hz, 1H); 8.01 (d, J=8 Hz, 1H); 8.16 (s, 1H); 8.22 (s, 1H); 9.56 (s, 1H). MS [DCI (reactant gas, ammonia)]: 635[M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:48]1[CH:53]=[CH:52][C:51]([CH:54]([CH3:73])[C:55]([C:61]2[CH:62]=[CH:63][C:64]3[O:69][CH2:68][C:67](=[O:70])[N:66]([CH3:71])[C:65]=3[CH:72]=2)([OH:60])[C:56]([F:59])([F:58])[F:57])=[C:50]([Cl:74])[CH:49]=1.[NH:75]1[CH2:80][CH2:79][CH:78]([C:81]([O:83][CH2:84][CH3:85])=[O:82])[CH2:77][CH2:76]1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:84]([O:83][C:81]([CH:78]1[CH2:79][CH2:80][N:75]([C:48]2[CH:53]=[CH:52][C:51]([CH:54]([CH3:73])[C:55]([OH:60])([C:61]3[CH:62]=[CH:63][C:64]4[O:69][CH2:68][C:67](=[O:70])[N:66]([CH3:71])[C:65]=4[CH:72]=3)[C:56]([F:59])([F:58])[F:57])=[C:50]([Cl:74])[CH:49]=2)[CH2:76][CH2:77]1)=[O:82])[CH3:85]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
To a suspension of 2,2′-bis(diphenylphosphino)-1,1′binaphthyl (3.1 mg), tris(dibenzylideneacetone)dipalladium (0) (1.5 mg) and sodium-tert.-butylate (19 mg) in toluene (15 ml) were added 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3, 80 mg) and ethyl piperidine-4-carboxylate (29 mg). The mixture was stirred at room temperature overnight. 2,2′-Bis(diphenylphosphino)-1,1′binaphthyl (3.1 mg), ethyl piperidine-4-carboxylate (29 mg) and tris(dibenzylideneacetone)dipalladium (0) (1.5 mg) were added and the mixture was stirred at 80° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc. The organic phase was washed with water, dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>4:1) to give the title compound (3 mg) as light yellow oil. MS (m/e)=555.3 [M+H+].
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6](O)(=[O:9])[CH2:7]C.C[C:12]1[CH:17]=[C:16]([C:18](C)(C)C)[C:15]([OH:22])=C(C(C)(C)C)[CH:13]=1>>[CH2:6]([O:9][C:15](=[O:22])[CH:16]([CH3:18])[CH:17]=[C:12]=[CH2:13])[CH3:7]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: C=C=CC(C)C(=O)OCC
Temperature: 150 °C

Procedure:
The autoclave is closed and the reaction mass is heated to 150° C. over a period of 50 minutes. The reaction mass is then maintained at a temperature of between 135°-160° C and at a pressure of 20 up to 60 psig for a period of 3 hours. At the end of this 3-hour period, the autoclave is cooled to room temperature and then opened. 12.6 g of sodium bicarbonate is then added to the reaction mass in order to neutralize the propionic acid. 30 g of Primol (see note 1) and 0.1 g of Ionol (see note 2) are added and the resulting reaction product is fractionally distilled at atmospheric pressure to a pot temperature of 129° C. A mixture of ethanol and ethyl propionate is distilled over. Vacuum is then applied to the distillation column and the resultant product, ethyl-2-methyl-3,4-pentadienoate is distilled at a vapor temperature of 65°-69° C at a pressure of 24-33 mm Hg as fractions 5-10 of the following fractions:
Reaction SMILES: [N:1]1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.N[C:20]1[C:28]2[C:23](=[CH:24][C:25]([Cl:35])=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]=2)[N:22]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:21]=1>C(Cl)Cl>[Cl:35][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:10]3[C:9]([O:8][CH3:7])=[CH:14][CH:13]=[CH:12][C:11]=3[S:15]([NH2:1])(=[O:17])=[O:16])=[N:21][N:22]2[CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])=[CH:27][C:26]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccncc1
Reactant: C[Si](C)(C)CCOCn1nc(N)c2cc(-c3ccccc3)c(Cl)cc21
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: COc1cccc(S(N)(=O)=O)c1-c1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.236 cm3 of pyridine and 26.5 mg of 3-methoxyphenylsulfonyl chloride are added to a solution of 54.1 mg of 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilylethoxy)methyl]indazole in 2 ml of methylene chloride. The reaction medium is stirred at ambient temperature for 24 hours and then evaporated. The purification of the crude product by chromatography on silica (eluent: methylenechloride/acetone (98/2, v/v)) makes it possible to obtain 70 mg of 1N-[6-chloro-5-phenyl-1-(2-(trimethylsilanyl)ethoxymethyl)-1H-indazol-3-yl]-3-methoxybenzenesulfonamide (colorless foam).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.COC(C)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH3:7])=[CH:12][CH:11]=1
Reactant: Cc1ccsc1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: COc1ccc(-c2sccc2C)cc1
Temperature: 25 °C

Procedure:
2-Bromo-3-methyl-thiophene (0.53 g, 3.00 mmol) was dissolved in 1,4-dioxane (35 ml) under an argon atmosphere. To this solution were added Pd(PPh3)4 (0.33 g, 0.28 mmol), 4-methoxyphenyl boronic acid (0.50 g, 3.30 mmol) and 2 M Na2CO3 (6 ml). The resultant mixture was stirred at 100° C. for 2 hours. The reaction was cooled to rt diluted with tert.butyl methyl ether and poured into water and extracted with tert.butyl methyl ether (2×). The combined organic extracts were washed with water, brine, dried (MgSO4.2H2O), filtered and concentrated under reduced pressure to yield a yellow oil that was purified over silica gel (n-heptane) to yield an oil: 0.32 g (48%), GC-MS: M=204.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]3[CH2:13][CH2:14][CH:15](O)[O:16][C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20](=[O:21])[CH2:25][CH:15]1[CH2:14][CH2:13][C:12]2[CH:18]=[CH:19][C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:10][C:11]=2[O:16]1)[CH3:24]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1CCc2ccc(OCc3ccccc3)cc2O1
Product: CCOC(=O)CC1CCc2ccc(OCc3ccccc3)cc2O1
Yield: 92.8 %

Procedure:
A 2.2 g sample of racemic-3,4-dihydro-7-(phenylmethoxy)-2h-1-benzopyran-2-ol was condensed with (carbethoxymethylene)triphenylphosphorane (3.2 g) using the procedure of Example 30. There was obtained 2.6 g (92.8%) of racemic-3,4-dihydro-7-(phenylmethoxy)-2H-1-benzopyran-2-acetic acid ethyl ester as a yellow oil, after column chromatographic purification. This material was hydrogenolyzed over 0.2 g of 10% palladium on carbon as described in Example 30. There was obtained 1.9 g of racemic-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-acetic acid ethyl ester as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH3:21][S:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:29][C:28]3[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:32][CH:31]=3)[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCc1ccc(S(C)(=O)=O)cc1

Procedure:
This compound was prepared from ethyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate and 4-methylsulfonyl benzaldehyde employing methods similar to those described in Example 265 and was obtained as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=[C:15]([C:18](O)=[O:19])[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:21]=1.C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=[C:15]([CH2:18][OH:19])[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:21]=1
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccc(O)cc1C=C2
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: O=S1(=O)c2ccc(O)cc2C=Cc2ccc(CO)cc21

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-hydroxy-dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:3])=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
Thionyl chloride (5 ml) and dimethylformamide (1 drop) were added to a solution of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-nitrobenzoic acid (1 g) in dichloromethane (5 ml), and the mixture was refluxed for 3 hours. After the reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1-benzyloxycarbonylaminoethyl)-3-nitrobenzoyl chloride as crystals. Then, the crystals were dissolved in dichloromethane (14 ml). The solution was dropwise added to a solution of 4-aminopyridine (250 mg) and diisopropylethylamine (375 mg) in dichloromethane (6 ml) under ice-cooling, and the mixture was stirred at room temperatue for 4 hours. After the reaction, water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=15:1) to give 940 mg of (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)-3-nitrobenzamide.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:22])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (1-(4-chloro-benzoyl)-piperidin-4-yl)-carbamic acid tert-butyl ester (46 g, 0.23 mmol) in CH2Cl2 (0.5 mL) was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for ½ hour. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between a saturated aqueous solution of NaHCO3 and ethyl acetate. The aqueous phase was extracted twice more with ethyl acetate. Then the combined organic layers were combined and concentrated in vacuo to provide the titled compound. MS (DCI) m/z 239 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[C:13](OC)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C1COCC1>[O:20]=[C:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1cccnc1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of n-butyl lithium in hexanes (9.0 mL, 1.6 M, 14 mmol) was added over 10 min. to a solution of dimethyl methylphosphonate (1.50 mL, 1.72 g, 13.8 mmol) in THF (60 mL) cooled in a dry ice/isopropanol bath. After 30 min., a solution of methyl nicotinate (757 mg, 5.52 mmol) in THF (6 mL) was added over 2 min. The solution was stirred in the cooling bath for 45 min. before being allowed to warm to 0° C. over 1 h. The reaction was quenched with saturated aq. NH4Cl (50 mL) and then partitioned between saturated aq. brine (50 mL) and methylene chloride (200 mL). The aq. layer was extracted with methylene chloride (2×100 mL). The combined organic layers were dried (sodium sulfate) decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with ethyl acetate followed by 97:3 v/v methylene chloride/CH3OH, gave material containing some residual impurity Further purification by flash column chromatography on silica gel, eluting with 50:50:5 v/v/v to 50:50:10 v/v/v toluene/ethyl acetate /CH3OH gave 1.15 g of the title compound. For the title compound: 1H NMR (500 MHz, CDCl3) δ9.26-9.20 (bs,1H), 8.83 (d, J=4, 1H), 8.34 (dt, J=8, 2, 1H), 7.70 (dd, J=8, 4, 1H), 3.82 (d, J=11, 6H), 3.67 (d, J=24, 2H).
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:7][C:6]1=[O:25])(=O)[CH2:2][CH3:3].Cl.[CH2:27]([O:30][NH2:31])[CH2:28][CH3:29].N1C=CC=CC=1.Cl>C(Cl)(Cl)Cl.O>[CH2:27]([O:30][NH:31][C:1](=[C:5]1[C:6](=[O:25])[CH2:7][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:9][C:10]1=[O:11])[CH2:2][CH3:3])[CH2:28][CH3:29]
Reactant: CCC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reactant: CCCON
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCONC(CC)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reaction time: 5 h

Procedure:
0.2 Gram of 2-propionyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 10 ml of chloroform and 0.07 g of propoxyamine hydrochloride and 0.5 ml of pyridine were added to the resulting solution which was then stirred at 50°-60° C. for 5 hours. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with chloroform. After removing chloroform, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.11 g of 2-(1-propoxyaminopropylidene)-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:40]([CH3:41])=[CH:39][C:13]([CH2:14][CH:15]([C:23]([NH:25][S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)(=[O:28])=[O:27])=[O:24])[C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:12][C:11]=1[CH3:42])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:43]C1C=CC(C(Cl)=O)=CC=1>>[CH2:21]([N:18]([CH2:19][CH3:20])[C:16](=[O:17])[CH:15]([CH2:14][C:13]1[CH:39]=[C:40]([CH3:41])[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:43])=[C:11]([CH3:42])[CH:12]=1)[C:23]([NH:25][S:26]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)(=[O:27])=[O:28])=[O:24])[CH3:22]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN(CC)C(=O)C(Cc1cc(C)c(NC(=O)c2ccccc2)c(C)c1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: CCN(CC)C(=O)C(Cc1cc(C)c(NC(=O)c2ccccc2F)c(C)c1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1

Procedure:
In the same manner as in Example 9, a crude product was obtained using the compound (331 mg) obtained in Example 137 (4) and 4-fluorobenzoyl chloride (82 μL). This was purified by silica gel column chromatography to give the title compound (239 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=1.ClC1C=C(Cl)C=CC=1C1[C:37]([C:38]2[NH:39][CH:40]=[CH:41][N:42]=2)=[CH:36][N:35]=[C:34]([NH:43][CH2:44][CH2:45][NH:46]C2C=CC([N+]([O-])=O)=CN=2)[N:33]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[C:37]([C:38]3[NH:39][CH:40]=[CH:41][N:42]=3)=[CH:36][N:35]=[C:34]([NH:43][CH2:44][CH2:45][NH:46][C:16]3[N:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=3)[N:33]=2)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(F)cc3C(F)(F)F)n2)nc1

Procedure:
6-{[2-({4-[4-fluoro-2-(trifluoromethyl)phenyl]-5-imidazol-2-ylpyrimidin-2-yl}amino)ethyl]amino}pyridine-3-carbonitrile was prepared from 4-fluoro-2-(trifluoromethyl)benzoyl chloride and 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl.C(OCC)(=O)C>[C:18]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)(=[O:20])[CH3:19]
Reactant: N#CCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CC#N)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a cooled (0° C.) and stirred solution of 4-aminobenzyl cyanide (2.38 g, 18.04 mmol) in anhydrous dichloromethane (30 ml) was added anhydrous triethylamine (7.54 ml, 54.12 mmol) followed by acetic anhydride (2.56 ml, 27.06 mmol) under nitrogen. The mixture was allowed to warm to room temperature and it was stirred for 18 h before it was diluted with ethyl acetate (150 ml) and-washed with 10% aqueous sodium bicarbonate (100 ml), 2M hydrochloric acid (50 ml), brine (50 ml), then dried (MgSO4) and concentrated to give 4-(acetylamino)benzyl cyanide as an orange solid. The crude nitrile (2.8 g) was dissolved in absolute ethanol (200 ml) and chloroform (4 ml) and it was hydrogenated at 50 psi over platinum (IV) oxide for 16 h. The catalyst was filtered off, washed with ethanol and the filtrate was concentrated under vacuum. The residue was dissolved in 2M sodium hydroxide (30 ml) and the product was extracted with dichloromethane (4×150 ml), then dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel, dichloromethane/methanol/ammonia, 85:15:1.5) gave 2.3 g (80%) of the title compound as a yellow solid. δ (360 MHz, CDCl3) 2.16 (3H, s), 2.71 (2H, t, J=6.8 Hz), 2.94 (2H, t, J=6.8 Hz), 7.14 (2H, d, J=8.3 Hz), 7.26 (1H, br s), 7.41 (2H, d, J=8.3 Hz).
Reaction SMILES: C(N(CC)CC)C.C(OC(Cl)=O)C.[C:14]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=1)(=[O:17])[CH2:15][CH3:16].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:31][CH:30]=1>CN(C)C=O.C(Cl)Cl>[C:14]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:40]2[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)[CH2:42][CH2:41]2)=[O:25])=[CH:26][CH:27]=1)(=[O:17])[CH2:15][CH3:16]
Reactant: CCC(=O)Nc1ccc(C(=O)O)cc1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 2 g of triethylamine in 5 ml of anhydrous dimethylformamide and then a solution of 2.15 g of chloroformic acid ethyl ester in 10 ml of methylene chloride is added dropwise to a solution, stirred at from -5° to 0°, of 3.8 g of p-propionamidobenzoic acid in 30 ml of anhydrous dimethylformamide. The reaction mixture is stirred for 30 minutes at from 0° to 5° and then a solution of 4.4 g of 1-[2-(4-chlorophenyl)ethyl]-piperazine in 25 ml of anhydrous dimethylformamide is added dropwise thereto. The suspension is stirred overnight at approximately 5° and concentrated by evaporation. 50 ml of water are added to the residue and the solution is rendered alkaline with 2N sodium hydroxide solution and extracted by shaking with methylene chloride. The combined organic phases are washed with water, dried over sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed over silica gel and the resulting oil is crystallised from acetone/diethyl ether, yielding 1-[4-(N-propionylamino)-benzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine having a melting point of 131°-132°.