Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([CH2:7][CH2:8][CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[NH:4][C:3]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].C1(OC)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH:5]([CH2:7][CH2:8][CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[NH:4][C:3]1=[S:21]
Reactant: CCCCCC(CCC1CN(C)C(=O)N1)OC(C)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCC(CCC1CN(C)C(=S)N1)OC(C)=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2.5 g (9.2 mmol) of 1-methyl-2-oxo-4-(3-acetoxyoctyl)-imidazolidine (Example 11) are dissolved in 80 ml of absolute toluene, 10 g of beach sand are added and the mixture is warmed to 90° C., with stirring. 2.50 g of P4S10.anisole are then added and stirring is continued at 90° C. for 2 hours. The reaction mixture is filtered, the residue on the filter is washed with toluene and the toluene phase is concentrated. The residue is chromatographed on silica gel in cyclohexane/ethyl acetate 1:1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([O:15][CH2:16][CH2:17][CH3:18])[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:19](=O)([O-])O.[Na+].CI>CN(C)C=O>[CH3:19][O:13][C:12](=[O:14])[CH:11]([O:15][CH2:16][CH2:17][CH3:18])[CH2:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2
Reactant: O=C([O-])O
Reactant: CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Crude rac-3-(1H-indol-5-yl)-2-propoxy-propionic acid was dissolved in 5 ml N,N-dimethylformamide, 0.54 g of sodium hydrogencarbonate was added followed by 0.32 nm of methyl iodide. The mixture was stirred at r.t. for 7 hours, then poured into ice water and extracted 3 times with ethyl acetate; after drying over MgSO4 and evaporation, the crude product was purified by chromatograph) (silicagel, eluent: gradient of n-heptane/ethyl acetate) to yield 0.47 g of rac-3-(1H-indol-5-yl)-2-propoxy-propionic acid methyl ester as light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:17][C:18]1[CH:19]=[C:20]([OH:39])[CH:21]=[CH:22][C:23]=1[CH:24]([CH3:38])[C:25]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([Cl:37])[CH:32]=1)([OH:30])[C:26]([F:29])([F:28])[F:27]>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=1[CH:24]([CH3:38])[C:25]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([Cl:37])[CH:32]=1)([OH:30])[C:26]([F:29])([F:28])[F:27])[O:39][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[F:1]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(c1ccc(Oc2ccc(C#N)cc2F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 120 °C

Procedure:
3,4-Difluorobenzonitrile (CAS Reg. No. 64248-62-0, 23 mg) and Cs2CO3 (13 mg) were added to a solution of 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19 step 5, 50 mg) in DMF (1 ml). The mixture was heated to 120° C. for 30 min in a microwave oven. The mixture was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (43 mg) as a white foam. MS (m/e)=485.2 [M+H+].
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>C(O)C>[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(=O)CCCNC(=O)OCc1ccccc1
Reactant: COCCN
Solvent: CCO
Product: COCCNC(=O)CCCNC(=O)OCc1ccccc1

Procedure:
5.02 g of 4-benzyloxycarbonylaminobutyric acid methyl ester are stirred under reflux in 35 ml of ethanol with 15 ml of 2-methoxyethylamine for 5 days. The reaction mixture is concentrated by evaporation and the residue is purified by means of FC (240 g of silica gel, dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.33.
Reaction SMILES: CC1(C)OC(=O)[C:5](=[CH:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:4](=O)[O:3]1.CCCCCC.C(OCC)(=O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[N:10]1[CH:9]=[CH:5][C:4](=[O:3])[N:12]2[C:11]=1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:14]=[CH:13]2
Reactant: CC1(C)OC(=O)C(=CNc2ncnc3ccccc23)C(=O)O1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1ccnc2c3ccccc3ncn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
A mixture of 2,2-dimethyl-5-[(4-quinazolinyl)amino]methylene-1,3-dioxane-4,6-dione, (3.5 g) in diphenylether (15 ml) was stirred for 10 minutes at 250°-260° C. and then cooled to ambient temperature. To the reaction mixture was added hexane and allowed to to stand at ambient temperature to give crystals, which were separated by filtration and washed with hexane to give crude crystals (3 g). The crude crystals were subjected to a column chromatography using silica gel (developing solvent: a mixture of ethyl acetate and hexane (3:7)). The eluate was concentrated under reduced pressure to give crystals, which were recrystallized from chloroform and hexane to give 4H-pyrimido[1,2-c]quinazoline-4-one (1.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:28][CH:29]=2)=[O:23])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[CH2:38]([OH:41])[CH2:39]C>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]3)=[CH:26][CH:25]=2)=[O:23])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:38]([O-:41])(=[O:23])[CH3:39]
Reactant: CCCO
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: CC(=O)O
Product: CC(=O)[O-]
Temperature: 82 °C

Procedure:
Imatinib base (3 g) was added to the solution of n-propanol (30 ml) and acetic acid (0.5 ml). The suspension was heated under reflux (82° C.) for 15 min providing thus a clear solution of imatinib acetate. Methanesulfonic acid (375 μl) was added providing the replacement of week acetic acid by stronger methanesulfonic acid and the volume of solution was reduced to ½ by evaporation at the vacuum evaporator at 20 mBar. Seeds of imatinib mesylate Form α were added (20 mg) and the solution was allowed to crystallize overnight. Crystals of imatinib mesylate Form a were recovered by filtration, washed with n-propanol, n-hexane and dried at 80° C. in a stream of nitrogen. Yield 2.97 g (83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][C:4]=1[N+:25]([O-])=O.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1>[NH2:25][C:4]1[CH:5]=[C:6]([C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:11]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[O:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccccc2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccccc2)cc1N
Temperature: 50 °C

Procedure:
7.37 g (20 mmols) of 3-(4-methoxy-3-nitrophenyl)-3-phenylacrylic acid morpholide were dissolved in 100 ml of ethanol, then 100 ml of water were added, the mixture was heated to 50° C., and 14.7 g (70 mmols) of sodium dithionite were added while stirring. The mixture as then refluxed for one hour, the ethanol was distilled off in vacuo, and water was added. The brown greasy substance thus obtained was dissolved in toluene and purified on a silica gel column. Elution was carried out first with toluene and then with a toluene/acetone mixture 80:20. The fractions containing the substance with Rf 0.26 (toluene/acetone 70:30) were concentrated by evaporation in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)#[N:2].[C:19]([O:23][C:24](=[O:37])[CH:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[C:30]([F:36])[CH:29]=1)[CH3:26])([CH3:22])([CH3:21])[CH3:20].O1C2C=CC(OC3N=CC=CC=3C(O)=O)=CC=2OC1.COC(=O)COC1C=CC(CN)=C(F)C=1>>[C:19]([O:23][C:24](=[O:37])[CH:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:9]([C:8]2[C:7]([O:6][C:5]3[CH:16]=[CH:17][CH:18]=[C:3]([C:1]#[N:2])[CH:4]=3)=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:11])=[C:30]([F:36])[CH:29]=1)[CH3:26])([CH3:20])([CH3:21])[CH3:22]
Reactant: N#Cc1cccc(Oc2ncccc2C(=O)O)c1
Reactant: CC(Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C
Agent: COC(=O)COc1ccc(CN)c(F)c1
Agent: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The compound of Formula (5.0.25) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(3-cyano-phenoxy)-nicotinic acid and (+)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid tert-butyl ester for the corresponding 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=1[C:10]([NH:12][C:13]1[CH:32]=[CH:31][C:16]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23](=[O:30])[CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1)=[O:11].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[OH:30][CH:23]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:19]([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:33]=[CH:34][CH:35]=[CH:36][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:32][CH:31]=2)[CH2:20][CH2:21][CH2:22]1
Reactant: Cc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
To a solution of 1-{4-[2-(2-methylphenyl)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (620 mg) in methanol (20 ml) was added sodium borohydride (49.4 mg) and the mixture was stirred at ambient temperature for 4 hours. The mixture was diluted with chloroform and the solution was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give a syrup and the residue was purified by silica gel column (30g, 1% methanol in chloroform) to give 5-hydroxy-1-{4-[2-(2-methylphenyl)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-1-benzazepine (580 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH3:19])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[Al](C(C)C)(C(C)C)C(C)C.CC(O)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH3:19])[C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)[OH:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(C(=O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: CC(C)[Al](C(C)C)C(C)C
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCc1ccc([C@@H](O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 50 °C

Procedure:
The procedure described by J. Yin et al., J. Org. Chem. 2006, 71, 840-843) was used. A mixture of tert-butyl[(1S)-2-(4-ethylphenyl)-1-methyl-2-oxoethyl]carbamate (555 mg, 2 mmol), Al(iPr)3 (81 mg, 0.4 mmol), 2-propanol (1.32 g, 22 mmol), and toluene (2.6 ml, 1.3 ml/mmol) was heated in a sealed vial at 50° C. overnight. Then the reaction mixture was cooled to r.t., quenched with aqueous HCl (1 N, 10 ml), and diluted with ethyl acetate (10 ml). The layers were separated, the organic layer was washed with water (80 ml), dried with Na2SO4, and concentrated. Trituration with n-heptane (30 ml) afforded the subtitle compound as colourless precipitate, 137 mg. n-Heptane solution was concentrated under reduced pressure, and the residue purified by flash chromatography in silica gel to give the second crop of the subtitle compound, 318 mg. Overall yield 455 mg (81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1.[N+:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([O-:21])=[O:20].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:22]([N+:19]([O-:21])=[O:20])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: COc1ccc(/C=C/C(=O)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(CC(=O)c1ccccc1)c1ccc(OC)cc1)[N+](=O)[O-]
Yield: 92.5 %

Procedure:
A solution of (2E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (5 g, 20.98 mmol) and ethyl nitroacetate (2.32 ml, 20.98 mmol) in triethylamine (8.77 ml, 62.94 mmol) was stirred at 75° C. for 4 h. Ethyl acetate (500 ml) was added and the solution obtained was washed with HCl 1N (4×250 ml), dried over Na2SO4 and evaporated under reduced pressure, to obtain 7.21 g of ethyl 3-(4-methoxyphenyl)-2-nitro-5-oxo-5-phenylpentanoate.
Reaction SMILES: C(OC([NH:8][C:9]([NH:24]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[ClH:32].[NH2:23][C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:24])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2N)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N=C(N)Nc1cccc(-c2ncccc2N)c1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-aminopyridin-2-yl)phenyl)guanidine (150 mg) in dichloromethane (1.5 ml) was added 4N hydrogen chloride in 1,4-dioxane (3 ml), and the mixture was stirred at room temperature for 26 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-aminopyridin-2-yl)phenylguanidine dihydrochloride (92 mg).
Reaction SMILES: [ClH:1].Cl.[C:3]1([NH2:11])[C:4]([NH2:10])=[CH:5][C:6]([NH2:9])=[CH:7][CH:8]=1.[OH:12][C:13]1[CH:14]=[C:15]([C:19]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=O)=O)[CH:16]=[CH:17][CH:18]=1>O1CCOCC1.O>[ClH:1].[ClH:1].[OH:12][C:13]1[CH:14]=[C:15]([C:19]2[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)=[N:10][C:4]3[C:3](=[CH:8][CH:7]=[C:6]([NH2:9])[CH:5]=3)[N:11]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(C(=O)c1cccc(O)c1)c1cccc(O)c1
Reactant: Nc1ccc(N)c(N)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc2nc(-c3cccc(O)c3)c(-c3cccc(O)c3)nc2c1
Yield: 168.5 %

Procedure:
40.4 mg (0.206 mmol) of 1,2,4-benzenetriamine dihydrochloride and 50 mg (0.20 mmol) of 3,3′-dihydroxybenzil were dissolved in 2 mL of 1:1 mixture of dioxane-water. The reaction was refluxed for 3 hours. Then solvent was removed in vacuo. The residue was dissolved in 2 mL of methanol and this solution was added dropwise to 40 mL of diethyl ether. The formed dark-red precipitate was collected, washed with ether and dried in vacuo to give 69.8 mg (92.6% yield) of the product. 97.6% purity by LC/MS (230 DAD). Mass-spec [ES+]=330.8. 1H NMR (500 MHz, MeOH-d4) 6.81–6.87 (2H, m), 6.96–6.98 (4H, m), 7.10 (1H, m), 7.13–7.16 (1H, t), 7.28–7.31 (1H, t), 7.56–7.58 (1H, m), 8.04–8.06 (1H, d).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CCOCC>[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A solution of 10.0 g (52.6 mmol) of 3-(trifluoromethyl)phenethyl alcohol in 75 mL of ether under nitrogen was treated with 10.53 g (55.2 mmol, 1.05 eq) p-toluenesulfonyl chloride. The solution was cooled to 0° and treated with 7.67 mL (5.57 g, 55.0 mmol, 1.05 eq) of triethylamine. The mixture was stirred at 0° for 30 minutes then warmed to room temperature and stirred for 16 hours. The precipitate was removed by filtration and washed with ether. The combined filtrate and ether was were evaporated under vacuum. The residue was redissolved in ethyl acetate and washed with 0.5N HCl and brine; the organic layer was removed, dried over sodium sulfate, filtered and concentrated under vacuum. Purification by flash chromatography on silica, eluting with 30% ethyl acetate/hexane, afforded 15.14 g (44.0 mmol, 84%) of the product. 1H NMR (200MHz, CDCl3): 2.44 (s,3H), 3.03 (t,7Hz,2H), 4.26 (t,7Hz,2H), 7.2-7.5 (m,6H), 7.66 (d,8Hz,2H). FAB-MS: calculated for C16H15F3SO3 344; found 345 (M+H,8%).
Reaction SMILES: [CH:1]1([Si:6]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16](O)(CC)[CH3:17].C[Si](C)(C)Cl>[O-]CC.[Na+]>[CH:11]([O:10][Si:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([O:13][CH2:14][CH3:15])[O:7][CH2:8][CH3:9])([CH2:16][CH3:17])[CH3:12]
Reactant: CCC(C)O
Reactant: CCO[Si](OCC)(OCC)C1CCCC1
Agent: CC[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CCO[Si](OCC)(OC(C)CC)C1CCCC1
Yield: 73.3 %

Procedure:
In a 500 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 29.6 g (0.127 mole) of cyclopentyl triethoxysilane, 151.1 g (2.04 mole) of sec-butyl alcohol and 286.5 mg (4.21 m mole) of sodium ethoxide, which were then reacted with each other in an oil bath of 50° C. for 10 hours under stirring. Then, trimethylchlorosilane was added to neutralize the alkali. Then, 24.2 g (0.0931 mole) of sec-butoxy cyclopentyl diethoxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. The yield was 73%
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][NH2:8])=[CH:3][CH:2]=1.[CH2:9]([CH2:11][CH2:12][CH2:13][C:14](CC([O-])=O)=[O:15])[CH3:10]>>[CH2:11]([C:12]1[CH2:13][C:14](=[O:15])[N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:8]=1)[CH2:9][CH3:10]
Reactant: CCCCCC(=O)CC(=O)[O-]
Reactant: NNc1ccncc1
Product: CCCC1=NN(c2ccncc2)C(=O)C1

Procedure:
From the reaction of 4-pyridylhydrazine and ethylbutyrylacetate, 2,4-dihydro-5-propyl-2-(4-pyridyl)-3H-pyrazol-3-one is obtained. Subsequent reaction wvith 2-ethylaniline yields 4-(2-ethyianilinomethylene)-2,4-dihydro-5-propyl-2-(4-pyridyl)-3H-pyrazol-3-one, Mp 159.2° C.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH:24]([C:25](O)=[O:26])[CH2:23][S:22](=[O:29])(=[O:28])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:25]([CH:24]1[CH2:23][S:22](=[O:29])(=[O:28])[CH2:21][N:20]1[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])(=[O:26])[NH2:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CS(=O)(=O)CC1C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CS(=O)(=O)CC1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
Carbonyldiimidazole (520 mg, 3.21 mmol) was added to an ice cold solution of 3-tert-butoxycarbonyl-1,1-dioxo-1,3-thiazolidine-4-carboxylic acid (Example 127 b, 304 mg, 1.15 mmol) in DMF (1 mL). After 5 min. the mixture was warmed to ambient temperature and stirred for 2 h. Gaseous NH3 was bubbled for 10 min through the solution while the temperature was kept below 20° C. Stirring was continued for 12 h at ambient temperature. The reaction mixture was poured into 30 mL ice/water/1N HCl and extracted with EtOAc (2×30 mL). The combined extracts were washed with ice/brine (20 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (197 mg, 65%) as white solid, MS (ESI) m/e=263.1 [M−H−].
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[N:3]=1.S(=O)(=O)(O)[OH:24].N([O-])=O.[Na+]>O>[OH:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[N:3]=1
Reactant: Nc1nc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1O
Temperature: 60 °C

Procedure:
14.0 g of 2-amino-3-nitro-6-(2-chloro-4-trifluoromethylphenoxy)pyridine prepared in Preparation Example 2 was poured into 29 ml of concentrated sulfuric acid, and the mixture was heated at 60° C. Thereafter, the resulting mixture was allowed to stand for cooling, and further cooled with ice to 0° to 10° C. An aqueous solution of 4.6 g of sodium nitrite and 14 ml of water was gradually added dropwise thereto at the same temperature while stirring whereby the mixture was allowed to react. After completion of the reaction, the reaction product was poured into water, followed by subjecting to purification in the same manner as in Preparation Example 2 to obtain 10.3 g of a titled compound having a melting point of 87° to 93° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][CH3:33])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])=[O:16])[C:10](=[O:34])[CH:9]1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42]CC2C=CC=CC=2)=[CH:38][CH:37]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][CH3:33])=[O:31])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:20])=[O:16])[C:10](=[O:34])[CH:9]1[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(OCc3ccccc3)cc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(O)cc2)C1=O

Procedure:
Protected-piperazinoneacetyl-gly-phe-NHCH3, 10a, (6.71 g, 1.00×10-2 mole) in ethanol (100 ml) is hydrogenated in a Parr apparatus at 40 psi over 10% Pd/C (0.5 g). After the reaction has absorbed one equivalent of hydrogen, the catalyst is filtered and washed with ethanol. The filtrate is evaporated at reduced pressure, affording 11a.
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[NH:9][C:10](=[O:12])[CH2:11][CH:5]2[CH2:4][NH:3][CH2:2]1.[Br:17]N1C(=O)CCC1=O>C(O)(=O)C.O>[Br:17][C:14]1[CH:15]=[CH:16][C:7]2[N:6]3[CH2:1][CH2:2][NH:3][CH2:4][CH:5]3[CH2:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1
Reactant: O=C1CC2CNCCN2c2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2CNCCN2c2ccc(Br)cc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 1D (1.54 g, 6.07 mmol) in acetic acid/water (1:1, 20 mL) was added N-bromosuccinimide (1.08 g, 6.07 mmol). The reaction mixture was stirred at room temperature for 2 hours. Product precipitated. The precipitate was collected to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.36 (d, J=8.54 Hz, 1 H), 7.16 (s, 1 H), 7.11 (d, J=8.85 Hz, 1 H), 3.54-3.63 (m, 1 H), 3.22-3.40 (m, 4 H), 2.93-3.07 (m, 2 H), 2.65-2.72 (m, 1 H), 2.08 (d, J=13.73 Hz, 1 H); MS (ESI) m/z 297.8 (M+H)+.