Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH2:9][CH3:10])=[C:3]([Cl:8])[C:4](OC)=[O:5].[CH:11]([NH2:13])=O.C[O-].[Na+]>CO>[Cl:8][C:3]1[C:4]([OH:5])=[N:13][CH:11]=[N:1][C:2]=1[CH2:9][CH3:10]
Reactant: CCC(N)=C(Cl)C(=O)OC
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ncnc(O)c1Cl
Reaction time: 12 h
Yield: 111.9 %

Procedure:
A mixture of 163.6 g (1.0 mol) of methyl 3-amino-2-chloro-2-pentenoate, 90.8 g (2.0 mol) of formamide and 150 ml of methanol is added dropwise with stirring to 485.8 ml of a 30% strength NaOMe solution in methanol at room temperature. The mixture is subsequently slowly heated to the reflux temperature over the course of 3 h, and is left to stir at this temperature for a further 12 h. Evaporation of the reaction mixture is followed by dissolving in a little H2O, adjustment to a pH of 3.8 with HCl and extraction with ethyl acetate. Drying over MgSO4 and evaporation provide 177.5 g of crude product which is subsequently recrystallized from water. Yield: 130.4 g (82%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:10][C:11]([CH3:16])=[CH:12][C:13](O)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].P(Cl)(Cl)(Cl)=O>>[OH:8][C:6]1[CH:5]=[C:4]2[C:3]([C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:10])[O:9]2)=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: CC(C)=CC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(O)cc2c1C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Anhydrous 5-methylbenzene-1,3-diol (3.678 g), 3,3-dimethylacrylic acid (3.3 mL) and aluminum chloride (14.76 g) were added to phosphoryl chloride (45 mL) and the mixture was shaken at room temperature for 6 hours. The reaction solution was poured into ice, and the precipitates were filtered, washed with water and dried. The precipitates were purified by column chromatography on silica gel (Solvent; petroleum ether/ethyl acetate=25/1) to give the titled compound (3.8 g) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Li])=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][CH:11]=1.O1CCCC1>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]([CH2:17][CH3:18])([OH:19])[C:13]2[CH:12]=[CH:11][C:10]([OH:9])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: [Li]c1ccc(Br)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(O)cc1)c1ccc(Br)cc1

Procedure:
To 400 ml. of a 0.5 molar ethereal 4-bromophenyl-lithium solution a solution of 7.5 g. of 4'-hydroxy-propiophenone in 37 ml. of dry tetrahydrofurane is added dropwise, with stirring at a temperature between -50° C. and -40° C. The reaction mixture is stirred at 0° C. for an additional hour, and is then decomposed with a mixture of ice and glacial acetic acid. The aqueous phase is extracted with ether, the ethereal phases are combined, and washed to neutral with water. After drying over anhydrous magnesium sulfate the solvent is distilled off under reduced pressure, and the residue is chromatographed on a silica gel column with a 7:3 mixture of benzene and ethyl acetate as an eluting agent. The solvent is distilled off in vacuo, and the residue is crystallized from a mixture of ethyl acetate and dichloromethane. 4.2 g. of the named compound are obtained, melting at 161° to 162° C.
Reaction SMILES: [F:1][C@:2]12[C@@H:21]([OH:22])[CH2:20][C@@:19]3([CH3:23])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:18])[CH3:17])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:25])[CH2:4][CH2:5][C:6](=[O:24])[CH:7]=1.[OH2:26]>CS(C)=O.CO.Cl>[C:21]([C@@H:14]1[CH2:13][C@@H:12]2[C@:19]([CH3:23])([CH2:20][C@H:21]([OH:22])[C@@:2]3([F:1])[C@H:11]2[CH2:10][CH2:9][C:8]2[C@:3]3([CH3:25])[CH2:4][CH2:5][C:6](=[O:24])[CH:7]=2)[C@H:15]1[C:16](=[O:18])[CH3:17])(=[O:26])[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: O
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Product: CC(=O)[C@H]1[C@H](C(=O)c2ccccc2)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-Phenyl-1-tetrahydropyranyloxyacetonitrile (1.3 g.) is added to a suspension of 57% sodium hydride-paraffin (275 mg.) in dry dimethylsulfoxide (20 ml.) in a nitrogen atmosphere. The mixture is stirred at room temperature for 90 minutes to yield a homogeneous solution of the anion. To the anion is added a solution of 9-fluoro-11β-hydroxypregna-4,16-diene-3,20-dione (1.04 g.) in dry dimethylsulfoxide. After 30 minutes, the mixture is poured into water and extracted with ethyl acetate. The extracts are combined, washed with water, dried over magnesium sulfate and evaporated to afford 2.55g. of a gum. This is dissolved in methanol (25 ml.), conc. hydrochloric acid (2 drops) is added and the solution is maintained in a bath at 55°-60°C for 5.0 hours. The methanol is evaporated in vacuo, the residue is dissolved in ethyl acetate, washed with a diluted sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to afford the crude product as a gum. This is absorbed on a dry column of silica gel (40 g.) and the column is eluted successively with chloroform, ethyl acetate-chloroform (1:9) and ethyl acetate. Crystallization of the material (1.1 g.) eluted with ethyl acetate-chloroform from acetone-hexane affords the analytical specimen (690 mg.), melting point 250° -252°C, dec.
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([Cl:14])[C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19].C(=O)([O-])[O-].[Na+].[Na+].[ClH:27]>O.CO.C(O)C.C(OCC)C>[ClH:14].[ClH:27].[S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:19][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])[C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: CN(C)CCN
Reactant: NS(=O)(=O)c1cc2c(Cl)nccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CN(C)CCNc1nccc2oc(S(N)(=O)=O)cc12
Temperature: 90 °C
Yield: 55 %

Procedure:
A mixture of 2-sulfamoyl-4-chloro-furo[3,2-c]pyridine (1.02 g, 4.4 mmol) in 2-(dimethylamino)ethylamine (1.4 ml, 12.8 mmol) was warmed at 90° C. for 8 hours. The cooled mixture was diluted with water and made basic with saturated sodium carbonate. The product was extracted into ethyl acetate/methanol, dried over anhydrous sodium sulfate, and filtered. The solution was evaporated to give crude product. This residue was dissolved in methanol and excess ethanolic HCl was added. After dilution with diethyl ether, the resultant gum was digested in ethanol to give a powder (0.86 g, 55% yield), mp: 275°-278° C. Recrystallization of this salt by dissolution in a minimum amount of warm water and subsequent dilution with ethanol gave pure dihyrochloride salt (0.56 g) mp: 281°-283° C.
Reaction SMILES: [CH:1](=[N:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:20]1.C[Si](C=[N+]=[N-])(C)C>CO>[CH:1](=[N:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:20])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1NN=Cc1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccccc1NN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
2-(N′-Benzylidene-hydrazino)-benzoic acid (5.0 g, 20.81 mmol) in 1:1 tetrahydrofuran and methanol (50 mL) was reacted with a solution of trimethylsilyl diazomethane in hexanes (2.0M, 12 mL, 25.0 mmol) at 0° C. for 1 hour then stirred at 25° C. for 48 hours. The solvent was removed under vacuum to give the title compound as a solid (6.00 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.87 (s, 3 H) 6.84 (td, J=7.54, 1.10 Hz, 1 H) 7.41 (m, 3 H) 7.54 (m, 1 H) 7.74 (m, 3 H) 7.86 (dd, J=8.09, 1.47 Hz, 1 H) 8.21 (s, 1 H) 11.02 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C1(C)C=CC=CC=1>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH:30]3[CH2:32][CH2:31]3)=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C2CC2)c1
Yield: 98.2 %

Procedure:
To a mixture of 1-Boc-piperazine (7.2 g), 2,3-dichloro-5-methylpyridine (5 g), palladium (II) acetate (179 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (499 mg) and sodium tert-butoxide (4.1 g) was added toluene (30 mL), and the mixture was refluxed for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). To a mixture of 4-(3-chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g), bis(tricyclohexylphosphine)palladium (II) dichloride (1 g), tripotassium phosphate (30 g) and cyclopropylboronic acid (5.5 g) were added toluene (80 mL) and water (4 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). 4-(3-Cyclopropyl-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g) was dissolved in chloroform (25 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added and the mixture was filtered to give the title compound (4.6 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30]CC)=O)=[C:26]([CH:33]=O)[N:25]=[C:24]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:36]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:46][NH2:47]>C(O)C>[CH3:44][O:43][C:41]([C:38]1[CH:39]=[CH:40][C:35]([C:24]2[N:23]=[C:22]([NH:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]4)=[CH:20][CH:19]=3)[C:27]3[C:28](=[O:30])[NH:47][N:46]=[CH:33][C:26]=3[N:25]=2)=[CH:36][CH:37]=1)=[O:42]
Reactant: CCOC(=O)c1c(C=O)nc(-c2ccc(C(=O)OC)cc2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2nc(Nc3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)c3c(=O)[nH]ncc3n2)cc1

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-formyl-2-(4-(methoxycarbonyl)phenyl)pyrimidine-5-carboxylate (0.5 g, 0.82 mmol) was dissolved in ethanol (5 mL), hydrazine hydrate (60 μL, 1.24 mmol) was added and the mixture is refluxed for 2.5 hours. The reaction mixture was cooled to obtain a solid precipitate. The precipitate was filtered and the solid dried under vacuum (0.4 g). 1H NMR (400 MHz, DMSO-d6): δ 13.41 (s, 1H), 11.52 (s, 1H), 8.52 (d, J=8.4 Hz, 2H), 8.34 (s, 1H), 8.13 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 3.90 (s, 3H), 3.51 (s, 2H), 3.29 (t, J=4.4 Hz, 4H), 2.34 (t, J=4.4 Hz, 4H), 1.39 (s, 9H); MS m/z 572.3 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH2:20][CH2:19][CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[CH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>O1CCCC1.C(O)C.C(O)(=O)C.[Pt]=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH2:20][CH2:19][CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:24][CH2:23]1
Reactant: O=C1C(=CC2CCN(Cc3ccccc3)CC2)Cc2cc(Nc3ncnc4c3CCC4)ccc21
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1c2ccc(Nc3ncnc4c3CCC4)cc2CC1CC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
0.53 g of platinum oxide was added to 1.35 g of 4-[1-oxo-2-(1-benzylpiperidin-4-yl)methyleneindan-5-yl]amino-5,6-dihydro-7H-cyclopenta[d]pyrimidine dissolved in a mixed solution of 60 ml of tetrahydrofuran, 60 ml of ethanol and 1 ml of acetic acid, and the mixture was stirred under a hydrogen stream at room temperature for 8 hours. After the catalyst was removed by filtration, the filtrate was condensed. The obtained residue was applied to silica gel column chromatography to obtain 1.31 g of the title compound as pale yellow powder.
Reaction SMILES: Br[C:2]1[C:3]([O:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[Li]C.C([Li])CCC.C([O:34]B(OC(C)C)OC(C)C)(C)C.[OH-].[Na+].OO>C1COCC1.CO>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[O:15][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[N:6]=[CH:7][C:2]=1[OH:34]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(Br)cn2)n1
Agent: OO
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(O)cn2)n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
N-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl)-4-methylthiazol-2-amine (2.66 mmol) is dissolved in THF (30 mL) and cooled to −78° C. MeLi (2.07 mL, 3.32 mmol) is slowly added and the reaction mixture is stirred for 10 minutes. n-Butyllithium (1.33 mL, 3.32 mmol) is added and the reaction mixture is stirred for 15 minutes. Triisopropylborate (0.613 mL, 2.66 mmol) is added and the reaction mixture is stirred for 30 minutes. The reaction mixture is warmed to 0° C., and methanol (5 mL), 10% aqueous NaOH (5.1 mL, 12.8 mmol), and 30% aqueous H2O2 (1.27 mL, 13.3 mmol) are added. The reaction mixture is stirred at 0° C. for 1 hour, then purified by silica gel chromatography (10-20% EtOAc in hexanes) to afford 4-(2,6-difluorophenoxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ol.
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)(O)=[O:2].[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O.O>[S:38]1[CH2:39][CH2:40][N:35]([C:1]([CH2:4][O:5][CH:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([C:17](=[O:34])[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[CH:20][CH:19]=3)[CH2:9][CH2:8][CH2:7]2)=[O:2])[CH2:36][CH2:37]1
Reactant: C1CSCCN1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)O)c3ccccc32)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)N3CCSCC3)c3ccccc32)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 5-carboxymethoxy-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.50 g) in dimethylformamide (60 ml) are added successively thiomorpholine (0.66 ml), diethyl cyanophosphate (0.89 g) and triethylamine (1.37 ml) with stirring under ice-cooling. The mixture is stirred for 30 minutes under ice-cooling, and at room temperature for 20 minutes. Water (60 ml) is added to the reaction solution, and extracted with dichloromethane. The extract is dried over magnesium sulfate, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=5:2→3:1), and recrystallized from ethyl acetate/n-hexane to give 5-(thiomorpholinocarbonylmethoxy)-1-[4-(2-methylbenzoylamino)benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.60 g) as white powder, m.p. 235°-237° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:32])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:32])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([F:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC1CCCCC1)c1c(O)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Yield: 78.7 %

Procedure:
Cyclohexylamine (2.95 mL, 25.78 mmol) was added to a solution of Compound 39 (4.4 g, 12.89 mmol) in toluene (50 mL) and refluxed for 3 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 4.0 g (78%) of white solids. M.P. 130-134° C. 1H NMR (DMSO-d6): δ 1.37 (m, 5H), 1.56 (m, 1H), 1.67 (m, 2H), 1.88 (m, 2H), 3.87 (m, 1H), 5.29 (s, 2H), 7.17 (m, 2H), 7.23 (m, 1H), 7.33 (m, 1H), 7.46 (dd, J=3.9, 9.1 Hz, 1H), 7.57 (td, J=2.9, 8.3 Hz, 1H), 7.81 (dd, J=2.9, 8.8 Hz, 1H). EIMS m/z 394 (M+1).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13].[C:17]1([C:23]2[C:27]([C:28]([F:31])([F:30])[F:29])=[C:26]([C:32](O)=O)[O:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CN(C=O)C.C(OCC)(=O)C>[C:17]1([C:23]2[C:27]([C:28]([F:30])([F:31])[F:29])=[C:26]([C:32]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[CH:6][C:5]=4[C:12]([F:14])([F:13])[F:15])[N:16]=3)[O:25][N:24]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=Cc1ccc(C(N)=NO)c(C(F)(F)F)c1
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of N′-hydroxy-2-(trifluoromethyl)-4-vinylbenzimidamide (460 mg, 2 mmol), 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid, Int-I (350 mg, 1.361 mmol), and DIEA (0.475 mL, 2.72 mmol) in DMF (10 mL) was added BOP—Cl (346 mg, 1.361 mmol). The reaction mixture was stirred at room temperature for 2 hours and then 1M TBAF in THF (1.361 mL, 1.361 mmol) was added. The reaction was stirred overnight, diluted with ethyl acetate, and washed with H2O. The organic layer was dried with MgSO2, filtered, and concentrated. The resulting solids were purified on a silica gel cartridge using an EtOAc/hexanes gradient to yield 56 mg of 5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-3-(2-(trifluoromethyl)-4-vinylphenyl)-1,2,4-oxadiazole. MS (m+1)=452. HPLC Peak RT=2.03 minutes (Analytical Method B).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH:3]1[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[H-].[Na+].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].O>O1CCCC1>[C:37]([O:36][C:34]([CH2:33][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH:3]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C:2]1=[O:1])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(NC1CN(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)CN(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
Under argon atmosphere a solution of 2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.94 g) that obtained from Referential Example 3 in anhydrous tetrahydrofuran (30 ml) was added to a suspension of 60% sodium hydride (400 mg) in anhydrous tetrahydrofuran (30 ml) at 0° C., the mixture was stirred at room temperature for one hour. Tert-butyl bromoacetate (1.46 g) in anhydrous tetrahydrofuran (15 ml) to this solution, the resultant mixture was stirred at room temperature for one hour. Water (300 ml) was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Isopropyl ether was added for trituration to the residue, filtered, to thereby obtain 1.74 g of the titled compound (Yield: 69.4%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:9]3[C:14]([C:15]=2[S:16][C:17]#[N:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>CS(C)=O.O.CCOC(C)=O.C(OCC)C>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[C:9]3[C:14]([C:15]=2[S:16][C:17]#[N:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:26])[O:4][N:3]=1.[OH:28][N:27]=[C:17]([S:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)[C:7]=1[C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[CH3:26])[NH2:18]
Reactant: NO
Agent: Cc1noc(C)c1-c1c(SC#N)c2ccccc2n1-c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: Cc1noc(C)c1-c1c(SC(N)=NO)c2ccccc2n1-c1ccc(O)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
4-(2-(3,5-Dimethylisoxazol-4-yl)-3-thiocyanato-1H-indol-1-yl)phenol was dissolved in DMSO and 10 eq 2 M hydroxylamine/NaHCO3 (aq) stock solution was added. The reaction was stirred at 65° C. overnight and then diluted with H2O. A precipitation was formed after stirring for 5 min. The mixture was diluted with EtOAc and diethylether, washed with NH4Cl (aq) and phases were partitioned. Organic phase was evaporated to dryness in vacuo and subjected to purification on reverse phase preparative HPLC to provide the title compound 2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl N′-hydroxycarbamimidothioate (E32). ES/MS m/z: 395.17 (M+H), 393.19 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.88 (broad s, 1H), 8.73 (broad s, 1H), 7.80-7.78 (m, 1H), 7.29-7.24 (m, 3H), 7.18 (d, 2H), 6.95 (d, 2H), 5.11 (broad s, 2H), 2.28 (s, 3H), 2.00 (s, 3H)