Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH:13]([CH3:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O)C.ClCCl.[BH4-].[Na+]>C1COCC1>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH:13]([CH3:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OC(C)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CC(O)c1ccc(C(=O)OC(C)c2ccccc2)cc1
Temperature: 0 °C
Yield: 96.9 %

Procedure:
32.17 g (0.12 mol) of methylbenzyl 4-acetylphenylcarboxylate, 50 ml of ethanol, 100 ml of dichloromethane and 50 ml of THF were supplied into a four-necked flask provided with a stirrer and a thermometer. Then 2.3 g (0.06 mol) of sodium borohydride was added at 15°-25° C. over a period of 10 minutes. The mixture was maintained at the same temperature for 2 hours and the reaction mixture was poured into ice-water and treated according to Example 19 to obtain 31.43 g (97% yield) of methylbenzyl 4-(1-hydroxyethyl)phenylcarboxylate (III-22).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14]>S(=O)(=O)(O)O>[Br:9][C:10]1[C:11]([CH3:19])=[C:12]([CH:16]=[C:17]([I:1])[CH:18]=1)[C:13]([OH:15])=[O:14]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc(I)cc1C(=O)O
Temperature: 7.5 °C
Reaction time: 3 h

Procedure:
N-Iodosuccinimide (5.8 g) is added in portions to an ice-cold solution of sulphuric acid (20 mL). The resulting mixture is stirred for 40 min before 3-bromo-2-methyl-benzoic acid (5.0 g) dissolved in sulphuric acid (20 mL) is added at such a rate that the solution temperature maintained below 5° C. The mixture is stirred at 5-10° C. for another 3 h before warming to room temperature over night. Then, the mixture is poured on crushed ice (300 g) and the resultant solution is extracted with ethyl acetate. The combined extracts are washed in succession with aqueous 10% Na2S2O3 solution (2×), water (3×), and brine (1×). After drying (MgSO4) the organic layer, the solvent is evaporated under reduced pressure to give a solid. The solid is triturated with 70° C.-warm water, separated from the water by filtration and dried. After the solid is triturated with little ether, filtered and dried, the product is obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=2[NH:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=2[NH:11][C:10](=[S:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2cc(F)ccc2C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(=S)Nc2cc(F)ccc2C1
Temperature: 90 °C
Yield: 137.8 %

Procedure:
To a solution of 8-fluoro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (3.24 g, 11.57 mmol) in toluene (50 mL), was added Lawesson's reagent (2.33 g, 5.78 mmol) at r.t. The reaction mixture was heated at 90° C. for 30-40 min. After completion of reaction, as confirmed by TLC, distilled water (50 mL) was added and the crude compound was extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4. The solvents were removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 2:8 EtOAc:Pet. ether) to afford pure 8-fluoro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert butyl ester (2.36 g, 69%) as light Yellow solid.
Reaction SMILES: [CH:1]([C:13]([O:15]CC)=O)([C:8](OCC)=[O:9])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C.[CH:22]([NH2:24])=[NH:23].Cl>C[O-].[Na+].CO>[OH:15][C:13]1[C:1]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([OH:9])[N:24]=[CH:22][N:23]=1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(O)ncnc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
Charge 394.5 L methanol into the reactor at room temperature. Charge 0.3682 Kg of sodium methoxide into the reactor at RT followed by triethyl ethane-1,1,2-tricarboxylate (93.31 Kg). Stir at RT for 3 hours. Heat the reaction to 40-50° C. and distill out methanol completely under vacuum. Charge 263 L of methanol into the reactor at 40-50° C. and distill out methanol completely under vacuum at 40-50° C. Charge 263 L of methanol into the reactor at 40-50° C. cool slowly to 10-15° C. to promote crystallization. Charge 54.54 Kg of sodium methoxide maintaining the temperature at 10-15° C. Heat the reaction slowly to RT and stir for 1 hour. Charge 26.3 Kg of Formamidine acetate into the reactor at RT and slowly raise the temperature of the reaction mass to reflux (65-68° C.). Stir for 2-9 hours by maintaining the temperature at 65-68° C. Slowly decrease the reaction temperature to 10-15° C. and adjust the pH of reaction to 1.5-2.0 by slowly adding the Methanolic HCl (15-18%) maintaining the temperature at 10-15° C. Cool the reaction to 0-5° C. and maintain for 1 hour. Filter the resulting solids via centrifuge at 0-5° C. and spin dry the wet cake for 30 minutes. Wash the wet cake with 26.3 L of chilled methanol (0-5° C.) and spin-dry the wet cake for 30 min. Dry the material under vacuum at 40-45° C. to afford ethyl 2-(4,6-dihydroxypyrimidin-5-yl)acetate (35.65 Kg, 76.6%) as a solid.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=1.[Na+].[Cl-]>CN(C=O)C.O>[CH:1]1([CH2:4][O:5][C:11]2[N:10]=[C:9]([NH2:8])[CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Nc1ccnc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccnc(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethanol (724 mg) was dissolved in DMF (4 mL) and treated with sodium hydride (401 mg, 60% in mineral oil) at 0° C. for 30 minutes. Then, a solution of 4-amino-2-chloro-pyrimidine (260 mg, CAS 7461-50-9 or made according to J. Am. Chem. Soc. 1930, 52, 1152-1157) in DMF (4 mL) was added drop by drop. The mixture was stirred at room temperature for 1 hour and then allowed to stir at 50° C. over night. The mixture was poured into water and the mixture was saturated with NaCl. The aqueous solution was then extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in heptane as an eluant. The desired product was obtained as a light yellow oil (169 mg). MS (EI): 166.2 (M+H+).
Reaction SMILES: [O-2:1].[O-2:2].[O-2:3].[Cr+6:4].O.[Br:6][CH2:7][CH:8]([OH:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1.[S:19](=[O:23])(=[O:22])([OH:21])[OH:20]>C1(C)C=CC=CC=1.CC(C)=O>[CH3:12][C:11]([CH3:16])=[O:10].[OH:22][S:19]([OH:23])(=[O:21])=[O:20].[O:1]=[Cr:4](=[O:3])=[O:2].[Br:6][CH2:7][C:8](=[O:18])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1
Reactant: [Cr+6]
Reactant: [O-2]
Reactant: OC(CBr)COc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: O=C(CBr)COc1cccc(Cl)c1
Product: O=[Cr](=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Jones' reagent was prepared by dissolving chromium trioxide (26.7 g.) in concentrated sulphuric acid (23 ml.) and making the solution up to 100 ml. total volume with water. This solution was added with stirring to a solution of 1-bromo-3-(3-chlorophenoxy)propan-2-ol (53.0 g.) in toluene (75 ml.) and acetone (50ml.) under an atmosphere of nitrogen, at such a rate as to keep the temperature between 0 and 5° C. When the addition was complete, the reaction mixture was allowed to warm to room temperature and was stirred at that temperature for 16 hours. Toluene (50 ml.) and water (50 ml.) were added to the mixture and the organic layer was separated and shaken with saturated sodium bicarbonate solution (50 ml.). The whole mixture was filtered through "Hyflo" (trade mark) kieselguhr, and the aqueous layer was separated and discarded. The organic layer was washed with water (50 ml.) and dried over magnesium sulphate, and the solvent was removed under reduced pressure at a temperature below 60° C., to give a residue of 1-bromo-3-(3-chlorophenoxy)propan-2-one; the n.m.r. spectrum in deuteriochloroform showed characteristic peaks at:
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11](=[N:14][C:15]#[N:16])SC)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>C1(C)C(C)=CC=CC=1>[C:15]([N:14]=[C:11]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[NH:10][CH2:9][C:8]1[CH:17]=[CH:18][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)#[N:16]
Reactant: CSC(=NC#N)NCc1ccc(C(C)(C)C)cc1
Reactant: NCCc1ccccn1
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1ccc(CNC(=NC#N)NCCc2ccccn2)cc1
Yield: 30.3 %

Procedure:
N-(4-t-butylbenzyl)N′-cyano-S-methylisothiourea (180 mg) was dissolved in xylene (10 ml) and to the solution was added 2-(2-aminoethyl)pyridine (86 mg), followed by refluxing for 7 hours. The resulting mixture was concentrated under reduced pressure and the obtained residue was purified by column-chromatography (acetone/ethyl acetate=1/1) to yield the compound 31-1 (70 mg, 30%) as a liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][N:6]1C(=O)C2C(=CC=CC=2)C1=O.O.NN.C(Cl)(Cl)[Cl:24]>CO>[ClH:24].[Br:1][C:2]1[CH:3]=[C:4]([O:5][NH2:6])[CH:17]=[CH:18][CH:19]=1
Reactant: ClC(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1Oc1cccc(Br)c1
Agent: NN
Solvent: CO
Solvent: O
Product: Cl
Product: NOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-(3-bromophenoxy)isoindoline-1,3-dione (1.85 g, 5.82 mmol) in chloroform (50 mL) and methanol (5.6 mL) under a nitrogen atmosphere was added hydrazine hydrate (0.88 mL, 17.4 mmol). The reaction mixture was stirred at ambient temperature for 15 h and concentrated in vacuo to give the crude product which was purified by flash column chromatography (SiO2, 70:30 hexanes/ethyl acetate). After removal of solvent in vacuo the free base was treated directly with 1.25M hydrochloric acid in methanol (25 mL). The resulting solution was concentrated in vacuo and the residue washed with ethyl acetate/hexane (5:95) to give O-(3-bromophenyl)hydroxylamine hydrochloride as a pale yellow solid: 1H NMR (CD3OD, 300 MHz) δ 7.43-7.36 (m, 3H), 7.18 (dt, J=7.8, 1.8 Hz, 1H); ESI MS m/z 187 [M+H]+
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:27]([NH:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[O:28])[CH:18]=[N:19][C:20]=2[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:27]([NH:29][N:30]3[CH2:31][CH2:32][N:33]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:34][CH2:35]3)=[O:28])[CH:18]=[N:19][C:20]=2[O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:11][CH:10]=1
Reactant: O=C(NN1CCNCC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCN(NC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
5-(4-Chlorophenyl)-N-(piperazin-1-yl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxamide 2,2,2-trifluoroacetate (1:1) (100 mg, 189 μmol) was combined with dichloromethane (5 mL) to give a white suspension. N,N-Diisopropylethylamine (122 mg, 165 μl, 945 μmol) and methanesulfonyl chloride (23.8 mg, 16.1 μl, 208 μmol) were added successively at 0° C. The reaction mixture was stirred for 1 h at 0° C. and subsequently concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in n-heptane). Recrystallization from ethyl acetate and n-heptane afforded the title compound (50 mg, 54%) as off-white solid; LC-MS (UV peak area/ESI) 98.0%, 493.0916 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C(N(C(C)C)CC)(C)C.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1,5-Dichloro-2-methyl-4-nitrobenzene (2.42 mmol, 500 mg) was dissolved in dry dimethylformamide (5 ml) and diisopropylethylamine (1 eq., 2.42 mmol, 0.413 ml), 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 eq., 2.42 mmol, 484 mg) were added at room temperature and the mixture was stirred at 100° C. overnight. The crude mixture was then cooled to room temperature and water was added; the aqueous solution was extracted with ethyl acetate (3×); organics were alternatively washed with brine and water. The organics were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound that was purified by chromatography (ethyl acetate/hexane) to yield the title compound, 98 mg, 11%, bright orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH:5]=[O:6])C.CC1C=CC(S([CH2:18][N+:19]#[C-:20])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:3][C:4]([C:5]1[O:6][CH:20]=[N:19][CH:18]=1)=[O:7]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cnco1
Yield: 621.6 %

Procedure:
To a solution of glyoxylic acid ethyl ester (50% w/w in toluene) (4 mL, 2 mmol) and Tosmic (3.86 g, 2 mmol) in MeOH (60 mL) was added K2CO3 (5.6 g, 4 mmol) and the mixture was stirred at reflux for 7 h. The solvent was then evaporated and 100 mL of water was added. This solution was saturated with sodium chloride and extracted with diethyl ether. The organic layer was washed with brine, dried (MgSO4) filtered and concentrated to give 1.58 g (60%) of oxazole-5-carboxylic acid methyl ester as white solid. m.p.=35-50° C.
Reaction SMILES: [CH2:1]1N2CN3CN(C2)CN1C3.[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH3:12].[OH2:20].Cl>CC(O)=O.C(OCC)C>[CH2:11]([C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([CH:18]=1)[CH:1]=[O:20])[CH3:12]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CCc1ccc(O)cc1
Reactant: O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
114 g of hexamethylenetetramine were added to a solution of 20 g of 4-ethylphenol in 400 ml of AcOH. The reaction solution was stirred for 5 hrs. at 100° C. Then, 150 ml of H2O and 150 ml of 25% HCl solution were added. The mixture was stirred for 1 hr. at 100° C. Then, it was left to cool to room temperature. The crude product was isolated by extraction with diethyl ether and purified by chromatography on silica gel. There were obtained 8.6 g of 5-ethyl-2-hydroxy-benzaldehyde as a light yellow liquid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
1-t-Butoxycarbonyl-4-(2-methoxyphenyl)piperidine (120 mg, 0.41 mmol) was dissolved in methylene chloride (2 ml). Thereto was added trifluoroacetic acid (2 ml) and the resulting solution was stirred at a room temperature for 1 hour. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate. This was washed with 1 N sodium hydroxide aqueous solution and saturated brine in that order, and then the solvent was evaporated under a reduced pressure to obtain 82 mg of the aforementioned compound of interest (0.43 mmol, 104% in yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-])[CH3:2].C[Si]([C:14]#[N:15])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:14]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[N:4]=1)#[N:15]
Reactant: C[Si](C)(C)C#N
Reactant: CCc1cccc[n+]1[O-]
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CCc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
2-Ethylpyridine N-oxide (3.0 g, 24.4 mmol) was dissolved in nitroethane (30 ml), and trimethylsilyl cyanide (2.4 g, 24.0 mmol) and N,N-dimethylcarbamoyl chloride (2.4 g, 21.9 mmol) were added thereto. The reaction mixture was stirred at room temperature for 3 days, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v) to give the titled compound (1.0, 31%).
Reaction SMILES: [Br:1][C:2]1[C:12]([N:13]([CH2:17][CH2:18]Cl)[CH2:14][CH2:15]Cl)=[C:11]([CH3:20])[C:5]2[CH2:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[C:3]=1[CH3:21].[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[Br:1][C:2]1[C:12]([N:13]2[CH2:17][CH2:18][N:28]([C:27]3[CH:29]=[CH:30][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH2:15][CH2:14]2)=[C:11]([CH3:20])[C:5]2[CH2:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[C:3]=1[CH3:21]
Reactant: COc1ccc(N)cc1
Reactant: Cc1c(Br)c(N(CCCl)CCCl)c(C)c2c1OC(C)(C)C2
Product: COc1ccc(N2CCN(c3c(C)c4c(c(C)c3Br)OC(C)(C)C4)CC2)cc1
Yield: 24.8 %

Procedure:
By using 6-bromo-N,N-bis(2-chloroethyl)-2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine (492 mg, 1.25 mmol) synthesized in Reference Example 152 and 4-methoxyaniline (185 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 117 to synthesize 138 mg of the title compound (yield 25%).
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=O)[C:5]=2[C:4]=1CC)[CH3:2].[Cl-].[OH:21][NH3+:22].O.[CH2:24](O)[CH3:25]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:16]=[C:15]([CH2:24][CH3:25])[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[N:22][OH:21])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: [NH3+]O
Reactant: CCO
Reactant: CCc1ccc2sc3ccccc3c(=O)c2c1CC
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Product: CCc1cc(CC)c2sc3ccccc3c(=NO)c2c1
Temperature: 115 °C
Reaction time: 21 h

Procedure:
7.0 g (26 mmol) of diethylthioxanthen-9-one are dissolved in 15 ml of hot ethanol and 15 ml of pyridine. Then hydroxylammonium chloride (3.6 g, 52 mmol) is added, and the reaction solution is stirred at 115° C. for 21 h. After cooling, water is added. The crude product is extracted with ethyl acetate, washed with water, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (1:30 to 1:10) as an eluent. The product (an isomeric mixture) is obtained as a slightly yellow solid. 1H NMR (CDCl3), δ[ppm]: 1.23-1.32 (m, 6H), 2.65-2.72 (m, 2H), 2.77-2.86 (m, 2H), 7.12(s, 1H), 7.30-7.36 (m, 2H), 7.45 (dd, 1/2H), 7.53-7.55 (m, 1H), 7.80 (dd, 1/2H), 8.03 Cd, 1/2H), 8.09-8.48 (bs, 1H), 8.34 (dd, 1/2H), wherein 1/2H means 1H of either isomer.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]#[N:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(N(CC)CC)C>C(O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16](=[N:20][OH:21])[NH2:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1nc(C#N)sc1C(=O)NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(C(N)=NO)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of N-benzyl-2-cyano-4-methylthiazole-5-carboxamide (0.15 g, 0.58 mmol) and hydroxylamine hydrochloride (0.09 g, 1.28 mmol) in ethanol (7 mL) was added triethylamine (0.2 mL, 1.43 mmol). The reaction mixture was heated to reflux for 3 hour, cooled to ambient temperature and concentrated in vacuo. The solid was washed with water and dried to afford the title compound in 70% yield (0.12 g): 1H NMR (300 MHz, CDCl3) δ 7.43-7.18 (m, 5H), 6.42 (br s, 1H), 5.74 (br s, 2H), 4.54 (d, J=5.3 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 291.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:14]=2)[C:5]([CH3:25])=[C:4]([CH3:26])[N:3]=1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:52]=[CH:51][C:39]([CH2:40][NH:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)=[CH:38][CH:37]=1>C1(C)C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:14]=[C:13]([CH2:12][NH:11][C:6]3[C:5]([CH3:25])=[C:4]([CH3:26])[N:3]=[C:2]([N:41]([CH2:40][C:39]4[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:52][CH:51]=4)[CH2:42][C:43]4[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=4)[C:7]=3[N+:8]([O-:10])=[O:9])[O:17][N:16]=2)=[CH:19][CH:20]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCc2cc(-c3ccc(F)cc3)no2)c1C
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2[N+](=O)[O-])cc1
Yield: 94 %

Procedure:
Under a nitrogen atmosphere, 2-chloro-N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-5,6-dimethyl-3-nitropyridin-4-amine (25.00 g, 66.35 mmol), toluene (250 mL), triethylamine (11.1 mL, 79.6 mmol), and N,N-bis(4-methoxybenzyl)amine (18.8 g, 73.0 mmol) were combined and heated at reflux for three days. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous potassium carbonate. The ethyl acetate layer was separated and concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed sequentially with water and brine. The combined aqueous fractions were extracted with ethyl acetate. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid was triturated with ethanol, isolated by filtration, and washed with diethyl ether to provide 37.29 g of N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethyl-3-nitropyridin-2,4-diamine as an orange solid.