[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:5]([CH2:7][C:8](OCC)=[O:9])=O.[ClH:17].[NH2:18]O.C(N(CC)CC)C>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:7]=[C:8]([Cl:17])[O:9][N:18]=2)[CH:13]=[C:14]([F:16])[CH:15]=1A mixture of ethyl 3,5-difluorobenzoylacetate (1.87 g, 8.19 mmol) and hydroxylamine hydrochloride (626 mg, 9.01 mmol) in acetic acid (24 ml) is stirred at reflux for 1 hr. The crude reaction mixture is concentrated in vacuo and azeotroped with toluene twice. The crude material is suspended in phosphorus oxychloride (37 ml) and triethyl amine (2.37 ml, 17.1 mmol) is added slowly. The reaction mixture is stirred at reflux for 2 days, concentrated in vacuo and azeothroped with toluene 3 times. The residue is dissolved in dichloromethane and passed on a plug of silica gel (elution with dichloromethane. After concentration in vacuo, the crude material is purified by flash chromatography (silica gel, dry loading, 5% diethyl ether in hexane) to give 3-(3,5-difluorophenyl)-5-chloroisoxazole (600 mg, 35%) as an off-white solid.
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