Abstract: In order to rapidly prepare novel lead compounds of fungicides, the method that involved both the combinatorial chemistry and the conventional synthesis was used. The fungicidal activity against Botrytis cinerea of the N-substituted-2-oxo-2-phenyl ethyl sulfonamide derivatives were investigated. Firstly, 2-oxo-2-phenyl ethyl sulfonyl chloride was prepared by the sulfonation and chlorination of acetophenone. Then 33 combinatorial libraries, which contained 105 compounds, were synthesized by the reaction of 2-oxo-2-phenyl ethyl sulfonyl chloride respectly with aniline, benzylamine or alkyl amine combination library. The yields ranged from 60% to 90% and the purity was 70%-95%. Twenty-nine compounds were synthesized in parallel with 10 active libraries, within which 10 active compounds were purified and identified. In vitro and in vivo, all combination libraries and compounds were screened by Botrytis cinerea. Finally, the high activity lead compound was quickly determined, which lay the foundation for further structural optimization.