A new convenient method for the synthesis of 1,4 -benzothiazepin-5-ones by a one-pot procedure including condensation of thiosalicylic acid with chloroacetone and the reaction of the resulting 2-(acetoxythio)benzoic acid without isolation with primary amines and isocyanides is proposed. This method can be used for the combinatorial search of compounds with biological activities in the 1,4-benzothiazepine series.