The objective of this invention is to provide a process of manufacturing cephem derivatives expressed by the following formula (1), wherein the compound (2) is reacted with an condensing agent of the compound (4) and 1-hydroxy-6-trifluoromethyl benzotriazole(5) and the mixture is acylated with 7-aminocephosporanic acid (3) or its derivatives. ##STR1## According to this invention, a desirous product with high purity may be obtained, which is more cost-saving and industrially feasible than the conventional methods, under the following process steps: Without protecting amino group of organic acid (2), conversion of the reactive derivatives under mild temperature is made and the acylation is directly carried out to obtain the final product.