Multisubstituted 2-aminothiophenes 1a-c can be readily cyanoacylated via reaction with cyanoacetic acid in presence of acetic anhydride under a microwave irradiation to form the corresponding cyanoacetamides 2a-c, which condensed with DMF-DMA to form the corresponding enamines 4 that reacted with hydrazine hydrate to yield the aminopyrazoles 5. Moreover the cyanoacetamides 2a-c reacted with a variety of arylidenmalononitrile to afford a novel pyrido[1,2-a]thieno[3,2-e]pyrimidine derivatives 12a-o. In addition the enamines 4a,b reacted with malononitrile to afford the pyrido[1,2-a]thieno[3,2-e]pyrimidine derivatives 19a,b. The cyanoacetamides 2a,b reacted also with salicylaldehyde to afford the quinoline derivatives 24a,b. Moreover the cyanoacetamides 2a,b reacted with the enaminones 25a-c to form the corresponding Pyridin-2-one derivatives 29a-c. Reactions of 2a,c with bezenediazonium chloride afford the arylhydrazones 30a,b that reacted with chloroacetonitrile to form the acyclic product 31 which could not be further cyclized to the corresponding 4-aminopyrazole. The X-ray crystallographic analyses of seven products could be obtained thus establishing with certainty the proposed structures in this work. Most of the synthesized compounds in this investigation were tested and evaluated as antimicrobial agents.