Treatment of arylidene malononitriles 2A–C with 1‐cyanomethylisoquinoline 1 afforded 4‐amino‐2‐arylpyrido[2,1‐a]isoquinoline‐1,3‐dicarbonitrile derivatives 5A–C, which converted to formimidates 6A–C via reaction with triethylorthoformate. Treatment of the latter compounds with hydrazine hydrate gave the corresponding amino–imino compounds 7A–C, which underwent Dimroth rearrangement to afford 13‐aryl‐1‐hydrazinylpyrimido[5′,4′:5,6]pyrido[2,1‐a]isoquinoline‐12‐carbonitrile 8A–C. The latter reacted with aldehyde to give 9a–i. Oxidative cyclization of the latter compounds 9a–i gave [1,2,4]triazolo[4″,3″:1′,6′]‐pyrimido[5′,4′:5,6]pyrido[2,1‐a]isoquinolines 10a,d,g. Such compounds isomerized to the thermodynamically more stable isomers [1,2,4]triazolo[1″,5″:1′,6′]pyrimido[5′,4′:5,6]‐pyrido[2,1‐a]isoquinolines 11a,d,g. Antimicrobial activities for some compounds were studied.