Versatile straightforward synthetic pathways for a novel series of annelated imidazo[2,1-c][1,2,4]triazole derivatives were performed. Our newly synthesized compounds were prepared from the reactive binucleophile 3-hydrazinyl-5-(4-methoxybenzylidene)-7-phenyl-5H-imidazo[2,1-c][1,2,4]triazol-6(7H)-one 2 applying different synthetic strategies including the multicomponent approach. The annelated derivatives are different imidazo [2',1':3,4][1,2,4]triazolo[5,1-c][1,2,4]triazepines 3-7; imidazo[2',1':3,4][1,2,4]triazolo [5,1-c][1,2,4,6]tetrazepine analogue 8. The newly synthesized compounds have been subjected to screening for in vitro anticancer activity. This screening had been conducted at the National Cancer Institute (NCI), USA at a single dose (10-5 M) against full NCI 60 cell panel. The screening results indicated a considerable anticancer activity for compound 7 against CNS cancer (SNP-75) cell line with growth inhibition percent 46.56. Moreover, a moderate anticancer activity against renal Cancer (UO-31) cell line was common with compounds 2 and 7 with growth inhibition percents 33.25 and 38.77; respectively.