Polysubstituted pyrido[1,2-a]benzimidazole derivatives are efficiently produced in moderate yields in a novel one-pot, four-component reaction from pyridine or 3-picoline, chloroacetonitrile, malononitrile, and aromatic aldehyde in refluxing acetonitrile. The mechanism of this novel reaction was believed involving the formation of polysubstituted benzenes with subsequent substitution and annulation reaction of pyridine. All pyrido[1,2-a]benzimidazoles, polysubstituted benzenes, polysubstituted indoles, and some key reaction intermediates are characterized by (1)H and (13)C NMR, MS, IR spectra, and elemental analysis as well as X-ray crystallography.