An efficient and simple synthesis of 3-cyano-2-pyridone derivatives (6a-f) through 3,4-dihydropyridin-2-one oxidation process is described. A greener method to synthesize 3,4-dihydropyridin-2-one has also been developed by rearranging 4H-pyran (4a-f) derivatives in aqueous medium applying H₂SO₄ as the catalyst source and microwave irradiation. The vasorelaxant activity of 3-cyano-2-pyridone derivatives (6a-f) was proved on isolated thoracic aorta rat rings with and without endothelium (+E and -E, respectively) pre-contracted with noradrenaline (0.1 μM). All compounds exhibited significant concentration-dependent and endothelium-independent vasorelaxant effects being the nitro derivatives (6a and f) and compound 6d the most potent with EC₅₀ of 7, 4.4 and 5 μM, respectively. Finally, a previously described 3D model of the central pore of human L-type calcium channel (LCC), modified to be on agreement with NCBI sequence NP_005174.2 for subunit alpha-1F isoform 1, was used to dock most active compounds. 6a, d and f lowest affinity energy structures were found docked in the same cavity conformed by IS6, IS5, IP and IIS6 helices. Nifedipine lowest energy structure was found in the cavity formed by IIS6, IIS5, IIP and IIIS6. Although nifedipine docked in a different cavity, the superposition of both, allowed us to observe that they were almost the same cavities, indicating that there exist subtle steric differences that lead to a different docking for nifedipine. All compounds docked with similar free energy of binding.