**Abstract**

Diazine alkaloid (pyridazine, pyrimidine and pyrazine) scaffold, a widespread two-nitrogen containing compounds in nature (DNA, RNA, flavors, and fragrances), constitutes a central building block for wide range of pharmacological applications. Diazines are reported to exhibit antimetabolite (antifolate and), anticancer, antibacterial, antiallergic, tyrosine kinase, antimicrobial, calcium channel antagonistic, anti-inflammatory, analgesic, antihypertensive, antileishmanial, antituberculostatic, anticonvulsant, diuretic and potassium-sparing, to antiaggressive activities. Pyridazine (1,2-diazine), pyrimidine (1,3-diazine) and pyrazine (1,4-diazine) are found as mono-systems, fused or annulated in pharmaceutical, agrochemical or materials. These six-membered heterocyclic aromatic moieties defined as privileged scaffolds constitute diverse chemical structures and as such hold substantial interest for organic, medicinal and biological chemists. This chapter will focus on elaboration of the different synthetic approaches applied in preparing pharmacologically active decorated diazines with special care on pyrimidines (non-fused substituted forms) that are endowed with clinical applications. Synthetic approaches applied in preparing selected FDA approved drugs with pyrimidine as a central unit bearing different substituents will be intensively explored. Special attention will be given to novel synthetic methodologies that served molecules with improved druglikeness and ADME-Tox properties.

**Keywords:** diazine, pyrimidine, chemistry, synthesis, methods, substituted, medicinal, bioactive, anticancer, ADME-Tox
