**1. Introduction**

Pyrimidine derivatives, broadly applied in therapeutic disciplines, owing to their high degree of structural diversity. This "privileged scaffold" and "derivatives" either as substituted or as fused systems gain wide interest due to plentiful biological activities reported over the years. Those versatile biological activities include (and not limited to) modulation of myeloid leukemia (for example imatinib, Dasatinib and nilotinib are pyrimidine-based drugs and well established treatments for leukemia) [1, 2], breast cancer and idiopathic pulmonary fibrosis [3], antimicrobial [4],

antifungal [5], antiparasitic [6], diuretic [7], antitumor [8–13], antifilarial [14], DNA topoisomerase II inhibitors [15], antitubercular agents [16], antimalarial [17] and antiplasmodial [18], anti-inflammatory and analgesic activities [19–21], anti-HIV [5, 22, 23], cardiovascular agents and antihypertensive [24, 25], antiulcer agents [18], hair disorders activities [26], calcium-sensing receptor antagonists, DPP-IV inhibitors [27, 28], antidiabetic [29], potent adenosine A2a receptor agonistic or antagonist action [30], TLR8 or [15] or interferon beta (IFN-β) modulators [31], vascular relaxation for ocular ciliary artery and neuroprotection on retinal ganglion cell [32], 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and coronary heart disease therapeutics [33], anticancer [8, 34–36], key intermediate for Vitamin B1 [37], pyruvate dehydrogenase kinase inhibitors [38]. In addition, many of pyrimidine derivatives are reported to possess potential central nervous system (CNS) and antidepressant properties [39], antihypnotic [40], anti-Alzheimer's Disease (AD) agents [41, 42], anticonvulsant [43], antiallergic [44] and for treatment of hypoglycemic and hypolipidemic activities [45, 46].

Over the years a large interest in fused pyrimidines compiled and exceeded in certain extent substituted pyrimidine derivatives. Though highly appealing the synthesis of fused pyrimidines- is beyond the scope of this chapter. Additionally, this chapter will not address in depth the diverse bioactivities neither in structure activity relationship (SAR), nor in detailed mechanism of actions (MOA). The main focus of this manuscript is to explore various synthetic methods employed to produce this diverse group of compounds.

Synthesis of pyrimidine and its derivatives gains a great deal of interest due to wide applications in medical and therapeutic.

The current chapter focuses on chemical process and methods to derivatize the pyrimidine heterocyclic core with di-, tri- and tetrasubstituted pyrimidines.
