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Antimetabolites are the key parts of the growing interdisciplinary area of many significant therapeutics. They have pivotal effects in medicinal chemistry, and comprehensive applications in biochemistry and biotechnology. Antifolates, purines and pyrimidines are the main classes of antimetabolites which are integrated into various pharmaceutical agents. As part of our program directed toward the development of new, simple, and efficient procedures for the synthesis of potential antimetabolites, we have recently reported different successful approaches for the syntheses of purine, folic acid, and pyrimidine analogues. Derivatives of these ring systems are interesting as antimetabolites in biochemical reactions. Up to date synthetic strategies of the three categories of antimetabolites have been exploited and highlighted throughout this book. The new insights for the current research of antimetabolites have offered significant opportunities for developing their synthetic approachesthat emulate our prospect in this book to be beneficial and valuable source to all scientists for drug discovery and developments.