A general approach to C3 modification of purine scaffold through various types of cross-coupling reactions has been established. Tuning substrate electronics and reaction conditions resulted in the development of highly efficient sp2-sp, sp2-sp2, and sp2-sp3 cross-coupling conditions for modification of 3-deazaadenine to access C3-modified adenine and hypoxanthine scaffolds. The optimized methodologies to access the corresponding 3-deazaadenosine phosphoramidites for solid-phase DNA synthesis have been demonstrated.