DFT‐calculations allow prediction of the reactivity of uncommon N‐heterocyclic scaffolds of pyrazolo[1,5‐a]pyrimidines and imidazo[1,2‐b]pyridazines and considerably facilitate their functionalization. The derivatization of these N‐heterocycles was realized using Grignard reagents for nucleophilic additions to 5‐chloropyrazolo[1,5‐a]pyrimidines and TMP2Zn ⋅ 2 MgCl2 ⋅ 2 LiCl allowed regioselective zincations. In the case of 6‐chloroimidazo[1,2‐b]pyridazine, bases such as TMP2Zn ⋅ MgCl2 ⋅ 2 LiCl, in the presence or absence of BF3 ⋅ OEt2, led to regioselective metalations at positions 3 or 8. Subsequent functionalizations were achieved with TMPMgCl ⋅ LiCl, producing various polysubstituted derivatives (up to penta‐substitution). X‐ray analysis confirmed the regioselectivity for key functional heterocycles. [ABSTRACT FROM AUTHOR]