Abstract A one‐pot multi‐component reaction strategy for the selective synthesis of 5‐trifluoromethyl pyrimidine derivatives has been established. This method avoids the inherent selectivity challenges in direct pyrimidine trifluoromethylation. The reaction demonstrates tolerance to various functional groups, yielding 5‐trifluoromethyl pyrimidine derivatives with up to 80% yields. Moreover, the practicality of this method has been underscored through scale‐up reactions.