An extremely effective and straightforward multi-component reaction strategy for the universally highly selective synthesis of 5-CF3 pyrimidine derivatives has been established. This method employs a distinctive trifluoromethylation-cyclization strategy, introducing an innovative reaction mechanism and avoiding the inherent selectivity challenges in direct pyrimidine trifluoromethylation. The no-table advantages of this work are the exceptional selectivity, extremely short reaction time, and convenience of a one-pot synthetic procedure.