AbstractFluorinated small molecules are commonly used in functional small‐molecule chemistry, and N‐difluoromethyl (N‐CF2H) compounds are particularly intriguing due to their unique and unexplored physiochemical properties. However, despite limited progress, a general methodological approach to the synthesis of N‐CF2H compounds remains elusive. Here, guided by computation, we present a simple and practical protocol to access N‐CF2H amides and related carbonyl derivatives. The protocol involves a one‐pot conversion of thioformamides through desulfurization‐fluorination and acylation, providing N‐difluoromethylcarbamoyl fluoride building blocks that can be further diversified to a variety of unexplored N‐CF2H carbonyl compounds with rich functionality. Additionally, preliminary studies on their properties and stability showcased their potential application in pharmaceuticals and agrochemicals.