Quinolones and their derivatives play a fundamental role as the pharmacophore for several drug molecules. In this vein, we sought to apply our reaction conditions to enhance their clinical development. A variety of 4-hydroxyquinolines with halide-substituents and electron-donating groups worked well under optimal conditions, delivering the corresponding N-difluoromethylated products in high yields (7h-7n). Interestingly, difluoromethylation of two hydroxy groups containing 1,10-phenanthroline-4,7-diol selectively underwent both N-and O-difluoromethylation within the molecule and gave the respective product 7o in 89% isolated yield, displaying the potential double difluoromethylation of the present method. The fused heterocyclic compound containing both triazole and pyrimidine rings, such as 5-Methyl-2-(methylthio) [1,2,4]triazolo [1,5a]pyrimidin-7-ol found in biologically active compounds also reacted efficiently to give 7p in high yield. Additionally, 4-quinolone of several therapeutic compounds proceeded smoothly to provide targeted difluoromethylated products 7q-7s (74 -78% yield). When conducting experiments with quinolin-4-ol and quinolone derivatives, minor amounts of Odifluoromethylated products were also detected. For confirmation, we have isolated Odifluoromethylated products (22% yield of 7n ′ ) of 6n and analysed them with NMR and HRMS. Next, we assessed this protocol for the late-stage functionalization of the quinolonebased drug. For instance, Ivacaftor (listed 13 th in the top-200-selling drugs in 2023), which is used to treat cystic fibrosis, could be selectively N-difluoromethylated in 64% isolated yield (7t), thus demonstrating the advantages of this simple operational approach. In addition, we also investigated the influence of the steric effect and subjected the unseen examples of 6u and 6v to difluoromethylation under standard conditions. As a result, difluoromethylation of 6u (carboxylate moiety is neighbor to C=O) favored selective Ndifluoromethylated product (7u) in 81% yield. Whereas difluoromethylation of 6v (carboxylate moiety is neighbor to N-H) favored selective O-difluoromethylated product (7v) in 78% yield (Figure ). These results clearly suggest that steric hindrance governs the selective O-and N-difluoromethylation in these reactions. Encouraged by the above results, we became interested in late-stage Ndifluoromethylation with bromo(difluoro)acetic acid in a straightforward manner (Figure ). Notably, four APIs, Azathioprine, Aprovel, Lansoprazole, and Mercaptopurine, were selectively N-difluoromethylated under standard conditions to give products 9a-9d, signifying tolerance of key functional groups in more complex settings. Azathioprine, which contains a purine ring and is used to treat rheumatoid arthritis, gave the corresponding product 9a (verified the chemical structure of 9a with ScXRD, CCDC: 2410064) in 71% isolated yield. Another drug molecule, Aprovel, bearing tetrazole ring system, is used to treat high blood pressure, also underwent N-difluoromethylation to afford the product 9b (verified the chemical structure 9b with ScXRD, CCDC: 2410078) in synthetically useful yield. Lansoprazole (used to treat stomach ulcers) also delivered corresponding Ndifluoromethylated product 9c in 72% isolated yield. Furthermore, Mercaptopurine, a chemotherapy drug, 61 was also feasible for double N-difluoromethylation and afforded 9d even in a higher yield (78%). These results underscore the functional group tolerance and the generality of this N-difluoromethylation procedure.