For instance, N-phenylquinolin-4-amine comprising -SCF3, -SF5, -SCH3, and diphenyl sulfide, including sulfonamide, were well accommodated in this protocol and delivered the respective N-difluoromethylated products in very good yields (3i-3p), highlighting the remarkable sulfur resistance of this method. Unlike conventional strategies, our reaction conditions were amenable to double N-difluoromethylation featuring the imine unit, giving 3q in 89% yield without eroding the diphenyl sulfide group. We also evaluated 2-methyl-Nphenylquinolin-4-amine, delivering the expected product (3r) in very good yield, and the chemical structure was unambiguously confirmed by single-crystal X-ray crystallography (3r is validated with ScXRD, CCDC: 2410062). The reaction demonstrated good tolerance to the ether functionalities and afforded the desired products in excellent yields (3s and 3t). The tolerance towards the alkene functional group (3u) is especially significant, as it provides opportunities for hydrofunctionalization and coupling reactions. Under optimal conditions, important crucial molecular skeletons, such as morpholine and piperazinecontaining drug fragments, were also proved compatible, delivering the desired products efficiently in high yields (3v-3aa). Azo compounds have been found to be promising candidates as drug carriers due to their versatile biological activities, but the survival of such a valuable functional group is very scarce. Interestingly, N-phenylquinolin-4-amine derivatives bearing azo moiety were successfully N-difluoromethylated in very good yields with this cost-effective approach (3ab-3ac). Additionally, our protocol also accommodated biologically relevant heterocycles and was readily converted to N-difluoromethylated products in a very selective manner (3ad-3ag). Additionally, it was noteworthy that Npyridyl-substituted aniline could proceed well and provide the corresponding 1-(difluoromethyl)-N-phenylpyridin-2(1H)-imine in 87% yield (3ah). N-(pyridin-2yl)pivalamide and tert-butyl (3-methylpyridin-2-yl)carbamate are valuable pyridine-based molecular frameworks, undergo the selective N-difluoromethylation in 95% and 93% yield, respectively (3ai and 3aj). The malaria treatment drug, amodiaquine, was successfully Ndifluoromethylated to access compound 3ak in 79% isolated yield. Neratinib, a protein kinase inhibitor used to treat breast cancer, was also N-difluoromethylated, albeit in 14% yield (3al) owing to less conversion. Further, amsacrine hydrochloride (m-AMSA hydrochloride, an anticancer agent) 48 can be directly difluoromethylated to give 3am in 60% yield with this simple procedure. In addition, difluoromethylation of Piroxicam (CP-16171), a pain relief drug, under standard conditions gave a mixture of corresponding N-and O-difluoromethylated products (3an + 3an′) in a ratio of 1:0.6 (determined by 1 H NMR), which were found to be nonseparable with column chromatography. However, crystallization of the nonseparable mixture (3an + 3an′) gave yellow crystals of the major N-difluoromethylated isomer (validated the chemical structure of 3an with ScXRD, CCDC: 2410066), and the minor isomer 3an′ did not result in any crystallization. Acalabrutinib, useful for the treatment of mantle cell lymphoma (MCL) in adults, was successfully converted into the desired product 3ao in a 41% isolated yield at 24 h of reaction time. Quinazolinamine derivatives are the common molecular frameworks in biologically active compounds. Several top-selling commercial drugs, such as gefitinib, erlotinib, osimertinib, and many more, comprise quinazoline core and are considered as a "privileged structure" in drug design. Since quinazolines have two nitrogen atoms, we sought to utilize one of them suitably for N-difluoromethylation in order to enhance their biological profiles. In this vein, commercially available drugs such as Erlotinib (used to treat non-small cell lung cancer and pancreatic cancer) and FAAH-IN-2 (O-Desmorpholinopropyl Gefitinib), a metabolite of Gefitinib underwent the current difluoromethylation process smoothly and afforded corresponding products in synthetically useful yields (Figure ). The exceptional tolerance of alkyne and halide functionality in these drugs provides a useful route for further diversification of medicinally relevant molecules. Surprisingly, 2,5dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine, a synthetic intermediate of anaplastic lymphoma kinase (ALK) inhibitors, 53 gave somewhat unexpected product 5chloro-1-(difluoromethyl)-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2(1H)-one (5c) under routine conditions. To get some insight into this unusual behavior, a crystal structure of 5c (CCDC: 2413970) was obtained, and it revealed the presence of a strong intramolecular hydrogen bonding between the H-atom of the free N-H bond and the O-atom of the SO2 functional group. We believe this could be a possible reason for the decrease in the acidity of the H-atom of the N-H bond, which restricts deprotonation. The nucleophilic addition of water on the ortho site of the pyrimidine ring (Ipso to the Cl atom), followed by the substitution of the chloride atom, leads to the formation of a stabilized Ndifluoromethylated product 5c. Most importantly, Kinetin, a plant hormone that regulates cell growth in plants, could also provide double difluoromethylated product (5d) in 81% isolated yield (validated the chemical structure of 5d with ScXRD, CCDC: 2410069). 2-((6chloro-2-methylpyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)thiazole-5carboxamide, a key intermediate of dasatinib drug, gave 61% isolated yield of a mixture of 5e and 5e ′ (ratio of 5e and 5e ′ is 1:0.9; determined by F NMR). To the best of our knowledge, the preparation of such novel N-difluoromethylated products holding imine functional groups is completely unknown. Next, under the same conditions, we surveyed the scope of the reaction with pyridin-4ol and quinolin-4-ol derivatives with bromo(difluoro)acetic acid (Figure ). Since functionalized pyridines are considered attractive scaffolds and found in many bioactive compounds, 1, 2 site-selective installation of the -CF2H group onto nitrogen atoms would create a valuable platform for the preparation of an array of N-difluoromethylated products. Unsubstituted 4-hydroxypyridine, 3-methylpyridin-4-ol, and halogen-substituted 4hydroxypyridines underwent the selective N-difluoromethylation with simultaneous formation of ketone functional group in good to excellent yields (7a-7e), underscores that chloride and iodo substituents are also tolerated by the reaction conditions. Gratifyingly, challenging pyridine derivatives such as (E)-3-(4-fluorostyryl)pyridin-4-ol and (E)-3-(4-(trifluoromethyl)styryl)pyridin-4-ol, also reacted smoothly to afford the corresponding difluoromethylated products 7f and 7g, with isolated yields of 76% and 78%, respectively.