Since Het-NCF2H motifs are prevalent in pharmaceutical settings and plant-based products, our goal was to design the reaction with readily available and inexpensive reagents, possibly under ambient and metal-free conditions. As briefly exemplified in Figure , we evaluated various difluoromethylation reagents (Figure ) for the difluoromethylation of the hydrochloride salt form of N-(3-fluoro-4morpholinophenyl)quinolin-4-amine (1a) as a model compound (validated the chemical structure of 1a with Single crystal X-ray diffraction (ScXRD) (CCDC: 2410081). Among the employed difluoromethylation reagents, ethyl bromodifluoroacetate (2a) (1.2 equiv.) gave (E)-1-(difluoromethyl)-N-(3-fluoro-4-morpholinophenyl)quinolin-4(1H)-imine (3a) in 55% isolated yield using 2.5 equivalents of K2CO3 and DMF (2 ml) at room temperature for 18 h (3a is validated with ScXRD, CCDC: 2413933). Under the same conditions, only an appreciable yield of 3a was achieved with chlorodifluoroacetic acid (2b) and diethyl (bromodifluoromethyl)phosphonate (2c). The reaction was unsuccessful with the TMS-CF2Br reagent (2d). To our delight, the desired product 3a was obtained in 92% isolated yield with bromo(difluoro)acetic acid (2e) as a CF2H reagent. In general, the synthetic utility of difluoromethylation methods in pharmaceutical manufacturing relies on the cost and commercial accessibility of difluoromethylation reagents, including simplified experimental settings. Compared to the price of other CF2H reagents (see ESI, Table ), bromo(difluoro)acetic acid is inexpensive, available in large quantities, and easy to handle even on a large scale, thereby improving cost efficiencies. Although this reagent (2e) has been known for a while in constructing a few fluorinated molecules, the ability to demonstrate N-difluoromethylation with complex N-heterocycles remains underexplored. Next, we screened the concentration of (2e) and observed that a minimum of 1.2 equiv. was required for an excellent yield of 3a (Figure ). Encouraged by the above-mentioned results, we continued our investigation with 2.5 equiv. of various bases and discovered that K2CO3 (92% of 3a) and Cs2CO3 (88% of 3a) are best among other bases, such as Na2CO3, KOH, and NaOH (27-79% of 3a) (Figure ). Considering the cost-effectiveness of the reaction, we proceeded the further optimization experiments with K2CO3 (B1). Further, we evaluated the concentration of K2CO3 and concluded that 2.5 equiv. is necessary for achieving a high yield of 3a (Figure ). We also carried out the reaction by using solvents such as DMSO, H2O, EtOH, THF, and DMF (Figure ). The best yield of 3a (92%) was obtained in DMF as a solvent, and other solvents yielded inferior results (15-49% of 3a). Upon screening the reaction time, we found that 18 h is optimal to achieve 3a in high yield (Figure ). We also adapted the EcoScale tool and calculated the value for the conversion of 1a to 3a, and the results have shown that this protocol is safe and economically viable (see the ESI, 7. With viable reaction conditions in hand for the difluoromethylation of N-heterocycles, the study was advanced with a full exploration of structural scope compatibility, and results were summarized in Figure . Various N-Phenylquinolin-4-amine compounds derived from medicinally relevant structural moieties were effectively difluoromethylated in high to excellent yields. The high functional group tolerance of C-X bonds (X = halogen) of Nphenylquinolin-4-amine is a valuable asset in all areas of preparative chemistry, especially in the pharmaceutical industry. Pleasingly, the reaction worked well with a range of halidesubstituted N-phenylquinolin-4-amine, giving the desired difluoromethylated products 3b-3h in high yields. Interestingly, no dehalogenation of the C-X bond or byproduct took place. Next, sulfur-containing compounds can be found in a broad range of drugs owing to their different biological activities. Specifically, -SCF3 and -SF5 are fascinating functional groups with significant potential in modern drug development. Bearing this in mind, a wide set of sulfur-based building blocks was demonstrated here with our optimized conditions.