Nitrogen heterocycles (N-heterocycles) are present in more than 85% of marketed and investigational drugs. Statistically, over the past few years, there has been an everincreasing amount of N-heterocycles per prescribed medicine. Notably, both five-and sixmembered N-heterocycles are especially valued for their prevalence among the best-selling clinically approved drugs worldwide to date (Figure ). These facts highlight the critical role of N-heterocycles in pharmacological function. Simultaneously, the introduction of fluorine atoms into N-heterocyclic substrates represents a powerful tool in biological research to enhance the therapeutic efficacy of structurally complex pharmaceutical molecules. Undoubtedly, the combination of these two (N-heterocycles + Fluoro substitution) distinctive different physicochemical properties is immensely occurring in new chemical entities (NCEs) with diverse biological functions, as exemplified by the expeditious construction of fluorinated motifs onto N-heterocyclic frameworks among the FDA-approved drug molecules. Complex N-heterocycles bearing the difluoromethyl moiety (Het-NCF2H) have always been attractive in the isostere-based drug design and development (Figure ). Also, the -NCF2H unit markedly influences lipophilicity, cellular membrane permeability, and conformational preferences (Figure ). While N-difluoromethylated products hold great promise as therapeutic targets, there is a scarcity of preparative methods. Consequently, designing robust protocols for both practical applications and fundamental research has become critically important. Historically, N-difluoromethylated compounds were produced by the insertion of a difluorocarbene into the N-H bond of N-heterocycles using various difluoromethylating agents. Generally, chlorodifluoromethane (Freon 22) is used as a key reagent to produce various -NCF2H motifs. Sometimes, bromo-and iododifluoromethane are also employed for the incorporation of CF2 carbene on Nheterocycles. However, such gaseous Freons are always avoided in the pharma industry, limiting the practical application of this reagent. Alternatively, other difluorocarbene precursors (e.g., ClCF2CO2Na, BrCF2CO2Et, TMSCF2Br, TMSCF3, etc.) have been developed. However, they are less pertinent in advancing N-difluoromethylation strategies. Further, depending on the type of N-heteroarene, difluoromethylation reagent, and reaction conditions, this method could provide exclusively either -NCF2H compounds and/or Ndifluoromethyl-2-pyridones (Figure ). Nevertheless, these approaches are restricted to simple N-heterocycles and have a quite narrow scope, as well as not applicable to latestage N-difluoromethylation with commercial drugs, despite the potential for broad application in modern drug discovery and medicinal chemistry. Late-stage functionalization (LSF) is a powerful tool and plays a vital role in advancing the drug optimization process. In fact, LSF in organofluorine chemistry is considered the most versatile for rapid modification of existing bioactive compounds to produce a wide range of new congeners that were previously unanticipated with potential significance in the pharmaceutical process. Considering this, the search for environmentally responsible, safer, and more reliable latestage N-difluoromethylation of structurally complex molecules (e.g., commercial drugs) exhibiting advanced functionalities with low-cost fluorinating agents under metal-free and ambient conditions remains a challenging but rewarding task.