In conclusion, we have extensively demonstrated the powerful potential of oxetane and azetidine sulfonyl fluorides to access broad chemical space of significant medicinal relevance. Divergent routes towards OSF and ASF reagents have been developed. 11 oxetane analogues of marketed drugs and bioactive compounds have been synthesized using these reagents to demonstrate their synthetic utility in a drug discovery context. OSFs and ASFs have been shown to be compatible with a broad range of nucleophile types, including primary and secondary amines, anilines, N-H azoles, sulfoximines, sulfonimidamides and phosphorous reagents to enable merging of these valuable pharmacophores. The SuFEx reaction pathway of the OSFs can now be fully exploited to access novel oxetano-S(VI) motifs. These novel motifs provide new design options for medicinal chemistry that may find use as valuable novel bioisosteres or replacements groups for medicinal chemists. We propose these oxetane and azetidine structures as much broader valuable chemical motifs beyond bioisosteres. These novel combinations of polar functional groups are likely to confer favorable properties in their own right, and access new chemical and intellectual property space. Moreover, the OSF and ASF reagents are readily reacted with functional molecules, enabling possible applications in the linkerology of PROTAC degraders or in molecular glues. We expect this work to highlight the value of these reagents in discovery for facile diversification and offer new opportunities in drug discovery.