Development of a selective and scalable N1-indazole alkylation

N1-Alkyl indazoles are a ubiquitous and privileged motif within medicinal chemistry, yet methods to selectively furnish N1-alkyl indazoles with simple alkyl side chains remain sparse. Herein, negative data from high-throughput experimentation (HTE) enabled a confident pivot of resource from continued optimisation to the development of an alternative reaction. This workflow culminated in a methodology for the synthesis of N1-alkyl indazoles. The procedure is highly selective for N1-alkylation, practical, and broad in scope, with no N2-alkyl products detected at completion. Mechanistic understandings were consistent with attributing the high selectivity to thermodynamic control. Additional data-driven process development led to this reaction being safely demonstrated on a 100 g scale, with potential for further scale up. This study highlights pragmatic principles followed to develop a necessitated methodology, suitable for large scale manufacture.