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Small molecule solutions to many contemporary societal challenges await discovery, but the artisanal and manual process via which this class of chemical matter is typically accessed limits the discovery of new functions. Automated assembly of (N‐methyl iminodiacetic acid) MIDA or (tetramethyl N‐methyl iminodiacetic acid) TIDA boronate building blocks via iterative C─C bond formation, an approach we call “block chemistry”, alternatively enables generalized and automated preparation of many different types of small molecules in a modular fashion. But in its current form, this engine cannot also leverage nitrogen atoms as iteration handles. Here, we disclose a new iteration‐enabling group, CbzT (p‐TIDA boronate‐substituted carboxybenzyl), that reversibly attenuates the reactivity of nitrogen atoms and enables generalized catch‐and‐release purification. CbzT is leveraged to achieve the automated modular synthesis of Imatinib (Gleevec), an archetypical clinically approved kinase inhibitor, in which building blocks are iteratively linked by both N─C and C─C bonds. This work substantially expands the types of small molecules that can be iteratively assembled in an automated modular fashion. It also advances the concept of intentionally developing chemistry that machines can do. 

Abstract Multifunctional organoboron compounds increasingly enable the simple generation of complex, Csp³‐rich small molecules. The ability of boron‐containing functional groups to modify the reactivity of α‐radicals has also enabled a myriad of chemical reactions. Boronic esters with vacant p‐orbitals have a significant stabilizing effect on α‐radicals due to delocalization of spin density into the empty orbital. The effect of coordinatively saturated derivatives, such as N‐methyliminodiacetic acid (MIDA) boronates and counterparts, remains less clear. Herein, we demonstrate that coordinatively saturated MIDA and TIDA boronates stabilize secondary alkyl α‐radicals via σ_B‐Nhyperconjugation in a manner that allows site‐selective C−H bromination. DFT calculated radical stabilization energies and spin density maps as well as LED NMR kinetic analysis of photochemical bromination rates of different boronic esters further these findings. This work clarifies that the α‐radical stabilizing effect of boronic esters does not only proceed via delocalization of radical character into vacant boron p‐orbitals, but that hyperconjugation of tetrahedral boron‐containing functional groups and their ligand electron delocalizing ability also play a critical role. These findings establish boron ligands as a useful dial for tuning reactivity at the α‐carbon.