Dynamic processes driven by non-covalent interactions (NCI), such as conformational exchange, molecular binding, and solvation, can strongly influence the rate constants of reactions with low activation barriers, especially at low temperatures. Examples of this may include hydrogen-atom-transfer (HAT) reactions involved in the oxidative stress of an active pharmaceutical ingredient (API). Here, we develop an automated workflow to generate HAT transition-state (TS) geometries for complex and flexible APIs and then systematically evaluate the influences of NCI on the free activation energies, based on the multi-conformational transition-state theory (MC-TST) within the framework of a multi-step reaction path. The two APIs studied: fesoterodine and imipramine, display considerable conformational complexity and have multiple ways of forming hydrogen bonds with the abstracting radical-a hydroxymethyl peroxyl radical. Our results underscore the significance of considering conformational exchange and multiple activation pathways in activation calculations. We also show that structural elements and NCIs outside the reaction site minimally influence TS core geometry and covalent activation barrier, although they more strongly affect reactant binding and consequently the overall activation barrier. We further propose a robust and economical fragment-based method to obtain overall activation barriers, by combining the covalent activation barrier calculated for a small molecular fragment with the binding free energy calculated for the whole molecule.