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We detail here distinctive departures from lead classical cholinesterase re‐activators, the pyridinium aldoximes, to achieve rapid CNS penetration and reactivation of AChE in the CNS (brain and spinal cord). Such reactivation is consistent with these non‐canonical re‐activators enhancing survival parameters in both mice and macaques following exposure to organophosphates. Thus, the ideal cholinesterase...