S1 Supporting Information: Expanding the Armory: Predicting and Tuning Covalent Warhead Reactivity. Richard Lonsdale, Jonathan Burgess, Nicola Colclough, Nichola Davies, Eva M. Lenz, Alexandra L. Orton and Richard A. Ward* Chemistry and DMPK, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK * Richard.A.Ward@astrazeneca.com Contents Table S1. GSH t 1/2 data for compounds 1, 3 and 8-52. ......................................................................... S3 Table S2. Experimental pK a values for Compounds 3a, 8a-17a, 19a, 25a-34a, 37a, 55a-57a. ........... S4 Table S3. GSH t 1/2 and QM data for compounds 56-86 containing a 2-chloroacetamide covalent warhead. ................................................................................................................................................ S5 Table S4. QM energies of compounds (E C ), Me-S adducts (E Add ), transition states (E TS ) and LUMO (E LUMO ) for 8-23. All energies calculated in Hartree at the M06-2X/6-31+G(d,p)-IEF-PCM level. .... S6 Figure S1. Geometries and energies of (a) transition state and (b) adduct formed during model reaction of 12 with MeS-. Calculated at the M06-2X/6-31+G(d,p)-IEF-PCM level relative to separate reactants. ............................................................................................................................................... S7 Figure S2. Plot of GSH half-life of aryl acrylamide compounds 8-23 against LUMO energy. Energies were calculated at the M06-2X/6-31+G(d,p)-IEF-PCM level. ............................................................. S7 Figure S3. Plot of GSH half-life of aryl acrylamide compounds 3 and 8-52 against LUMO energy. Energies were calculated at the M06-2X/6-31+G(d,p)-IEF-PCM level. .............................................. S8 Figure S4. Lowest unoccupied molecular orbital (LUMO) of 24......................................................... S8 Figure S5. Plot of GSH t 1/2 against 13 C NMR chemical shift (in ppm) for compounds 8-17 and 19. ... S9 Figure S6. Plot of GSH t 1/2 against 1 H NMR chemical shift (in ppm) for compounds 8-17 and 19. .... S9 Figure S7. Plot of GSH t1/2 against adduct formation energy for compounds 8-17 and 19. Energies were calculated at the M06-2X/6-31+G(d,p)-IEF-PCM level. ........................................................... S10 Figure S8. Plot of measured against calculated 13 C chemical shifts for C b of compounds 8-17 and 19. ............................................................................................................................................................ S10