In the crystal structure of compound 20, Roche's first generation reversible BTK inhibitor, the dimethylaniline moiety is found in close proximity to Tyr551 (Figure ). If the dimethylaniline was converted to a sulfonyl fluoride, reactivity with tyrosine could be possible. Roche's synthesis of 20, contains numerous C-C and C-N bond formation steps such as Suzuki coupling, SNAr, and Buchwald-Hartwig coupling. These bond forming steps would require that the sulfonyl fluoride be installed in the last step; however, this is complicated by the fact that carrying an aryl halide through multiple cross coupling steps would also not be feasible. SPGs therefore could be ideal for this application. 1. CuI (6 mol%), HMPNC (6 mol%), SES-Na (1.5 equiv), and K3PO4 (1 equiv), DMSO, 100 °C, 24h, 82%; 2. TFA:CH2Cl2 then, 23 (3 equiv), Pd(OAc)2 (9 mol%), XantPhos (10 mol%), Cs2CO3 (1.4 equiv), dioxane, 110 °C, 24 h, 63%; 3. NaBH4 (4 equiv), CH2Cl2:IPA, 5 °C, 1 h; 4. 22 (2 equiv), XphosPdG2 (5 mol%), K3PO4 (2 equiv), dioxane:water, 130 °C MW, 90 min, 57% (two steps); 5. TBAF (10 equiv), MeCN, 80 °C, 16 h, then selectfluor (4 equiv), 23 °C 2 h., 53 %. Amine 24 was chosen over the corresponding amide as a starting material due to availability of the material and a lack of reactivity of the amide when a para-withdrawing group is present (Figure ). SES sulfinate was easily coupled to amine 24 in 82% yield. In a manner similar to the process route, the amine was then coupled to 2-chloro-4-bromobenzaldehyde in the presence of palladium at 110 °C. No degradation of the sulfone was observed. The aryl chloride was then subsequently coupled to boronate ester 22 in moderate yield, and the aldehyde was reduced, again with no degradation of the sulfone. Finaly deprotection/fluorination of the SES group was accomplished with TBAF at 70 °C followed by selectfluor addition to yield SF 21. Compound 21 was tested in a BTK kinase glo assay and was found to have an initial IC50 of 23 µM (Figure ). The IC50 decreased as the preincubation time increased, indicating that compound 21 displays irreversible binding behavior. Further efforts are ongoing to elaborate the structure of 21 and elucidate the kinetics of its binding and reactivity.