The methyl-and chloro-substituted phenols were accessed from commercially available nitriles by cobalt (II) facilitated borahydride reduction, while the fluoro-, methoxy-, and trifluromethylsubstituted phenols required a two-step synthesis from the aldehyde by hydroxamate formation and reduction using zinc dust (Scheme 1). The pKas of the para-phenols (1, 4-8) and meta-phenols (2, 9-13) were determined from their 1 H-NMR spectra (Figure ). It has been previously determined that the pKa of a wide range of substituted phenols in water can be accurately calculated from the chemical shift of the phenolic proton in d6-DMSO. Using this relationship, the pKa (H2O) of the phenolic thieno [2,3d]pyrimidines (1-2, 4-13) varied over 2 log units from 8.30 to 10.43 (Table ). Notably, the paraphenol (1) and meta-phenol (2) had nearly identical pKa indicating that effect of the benzylamine substituent was essentially neutral. A plot of the Hammett substituent constant against pKa (H2O) showed a correlation with R 2 = 0.99 (Figure ), indicating that the inductive and mesomeric effect of the R 3 substituent was the primary regulator of phenol acidity in both series. In the para-phenol series (4-8) the fluoro-substituted analog (6) showed ~5-fold improved activity in the ERa LiSA compared to the unsubstituted phenol (1) (Table ). However, the other analogs had weaker activity, with the overall rank order being F > H > Cl > CF3 > OCH3 > CH3.