Establishing the Heteroaryl Library. Parent heteroarene cores were selected based on commercially available unsubstituted heteroaromatic compounds with five-and sixmembered rings, as well as 5,6-and 6,6-fused ring systems from the Reaxys® database (Fig. ). Only compounds with C, N, O, and S atoms in the heteroaromatic rings were included. A total of 238 unsubstituted parent heteroarenes were selected, including 23 five-membered heteroarenes, 9 six-membered heteroarenes, 157 5,6-fused rings, 47 6,6-fused rings, plus benzene and naphthalene. This results in 812 regioisomers of unsubstituted heteroaryl groups. Next, each unsubstituted heteroaryl group was functionalized using the RDKit 33 "ReactionFromSmarts" function to substitute a C-H bond on the heteroaromatic ring with a substituent to generate mono-substituted heteroaryl groups. The substituents used include 12 common electron-donating and electron-withdrawing groups-NMe₂, NH₂, OH, OMe, Me, TMS, F, Cl, Br, Ac, CN, and NO₂. This resulted in approximately 31,500 unique heteroaryl groups (Fig. ). To calculate the steric and electronic properties of each heteroaryl group (ArHet), SMILES strings of three compounds were used, including ArHet-H, ArHet-CO2H, and ArHet-CO2 -. The RDKit Experimental-Torsion Distance Geometry (ETDG) method was used to generate 3D structures as Gaussian 16 input files for subsequent DFT calculations.