We consider 42 common substituents (including H) at seven different positions, as shown in Figure , resulting in more than 230 billion molecules (slightly less than 42 7 due to permutational symmetry). To our knowledge this compound library is the largest library considered thus far. For example, it is three orders of magnitude larger than the "ultra-large" library of 170 million compounds used by Shoichet, Irwin, and coworkers. While there has been a few virtual screening studies of thousands of reaction energies, corresponding screening studies of barrier heights typically involve less than 100 molecules (e.g. ). Thus, screening barrier heights for billions or even thousands of molecules represents a fundamental challenge.