Figure : The substituents and positions considered in this study. Substitutions at position 8 is not considered, since removal of one cyano group has been shown to cause problems with the back reaction. The substituents are separated into electron withdrawing groups (EWG) and electron donating groups (EDG). There are a total of 42 different substituents counting hydrogen and phenyl resulting in more than 230 billion molecules (slightly less than 42 7 due to permutational symmetry). This paper is organized as follows. First we demonstrate the utility of semiempirical quantum mechanics (SQM) by screening all 35,588 singly and doubly substituted DHAs. Then we use a simple linear regression model and a gradient boosting decision tree (GBDT) trained on SQM data, to screen all 230 billion molecules. Finally, the linear regression model is then used to demonstrate that the best molecules predicted by that model can be found efficiently using a genetic algorithm (GA), suggesting that a GA could be used to screen even larger chemical spaces, perhaps using SQM directly rather than machine learning.