RegioSQM consists of two Linux Bash scripts, one that automatically generates all MOPAC input files given a list of SMILES strings and one that extracts energies from the MOPAC output files, identifies the most reactive arene atom(s), and generates a 2D representation of the molecule and highlights the likely sit of reaction (see SI for examples). All scripts are made available on GitHub under the MIT open source license (see SI for details). The SMILES strings for all molecules are provided in SI and the results can thus be reproduced by installing the necessary software and running the two scripts. RegioSQM users needs to install RDKit, OpenBabel, and MOPAC2016 on a Linux computer or partition. RDKit and OpenBabel are open source packages, while MOPAC2016 is freely available to academic researchers. The computational cost per molecule depends on the size of the molecule and the number of energy minimizations, where the latter is a function of the number of rotateable bonds and the number of protonated isomers for a given molecule. The prediction of the most reactive site of a relatively small molecule like 3-(1-methyl-1H-imidazol-5-yl)pyridine (11) requires 2-3 minutes on a single CPU. A relatively large and flexible molecule like 6 requires 45-60 minutes on a single CPU. Each energy minimization is run on a single CPU, so the computation time is reduced almost linearly with the number of CPUs. For example by using 24 CPUs the time requirement for 6 is reduced to 2-3 minutes. The computational cost could be further reduced by using Merck molecular force field (MMFF) energy minimized structures and PM3 single point energy calculations. However, when applied to the Kruszyk dataset this resulted in 22 incorrect predictions using chloroform as a solvent and a 1 kcal/mol energy cutoff. (3, 8), or SO 2 Cl 2 in acetic acid (5). The green and red circles denote sites with standard free energies below 1 kcal/mol and 3 kcal/mol, respectively. The site of reaction is indicated by the black ring. The references to the experimental data can be found in Supplementary Information.