In this study, we introduce a quantum mechanics-based computational workflow specifically developed to predict regioselectivity in C-H functionalization reactions involving directing groups following the CMD mechanism. This workflow employs (semi-empirical) quantum calculations in a hierarchical way to predict regioselective outcomes, delivering results within seconds to minutes. For substrates that are expected to follow the electrophilic aromatic substitution mechanism without the influence of DGs, we refer the reader to previous work done by and Ree et al. . The there developed RegioSQM predicts the regioselectivity of reactions following the electrophilic aromatic substitution mechanism within seconds to minutes using a web interface or a Python module. Similarly to previous works , we focus on the CMD step, the first and commonly the rate-determining step in C-H activation, and consider the prototypical Pd(OAc) 2 catalyst. Using a selective approach, we calculate the relative energies of all relevant palladacycle intermediates using QM methods. We determine the relevant reaction sites either by a set of SMART patterns or by screening all possible reaction sites using the Merck molecular force field calculated ring strain energy, for details see subsection 4.3. This restriction allows us to rapidly predict the regioselectivity for C-H-activations via the CMD mechanism within seconds to minutes on standard consumer hardware. The workflow accommodates various directing groups (DGs) and reaction conditions and can be extended to include not only ortho-activations, as detailed in section 4.