Nevertheless, the high prevalence of C-H bonds in organic compounds presents a substantial challenge in achieving site-specific functionalization. A principal strategy to circumvent this challenge leverages directing groups (DGs) within the substrate, which coordinate to the metal centre of the catalyst, thereby dictating the site of C-H activation. Common DGs include unsaturated heteroatoms and alkenyl groups, which have proven effective in guiding the regioselectivity of these reactions. Mechanistic studies with Palladium(II) acetate (Pd(OAc 2 )) as catalyst support the following mechanism of C-H activation, called concerted metal deprotonation (CMD). In a concerted mechanism, the Pd atom of the catalyst forms a sigma bond to an aromatic carbon, which increases the acidity of the adjacent (alpha) proton. This allows for the simultaneous abstraction of this proton by a carboxylate ligand. A directing group facilitates this step as it stabilizes the complex through coordination to the Pd atom, thereby lowering the reaction barrier. A depiction of the CMD step is shown in Figure . Upon C-H bond breaking, the Pd Figure . Overview of the predictive workflow: For the shown substrate on the left, three unique activation sites are possible (labelled H a-c ) with two directing groups, a pyridine (blue) and an oxime-ether (red). The latter has two potentially directing atoms, nitrogen and oxygen. The transition state structures of the rate-determining concerted metallation deprotonation (CMD) step are shown in the left column. In this work, we generate the structures of the proceeding palladacycle intermediate, shown in the right column. For each structure, we perform a conformer search followed by a low level optimization (GFN1-xTB) followed by an optional higher level single-point calculation (r 2 SCAN-3c). The lowest energy complex is selected and the corresponding reaction site is considered to be most likely to be activated, marked in green.