With a predictive model for PTDI SNAr in hand, we next sought to validate it. In line with our objective of demonstrating general utility for this reaction, especially compared to traditional thioetherification approaches, we selected fourteen known targets (APIs, antibiotics, inhibitors, activators, fungicides, luminescence sensitizers, etc.) for target-oriented synthesis (Scheme 5). 1a,25 Each target was previously prepared using base-or TM mediated thioetherification reactions starting from a halogenated heterocycle and thiol (for literature preparation refer to reference 25 or see Scheme S10). In turn, we predicted if the reaction was viable using the developed decision tree model and then tested each reaction experimentally. In some cases, alternative building blocks were used due to challenges with sourcing. Alternative solvents (DMF or pyridine) were used when solubility or stability was an issue. For these fourteen targets, product formation is predicted for eleven of them. In comparison to the dataset, the validation reactions include both in-sample electrophiles and nucleophiles, as well as out-of-sample reactants (see visualization of the dataset including training, test, and validation information in SI, Data Science section). Remarkably, 10/14 TOS could be realized using PTDI SNAr including three reactions completely outof-sample, highlighting the strong performance of our model. In most cases, yield, safety, cost, sustainability, and simplicity was improved compared to literature reports. One unique target was azathioprine (P59), which has two possible PTDI SNAr disconnections (Scheme 5, disconnection prediction). 25a Notably, only one disconnection was successful, which was accurately predicted by the model. Combined, these results also expanded our substrate scope to include additional functional groups (carboxylic acid, sulfonamide, hemiaminal, tetrafluorophenyl) and electrophile classes (3-aminopyrimidine, 4-aminoquinazoline, guanine, adenine, and 6-aminouracil). Finally, a PTDI SNAr heterodimerization (traceless thiolation-thioetherification sequence) could be realized to afford P71, which represents a formal synthesis of SHP2 inhibitor This strategy obviates a 3-step sequence involving two TM mediated cross-coupling reactions and lays the foundation for rapid generation of complex thioethers from readily available halogenated heterocycles without requiring difficult to access thiophenols.