The next case study was selected from industry -Salmeterol is an important drug for Asthma treatment. Salmeterol can be produced via a nucleophilic substitution (SN2) reaction (Figure ). Due to the large carbon chain within the molecule, the task of identifying the correct disconnection site becomes more challenging. The node (atom) weight is shown in Figure . For this substitution reaction, the stabilisation arises from the stronger amine-carbon bond compared to the starting materials. As seen before, the vanilla Transformer fails to identify the amine group, instead, it gives importance to individual carbons along the carbon chain (subplot a). Conversely, the masked attention mechanism focuses on the amine group, but it still faces a similar challenge of attending to irrelevant atoms within the molecule (subplot b). Surprisingly, neither of the two GNN models was capable of predicting the correct reaction centre. The EGAT model predicts the attachment of a benzene ring at the end of the chain (subplot e). Often, substituted benzene rings are utilised as early building blocks for pharmaceuticals as they have a rich chemistry for substitution and tend to remain inert through further functionalisation. With this in mind, many experienced synthetic chemists would likely not classify this as a reasonable bond disconnection. The GNNExplainer struggles to identify an important subgraph for this prediction with a fidelity of 0 (Table ). An explanation for this prediction can therefore not be provided with full confidence, as a fidelity of 0 indicates uncertainty within the returned subgraph GS by the GNNExplainer. The D-MPNN proposes to react on the secondary alcohol (subplot f). This is a viable synthesis route as shown in Figure . The epoxide can be nucleophilically attacked by the amine . For this reaction to happen, the epoxide needs to be fixed in orientation for the correct alcohol to be released. Thus, the greatest challenge lies in maintaining exact stereocontrol. This reaction proceeds generally due to the release of steric strain on the epoxide. The model identifies the amine group and the adjacent carbon as most important to the reaction (subplot d). Both of these groups are indeed important to the reaction; however, it is likely that the model cannot appreciate the presence of a strained 3-membered ring. This reaction centre was probably selected by the model due to the concentrated presence of heteroatoms, rather than its chemical understanding. This hypothesis is further supported by querying the GNNExplainer for the SN2 reaction (ESI Section S4.3). It is observed that both GNN models cannot provide adequate reasoning for selecting the SN2, similar to the attention models. This shows that when the carbon chain is long and there are multiple potential disconnection sites, the graph models struggle to identify the correct chemistry.