In contrast, the ratio of rejected routed in the case of +/-and +/+ database configurations was greater than 50%, whereas for other configurations this value remained below 1%. Interestingly, we only observed rejected routes at search depth 1 for database configurations if they involved multiproduct reactions. This behaviour can be explained by step 4 in the SynGPS route finding algorithm. After multiproduct and ambiguous reactions are removed in step 2), then many substances nodes are now leaf nodes and simultaneously not starting materials. Then since they are not marked as starting materials, the algorithm will remove those substances and also the corresponding reactions. Then often one can end up with a graph of only the target molecule remaining and no viable routes. This is explained in more detail elsewhere . Furthermore, we provide additional explanation as to how the SP-query influences the downstream synthesis route detection step in a non-deterministic manner in section "??" and in Figure S??, in SI.