Retrosynthesis example and the reaction rules. (a) Part of the retrosynthetic tracing steps is shown while tracing loop limit is 2. If a substrate is produced from a target, the reverse of applied reaction rule is enrolled with the substrate and target. For the first generation inner loop, 62 primary substrate candidates are identified; in addition, 4,917 secondary substrate candidates are identified for the second generation outer loop. Among the substrate candidates, 233 compounds are identified in the KEGG database. 2-ketoisovalerate is selected as a starting chemical and the two viable routes are shown in the dashed box at the bottom. The compound ids are from KEGG database. (b) Reaction rules presented in (a) are listed. Every rule is basically defined as forward direction. For example, C.1 is exactly the same as F.C.1 while B.C.1 is defined as the reverse reaction of F.C.1.