About one-eighth of the USPTO reaction data are composite reactions. It is of interest, therefore, to investigate whether their ITS graphs can be derived as the consecutive application of two or more single-step reactions. To this end, we used the 169 single-step rules from Q complete and combined them to more than 16,000 two-step rules. Somewhat surprisingly, only three of the rules in the template library are composites of rules for single-step reactions observed in the same data. These three cases are shown in Fig S4 . We suspect that the direct rule composition fails because (a) the composite reactions take place in different parts of the molecule, and hence there is little or no overlap of the reaction centers of the individual steps, and (b) the templates used for the consecutive steps may involve inconsistent extended contexts. Given a library of patterns for single-step reactions, it is also possible to ask whether a given reaction can be explained by a sequence of single-step reactions. In contrast to rule composition, this approach does not expect a large overlap of the reaction centers.