On the other hand, high amcd values indicated alchemical transmutations that cannot be realized easily, such as scaffold-hopping changes. Note that the RXNMapper assigned corresponding atoms mostly in a correct manner even for pairs giving high amcd values. For example, tetrabenazine is paired with hydrocodone by seven of the eight molecule fingerprints used for pairing. The transformation features an exotic double-ring formation accompanied by a reshuffling of the 23 atoms (Figure ). A similarly exotic alchemical change relates afatinib with osimertinib, an analog matched by all eight fingerprints used for pairing (Figure ). In the EGFR set, a double linker modification preserving activity relates CHEMBL469997 to CHEMBL181275, whereby the benzyl ether linker is obtained by combining an oxygen atom of the sulfone with a methylene group of the aminobutanol second linker group (Figure ). In another scaffold hopping change between CHEMBL469997 and CHEMBL181275, an aniline substituent is incorporated into the adjacent bicyclic system to form a condensed tricyclic heteroaromatic group, resulting in an interesting activity increase (Figure ).