In the new sub-route proposed in the previous section, a critical step for the formation of scaffold of S-Zanubrutinib was a ring-closing transformation. As shown in Fig. , the target transformation involved bond formation between the alpha-carbon of the aldehyde group and the amine group. After carefully tuning the selection of substructures (as highlighted in Fig. ), three analogue reactions were found, encouraging further validation in the lab. The last chemical transformation to explore was the removal of hydroxyl group on the bicyclic ring, giving rise to the final product. To our surprise, only one analogue route was found in which the chemical transformation sharing the same substructures as highlighted in Fig. . This sub-route was in line with general chemical knowledge, i.e., a dehydration step followed by a hydrogenation process. The hydrogenation part was relatively easier to carry out in practice compared to dehydration. Therefore, a single step dehydration reaction with substructure highlighted at the bottom of Fig. was searched leading to another reaction as shown in Fig. . Both dehydration reactions happened at a high steric hindrance site. We hypothesised that solid acid catalysts could be applicable to this substrate, since there are no bulky groups around the hydroxyl group. Nevertheless, for both analogue dehydration reactions, the adjacent nitrogen was a tertiary amine instead of secondary amine, and the bonding pattern of carbon linking to the hydroxyl group was also different (i.e., tertiary vs quaternary). Therefore, feasibility of the proposed sub-route still needs to be verified.