*3.2. Mass Analysis*

Compounds **3a**–**d** have a common pharmacophore—ketoprofen. The only difference in these compounds is in the *N*-containing heterocyclic rings—pyrrolidine, piperidine, benzo[*b*]piperidine, and benzo[*c*]piperidine. We used mass spectrometry to probe their structure. The heterocyclic rings and ketoprofen are linked by a common structural fragment N-C(=O)-C. Under MS/MS conditions, three pathways of molecular ion fragmentation were established. The main fragmentation pathways of compounds **3a**–**d** include the cleavage of the N–C (path 1), C–C (path 2) bonds and the cleavage of the structural fragment C–C(=O)–C (path 3) connecting the two aromatic cores (Scheme 2).

**Scheme 2.** General fragmentation scheme of ketoprofen derivatives **3a**–**d**.

Cleavage of the N-C bond (path 1) provides important information about the structure of the heterocyclic ring (*m*/*z* 72, 86, 134) (Scheme 2, Figures S14, S16, S18 and S20). Cleavage of the C-C bond (path 2) leads to a resonance-stable aromatic cation (*m*/*z* 209) characteristic of ketoprofen, established in our previous studies (Scheme 2) [42]. Under ESI-MS conditions, the same ion undergoes loss of the CH3 radical to yield an ion with *m*/*z* 194. Furthermore, the fragment ion with *m*/*z* 131 results from the retrocyclization of the resonance cation *m*/*z* 209 (Scheme 2). Fragmentation carried out in route 3 gave an *m*/*z* 105 ion resulting from

cleavage of the diphenyl ketone fragment (Scheme 2). Compounds **3c** and **3d** are isomers and have ion *m*/*z* 370 (Figures S17 and S19). In the fragmentation between the two isomers, a significant difference is observed, which is mainly expressed in the splitting of ion *m*/*z* 134 (Figures S18 and S20).

It is the product ion of both isomers, i.e., it corresponds to benzo[*b*]piperidine (1,2,3,4 tetrahydroquinoline nucleus) and benzo[*c*]piperidine (1,2,3,4 tetrahydroisoquinoline nucleus). In the MS/MS experiment, only benzo[*c*]piperidine was found to fragment to the characteristic ion with *m*/*z* 117 (Figure S20) [43]. Furthermore, a difference in the *m*/*z* 209 and *m*/*z* 105 ion intensities was observed in favor of benzo[*b*]piperidine, with the ratio between the two intensities being 2.17 and 1.45 for 209 and 105, respectively (Figures S18 and S20).
