*3.1. Synthesis*

In the present article, we report the successful synthesis of new furan hybrid molecules with different N-containing compounds, such as pyrrolidine **5a**, piperidine **5b**, 1,2,3,4 tetrahydroquinoline **5c,** and 1,2,3,4-tetrahydroisoquinoline **5d** (Figure 3), as shown in Scheme 1. In Scheme 1, we report the successful synthesis of new furan hybrid molecules with various N-containing compounds, such as pyrrolidine **5a**, piperidine **5b**, 1,2,3,4 tetrahydroquinoline **5c**, and 1,2,3,4-tetrahydroisoquinoline **5d**.

**Scheme 1.** Synthesis of hybrid molecules **7a–d**.

For this purpose, furan-2-carbonyl chloride 6 is added to a solution of the corresponding amine 5 (1 mmol) in dichloromethane. The reaction mixture is stirred for a further 10 min and then an excess of triethylamine (1.5 mmol) is carefully added dropwise. The secondary amines **5a–d** were fully acylated for the next 30 min (TLC).

The reaction generally works in high yields. All yields are above 90%, as can be seen in the experimental section. All compounds are fully characterized by UV, 1H-, and 13C-NMR and HRMS spectra.

**Figure 3.** Secondary amines took place in the acylation reaction.

All obtained compounds **7a**, **7c**, and **7d** are new compounds. Compound **7b**, the hybrid molecule of furan **6** and piperidine **5b**, has been previously reported [20–22].

Comparing the 1H-NMR data for compound **7b** obtained by us with the same reported by Ramkumar and Chandrasekaran can be seen the match in the spectra [23]. 1H NMR (CDCl3, 400 MHz): δ = 7.34 (d, *J* = 0.8 Hz, 1 H, ArH), 6.79 (dd, *J*<sup>1</sup> = 3.4 Hz, *J*<sup>2</sup> = 0.8 Hz, 1 H, ArH), 6.31–6.33 (m, 1 H, ArH), 3.55 (s, 4 H, CH2), 1.48–1.55 (m, 6H, CH2).

A broadened singlet is observed for the methylene groups on both sides of the nitrogen atom at 3.55 ppm by them and at 3.66 ppm by us. The protons from the furan core also match, being slightly shifted (from 7.34 ppm to 7.40 ppm, from 6.79 ppm to 6.85 ppm, and from 6.31–6.33 ppm to 6.39 ppm). The rest of the signals from the hydrogenated nitrogen-containing core appear as one multiplet for six protons in the interval from 1.48 to 1.55 (m, 6H, CH2) in the Ramkumar 1H-NMR spectra. In the 1H-NMR spectrum obtained by us, two multiplets stand out from 1.65–1.60 for two protons and from 1.59–1.54 for four protons, respectively. Based on the coincidence of all of these data, it can be asserted without doubt that we have succeed in obtaining the same compound.

The four compounds have been given the names hybrid 1 (**H1**)- **7a**, hybrid 2 (**H2**)- **7b**, hybrid 3 (**H3**)- **7c**, and hybrid 4 (**H4**)- **7d** for biological evaluation research.

The newly synthesized compounds (**H1–4**) differ mainly in the N-containing heterocycles. In order to investigate the structure of the new hybrid molecules, we used mass spectrometry. We used ESI in positive ionization mode. The fragmentation of the furan derivatives **H1–4** proceeds according to the mechanism presented in Scheme 2.

**Scheme 2.** Possible fragmentation pathways of compounds **H1–4** under ESI-MS/MS conditions. **1-H1**—fragmentation of pyrrolidine-furan **H1**. **1-H2**—fragmentation of **H2** compounds. **1-H3**—fragmentation of compounds **H3**. **1-H4**—fragmentation of compounds **H4**. **H3** and **H4** can be considered derivatives of piperidine, since its structure contains a piperidine ring (ring B)—benzo[b]piperidine (1,2,3,4 tetrahydroquinoline skeleton) for **H3** and benzo[c]piperidine (1,2,3,4 tetrahydroisoquinoline core) for **H4**.

The structural fragment that connects the furan (ring A) and heterocyclic (ring B) rings in furan derivatives is C-C(O)-N. Several fragmentation pathways originate from here. The main fragmentation pathways of compounds **H1–4** involve the cleavage of C-N (path 1), C-C (path 2) bonds, and retro cyclization of heteroring B with a cleavage of bonds at position a/d for **H1**, b/f for **H2**, c/f, c/e for **H3**, and a/f for **H4** (Scheme 2). The cleavage of the C-N bond (pathway 1) provides important information about the structure of the heterocyclic ring (*m*/*z* 70, 84, 132) and the furan ion at *m*/*z* 95. The structure of compounds **H1** and **H2** does not contain fused rings. Ring B, in their structure, is respectively pyrrolidine and piperidine. The retro cyclization of ring B is associated with the cleavage of the a/d bonds for **H1,** and b/f for **H4**, resulting in the same ion with *m*/*z* 124 (Figures S14 and S16).

The structure of compounds **H3** and **H4** contain fused rings: benzo[b]piperidine (1,2,3,4 tetrahydroquinoline nuclei) and benzo[c]piperidine (1,2,3,4 tetrahydroisoquinoline nuclei), respectively.

In the presence of an additional benzene nucleus during fragmentation, the formation of additional characteristic ions is observed, by which the isomers **H3** and **H4** are clearly distinguished. For both isomers, the ions *m*/*z* 132 (path 1) and *m*/*z* 160 (path 2) were obtained. Additional fragmentation pathways depend on the position of the nitrogen atom in the structure of compounds **H3** and **H4** (Scheme 2, Figures S18 and S20). For compound **H3**, which contains benzo[b]piperidine in its structure, the fragmentation proceeds in other ways, different from its isomer. Under MS conditions, a neutral CO molecule (28 au) is lost from the structure of compound **H3**, where a retro cyclization follows and leads to the *m*/*z* 172 ion. A molecule of H2O (18 au) is lost from the same ion and an ion of *m*/*z* 154 is obtained (Scheme 2, Figure S18). These two ions are not produced in the fragmentation of compound **H4**. Additionally, the fragmentation of the *m*/*z* 160 ions produced an *m*/*z* 118 ion. In fact, ions *m*/*z* 118, *m*/*z* 154 and *m*/*z* 172 are characteristic of compound **H3** (Figure S18), while compound **H4** is ion *m*/*z* 117, which is the result of the retro cyclization of benzo[c]piperidine in position a/f (Scheme 2, Figure S20).
