## 2 Results

Table 2: 5-Phenyl-1,3,4-oxadiazol derivatives (**4a-e**) obtained from cyclization of the corresponding \(N\),\(N\)’-diacylhydrazines. The best results were achieved by conducting the reaction using aprotic acetonitrile as a solvent, and a base in the form of sodium carbonate Na\({}_{2}\)CO\({}_{3}\), which also enhanced the elimination of inorganic compounds in the subsequent extraction process (Table 3, Entry 8). The reaction mixture was refluxed for about 8-12 h while the progress of the reaction was monitored by TLC. The use of microwave irradiation at this stage of the synthesis did not improve the reaction rate or the yield of final products. A series of products (7a-e) was thus obtained with a yield of 66-93% (Table 4, Entries 1-5). All products were purified by column chromatography using silica gel as stationary phase and ethyl acetate as the mobile one. \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Entry** & **n (a)** & **R** & **Product** & **Yield (\%)** \\ \hline
1 & 1 & 4-(Bromomethyl)phenyl & **7a** & 93 \\
2 & 1 & Bromomethyl & **7b** & 79 \\
3 & 2 & 2-Bromoethyl & **7c** & 69 \\
4 & 3 & 3-Bromopropyl & **7d** & 71 \\
5 & 4 & 4-Bromobutyl & **7e** & 66 \\ \hline \hline \end{tabular} \({}^{\text{(a)}}\) number of -CH\({}_{2}\)- groups.  
\end{table} 
Table 4: 5-Phenyl-1,3,4-oxadiazole derivatives containing an ester group (7a-e) formed by substitution with diisopropyl iminodiacetate (6). \begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Entry** & **Solvent** & **Base** & **Temperature** & **Conditions** & **Yield (\%)** \\ \hline
1 & DMF & TEA & 150 & \(\Delta\)t (a) & 49 \\
2 & Acetonitrile & TEA & 80 & \(\Delta\)t & 59 \\
4 & DMF & TEA & 150 & MW (b) & 51 \\
5 & Acetonitrile & TEA & 80 & MW & 65 \\
7 & DMF & Na\({}_{2}\)CO\({}_{3}\) & 150 & \(\Delta\)t & 77 \\
8 & Acetonitrile & Na\({}_{2}\)CO\({}_{3}\) & 80 & \(\Delta\)t & 93 \\
10 & DMF & Na\({}_{2}\)CO\({}_{3}\) & 150 & MW & 80 \\
11 & Acetonitrile & Na\({}_{2}\)CO\({}_{3}\) & 80 & MW & 93 \\ \hline \hline \end{tabular} \({}^{\text{(a)}}\) Conventional heating: \(\Delta\)t, oil bath, 70 \({}^{\circ}\)C; \({}^{\text{(b)}}\) MW heating: 100 W, 70 \({}^{\circ}\)C.  
\end{table} 
Table 3: Optimization of the reaction for 2-(4-bromomethyl)phenyl)-5-phenyl-1,3,4-oxadiazol (4a) and diisopropyl iminodiacetate (6). The last step of the synthesis was to carry out hydrolysis in order to restore the carboxyl group from the ester group. Typical acidic hydrolysis conducted in aqueous methanol solution in the presence of a catalytical amount of strong sulfuric acid H\({}_{2}\)SO\({}_{4}\) was ineffective; we observed only the partial cleavage of ester groups. Thus, we decided to use alkaline hydrolysis to carry out the reaction for unsymmetrical 1,3,4-oxadiazol derivatives (7a-e). For this purpose, we used sodium hydroxide NaOH in a molar ratio of 10:1 to the ester, and a mixture of water and methanol as a solvent (Scheme 5). Due to the risk of decomposition of the oxadiazole ring, the reaction mixture was heated in the range of 50-60 \({}^{\circ}\)C for about 30 min. The final crude products (8a-e) were purified by recrystallization from methanol, yielding pure 5-phenyl-1,3,4-oxadiazol derivatives bearing bis(carboxymethyl)amino groups in yields varying from 41% to 51% (Table 5, Entries 1-5). The structure of the products was confirmed by nuclear magnetic resonance spectroscopy (1H and 13C NMR) (see Supplementary Materials). Among the 5-phenyl-1,3,4-oxadiazol derivatives containing the ester group (7a-e) that have not yet been described in the literature, the most specific signals were a doublet at 1.26 ppm and a multiplet at 5.00 ppm for the isopropyl group. The signal, which occurred at 3.50-3.60 ppm, was in turn associated with the iminodiacetate residue. Other signals, which were characteristic of the benzene ring directly attached to the oxadiazole moiety, occurred in the range between 7.50 and 8.16 ppm.