Substituted tetrazoles as multipurpose screening compounds

Abstract

Tetrazoles are small functional heterocycles that are suited to serve simultaneously as aromatic platform for diversity and as functional interaction motif. Furthermore, the tetrazole ring and its deprotonated tetrazolate counterpart are metal ion complexing ligands that possess a rich variety of binding and bridging modes. We recently demonstrated that fragments containing the tetrazole moiety and a metal chelating hydrazide group are well suited to discover selective screening hits with high ligand efficiency for a given protein target. Here, we report the synthesis and characterization of new polydentate tetrazole-containing screening compounds and their synthetic precursors as well as their deposition in a multipurpose screening library in the frame of the EU-OPENSCREEN network. The pure and well-characterized screening compounds could be useful to aid drug discovery programs for multiple or hitherto undruggable targets by enclosure of under-represented tetrazole derivatives.

Graphical Abstract

Experimental section

General. All starting materials (aldehydes and ketones, halogenated acid esters, aromatic heterocycles) and solvents, unless otherwise noted, were obtained from Sigma–Aldrich, VWR or ABCR GmbH & Co. KG, and used without further purification. Column chromatography was done on silica gel from Macherey-Nagel (particle size 50–100 $\upmu$m, 140–270 mesh ASTM). Melting points were determined using a hot stage microscope by Kofler PHMK 81/3035 ‘Boëtius’(VEB Wägetechnik Rapido) with 16-fold amplification or Büchi melting point apparatus M-565, and are uncorrected. Microwave-assisted synthesis was performed using a Discover LabMate (‘closed vessel’ mode, 10 mL total capacity vessel, temperature control via IR sensor) synthesizer from CEM. The parameter ‘PowerMax’ indicates a permanent radiation of microwaves simultaneously to intense cooling. Acylhydrazones are subject to isomerism at the amide-moiety. Nuclear magnetic resonance (NMR) spectra were recorded using an Avance III instrument with Ultrashield 400 ($^{1}$H: 400.2 MHz, $^{13}$C: 100.6 MHz) from Bruker at $25 \ {^{\circ }}$C with tetramethylsilane (TMS) as internal standard, using ppm scale. Abbreviations are defined as follows: s = singlet, d = doublet, t = triplet, q = quartet, qu = quintet. High resolution mass spectra (HRMS) were obtained after high performance liquid chromatography (HPLC) with a mass spectrometer (LC-IT-TOF) from Shimadzu based on a deviance tolerance limit $\le$ 5 ppm. Mid-infrared spectra were recorded on a Nicolet IR200 FT-IR from Thermo Electron Corporation with diamond ATR accessory.

General procedure A for the synthesis of compounds 46–48: Sodium cyanide (1.5 eq) was suspended in DMSO at room temperature. Subsequently, the appropriate chlorinated acid ester (1.0 eq) was added dropwise while the temperature of the resulting mixture was kept at $40 \ {^{\circ }}$C. The suspension was then heated to $50\ {^{\circ }}$C for 3 h, and stirred for another 15 h at room temperature. Sodium hydroxide was added, and the reaction mixture was diluted with water until all solids had dissolved. The solution was exhaustively extracted with diethyl ether, dried over Na$_{2}$SO$_{4}$, and concentrated under reduced pressure to obtain a colorless oil.

Ethyl 2-cyanoacetate (46): This compound is commercially available.

Ethyl 3-cyanopropanoate (47): Following general procedure A, applying 20.0 g halogenated ester 44 (1.0 eq, 150 mmol), 10.5 g sodium cyanide (1.5 eq, 220 mmol), 45 mL DMSO, and 1.50 g sodium hydroxide. Yield: 15.1 g (119 mmol, 79%); colorless oil; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.20 (t, 3H, $J~=~$7.1 Hz), 2.68 (s, 4H), 4.11 (q, 2H, J = 7.1 Hz,); $^{13}$C-NMR (DMSO-$d_{6})$: $\delta$ = 12.4, 14.0, 29.2, 60.5, 119.8, 170.6; HRMS (ESI, $\hbox {m}/z)$ $[M +\hbox {H}^{+}]$: calcd for C$_{6}$H$_{10}$NO$_{2}^{+}$: 128.0712, found: 128.0701; IR ($\tilde{\nu }$): 1729 (s), 2250 (w) $\hbox {cm}^{-1}$.

Ethyl 4-cyanobutanoate (48): Following general procedure A, applying 50.0 g halogenated ester 45 (1.0 eq, 332 mmol), 23.9 g sodium cyanide (1.5 eq, 498 mmol), 113 mL DMSO, and 3.00 g sodium hydroxide. Yield: 38.9 g (276 mmol, 83%); colorless oil; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.19 (t, 3H, $J = 7.1$ Hz,), 1.81 (qu, 2H, J = 7.3 Hz), 2.40 (t, 2H, J = 7.3 Hz), 2.53 (t, 2H, J = 7.3 Hz), 4.07 (q, 2H, J = 7.1 Hz); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.0, 15.6, 20.5, 32.2, 60.0, 120.2, 171.8; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{7}$H$_{11}$NO$_{2}^{+}$: 142.0868, found: 142.0869; IR ($\nu )$: 1727 (s), 2245 (w) cm$^{-1}$.

General procedure B for the synthesis of compounds 49–51: The appropriate cyano acid ester (1.0 eq), sodium azide (1.1 eq), and ammonium chloride (0.2 eq) were suspended in DMF. The reaction mixture was heated to 95–125 ${^{\circ }}$C for 8–24 h. Subsequently the solvent was removed under reduced pressure. The resulting residue was diluted with water and adjusted to pH 1 with concentrated hydrochloric acid (CAUTION: Release of HN$_{3}$!). The desired product was obtained by precipitation or extraction.

Ethyl 2-(1 H -tetrazol-5-yl)acetate (49): Following general procedure B, applying 23.0 g cyano acid ester 46 (1.0 eq, 200 mmol), 14.3 g sodium azide (1.1 eq, 220 mmol), 2.30 g ammonium chloride (0.2 eq, 43 mmol), 220 mL DMF, and 220 mL water for 8 h at $95 \ {^{\circ }}$C. The reaction was worked up by filtering off the precipitate, followed by recrystallization from propan-2-ol. Yield: 17.6 g (113 mmol, 56%); colorless solid; mp: $125\ {^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.21 (t, 3H, $J~=~$7.0 Hz), 4.12–4.17 (q, 2H, J = 7.0 Hz), 4.17 (s, 2H), 16.34 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.0, 29.5, 61.3, 150.4, 167.7; HRMS (ESI,m / z) [M+H$^{+}$]: calcd for C$_{5}$H$_{9}$N$_{4}$O$_{2}^{+}$: 157.0726, found: 157.0727; IR ($\tilde{\nu }$): 1741 (s) $\hbox {cm}^{-1}$.

Ethyl 3-(1 H -tetrazol-5-yl)propanoate (50): Following general procedure B, applying 17.8 g cyano acid ester 47 (1.0 eq, 140 mmol), 10.0 g sodium azide (1.1 eq, 154 mmol), 1.80 g ammonium chloride (0.2 eq, 34 mmol), 70 mL DMF, and 70 mL water for 8 h at $105 \ {^{\circ }}$C. The crude solution was worked up by diluting with brine, and extracting exhaustively with ethyl acetate, drying the combined organic phases over Na$_{2}$SO$_{4}$, and concentrating under reduced pressure. The resulting colorless oil was cooled to −18 ${^{\circ }}$C, filtering off the resulting precipitate, and washing with diethyl ether gave compound 50. Yield: 9.47 g (55.7 mmol, 42%); colorless solid; mp: $84-85\ {^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.16 (t, 3H, $J~=~$7.0 Hz), 2.83 (t, 2H, J = 7.2 Hz), 3.12 (t, 2H, J = 7.2 Hz), 4.06 (q, 2H, J = 7.0 H), 16.04 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.0, 18.5, 30.7, 60.2, 155.2, 171.4; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{6}$H$_{11}$N$_{4}$O$_{2}^{+}$: 171.0882, found: 171.0878; IR ($\nu$): 1719 (s) cm$^{-1}$.

Ethyl 4-(1 H -tetrazol-5-yl)butanoate (51): Following general procedure B, applying 38.0 g cyano acid ester 48 (1.0 eq, 270 mmol), 19.3 g sodium azide (1.1 eq, 297 mmol), 3.80 g ammonium chloride (0.2 eq, 72 mmol), 135 mL DMF, and 135 mL water for 24 h at $125\ {^{\circ }}$C. To work up the solution, it was exhaustively extracted with ethyl acetate, the collected organic phases dried over Na$_{2}$SO$_{4}$, and concentrated under reduced pressure. The orange oil was cooled to −18 ${^{\circ }}$C, filtering off the resulting precipitate, and recrystallization from diethyl ether gave compound 51. Yield: 7.50 g (40.8 mmol, 15%); colorless solid; mp: 49–52 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.18 (t, 3H, $J~=~$7.1 Hz), 1.96 (qu, 2H, J = 7.4 Hz), 2.39 (t, 2H, J = 7.4 Hz), 2.92 (t, 2H, J = 7.4 Hz), 4.06 (q, 2H, J = 7.1 Hz), 16.04 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.0, 21.9, 22.2, 32.4, 59.8, 155.4, 172.2; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{7}$H$_{13}$N$_{4}$O$_{2}^{+}$: 185.1039, found: 185.1030; IR ($\nu$): 1723 (s) cm$^{-1}$.

General procedure C for the synthesis of compounds 1, 52, and 53: The appropriate tetrazole acid ester (1.0 eq), and hydrazine hydrate solution (80% 50% hydrazine, 3.0–12.3 eq) were heated by microwave irradiation ($p_{\mathrm{max}}$ = 17 bar, $\vartheta _{\mathrm{max}}$ = $115 \ {^{\circ }}$C, $p_{\mathrm{max}}$ = 200 W, ramp time = 1 min, hold time = 5 min, continuous irradiation and stirring).

2-(1 H -Tetrazol-5-yl)acetic acid hydrazide (1): Following general procedure C, applying 16.6 g tetrazole acid ester 49 (1.0 eq, 106 mmol), and 20.4 mL hydrazine hydrate solution (80% 50% hydrazine, 3.0 eq, 318 mmol, 10.2 g). 50 mL ethanol were added, and the solution cooled to $0\ {^{\circ }}$C. Filtering off the resulting precipitate and washing with ethanol gave compound 1. Yield: 16.3 g (110 mmol, >95%); colorless solid; mp: 158–159 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 3.52 (s, 2H); $^{13}$C-NMR (DMSO-$d-_{6})$ $\delta$ = 31.6, 155.5, 168.5; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{3}$H$_{7}$N$_{6}$O$^{+}$: 143.0681, found: 143.0669; IR ($\nu$): 1525 (w), 1568 (w), 1624 (w), 1675 (m) cm$^{-1}$.

3-(1 H -Tetrazol-5-yl)propanoic acid hydrazide (52): Following general procedure C, applying 7.91 g tetrazole acid ester 50 (1.0 eq, 46 mmol), and 30.0 mL hydrazine hydrate solution (80% 50% hydrazine, 10.2 eq, 469 mmol, 15.0 g). 20 mL ethanol were added, and the solution cooled to −18 ${^{\circ }}$C. Filtering off the resulting precipitate and washing with ethanol gave compound 52. Yield: 7.38 g (47 mmol, >95%); colorless solid; mp: $136{-}139 \ {^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.38–2.42 (m, 2H), 2.85–2.90 (m, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 21.4, 33.1, 159.6, 171.3; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{4}$H$_{9}$N$_{6}$O$^{+}$: 157.0838, found 157.0835; IR ($\nu$): 1567 (m), 1596 (m) cm$^{-1}$.

4-(1 H -Tetrazol-5-yl)butanoic acid hydrazide (53): Following general procedure C, applying 7.06 g tetrazole acid ester  51 (1.0 eq, 38 mmol), and 30.0 mL hydrazine hydrate solution (80% 50% hydrazine, 12.3 eq, 469 mmol, 15.0 g). All volatiles were removed under reduced pressure, and residual hydrazine removed by azeotropic distillation with ethanol. Recrystallization from methanol/diethyl ether 3:1 gave compound 53. Yield: 6.04 g (36 mmol, 93%); colorless solid; mp: $113{-}115 \ {^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.82 (qu, 2H, J = 7.6 Hz), 2.06 (t, 2H, $J~=~$7.6 Hz), 2.66 (t, 2H, J = 7.6 Hz); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 24.4, 24.8, 33.1, 159.6, 171.5; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{5}$H$_{11}$N$_{6}$O$^{+}$: 171.0994, found: 171.0990; IR ($\nu$): 1521 (m), 1648 (s), 3288 (m) cm$^{-1}$.

General procedure D for the synthesis of compounds 2–7: Ethyl 2-(1H-tetrazol-5-yl)acetic acid hydrazide (1) (1.0 eq), and the appropriate aldehyde or ketone (4.0 eq) were suspended in 6 mL methanol. The reaction mixture was heated by microwave irradiation ($p_\mathrm{max}$ = 17 bar, $\vartheta$ $_\mathrm{max}$ = $80 \ {^{\circ }}$C, $p_\mathrm{max}$ = 100 W, ramp time = 1 min, hold time = 2 min, continuous irradiation and stirring).

( E )-4-({2-[2-(1 H -Tetrazol-5-yl) acetyl]hydrazono}methyl)benzoic acid (2): Following general procedure D, applying 300 mg ethyl 2-(1H-tetrazol-5-yl)acetate (1) (1.0 eq, 2.11 mmol), and 1.27 g 4-formylbenzoic acid (4.0 eq, 8.45 mmol). The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered, and washed with boiling ethyl acetate. Yield: 196 mg (0.72 mmol, 34%); colorless solid; $284{-}286 \ {^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 4.06 (s, 2H), 4.47 (s, 2H), 7.81–7.84 (m, 2H), 7.97–8.13 (m, 2H), 8.28 (s, 1H), 8.80 (s, 1H), 11.89 (s, 1H), 12.01 (s, 1H), 16.00 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 28.4, 29.9, 127.0, 127.2, 129.6, 129.7, 131.7, 131.8, 137.9, 138.0, 142.9, 146.2, 163.1, 166.9, 167.7; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{11}$H$_{11}$N$_{6}$O$_{3}^{+}$: 274.0814, found: 274.0811; IR ($\tilde{\nu }$): 1672 (m), 1707 (w) cm$^{-1}$.

( E ) -N $^{\prime }$ -(4-Hydroxybenzylidene)-2-(1 H -tetrazol-5-yl)acetic acid hydrazide (3): Following general procedure D, applying 300 mg ethyl 2-(1H-tetrazol-5-yl)acetate (1) (1.0 eq, 2.11 mmol), and 1.03 g 4-hydroxy-benzaldehyde (4.0 eq, 8.45 mmol). The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with boiling ethyl acetate. Yield: 378 mg (1.54 mmol, 68%); colorless solid; mp: 283–285 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 4.00 (s, 2H), 4.39 (s, 2H), 6.80–6.82 (m, 2H), 7.51–7.70 (m, 2H), 8.10 (s, 1H), 8.56 (s, 1H), 9.92 (s, 1H), 11.53 (s, 1H), 11.65 (s, 1H), 16.16 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 28.3, 29.8, 115.7, 124.9, 128.7, 129.0, 144.3, 147.6, 159.3, 159.6, 162.3, 168.1; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{10}$H$_{11}$N$_{6}$O$_{2}^{+}$: 247.0938, found: 247.0938; IR ($\tilde{\nu }$): 1603 (w), 1671 (s) cm$^{-1}$.

( E ) -N $^{\prime }$ -(3-Hydroxybenzylidene)-2-(1 H -tetrazol-5-yl)acetic acid hydrazide (4): Following general procedure D, applying 300 mg ethyl 2-(1H-tetrazol-5-yl)acetate (1) (1.0 eq, 2.11 mmol), and 1.03 g 3-hydroxy-benzaldehyde (1.0 eq, 8.45 mmol). The solution was cooled to $-18\,{^{\circ }}$C, and the resulting precipitate was filtered and washed with boiling diethyl ether. Yield: 330 mg (1.34 mmol, 63%); colorless solid; mp: 241–244 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 4.03 (s, 2H), 4.42 (s, 2H), 6.82–6.84 (m, 1H), 7.07–7.26 (m, 3H), 7.95 (s, 1H), 8.12 (s, 1H), 9.61 (s, 1H), 11.69 (s, 1H), 11.80 (s, 1H), 16.23 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 28.3, 29.8, 112.6, 112.8, 117.3, 117.6, 118.4, 118.9, 129.9, 135.2, 144.3, 147.4, 151.0, 157.6, 162.7, 168,4; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{10}$H$_{11}$N$_{6}$O$_{2}^{+}$: 247.0938, found: 247.0949; IR ($\tilde{\nu }$): 1586 (w), 1650 (m) cm$^{-1}$.

( E ) -N $^{\prime }$ -(2-Hydroxybenzylidene)-2-(1 H -tetrazol-5-yl)acetic acid hydrazide (5): Following general procedure D, applying 300 mg ethyl 2-(1H-tetrazol-5-yl)acetate (1) (1.0 eq, 2.11 mmol), and 883 $\upmu$L 2-hydroxy-benzaldehyde (4.0 eq, 8.45 mmol, 1.03 g). The solution was cooled to −18 ${^{\circ }}\hbox {C}$, and the resulting precipitate was filtered and washed with boiling ethyl acetate. Yield: 366 mg (1.49 mmol, 59%); beige solid; mp: 250–251 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 4.06 (s, 2H), 4.41 (s, 2H), 6.84–7.70 (m, 4H), 8.34 (s, 1H), 8.44 (s, 1H), 10.95 (s, 1H), 11.66 (s, 1H), 12.06 (s, 1H), 16.26 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 28.5, 29.6, 116.1, 116.4, 118.6, 119.4, 120.0, 126.3, 129.1, 131.3, 131.6, 141.4, 147.4, 151.1, 156.4, 157.3, 162.7, 168.1; HRMS (ESI, m / z) [M-H$^{-}$]: calcd for C$_{10}$H$_{9}$N$_{6}$O$_{2}^{-}$: 245.0792, found: 245.0792; IR ($\tilde{\nu }$): 1604 (w), 1674 (m) cm$^{-1}$.

( E ) -N $^{\prime }$ -(4-Hydroxy-3-methoxybenzylidene)-2-(1 H -tetrazol-5-yl)acetic acid hydrazide (6): Following general procedure D, applying 300 mg ethyl 2-(1H-tetrazol-5-yl)acetate (1) (1.0 eq, 2.11 mmol), and 1.28 g 4-hydroxy-3-methoxy-benzaldehyde (4.0 eq, 8.45 mmol). The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with diethyl ether. Yield: 225 mg (0.82 mmol, 37%); colorless solid; mp: 263–266 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 3.81 (s, 3H), 3.82 (s, 3H), 4.00 (s, 2H), 4.40 (s, 2H), 6.81 (d, 1H), 6.83 (d, 1H), 7.05 (dd, 1H), 7.10 (dd, 1H), 7.23 (d, 1H), 7.27 (d, 1H), 7.90 (s, 1H), 8.09 (s, 1H), 9.51 (s, 1H), 9.56 (s, 1H), 11.56 (s, 1H), 11.67 (s, 1H), 16.21 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 28.6, 29.8, 55.6, 109.2, 115.4, 121.6, 122.1, 125.3, 125.4, 144.4, 147.8, 148.0, 148.8, 149.1, 162.4, 168.1; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{11}$H$_{12}$N$_{6}$O$_{3}^{+}$: 277.1044, found: 277.1038; IR ($\tilde{\nu }$): 1512 (m), 1600 (w), 1666 (s) cm$^{-1}$.

( E ) -N $^{\prime }$ -(1-(4-Hydroxyphenyl)ethyliden)-2-(1 H -tetrazol-5-yl)acetic acid hydrazide (7): Following general procedure D applying 300 mg ethyl 2-(1H-tetrazol-5-yl)acetate (1) (1.0 eq, 2.11 mmol), and 1.15 g 1-(4-hydroxyphenyl)ethanone (4.0 eq, 8.45 mmol). The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with boiling diethyl ether. Yield: 387 mg (1.49 mmol, 71%); colorless needles; mp: 254–257 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.21 (s, 3H), 2.26 (s, 3H), 4.14 (s, 2H), 4.42 (s, 2H), 6.77–6.80 (m, 2H), 7.62–7.66 (m, 2H), 9.74 (s, 1H), 9.77 (s, 1H), 10.69 (s, 1H), 10.80 (s, 1H), 16.19 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.7, 14.1, 28.9, 29.6, 115.1, 127.7, 128.0, 128.7, 148.9, 151.2, 153.0, 158.8, 162.9, 169.1; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{11}$H$_{13}$N$_{6}$O$_{2}^{+}$: 261.1095, found: 261.1087; IR ($\tilde{\nu }$): 1580 (w), 1607 (w), 1654 (m) cm$^{-1}$.

General procedure E for the synthesis of compounds 8–17: Ethyl 3-(1H-tetrazol-5-yl)propanoic acid hydrazide (52) (1.0 eq), and the appropriate aldehyde or ketone (4.0 eq) were suspended in 6 mL methanol. The reaction mixture was heated by microwave irradiation ($p_\mathrm{max}$ = 17 bar, $\vartheta$ $_\mathrm{max}$ = 80 ${^{\circ }}\hbox {C}$, $p_\mathrm{max}$ = 100 W, ramp time = 1 min, hold time = 2 min, continuous irradiation and stirring).

( E ) -N $^{\prime }$ -(4-Hydroxybenzylidene)-3-(1 H -tetrazol-5-yl)propanoic acid hydrazide (8): Following general procedure E, applying 300 mg ethyl 3-(1H-tetrazol-5-yl)propanoate (52) (1.0 eq, 1.92 mmol), and 967 mg 4-hydroxy-benzaldehyde (4.0 eq, 7.68 mmol). The solution was cooled to −18 ${^{\circ }}\hbox {C}$, and the resulting precipitate was filtered and washed with boiling ethyl acetate. Yield: 58 mg (0.22 mmol, 11%); beige solid; mp: 229–234 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.73 (t, 2H, J = 7.2 Hz), 3.14 (m, 4H), 6.80–6.82 (m, 2H), 7.49–7.51 (m, 2H), 7.89 (s, 1H), 8.04 (s, 1H), 9.88 (s, 1H), 11.17 (s, 1H), 11.29 (s, 1H), 16.04 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 18.0, 18.6, 29.5, 31.2, 115.7, 125.2, 128.4, 128.7, 143.3, 146.4, 159.1, 159.3, 166.5, 172.1; HRMS (ESI, m / z) [M–H$^{-}$]: calcd for C$_{11}$H$_{11}$N$_{6}$O$_{2}^{-}$: 259.0949, found: 259.0954; IR ($\tilde{\nu }$): 1606 (w), 1666 (s) cm$^{-1}$.

( E ) -N $^{\prime }$ -(3-Hydroxybenzylidene)-3-(1 H -tetrazol-5-yl)propanoic acid hydrazide (9): Following general procedure E, applying 300 mg ethyl 3-(1H-tetrazol-5-yl)propanoate (52) (1.0 eq, 1.92 mmol), and 967 mg 3-hydroxy-benzaldehyde (4.0 eq, 7.68 mmol). The solution was cooled to −18 ${^{\circ }}\hbox {C}$, and the resulting precipitate was filtered and washed with boiling diethyl ether. Yield: 110 mg (0.44 mmol, 22%); beige solid; mp: 123–125 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.74 (t, 2H, J = 7.6 Hz), 3.16–3.18 (m, 4H), 6.79–7.30 (m, 4H), 7.91 (s, 1H), 8.05 (s, 1H), 9.60 (s, 1H), 11.32 (s, 1H), 11.45 (s, 1H), 16.02 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 17.9, 18.5, 29.5, 31.2, 112.3, 112.5, 117.1, 117.3, 118.4, 118.7, 129.8, 129.9, 135.4, 135.5, 143.2, 146.1, 155.7, 157.6, 166.8, 172.4; HRMS (ESI, m / z) [M–H$^{-}$]: calcd for C$_{11}$H$_{11}$N$_{6}$O$_{2}^{-}$: 259.0949, found: 259.0958, calcd for C$_{22}$H$_{23}$N$_{12}$O$_{4}^{-}$: 519.1971, found: 519.2013 IR ($\tilde{\nu }$): 1545 (m), 1654 (w) cm$^{-1}$.

( E ) -N $^{\prime }$ -(2-Hydroxybenzylidene)-3-(1 H -tetrazol-5-yl)propanoic acid hydrazide (10): Following general procedure E, applying 300 mg ethyl 3-(1H-tetrazol-5-yl)propanoate (52) (1.0 eq, 1.92 mmol), and 803 $\upmu$L 2-hydroxy-benzaldehyde (4.0 eq, 7.68 mmol, 938 mg). The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with boiling ethyl acetate. Yield: 223 mg (0.88 mmol, 44%); colorless solid; mp: 197–200 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.78 (t, 2H, J = 7.0 Hz), 3.16–3.21 (m, 4H), 6.85–7.67 (m, 4H), 8.29 (s, 1H), 8.35 (s, 1H), 10.10 (s, 1H), 11.35 (s, 1H), 11.75 (s, 1H), 16.05 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 17.8, 18.3, 29.4, 30.8, 116.0, 116.2, 118.5, 119.2, 119.3, 119.9, 126.5, 129.2, 131.0, 131.2, 140.9, 146.5, 156.3, 157.2, 166.5, 172.0; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{11}$H$_{13}$N$_{6}$O$_{2}^{+}$: 261.1095, found: 261.1083, [M-H$^{-}$]: calcd for C$_{22}$H$_{23}$N$_{12}$O$_{4}^{-}$: 519.1971, found: 519.1961 IR ($\tilde{\nu }$): 1669 (s) cm$^{-1}$.

( E ) -N $^{\prime }$ -(4-Hydroxy-3-methoxybenzylidene)-3-(1 H -tetrazol-5-yl)propanoic acid hydrazide (11): Following general procedure E, applying 300 mg ethyl 3-(1H-tetrazol-5-yl)propanoate (52) (1.0 eq, 1.92 mmol), and 1.17 g 4-hydroxy-3-methoxy-benzaldehyde (4.0 eq, 7.69 mmol). The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with diethyl ether. Yield: 403 mg (1.39 mmol, 73%); pale yellow solid; mp: 268–271 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.72 (t, 2H), 3.16 (m, 4H), 3.81 (s, 3H), 6.81–7.23 (m, 3H), 7.88 (s, 1H), 8.02 (s, 1H), 9.48 (s, 1H), 11.20 (s, 1H), 11.31 (s, 1H), 16.01 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 18.0, 18.6, 29.6, 31.2, 55.5, 109.0, 109.5, 115.4, 115.6, 121.0, 121.9, 125.6, 143.5, 146.6, 147.9, 148.0, 148.6, 148.8, 166.5, 172.1; HRMS (ESI, m / z) [M–H$^{-}$]: calcd for C$_{12}$H$_{13}$N$_{6}$O$_{3}^{-}$: 289.1055, found: 289.1067; IR ($\tilde{\nu }$): 1600 (w), 1653 (s) cm$^{-1}$.

( E ) -N $^{\prime }$ -(1-(4-Hydroxyphenyl)ethyliden)-3-(1 H -tetrazol-5-yl)propanoic acid hydrazide (12): Following general procedure E, applying 300 mg ethyl 3-(1H-tetrazol-5-yl)propanoate (52) (1.0 eq, 1.92 mmol), and 1.05 g 1-(4-hydroxyphenyl)-ethanone (4.0 eq, 7.68 mmol). The solution was cooled to −18 ${^{\circ }}\hbox {C}$, and the resulting precipitate was filtered and washed with boiling diethyl ether. Yield: 341 mg (1.24 mmol, 65%); pale yellow solid; mp: 256–257 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.18 (s, 3H), 2.19 (s, 3H), 2.84 (t, 2H, J = 7.2 Hz), 3.15–3.18 (m, 4H), 6.76–6.80 (m, 2H), 7.61–7.64 (m, 2H), 9.73 (s, 1H), 10.33 (s, 1H), 10.41 (s, 1H), 16.00 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.4, 13.9, 18.0, 18.8, 30.0, 31.2, 115.0, 115.1, 127.5, 127.8, 129.0, 147.6, 151.8, 158.5, 167.1, 173.0; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{12}$H$_{15}$N$_{6}$O$_{2}^{+}$: 275.1251, found: 275.1244; IR ($\tilde{\nu }$): 1510 (w), 1541 (w), 1649 (m) cm$^{-1}$.

( E ) -N $^{\prime }$ -Benzylidene-3-(1 H -tetrazol-5-yl)propanoic acid hydrazide (13): Following general procedure E, applying 300 mg ethyl 3-(1H-tetrazol-5-yl)propanoate (52) (1.0 eq, 1.92 mmol), and 775 $\upmu$L benzaldehyde (4.0 eq, 7.68 mmol, 815 mg). The solution was cooled to −18 ${^{\circ }}\hbox {C}$, and the resulting precipitate was filtered and washed with diethyl ether. Yield: 280 mg (1.15 mmol, 59%); colorless solid; mp: 195–197 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.77 (t, 2H, J = 7.2 Hz), 3.16–3.20 (m, 4H), 7.41–7.69 (m, 5H), 8.00 (s, 1H), 8.16 (s, 1H), 11.39 (s, 1H), 11.52 (s, 1H), 16.05 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 18.0, 18.5, 29.5, 31.2, 126.7, 127.0, 128.8, 129.8, 130.0, 134.2, 134.3, 143.0, 146.1, 155.7, 166.9, 172.5; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{11}$H$_{13}$N$_{6}$O$^{+}$: 245.1145, found: 245.1143; IR ($\tilde{\nu }$): 1661 (s) cm$^{-1}$.

( E ) -N $^{\prime }$ -(1-Phenylethyliden)-3-(1 H -tetrazol-5-yl)propanoic acid hydrazide (14): Following general procedure E, applying 300 mg ethyl 3-(1H-tetrazol-5-yl)propanoate (52) (1.0 eq, 1.92 mmol), and 900 $\upmu$L 1-phenylethanone (4.0 eq, 7.68 mmol, 923 mg). The solution was cooled to −18 ${^{\circ }}\hbox {C}$, and the resulting precipitate was filtered and washed with boiling diethyl ether. Yield: 350 mg (1.36 mmol, 71%); colorless solid; mp: 200–203 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.25 (s, 3H), 2.26 (s, 3H), 2.88 (t, 2H, J = 7.2 Hz), 3.16–3.25 (m, 4H), 7.40–7.80 (m, 5H), 10.48 (s, 1H), 10.59 (s, 1H), 16.03 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.5, 14.1, 18.0, 18.7, 30.0, 31.2, 126.0, 126.3, 128.3, 128.4, 129.0, 129.2, 138.2, 147.2, 151.2, 155.7, 167.5, 173.3; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{12}$H$_{15}$N$_{6}$O$^{+}$: 259.1302, found: 259.1303; IR ($\tilde{\nu }$): 1665 (s) cm$^{-1}$.

( E ) -N $^{\prime }$ -(4-Methoxybenzylidene)-3-(1 H -tetrazol-5-yl)propanoic acid hydrazide (15): Following general procedure E, applying 600 mg ethyl 3-(1H-tetrazol-5-yl)propanoate (52) (1.0 eq, 3.85 mmol), and 1.87 mL 4-methoxybenzaldehyde (4.0 eq, 15.4 mmol, 2.10 g). The solution was cooled to −18 ${^{\circ }}\hbox {C}$, and the resulting precipitate was filtered and washed with boiling diethyl ether. Yield: 872 mg (3.18 mmol, 83%); colorless solid; mp: 240–243 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.74 (m, 2H), 3.16 (m, 4H), 3.80 (s, 3H), 6.98–7.00 (m, 2H), 7.60–7.94 (m, 2H), 8.09 (s, 1H), 8.64 (s, 1H), 11.25 (s, 1H), 11.37 (s, 1H), 15.86 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 18.0, 18.6, 29.5, 31.2, 55.3, 114.3, 126.8, 128.3, 128.6, 142.9, 146.0, 160.6, 160.7, 166.6, 172.2; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{12}$H$_{15}$N$_{6}$O$_{2}^{+}$: 275.1251, found: 275.1248; IR ($\tilde{\nu }$): 1514 (w), 1606 (m), 1642 (m) $\hbox {cm}^{-1}$.

( E ) -N $^{\prime }$ -(1-(4-Methoxyphenyl)ethyliden)-3-(1 H -tetrazol-5-yl)propanoic acid hydrazide (16): Following general procedure E, applying 300 mg ethyl 3-(1H-tetrazol-5-yl)propanoate (52) (1.0 eq, 1.92 mmol), and 1.16 g 1-(4-methoxyphenyl)ethanone (4.0 eq, 7.68 mmol). The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with boiling ethyl acetate. Yield: 217 mg (0.75 mmol, 39%); colorless solid; mp: 193–194 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.21 (s, 3H), 2.22 (s, 3H), 2.85–2.87 (m, 2H), 3.15–3.19 (m, 4H), 3.79 (s, 3H), 6.95–6.97 (m, 2H), 7.73–7.75 (m, 2H), 10.39 (s, 1H), 10.47 (s, 1H), 16.00 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.3, 13.9, 17.9, 18.7, 30.0, 31.1, 55.1, 113.5, 113.6, 127.3, 127.6, 130.5, 147.2, 151.2, 155.7, 159.9, 160.1, 167.1, 173.0; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{13}$H$_{17}$N$_{6}$O$_{2}^{+}$: 289.11408, found: 289.1398; IR ($\tilde{\nu }$): 1650 (s) cm$^{-1}$.

( E ) -N $^{\prime }$ -(1-(Pyridin-4-yl)ethyliden)-3-(1 H -tetrazol-5-yl)propanoic acid hydrazide (17): Following general procedure E, applying 300 mg ethyl 3-(1H-tetrazol-5-yl)propanoate (52) (1.0 eq, 1.92 mmol), and 846 $\upmu$L 1-(4-pyridinyl)-ethanone (4.0 eq, 7.68 mmol, 931 mg). The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with diethyl ether. Yield: 389 mg (1.50 mmol, 80%); pale yellow solid; mp: 196–199 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.25 (s, 3H), 2.27 (s, 3H), 2.91 (t, 2H, J = 6.6 Hz), 3.17–3.20 (m, 2H), 3.24 (m, 2H), 7.69–7.73 (m, 2H), 8.61–8.63 (m, 2H), 10.69 (s, 1H), 10.82 (s, 1H), 16.06 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.0, 13.5, 17.9, 18.6, 30.0, 31.2, 120.2, 120.4, 145.1, 145.3, 148.4, 149.9, 150.0, 155.7, 167.9, 173.7; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{11}$H$_{14}$N$_{7}$O$^{+}$: 260.1254, found: 260.1242; IR ($\tilde{\nu }$): 1583 (m), 1672 (s) $\hbox {cm}^{-1}$.

General procedure F for the synthesis of compounds 18–27: Ethyl 4-(1H-tetrazol-5-yl)butanoic acid hydrazide (53) (1.0 eq), and the appropriate aldehyde or ketone (4.0 eq) were suspended in 6 mL methanol. The reaction mixture was stirred for 30 min at room temperature.

( E ) -N $^{\prime }$ -(4-Hydroxybenzylidene)-4-(1 H -tetrazol-5-yl)butanoic acid hydrazide (18): Following general procedure F, applying 300 mg ethyl 4-(1H-tetrazol-5-yl)butanoate (53) (1.0 eq, 1.76 mmol), and 861 mg 4-hydroxy-benzaldehyde (4.0 eq, 7.04 mmol). The solution was cooled to −18 ${^{\circ }}\hbox {C}$, and the resulting precipitate was filtered and washed with boiling ethyl acetate. Yield: 200 mg (0.73 mmol, 42%); beige solid; mp: 210–211 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.99–2.02 (m, 2H), 2.25 (t, 2H, J = 6.0 Hz), 2.67 (t, 2H, J = 6.4 Hz), 2.93–2.98 (m, 2H), 6.81 (m, 2H), 7.43–7.51 (m, 2H), 7.87 (s, 1H), 8.03 (s, 1H), 9.86 (s, 1H), 11.08 (s, 1H), 11.16 (s, 1H), 16.03 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 22.1–22.8, 31.0, 32.9, 115.5, 125.2, 128.2, 128.6, 142.9, 146.1, 158.9, 159.1, 167.4, 173.1; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{12}$H$_{15}$N$_{6}$O$_{2}^{+}$: 275.1251, found: 275.1246; IR ($\tilde{\nu }$): 1513 (m), 1539 (w), 1571 (w), 1607 (m), 1658 (s) cm$^{-1}$.

( E ) -N $^{\prime }$ -(3-Hydroxybenzylidene)-4-(1 H -tetrazol-5-yl)butanoic acid hydrazide (19): Following general procedure F, applying 300 mg ethyl 4-(1H-tetrazol-5-yl)butanoate (53) (1.0 eq, 1.76 mmol), and 861 mg 3-hydroxy-benzaldehyde (4.0 eq, 7.04 mmol). The reaction mixture was evaporated under reduced pressure, and the residue was washed with boiling diethyl ether. Yield: 183 mg (0.67 mmol, 39%); beige solid; mp: 90–94 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.98–2.05 (m, 2H), 2.28 (t, 2H, J = 7.4 Hz), 2.71 (t, 2H, J = 7.2 Hz), 2.92–2.99 (m, 2H), 6.79–6.81 (m, 1H), 7.00–7.24 (m, 3H), 7.89 (s, 1H), 8.04 (s, 1H), 9.59 (s, 1H), 11.23 (s, 1H), 11.32 (s, 1H), 16.06 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 21.9–22.6, 30.9, 32.9, 112.4, 116.9, 117.1, 118.0, 118.6, 129.7, 135.4, 135.5, 142.8, 145.9, 157.5, 167.7, 173.4; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{12}$H$_{15}$N$_{6}$O$_{2}^{+}$: 275.1251, found: 275.1249; IR ($\tilde{\nu }$): 1557 (m), 1582 (w), 1663 (s) cm$^{-1}$.

( E ) -N $^{\prime }$ -(2-Hydroxybenzylidene)-4-(1 H -tetrazol-5-yl)butanoic acid hydrazide (20): Following general procedure F, applying 300 mg ethyl 4-(1H-tetrazol-5-yl)butanoate (53) (1.0 eq, 1.76 mmol), and 737 $\upmu$L 2-hydroxy-benzaldehyde (4.0 eq, 7.04 mmol, 861 mg). The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with boiling ethyl acetate. Yield: 125 mg (0.46 mmol, 26%); colorless solid; mp: 171–174 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.02–2.05 (m, 2H), 2.32 (t, 2H, J = 6.8 Hz), 2.69 (t, 2H, J = 6.8 Hz), 2.94–2.97 (m, 2H), 6.84–7.71 (m, 4H), 8.27 (s, 1H), 8.34 (s, 1H), 10.09 (s, 1H), 11.17 (s, 1H), 11.27 (s, 1H), 11.63 (s, 1H), 16.05 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 22.2–22.7, 31.0, 32.7, 116.1, 116.3, 118.6, 119.3, 119.4, 120.0, 126.6, 129.4, 130.9, 131.2, 140.8, 146.5, 156.3, 157.3, 167.7, 173.1; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{12}$H$_{15}$N$_{6}$O$_{2}^{+}$: 275.1251, found: 275.1249; IR ($\tilde{\nu }$): 1546 (m), 1564 (w), 1607 (w), 1621 (w), 1662 (s) cm$^{-1}$.

( E ) -N $^{\prime }$ -(4-Hydroxy-3-methoxybenzylidene)-4-(1 H -tetrazol-5-yl)butanoic acid hydrazide (21): Following general procedure F, applying 300 mg ethyl 4-(1H-tetrazol-5-yl)butanoate (53) (1.0 eq, 1.76 mmol), and 1.07 g 4-hydroxy-3-methoxy-benzaldehyde (4.0 eq, 7.04 mmol). The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with diethyl ether. Yield: 298 mg (0.98 mmol, 55%); beige solid; mp: 228–231 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.02 (m, 2H), 2.26 (t, 2H, J = 6.8 Hz), 2.69 (t, 2H, J = 6.8 Hz), 2.91–2.99 (m, 2H), 3.81 (s, 3H), 6.97–7.25 (m, 3H), 7.85 (s, 1H), 8.02 (s, 1H), 9.47 (s, 1H), 11.12 (s, 1H), 11.18 (s, 1H), 16.06 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 22.2–22.9, 31.0, 33.0, 55.5, 108.9, 109.3, 115.4, 115.5, 120.9, 121.9, 125.7, 143.1, 146.5, 147.9, 148.0, 148.5, 148.8, 155.7, 167.5, 173.3; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{13}$H$_{17}$N$_{6}$O$_{3}^{+}$: 305.1357, found: 305.1351; IR ($\tilde{\nu }$): 1513 (w), 1601 (w), 1662 (s) cm$^{-1}$.

( E ) -N $^{\prime }$ -[1-(4-Hydroxyphenyl)ethylidene]-4-(1 H -tetrazol-5-yl)butanoic acid hydrazide (22): Following general procedure F, applying 300 mg ethyl 4-(1H-tetrazol-5-yl)-butanoate (53) (1.0 eq, 1.76 mmol), and 861 mg 1-(4-hydroxyphenyl)ethanone (4.0 eq, 7.04 mmol). The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with boiling diethyl ether. Yield: 200 mg (1.44 mmol, 42%); beige solid; mp: 210–211 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.98–2.05 (m, 2H), 2.16 (s, 3H), 2.18 (s, 3H), 2.37 (t, 2H, J = 7.2 Hz), 2.72 (t, 2H, J = 7.2 Hz), 2.92–2.99 (m, 2H), 6.76–6.78 (m, 2H), 7.55–7.64 (m, 2H), 9.71 (s, 1H), 10.19 (s, 1H), 10.30 (s, 1H), 16.04 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.2, 13.8, 22.2–22.9, 31.5, 32.8, 114.9, 115.0, 127.3, 127.7, 129.0, 147.1, 151.4, 155.7, 158.3, 158.5, 168.0, 174.1; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{13}$H$_{17}$N$_{6}$O$_{2}^{+}$: 289.1408, found: 289.1406; IR ($\tilde{\nu }$): 1508 (m), 1533 (w), 1594 (w), 1617 (w), 1636 (m) cm$^{-1}$.

( E ) -N $^{\prime }$ -Benzylidene-4-(1 H -tetrazol-5-yl)butanoic acid hydrazide (23): Following general procedure F, applying 300 mg ethyl 4-(1H-tetrazol-5-yl)-butanoate (53) (1.0 eq, 1.76 mmol), and 711 $\upmu$L benzaldehyde (4.0 eq, 7.04 mmol, 748 mg). The solution was cooled to −18 ${^{\circ }}\hbox {C}$, and the resulting precipitate was filtered and washed with diethyl ether. Yield: 280 mg (0.82 mmol, 46%); colorless solid; mp: 189–190 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.02–2.06 (m, 2H), 2.29 (t, 2H, J = 7.4 Hz), 2.72 (t, 2H, J = 7.2 Hz), 2.92–2.99 (m, 2H), 7.39–7.69 (m, 5H), 7.98 (s, 1H), 8.15 (s, 1H), 11.29 (s, 1H), 11.38 (s, 1H), 16.04 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 22.2–22.8, 31.1, 33.0, 126.6, 126.9, 128.8, 129.7, 129.9, 134.2, 134.3, 142.6, 145.9, 167.8, 173.6; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{12}$H$_{15}$N$_{6}$O$^{+}$: 259.1302, found: 259.1299; IR ($\tilde{\nu }$): 1538 (w), 1572 (w), 1670 (m) cm$^{-1}$.

( E ) -N $^{\prime }$ -(1-Phenylethylidene)-4-(1 H -tetrazol-5-yl)butanoic acid hydrazide (24): Following general procedure F, applying 300 mg ethyl 4-(1H-tetrazol-5-yl)-butanoate (53) (1.0 eq, 1.76 mmol), and 826 $\upmu$L phenylethanone (4.0 eq, 7.04 mmol, 847 mg). The solution was cooled to −18 ${^{\circ }}\hbox {C}$, and the resulting precipitate was filtered and washed with boiling diethyl ether. Yield: 112 mg (0.41 mmol, 24%); colorless solid; mp: 174–175 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.99–2.07 (m, 2H), 2.23 (s, 3H), 2.26 (s, 3H), 2.40 (t, 2H, J = 7.2 Hz), 2.76 (t, 2H, J = 7.2 Hz), 2.93–3.00 (m, 2H), 7.39–7.79 (m, 5H), 10.34 (s, 1H), 10.48 (s, 1H), 16.04 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.5, 14.1, 22.2–22.9, 31.6, 32.9, 125.9, 126.3, 128.3, 128.9, 129.1, 138.2, 138.3, 147.0, 150.9, 155.7, 168.4, 174.5; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{13}$H$_{17}$N$_{6}$O$^{+}$: 273.1458, found: 273.1455; IR ($\tilde{\nu }$): 1537 (w), 1560 (w), 1638 (m) cm$^{-1}$.

( E ) -N $^{\prime }$ -(4-Methoxybenzylidene)-4-(1 H -tetrazol-5-yl)butanoic acid hydrazide (25): Following general procedure F, applying 300 mg ethyl 4-(1H-tetrazol-5-yl)-butanoate (53) (1.0 eq, 1.76 mmol), and 854 $\upmu$L 4-methoxy-benzaldehyde (4.0 eq, 7.04 mmol, 960 mg). The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with boiling diethyl ether. Yield: 337 mg (0.85 mmol, 66%); colorless solid; mp: 200–203 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.97–2.05 (m, 2H), 2.27 (t, 2H, J = 7.2 Hz), 2.70 (t, 2H, J = 7.4 Hz), 2.92–2.99 (m, 2H), 3.79 (s, 1H), 6.97–7.01 (m, 2H), 7.55–7.63 (m, 2H), 7.92 (s, 1H), 8.08 (s, 1H), 11.16 (s, 1H), 11.24 (s, 1H), 16.01 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 22.2–22.8, 31.1, 33.0, 55.3, 114.3, 126.9, 128.2, 128.5, 142.5, 145.8, 160.5, 160.7, 167.6, 173.3; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{13}$H$_{17}$N$_{6}$O$_{2}^{+}$: 289.1408, found: 289.1407; IR ($\tilde{\nu }$): 1514 (w), 1605 (m), 1657 (m) cm$^{-1}$.

( E ) -N $^{\prime }$ -(1-(4-Methoxyphenyl)ethylidene)-4-(1 H -tetrazol-5-yl)butanoic acid hydrazide (26): Following general procedure F, applying 300 mg ethyl 4-(1H-tetrazol-5-yl)butanoate (53) (1.0 eq, 1.76 mmol), and 1.06 g 1-(4-methoxyphenyl)-ethanone (4.0 eq, 7.04 mmol). The reaction mixture was evaporated under reduced pressure, and the residue was washed with boiling ethyl acetate. Yield: 73 mg (0.24 mmol, 14%); colorless solid; mp: 168–171 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.00–2.04 (m, 2H), 2.19 (s, 3H), 2.21 (s, 3H), 2.38 (t, 2H, J = 7.0 Hz), 2.74 (t, 2H, J = 7.0 Hz), 2.92–2.99 (m, 2H), 3.79 (s, 3H), 6.94–6.96 (m, 2H), 7.66–7.74 (m, 2H), 10.25 (s, 1H), 10.37 (s, 1H), 16.03 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.3, 13.8, 22.1–22.9, 31.5, 32.8, 55.1, 113.5, 113.6, 127.3, 127.6, 130.6, 146.8, 150.9, 159.9, 160.0, 168.1, 174.2; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{14}$H$_{19}$N$_{6}$O$_{2}^{+}$: 303.1564, found: 303.1566; IR ($\tilde{\nu }$): 1510 (m), 1649 (m) cm$^{-1}$.

( E ) -N $^{\prime }$ -(1-(Pyridin-4-yl)ethylidene)-4-(1 H -tetrazol-5-yl)butanoic acid hydrazide (27): Following general procedure F, applying 300 mg ethyl 4-(1H-tetrazol-5-yl)butanoate (53) (1.0 eq, 1.76 mmol), and 860 $\upmu$L 1-(4-pyridyl)ethanone (4.0 eq, 7.04 mmol, 946 mg). The reaction mixture was evaporated under reduced pressure, and the residue was washed with diethyl ether. Yield: 327 mg (1.20 mmol, 70%); colorless solid; mp: 228–229 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.00–2.07 (m, 2H), 2.24 (s, 3H), 2.26 (s, 3H), 2.44 (t, 2H, J = 7.2 Hz), 2.80 (t, 2H, J = 7.2 Hz), 2.94–3.01 (m, 2H), 7.66–7.71 (m, 2H), 8.60–8.61 (m, 2H), 10.55 (s, 1H), 10.72 (s, 1H), 16.05 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 12.9, 13.4, 22.2–22.8, 31.5, 32.9, 120.1, 120.4, 144.7, 145.1, 145.3, 148.2, 149.9, 155.8, 168.8, 174.8; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{12}$H$_{16}$N$_{7}$O$^{+}$: 274.1411, found: 274.1404; IR ($\tilde{\nu }$): 1592 (m), 1682 (s) cm$^{-1}$.

General procedure G for the synthesis of compounds 28–38: The appropiate aldehyde or ketone (1.0 eq), hydrazine hydrate (80% 50% hydrazine, 1.0 eq), and 1.0 mL acetic acid were suspended in 6 mL water. The reaction mixture was heated by microwave irradiation ($p_\mathrm{max}$ = 17 bar, $\vartheta$ $_\mathrm{max}$ = 100 ${^{\circ }}\hbox {C}$, $p_\mathrm{max}$ = 200 W, ramp time = 1 min, hold time = 4 min, continuous irradiation and stirring).

4-Carboxybenzaldazine (28): Following general procedure G, applying 301 mg 4-carboxybenzaldehyde (1.0 eq, 2.00 mmol), 128 $\upmu$L hydrazine hydrate (80%  50% hydrazine, 1.0 eq, 2.00 mmol, 64 mg), and 6 mL methanol. The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with water. Yield: 400 mg (1.35 mmol, 68%); yellow solid; mp: >360 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 8.00–8.08 (m, 8H), 8.80 (s, 2H), 13.21 (s, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 128.5, 129.5, 133.1, 137.5, 161.0, 166.8; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{16}$H$_{13}$N$_{2}$O$_{4}^{+}$: 297.0870, found: 297.0864; IR ($\tilde{\nu }$): 1608 (w), 1623 (w), 1673 (s) cm$^{-1}$.

4-Hydroxybenzaldazine (29): Following general procedure G, applying 244 mg 4-hydroxy-benzaldehyde (1.0 eq, 2.00 mmol), and 128 $\upmu$L hydrazine hydrate (80%  50% hydrazine, 2.00 mmol, 64 mg). The solution was cooled to room temperature, and the resulting precipitate was filtered and washed with water. Yield: 216 mg (0.90 mmol, 90%); orange solid; mp: 285–287 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 6.85–6.88 (m, 4H), 7.68–7.70 (m, 4H), 8.56 (s, 2H), 10.07 (s, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 115.6, 125.1, 130.0, 160.2, 160.3; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{14}$H$_{13}$N$_{2}$O$_{2}^{+}$: 241.0972, found: 241.0978; IR ($\tilde{\nu }$): 1510 (w), 1561 (w), 1586 (m), 1606 (m) cm$^{-1}$.

3-Hydroxybenzaldazine (30): Following general procedure G, applying 244 mg 3-hydroxy-benzaldehyde (1.0 eq, 2.00 mmol), and 128 $\upmu$L hydrazine hydrate (80%  50% hydrazine, 1.0 eq, 2.00 mmol, 64 mg). The solution was cooled to room temperature, and the resulting precipitate was filtered and washed with water. Yield: 187 mg (0.78 mmol, 70%); beige solid; mp: 205–207 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 6.91–7.32 (m, 8H), 8.60 (s, 2H), 9.71 (s, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 114.0, 118.5, 119.8, 129.8, 135.0, 157.6, 161.4; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{14}$H$_{13}$N$_{2}$O$_{2}^{+}$: 241.0972, found: 241.0973; IR ($\tilde{\nu }$): 1573 (w), 1615 (w) cm$^{-1}$.

2-Hydroxybenzaldazine (31): This compound was isolated as a side-product during the synthesis of 5. Hence, the ethyl acetate filtrate was evaporated under reduced pressure, and the resulting residue washed with water. Yield: 54 mg (0.23 mmol, 10%); lemon yellow solid; mp: 217–218 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 6.96–7.71 (m, 8H), 9.01 (s, 2H), 11.13 (s, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 116.5, 118.2, 119.6, 130.8, 133.2, 158.6, 162.8; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{12}$H$_{11}$N$_{2}$O$_{2}^{+}$: 239.0826, found: 239.0825; IR ($\tilde{\nu }$): 1571 (w), 1616 (m) cm$^{-1}$.

4-Hydroxy-3-methoxybenzaldazine (32): Following general procedure G, applying 304 mg 4-hydroxy-3-methoxybenzaldehyde (1.0 eq, 2.00 mmol), and 128 $\upmu$L hydrazine hydrate (80%  50% hydrazine, 1.0 eq, 2.00 mmol, 64 mg). The solution was cooled to room temperature, and the resulting precipitate was filtered and washed with water. Yield: 139 mg (0.46 mmol, 46%); yellow solid; mp: 172–173 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 3.84 (s, 6H), 6.87–7.46 (m, 6H), 8.58 (s, 2H), 9.70 (s, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 55.4, 109.9, 115.4, 123.4, 125.4, 147.9, 149.8, 160.5; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{16}$H$_{17}$N$_{2}$O$_{4}^{+}$: 301.1183, found: 301.1185; IR ($\tilde{\nu }$):): 1504 (m), 1599 (w) cm$^{-1}$.

(4-Hydroxyphenyl)methylketazine (33): Following general procedure G, applying 272 mg 1-(4-hydroxyphenyl)ethanone (1.0 eq, 2.00 mmol), and 128 $\upmu$L hydrazine hydrate (80%  50% hydrazine, 1.0 eq, 2.00 mmol, 64 mg). The solution was cooled to room temperature, and the resulting precipitate was filtered and washed with water. Yield: 122 mg (0.46 mmol, 46%); pale yellow solid; mp: 224 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.25 (s, 6H), 6.81–6.83 (m, 4H), 7.76–7.78 (m, 4H), 9.80 (s, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.2, 115.0, 128.0, 129.1, 157.6, 158.9; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{16}$H$_{17}$N$_{2}$O$_{2}^{+}$: 269.1285, found: 269.1278; IR ($\tilde{\nu }$): 1512 (w) cm$^{-1}$.

Benzaldazine (34): Following general procedure G, applying 202 $\upmu$L benzaldehyde (1.0 eq, 2.00 mmol, 212 mg), 128 $\upmu$L hydrazine hydrate (80%  50% hydrazine, 2.00 mmol, 64 mg), and 6 mL methanol. The solution was cooled to −18 ${^{\circ }}$C, and the resulting precipitate was filtered and washed with water. Yield: 84 mg (0.40 mmol, 19%); lemon yellow solid; mp: 85–86 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 7.50–7.71 (m, 10H), 8.73 (s, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 128.3, 128.8, 131.3, 133.7, 161.4; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{14}$H$_{13}$N$_{2}^{+}$: 209.1073, found: 209.1082; IR ($\tilde{\nu }$): no significant absorbance above $\tilde{\nu }$ = 1500 cm$^{-1}$.

Phenylmethylketazine (35): This compound was isolated as a side-product during the synthesis of 14. Hence, the diethyl ether filtrate was evaporated under reduced pressure, and the resulting residue washed with water. Yield: 104 mg (2.27 mmol, 21%); lemon yellow solid; mp: 119–120 ${^{\circ }}\hbox {C}$; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.28 (s, 6H), 7.45–7.94 (m, 10H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.7, 126.5, 128.4, 129.7, 137.9, 157.3; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{16}$H$_{17}$N$_{2}^{+}$: 237.1386, found: 237.1376; IR ($\tilde{\nu }$): no significant absorbance above $\tilde{\nu }$ = 1500 cm$^{-1}$.

4-Methoxybenzaldazine (36): This compound was isolated as a side-product during the synthesis of 15. Hence, the diethyl ether filtrate was evaporated under reduced pressure, and the resulting residue washed with water. Yield: 63 mg (0.24 mmol, 11%); yellow needles; mp: 168–169 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 3.83 (s, 6H), 7.04–7.07 (m, 4H), 7.80–7.83 (m, 4H), 8.64 (s, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 55.4, 114.4, 126.6, 130.0, 160.5, 161.7; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{16}$H$_{17}$N$_{2}$O$_{2}^{+}$: 269.1285, found: 269.1291; IR ($\tilde{\nu }$):): no significant absorbance above $\tilde{\nu }$ = 1500 cm$^{-1}$.

(4-Methoxyphenyl)methylketazine (37): This compound was isolated as a side-product during the synthesis of 3i. Hence the ethyl acetate filtrate was evaporated under reduced pressure, and the resulting residue washed with water. Yield: 350 mg (1.18 mmol, 56%); yellow solid; mp: 197–198 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.32 (s, 6H), 3.86 (s, 6H), 6.92–6.96 (m, 4H), 7.86–7.90 (m, 4H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.8, 55.4, 113.6, 128.1, 131.3, 157.8, 160.8; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{18}$H$_{21}$N$_{2}$O$_{2}^{+}$: 297.1598, found: 297.1595; IR ($\tilde{\nu }$): no significant absorbance above $\tilde{\nu }$ = 1500 cm$^{-1}$.

(Pyridin-4-yl)methylketazine (38): Following general procedure G, applying 220 $\upmu$L 1-(pyridin-4-yl)ethanone (1.0 eq, 2.00 mmol, 242 mg), and 128 $\upmu$L hydrazine hydrate (80%  50% hydrazine, 1.0 eq, 2.00 mmol, 64 mg). The solution was cooled to room temperature, and the resulting precipitate was filtered and washed with water. Yield: 131 mg (0.55 mmol, 55%); pale yellow solid; mp: 120–123 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.25 (s, 6H), 7.83–7.85 (m, 4H), 8.69–8.71 (m, 4H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.5, 120.6, 144.2, 150.1, 155.4; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{14}$H$_{15}$N$_{4}^{+}$: 239.1291, found: 239.1280; IR ($\tilde{\nu }$): 1591 (w) cm$^{-1}$.

General procedure H for the synthesis of compounds 54–56: The appropiate aldehyde (1.0 eq), ethyl 2-cyano acetate (1.0 eq), acetic acid (0.2 eq), and piperidine (0.1 eq) were dissolved in toluene in a round-bottom flask, which was equipped with a Dean-Stark apparatus. The reaction mixture was refluxed until no more water settled in the distilling trap. After cooling to room temperature, the solution was exhaustively extracted with brine, dried over Na$_{2}$SO$_{4}$, and evaporated under reduced pressure. The crude product was recrystallized from 2-propanol.

Ethyl ( E )-2-cyano-3-(4-methoxyphenyl)acrylate (54): Following general procedure H, applying 4.90 mL 4-methoxybenzaldehyde (1.0 eq, 40.0 mmol, 5.44 g), 4.30 mL ethyl 2-cyanoacetate (1.0 eq, 40.0 mmol, 4.52 g), 450 $\upmu$L acetic acid (0.2 eq, 8.00 mmol, 480 mg), 400 $\upmu$L piperidine (0.1 eq, 4.00 mmol, 341 mg), and 100 mL toluene. The reaction mixture was refluxed for 4 h. Yield: 8.25 g (35.7 mmol, 83%); lemon yellow solid; mp: 77–81 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.30 (t, 3H, J = 7.2 Hz), 3.87 (s, 3H), 4.30 (q, 2H, J = 7.2 Hz), 7.14–7.17 (m, 2H), 8.08–8.10 (m, 2H), 8.31 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.0, 55.8, 62.1, 98.6, 115.0, 116.2, 124.0, 133.5, 154.5, 162.4, 163.6; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{13}$H$_{14}$NO$_{3}^{+}$: 232.0968, found: 232.0963; IR ($\tilde{\nu }$): 1561 (m), 1714 (m) cm$^{-1}$.

Ethyl ( E )-2-cyano-3-(3-phenoxyphenyl)acrylate (55): Following general procedure H, applying 5.89 mL 3-phenoxybenzaldehyde (1.0 eq, 34.1 mmol, 6.76 g), 3.64 mL ethyl 2-cyanoacetate (1.0 eq, 34.1 mmol, 3.86 g), 390 $\upmu$L acetic acid (0.2 eq, 6.33 mmol, 410 mg), 340 $\upmu$L piperidine (0.1 eq, 3.41 mmol, 290 mg), and 200 mL toluene. Yield: 7.23 g (24.7 mmol, 72%); yellow solid; mp: 41–43 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.30 (t, 3H, J = 7.2 Hz), 4.31 (q, 2H, J = 7.2 Hz), 7.07 (m, 2H), 7.09–7.10 (m, 1H), 7.27–7.28 (m, 1H), 7.41–7.43 (m, 2H), 7.58–7.62 (m, 1H), 7.71–7.72 (m, 1H), 7.80–7.82 (m, 1H), 8.40 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.9, 62.4, 103.5, 115.3, 119.0, 119.7, 123.0, 124.1, 127.5, 130.2, 131.0, 133.1, 154.3, 155.8, 157.2, 161.6; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{18}$H$_{16}$NO$_{3}^{+}$: 294.1125, found: 294.1131; IR ($\tilde{\nu }$): 1717 (w) cm$^{-1}$.

Ethyl ( E )-2-cyano-3-(4-bromphenyl)acrylate (56): Following general procedure H, applying 7.74 g 4-brombenzaldehyde (1.0 eq, 42.0 mmol), 4.50 mL ethyl 2-cyanoacetate (1.0 eq, 42.0 mmol, 4.77 g), 450 $\upmu$L acetic acid (0.2 eq, 8.00 mmol, 480 mg), 400 $\upmu$L piperidine (0.1 eq, 4.00 mmol, 341 mg), and 100 mL toluene. The reaction mixture was refluxed for 2 h. Yield: 8.68 g (31.0 mmol, 87%); lemon yellow solid; mp: 93 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.31 (t, 3H, J = 7.2 Hz), 4.32 (q, 2H, J = 7.2 Hz), 7.80–7.83 (m, 2H), 7.96–8.00 (m, 2H), 8.39 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.0, 62.5, 103.3, 115.4, 127.2, 130.5, 132.4, 153.8, 161.6; HRMS (ESI, m / z) [M+Na$^{+}$]: calcd for C$_{12}$H$_{9}$BrNNaO$_{2}^{+}$: 300.9787, found: 300.0986; IR ($\tilde{\nu }$): 1581 (m), 1721 (s) cm$^{-1}$.

General procedure I for the synthesis of compounds 57–58: The appropiate acrylate (0.1 eq), potassium formate (2.0 eq), and palladium acetate (0.02 eq) were suspended in DMF under argon. The reaction mixture was heated at 45 ${^{\circ }}$C for several hours with vigorous stirring. Subsequently, the suspension was diluted with water and extracted exhaustively with diethyl ether. The organic phase was dried over Na$_{2}$SO$_{4}$ and evaporated under reduced pressure.

Ethyl 2-cyano-3-(4-methoxyphenyl)propanoate (57): Following general procedure I, applying 6.00 g ethyl (E)-2-cyano-3-(4-methoxyphenyl)-acrylate 54 (1.0 eq, 25.8 mmol), 4.33 g potassium formate (2.0 eq, 51.6 mmol), 116 mg palladium acetate (0.02 eq, 0.52 mmol), and 50 mL DMF. The reaction mixture was heated for 72 h, diluted with 100 mL water, and extracted with diethyl ether exhaustively. Yield: 2.69 g (11.5 mmol, 44%); pale brown oil; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.20 (t, 3H, J = 7.2 Hz), 3.10 (m, 2H), 3.74 (s, 3H), 4.17 (q, 2H, J = 7.2 Hz), 4.46 (m, 1H), 6.89–6.91 (m, 2H), 7.19–7.21 (m, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.8, 33.7, 39.0, 55.0, 62.2, 113.9, 117.1, 127.8, 130.2, 158.5, 166.0; HRMS (ESI, m / z) [M+Na$^{+}$]: calcd for C$_{13}$H$_{15}$NNaO$_{3}^{+}$: 256.0944, found: 256.0935; IR ($\tilde{\nu }$): 1513 (m), 1740 (m) cm$^{-1}$.

Ethyl 2-cyano-3-(3-phenoxyphenyl)propanoate (58): Following general procedure I, applying 7.23 g ethyl (E)-2-cyano-3-(4-phenoxyphenyl)-acrylate 55 (1.0 eq, 24.7 mmol), 4.16 g potassium formate (2.0 eq, 49.5 mmol), 110 mg palladium acetate (0.02 eq, 0.49 mmol), and 60 mL DMF. The reaction mixture was heated for 27 h, diluted with 100 mL water, and extracted exhaustively with ethyl acetate. The crude product was purified through column chromatography with light petroleum and ethyl acetate (7:3). Yield: 1.19 g (5.11 mmol, 21%); pale yellow oil; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.17 (t, 3H, J = 7.2 Hz), 3.15–3.20 (m, 2H), 4.14 (q, 2H, J = 7.2 Hz), 4.56 (m, 1H), 6.70 (m, 1H), 7.02 (m, 3H), 7.08 (m, 1H), 7.15 (m, 1H), 7.37 (m, 1H), 7.39 (m, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.7, 34.1, 38.5, 62.2, 116.9, 117.5, 118.5, 119.3, 123.4, 124.2, 130.0, 130.1, 138.2, 156.5–156.6, 165.8; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{18}$H$_{18}$NO$_{3}^{+}$: 296.1136, found: 296.1126; IR ($\tilde{\nu }$): 1741 (s) cm$^{-1}$.

Ethyl 2-cyano-3-phenylpropanoate (59): 3.40 g Sodium (1.0 eq, 148 mmol) were dissolved in 84 mL ethanol (1.0 eq, 144 mmol, 66.0 g). 7.90 mL ethyl 2-cyanoacetate (1.0 eq, 148 mmol, 8.40 g), and 17.5 mL benzyl bromide (1.0 eq, 148 mmol, 25.3 g) were added dropwise. The reaction mixture was heated for 6 h at 60 ${^{\circ }}$C. After cooling to room temperature, the suspension was diluted with 50 mL water, adjusted at pH 1 with hydrochloric acid, and extracted exhaustively with diethyl ether. The organic layer was evaporated under reduced pressure, and distilled at 0.3 mbar and 170–180 ${^{\circ }}$C. Yield: 2.18 g (10.7 mmol, 5%); colorless oil; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.19 (t, 3H, J = 7.2 Hz), 3.17 (m, 2H), 4.18 (q, 2H, J = 7.2 Hz), 4.53 (m, 1H), 7.28–7.36 (m, 5H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.8, 34.4, 38.7, 62.2, 117.0, 127.3, 128.5, 129.1, 136.0, 166.0; HRMS (ESI, m / z) [M–H$^{-}$]: calcd for C$_{12}$H$_{12}$NO$_{2}^{-}$: 202.0874, found: 202.0874; IR ($\tilde{\nu }$): 1740 (s) cm$^{-1}$.

Ethyl 2-benzyl-2-cyano-3-phenylpropanoate (65): 0.90 g Sodium (1.0 eq, 39.1 mmol) were dissolved in 22 mL ethanol (1.0 eq, 37.7 mmol, 17.4 g). 4.10 mL ethyl 2-cyanoacetate (1.0 eq, 38.5 mmol, 4.35 g), and 9.0 mL benzyl bromide (2.0 eq, 75.8 mmol, 13.0 g) were added dropwise. The reaction mixture was heated for 6 h at 60 ${^{\circ }}$C. After cooling to room temperature, the suspension was diluted with 50 mL water, adjusted at pH 1 with hydrochloric acid, and extracted with diethyl ether exhaustively. The organic layer was evaporated under reduced pressure, and distilled at 0.3 mbar and 165–170 ${^{\circ }}$C. Yield: 4.10 g (14.0 mmol, 35%); colorless oil; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 0.98 (t, 3H, J = 7.2 Hz), 3.24 (s, 2H), 3.34 (s, 2H), 4.01 (q, 2H, J = 7.2 Hz), 7.25–7.36 (m, 10H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.6, 42.3, 53.4, 62.2, 118.4, 127.6, 128.4, 129.8, 134.6, 167.6; HRMS (ESI, m / z) [$M+$H$^{+}$]: calcd for C$_{19}$H$_{20}$NO$_{2}^{+}$: 294.1489, found: 294.1478; IR ($\tilde{\nu }$): 1735 (w) cm$^{-1}$.

General procedure J for the synthesis of compounds 60, 61 and 66: The appropiate propanoate nitrile (1.0 eq), sodium azide (1.1 eq), and ammonium chloride (0.1 eq) were suspended in DMF, and the reaction mixture was heated at 95 ${^{\circ }}$C for several hours. The suspension was evaporated under reduced pressure, diluted with water, adjusted to pH 1 (CAUTION: Release of HN$_{3}$!), and extracted exhaustively with ethyl acetate. The crude product was purified through column chromatography with light petroleum, ethyl acetate and acetic acid.

Ethyl 3-(4-methoxyphenyl)-2-(1 H -tetrazol-5-yl)propanoate (60): Following general procedure J, applying 2.00 g ethyl 2-cyano-3-(4-methoxyphenyl)propanoate 57 (1.0 eq, 8.60 mmol), 615 mg sodium azide (1.1 eq, 9.46 mmol), 46 mg ammonium chloride (0.1 eq, 0.86 mmol), and 75 mL DMF. The reaction mixture was heated for 24 h, diluted with 50 mL water, and extracted exhaustively with ethyl acetate. The column chromatography was started with light petroleum, ethyl acetate and acetic acid 18:2:1 to elute remaining nitrile, and changed to 5:5:1 to elute the tetrazole. Yield: 500 mg (1.81 mmol, 20%); colorless solid; mp: 79–85 ${^{\circ }}$C; $^{1}$H-NMR (CDCl$_{3})$ $\delta$ = 1.25 (t, 3H, J = 7.2 Hz), 3.34 (m, 2H), 3.73 (s, 3H), 4.21 (q, 2H, J = 7.2 Hz), 4.55 (m, 1H), 6.71–6.73 (m, 2H), 6.78–6.81 (m, 2H); $^{13}$C-NMR (CDCl$_{3})$ $\delta$ = 14.2, 38.6, 43.7, 55.4, 62.7, 114.3, 127.6, 130.2, 159.2, 171.3; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{13}$H$_{17}$N$_{4}$O$_{3}^{+}$: 277.1295, found: 277.1296; IR ($\tilde{\nu }$): 1514 (s), 1724 (s) cm$^{-1}$.

Ethyl 3-phenyl-2-(1 H -tetrazol-5-yl)propanoate (61): Following general procedure J, applying 1.50 g ethyl 2-cyano-3–phenylpropanoate 59 (1.0 eq, 7.40 mmol), 529 mg sodium azide (1.1 eq, 8.14 mmol), 40 mg ammonium chloride (0.1 eq, 0.74 mmol), and 75 mL DMF. The reaction mixture was heated for 48 h, diluted with 50 mL water, and extracted exhaustively with ethyl acetate. The column chromatography was conducted with light petroleum, ethyl acetate and acetic acid 35:15:1. Yield: 900 mg (3.66 mmol, 48%); colorless solid; mp: 65–69 ${^{\circ }}$C; $^{1}$H-NMR (CDCl$_{3})$ $\delta$ = 1.23 (t, 3H, J = 7.2 Hz), 3.42 (m, 2H), 4.21 (q, 2H, J = 7.2 Hz), 4.62 (m, 1H), 6.94 (m, 5H); $^{13}$C-NMR (CDCl$_{3})$ $\delta$ = 14.0, 39.1, 43.5, 62.5, 127.5, 128.7, 128.9, 135.6, 153.7, 171.0; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{12}$H$_{15}$N$_{4}$O$_{2}^{+}$: 247.1190, found: 247.1188; IR ($\tilde{\nu }$): 1730 (s) cm$^{-1}$.

Ethyl 2-benzyl-3-phenyl-2-(1 H -tetrazol-5-yl)propanoate (66): Following general procedure J, applying 3.60 g ethyl 2-benzyl-2-cyano-3-phenylpropanoate 65 (1.0 eq, 12.0 mmol), 858 mg sodium azide (1.1 eq, 13.2 mmol), 64 mg ammonium chloride (0.1 eq, 1.21 mmol), and 75 mL DMF. The reaction mixture was heated for 22 h, diluted with 50 mL water, and extracted exhaustively with ethyl acetate. The column chromatography was conducted with light petroleum, ethyl acetate and acetic acid 35:15:1. Yield: 350 mg (1.04 mmol, 9%); colorless solid; mp: 131–136 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.47 (t, 3H, J = 7.2 Hz), 3.63 (m, 2H), 3.78 (m, 2H), 4.30 (q, 2H, J = 7.2 Hz), 6.70–7.12 (m, 10H), 12.63 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.3, 46.5, 56.1, 62.7, 127.7, 128.7, 129.2, 135.2, 156.3, 172.4; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{19}$H$_{21}$N$_{4}$O$_{2}^{+}$: 337.1659, found: 337.1644; IR ($\tilde{\nu }$): 1737 (w) cm$^{-1}$.

General procedure K for the synthesis of compounds 62 and 63: Diethyl aluminum chloride solution in toluene was added dropwise to sodium azide in a three-neck round-bottom flask equipped with reflux condenser and internal thermometer. The colorless slurry was stirred for 15 min under cooling in an ice bath, and for another 4 h at room temperature. Subsequently, the appropriate nitrile was added dropwise. The reaction mixture was heated at 80 ${^{\circ }}$C for several hours. After completion (checked by TLC), the flask was cooled in an ice bath, and a solution of sodium hydroxide and sodium nitrite in water was added. The pH was adjusted to 1 with concentrated hydrochloric acid (CAUTION: Release of HN$_{3}$!) whereupon brown fumes and colorless foam developed. The reaction mixture was extracted exhaustively with ethyl acetate and evaporated under reduced pressure.

3-(4-Methoxyphenyl)-2-(1 H -tetrazol-5-yl)propanoic acid (62): Following general procedure K, applying 4.90 mL diethyl aluminum chloride solution in toluene (25% diethyl aluminum chloride, 1.4 eq, 9.02 mmol, 1.09 g), 586 mg sodium azide (1.4 eq, 9.02 mmol), and 1.50 g ethyl 2-cyano-3-(4-methoxyphenyl)propanoate 57 (1.0 eq, 6.44 mmol). The reaction mixture was heated for 15 h. The workup was conducted with 1.08 g sodium hydroxide (4.2 eq, 27.1 mmol) and 1.87 g sodium nitrite (4.2 eq, 27.1 mmol) in 7.20 mL water, and 3 $\times$ 30 mL ethyl acetate. The organic layer was concentrated to 20 mL, and cooled to −18 ${^{\circ }}$C for several hours. The resulting precipitate was filtered and washed with toluene. Yield: 581 mg (2.10 mmol, 52%); off-white shiny solid; mp: 174–178 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 3.13–3.19 (m, 1H), 3.33–3.38 (m, 1H), 3.67 (s, 3H), 4.38 (m, 1H), 6.76–6.78 (m, 2H), 7.04–7.06 (m, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 35.0, 43.3, 54.9, 113.7, 129.4, 129.8, 157.9, 170.8; HRMS (ESI, m / z) [M+Na$^{+}$]: calcd for C$_{11}$H$_{11}$N$_{4}$NaO$_{3}^{+}$: 270.0729, found: 270.0727; IR ($\tilde{\nu }$): 1511 (m), 1711 (w), 1734 (w) cm$^{-1}$.

3-(3-Phenoxyphenyl)-2-(1 H -tetrazol-5-yl)propanoic acid (63): Following general procedure K, applying 8.80 mL diethyl aluminum chloride solution in toluene (25% diethyl aluminum chloride, 2.4 eq, 16.3 mmol, 1.97 g), 1.06 g sodium azide (2.4 eq, 16.3 mmol), and 2.00 g ethyl 2-cyano-3-(3-phenoxyphenyl)propanoate 58 (1.0 eq, 6.78 mmol). The reaction mixture was heated for 24 h. The workup was conducted with 2.74 g sodium hydroxide (4.2 eq, 68.5 mmol) and 4.72 g sodium nitrite (4.2 eq, 68.5 mmol) in 20 mL water, and 3 $\times$ 50 mL ethyl acetate. The organic layer was concentrated under reduced pressure and purified through column chromatography, which was started with light petroleum and acetid acid (8:2), and continued with light petroleum, ethyl acetate and acetic acid (4:1:1). Yield: 200 mg (0.65 mmol, 10%); beige solid; mp: 150–153 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 3.17–3.23 (m, 1H), 3.38–3.43 (m, 1H), 4.43 (m, 1H), 6.77–6.78 (m, 1H), 6.82–6.83 (m, 1H), 6.88–6.91 (m, 2H), 6.93–6.95 (m, 1H), 7.11–7.15 (tt, 1H), 7.21–7.25 (t, 1H), 7.35–7.39 (m, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 35.6, 42.9, 116.7, 118.2, 119.1, 123.2, 123.9, 129.8, 129.9, 139.9, 154.3, 156.2, 156.5, 170.7; HRMS (ESI, m / z) [M+Na$^{+}$]: calcd for C$_{16}$H$_{13}$N$_{4}$NaO$_{3}^{+}$: 332.0885, found: 332.0887; IR ($\tilde{\nu }$): 1584 (w), 1711 (w), 1733 (vw) cm$^{-1}$.

General procedure L for the synthesis of compounds 39 and 40: The appropriate 2-(1H-tetrazol-5-yl)propanoate was dissolved in hydrazine hydrate solution (80% 50% hydrazine), and heated under reflux for several hours. All volatiles were removed under reduced pressure, and residual hydrazine removed by azeotropic distillation with ethanol. The crude product was dried in a desiccator over sulfuric acid.

3-(4-Methoxyphenyl)-2-(1 H -tetrazol-5-yl)propanoic acid hydrazide (39): Following general procedure L, applying 400 mg ethyl 3-(4-methoxyphenyl)-2-(1H-tetrazol-5-yl)propanoate 60 (1.0 eq, 1.50 mmol), and 5 mL hydrazine hydrate solution (80%  50% hydrazine, 54 eq, 80.5 mmol, 2.58 g). The reaction mixture was heated for 8 h. The crude product was dissolved in 5 mL methanol, overlaid with 10 mL toluene, and the resulting two-phase solution closed with tin foil, leaving a few holes for evaporation. After 3 d the resulting colorless crystals were filtered off. Yield: 120 mg (0.46 mmol, 30%); colorless solid; mp: 138–142 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 3.17 (m, 2H), 3.68 (s, 3H), 3.90 (m, 1H), 6.73–6.76 (m, 2H), 7.01–7.03 (m, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 36.5, 44.3, 54.9, 113.2, 129.8, 131.9, 157.4, 159.2, 170.7; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{11}$H$_{15}$N$_{6}$O$_{2}^{+}$: 263.1251, found: 263.1248; IR ($\tilde{\nu }$): 1510 (s), 1676 (w) cm$^{-1}$.

3-Phenyl-2-(1 H -tetrazol-5-yl)propanoic acid hydrazide (40): Following general procedure L, applying 700 mg ethyl 3-phenyl-2-(1H-tetrazol-5-yl)propanoate 61 (1.0 eq, 2.80 mmol), and 10 mL hydrazine hydrate solution (80%  50% hydrazine, 58 eq, 161 mmol, 5.15 g). The reaction mixture was heated for 27 h. Yield: 650 mg (2.80 mmol, >95%); colorless solid; mp: 155–165 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 3.21 (m, 2H), 3.91 (m, 1H), 7.11–7.19 (m, 5H), 9.11 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 37.2, 43.7, 125.7, 127.8, 128.7, 140.0, 159.4, 170.7; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{10}$H$_{13}$N$_{4}$O$^{+}$: 233.1145, found: 233.1145; IR ($\tilde{\nu }$): 1680 (w) cm$^{-1}$.

5-(4-Methoxyphenethyl)-1 H -tetrazole (64): This compound was isolated during the trial to synthesize 3-(4-methoxyphenyl)-2-(1H-tetrazol-5-yl)propanoic acid hydrazide 39 starting from 3-(4-methoxyphenyl)-2-(1H-tetrazol-5-yl)propanoic acid 62. For this purpose, 200 mg propanoic acid 62 (1.0 eq, 0.81 mmol), and 151 $\upmu$L hydrazine hydrate solution (80%  50% hydrazine, 3.0 eq, 2.42 mmol, 77.4 mg) were suspended in 50 mL toluene and 35 mL 1-butanol in a round-bottom flask which was equipped with a Dean-Stark apparatus. The reaction mixture was heated at 111 ${^{\circ }}$C for 14.5 h and, then, evaporated under reduced pressure. The crude product was dissolved in 20 mL methanol, overlaid with 20 mL toluene, and the resulting two-phase solution closed with tin foil, leaving a few holes for evaporation. After 3 d the resulting colorless needles were filtered off and washed with diethyl ether. Yield: 33 mg (0.16 mmol, 15%); colorless needles; mp: 137–139 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 2.95–2.99 (t, 2H), 3.12–3.16 (t, 2H), 3.70 (s, 3H), 6.82–6.84 (m, 2H), 7.10–7.12 (m, 2H), 16.00 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 24.8, 31.8, 54.9, 113.7, 129.1, 131.7, 157.6; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{10}$H$_{11}$N$_{4}$NaO$^{+}$: 226.0831, found: 226.0835; IR ($\tilde{\nu }$): 1512 (m) cm$^{-1}$.

3-(1 H -Tetrazol-5-yl)benzoic acid (68): 1.00 g 3-cyanobenzoic acid (1.0 eq, 6.80 mmol), 930 mg sodium azide (2.1 eq, 14.3 mmol), and 37 mg ammonium chloride (0.1 eq, 0.69 mmol) were suspended in 30 mL DMF. The reaction mixture was heated at 100 ${^{\circ }}$C for 30.5 h. The solvent was removed under reduced pressure, the crude product was dissolved in 40 mL water, and the pH adjusted to 1 with concentrated hydrochloric acid (CAUTION: Release of HN$_{3}$!). The resulting precipitate was filtered, washed with water, and recrystallized from ethanol. Yield: 440 mg (2.32 mmol, 34%); colorless solid; mp: 75–77 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 7.75–7.79 (t, 1H), 8.14–8.16 (m, 1H), 8.30–8.32 (m, 1H), 8.65 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 124.7, 127.6, 129.8, 131.0, 131.7, 131.9, 166.5; HRMS (ESI, m / z) [M-H$^{-}$]: calcd for C$_{8}$H$_{5}$N$_{4}$O$_{2}^{-}$: 189.0418, found: 189.0416; IR ($\tilde{\nu }$): 1647 (w) cm$^{-1}$.

Ethyl 3-(1 H -tetrazol-5-yl)benzoate (69): 400 mg 3-(1H-tetrazol-5-yl)benzoic acid (68) (1.0 eq, 2.10 mmol), and 256 $\upmu$L sulfuric acid (4.5 eq, 9.90 mmol, 968 mg) were dissolved in 20 mL ethanol, and the reaction mixture was heated at 80 ${^{\circ }}$C for 26 h. The solvent was removed under reduced pressure, the residue was diluted with 30 mL water, and extracted exhaustively with diethyl ether. The organic layer was finally evaporated to obtain the compound as a colorless solid. Yield: 330 mg (1.51 mmol, 72%); colorless solid; mp: 144–148 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.37 (t, 3H), 4.38 (q, 2H), 7.75–7.79 (t, 1H), 8.13–8.15 (m, 1H), 8.30–8.32 (m, 1H), 8.63 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.1, 61.2, 124.9, 127.4, 130.0, 131.0, 131.3, 131.5, 165.0; HRMS (ESI, m / z) [M–H$^{-}$]: calcd for C$_{10}$H$_{9}$N$_{4}$O$_{2}^{-}$: 217.0731, found: 217.0731; IR ($\tilde{\nu }$): 1686 (m) cm$^{-1}$.

3-(1 H -Tetrazol-5-yl)benzohydrazide (41): 250 mg ethyl 3-(1H-tetrazol-5-yl)benzoate (69) (1.0 eq, 1.15 mmol) were dissolved in 5 mL hydrazine hydrate solution (80%  50% hydrazine, 40 eq, 39.3 mmol, 2.58 g), and the reaction mixture was heated at 90 ${^{\circ }}$C for 8 h. The solvent was removed under reduced pressure, and the crude product was dissolved in 10 mL water and 30 mL diethyl ether. After cooling at −18 ${^{\circ }}$C for several hours, the resulting precipitate was filtered, and washed with diethyl ether. Yield: 110 mg (0.54 mmol, 46%); colorless solid; mp: 211–215 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 7.47–7.51 (t, 1H), 7.73–7.75 (m, 1H), 8.11–8.13 (m, 1H), 8.47 (s, 1H), 9.87 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 124.8, 125.8, 128.3, 128.4, 131.5, 133.7, 159.5, 166.0; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{8}$H$_{9}$N$_{6}$O$^{+}$: 205.0832, found: 205.0830; IR ($\tilde{\nu }$): 1541 (m), 1585 (w), 1630 (m) cm$^{-1}$.

Ethyl 4-cyanobenzoate (71): 4.81 g ethyl 4-aminobenzoate (1.0 eq, 29.0 mmol) were dissolved in a solution of 20 mL methanol, and diluted hydrochloric acid (1:1), and cooled to 5 ${^{\circ }}$C. Subsequently, 2.65 g sodium nitrite (1.3 eq, 37.0 mmol) in 30 mL water were added dropwise. 3.14 g copper(I)-cyanide (1.2 eq, 35.0 mmol) and 4.81 g sodium cyanide (3.4 eq, 98.0 mmol) were dissolved in 25 mL water under vigorous stirring at 40 ${^{\circ }}$C during 30 min. The first solution was added dropwise to the second one. To avoid foam formation a few drops 1–octanol were added. The brown suspension was extracted exhaustively with diethyl ether. The organic layer was evaporated under reduced pressure and cooled to −18 ${^{\circ }}$C for several hours. The resulting precipitate was filtered, and washed with water. Yield: 940 mg (5.37 mmol, 19%); colorless solid; mp: 50–51 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.33 (t, 3H), 4.35 (q, 2H), 7.99–8.01 (m, 2H), 8.08–8.10 (m, 2H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 13.9, 61.4, 115.3, 118.0, 129.7, 132.7, 133.7, 164.4; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{10}$H$_{10}$NO$_{2}^{+}$: 176.0706, found: 176.0707; IR ($\tilde{\nu }$): 1716 (s) cm$^{-1}$.

Ethyl 4-(1 H -tetrazol-5-yl)benzoate (72): 700 mg ethyl 4-cyanobenzoate 71 (1.0 eq, 4.00 mmol), 300 mg sodium azide (1.1 eq, 4.40 mmol), and 22 mg ammonium chloride (0.1 eq, 0.40 mmol) were suspended in 50 mL DMF. The orange reaction mixture was heated at 95 ${^{\circ }}$C for 70 h. The solvent was removed under reduced pressure, the crude product was dissolved in 50 mL water, and the pH adjusted to 1 with concentrated hydrochloric acid (CAUTION: Release of HN$_{3}$!). The resulting precipitate was filtered and washed with water. Yield: 400 mg (1.83 mmol, 46%); beige solid; mp: 158–161 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 1.35 (t, 3H), 4.36 (q, 2H), 8.15–8.21 (m, 4H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 14.1, 61.1, 127.2, 128.5, 130.0, 131.9, 132.7, 165.0; HRMS (ESI, m / z) [M-H$^{-}$]: calcd for C$_{10}$H$_{9}$N$_{4}$O$_{2}^{-}$: 217.0731, found: 217.0728; IR ($\tilde{\nu }$): 1695 (s) cm$^{-1}$.

4-(1 H -Tetrazol-5-yl)benzohydrazide (42): 320 mg ethyl 4-(1H-tetrazol-5-yl)benzoate (72) (1.0 eq, 1.47 mmol) were dissolved in 5 mL hydrazine hydrate solution (80%  50% hydrazine, 26.7 eq, 39.3 mmol, 2.58 g), and the reaction mixture was heated at 90 ${^{\circ }}$C for 3.5 h. 20 mL ethanol and 30 mL diethyl ether were added, and the flask was cooled to −18 ${^{\circ }}$C for several hours. The resulting precipitate was filtered and washed with diethyl ether. Yield: 250 mg (1.23 mmol, 83%); colorless solid; mp: 307–310 ${^{\circ }}$C; $^{1}$H-NMR (DMSO-$d_{6})$ $\delta$ = 7.83–7.85 (m, 2H), 7.99–8.03 (m, 2H), 9.76 (s, 1H); $^{13}$C-NMR (DMSO-$d_{6})$ $\delta$ = 125.8, 127.4, 132.5, 132.7, 158.6, 165.6; HRMS (ESI, m / z) [M+H$^{+}$]: calcd for C$_{8}$H$_{9}$N$_{6}$O$^{+}$: 205.0832, found: 205.0829; IR ($\tilde{\nu }$): 1643 (s) cm$^{-1}$.