## 2 Synthesis of 1,3,4-Oxadiazole Precursors  
A wide group of five-membered heterocycles, called oxadiazoles, contain one oxygen and two nitrogen atoms in their structure. There are four isomers of these systems (Figure 1), of which the 1,2,3-oxadiazole (Figure 1a) is the least stable due to the possibility of a ring-opening reaction to formyldiazomethane. In consequence, it only occurs in expanded arrangements in which such a transformation has difficulty taking place [11]. The remaining isomeric oxadiazoles exist in stable forms as the simplest systems with an unsubstituted ring [11]. Among the presented isomers, 1,3,4-oxadiazole and its derivatives are of particular scientific interest due to their broad application potential in many fields (Scheme 1). They are widely used in pharmacology due to their valuable biological properties, such as antibacterial, antifungal, antitumor, and anti-inflammatory properties [13; 14; 15; 16; 17; 18; 19; 20]. Their fungicidal, herbicidal, and insecticidal properties are useful for agricultural applications [21; 22; 23; 24; 25]. A detailed study dedicated to the biological importance of 1,3,4-oxadiazoles and their application in medicine and agriculture was published recently by [PERSON] and [PERSON] [26]. The electron-deficient oxadiazole ring, in combination with other aromatic groups, is responsible for the unique electronic properties of such compounds, which are responsible for their applications in material engineering [27; 28; 29; 30; 31] and optoelectronics [32; 33; 34; 35; 36; 37]. The synthesis of 1,3,4-oxadiazole using formylhydrazone ethylformate was described in the 1960s. The variety of substrates that can be used to prepare such a heterocyclic core became the inspiration of some literature reviews [38; 39; 17]. The most important methods to synthesize 1,3,4-oxadiazoles involve the cyclodehydration of diacylglycerolhydrazine derivatives (Scheme 2a) and the oxidative cyclization of acylhydrazones (Scheme 2d). Other synthetic routes include the direct cyclocondensation of acid hydrazides using aldehydes or carboxylic acids (Scheme 2b), triethyl orthoesters, or trifluoromethyl derivatives (Scheme 2c). Other possibilities include transformations of heterocyclic arrangements, including 1,2,4-oxadiazoles (Scheme 2e) or 1,2,3,4-tetrazoles (Scheme 2f) [38; 17; 39]. One of the most interesting subgroups of 1,3,4-oxadiazoles, in terms of electronic properties and stability, are compounds in which the 1,3,4-oxadiazol core is directly conjugated to other aromatic or heteroaromatic moieties. A literature review of the last decades shows that three general methods are used to obtain such derivatives: (a) direct aylation of 1,3,4-oxadiazoles, (b) cyclization of 1,3,4-oxadiazol derivatives substituted with an unsaturated group with subsequent aromatization, and (c) coupling of halogen-containing 1,3,4-oxadiazoles with other organometallics (Scheme 3). Figure 1: Four isomeric structures of oxadiazole: (**a**) 1,2,3-oxadiazole; (**b**) 1,2,4-oxadiazole; (**c**) 1,2,5-oxadiazole; and (**d**) 1,3,4-oxadiazole. The vast group of direct aylation methods includes reactions with aryl halides, organometallics, and compounds bearing different functionalities (a). The second most popular group of methods (b) mainly uses _ortho_-substituted phenols, thiophenols, and amines containing an unsaturated group, which can be converted into aromatic fragments. The least popular are cross-coupling reactions that use organoboron compounds (c). **Scheme 3. ** General concept for the expansion of the 1,3,4-oxadiazole scaffold via aromatic moieties. **3. Direct Arylation of 1,3,4-Oxadiazoles Using Aryl Halides**  
_3.1. Reactions with Aryl lodides_  
A literature study of the last two decades revealed that aryl halides (iodides, bromides, chlorides, fluorides) are particularly useful partners for 1,3,4-oxadiazoles in direct arylations and lead to conjugated arrangements. A review of the reactions of monosubstituted 1,3,4-oxadiazoles with a range of aryl iodides is presented in Scheme 4.