## 2 Results  
One of the most straightforward approaches to prepare substituted pyrimidines is via Suzuki coupling of halogenated pyrimidines with boronic acids [20; 21]. There have been a variety of studies performed in order to propose the reaction mechanism underlaying the Suzuki-Miyaura coupling, consisting of several key steps. The initial pre-catalyst activation allows the formation of Pd(0) species. In the second step, during oxidative addition of aryl halide to the palladium center, the insertion of metal atom into the C\({}_{\text{Ipson}}\) and halide (X) bond occurs and the complex [aryl-Pd(II)(L\({}_{n}\))-X] forms, where L represents the potentially bound ligand to the palladium centre, with n ranging from 1 to 4 [28]. Then the oxygen-containing nucleophilic (either hydroxide from base followed by addition of boronic acid RB(OH)\({}_{2}\), or boronate RB(OH)\({}_{3}\)-) replaces the halide group at palladium, which is later followed by transmetalation leading to the formation of aryl-Pd(II)(L\({}_{n}\))-R species. The final step includes reductive elimination of a product aryl-R with newly formed C-C bond, and regeneration of Pd(II) to Pd(0) [29]. In this study, Suzuki cross-coupling reaction between commercially available 2,4-dichloropyrimidine (**1**) and phenylboronic acid (**2**) was used as a model reaction to select appropriate catalyst, catalyst loading, solvent(s), and optimal  
Figure 1: Representative drugs with pyrimidine moiety on the market: anticancer (e.g., imatinib [6]), antiviral (e.g., zidovudine [7]), antibacterial (e.g., trimethoprim [8]), antihyperlipidemic (e.g., rosvastatin [9; 27]), antihypertensive (e.g., minorcidil), and antimalarial (e.g., pyrimethamine). reactions conditions (temperature, time). Our first attempt was to systemically screen the most common solvents used in Suzuki coupling reactions. Based on previous studies [21], tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) along with potassium carbonate K2 CO3 as a base was selected as the starting catalytic system (Scheme 1). A good selection of appropriate solvent for cross-coupling reactions is imperative. The screening of most common solvents for cross-coupling reactions (i.e., H2O, MeOH, THF, DMF, 1,4-dioxane, isopropanol, ethylene glycol) was performed at a room temperature (r.t.) and higher temperatures (60-100 \({}^{\circ}\)C), with yields determined by LC-MS being obtained after 1 h, 2 h, and 24 h (see Supporting Information, Table S1). The highest yields were obtained for less polar solvents, like isopropanol (64%) and 1,4-dioxane (72%), contrary to polar H2O, MeOH, DMF, and ethylene glycol, which corresponds to the observation made by [PERSON] about Pd(PPh3)4 [30]. The choice of solvent (therefore its boiling point) defines the maximum operating temperature [31]. On the set of less polar solvents THF, isopropanol, and 1,4-dioxane with boiling points of 66 \({}^{\circ}\)C, 83 \({}^{\circ}\)C, and 101 \({}^{\circ}\)C, respectively, we confirmed that higher temperatures vastly improve the yield of reaction due to the high activation barriers reagents need to overcome for successful coupling. The C2 side product was formed in less than 8%, which is consistent with the literature reports [24]. We decided to repeat the reaction in four best solvents (i.e., THF, DMF, 1,4-dioxane and isopropanol) and isolate the pure product 3 by column chromatography. The isolated yields are presented in Table 1. The highest yield of 71% was obtained for non-polar 1,4-dioxane, which has been reported to complement Pd(PPh3)4 [30], thus we decided to proceed with further optimization in this solvent. In a continuation of our study, we screened the most common commercially available palladium catalysts for this type of reaction. Tris(dibenzylideneacetone)palladium(0) (Pd2 dba3) was not efficient for this type of reaction as has already been observed [32; 33], whereas as an adduct with chloroform (Pd2 dba3. CHCl3) and together with tri-_tert_-butylphosphonium tetrafluoroborate (TTBP.