**4. Conclusion**

This manuscript brings a focused perspective of synthetic methods employed in producing bioactive pyrimidine-based derivatives. A special consideration is given to the FDA approved pyrimidine-based drugs, however, approaches to synthesize bioactive synthons endowed with in interesting bioactivities are also included.

Synthetic approaches used for preparing pyrimidine-cored structures varied from nucleophilic substitution to C-C, C-N cross-coupling or heterocyclization of complementary dielectrophilic (+)C–C–C(+) and dinucleophilic ()N-C-N() fragments. Converting the carbonyl/or hydroxyl group to chloride using POCl3 was often employed in facilitating the substitution reaction at the desired site. In other cases, oxidizing methyl thioether to sulfone offers a convenient option for substitution reactions.

It was noted that reactivity of the four possible sites (C2, C4, C4 and C6) is affected by a prior existence of substitutes or the type of the linkages (C-C, C-N, C-S or C-O).

#### **4.1 Decorated pyrimidines: privileged scaffolds meeting the Mission**

The 2,3-diazine (pyrimidine) is found in the core of wide range of bioactive drugs and drug candidates. That includes natural products (from bacteria all along until mammalians) sources and synthetic pharmaceuticals. A wide-range of activities were associated with pyrimidine and derivatives (antibacterial, antitumor, antiviral, analgesic, antiarrhythmic, antifungal [106], antimalarial, anticonvulsant, sought be. Thus, the structure is considered by medicinal chemists, drug discovery researchers and pharmacologist as medicinally privileged scaffold.

#### **4.2 Two strategies to afford diverse derivatives**

#### *4.2.1 Post Heterocyclization*

One main strategy in derivatizing pyrimidine get advantage of the availability of halogenated core synthons [mono-, di- or trichloro-pyrimidines]. An approach defines as "post- heterocyclization modification. In such cases, halogenated pyrimidine (frequently 2,4-dichloropyrimidine (38) or 2,4,6-trichloropyrimidine (109)) proved to be highly treasured when subjected to modifying reaction conditions and reagents and afforded the desired products. 2,4-dichloropyrimidine (38), 2,4,6 trichloropyrimidine (109) or similar analogues are made use of in preparing long list of modified pyrimidines. In such case, synthetic methods used in decorating pyrimidine-cored analogues were diverse and include nucleophilic substitution, C-C, C-N, C-O and C-S cross-coupling employing Suzuki or Ullmann conditions or amide coupling.

#### *4.2.2 Constructing while Heterocyclization*

In the cases where the desired product is not feasible via coupling or substitution, cross-coupling to reactive form of the heterocyclic core, alternative approaches were implemented. Constructing of the substituted pyrimidines via heterocyclization of predetermined "designed" components i.e. starting from derivatized parts that upon applying matching reaction conditions a "merged" modified core is amalgamated. For example, the syntheses of 2,4,5,6-terasubstituted pyrimidines were made possible by "fusion" of ß-ketoester derivatives with the corresponding amidine or guanidine elements. All should be conducted under carefully designed and appropriate implemented reaction conditions.

#### **4.3 Cases elaborated**

Four examples of FDA approved 2,4-disubstitited pyrimidine drugs Pazopanib (21), Remibrutinib (31), Dabrafenib (60) and Rilpivirine (62) were discussed in particular. Examples 4,5,6-trisubstituted pyrimidines like Remibrutinib (31), 2,4 diamino-6-alkyl- or 6-aryl-pyrimidine derivatives were also presented. The approach starting from 2,4,6-trichloropyrimidine (109), giving rise to N-trisubstituted pyrimidine derivatives like Buparlisib [NVP-BKM120] (115) were discussed. A light was shed on 2,4,5,6-tetrasubstituted pyrimidines like Bay 41–4109 (135) and 2-amino-4,6 disubstituted pyrimidines, Etravirine (TMC 125) (63), 2,4-diamino-6-piperidinopyrimidine 3-oxide Minoxidil (171).

#### **4.4 No means to delineate all**

This manuscript aimed at briefing the reader, in an elaborative manner, with some instances and show-case of chemical process affording selected examples of FDAapproved therapeutics. The focus is on approaches employed the "postheterocyclization" modification methods.
