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Heterocycles incorporating a pyrimidopyrimidine scaffold have aroused great interest from researchers in the field of medical chemistry because of their privileged biological activities; they are used as anti-bacterial, antiviral, anti-tumor, anti-allergic, antihypertensive, anticancer, and hepatoprotective agents. Therefore, the present study aims to investigate the chemistry of heterocycles incorporating pyrimido[1,6-a]pyrimidine and pyrimido[1,6-c]pyrimidine skeletons and their biological characteristics. The main sections discuss (1) the synthetic routes to obtain substituted pyrimidopyrimidines, pyrimido[1,6-a]pyrimidin-diones, pyrimidoquinazolines, tricyclic, tetracyclic, and binary systems; (2) the reactivity of the substituents attached to the pyrimidopyrimidine skeleton, including thione and amide groups, nucleophilic substitutions, condensations, ring transformations, and coordination chemistry; (3) compounds of this class of heterocycles containing a significant characteristic scaffold and possessing a wide range of biological characteristics.

The aim of this work is to discuss the chemistry of pyrido[3,4-d]pyrimidines as one of the most important heterocyclic compounds with remarkable synthetic, biological and medical applications. In this overview, the chemistry of heterocyclic compounds incorporated the pyrido[3,4-d]pyrimidine scaffold as demonstrated by chemical reactions and different preparation processes. The anticipated compounds were synthesized from pyridine or pyrimidine compounds and a description of the reactivity of substituents attached to ring carbon and nitrogen atoms is discussed. On the other hand, the synthesis and reactions of fused heterocycles incorporated pyrido[3,4-d]pyrimidine scaffold is described. The diamine analogs included pyrido[3,4-d]pyrimidine core were reported as tyrosine kinase inhibitors. The chemical reactions of certain unexpected and chemically substantial compounds have been discussed.

The present study provides an overview of the chemistry and biological significance of pyrimido[4,5-d]pyrimidine and pyrimido[5,4-d]pyrimidine analogs as types of bicyclic [6 + 6] systems. The main sections include: (1) synthesis methods; (2) the reactivities of the substituents linked to the ring carbon and nitrogen atoms; and (3) biological applications. A discussion demonstrating the proposed mechanisms of unexpected synthetic routes is intended. The aim of this study is to discuss the synthetic significance of the titled compounds and to establish the biological characteristics of this class of compounds as studied to date, where the compounds have been applied on a large scale in the medical and pharmaceutical fields. This survey will help researchers in the fields of synthetic organic and medicinal chemistry to undertake and improve new approaches for the construction of new standard biological components.

4-Formylphenyl benzoate was utilized as a versatile precursor for the construction of new series of heterocyclic scaffolds that contain thiazole and thiazolidin-5-one rings. The antibacterial activity of these scaffolds against two types of bacteria was screened and most of them exhibited good activity. Among the synthesized thiazole derivatives, compounds 5, 6, and 8a showed antibacterial activity close to the standard chemotherapeutic (Ampicillin).

The versatile hitherto reported 3-(1H-indol-3-yl)-1H-pyrazol-5-amine () was synthesized by the reaction of 3-cyanoacetylindole () with hydrazine hydrate in refluxing ethanol and used as a key intermediate for the synthesis of novel pyrazolo[1,5-a]pyrimidines via its reactions with appropriate 1,3-biselectrophilic reagents or through three-component condensations with triethyl orthoformate and compounds possessing an activated methylene group. Besides, the applicability and synthetic potency of () to attain polyfunctionally substituted imidazo[1,2-b]pyrazole, pyrazolo[1,5-a][1,3]diazepine and pyrazolo[1,5-c][1,3,5]thiadiazine derivatives of an expected pharmaceutical interest have been investigated. The mechanistic aspects for the formation of the newly synthesized compounds are discussed.

A general mild and efficient protocol for the synthesis of amidochloroalkylnaphthol libraries was achieved utilizing SiO2–ZnCl2 (silzic) as a reusable heterogeneous catalyst via Ritter-type reaction, through one-pot, three-component condensation of various aldehydes, chloroacetonitrile, and β-naphthol under solvent-free reaction conditions. The amidochloroalkylnaphthols were cyclized to its related oxazepinones, and their anticancer and antioxidant activities were studied.

2-Thiazolylhydrazonomalononitrile (1) was used as key intermediate for the synthesis of polyfunctionally substituted heterocycles (e.g. pyridazine, tetrazole, pyrimidines, 1,5-benzo diazepine, benzoimidazo[1,2-a]pyrimidine, triazolo[4,3-a]pyrimidine, pyrazole, pyrazolo[1,5-a]triazines, pyrazolo[1,5-a]pyrimidine and 1,5-benzoxazocine) incorporating thiazole moiety via its reactions with some carbon and nitrogen nucleophiles. Structures of the newly synthesized compounds were established by elemental analysis and spectral data. The mechanistic aspects for the formation of the new compounds were also discussed.

This review highlighted the methods used for the synthesis of different heterocyclic compounds derived from 3-(1H-indol-3-yl)-3-oxopropanenitrile. The reactivity and their synthetic importance were investigated. In this context, recent progress in the synthesis and use of 3-(1H-indol-3-yl)-3-oxopropanenitrile as precursors for heterocyclic compounds is reviewed.

2-Thiazolylhydrazonomalononitrile (1) was used as key intermediate for the synthesis of polyfunctionally substituted heterocycles (e.g. pyridazine, tetrazole, pyrimidines, 1,5-benzo diazepine, benzoimidazo[1,2-a]pyrimidine, triazolo[4,3-a]pyrimidine, pyrazole, pyrazolo[1,5-a]triazines, pyrazolo[1,5-a]pyrimidine and 1,5-benzoxazocine) incorporating thiazole moiety via its reactions with some carbon and nitrogen nucleophiles. Structures of the newly synthesized compounds were established by elemental analysis and spectral data. The mechanistic aspects for the formation of the new compounds were also discussed.

A novel multicomponent synthesis of highly substituted pyrazolo[1,5-a]pyrimidine derivatives starting from simple and readily available reactants is described. Three-component condensation of 4-(thiazol-2-yldiazenyl)-1H-pyrazole-3,5-diamine with triethyl orthoformate and carbonyl compounds or nitriles containing an activated methylene group gave substituted pyrazolo[1,5-a]pyrimidines. An analogous reaction of 4-(thiazol-2-yldiazenyl)-1H-pyrazole-3,5-diamine with ethyl acetoacetate and benzaldehyde in an effective one-pot process furnished ethyl 2-amino-5-methyl-7-phenyl-3-(thiazol-2-yldiazenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate.