Substituted Pyrazoles and Their Heteroannulated Analogs—Recent Syntheses and Biological Activities

Pyrazoles are considered privileged scaffolds in medicinal chemistry. Previous reviews have discussed the importance of pyrazoles and their biological activities; however, few have dealt with the chemistry and the biology of heteroannulated derivatives. Therefore, we focused our attention on recent topics, up until 2020, for the synthesis of pyrazoles, their heteroannulated derivatives, and their applications as biologically active moieties. Moreover, we focused on traditional procedures used in the synthesis of pyrazoles.


Introduction
Pyrazoles consist of two nitrogen atoms adjacent to three carbon atoms in a fivemembered aromatic ring structure ( Figure 1). Due to the broad spectrum of biological activities, the pyrazole ring is considered an interesting class in drug discovery [1].

Introduction
Pyrazoles consist of two nitrogen atoms adjacent to three membered aromatic ring structure ( Figure 1). Due to the broad activities, the pyrazole ring is considered an interesting class in d Unsubstituted pyrazole can be represented in three tautome  Unsubstituted pyrazole can be represented in three tautomeric forms [2] (Figure 2).

Introduction
Pyrazoles consist of two nitrogen atoms adjacent to three membered aromatic ring structure ( Figure 1). Due to the broad activities, the pyrazole ring is considered an interesting class in d Unsubstituted pyrazole can be represented in three tautome  Interestingly, pyrazoles as a class of azoles, are found in naturally occurring compounds. Kikuchi et al. [3] reported on two compounds, 1-[2-(5-hydroxymethyl-1H-pyrrole-biological, agrochemical, and pharmacological properties [4]. Moreover, a large number of structurally diverse natural compounds containing azole nucleus constitute an important class of biologically active heterocycles that are gaining more attention in the field of medicinal chemistry [5]. Many pyrazoles have shown luminescent and fluorescent agents. Some of these compounds have important applications in material chemistry [6] and as brightening agents [7]. Others exhibit solvatochromic [8] and electroluminescence [9] properties. Moreover some pyrazoles act as semiconductors [10], liquid crystals [11], and organic light-emitting diodes [12].
Pyrazoles are frequently observed as bioactive components in commercially available medicines. For example, rimonabant is a cannabinoid ligand and is used for treating obesity; fomepizole prevents alcohol dehydrogenase, celecoxib is a nonsteroidal antiinflammatory drug (NSAID), specifically, a COX-2 inhibitor, which relieves pain and inflammation, and sildenafil is a PDE 5 inhibitor used in the treatment of erectile dysfunction [39] (Figure 4). This review summarizes the updated methods (until the end of 2020) that are generally used to prepare substituted pyrazoles and their heteroannulated pyrazoles and sheds light on their biological activities. Different approaches can be considered for synthesizing pyrazoles, such as 2 + 2 + 1, 2 + 3, 4 + 1, 6 − 1, etc. (Scheme 1). light on their biological activities. Different approaches can be considered for synthesizing pyrazoles, such as 2 + 2 + 1, 2 + 3, 4 + 1, 6 − 1, etc. (Scheme 1).

Scheme 1.
The general approach to form pyrazole derivatives.
In addition, these methods can be combined with metal-catalyzed, organo-catalyzed flow chemistry, and other methods. In this context, many methods address atom economy ("green") and multi-component reactions.

Cyclocondensation of Hydrazines with 1,3-Dicarbonyl Compounds
Cyclocondensation of 1,3-dicarbonyl compounds 3 with substituted hydrazines gave the corresponding substituted pyrazoles regioisomers 5 and 5′ (Scheme 2) in differ ent yield percentages depending on the electronic effects, such as the inductive (electron or withdrawing character) and the steric factors of both substituents R 1 and R 3 (R 1 and R are unequal). For example, if R 1 constitutes an aryl group and R 3 constitutes an alkyl sub stituent, the reaction proceeds, under conventional conditions, to give the regioisomer as the major product, whereas 5′ is formed in traces. The selectivity obtained is of the orde of 98:2 (i.e., R 1 = Ar and R 3 = CH3) [40]. In addition, these methods can be combined with metal-catalyzed, organo-catalyzed, flow chemistry, and other methods. In this context, many methods address atom economy ("green") and multi-component reactions.

Cyclocondensation of Hydrazines with 1,3-Dicarbonyl Compounds
Cyclocondensation of 1,3-dicarbonyl compounds 3 with substituted hydrazines 4 gave the corresponding substituted pyrazoles regioisomers 5 and 5 (Scheme 2) in different yield percentages depending on the electronic effects, such as the inductive (electron or withdrawing character) and the steric factors of both substituents R 1 and R 3 (R 1 and R 3 are unequal). For example, if R 1 constitutes an aryl group and R 3 constitutes an alkyl substituent, the reaction proceeds, under conventional conditions, to give the regioisomer 5 as the major product, whereas 5 is formed in traces. The selectivity obtained is of the order of 98:2 (i.e., R 1 = Ar and R 3 = CH 3 ) [40]. ZnO (nano) 10 15 95 5 ZnO (nano) 10 25 85 6 ZnO (nano) 20 15 93 In 2006, Heller and Natarajan synthesized pyrazoles 5 from the reaction between hydrazine and 1,3-diketones (Scheme 6). The diketo compounds 3 were successfully prepared in good yields by lithiation, using lithium bis(trimethylsilyl)amide (LiHMDS), followed by subsequent addition of the acid chlorides (Scheme 6) [38].

With α,β-Unsaturated Ketones
The regioselectivity of the reaction of various β-aminoenones on different monoalk acetyl-, methoxycarbonylhydrazine, and semicarbazide was studied by Alberola et [45]. They found that the smallest bulky group, when attached at the β-position of t enone, obtained high regioselectivity from the reaction of β-aminoenones 16a-c, wh possessed the least bulky substituent (CH3) in the β-position with alkyl hydrazines 4, DMSO. Subsequently, pyrazoles 5a-c and 5′a-c were obtained with high regioselectiv (Scheme 8) [45]. When different β-aminoenones 16a-c with bulkier β-substituents w used, the reactivity towards product formation decreased, but more important than t decrease in reactivity was the drop in regioselectivity. This phenomenon was grea when R 1 and the alkyl hydrazine were bulkier [45]. Compounds 5a-c were formed in yie percentages from 78-97% compared with their regioisomers 5′a-c [45].

With α,β-Unsaturated Ketones
The regioselectivity of the reaction of various β-aminoenones on different monoalkyl, acetyl-, methoxycarbonylhydrazine, and semicarbazide was studied by Alberola et al. [45]. They found that the smallest bulky group, when attached at the β-position of the enone, obtained high regioselectivity from the reaction of β-aminoenones 16a-c, which possessed the least bulky substituent (CH 3 ) in the β-position with alkyl hydrazines 4, in DMSO. Subsequently, pyrazoles 5a-c and 5 a-c were obtained with high regioselectivity (Scheme 8) [45]. When different β-aminoenones 16a-c with bulkier β-substituents were used, the reactivity towards product formation decreased, but more important than this decrease in reactivity was the drop in regioselectivity. This phenomenon was greater when R 1 and the alkyl hydrazine were bulkier [45]. Compounds 5a-c were formed in yield percentages from 78-97% compared with their regioisomers 5 a-c [45].
Rao et al. [48] described a method to prepare pyrazole derivative 5 via condensation of a chalcone 22 with p-((t-butyl)phenyl)hydrazine 4 in the presence of copper triflate and 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM-PF6] 23 as a catalyst. The reaction proceeded via the formation of compound 24 (Scheme 11) [48]. Further optimization of the reaction conditions was carried out by changing solvents, catalysts, and catalyst loading. The use of 20 mol% Cu(OTf)2 in 23 gave the desired product 5 in excellent yield (82%). When Cu(OTf)2 was replaced with other catalysts, such as p-TSA, Sc(OTf)3 Ce(OTf)3, Zn(OTf)2, AgOTf, or Yb(OTf)3, a mixture of 24 and 5 was observed. The use of Ce(OTf)3 in 23 resulted in a 75% yield of 24 along with 10% of 5, whereas the use of p-TSA in 23 gave 69% of 24. The obtained data indicate that Cu(OTf)2 was involved in the aerobic oxidation of 24 to 5. It is necessary to mention that 5 was not formed in the absence of Cu(OTf)2 in 23 ionic liquids, and only 24 was isolated in 20% yield along with the starting material, and the yield of 24 did not increase with increasing the time up to 2 h [48]. Kovacs et al. [47] developed a technique for preparing 3,5-disubstituted pyrazole 5 via Cu/Fe catalyzed coupling between phenylacetylene (20) and an oxime 19 in DMF as a solvent provided the β-aminoenone 21. In the one-pot procedure, the valuable β-aminoenone was transformed into 5 with the addition of hydrazine hydrate (Scheme 10) [47]. Kovacs et al. [47] developed a technique for preparing 3,5-disubstituted pyrazol via Cu/Fe catalyzed coupling between phenylacetylene (20) and an oxime 19 in DMF a solvent provided the β-aminoenone 21. In the one-pot procedure, the valuable β-am noenone was transformed into 5 with the addition of hydrazine hydrate (Scheme 10) [4 Scheme 10. Synthesis of 3,5-diphenyl-1H-pyrazole 5.
Rao et al. [48] described a method to prepare pyrazole derivative 5 via condensati of a chalcone 22 with p-((t-butyl)phenyl)hydrazine 4 in the presence of copper triflate a 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM-PF6] 23 as a catalyst. The action proceeded via the formation of compound 24 (Scheme 11) [48]. Further optimi tion of the reaction conditions was carried out by changing solvents, catalysts, and catal loading. The use of 20 mol% Cu(OTf)2 in 23 gave the desired product 5 in excellent yie (82%). When Cu(OTf)2 was replaced with other catalysts, such as p-TSA, Sc(OT Ce(OTf)3, Zn(OTf)2, AgOTf, or Yb(OTf)3, a mixture of 24 and 5 was observed. The use Ce(OTf)3 in 23 resulted in a 75% yield of 24 along with 10% of 5, whereas the use of p-T in 23 gave 69% of 24. The obtained data indicate that Cu(OTf)2 was involved in the aero oxidation of 24 to 5. It is necessary to mention that 5 was not formed in the absence Cu(OTf)2 in 23 ionic liquids, and only 24 was isolated in 20% yield along with the starti material, and the yield of 24 did not increase with increasing the time up to 2 h [48]. tion of the reaction conditions was carried out by changing solvents, catalysts, and catalyst loading. The use of 20 mol% Cu(OTf)2 in 23 gave the desired product 5 in excellent yield (82%). When Cu(OTf)2 was replaced with other catalysts, such as p-TSA, Sc(OTf)3, Ce(OTf)3, Zn(OTf)2, AgOTf, or Yb(OTf)3, a mixture of 24 and 5 was observed. The use of Ce(OTf)3 in 23 resulted in a 75% yield of 24 along with 10% of 5, whereas the use of p-TSA in 23 gave 69% of 24. The obtained data indicate that Cu(OTf)2 was involved in the aerobic oxidation of 24 to 5. It is necessary to mention that 5 was not formed in the absence of Cu(OTf)2 in 23 ionic liquids, and only 24 was isolated in 20% yield along with the starting material, and the yield of 24 did not increase with increasing the time up to 2 h [48]. Scheme 11. Synthesis of 1,3,5-trisubstituted pyrazole 5.
Bonacorso et al. [49] synthesized a series of 3-aryl(alkyl)-5-triflfluoromethyl-1H-pyrazoles 27a-g from the reaction of 4-alkoxy-4-aryl(alkyl)-1,1,1-triflfluoro-3-buten-2-ones 25 with thiosemicarbazide (14). The reaction gave the corresponding 5-hydroxy-5-triflfluoromethyl-1-pyrazole thiocarboxamides 26. Subsequently, dehydration and removal of the thiocarboxyamide group with sulfuric acid 96% produced the desired products 27a-g in 57-75% yields (Scheme 12) [49]. It was concluded that the presence of the thiocarboxyamide group on position 1 of the pyrazolines 26 acts as a protective group with an electron-withdrawing effect, hindering the elimination of water and the subsequent aromatization of the fivemembered ring. The presence of a trifluoromethyl group on the vinyl ketones 25 and the thiocarboxyamide group on the dinucleophile (thiosemicarbazide) was the determining factor of the regiochemistry of the reaction. Moreover, the presence of α-alkyland β-alkyl[aryl]-substituent on the vinyl ketones 25 did not show observable effects on the regiochemistry of the reaction.
Molecules 2021, 26, x FOR PEER REVIEW g in 57-75% yields (Scheme 12) [49]. It was concluded that the presence of the thioc yamide group on position 1 of the pyrazolines 26 acts as a protective group with a tron-withdrawing effect, hindering the elimination of water and the subsequent ar zation of the five-membered ring. The presence of a trifluoromethyl group on th ketones 25 and the thiocarboxyamide group on the dinucleophile (thiosemicarbazid the determining factor of the regiochemistry of the reaction. Moreover, the presenc alkyl-and β-alkyl[aryl]-substituent on the vinyl ketones 25 did not show observa fects on the regiochemistry of the reaction. Synthesis of pyrazoles substituted by thiophene moiety 29 could be carried the reaction of chalcone-type compound 28 with phenyl hydrazine hydrochloride via 3 + 2 annulations (Scheme 13). The obtained thiophene-pyrazole hybrids 2 screened as antimicrobial and antioxidant agents (Scheme 13) [50]. Synthesis of pyrazoles substituted by thiophene moiety 29 could be carried during the reaction of chalcone-type compound 28 with phenyl hydrazine hydrochloride 4-HCl via 3 + 2 annulations (Scheme 13). The obtained thiophene-pyrazole hybrids 29 were screened as antimicrobial and antioxidant agents (Scheme 13) [50]. Synthesis of pyrazoles substituted by thiophene moiety 29 could be carried duri the reaction of chalcone-type compound 28 with phenyl hydrazine hydrochloride 4-H via 3 + 2 annulations (Scheme 13). The obtained thiophene-pyrazole hybrids 29 w screened as antimicrobial and antioxidant agents (Scheme 13) [50]. A series of dihydropyrazole-1-carboxamides 32a-o were obtained by the base-catalyzed condensation of isoxazolyl chalcones 30 with semicarbazide (31) (Scheme 14) [51]. The preliminary in vitro antitubercular activity of the synthesized pyrazoles 32a-o was performed by the microplate Alamar Blue assay (MABA) using isoniazid (0.25 µg/mL) as the positive control. Similarly, pyrazole derivatives 36a-c were obtained via reaction of α,β-unsatura ketones 35, together with hydrazine, as indicated in Scheme 15. The carboxylated mu walled carbon nanotubes/dolomite (MWCNTs) successfully grafted the surface of the tained compounds. Good antibacterial activity toward some pathogenic types of bacte was found for the synthesized compounds [52]. Scheme 15. Synthesis of pyrazole derivatives 36a-c.

With Acetylenic Compounds
The cyclocondensation reaction of acetylenic ketones 37 with hydrazine derivati Similarly, pyrazole derivatives 36a-c were obtained via reaction of α,β-unsaturated ketones 35, together with hydrazine, as indicated in Scheme 15. The carboxylated multiwalled carbon nanotubes/dolomite (MWCNTs) successfully grafted the surface of the obtained compounds. Good antibacterial activity toward some pathogenic types of bacteria was found for the synthesized compounds [52]. Similarly, pyrazole derivatives 36a-c were obtained via reaction of α,β-unsaturated ketones 35, together with hydrazine, as indicated in Scheme 15. The carboxylated multi walled carbon nanotubes/dolomite (MWCNTs) successfully grafted the surface of the ob tained compounds. Good antibacterial activity toward some pathogenic types of bacteria was found for the synthesized compounds [52]. Scheme 15. Synthesis of pyrazole derivatives 36a-c.
Ji et al. [55] reported on an efficient procedure for synthesizing 3-trifluoromethylp razole 5 in 60% yield via trifluoromethylation/cyclization of acetylenic ketones 38 w phenylhydrazine (4) using (1-trifluoromethyl-1,2-benziodoxol-3(1H)-one) (Togni reage (Scheme 18) [55]. Ma et al. [56] developed an efficient copper-catalyzed reaction to prepare polysubs tuted pyrazoles 43 from phenylhydrazones 41 and dialkyl acetylenedicarboxylates (Scheme 19). Table 2 summarizes the reaction conditions from the molar ratios of the c alyst and base. Moreover, the reaction yields the products in the absence of a catalyst a case of nitrogen atmosphere. The best condition was equal equivalents of the starting su stances, base, catalyst, and N2 atmosphere [56].  Ma et al. [56] developed an efficient copper-catalyzed reaction to prepare polysubstituted pyrazoles 43 from phenylhydrazones 41 and dialkyl acetylenedicarboxylates 42 (Scheme 19). Table 2 summarizes the reaction conditions from the molar ratios of the catalyst and base. Moreover, the reaction yields the products in the absence of a catalyst and case of nitrogen atmosphere. The best condition was equal equivalents of the starting substances, base, catalyst, and N 2 atmosphere [56].
Synthesis of pyrazole derivatives 69a-c bearing imidazo [4,5-b]indole moiety was achieved by the reaction of ylidenes 68a-c with hydrazine hydrate (Scheme 28). The obtained products were successfully examined for their antibacterial activities against four bacterial strains (Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa) and antifungal activities against two fungi (Aspergillus flavus and Candida albicans) [64].
Compounds 77a-f were evaluated for their COX inhibition, AI activity, ulcerogenic liability, and anti-diabetic activity. The target compounds were assessed in vitro against α-glucosidase and β-glucosidase, in vivo hypoglycemic activity in addition to PPARγ activation study. Two derivatives gave higher COX-2 S.I. (8.69-9.26) than the COX-2 selective drug celecoxib (COX-2 S.I. = 8.60) and showed the highest AI activities and the lowest ulcerogenic than other derivatives. Moreover, these derivatives showed higher inhibitory activities against αand β-glucosidase (% inhibitory activity = 62.15 and 55.30 for α-glucosidase and 57.42 and 60.07 for β-glucosidase) than reference compounds (acarbose with % inhibitory activity = 49.50 for α-glucosidase and D-saccharic acid 1,4-lactone monohydrate with % inhibitory activity = 53.42 for β-glucosidase) and also showed good PPAR-γ activation and good hypoglycemic effect in comparison to pioglitazone and rosiglitazone.

Multicomponent Synthesis
Liu et al. [87] reported on a one-pot, three-component approach consisting of acid chlorides, terminal alkynes, and hydrazine catalyzed by Pd(PPh 3 ) 2 Cl 2 /CuI to give 3,5diaryl-1H-pyrazoles 5 in moderate to good yields (Scheme 51). However, the aliphatic alkyne 1-octyne led to its corresponding pyrazole derivative in only 15% yield [87]. A general procedure for the preparation of compounds 5 was described as a mixture of PdCl 2 (PPh 3 ) 2 (0.01 mmol), CuI (0.03 mmol), Et 3 N (2.0 mmol) acid chloride (1.5 mmol), and alkyne 20 (1.0 mmol) in THF (5 mL) was stirred at room temperature for 2 h under N 2 . Then hydrazine (3.0 mmol) in CH 3 CN (2 mL) was added, and the reaction mixture continued to stir for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane. Column chromatography to obtain the pure products 5.

Multicomponent Synthesis
Liu et al. [87] reported on a one-pot, three-component app chlorides, terminal alkynes, and hydrazine catalyzed by Pd(PPh aryl-1H-pyrazoles 5 in moderate to good yields (Scheme 51). Ho kyne 1-octyne led to its corresponding pyrazole derivative in onl eral procedure for the preparation of compounds 5 was des PdCl2(PPh3)2 (0.01 mmol), CuI (0.03 mmol), Et3N (2.0 mmol) acid alkyne 20 (1.0 mmol) in THF (5 mL) was stirred at room tempe Then hydrazine (3.0 mmol) in CH3CN (2 mL) was added, and th tinued to stir for 16 h. The reaction mixture was diluted with w dichloromethane. Column chromatography to obtain the pure pr  (6) in the presence of sodium ben lution (Scheme 52) was reported to give compounds 118 [88]. Sod as the mild basic catalyst. Table 3 summarizes the trials using di The four-component reaction of aromatic aldehydes 34, malononitrile, phenylhydrazine (4), and ethyl acetoacetate (6) in the presence of sodium benzoate in an aqueous solution (Scheme 52) was reported to give compounds 118 [88]. Sodium benzoate was used as the mild basic catalyst. Table 3 summarizes the trials using different molar % of catalysts and the corresponding yields of products [88].   35 81 It was reported that the pyrazoles 5 were obtained in 59-93% yields during the tion of palladium-catalyzed four-component coupling of phenylacetylene (20), hydra derivatives 4, aryl iodide, carbon monoxide under ambient pressure, and room temp ture for 24 to 36 h (Scheme 53) [89].   35 81 It was reported that the pyrazoles 5 were obtained in 59-93% yields during the reaction of palladium-catalyzed four-component coupling of phenylacetylene (20), hydrazine derivatives 4, aryl iodide, carbon monoxide under ambient pressure, and room temperature for 24 to 36 h (Scheme 53) [89]. It was reported that the pyrazoles 5 were obtained in 59-93% yields during t tion of palladium-catalyzed four-component coupling of phenylacetylene (20), hy derivatives 4, aryl iodide, carbon monoxide under ambient pressure, and room te ture for 24 to 36 h (Scheme 53) [89].   35 81 It was reported that the pyrazoles 5 were obtained in 59-93% yields during the re tion of palladium-catalyzed four-component coupling of phenylacetylene (20), hydraz derivatives 4, aryl iodide, carbon monoxide under ambient pressure, and room tempe ture for 24 to 36 h (Scheme 53) [89].

Eco-Friendly Methods for Pyrazole Synthesis
Beyzaei et al. [91] synthesized polysubstituted pyrazoles 65 in 84-91% yields through a two-step, one-pot procedure. In this technique, the reaction of 2,4-dinitrophenylhydrazine, malononitrile, and different aldehydes 34 in deep eutectic solvent (DES) were carried out (Scheme 55) [91]. Under microwave irradiation, the reaction of 1,3-diketones 3 with phenylhydrazine (4) in the presence of organic nanocatalyst in an aqueous medium produced pyrazoles 5 in 78-98% yields (Scheme 58) [94]. A grinding induced the formation of highly substituted pyrazoles 6 malononitrile, functionalized aldehydes 34, and phenylhydrazine (4). Singh this procedure utilizing IL 121 as a catalyst without the formation of an (Scheme 60). Most importantly, simple handling and attainment of high y are the advantages of this methodology [96]. Facile formation of functionalized pyrazole derivatives 120 under solvent-less conditions was achieved by treating 4 with aldehydes 34 and acetoacetic ester (6). This methodology showed the synthetic potential of microwave irradiation and scandium (III) triflate Sc(OTf) 3 as a catalyst (Scheme 59) [95]. A grinding induced the formation of highly substituted pyrazoles 65 by applying malononitrile, functionalized aldehydes 34, and phenylhydrazine (4). Singh et al. reported this procedure utilizing IL 121 as a catalyst without the formation of any byproducts (Scheme 60). Most importantly, simple handling and attainment of high yield up to 97% are the advantages of this methodology [96].  Peng and co-workers reacted 5-alkoxycarbonyl-2-amino-4-aryl-3-cyano-6-methyl-4H-pyrans 123 with hydrazine hydrate in the presence of a catalytic quantity of piperazine, and the corresponding pyranopyrazoles 118 were obtained (Scheme 62). The strategy of the synthesis was carried out in three methods, namely (i) heating; (ii) exposure to microwave irradiation; (iii) exposure to a combination of microwave and ultrasound irra-  Peng and co-workers reacted 5-alkoxycarbonyl-2-amino-4-aryl-3-cyano-6-meth 4H-pyrans 123 with hydrazine hydrate in the presence of a catalytic quantity of pipe zine, and the corresponding pyranopyrazoles 118 were obtained (Scheme 62). The st egy of the synthesis was carried out in three methods, namely (i) heating; (ii) exposure microwave irradiation; (iii) exposure to a combination of microwave and ultrasound ir diation (CMUI). The procedure was later found to be excellent in yield within a short ti (Scheme 62) [98]. Peng and co-workers reacted 5-alkoxycarbonyl-2-amino-4-aryl-3-cyano-6-methyl-4Hpyrans 123 with hydrazine hydrate in the presence of a catalytic quantity of piperazine, and the corresponding pyranopyrazoles 118 were obtained (Scheme 62). The strategy of the synthesis was carried out in three methods, namely (i) heating; (ii) exposure to microwave irradiation; (iii) exposure to a combination of microwave and ultrasound irradiation (CMUI). The procedure was later found to be excellent in yield within a short time (Scheme 62) [98]. zine, and the corresponding pyranopyrazoles 118 were obtained (Scheme 62). The strat egy of the synthesis was carried out in three methods, namely (i) heating; (ii) exposure to microwave irradiation; (iii) exposure to a combination of microwave and ultrasound irra diation (CMUI). The procedure was later found to be excellent in yield within a short tim (Scheme 62) [98]. It was reported that the reaction of (2-cyano-3-furan/thiophen-2-yl)acrylo with 3-aminopyrazolin-5-one (125) in the presence of the base, which, via Mi tion to afford 3-aminopyrano[2,3-c]pyrazoles 126 (Scheme 64) [100]. It was reported that the reaction of (2-cyano-3-furan/thiophen-2-yl)acr with 3-aminopyrazolin-5-one (125) in the presence of the base, which, via tion to afford 3-aminopyrano[2,3-c]pyrazoles 126 (Scheme 64) [100]. Hafez and co-workers reacted 2-oxo-3-substituted indole 127 with pyr boiling ethanol and catalyzed by Et3N to prepare spiropyranylindolones 12 [101]. Hafez and co-workers reacted 2-oxo-3-substituted indole 127 with pyrazolone 128 boiling ethanol and catalyzed by Et3N to prepare spiropyranylindolones 129 (Scheme 6 [101]. Enders and co-workers prepared the enantioselective tetrahydropyrano-pyrazoles 131 from the reaction of pyrazolone 128, α,β-unsaturated aldehydes, and Wittig reagent 130 in the presence of secondary amines, such as catalysts (Scheme 68) [104]. Lu and co-workers reported on a one-pot synthesis of pyranopyrazoles 118 via Suzuki coupling between 4-bromobenzaldehyde and aryl boronic acid 132 together with KF·2H 2 O as a dehalogenating agent in the presence of Pd/C at 80 • C. Firstly, 4-bromobenzaldehyde and aryl boronic acid was added to form substituted biphenyl aldehydes; subsequently, other reagents were added and allowed to react for 5-6 h (Scheme 69) [105].

Pyrazolopyrimidine
Pyrazolopyrimidines are considered the structural analogs of the biogenic purine class. Pyrazolopyrimidines are of interest as potential bioactive molecules. Pyrazolopyrimidines have four known structures, as illustrated in Figure 6.

Pyrazolopyrimidine
Pyrazolopyrimidines are considered the structural analogs of the biogenic purine class. Pyrazolopyrimidines are of interest as potential bioactive molecules. Pyrazolopyrimidines have four known structures, as illustrated in Figure 6. One of the essential pharmacological applications of pyrazolo[4,3-d]pyrimidine derivatives is Sildenafil (Viagra ®® , 134) and its analogs 135 (Figure 7). Compounds 135 were used as a selective phosphodiesterase 5 (PDE5) to treat male erectile dysfunction as an oral agent. Recently, a series of Sildenafil analogs (R = Me, Et; R2 = Me, Et, -CH2CH2OH) was prepared, and the in vitro PDE5 inhibitory activities were evaluated; the results revealed improved activity and selectivity [107].

Thienopyrazoles
There are three different regioisomers of thienopyrazoles, as shown in Figure 9.

Thienopyrazoles
There are three different regioisomers of thienopyrazoles, as shown in Figure 9.

Furopyrazole
Furopyrazoles are known to have antitumor, antiproliferative, and an tivities. Aziz et al. observed that equimolecular amounts of 3-methyl-4 zolin-5-one (197) and malononitrile reacted in absolute ethanol in the pre dine under reflux for 3 h to give furo [2,3-c]
Galunisertib ( Figure 10) is known as 6-quinoline carboxamide of pyrazole derivative 230 [155], and it is an oral drug that is described as an available, small molecule antagonist of the tyrosine kinase transforming growth factor-beta (TGF-β) receptor type 1 (TGFBR1), with potential antineoplastic activity.
antiproliferative EGFR-TK inhibition activity against many tumor cell lines. Moreov series of pyrazole/quinolones 61a-f ( Figure 10) showed remarkable anticancer acti [61]. Compounds 61a, 61c, and 61f showed a significant decrease in inflammatory m tors TNFα and CRB greater than NAC when compared to model group exhibited a nificant decrease in comparison to NAC, especially compound 61c whose found CRB 1.90 (mg/dL) in comparison to NAC of conc 2.13 mg/dL.  Another pyrazolo-anticancer drug known as Lorlatinib 231 (Figure 10) [156] is an orally available drug known as ATP-competitive inhibitor of the receptor tyrosine kinases, anaplastic lymphoma kinase (ALK), and C-ros oncogene 1 (Ros1), with potential antineoplastic activity. Lorlatinib binds to and inhibits both ALK and ROS1 kinases. The kinase inhibition leads to disruption of ALK-and ROS1-mediated signaling and eventually inhibits tumor cell growth in ALK-and ROS1-overexpressing tumor cells.
Compound 251 inhibits activity against both Gram-positive and Gram-negative bacteria [171]. In addition, pyrazole derivatives 252-253 ( Figure 14) were prepared and screened for their antibacterial and antifungal activities using ampicillin and norcadine as standard drugs. All compounds were screened for their antimicrobial activities [172].
In 2020, Alnufaie et al. reported on the synthesis of series of naphthyl-substituted pyrazole-derived hydrazones 260 [174]. standard drugs. All compounds were screened for their antimicrobial activities [172].
Similarly, the same group published on the synthesis and antimicrobial studies of 31 coumarin-substituted pyrazole derivatives 264 [175]. The reaction of 4-hydrazinobenzoic acid 256 with fluoro 261a and hydroxy 261b substituted 3-acetylcoumarin formed the corresponding hydrazones 262a,b, which were subjected to further reaction with POCl 3 /DMF to give the formyl-substituted pyrazole derivatives 363a,b (Scheme 114). A series of hydrazone derivatives were then obtained via the reaction of 263a,b with various hydrazine derivatives (Scheme 114) [175]. Some of these compounds have shown potent activity against methicillin-resistant Staphylococcus aureus (MRSA) with MIC as low as 3.125 µg/mL. These results are very significant, as MRSA strains have emerged as one of the most menacing pathogens of humans, and this bacterium is bypassing HIV (in terms of fatality rate). Some pyrazole derivatives inhibited the growth of cell lines with an IC 50 around 15 µg/mL [175].
ing pyrazoles 260 (Scheme 113) [174]. Many of these pyrazoles showed potent grow hibitory properties for planktonic Staphylococcus aureus and Acinetobacter baumanni its drug-resistant variants with MIC values as low as 0.78 and 1.56 μg/mL, respect These compounds also show potent activity against Staphylococcus aureus and Acine ter baumannii biofilm formation and eradication properties [174]. Similarly, the same group published on the synthesis and antimicrobial studies coumarin-substituted pyrazole derivatives 264 [175]. The reaction of 4-hydrazinobe acid 256 with fluoro 261a and hydroxy 261b substituted 3-acetylcoumarin formed th responding hydrazones 262a,b, which were subjected to further reaction with POCl3 to give the formyl-substituted pyrazole derivatives 363a,b (Scheme 114). A series o drazone derivatives were then obtained via the reaction of 263a,b with various hydr derivatives (Scheme 114) [175]. Some of these compounds have shown potent ac against methicillin-resistant Staphylococcus aureus (MRSA) with MIC as low as μg/mL. These results are very significant, as MRSA strains have emerged as one most menacing pathogens of humans, and this bacterium is bypassing HIV (in ter fatality rate). Some pyrazole derivatives inhibited the growth of cell lines with a around 15 μg/mL [175].  Sahu et al. also prepared 4-((5-(4-chlorophenyl)-4,5-dihydro-1H-pyra yl)amino)phenol (18) (Figure 15), which showed antimicrobial activity and antibac activity. Antifungal activity was tested on Sabouraud Dextrose Agar plates by the plate method against Candida albicans and Aspergillus niger. In both of these assays, c loxacin and clotrimazole were used as standard drugs [46]. Sahu et al. also prepared 4-((5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)amino) phenol (18) (Figure 15), which showed antimicrobial activity and antibacterial activity. Antifungal activity was tested on Sabouraud Dextrose Agar plates by the cup-plate method against Candida albicans and Aspergillus niger. In both of these assays, ciprofloxacin and clotrimazole were used as standard drugs [46]. Sahu et al. also prepared 4-((5-(4-chlorophenyl)-4,5-dihydro-1H-py yl)amino)phenol (18) (Figure 15), which showed antimicrobial activity and antib activity. Antifungal activity was tested on Sabouraud Dextrose Agar plates by t plate method against Candida albicans and Aspergillus niger. In both of these assays loxacin and clotrimazole were used as standard drugs [46].

Antiviral Activity
It was reported that the derivative containing the R = Cl group of a series of 4,5disubstituted pyrazole derivatives 273 ( Figure 18) showed broad potent antiviral activity against a broad panel of viruses in different cells cultures (HEL Cell cultures) [181]. Moreover, substituted pyrazole derivatives 274 ( Figure 18) showed good antiviral activity against hepatitis A [182].

Antiviral Activity
It was reported that the derivative containing the R = Cl group of substituted pyrazole derivatives 273 ( Figure 18) showed broad potent against a broad panel of viruses in different cells cultures (HEL Cell cultu over, substituted pyrazole derivatives 274 ( Figure 18) showed good against hepatitis A [182].

Anti-Alzheimer's Activity
A series of 3,5-diaryl pyrazoles 5 (Figure 19) was assayed for their monoamine oxidase-A (MAO-A) and monoamine oxidase B (MAO-B) re compounds show inhibitory activity with concentration values in the n

Anti-Alzheimer's Activity
A series of 3,5-diaryl pyrazoles 5 ( Figure 19) was assayed for their ability to inhibit monoamine oxidase-A (MAO-A) and monoamine oxidase B (MAO-b) reversibly. Several compounds show inhibitory activity with concentration values in the nanomolar range [183]. Kuduk et al. identified compound 275 (Figure 19) as a potent and selective full agonist of the M1 positive allosteric modulators [184]. In the same manner, compound 275 showed good inhibitory activity against MAO-A and MAO-B but low selectivity (IC 50 MAO-A = 9.00 nM, IC 50 MAO-B = 8.00 nM, and SI = 1.00). Interestingly, it was reported that treatment of Cognitive impairment associated w Alzheimer's disease (AD) and schizophrenia was associated with α7 nicotinic acetylc line receptor (α7nAChR) that represented promising therapeutic candidates [190]. compound 282 (Figure 20) was found, a potent and selective full agonist of the α7 nAC demonstrated improved plasma stability, brain levels, and efficacy in behavioral cog tion models.
On the other side, it was demonstrated that pyrazole 283 proved to be a potent selective fair pharmacokinetic profile accompanied by efficacy in rodent behavioral c nition models. Compound 284 (Figure 20) was investigated and found as the most po inhibitor of α7 nAChR with an IC50 value of 0.07 µ M [191]. Astra Zeneca AB develo diverse series of pyrazole derivatives as positive allosteric modulators (PAMs).
Compound 285 (Figure 20) expressed good activity by inhibiting nicotinic acetylc A group of pyrazolyl and thienyl aminohydatoins was prepared by Malamas et al. and was tested as potent BACE1 inhibitors [185]. The n-butyl analog 276 was the most potent analog, with an IC 50 value of 8 nM.
Zou et al. reported on the synthesis of a series of pyrazole-based compound 277 ( Figure 19) and identified as C-terminus β-secretase 1 (BACE1) inhibitors [186]. Further, modification over the pyrazole scaffold leads to the identification of compound 278 as a potent inhibitor of BACE1 with an IC 50 value of 0.025 µM.
Results reported by Han et al. indicated that the most active analogs 279 ( Figure 19) exhibited higher inhibitory activities, with significant brain A β-lowering effects, as well as favorable aqueous solubility [187].
As acetylcholinesterase (AChE) inhibitors, pyrazolotacrines 280 ( Figure 20) were reported by Silva et al. The results showed that compound 280 was the most potent inhibitor of AChE, which inhibited the enzyme above with an IC 50 value of 0.069 µM [188]. Whereas Khoobi et al. synthesized compound 281 bearing 3,4-dimethoxyphenyl group was the most potent compound against acetylcholinesterase (AChE) [189], being more active than the reference drug tacrine.

Insecticides and Herbicides
Synthesized pyrazoline-type insecticides 287 ( Figure 21) were achieved and exa ined the mechanism of action of these compounds based on available electrophysiologic pharmacological, and toxicological information, and they were found to act at neuron target sites [194]. Interestingly, it was reported that treatment of Cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia was associated with α7 nicotinic acetylcholine receptor (α7nAChR) that represented promising therapeutic candidates [190]. As compound 282 (Figure 20) was found, a potent and selective full agonist of the α7 nAChR demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models.
On the other side, it was demonstrated that pyrazole 283 proved to be a potent and selective fair pharmacokinetic profile accompanied by efficacy in rodent behavioral cognition models. Compound 284 (Figure 20) was investigated and found as the most potent inhibitor of α7 nAChR with an IC 50 value of 0.07 µM [191]. Astra Zeneca AB developed diverse series of pyrazole derivatives as positive allosteric modulators (PAMs).

Insecticides and Herbicides
Synthesized pyrazoline-type insecticides 287 ( Figure 21) were achieved and examined the mechanism of action of these compounds based on available electrophysiological, pharmacological, and toxicological information, and they were found to act at neuronal target sites [194].

Insecticides and Herbicides
Synthesized pyrazoline-type insecticides 287 ( Figure 21) were achieved and exam ined the mechanism of action of these compounds based on available electrophysiological pharmacological, and toxicological information, and they were found to act at neurona target sites [194]. Compounds 1,5-diarylpyrazole derivative 288 ( Figure 21) were prepared and showed noticeable pre-emergent herbicide activities against various kinds of weeds [195]

Anti-HIV
Charles and coworkers constructed 3-cyanophenoxypyrazoles 294 ( Figure 24) and investigated it in vitro against HIV. The compounds illustrated excellent anti-HIV affinity with inhibition of wild type RT (IC 50 = 0.034-0.6 µM) [199]. cuff method using clonidine as a reference standard. The obtained compo appreciable hypotensive activities.

Anti-HIV
Charles and coworkers constructed 3-cyanophenoxypyrazoles 294 (F investigated it in vitro against HIV. The compounds illustrated excellent an with inhibition of wild type RT (IC50= 0.034-0.6 µ M) [199].   Figure 25) were synthesized, and the compounds were investigated the biological activity in metabolic disorders, and their hypoglycemic activity in an in vivo model were tested. Interestingly, a high degree of correlation was observed between the predicted pK i and hypoglycemic effect after administration. Compounds 295-297 showed significant plasma glucose reduction with decreases of 60%, 64%, and 60%, respectively [200].

Anti-Oxidant Activity
In 2021, Vagish C. B. et al. [201] reported that the synthesized compounds 298 26), which revealed modest to good antioxidant activities. The synthesized pyrazol were screened for their antioxidant activity by in vitro DPPH and hydroxyl radica enging activity. Assessment result showed that compounds 3-(4-chlorophenyl)-5chlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole 298a revealed % radical scaveng tivity  Mantzanidou et al. [202] evaluated the antioxidant activity of pyrazole deriva and 299a. Compounds 5a and 299a were found as the most lipophilic compoun showed antioxidant activity using the ABTS radical cation (ABTS+) generated t potassium persulfate by oxidation with no participation of an intermediary radic synthesis of the pyrazolines and pyrazole derivatives was accomplished via the c sation of substituted suitable chalcones and hydrazine hydrate in absolute ethano presence of drops of glacial acetic acid, as presented in Scheme 115 [202].

Conclusions
There is a growing body of evidence that pyrazole and its heteroannulated tives provide a viable and valuable area for drug discovery. Here, we illustrated a view of the many efficient, mild, operationally simple, and non-conventional sy methods to access a library of highly functionalized pyrazole together with their annulated derivatives. We also shed more light on the broad range of biological ac displayed by these scaffolds that can optimally present a way to capture their in values. The ability to predict drug-like and lead-like properties along with recent t logical advances could be sufficient to revitalize the exploitation of the value of py and their heteroannulated derivatives in the quest for new drugs.
Previous studies have shown that the structural modification on the differen tions of the basic molecule allows for improving its pharmacological profile, givin timicrobial, anticonvulsant, analgesic, anti-inflammatory, anti-viral, anti-malari anti-cancer properties. Recently, researchers have established the design of more pyrazole derivatives having a great diversity of biological activity. Afterward, th thesized the prospective biologically active classes and finally screened the synth compounds towards the aim and type of biological activity.

Conclusions
There is a growing body of evidence that pyrazole and its heteroannulated derivatives provide a viable and valuable area for drug discovery. Here, we illustrated an overview of the many efficient, mild, operationally simple, and non-conventional synthetic methods to access a library of highly functionalized pyrazole together with their heteroannulated derivatives. We also shed more light on the broad range of biological activities displayed by these scaffolds that can optimally present a way to capture their intrinsic values. The ability to predict drug-like and lead-like properties along with recent technological advances could be sufficient to revitalize the exploitation of the value of pyrazoles and their heteroannulated derivatives in the quest for new drugs.
Previous studies have shown that the structural modification on the different positions of the basic molecule allows for improving its pharmacological profile, giving it antimicrobial, anticonvulsant, analgesic, anti-inflammatory, anti-viral, anti-malarial, and anti-cancer properties. Recently, researchers have established the design of more potent pyrazole derivatives having a great diversity of biological activity. Afterward, they synthesized the prospective biologically active classes and finally screened the synthesized compounds towards the aim and type of biological activity.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.