Recent Advances in the Synthesis of Pyrazole Derivatives: A Review

: Pyrazole, characterized by a ﬁve-membered heterocyclic structure featuring two neighboring nitrogen atoms, serves as a core element. Pyrazoles hold a privileged status as versatile frameworks in various sectors of the chemical industry, including medicine and agriculture. Previous reviews have extensively highlighted the signiﬁcance of pyrazoles and their diverse biological activities, encompassing roles such as antituberculosis, antimicrobial, antifungal, anti-inﬂammatory, anticancer, and antidiabetic agents. Consequently, they have garnered substantial interest from researchers. The aim of this review is to offer a comprehensive overview of the published research related to the synthesis of pyrazole derivatives, encompassing a discussion of diverse methods for accessing the pyrazole moiety. These methods span from utilizing transition-metal catalysts and pho-toredox reactions to employing one-pot multicomponent processes, novel reactants, and innovative reaction types. It encompasses studies conducted by numerous scientists worldwide, showcasing collective efforts in advancing the methodologies and applications of pyrazole derivatives.


Introduction
Over the past decade, there has been a significant increase in interest in pyrazole chemistry, primarily driven by the discovery of fascinating properties demonstrated by numerous pyrazole derivatives.The term "pyrazole" was initially discovered by Ludwig Knorr in 1883 [1], while Edward Buchner is recognized as the first to synthesize it in 1889 [2].Pyrazoles, as five-membered heterocycles, belong to a class of compounds highly valued in organic synthesis.Within the azole family, they are among the most extensively studied groups of compounds.Over the years, a vast array of synthesis methods and synthetic analogues have been documented, highlighting their significant importance in research and applications [3].Furthermore, the pyrazole fragment plays a crucial role in numerous organic ligands and serves as an essential coordinator.Recent research has uncovered intriguing applications of the pyrazole structure in organic synthesis, where it acts as both a directing and transforming group [4,5].Pyrazole serves as a fundamental element present in various small molecules, exhibiting a diverse array of agricultural and pharmaceutical activities [3].Specifically, they are classified as inhibitors of protein glycation, exhibiting properties such as anti-inflammatory, antibacterial, antifungal, anticancer, antidiabetic, antioxidant, antidepressant, anti-tuberculosis, and antiviral activities [3,[6][7][8].Additionally, certain pyrazoles find applications in supramolecular and polymer chemistry, in the food industry, and are utilized as cosmetic colorings [8].In recent years, a number of FDAapproved and commercially available drugs, both patented and non-patented, have been formulated using pyrazole derivatives [9] (Figure 1).This trend highlights the extensive utilization of these groups in the creation of novel bioactive compounds.This review provides a succinct overview of pyrazole pharmacophore synthesis, making it a valuable reference guide for researchers exploring this field.The review is loosely organized into chemical synthesis categories.
Reactions 2023, 4, FOR PEER REVIEW 2 lights the extensive utilization of these groups in the creation of novel bioactive compounds.This review provides a succinct overview of pyrazole pharmacophore synthesis, making it a valuable reference guide for researchers exploring this field.The review is loosely organized into chemical synthesis categories.

The Primary Approaches for Obtaining the Pyrazole Nucleus
Pyrazole, as an aromatic heterocycle with π-electron excess, displays distinct reactivity patterns in organic chemistry.Nucleophilic attacks are favored at positions 3 and 5, while electrophilic substitution reactions preferentially take place at position 4 [10] (Figure 2).Unsubstituted pyrazole can be represented in three distinct tautomeric forms, as illustrated in Figure 3.This propriety adds to the versatility and complexity of pyrazole s

The Primary Approaches for Obtaining the Pyrazole Nucleus
Pyrazole, as an aromatic heterocycle with π-electron excess, displays distinct reactivity patterns in organic chemistry.Nucleophilic attacks are favored at positions 3 and 5, while electrophilic substitution reactions preferentially take place at position 4 [10] (Figure 2).loosely organized into chemical synthesis categories.

The Primary Approaches for Obtaining the Pyrazole Nucleus
Pyrazole, as an aromatic heterocycle with π-electron excess, displays distin tivity patterns in organic chemistry.Nucleophilic attacks are favored at positions while electrophilic substitution reactions preferentially take place at position 4 [10] 2).Unsubstituted pyrazole can be represented in three distinct tautomeric form lustrated in Figure 3.This propriety adds to the versatility and complexity of py Unsubstituted pyrazole can be represented in three distinct tautomeric forms, as illustrated in Figure 3.This propriety adds to the versatility and complexity of pyrazole's chemical behavior and has significant implications in various chemical reactions and processes.
Reactions 2023, 4, FOR PEER REVIEW chemical behavior and has significant implications in various chemical reactions and cesses.In the realm of organic chemistry, pyrazoles bearing diverse substitutions with matic and heteroaromatic groups exhibit a plethora of biological activities, making t exceptionally captivating.Since the first syntheses described by Knorr [1], the various proaches to accessing the pyrazole nucleus have undergone numerous modifications vancing their synthetic versatility and potential applications in various fields.In thi view, we will delve into this evolutionary process and explore the commonly emplo methods to obtain substituted pyrazoles, namely:  Cyclocondensation of hydrazine s and similar nuclei with carbonyl systems;  Multicomponent reactions;  Dipolar cycloadditions.

Pyrazoles from 1,3-Diketones
Cyclocondensation of hydrazine derivatives with 1,3-dicarbonyl compounds sents a straightforward and rapid method for obtaining polysubstituted pyrazoles.K and his collaborators [1] accomplished the initial synthesis of substituted pyrazole 1883.They reacted hydrazine derivatives with β-diketones 1, providing the formatio a mixture of two regioisomers 2 and 3, where the substituted heteroatom is either ne the R1 or the R3 substituents (Scheme 1).In the realm of organic chemistry, pyrazoles bearing diverse substitutions with aromatic and heteroaromatic groups exhibit a plethora of biological activities, making them exceptionally captivating.Since the first syntheses described by Knorr [1], the various approaches to accessing the pyrazole nucleus have undergone numerous modifications, advancing their synthetic versatility and potential applications in various fields.In this review, we will delve into this evolutionary process and explore the commonly employed methods to obtain substituted pyrazoles, namely: Reactions 2023, 4, FOR PEER REVIEW 3 chemical behavior and has significant implications in various chemical reactions and processes.In the realm of organic chemistry, pyrazoles bearing diverse substitutions with aromatic and heteroaromatic groups exhibit a plethora of biological activities, making them exceptionally captivating.Since the first syntheses described by Knorr [1], the various approaches to accessing the pyrazole nucleus have undergone numerous modifications, advancing their synthetic versatility and potential applications in various fields.In this review, we will delve into this evolutionary process and explore the commonly employed methods to obtain substituted pyrazoles, namely:  Cyclocondensation of hydrazine s and similar nuclei with carbonyl systems;  Multicomponent reactions;  Dipolar cycloadditions.

Pyrazoles from 1,3-Diketones
Cyclocondensation of hydrazine derivatives with 1,3-dicarbonyl compounds presents a straightforward and rapid method for obtaining polysubstituted pyrazoles.Knorr and his collaborators [1] accomplished the initial synthesis of substituted pyrazoles in 1883.They reacted hydrazine derivatives with β-diketones 1, providing the formation of a mixture of two regioisomers 2 and 3, where the substituted heteroatom is either next to the R1 or the R3 substituents (Scheme 1).

Cyclocondensation of hydrazine's and similar nuclei with carbonyl systems;
Reactions 2023, 4, FOR PEER REVIEW 3 chemical behavior and has significant implications in various chemical reactions and processes.In the realm of organic chemistry, pyrazoles bearing diverse substitutions with aromatic and heteroaromatic groups exhibit a plethora of biological activities, making them exceptionally captivating.Since the first syntheses described by Knorr [1], the various approaches to accessing the pyrazole nucleus have undergone numerous modifications, advancing their synthetic versatility and potential applications in various fields.In this review, we will delve into this evolutionary process and explore the commonly employed methods to obtain substituted pyrazoles, namely:  Cyclocondensation of hydrazine s and similar nuclei with carbonyl systems;  Multicomponent reactions;  Dipolar cycloadditions.

Pyrazoles from 1,3-Diketones
Cyclocondensation of hydrazine derivatives with 1,3-dicarbonyl compounds presents a straightforward and rapid method for obtaining polysubstituted pyrazoles.Knorr and his collaborators [1] accomplished the initial synthesis of substituted pyrazoles in 1883.They reacted hydrazine derivatives with β-diketones 1, providing the formation of a mixture of two regioisomers 2 and 3, where the substituted heteroatom is either next to the R1 or the R3 substituents (Scheme 1).

Multicomponent reactions;
Reactions 2023, 4, FOR PEER REVIEW 3 chemical behavior and has significant implications in various chemical reactions and processes.In the realm of organic chemistry, pyrazoles bearing diverse substitutions with aromatic and heteroaromatic groups exhibit a plethora of biological activities, making them exceptionally captivating.Since the first syntheses described by Knorr [1], the various approaches to accessing the pyrazole nucleus have undergone numerous modifications, advancing their synthetic versatility and potential applications in various fields.In this review, we will delve into this evolutionary process and explore the commonly employed methods to obtain substituted pyrazoles, namely:  Cyclocondensation of hydrazine s and similar nuclei with carbonyl systems;  Multicomponent reactions;  Dipolar cycloadditions.

Pyrazoles from 1,3-Diketones
Cyclocondensation of hydrazine derivatives with 1,3-dicarbonyl compounds presents a straightforward and rapid method for obtaining polysubstituted pyrazoles.Knorr and his collaborators [1] accomplished the initial synthesis of substituted pyrazoles in 1883.They reacted hydrazine derivatives with β-diketones 1, providing the formation of a mixture of two regioisomers 2 and 3, where the substituted heteroatom is either next to the R1 or the R3 substituents (Scheme 1).Dipolar cycloadditions.
chemical behavior and has significant implications in various chemical reactions and pro cesses.In the realm of organic chemistry, pyrazoles bearing diverse substitutions with aro matic and heteroaromatic groups exhibit a plethora of biological activities, making them exceptionally captivating.Since the first syntheses described by Knorr [1], the various ap proaches to accessing the pyrazole nucleus have undergone numerous modifications, ad vancing their synthetic versatility and potential applications in various fields.In this re view, we will delve into this evolutionary process and explore the commonly employed methods to obtain substituted pyrazoles, namely:  Cyclocondensation of hydrazine s and similar nuclei with carbonyl systems;  Multicomponent reactions;  Dipolar cycloadditions.

Pyrazoles from 1,3-Diketones
Cyclocondensation of hydrazine derivatives with 1,3-dicarbonyl compounds presents a straightforward and rapid method for obtaining polysubstituted pyrazoles.Knorr and his collaborators [1] accomplished the initial synthesis of substituted pyrazoles in 1883.They reacted hydrazine derivatives with β-diketones 1, providing the formation of a mixture of two regioisomers 2 and 3, where the substituted heteroatom is either next to the R 1 or the R 3 substituents (Scheme 1).
Konwar et al. [11] established an eco-friendly procedure for synthesizing pyrazole derivatives, employing lithium perchlorate as a Lewis acid catalyst.Initially, they react with acetylacetone and 2,4-dinitriphenylhydrazine as a model to determine the optimized reaction conditions.At first, they attempted the reaction solely with solvents, without adding any catalyst, but it did not proceed at all, highlighting the need for a catalyst.The synthetic pathway consisted of the reaction of hydrazines 5 with 1,3-diketones 4 in the presence of ethylene glycol.Pyrazoles 6 were afforded in good to excellent yields (70-95%) at room temperature (Scheme 2, Table 1).
Konwar et al. [11] established an eco-friendly procedure for synthesizing pyrazole derivatives, employing lithium perchlorate as a Lewis acid catalyst.Initially, they reac with acetylacetone and 2,4-dinitriphenylhydrazine as a model to determine the optimized reaction conditions.At first, they attempted the reaction solely with solvents, without add ing any catalyst, but it did not proceed at all, highlighting the need for a catalyst.The synthetic pathway consisted of the reaction of hydrazines 5 with 1,3-diketones 4 in the presence of ethylene glycol.Pyrazoles 6 were afforded in good to excellent yields (70-95% at room temperature (Scheme 2, Table 1).Scheme 2. Synthesis of 1,3,5-substituted pyrazoles from substituted acetylacetone.Xu et al. [12] reported the synthesis of 5-aryl-3-trifluoromethyl pyrazoles, which in volved a silver-catalyzed reaction using N′-benzylidene tolylsulfonohydrazides 7 and ethyl 4,4,4-trifluoro-3-oxobutanoate 8 as precursors.The process entailed sequentia steps of nucleophilic addition, intramolecular cyclization, elimination, and ultimately [1,5]-H shift, resulting in the formation of trifluoromethylated pyrazole derivatives 9 in yields ranging from moderate to excellent (Scheme 3).During the optimization process the yield of the product improved when the reaction temperature was raised to 60 °C However, increasing the temperature beyond 60 °C led to a decrease in the yield.The Scheme 1.The synthesis of polysubstituted pyrazoles using hydrazine derivatives and 1,3-dicarbonyl compounds.
Scheme 1.The synthesis of polysubstituted pyrazoles using hydrazine derivatives and 1,3-dic bonyl compounds.Konwar et al. [11] established an eco-friendly procedure for synthesizing pyraz derivatives, employing lithium perchlorate as a Lewis acid catalyst.Initially, they re with acetylacetone and 2,4-dinitriphenylhydrazine as a model to determine the optimiz reaction conditions.At first, they attempted the reaction solely with solvents, without ad ing any catalyst, but it did not proceed at all, highlighting the need for a catalyst.T synthetic pathway consisted of the reaction of hydrazines 5 with 1,3-diketones 4 in presence of ethylene glycol.Pyrazoles 6 were afforded in good to excellent yields (70-95 at room temperature (Scheme 2, Table 1).
Scheme 2. Synthesis of 1,3,5-substituted pyrazoles from substituted acetylacetone.Xu et al. [12] reported the synthesis of 5-aryl-3-trifluoromethyl pyrazoles, which volved a silver-catalyzed reaction using N′-benzylidene tolylsulfonohydrazides 7 a ethyl 4,4,4-trifluoro-3-oxobutanoate 8 as precursors.The process entailed sequen steps of nucleophilic addition, intramolecular cyclization, elimination, and ultimate [1,5]-H shift, resulting in the formation of trifluoromethylated pyrazole derivatives 9 yields ranging from moderate to excellent (Scheme 3).During the optimization proce the yield of the product improved when the reaction temperature was raised to 60 However, increasing the temperature beyond 60 °C led to a decrease in the yield.T Cu(OTf)2 transition catalyst resulted in a 60% yield, whereas Fe(OTf)3 showed no prod tive outcome.In comparison to toluene, THF or dioxane provided a lower yield of product.Additionally, K2CO3 exhibited higher effectiveness compared to NaH, t-BuO and t-BuONa.Furthermore, incorporating neocuproine as a ligand resulted in the m Scheme 2. Synthesis of 1,3,5-substituted pyrazoles from substituted acetylacetone.Xu et al. [12] reported the synthesis of 5-aryl-3-trifluoromethyl pyrazoles, which involved a silver-catalyzed reaction using N -benzylidene tolylsulfonohydrazides 7 and ethyl 4,4,4-trifluoro-3-oxobutanoate 8 as precursors.The process entailed sequential steps of nucleophilic addition, intramolecular cyclization, elimination, and ultimately, [1,5]-H shift, resulting in the formation of trifluoromethylated pyrazole derivatives 9 in yields ranging from moderate to excellent (Scheme 3).During the optimization process, the yield of the product improved when the reaction temperature was raised to 60 • C.However, increasing the temperature beyond 60 • C led to a decrease in the yield.The Cu(OTf) 2 transition catalyst resulted in a 60% yield, whereas Fe(OTf) 3 showed no productive outcome.In comparison to toluene, THF or dioxane provided a lower yield of the product.Additionally, K 2 CO 3 exhibited higher effectiveness compared to NaH, t-BuOK, and t-BuONa.Furthermore, incorporating neocuproine as a ligand resulted in the most favorable performance with a yield exceeding 99%.In contrast, employing 2,2 -bipyridine or 1,10-phenanthroline as ligands led to lower yields of 57% and 92%, respectively.
Reactions 2023, 4, FOR PEER REVIEW 6 Scheme 5.The synthetic route of pyrazoles from arenes and carboxylic acids via one-pot synthesis.
Girish et al. [15] conducted a remarkable study where they introduced a highly efficient and environmentally friendly approach using nano-ZnO catalyst for synthesizing 1,3,5-substituted pyrazole derivatives 19.The process involved the condensation of phenylhydrazine 18 with ethyl acetoacetate 17 under controlled conditions (see Scheme 6).
Scheme 5.The synthetic route of pyrazoles from arenes and carboxylic acids via 'one-pot' synthesis.
Girish et al. [15] conducted a remarkable study where they introduced a highly efficient and environmentally friendly approach using nano-ZnO catalyst for synthesizing 1,3,5-substituted pyrazole derivatives 19.The process involved the condensation of phenylhydrazine 18 with ethyl acetoacetate 17 under controlled conditions (see Scheme 6).The key advantages of this method include its exceptional yield, reaching an impressive 95%, short reaction time, and straightforward work-up procedure.The combination of excellent yield, short reaction time, and ease of handling makes this method a promising and valuable addition to the field of pyrazole derivative synthesis.
Scheme 5.The synthetic route of pyrazoles from arenes and carboxylic acids via one-pot synthesis Girish et al. [15] conducted a remarkable study where they introduced a highly effi cient and environmentally friendly approach using nano-ZnO catalyst for synthesizing 1,3,5-substituted pyrazole derivatives 19.The process involved the condensation of phe nylhydrazine 18 with ethyl acetoacetate 17 under controlled conditions (see Scheme 6) The key advantages of this method include its exceptional yield, reaching an impressive 95%, short reaction time, and straightforward work-up procedure.The combination o excellent yield, short reaction time, and ease of handling makes this method a promising and valuable addition to the field of pyrazole derivative synthesis.Scheme 6. Synthesis of 3-methyl-1-phenyl-1H-pyrazol-5-ol using Nano-ZnO as catalyst.
In their work, Gosselin et al. [16] described a remarkably regioselective synthesis o 1-aryl-3,4,5-substituted pyrazoles 22, which involves the condensation of 1,3-diketone 20 with arylhydrazines 21 (see Scheme 7).Notably, this reaction takes place efficiently a room temperature in N,N-dimethylacetamide, resulting in the formation of pyrazole with high yields ranging from 59% to 98%.In their study, Heller and Natarajan [17] introduced a highly innovative approach to the synthesis of pyrazoles in situ.The process involved the direct synthesis of 1,3diketones 25 from ketones 23 and acid chlorides 24, which were subsequently transformed into pyrazoles 26 by the addition of hydrazine in good to excellent yields (see Scheme 8) This approach exhibits exceptional speed, generality, and chemoselectivity, enabling the synthesis of pyrazoles that were previously inaccessible, along with challenging pyrazole-Scheme 6. Synthesis of 3-methyl-1-phenyl-1H-pyrazol-5-ol using Nano-ZnO as catalyst.
Scheme 5.The synthetic route of pyrazoles from arenes and carboxylic acids via one-pot synthesis Girish et al. [15] conducted a remarkable study where they introduced a highly efficient and environmentally friendly approach using nano-ZnO catalyst for synthesizing 1,3,5-substituted pyrazole derivatives 19.The process involved the condensation of phenylhydrazine 18 with ethyl acetoacetate 17 under controlled conditions (see Scheme 6) The key advantages of this method include its exceptional yield, reaching an impressive 95%, short reaction time, and straightforward work-up procedure.The combination of excellent yield, short reaction time, and ease of handling makes this method a promising and valuable addition to the field of pyrazole derivative synthesis.Scheme 6. Synthesis of 3-methyl-1-phenyl-1H-pyrazol-5-ol using Nano-ZnO as catalyst.
In their work, Gosselin et al. [16] described a remarkably regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles 22, which involves the condensation of 1,3-diketones 20 with arylhydrazines 21 (see Scheme 7).Notably, this reaction takes place efficiently at room temperature in N,N-dimethylacetamide, resulting in the formation of pyrazoles with high yields ranging from 59% to 98%.In their study, Heller and Natarajan [17] introduced a highly innovative approach to the synthesis of pyrazoles in situ.The process involved the direct synthesis of 1,3diketones 25 from ketones 23 and acid chlorides 24, which were subsequently transformed into pyrazoles 26 by the addition of hydrazine in good to excellent yields (see Scheme 8) This approach exhibits exceptional speed, generality, and chemoselectivity, enabling the synthesis of pyrazoles that were previously inaccessible, along with challenging pyrazole-Scheme 7. Synthesis of 3-trifluoromethyl-substituted pyrazoles.
In their study, Heller and Natarajan [17] introduced a highly innovative approach to the synthesis of pyrazoles in situ.The process involved the direct synthesis of 1,3diketones 25 from ketones 23 and acid chlorides 24, which were subsequently transformed into pyrazoles 26 by the addition of hydrazine in good to excellent yields (see Scheme 8).This approach exhibits exceptional speed, generality, and chemoselectivity, enabling the synthesis of pyrazoles that were previously inaccessible, along with challenging pyrazolecontaining fused rings.The fusion of rapidity, generality, and chemoselectivity in this approach makes it a valuable asset in the arsenal of synthetic chemists, opening new avenues for the creation of diverse pyrazole-based compounds with enhanced complexity and utility.
Komendantova and her team work devised an innovative method for the synthesis of 3,4-dicarbonyl-substituted pyrazoles 29 [18].This approach involves the use of a broad array of 1,3-dicarbonyl compounds 27 and oxamic acid thiohydrazides 28 in an iodinepromoted cascade imination/halogenation/cyclization/ring contraction reaction in the presence of catalytic amounts of TsOH, accompanied by sulfur elimination (see Scheme 9).The result is a highly efficient and straightforward route to functionalized pyrazoles, utilizing readily available substrates and mild reaction conditions.containing fused rings.The fusion of rapidity, generality, and chemoselectivity in this approach makes it a valuable asset in the arsenal of synthetic chemists, opening new avenues for the creation of diverse pyrazole-based compounds with enhanced complexity and utility.
Komendantova and her team work devised an innovative method for the synthesis of 3,4-dicarbonyl-substituted pyrazoles 29 [18].This approach involves the use of a broad array of 1,3-dicarbonyl compounds 27 and oxamic acid thiohydrazides 28 in an iodinepromoted cascade imination/halogenation/cyclization/ring contraction reaction in the presence of catalytic amounts of TsOH, accompanied by sulfur elimination (see Scheme 9).The result is a highly efficient and straightforward route to functionalized pyrazoles, utilizing readily available substrates and mild reaction conditions.Scheme 9. Synthesis of substituted pyrazoles from 1,3-diketones and hydrazine derivatives.
Yan et al. [19] made a remarkable discovery by uncovering a new metal-oxo-clusters-based inorganic framework called "3D platelike ternary-oxo-cluster" (NaCoMo), which serves as an efficient catalyst for generating novel pyrazole derivatives.Moreover, this catalyst exhibits exceptional catalytic activity in the condensation and cyclization reaction of sulfonyl hydrazides 30 and 1,3-diketones 31 to synthesize the pyrazoles 32, leading to an impressive yield of up to 99% for the desired product (see Scheme 10).The successful synthesis of NaCoMo signifies the introduction of a new type of non-classical polyoxometalates.
Komendantova and her team work devised an innovative method for the synthesis of 3,4-dicarbonyl-substituted pyrazoles 29 [18].This approach involves the use of a broad array of 1,3-dicarbonyl compounds 27 and oxamic acid thiohydrazides 28 in an iodinepromoted cascade imination/halogenation/cyclization/ring contraction reaction in the presence of catalytic amounts of TsOH, accompanied by sulfur elimination (see Scheme 9).The result is a highly efficient and straightforward route to functionalized pyrazoles, utilizing readily available substrates and mild reaction conditions.Scheme 9. Synthesis of substituted pyrazoles from 1,3-diketones and hydrazine derivatives.
Yan et al. [19] made a remarkable discovery by uncovering a new metal-oxo-clusters-based inorganic framework called "3D platelike ternary-oxo-cluster" (NaCoMo), which serves as an efficient catalyst for generating novel pyrazole derivatives.Moreover, this catalyst exhibits exceptional catalytic activity in the condensation and cyclization reaction of sulfonyl hydrazides 30 and 1,3-diketones 31 to synthesize the pyrazoles 32, leading to an impressive yield of up to 99% for the desired product (see Scheme 10).The successful synthesis of NaCoMo signifies the introduction of a new type of non-classical polyoxometalates.
Yan et al. [19] made a remarkable discovery by uncovering a new metal-oxo-clustersbased inorganic framework called "3D platelike ternary-oxo-cluster" (NaCoMo), which serves as an efficient catalyst for generating novel pyrazole derivatives.Moreover, this catalyst exhibits exceptional catalytic activity in the condensation and cyclization reaction of sulfonyl hydrazides 30 and 1,3-diketones 31 to synthesize the pyrazoles 32, leading to an impressive yield of up to 99% for the desired product (see Scheme 10).The successful synthesis of NaCoMo signifies the introduction of a new type of non-classical polyoxometalates.
Scheme 10.Synthesis of substituted pyrazoles using NaCoMo as catalyst.
Chandak and his collaborators documented an environmentally friendly and cient aqueous synthesis of pyrazoles 35 via the condensation of hydrazines or hydraz 34 with 1,3-diketones 33 at room temperature, utilizing Amberlyst-70 as the catalyst Scheme 11) [20].This innovative protocol benefits from the use of resinous, nontoxic, t Scheme 10.Synthesis of substituted pyrazoles using NaCoMo as catalyst.
Chandak and his collaborators documented an environmentally friendly and efficient aqueous synthesis of pyrazoles 35 via the condensation of hydrazines or hydrazides 34 with 1,3-diketones 33 at room temperature, utilizing Amberlyst-70 as the catalyst (see Scheme 11) [20].This innovative protocol benefits from the use of resinous, nontoxic, thermally stable, and cost-effective Amberlyst-70 as a heterogeneous catalyst, in addition to offering a simple reaction workup, thus presenting valuable eco-friendly attributes.
Chandak and his collaborators documented an environmentally friendly and efficient aqueous synthesis of pyrazoles 35 via the condensation of hydrazines or hydrazides 34 with 1,3-diketones 33 at room temperature, utilizing Amberlyst-70 as the catalyst (see Scheme 11) [20].This innovative protocol benefits from the use of resinous, nontoxic, thermally stable, and cost-effective Amberlyst-70 as a heterogeneous catalyst, in addition to offering a simple reaction workup, thus presenting valuable eco-friendly attributes.Liu et al. [21] made an exciting discovery of a novel Keggin-based U-POW (U(VI)containing polytungstates) tetramer, referred to as U4.This tetramer showcased remarkable bifunctional Lewis s acid-base catalytic properties and exhibited excellent performance in the synthesis of pyrazoles 38 via the condensation of diverse hydrazines 37 with 1,3-diketones 36 under mild reaction conditions (see Scheme 12).This groundbreaking work not only presents a rare case of tetrameric U-POWs but also highlights the application of U-POWs in catalytic synthesis chemistry, potentially advancing the fields of POM (actinide-containing polyoxometalates) chemistry, actinide chemistry, and catalytic chemistry.Chandak and his collaborators documented an environmentally friendly and effi cient aqueous synthesis of pyrazoles 35 via the condensation of hydrazines or hydrazide 34 with 1,3-diketones 33 at room temperature, utilizing Amberlyst-70 as the catalyst (see Scheme 11) [20].This innovative protocol benefits from the use of resinous, nontoxic, ther mally stable, and cost-effective Amberlyst-70 as a heterogeneous catalyst, in addition to offering a simple reaction workup, thus presenting valuable eco-friendly attributes.
Liu et al. [21] made an exciting discovery of a novel Keggin-based U-POW (U(VI)containing polytungstates) tetramer, referred to as U4.This tetramer showcased remarka ble bifunctional Lewis s acid-base catalytic properties and exhibited excellent perfor mance in the synthesis of pyrazoles 38 via the condensation of diverse hydrazines 37 with 1,3-diketones 36 under mild reaction conditions (see Scheme 12).This groundbreaking work not only presents a rare case of tetrameric U-POWs but also highlights the applica tion of U-POWs in catalytic synthesis chemistry, potentially advancing the fields of POM (actinide-containing polyoxometalates) chemistry, actinide chemistry, and catalyti chemistry.

Pyrazoles from Vinyl Ketones and Vinyl Ketones Having a Leaving Group
As a general trend, the condensation of hydrazines with R-enones predominantly yields pyrazolines in a regioselective manner.Subsequently, to acquire the corresponding pyrazoles, these pyrazolines must undergo oxidation (see Scheme 13).
The α,β-Vinyl ketones that possess a leaving group can undergo a reaction with hydrazine derivatives, leading to the formation of pyrazolines.Subsequently, by eliminating the leaving group, the desired pyrazoles are generated (see Scheme 13).
The Corradi group conducted a study under microwave irradiation and solvent-free reaction conditions, wherein they successfully synthesized novel 3,5-disubstituted-1Hpyrazoles 40 [22] (see Scheme 14).This was achieved via the cycloaddition of tosylhydrazones and α,β-unsaturated carbonyl compounds containing a β-hydrogen 39.The cycloaddition reaction was investigated using three different ketones: trans-4-phenyl-3buten-2-one, β-ionone, and trans-chalcone.Notably, the corresponding 3,5-disubstituted-1H-pyrazoles 40 were obtained in high yields and with short reaction times.To assess the environmental impact, the proposed synthetic route was compared to the classical synthetic route, aiming to provide a reliable methodology and tool for measuring their ecological implications.

Pyrazoles from Vinyl Ketones and Vinyl Ketones Having a Leaving Group
As a general trend, the condensation of hydrazines with R-enones predominantly yields pyrazolines in a regioselective manner.Subsequently, to acquire the corresponding pyrazoles, these pyrazolines must undergo oxidation (see Scheme 13).
The α,β-Vinyl ketones that possess a leaving group can undergo a reaction with hydrazine derivatives, leading to the formation of pyrazolines.Subsequently, by eliminating the leaving group, the desired pyrazoles are generated (see Scheme 13).
The Corradi group conducted a study under microwave irradiation and solvent-free reaction conditions, wherein they successfully synthesized novel 3,5-disubstituted-1Hpyrazoles 40 [22] (see Scheme 14).This was achieved via the cycloaddition of tosylhydrazones and α,β-unsaturated carbonyl compounds containing a β-hydrogen 39.The cycloaddition reaction was investigated using three different ketones: trans-4-phenyl-3-buten-2-one, β-ionone, and trans-chalcone.Notably, the corresponding 3,5-disubstituted-1H-pyrazoles 40 were obtained in high yields and with short reaction times.To assess the environmental impact, the proposed synthetic route was compared to the classical synthetic route, aiming to provide a reliable methodology and tool for measuring their ecological implications.Scheme 14. Microwave-assisted one-pot synthesis of pyrazole derivatives.
The Corradi group conducted a study under microwave irradiation and solvent-free reaction conditions, wherein they successfully synthesized novel 3,5-disubstituted-1Hpyrazoles 40 [22] (see Scheme 14).This was achieved via the cycloaddition of tosylhydra zones and α,β-unsaturated carbonyl compounds containing a β-hydrogen 39.The cy cloaddition reaction was investigated using three different ketones: trans-4-phenyl-3-bu ten-2-one, β-ionone, and trans-chalcone.Notably, the corresponding 3,5-disubstituted-1H-pyrazoles 40 were obtained in high yields and with short reaction times.To assess the environmental impact, the proposed synthetic route was compared to the classical syn thetic route, aiming to provide a reliable methodology and tool for measuring their eco logical implications.Scheme 14. Microwave-assisted one-pot synthesis of pyrazole derivatives.Scheme 14. Microwave-assisted one-pot synthesis of pyrazole derivatives.
Huang and Katzenellenbogen [23] successfully obtained a series of 4-alkyl-1,3,5triarylpyrazoles 44 in a regioselective manner via the oxidation of pyrazolines 43.These pyrazolines were initially prepared via a cyclocondensation reaction between phenyl and 4-methoxyphenylhydrazine and chalcones 41, followed by alkylation at the C-4 position of the pyrazoline ring in 42 (see Scheme 15).
In their study, Rao and his collaborators demonstrated a condensation reaction of an α,β-ethylenic ketone 45 with p-(4-(tert-butyl)phenyl) hydrazine 46 using copper triflate and 1-butyl-3-methylimidazolium hexafluorophosphate [bmim] (PF6) as catalysts, leading to the formation of pyrazoline 47.Subsequent in situ oxidation of this pyrazoline yielded the corresponding 1,3,5-trisubstituted pyrazole 48 [24] (see Scheme 16).The reaction protocol facilitated the production of 1,3,5-triarylpyrazoles with good yields (approximately 82%) via a one-pot addition-cyclocondensation between chalcones and arylhydrazines, followed by oxidative aromatization without the need for an additional oxidizing reagent.Notably, the catalyst displayed remarkable recyclability, retaining its catalytic activity for more than four cycles without significant loss.Another study described by Bhat and his team work consists of the synthesis of 3,5diaryl-1H-pyrazoles starting with β-arylchalcones 49.The process involved the reaction with hydrogen peroxide, leading to the formation of epoxides 50.Following this, the addition of hydrazine monohydrate resulted in pyrazoline intermediates 51, which upon dehydration yielded the desired 3,5-diaryl-1H-pyrazoles 52 [25] (see Scheme 17).Another study described by Bhat and his team work consists of the synthesis of 3,5diaryl-1H-pyrazoles starting with β-arylchalcones 49.The process involved the reaction with hydrogen peroxide, leading to the formation of epoxides 50.Following this, the addition of hydrazine monohydrate resulted in pyrazoline intermediates 51, which upon dehydration yielded the desired 3,5-diaryl-1H-pyrazoles 52 [25] (see Scheme 17).Stephan and his co-workers made a groundbreaking discovery by unveiling a novel method for synthesizing pyrazole derivatives [27].Initially, they efficiently synthesized 3-(hetero)aryl propenals and propenones using a Heck reaction involving (hetero)aryl Scheme 17.The synthetic pathway to 3,5-diaryl-1H-pyrazoles 52.
In 2020, Gerus et al. [26] conducted a study on the fluorination of enone 53 using XeF 2 in the presence of BF 3 •Et 2 O.The addition of pyridine to the reaction mixture resulted in the formation of fluoroenone 54, achieving a yield of 68%.Subsequently, the reaction of fluoroenone 54 with hydrazine sulfate yielded fluoropyrazole 55, demonstrating an impressive yield of 87% (see Scheme 18).In 2020, Gerus et al. [26] conducted a study on the fluorination of enone 53 using XeF2 in the presence of BF3•Et2O.The addition of pyridine to the reaction mixture resulted in the formation of fluoroenone 54, achieving a yield of 68%.Subsequently, the reaction of fluoroenone 54 with hydrazine sulfate yielded fluoropyrazole 55, demonstrating an impressive yield of 87% (see Scheme 18).Stephan and his co-workers made a groundbreaking discovery by unveiling a novel method for synthesizing pyrazole derivatives [27].Initially, they efficiently synthesized 3-(hetero)aryl propenals and propenones using a Heck reaction involving (hetero)aryl Stephan and his co-workers made a groundbreaking discovery by unveiling a novel method for synthesizing pyrazole derivatives [27].Initially, they efficiently synthesized 3-(hetero)aryl propenals and propenones using a Heck reaction involving (hetero)aryl bromides 56 and acrolein or vinyl ketones 57.This reaction was carried out under a combination of Jeffery's and Fu's conditions, utilizing Beller's CataCXium Ptb ligand.The resulting 3-substituted α,β-unsaturated carbonyl derivatives served as valuable threecarbon building blocks.Using this straightforward approach, they successfully synthesized 3-(hetero)aryl and 3,5-diarylpyrazoles 58 with a broad range of substitution patterns via consecutive three-and pseudo-four-component syntheses, achieving modest to excellent yields (see Scheme 19).This concise and modular methodology proves to be highly suitable for preparing substance libraries of diversified pyrazoles.Stephan and his co-workers made a groundbreaking discovery by unveiling a novel method for synthesizing pyrazole derivatives [27].Initially, they efficiently synthesized 3-(hetero)aryl propenals and propenones using a Heck reaction involving (hetero)aryl bromides 56 and acrolein or vinyl ketones 57.This reaction was carried out under a combination of Jeffery s and Fu s conditions, utilizing Beller s CataCXium Ptb ligand.The resulting 3-substituted α,β-unsaturated carbonyl derivatives served as valuable three-carbon building blocks.Using this straightforward approach, they successfully synthesized 3-(hetero)aryl and 3,5-diarylpyrazoles 58 with a broad range of substitution patterns via consecutive three-and pseudo-four-component syntheses, achieving modest to excellent yields (see Scheme 19).This concise and modular methodology proves to be highly suitable for preparing substance libraries of diversified pyrazoles.Paul Raj et al. [28] established a highly efficient protocol for synthesizing pyrazoles 61 via the oxidative [3 + 2] cycloaddition of electron-deficient terminal olefins 59 with α-diazoesters and amides 60, using Oxone and cetyltrimethyl ammonium bromide (CTAB) as catalysts (see Scheme 20).Notably, this protocol offers several key advantages, including shorter reaction times, moderate to excellent yields, and good regioselectivity.
Iminov and his colleagues devised a method to obtain the pyrazole moiety.It consists of the acylation of tert-butyl 3-(methylamino)but-2-enoate 65 using fluorinated acetic acid anhydrides at the enamine carbon atom [30].Subsequently, the resulting product 66 was reacted with alkyl hydrazines, leading to mixtures of isomeric pyrazoles.These mixtures were separated via column chromatography to provide compounds 67 and 68, yielding moderate to poor results in terms of yields (see Scheme 22).Scheme 20.Synthesis of 3,5-substituted pyrazoles using CTAB as catalyst.
Iminov and his colleagues devised a method to obtain the pyrazole moiety.It consists of the acylation of tert-butyl 3-(methylamino)but-2-enoate 65 using fluorinated acetic acid anhydrides at the enamine carbon atom [30].Subsequently, the resulting product 66 was reacted with alkyl hydrazines, leading to mixtures of isomeric pyrazoles.These mixtures were separated via column chromatography to provide compounds 67 and 68, yielding moderate to poor results in terms of yields (see Scheme 22).Tian et al. [31] devised a practical protocol to synthesize 4-sulfonyl pyrazoles.They achieved this by reacting readily available N,N-dimethyl enaminones 69 with sulfonyl hydrazines 70 under the catalysis of molecular iodine in the presence of TBHP and Na-HCO3 at room temperature.The resulting pyrazole products 71 were formed via a tandem C(sp 2 )-H sulfonylation and pyrazole annulation process, without requiring any transition metal catalyst or reagent (see Scheme 23).This innovative approach offers a convenient Scheme 21.Synthesis of 3,5-diaryl-4,5-dihydro-1H-pyrazole-1-carboximidamides 64 under ultrasonic irradiation.
ride 63 under ultrasonic irradiation, as shown in Scheme 21.
Iminov and his colleagues devised a method to obtain the pyrazole moiety.It consists of the acylation of tert-butyl 3-(methylamino)but-2-enoate 65 using fluorinated acetic acid anhydrides at the enamine carbon atom [30].Subsequently, the resulting product 66 was reacted with alkyl hydrazines, leading to mixtures of isomeric pyrazoles.These mixtures were separated via column chromatography to provide compounds 67 and 68, yielding moderate to poor results in terms of yields (see Scheme 22).Tian et al. [31] devised a practical protocol to synthesize 4-sulfonyl pyrazoles.They achieved this by reacting readily available N,N-dimethyl enaminones 69 with sulfonyl hydrazines 70 under the catalysis of molecular iodine in the presence of TBHP and Na-HCO3 at room temperature.The resulting pyrazole products 71 were formed via a tandem C(sp 2 )-H sulfonylation and pyrazole annulation process, without requiring any transition metal catalyst or reagent (see Scheme 23).This innovative approach offers a convenient Scheme 22. Synthetic routes for pyrazoles 67 and 68.
Tian et al. [31] devised a practical protocol to synthesize 4-sulfonyl pyrazoles.They achieved this by reacting readily available N,N-dimethyl enaminones 69 with sulfonyl hydrazines 70 under the catalysis of molecular iodine in the presence of TBHP and NaHCO 3 at room temperature.The resulting pyrazole products 71 were formed via a tandem C(sp 2 )-H sulfonylation and pyrazole annulation process, without requiring any transition metal catalyst or reagent (see Scheme 23).This innovative approach offers a convenient and efficient method for constructing novel pyrazoles containing a sulfonyl side chain in the heterocycle.
Reactions 2023, 4, FOR PEER REVIEW 13 and efficient method for constructing novel pyrazoles containing a sulfonyl side chain in the heterocycle.

Pyrazoles from Acetylenic Ketones
The formation of pyrazoles via the cyclocondensation reaction of hydrazine derivatives 73 with acetylenic ketones 72 has been a well-known process for over a century [32].However, despite its long-standing recognition, the reaction continues to yield a mixture of two regioisomers, namely 74 and 75 (as shown in Scheme 24).Scheme 24.Synthetic routes for the regioisomers 74 and 75 using cyclocondensation reaction of Scheme 23.Synthetic routes for pyrazoles 71 using I 2 /TBHP, NaHCO 3 as catalyst.

Pyrazoles from Acetylenic Ketones
The formation of pyrazoles via the cyclocondensation reaction of hydrazine derivatives 73 with acetylenic ketones 72 has been a well-known process for over a century [32].However, despite its long-standing recognition, the reaction continues to yield a mixture of two regioisomers, namely 74 and 75 (as shown in Scheme 24).

Pyrazoles from Acetylenic Ketones
The formation of pyrazoles via the cyclocondensation reaction of hydrazine deriva tives 73 with acetylenic ketones 72 has been a well-known process for over a century [32] However, despite its long-standing recognition, the reaction continues to yield a mixture of two regioisomers, namely 74 and 75 (as shown in Scheme 24).Scheme 24.Synthetic routes for the regioisomers 74 and 75 using cyclocondensation reaction o hydrazine derivatives 73 on the acetylenic ketones 72.

Meng et al.
[5] introduced a novel visible-light-promoted cascade of Glaser cou pling/annulation, enabling the one-pot synthesis of polysubstituted pyrazoles 80 from al kyne 79 and hydrazine derivatives (see Scheme 26).This method stands out due to its mild reaction conditions, utilization of readily available starting materials, and the eco-friendly Scheme 24.Synthetic routes for the regioisomers 74 and 75 using cyclocondensation reaction of hydrazine derivatives 73 on the acetylenic ketones 72.Scheme 24.Synthetic routes for the regioisomers 74 and 75 using cyclocondensation reaction o hydrazine derivatives 73 on the acetylenic ketones 72.

Meng et al.
[5] introduced a novel visible-light-promoted cascade of Glaser cou pling/annulation, enabling the one-pot synthesis of polysubstituted pyrazoles 80 from al kyne 79 and hydrazine derivatives (see Scheme 26).This method stands out due to its mild reaction conditions, utilization of readily available starting materials, and the eco-friendly Scheme 25.Synthetic routes for pyrazoles 78 via one-pot reaction.

Meng et al.
[5] introduced a novel visible-light-promoted cascade of Glaser coupling/annulation, enabling the one-pot synthesis of polysubstituted pyrazoles 80 from alkyne 79 and hydrazine derivatives (see Scheme 26).This method stands out due to its mild reaction conditions, utilization of readily available starting materials, and the eco-friendly oxidant, O 2 .Notably, it exhibits excellent functional group tolerance and efficiency while accommodating a wide range of substituted phenyl acetylenes and hydrazines.The proposed mechanistic pathways involve photochemical irradiation, intramolecular hydrogen-atom-abstraction (HAT), and enamine-to-imine tautomerization to elucidate the underlying transformation steps.
Reactions 2023, 4, FOR PEER REVIEW 14 oxidant, O2.Notably, it exhibits excellent functional group tolerance and efficiency while accommodating a wide range of substituted phenyl acetylenes and hydrazines.The proposed mechanistic pathways involve photochemical irradiation, intramolecular hydrogen-atom-abstraction (HAT), and enamine-to-imine tautomerization to elucidate the underlying transformation steps.
Scheme 26.Synthetic routes for pyrazoles 80 via one-pot reaction.
Bhaskaran and his team devised a highly efficient, metal-free approach for synthesizing pyrazoles and chromenopyrazoles (87) using aldehyde hydrazones and acetylenic esters 86 [34].This method allowed them to create a library of molecules with a wide range of functional groups, utilizing both symmetrical and unsymmetrical hydrazones and alkynes.The resulting derivatives were isolated in moderate to good yields (Scheme 28).
Bhaskaran and his team devised a highly efficient, metal-free approach for synthesizing pyrazoles and chromenopyrazoles (87) using aldehyde hydrazones and acetylenic esters 86 [34].This method allowed them to create a library of molecules with a wide range of functional groups, utilizing both symmetrical and unsymmetrical hydrazones and alkynes.The resulting derivatives were isolated in moderate to good yields (Scheme 28).Bhaskaran and his team devised a highly efficient, metal-free approach for synthe sizing pyrazoles and chromenopyrazoles (87) using aldehyde hydrazones and acetylenic esters 86 [34].This method allowed them to create a library of molecules with a wide range of functional groups, utilizing both symmetrical and unsymmetrical hydrazones and al kynes.The resulting derivatives were isolated in moderate to good yields (Scheme 28).Savel'ev et al. [35] devised a highly effective method for synthesizing 1,3,5-trisubstituted pyrazoles using acetylenic ketones derived from ethyl 5-ethynylanthranilate in reactions with substituted hydrazines and hydrazides.During the study, they demonstrated that the cyclization of ethyl 5-(3-aryl-3-oxopropinyl)anthranilates 88 with arylhydrazines occurred with excellent regioselectivity, resulting in 1,3,5-trisubstituted pyrazoles 89 carrying an anthranilate moiety at position C-3.However, in the reactions of ethyl 5-(3-aryl-3oxopropinyl)anthranilates with N-methyland N-tert-butylhydrazines, a significant deterioration of regioselectivity was observed 92 and 93.In some cases, the initial products formed were 5-hydroxypyrazolines 90.These 5-hydroxypyrazolines underwent dehydration in the presence of pyridine and thionyl chloride in benzene, eventually yielding the desired 1,3,5-trisubstituted pyrazoles 91, as exemplified by the reactions of ethyl 5-[3-(4fluorophenyl)-3-oxopropinyl]anthranilate with benzoyl and isonicotinoyl hydrazides (see Scheme 29).
Thirukovela and his team achieved a significant milestone in 2019 by developing an advanced one-pot regioselective synthesis of 3,5-disubstituted and 3,4,5-trisubstituted pyrazoles [36].They employed a Cu-free protocol, utilizing in situ generated Pd-nanoparticles (PdNPs) as the catalyst in an environmentally friendly PEG-400/H 2 O medium (see Scheme 30).This innovative approach represents a notable advancement in the field of pyrazole synthesis.
Topchiy et al. [37] demonstrated an efficient method for synthesizing 3-CF 3 -pyrazoles 99 by employing a silver-catalyzed reaction between trifluoromethylated ynones 97 and aryl (alkyl) hydrazines 98.The reaction exhibited remarkable speed, with rapid heterocyclization occurring within just 1 h at room temperature, utilizing AgOTf as the catalyst at a loading of 1 mol % (see Scheme 31).This process led to the highly regioselective formation of various 3-CF 3 -pyrazoles, achieving exceptional yields of up to 99% for the isolated products.The researchers further investigated the reaction mechanism and discovered that it involves the formation of a hemiaminal as a crucial intermediate, shedding light on the underlying chemical pathways responsible for the synthesis of 3-CF 3 -pyrazoles.
Thirukovela and his team achieved a significant milestone in 2019 by developing an advanced one-pot regioselective synthesis of 3,5-disubstituted and 3,4,5-trisubstituted pyrazoles [36].They employed a Cu-free protocol, utilizing in situ generated Pd-nanoparticles (PdNPs) as the catalyst in an environmentally friendly PEG-400/H2O medium (see Scheme 30).This innovative approach represents a notable advancement in the field of pyrazole synthesis.Topchiy et al. [37] demonstrated an efficient method for synthesizing 3-CF3-pyrazoles 99 by employing a silver-catalyzed reaction between trifluoromethylated ynones 97 and aryl (alkyl) hydrazines 98.The reaction exhibited remarkable speed, with rapid heterocyclization occurring within just 1 h at room temperature, utilizing AgOTf as the catalyst at a loading of 1 mol % (see Scheme 31).This process led to the highly regioselective formation of various 3-CF3-pyrazoles, achieving exceptional yields of up to 99% for the isolated products.The researchers further investigated the reaction mechanism and discovered that it involves the formation of a hemiaminal as a crucial intermediate, shedding light on the underlying chemical pathways responsible for the synthesis of 3-CF3-pyrazoles.Topchiy et al. [37] demonstrated an efficient method for synthesizing 3-CF3-py zoles 99 by employing a silver-catalyzed reaction between trifluoromethylated ynones and aryl (alkyl) hydrazines 98.The reaction exhibited remarkable speed, with rapid h erocyclization occurring within just 1 h at room temperature, utilizing AgOTf as the ca lyst at a loading of 1 mol % (see Scheme 31).This process led to the highly regioselect formation of various 3-CF3-pyrazoles, achieving exceptional yields of up to 99% for t isolated products.The researchers further investigated the reaction mechanism and d covered that it involves the formation of a hemiaminal as a crucial intermediate, sheddi light on the underlying chemical pathways responsible for the synthesis of 3-CF3-py zoles.
Scheme 31.The synthesis of pyrazole derivatives 99 utilizing AgOTf as the catalyst.
Yu et al. [38] established a straightforward approach for synthesizing 4-chalcogen ated pyrazoles 102 via electrophilic chalcogenation and cyclization of α,β-alkynic hyd zones 100.The cyclization of α,β-alkynic aldehyde hydrazones could be triggered by e ploying either sulfenyl chloride or the in situ-generated S-electrophiles from the reacti Scheme 31.The synthesis of pyrazole derivatives 99 utilizing AgOTf as the catalyst.
Yu et al. [38] established a straightforward approach for synthesizing 4-chalcogenylated pyrazoles 102 via electrophilic chalcogenation and cyclization of α,β-alkynic hydrazones 100.The cyclization of α,β-alkynic aldehyde hydrazones could be triggered by employing either sulfenyl chloride or the in situ-generated S-electrophiles from the reaction of NCS and arythiol 101 (see Scheme 32).This innovative method was effectively utilized in the synthesis of the sulfenyl analogue of celecoxib, demonstrating its versatility and potential for accessing valuable chalcogenylated pyrazole derivatives.

Pyrazoles from Diazo Compounds
Li et al. [39] conducted an investigation on the 1,3-dipolar cycloaddition of N-tosylhydrazones 103 with acetylene gas using a balloon setup.Throughout the study, various bases and solvents were tested, and K2CO3 was identified as the most efficient base to facilitate this reaction.When dealing with N-tosylhydrazones derived from aldehydes, DMSO yielded superior results, whereas NMP proved to be a more appropriate solvent for the reaction of ketone N-tosylhydrazones.As a result of their work, Li and colleagues successfully provided a series of pyrazoles 104 in moderate to good yields (see Scheme 33).This practical approach is easy to handle and holds promise for potential industrial applications.

Dipolar Cycloadditions 2.2.1. Pyrazoles from Diazo Compounds
Li et al. [39] conducted an investigation on the 1,3-dipolar cycloaddition of Ntosylhydrazones 103 with acetylene gas using a balloon setup.Throughout the study, various bases and solvents were tested, and K 2 CO 3 was identified as the most efficient base to facilitate this reaction.When dealing with N-tosylhydrazones derived from aldehydes, DMSO yielded superior results, whereas NMP proved to be a more appropriate solvent for the reaction of ketone N-tosylhydrazones.As a result of their work, Li and colleagues successfully provided a series of pyrazoles 104 in moderate to good yields (see Scheme 33).This practical approach is easy to handle and holds promise for potential industrial applications.
Condition A or B 100 101 102 Scheme 32.The synthetic route for pyrazoles 102.

Pyrazoles from Diazo Compounds
Li et al. [39] conducted an investigation on the 1,3-dipolar cycloaddition of N-tosylhydrazones 103 with acetylene gas using a balloon setup.Throughout the study, various bases and solvents were tested, and K2CO3 was identified as the most efficient base to facilitate this reaction.When dealing with N-tosylhydrazones derived from aldehydes DMSO yielded superior results, whereas NMP proved to be a more appropriate solvent for the reaction of ketone N-tosylhydrazones.As a result of their work, Li and colleagues successfully provided a series of pyrazoles 104 in moderate to good yields (see Scheme 33).This practical approach is easy to handle and holds promise for potential industria applications.
Devi and his colleagues devised a novel approach involving a formal 1,3-dipolar cycloaddition of α-diazo phosphonates, sulfones, and trifluoromethanes 106 with 2,4,6-trisubstituted pyrylium tetrafluoroborate salts 105 [40].This innovative approach led to the synthesis of functionalized pyrazole-chalcones 107 (see Scheme 34).The reaction proceeds via an initial nucleophilic addition of diazo substrates to pyrylium salts, followed by a base-mediated pyrylium ring-opening and intramolecular 1,5-cyclization, resulting in formal 1,3-dipolar cycloaddition products.Afterward, the products underwent a Nazarov-type cyclization upon hydride reduction, followed by acidic workup, leading to the Devi and his colleagues devised a novel approach involving a formal 1,3-dipolar cycloaddition of α-diazo phosphonates, sulfones, and trifluoromethanes 106 with 2,4,6trisubstituted pyrylium tetrafluoroborate salts 105 [40].This innovative approach led to the synthesis of functionalized pyrazole-chalcones 107 (see Scheme 34).The reaction proceeds via an initial nucleophilic addition of diazo substrates to pyrylium salts, followed by a base-mediated pyrylium ring-opening and intramolecular 1,5-cyclization, resulting in formal 1,3-dipolar cycloaddition products.Afterward, the products underwent a Nazarov-type cyclization upon hydride reduction, followed by acidic workup, leading to the formation of the corresponding indenyl-pyrazoles in high yields.This methodology presents a promising strategy for the efficient synthesis of functionalized pyrazole-chalcones and indenyl-pyrazoles with potential applications in various fields.

Pyrazoles from Nitrilimines
In a notable contribution, Ledovskaya and her team discovered that the mild organic base trimethylamine (TEA) effectively facilitated the 1,3-dipolar cycloaddition of vinyl ethers 115 and hydrazonoyl chlorides 114, leading to the formation of 1,3-disubstituted pyrazoles 116 with absolute regioselectivity [43] (as shown Scheme 37).

Pyrazoles from Nitrilimines
In a notable contribution, Ledovskaya and her team discovered that the mild organic base trimethylamine (TEA) effectively facilitated the 1,3-dipolar cycloaddition of viny ethers 115 and hydrazonoyl chlorides 114, leading to the formation of 1,3-disubstituted pyrazoles 116 with absolute regioselectivity [43] (as shown Scheme 37).In another study, Zhu et al. [44] presented a study involving a CuCl-catalyzed oxi dative coupling reaction between aldehyde hydrazones 117 and maleimides 118, which enables the synthesis of dihydropyrazoles 119 under mild conditions.Employing this method, a diverse range of pyrrolo [3,4-c]pyrazoles was readily accessible from dihydro pyrazoles using a one-step oxidation process (as depicted in Scheme 38).Yi and colleagues introduced an innovative approach involving a silver-mediated [3 + 2] cycloaddition of alkynes and N-isocyanoiminotriphenylphosphorane (NIITP) to con struct monosubstituted pyrazoles [45].This reaction occurs under mild conditions, exhib iting a wide substrate scope and excellent tolerance towards various functional groups Mechanistic investigations revealed that NIITP is activated by Mo(CO)6, subsequently en gaging in a [3 + 2] cycloaddition with a silver acetylide intermediate (as shown in Scheme 39).In another study, Zhu et al. [44] presented a study involving a CuCl-catalyzed oxidative coupling reaction between aldehyde hydrazones 117 and maleimides 118, which enables the synthesis of dihydropyrazoles 119 under mild conditions.Employing this method, a diverse range of pyrrolo [3,4-c]pyrazoles was readily accessible from dihydropyrazoles using a one-step oxidation process (as depicted in Scheme 38).In a notable contribution, Ledovskaya and her team discovered that the mild organic base trimethylamine (TEA) effectively facilitated the 1,3-dipolar cycloaddition of viny ethers 115 and hydrazonoyl chlorides 114, leading to the formation of 1,3-disubstituted pyrazoles 116 with absolute regioselectivity [43] (as shown Scheme 37).In another study, Zhu et al. [44] presented a study involving a CuCl-catalyzed oxi dative coupling reaction between aldehyde hydrazones 117 and maleimides 118, which enables the synthesis of dihydropyrazoles 119 under mild conditions.Employing this method, a diverse range of pyrrolo [3,4-c]pyrazoles was readily accessible from dihydro pyrazoles using a one-step oxidation process (as depicted in Scheme 38).Yi and colleagues introduced an innovative approach involving a silver-mediated [3 + 2] cycloaddition of alkynes and N-isocyanoiminotriphenylphosphorane (NIITP) to con struct monosubstituted pyrazoles [45].This reaction occurs under mild conditions, exhib iting a wide substrate scope and excellent tolerance towards various functional groups Mechanistic investigations revealed that NIITP is activated by Mo(CO)6, subsequently en gaging in a [3 + 2] cycloaddition with a silver acetylide intermediate (as shown in Scheme 39).Yi and colleagues introduced an innovative approach involving a silver-mediated [3 + 2] cycloaddition of alkynes and N-isocyanoiminotriphenylphosphorane (NIITP) to construct monosubstituted pyrazoles [45].This reaction occurs under mild conditions, exhibiting a wide substrate scope and excellent tolerance towards various functional groups.Mechanistic investigations revealed that NIITP is activated by Mo(CO) 6 , subsequently engaging in a [3 + 2] cycloaddition with a silver acetylide intermediate (as shown in Scheme 39).
For the first time, Han and his team successfully synthesized a novel and efficient difluoromethyl building block, namely difluoroacetohydrazonoyl bromides [46].Demonstrating its synthetic versatility, this reagent enables the construction of difluoromethyl organic compounds via effective regioselective [3 + 2] cycloaddition reactions with ynones, alkynoates, and ynamides.These reactions offer a novel and efficient protocol to access difluoromethylsubstituted pyrazoles 126 and 127 with high yields, representing a significant advancement in difluoromethyl chemistry (as shown in Scheme 40).For the first time, Han and his team successfully synthesized a novel and efficient difluoromethyl building block, namely difluoroacetohydrazonoyl bromides [46].Demonstrating its synthetic versatility, this reagent enables the construction of difluoromethyl organic compounds via effective regioselective [3 + 2] cycloaddition reactions with ynones, alkynoates, and ynamides.These reactions offer a novel and efficient protocol to access difluoromethyl-substituted pyrazoles 126 and 127 with high yields, representing a significant advancement in difluoromethyl chemistry (as shown in Scheme 40).Kula et al. [47] in 2022 explored the experimental and theoretical studies on the reaction between (E)-3,3,3-trichloro-1-nitroprop-1-ene 112 and N-(4-bromophenyl)-C-arylnitrylimine 128.The title process led to the formation of the corresponding pyrazoles 130 and 132 (see Scheme 41).

Pyrazoles from Sydnones
Bouton et al. [48] successfully synthesized the C-nucleoside natural products, formycin B, and pyrazofurin 134, in seven steps, utilizing a sydnone riboside 133 as a shared intermediate.The sydnone ribosides were created using a direct Lewis acid-catalyzed dehydrative glycosylation reaction.It was demonstrated that these intermediates could be employed for the diversity-oriented synthesis of pyrazole C-nucleoside analogues via thermal 1,3-dipolar cycloaddition reactions with various alkynes (as shown in Scheme 42).This approach not only provided access to the pyrazole C-nucleoside natural products but also opened up new possibilities for exploring the chemical space of nucleosides.Lakeland and his research team reported a regioselective reaction achieved via a visible-light photoredox process, employing Ru(bpy)3(PF6)2 as the catalyst [49] (as depicted in Scheme 43).This innovative approach enabled the synthesis of a wide range of 1,4disubstituted pyrazoles 137 with excellent yields.

Pyrazoles from Sydnones
Bouton et al. [48] successfully synthesized the C-nucleoside natural products, formycin B, and pyrazofurin 134, in seven steps, utilizing a sydnone riboside 133 as a shared intermediate.The sydnone ribosides were created using a direct Lewis acid-catalyzed dehydrative glycosylation reaction.It was demonstrated that these intermediates could be employed for the diversity-oriented synthesis of pyrazole C-nucleoside analogues via thermal 1,3-dipolar cycloaddition reactions with various alkynes (as shown in Scheme 42).This approach not only provided access to the pyrazole C-nucleoside natural products but also opened up new possibilities for exploring the chemical space of nucleosides.

Pyrazoles from Sydnones
Bouton et al. [48] successfully synthesized the C-nucleoside natural products, formycin B, and pyrazofurin 134, in seven steps, utilizing a sydnone riboside 133 as a shared intermediate.The sydnone ribosides were created using a direct Lewis acid-catalyzed dehydrative glycosylation reaction.It was demonstrated that these intermediates could be employed for the diversity-oriented synthesis of pyrazole C-nucleoside analogues via thermal 1,3-dipolar cycloaddition reactions with various alkynes (as shown in Scheme 42).This approach not only provided access to the pyrazole C-nucleoside natural products but also opened up new possibilities for exploring the chemical space of nucleosides.Lakeland and his research team reported a regioselective reaction achieved via a visible-light photoredox process, employing Ru(bpy)3(PF6)2 as the catalyst [49] (as depicted in Scheme 43).This innovative approach enabled the synthesis of a wide range of 1,4disubstituted pyrazoles 137 with excellent yields.Lakeland and his research team reported a regioselective reaction achieved via a visible-light photoredox process, employing Ru(bpy) 3 (PF 6 ) 2 as the catalyst [49] (as depicted in Scheme 43).This innovative approach enabled the synthesis of a wide range of 1,4disubstituted pyrazoles 137 with excellent yields.Scheme 43.Synthesis of pyrazoles 137 using Ru(II)-catalyzed photoredox cycloaddition.
Delaunay et al. [50] presented a significant research study on the [3 + 2] dipolar cy cloaddition of 4-halosydnones with 1-haloalkynes, offering a straightforward route to ac cess 3,5-dihalopyrazoles.These dihalopyrazoles serve as valuable scaffolds for generating unsymmetrically 3,5-substituted pyrazole derivatives via site-selective Pd-catalyzed cross-coupling reactions.For instance, they demonstrated the flexible introduction of dif ferent (hetero)aryl substituents at the C-5 and C-3 positions of the PMP-protected pyra zole nucleus in a one-pot operation, utilizing sequential reactions with various boronic acids (as depicted in Scheme 44).This method offers a versatile strategy for the synthesis of diverse pyrazole derivatives.

Multicomponent Synthesis
Multicomponent Synthesis (MCS) is a powerful and innovative strategy in organic chemistry that has revolutionized the field of chemical synthesis.It is a method of con structing complex molecules by combining multiple starting materials in a single reaction step.This approach contrasts with traditional organic synthesis, which often involves se quential reactions and the use of protecting groups, leading to increased steps and waste generation.
Among the numerous significant studies mentioned in the literature, Chen et al. [51 introduced a transition metal-free method utilizing molecular iodine as a catalyst to syn thesize sulfonated pyrazoles from sulfonyl hydrazides, 1,3-diketones, and sodium sul finates under conditions.This innovative approach enabled the direct one-step for mation of pyrazoles with two distinct sulfonyl groups.Through control experiments, the reaction described in [51] was elucidated, and a plausible mechanism was attributed to it The process involves the facile generation of sulfonyl iodide by the interaction of sodium sulfinate 144 and molecular iodine.Subsequently, the condensation of sulfonyl hydra Scheme 43.Synthesis of pyrazoles 137 using Ru(II)-catalyzed photoredox cycloaddition.
Delaunay et al. [50] presented a significant research study on the [3 + 2] dipolar cycloaddition of 4-halosydnones with 1-haloalkynes, offering a straightforward route to access 3,5-dihalopyrazoles.These dihalopyrazoles serve as valuable scaffolds for generating unsymmetrically 3,5-substituted pyrazole derivatives via site-selective Pd-catalyzed crosscoupling reactions.For instance, they demonstrated the flexible introduction of different (hetero)aryl substituents at the C-5 and C-3 positions of the PMP-protected pyrazole nucleus in a one-pot operation, utilizing sequential reactions with various boronic acids (as depicted in Scheme 44).This method offers a versatile strategy for the synthesis of diverse pyrazole derivatives.Delaunay et al. [50] presented a significant research study on the [3 + 2] dipolar cycloaddition of 4-halosydnones with 1-haloalkynes, offering a straightforward route to access 3,5-dihalopyrazoles.These dihalopyrazoles serve as valuable scaffolds for generating unsymmetrically 3,5-substituted pyrazole derivatives via site-selective Pd-catalyzed cross-coupling reactions.For instance, they demonstrated the flexible introduction of different (hetero)aryl substituents at the C-5 and C-3 positions of the PMP-protected pyrazole nucleus in a one-pot operation, utilizing sequential reactions with various boronic acids (as depicted in Scheme 44).This method offers a versatile strategy for the synthesis of diverse pyrazole derivatives.

Multicomponent Synthesis
Multicomponent Synthesis (MCS) is a powerful and innovative strategy in organic chemistry that has revolutionized the field of chemical synthesis.It is a method of constructing complex molecules by combining multiple starting materials in a single reaction step.This approach contrasts with traditional organic synthesis, which often involves sequential reactions and the use of protecting groups, leading to increased steps and waste generation.
Among the numerous significant studies mentioned in the literature, Chen et al. [51] introduced a transition metal-free method utilizing molecular iodine as a catalyst to synthesize sulfonated pyrazoles from sulfonyl hydrazides, 1,3-diketones, and sodium sulfinates under mild conditions.This innovative approach enabled the direct one-step formation of pyrazoles with two distinct sulfonyl groups.Through control experiments, the reaction described in [51] was elucidated, and a plausible mechanism was attributed to it.The process involves the facile generation of sulfonyl iodide by the interaction of sodium sulfinate 144 and molecular iodine.Subsequently, the condensation of sulfonyl hydrazides 142 and 1,3-diketones 143 forms an imine, which undergoes tautomerization to Scheme 44.The synthetic route for pyrazoles 141.

Multicomponent Synthesis
Multicomponent Synthesis (MCS) is a powerful and innovative strategy in organic chemistry that has revolutionized the field of chemical synthesis.It is a method of constructing complex molecules by combining multiple starting materials in a single reaction step.This approach contrasts with traditional organic synthesis, which often involves sequential reactions and the use of protecting groups, leading to increased steps and waste generation.
Among the numerous significant studies mentioned in the literature, Chen et al. [51] introduced a transition metal-free method utilizing molecular iodine as a catalyst to synthesize sulfonated pyrazoles from sulfonyl hydrazides, 1,3-diketones, and sodium sulfinates under mild conditions.This innovative approach enabled the direct one-step formation of pyrazoles with two distinct sulfonyl groups.Through control experiments, the reaction described in [51] was elucidated, and a plausible mechanism was attributed to it.The process involves the facile generation of sulfonyl iodide by the interaction of sodium sulfinate 144 and molecular iodine.Subsequently, the condensation of sulfonyl hydrazides 142 and 1,3-diketones 143 forms an imine, which undergoes tautomerization to yield its enol form.
An in situ generated sulfonyl iodide, derived from the enol form, undergoes nucleophilic attack leading to an intermediate, ultimately resulting in the desired products 145 via an intramolecular condensation (as depicted in Scheme 45).
Reactions 2023, 4, FOR PEER REVIEW 23 yield its enol form.An in situ generated sulfonyl iodide, derived from the enol form, undergoes nucleophilic attack leading to an intermediate, ultimately resulting in the desired products 145 via an intramolecular condensation (as depicted in Scheme 45).
Scheme 45.Synthesis of sulfonated pyrazoles 145 via transition metal-free method, using molecular iodine as a catalyst.
In another study, Jacob and colleagues presented an exceptionally efficient one-pot procedure to synthesize 4-organylselanylpyrazoles 148 by means of direct cyclocondensation and C-H bond selenylation reactions.This method commences with hydrazines 146, 1,3-diketones 27, and diorganyl diselenides 147, employing Oxone as the promoting agent.The products were obtained using a metal catalyst-free approach, operating under mild conditions, leading to short reaction times, and yielding products in moderate to excellent yields [52] (see Scheme 46).A recent groundbreaking contribution by Pearce and colleagues introduced a novel fragment combination mode [NC] + [CC] + [N] utilizing a multicomponent oxidative coupling to synthesize multi-substituted pyrazoles.These innovative reactions involved the formation of diazatitana-cyclohexadiene intermediates by combining alkynes, nitriles, and titanium imido complexes, leading to pyrazole derivatives 152 via a 2-electron oxidation process catalyzed by the oxidant TEMPO [53] (see Scheme 47).
Scheme 45.Synthesis of sulfonated pyrazoles 145 via transition metal-free method, using molecular iodine as a catalyst.
In another study, Jacob and colleagues presented an exceptionally efficient one-pot procedure to synthesize 4-organylselanylpyrazoles 148 by means of direct cyclocondensation and C-H bond selenylation reactions.This method commences with hydrazines 146, 1,3-diketones 27, and diorganyl diselenides 147, employing Oxone as the promoting agent.The products were obtained using a metal catalyst-free approach, operating under mild conditions, leading to short reaction times, and yielding products in moderate to excellent yields [52] (see Scheme 46).
Reactions 2023, 4, FOR PEER REVIEW 23 yield its enol form.An in situ generated sulfonyl iodide, derived from the enol form, undergoes nucleophilic attack leading to an intermediate, ultimately resulting in the desired products 145 via an intramolecular condensation (as depicted in Scheme 45).
Scheme 45.Synthesis of sulfonated pyrazoles 145 via transition metal-free method, using molecular iodine as a catalyst.
In another study, Jacob and colleagues presented an exceptionally efficient one-pot procedure to synthesize 4-organylselanylpyrazoles 148 by means of direct cyclocondensation and C-H bond selenylation reactions.This method commences with hydrazines 146, 1,3-diketones 27, and diorganyl diselenides 147, employing Oxone as the promoting agent.The products were obtained using a metal catalyst-free approach, operating under mild conditions, leading to short reaction times, and yielding products in moderate to excellent yields [52] (see Scheme 46).A recent groundbreaking contribution by Pearce and colleagues introduced a novel fragment combination mode [NC] + [CC] + [N] utilizing a multicomponent oxidative coupling to synthesize multi-substituted pyrazoles.These innovative reactions involved the formation of diazatitana-cyclohexadiene intermediates by combining alkynes, nitriles, and titanium imido complexes, leading to pyrazole derivatives 152 via a 2-electron oxidation process catalyzed by the oxidant TEMPO [53] (see Scheme 47).A recent groundbreaking contribution by Pearce and colleagues introduced a novel fragment combination mode [NC] + [CC] + [N] utilizing a multicomponent oxidative coupling to synthesize multi-substituted pyrazoles.These innovative reactions involved the formation of diazatitana-cyclohexadiene intermediates by combining alkynes, nitriles, and titanium imido complexes, leading to pyrazole derivatives 152 via a 2-electron oxidation process catalyzed by the oxidant TEMPO [53] (see Scheme 47).Scheme 47. Organotitanium promoted the synthesis of pyrazoles 152.
In 2021, Mali and colleagues introduced an efficient and environmentally friendly multicomponent approach, catalyzed by taurine, for the synthesis of densely substituted therapeutic core dihydropyrano [2,3-c]pyrazoles 157 [54] (see Scheme 48).This pioneering method enabled the synthesis of a diverse array of 1,4-dihydropyrano[2,3-c]pyrazoles, incorporating isonicotinamide, spirooxindole, and indole moieties.The application of these synthetic strategies and technologies led to the creation of novel compounds.In another study, Shahbazi and collaborators successfully prepared a range of pyranopyrazoles 162 using a convenient one-pot four-component reaction involving ethyl acetoacetate 160, hydrazine hydrate 158, aldehydes 161, and malononitrile 159.They employed Co3O4-SiO2-NH2 nanocomposites as the catalyst in this process [55] (see Scheme 49).The study highlights numerous benefits, such as remarkably short reaction times, outstanding yields, an environmentally friendly approach, straightforward purification methods, and the economical accessibility of the catalyst.In 2021, Mali and colleagues introduced an efficient and environmentally friendly multicomponent approach, catalyzed by taurine, for the synthesis of densely substituted therapeutic core dihydropyrano [2,3-c]pyrazoles 157 [54] (see Scheme 48).This pioneering method enabled the synthesis of a diverse array of 1,4-dihydropyrano[2,3-c]pyrazoles, incorporating isonicotinamide, spirooxindole, and indole moieties.The application of these synthetic strategies and technologies led to the creation of novel compounds.In 2021, Mali and colleagues introduced an efficient and environmentally frien multicomponent approach, catalyzed by taurine, for the synthesis of densely substitu therapeutic core dihydropyrano [2,3-c]pyrazoles 157 [54] (see Scheme 48).This pioneer method enabled the synthesis of a diverse array of 1,4-dihydropyrano[2,3-c]pyrazo incorporating isonicotinamide, spirooxindole, and indole moieties.The application these synthetic strategies and technologies led to the creation of novel compounds.In another study, Shahbazi and collaborators successfully prepared a range of p ranopyrazoles 162 using a convenient one-pot four-component reaction involving et acetoacetate 160, hydrazine hydrate 158, aldehydes 161, and malononitrile 159.They e ployed Co3O4-SiO2-NH2 nanocomposites as the catalyst in this process [55] (see Sche 49).The study highlights numerous benefits, such as remarkably short reaction times, o standing yields, an environmentally friendly approach, straightforward purificat methods, and the economical accessibility of the catalyst.In another study, Shahbazi and collaborators successfully prepared a range of pyranopyrazoles 162 using a convenient one-pot four-component reaction involving ethyl acetoacetate 160, hydrazine hydrate 158, aldehydes 161, and malononitrile 159.They employed Co 3 O 4 -SiO 2 -NH 2 nanocomposites as the catalyst in this process [55] (see Scheme 49).The study highlights numerous benefits, such as remarkably short reaction times, outstanding yields, an environmentally friendly approach, straightforward purification methods, and the economical accessibility of the catalyst.

Conclusions
Pyrazoles constitute a class of five-membered heterocyclic compounds that contain two nitrogen atoms.They play a crucial role in drug development, acting as essential hit compounds for designing innovative pharmacological agents to target a variety of clinically significant infections.The extensive pharmaceutical applications of pyrazoles have driven swift progress in pyrazole synthesis methodologies.In the last decade, numerous effective and versatile approaches have arisen, encompassing the use of transition-metal catalysts and photoredox reactions, as well as one-pot multicomponent processes, novel reactants, and innovative reaction modalities.These developments have significantly contributed to the synthesis and functionalization of pyrazole derivatives.The comprehensive information presented in this review will prove valuable for aspiring researchers looking to delve into the world of pyrazole derivatives.By gaining insights from this review, researchers can explore the possibility of other derivatizations to expand the repertoire of pyrazole-based compounds.However, there is still room for further investigation, especially in cases where the pyrazole unit itself plays a pivotal role in the compound's mode of action, as well as situations where the pyrazole serves more as a structural element.These aspects warrant further exploration to fully comprehend the diverse potential and applications of pyrazole derivatives.Nevertheless, these reactions have the potential to provide very interesting molecular structures.In view of the growing importance of pyrazoles, we believe that the development of new synthetic routes using condensations, cycloadditions, and other potential methods will enhance our understanding of this field in the future.

Scheme 35 .
Scheme 35.The synthetic route for pyrazoles 110 using Al(OTf)3 as the catalyst.

Scheme 35 .
Scheme 35.The synthetic route for pyrazoles 110 using Al(OTf)3 as the catalyst.

Scheme 35 .
Scheme 35.The synthetic route for pyrazoles 110 using Al(OTf) 3 as the catalyst.

Scheme 48 .
Scheme 48. Green Multicomponent Approach for the Synthesis of pyrazoles 157.

Scheme 48 .
Scheme 48. Green Multicomponent Approach for the Synthesis of pyrazoles 157.

Scheme 48 .
Scheme 48. Green Multicomponent Approach for the Synthesis of pyrazoles 157.

Table 1 .
Effect of substituents on pyrazole synthesis.

Table 1 .
Effect of substituents on pyrazole synthesis.

Table 1 .
Effect of substituents on pyrazole synthesis.