Name: 4-Carboxypyrazole | 4-Carboxypyrazole
Brand: Ambeed
SKU: A118060
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4-Carboxypyrazole is an endogenous metabolite.

Synonyms: 4-Carboxypyrazole

4.5 *For Research Use Only !

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Quality Control of 4-Carboxypyrazole Purity: 98% SDS Specification

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Surveying the scope of aromatic decarboxylations catalyzed by prenylated-flavin dependent enzymes

Anushree Mondal ; Pronay Roy ; Jaclyn Carrannatto ; Prathamesh M. Datar ; Daniel J. DiRocco ; Katherine Huntera and E. Neil G. Marsh

DOI: 10.1039/D4FD00006D PubMed ID: 38837123 Faraday Discuss.,2024,252,208-222.

Abstract: The prenylated-flavin mononucleotide-dependent decarboxylases (also known as UbiD-like enzymes) are the most recently discovered family of decarboxylases. The modified flavin facilitates the decarboxylation of unsaturated carboxylic acids through a novel mechanism involving 1,3-dipolar cyclo-addition chemistry. UbiD-like enzymes have attracted considerable interest for biocatalysis applications due to their ability to catalyse (de)carboxylation reactions on a broad range of aromatic substrates at otherwise unreactive carbon centres. There are now ∼35[thin space (1/6-em)]000 protein sequences annotated as hypothetical UbiD-like enzymes. Sequence similarity network analyses of the UbiD protein family suggests that there are likely dozens of distinct decarboxylase enzymes represented within this family. Furthermore, many of the enzymes so far characterized can decarboxylate a broad range of substrates. Here we describe a strategy to identify potential substrates of UbiD-like enzymes based on detecting enzyme-catalysed solvent deuterium exchange into potential substrates. Using ferulic acid decarboxylase (FDC) as a model system, we tested a diverse range of aromatic and heterocyclic molecules for their ability to undergo enzyme-catalysed H/D exchange in deuterated buffer. We found that FDC catalyses H/D exchange, albeit at generally very low levels, into a wide range of small, aromatic molecules that have little resemblance to its physiological substrate. In contrast, the sub-set of aromatic carboxylic acids that are substrates for FDC-catalysed decarboxylation is much smaller. We discuss the implications of these findings for screening uncharacterized UbiD-like enzymes for novel (de)carboxylase activity.

Purchased from AmBeed: 27916-43-4 ; 2438-05-3 ; 501-89-3 ; 42287-94-5 ; 776-79-4 ; 53473-36-2 ; 7251-61-8 ; 42287-97-8 ; 1621-91-6 ; 37718-11-9 ; 288-13-1 ; 86-73-7 ; 104-53-0 ; 2018-90-8 ; 87-66-1 ; 135-19-3 ; 1664-57-9 ; 289-80-5 ; 693-95-8 ; 55-22-1 ; 102-93-2 ; 1477-50-5 ; 1632-76-4 ; 4780-79-4 ; 16642-79-8 ; 3581-89-3 ; 501-97-3 ; 771-50-6 ; 98-98-6 ; 619-64-7 ; 100-51-6 ; 402-45-9 ; 59-67-6 ; 93-60-7 ; 273-53-0 ; 2084-13-1 ; 51-17-2 ; 2459-09-8 ; 2459-07-6 ; 95-16-9 ; 459-31-4 ; 90-05-1 ; 150-76-5 ; 103-25-3 ; 271-44-3 ; 6293-56-7 ; 2550-26-7 ; 288-32-4 ; 501-52-0 ; 2001-32-3 ; 1592-38-7 ; 95-15-8 ; 91-19-0 ; 1122-61-8 ; 3724-19-4 ; 20173-24-4 ; 118-31-0 ; 6125-24-2 ; 60-12-8 ; 90-15-3 ; 120-72-9 ; 822-36-6 ; 288-47-1 ; 288-42-6 ; 2038-57-5 ; 38628-51-2 ; 1929-29-9 ; 15009-91-3 ; 1505-50-6 ; 581-40-8 ; 616-47-7 ; 1571-33-1

Spatially confined protein assembly in hierarchical mesoporous metal-organic framework

Wang, Xiaoliang ; He, Lilin ; Sumner, Jacob ; Qian, Shuo ; Zhang, Qiu ; O′Neill, Hugh , et al.

DOI: 10.1038/s41467-023-36533-w PubMed ID: 36810582 Nat. Commun.,2023,14(1):973.

Abstract: Immobilization of biomols. into porous materials could lead to significantly enhanced performance in terms of stability towards harsh reaction conditions and easier separation for their reuse. Metal-Organic Frameworks (MOFs), offering unique structural features, have emerged as a promising platform for immobilizing large biomols. Although many indirect methods have been used to investigate the immobilized biomols. for diverse applications, understanding their spatial arrangement in the pores of MOFs is still preliminary due to the difficulties in directly monitoring their conformations. To gain insights into the spatial arrangement of biomols. within the nanopores. We used in situ small-angle neutron scattering (SANS) to probe deuterated green fluorescent protein (d-GFP) entrapped in a mesoporous MOF. Our work revealed that GFP mols. are spatially arranged in adjacent nanosized cavities of MOF-919 to form "assembly" through adsorbate-adsorbate interactions across pore apertures. Our findings, therefore, lay a crucial foundation for the identification of proteins structural basics under confinement environment of MOFs.

Purchased from AmBeed: 37718-11-9

Product Details of 4-Carboxypyrazole

CAS No. :	37718-11-9
Formula :	C₄H₄N₂O₂
M.W :	112.09
SMILES Code :	C1=N[NH]C=C1C(O)=O
Synonyms :	4-Carboxypyrazole
MDL No. :	MFCD00011558
InChI Key :	IMBBXSASDSZJSX-UHFFFAOYSA-N
Pubchem ID :	3015937

Safety of 4-Carboxypyrazole

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Application In Synthesis of 4-Carboxypyrazole

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 37718-11-9 ]

[ 37718-11-9 ] Synthesis Path-Downstream 1~35

1
[ 7554-65-6 ]
[ 37718-11-9 ]

References: [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 8290 - 8294.
Angew. Chem.,2013,vol. 125,p. 8448 - 8452,5.
[2],1958,vol. 48,p. 140,152.

2
[ 2075-45-8 ]
[ 591-51-5 ]
[ 37718-11-9 ]

References: [1]Justus Liebigs Annalen der Chemie,1959,vol. 625,p. 55,60.

3
[ 37718-11-9 ]
[ 64-17-5 ]
[ 37622-90-5 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 10424 - 10442.
[2]Journal of the American Chemical Society,1949,vol. 71,p. 4000.

4
[ 37718-11-9 ]
[ 288-13-1 ]

References: [1]Chemische Berichte,1902,vol. 35,p. 34.

5
[ 10199-68-5 ]
[ 37718-11-9 ]

References: [1]Chemische Berichte,1902,vol. 35,p. 34.

6
[ 401647-24-3 ]
[ 37718-11-9 ]

References: [1]Journal of the American Chemical Society,1949,vol. 71,p. 4000.

7
[ 96780-98-2 ]
[ 37718-11-9 ]

References: [1]Journal of Heterocyclic Chemistry,1984,vol. 21,p. 1727 - 1731.
[2]Journal of Heterocyclic Chemistry,1984,vol. 21,p. 1727 - 1731.

8
[ 37718-11-9 ]
[ 2149-70-4 ]
[ 261368-13-2 ]
{(R)-1-[((S)-1-Carbamimidoyl-2-hydroxy-piperidin-3-ylcarbamoyl)-methyl]-carbamoyl}-3-[(1H-pyrazole-4-carbonyl)-amino]-propyl}-carbamic acid benzyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 3459 - 3464.

10
[ 2075-45-8 ]
[ 60-29-7 ]
butyl lithium (2 mol) [ No CAS ]
[ 37718-11-9 ]

References: [1]Justus Liebigs Annalen der Chemie,1959,vol. 625,p. 55,60.

11
pyrazole-tricarboxylic acid-(3.4.5) [ No CAS ]
[ 288-13-1 ]
[ 37718-11-9 ]

References: [1]Justus Liebigs Annalen der Chemie,1894,vol. 279,p. 232.
Chemische Berichte,1895,vol. 28,p. 693.

12
[ 2075-45-8 ]
[ 60-29-7 ]
butyl lithium (1 mol) [ No CAS ]
[ 37718-11-9 ]
4-bromo-1H-pyrazole-5-carboxylic acid [ No CAS ]

References: [1]Justus Liebigs Annalen der Chemie,1959,vol. 625,p. 55,60.

13
[ 37718-11-9 ]
[ 109-55-7 ]
H₃⁺N(C₄H₂NCH₃CONH)3CH₂CH₂-(R)-CHNH(Fmoc)(CONHC₄H₂NCH₃)(CONHC₃HN₂CH₃)2CONHC₄H₂NCH₃CONHCH₂CH₂CO₂CH₂C₆H₄CH₂CONH-poly(styrene-divinylbenzene) [ No CAS ]
C₅₆H₆₉N₂₃O₁₀*2H⁽¹⁺⁾ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2000,vol. 8,p. 2467 - 2474.

14
[ 37718-11-9 ]
[ 863630-51-7 ]
C₁₈H₂₃N₃O₂ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5537 - 5542.

15
[ 37718-11-9 ]
[ 863630-52-8 ]
C₁₉H₂₅N₃O₂ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5537 - 5542.

16
[ 37622-90-5 ]
[ 37718-11-9 ]

References: [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 7210 - 7232.
[2]Patent: EP1176140,2002,A1 .Location in patent: Page 47.

17
[ 37718-11-9 ]
N-[((5S)-3-{4-[exo-(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide [ No CAS ]
N-[((5S)-3-{3-fluoro-4-[exo-(1R,5S)-3-(1H-pyrazole-4-carbonyl)-3-azabicyclo[3.1.0]hex-6-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 23℃; for 17h;	To a solid mixture of N-[((5S)-3-{O4-[exo-(1R,5S)-3-azabicyclo [3.1. 0] hex-6- YL]-3-FLUOROPHENYL}-2-OXO-1, 3-oxazolidin-5-yl) methyl] acetamide (0.12 g, 0.36 mmol, 1 equivalent), HOBT (74 mg, 0.54 mmol, 1.5 equiv. ), EDCI (120 mg, 0.626 mmol, 1.74 equiv. ) and <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> (47 mg, 0.42 mmol, 1.2 equiv. ) at 23°C was added DMF (5 mL), followed by DIEA (0.3 mL, 1.7 mmol, 4.7 equiv. ). The reaction mixture was stirred at the same temperature for 17 hours, diluted with saturated NaHC03 aqueous and extracted with CH2C12 (3X100 mL). The combined organic layers were washed (H20, brine), dried (NaSO4), filtered and evaporated to dryness. The crude product was purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 0 to 5percent methanol in methylene chloride. Relevant fractions were combined to give the title compound. Yield 0.059 g (38percent). MS (m/z): [M+H] + = 428. HPLC (SYMMETRY C18 3.5 JIM, 4.6 x 30 mm column; gradient elution 2percent- 98percent MECN with 0. 1percent TFA over 5 min; 2 mL/min rate): retention time = 1.71 min. H NMR (300 MHz, DMSO-d6): 1.69 (m, 1H), 1.81 (s, 3H), 1.99 (bs, 1H), 2.07 (bs, 1H), 3.39 (t, J=5. 4 Hz, 2H), 3.52 (m, 1H), 3.69 (m, 1H), 3.98 (m, 3H), 4.08 (t, J=8. 7 Hz, 1H), 4.71 (m, 1H), 7.09 (t, J=8. 7 Hz, 1H), 7.19 (m, 1H), 7.44 (dd, J=12. 9 Hz, 2.1 Hz, 1H), 7.82 (s, 1H), 8.16 (s, 1H), 8.24 (t, J=6. 0 Hz, 1H).

References: [1]Patent: WO2004/89943,2004,A1 .Location in patent: Page 121-122.

18
[ 110-87-2 ]
[ 37718-11-9 ]
[ 848818-59-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With toluene-4-sulfonic acid; In DMF (N,N-dimethyl-formamide); ethyl acetate; at 20℃; for 3h;	Step 1 : Preparation of L-(TETRAHYDRO-PYRAN-2-YL)-LH-PYRAZOLE-4-CARBOXYLIC acid :; To a solution of 4-pyrazole carboxylic acid (6. 3 mmol, 947 mg) in ETOAC/DMF (50/5ML) at room temperature was added 3, 4-dihydro-2H-pyran (12. 45mmoles, 1. 135ML) followed bypara-toluenesulfonic acid (0. leq, 79mg). The mixture was stirred for 3 hours. Upon completion, the reaction mixture was concentrated under vacuum and the residue partitioned between saturated aqueous sodium carbonate (150ml) and EtOAc (50ML), the aqueous layer was decanted and acidified to pH 5 then extracted with EtOAc (4X100ML). The EtOAc layers were combined, dried over NA2S04 and concentrated to afford the title compound as a white solid (1. 46g, 90%). LH NMR (400 MHz, DMSO-d6) 5 12. 44 (s, 1H, Broad) ; 8. 36 (s, 1H, Broad) ; 7. 84 (s, 1H) ; 5. 44 (dd, 1H, J=9. 9, 2. 1) ; 3. 96-3. 91 (m, 1H) ; 3. 65- 3. 59 (m, 1H) ; 2. 15-2. 05 (m, 1H) ; 1. 94-1. 87 (m, 2H) ; 1. 71-1. 60 (m, 1H) ; 1. 56-1. 48 (m, 1H). LCMS : method A, Rt =1. 95 min, [MH+=197].
70%	With toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 20℃; for 20h;	Step 6.1, 1-(tetrahydro-2H-pyran-2-yl)-<strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> To a suspension of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (50 g, 446 mmol) in 500 mL of DMF are added para-toluenesulfonic acid (8.48 g, 44 mmol) and DHP (132 mL, 1561 mmol). The reaction medium turns yellow and then black after stirring at room temperature for 20 hours. The reaction mixture is poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The aqueous phase is acidified to pH 3 by adding 6M hydrochloric acid solution. The precipitate formed is filtered off and washed with water and then dried under vacuum at 50 C. to give 61.2 g of a white powder (yield: 70%).
70%	With toluene-4-sulfonic acid; at 20℃; for 20h;	Step 6.1. 1 -(tetrahydro-2H-pyran-2-yl)-1 H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> To a suspension of 1 /-/-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (50 g, 446 mmol) in 500 mL of DMF are added para-toluenesulfonic acid (8.48 g, 44 mmol) and DHP (132 mL, 1561 mmol). The reaction medium turns yellow and then black after stirring at room temperature for 20 hours. The reaction mixture is poured into saturated aqueous NaHC03 solution and extracted with EtOAc. The aqueous phase is acidified to pH 3 by adding 6M hydrochloric acid solution. The precipitate formed is filtered off and washed with water and then dried under vacuum at 50C to give 61.2 g of a white powder (yield: 70%). LCMS (Method D): MH+ = 197.1 , RT = 0.60 min

70%	With toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 20℃; for 20h;	Step 6.1. 1-(tetrahydro-2H-pyran-2-yl)-<strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> To a suspension of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (50 g, 446 mmol) in 500 mL of DMF are added para-toluenesulfonic acid (8.48 g, 44 mmol) and DHP (132 mL, 1561 mmol). The reaction medium turns yellow and then black after stirring at room temperature for 20 hours. The reaction mixture is poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The aqueous phase is acidified to pH 3 by adding 6M hydrochloric acid solution. The precipitate formed is filtered off and washed with water and then dried under vacuum at 50C to give 61.2 g of a white powder (yield: 70%). LCMS (Method D): MH+= 197.1, RT = 0.60 min
70%	With toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 5 - 25℃; for 20h;	To a suspension of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (50 g, 446 mmol) in 500 mL of DMF are added para-toluenesulfonic acid (8.48 g, 44 mmol) and DHP (132 mL, 1561 mmol). The reaction medium turns yellow and then black after stirring at room temperature for 20 hours. The reaction mixture is poured into saturated aqueous NaHCO3 solution and extracted with EtOAc. The aqueous phase is acidified to pH 3 by adding 6M hydrochloric acid solution. The precipitate formed is filtered off and washed with water and then dried under vacuum at 50 C. to give 61.2 g of a white powder (yield: 70%). [0867] LCMS (Method D): MH+=197.1, RT=0.60 min
70%	With toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 20℃; for 20h;Darkness;	To a suspension of lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (50 g, 446 mmol) in 500 ml DMF was added p-toluenesulfonic acid(8.48 g, 44 mmol) and DHP (132 mL, 1561 mmol).The reaction medium turned yellow and then changed at room temperature for 20 hoursblack. The reaction mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc. The aqueous phase was added by the addition of 6M hydrochloric acid solutionTo pH = 3. The resulting precipitate was filtered off and washed with water and then dried in vacuo at 50 C to give 61.2 g of a white powder(Yield: 70%).

References: [1]Patent: WO2005/28474,2005,A2 .Location in patent: Page/Page column 174-175.
[2]Patent: US2013/79337,2013,A1 .Location in patent: Paragraph 0858; 0859.
[3]Patent: WO2013/45400,2013,A1 .Location in patent: Page/Page column 60.
[4]Patent: EP2573073,2013,A1 .Location in patent: Paragraph 0094.
[5]Patent: US2014/235616,2014,A1 .Location in patent: Paragraph 0866-0867.
[6]Patent: CN103012397,2017,B .Location in patent: Paragraph 0960; 0961; 0962.
[7]Journal of Medicinal Chemistry,2019,vol. 62,p. 7210 - 7232.

19
[ 37718-11-9 ]
C₁₃H₁₇F₂NO₂ [ No CAS ]
N-({(2R,5R)-5-[(3,4-difluorophenoxy)methyl]tetrahydro-2H-pyran-2-yl}methyl)-1H-pyrazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of tert-butyl { [(5S)-5-(hydroxymethyl)tetrahydro-2H-pyran-2- yl] methyl} carbamate (300 mg, 1.22 mmol) and 3,4-difluorophenol (397.7 mg, 3.06 mmol) in THF (4.9 mL), were added PPh3 (737.7 mg, 2.81 mmol) and DIAD (0.56 mL, 2.32 mmol) at 0 °C. The mixture was irradiated by microwave at 180 °C for 5 min. Then the mixture was cooled to room temprature and was diluted AcOEt. The oganic layer was washed with 2N NaOH aq. and brine. The organic layer was dried over Na2SO4, was filtered and evaporated. The crude product was purified by silica gel column chromatography (hexane: AcOEt = 50: 1-20: 1) to give tert-butyl ({(2R, SR)-5-[(3, 4- difluorophenoxy) methyl] tetrahydro-2H-pyran-2-yl} methyl) carbamate (55.5 mg, 0.155 mmol) This was dissolved in HCl-MeOH (1 mL) and the mixture was stirred at 40 °C for 2hr. The mixture was evaporated to give the crude amine. The amine was dissolved in DMF (2 mL) and were added lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (17.4 mg, 0.155 mmol), Et3N (0.064 mL, 0.466 mmol), HOBt (28.5 mg, 0.186 mmol) and WSC (35.6 mg, 0.186 mmol) at 0 °C. The mixture was stirred at room temperature overnight. 2N NaOH aq was added to the mixture and the mixture was stirred at room temperature for 1 hr. The mixture was extracted with AcOEt and the organic layer was washed with brine. The organic layer was dried over Na2S04, was filtered and evaporated. The crude product was purified by silica gel column chromatography (CH2CI2 : MeOH = 20 : 1) to give the titled compound. 'H NMR (DMSO-d) 6 : 13.08 (br, 1H), 8.17-7. 92 (m, 3H), 7.35-7. 25 (m, 1H), 7.13-7. 05 (m, 1H), 6. 84-6. 75 (m, 1H), 4.14 (t, J = 9.1 Hz, 1H), 4.03-3. 87 (m, 2H), 3.58-3. 11 (m, 4H), 1.94 (br, 1H), 1. 88-1. 64 (m, 2H), 1.53-1. 29 (m, 2H) ppm. MS (ESI): 352.20 (M+H) +, 350.15 (M-H)-

References: [1]Patent: WO2005/80317,2005,A2 .Location in patent: Page/Page column 110-111.

20
[ 37718-11-9 ]
C₁₃H₁₈ClNO₂ [ No CAS ]
N-({(2R,5R)-5-[(4-chlorophenoxy)methyl]tetrahydro-2H-pyran-2-yl}methyl)-1H-pyrazole-4-carboxamide [ No CAS ]
3-amino-N-({(2R,5R)-5-[(4-ethylphenoxy)methyl]tetrahydro-2H-pyran-2-yl}methyl)-1H-pyrazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of LiAlH4 (119.7 mg, 3., 15 mmol) in THF (10 mL) the solution of 2- (azidomethyl)-5- [ (4-chlorophenoxy) methyl] tetrahydro-2H-pyran (444.3 mg, 1. 58 mmol) in THF (6 mL) was added at 0 °C. Then the mixture was stirred at 0 °C for 1.25 hr. The reaction was quenched by Na2S04-10H20 (1. 6 g, 4.97 mmol) and KF (200 mg, 3.44 mmol). The mixture was stirred at room temperature for lhr. The mixture was filtered through a pad of celite and the filtrate was evaporated to give the crude compound. To a solution of the crude compound in DMF (5 mL), were added lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (177.1 mg, 1.58 mmol), HOBt (290.4 mg, 1.90 mmol) and WSC (363.5 mg, 1.90 mmol) at 0 °C. The mixture was stirred at room temperature overnight. 2N NaOH aq was added to the mixture and the mixture was stirred at room temperature for 1 hr. The mixture was extracted with AcOEt and the organic layer was washed with brine. The organic layer was dried over Na2S04, was filtered and evaporated. The crude product was purified by silica gel column chromatography (CHzCI2 : MeOH = 20 : 1) to give the mixture of 4 stereoisomers. 4 stereoisomers were separated by Chiral column (Chiralcel OJ-H, 20 mm I. D. x 250 mm (No. OJHOCJ-DH004), DAICEL) using n-Hexane: EtOH: Et2NH = 88: 12: 0.1 as an eluent (18. 9 mLJmin). Example 120 N-({(2R,5R)-5-[(4-Chlorophenoxy)methyl]tetrahydro-2H-pyran-2-yl}methyl)-1H-pyrazole- 4-carboxamide Retention time 12 min-20 min (13 min) lH NMR (DMSO-d) 8 : 13. 10 (br, 1H), 8.23-7. 83 (m, 3H), 7.33 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.14 (t, J = 9.0 Hz, 1H), 4.05-3. 86 (m, 2H), 3. 58-3. 12 (m, 4H), 1.95 (br, 1H), 1.89-1. 66 (m, 2H), 1.53-1. 20 (m, 2H) ppm. MS (ESI) : 350.05 (M+H) +, 348. 06 (M-H)- Example 121 N-({(2S,5S)-5-[(4-Chlorophenoxy)methyl]tetrahydro-2H-pyran-2-yl}methyl)-1H-pyrazole- 4-carboxamide Retetntion time 20 min-24 min (22 min) 'H NMR (DMSO-d) b : 13.09 (br, 1H), 8. 20-7. 85 (m, 3H), 7.32-7. 28 (m, 2H), 7.04-6. 94 (m, 2H), 4.14 (t, J= 8.7 Hz, 1H), 4.05-3. 86 (m, 2H), 3.60-3. 10 (m, 4H), 1.95 (br, 1H), 1. 86-1. 64 (m, 2H), 1.53-1. 20 (m, 2H) ppm. MS (ESI): 350.04 (M+H)+, 348.06 (M-H)-

References: [1]Patent: WO2005/80317,2005,A2 .Location in patent: Page/Page column 111.

21
[ 37718-11-9 ]
[ 103286-53-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With thionyl chloride; for 18h;Heating / reflux;	Step B: 1H-pyrazole-4-carbonyl chloride; A mixture of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (1.03 g, 9.2 mmol) in thionyl chloride (20 mL) was heated for 18 h at reflux. Upon evaporation, 1.16 g (97percent) of a white solid was obtained.
97%	With thionyl chloride; for 18h;Reflux;	Step B: 1H-pyrazole-4-carbonyl chlorideA mixture of <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (1.03 g, 9.2 mmol) in thionyl chloride (20 mL) was heated for 18 h at reflux. Upon evaporation, 1.16 g (97percent) of a white solid was obtained.
	With thionyl chloride; at 90℃; for 18h;	Step 1: 4-pyrazolecarbonyl chloride A mixture of <strong>[37718-11-9]4-pyrazolecarboxylic acid</strong> (600 mg) in thionyl chloride (5 mL) was heated to 90° C. under nitrogen. After 18 hr., the mixture was allowed to cool to room temperature and the solvent removed in vacuo to provide 579 mg of 4-pyrazolecarbonyl chloride 12, which was used without further purification for the next step (Step 2). El-HRMS m/e calcd for C16H11N3OS (M+) 293.0623, found 293.0621.

	With thionyl chloride; In dichloromethane; at 40℃;	A 250-mL round-bottom flask was charged with lH-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong> (5.00 g, 44.6 mmol, 1.00 equiv), DCM (50 mL), and thionyl chloride (21.3 g, 179 mmol, 4.00 equiv). The resulting solution was stirred overnight at 40 °C and concentrated under reduced pressure to provide 6.00 g (crude) of lH-pyrazole-4-carbonyl chloride as a white solid.
	With oxalyl dichloride; N,N-dimethyl-formamide; at 0 - 30℃; for 2h;	In a 3L three-necked bottle, <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (SM1, 112.0 g, 1.0 mol) and DMF (500 ml) were added and controlled.The system temperature is 0-5°C, and a solution of 254 g (2.0 mol) oxalyl chloride in DMF (500 ml) is slowly added dropwise to the solution of oxalyl chloride in DMF.During the liquid process, the temperature of the control system is maintained at 0-5°C. After the DMF solution of the acyl chloride reagent is added dropwise,Warm to room temperature (25-30°C) and stir for 2h. Then spin to obtain <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> chloride;

References: [1]Patent: US2007/244092,2007,A1 .Location in patent: Page/Page column 27.
[2]Patent: US2011/86853,2011,A1 .Location in patent: Page/Page column 26.
[3]Patent: US2006/30589,2006,A1 .Location in patent: Page/Page column 8.
[4]Patent: WO2017/87858,2017,A1 .Location in patent: Paragraph 00190.
[5]European Journal of Inorganic Chemistry,2018,vol. 2018,p. 1068 - 1072.
[6]Patent: CN107915738,2018,A .Location in patent: Paragraph 0075; 0076; 0093; 0105.

22
[ 3240-94-6 ]
[ 37718-11-9 ]
[ 874196-88-0 ]

Yield	Reaction Conditions	Operation in experiment
70%		<strong>[37718-11-9]1H-Pyrazole-4-carboxylic acid</strong> (300 mg, 2.1 mmol), 4-(2-chloroethyl)morpholine (822 mg, 4.3 mmol) and potassium carbonate (1.2 g, 8.6 mmol) are dissolved in dimethylformamide (12 ml) and stirred for 6.5 h at 75° C. Aftr stnding for another 18 h at ambient temperature, the reaction mixture was treated with water (25 ml) and extracted four times with ethyl acetate (25 ml each). The combined organic layers are extracted four times with water, dryed with magnesium sulphate and evaporated in vacuo. Flash chromatography (silice, eluent dichloromethane containing 4percent methanol) afforded the title compound as colorles liquid (70percent yield). MS: m/e=254(M+H+). Following the general method of example 30 the compounds of examples 31 to 32 were prepared.

References: [1]Patent: US2006/19949,2006,A1 .Location in patent: Page/Page column 10-11.

23
[ 37718-11-9 ]
lmL acetyl chloride [ No CAS ]
methyl 3-pyrazolecarboxylate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.6 g(90%)	In methanol;	Methyl 3-pyrazolcarboxylate hydrochloride 10 mL of methanol at 0° C. was treated dropwise with lmL acetyl chloride, followed by addition of 2.0 g(17.84 mmol) of 4-pyrazolcarboxylic acid, followed by warming the mixture at reflux for 18 h. The solution was cooled and concentrated in vacuo to afford 2.6 g(90percent) of the title compound as a white solid. 1 H NMR (CD3 OD) delta8.25, 3.86.

References: [1]Patent: US6124334,2000,A .

24
[ 37718-11-9 ]
[ 103922-89-0 ]
[ 2942-58-7 ]
N-[4-(4-piperidinomethyl-pyridin-2-yloxy)-cis-2-butenyl]pyrazole-4-carboxamide [ No CAS ]