[ CAS No. 253315-22-9 ] {[proInfo.proName]}

Name: 253315-22-9|6-(1H-Pyrazol-1-yl)nicotinic acid|97%
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Quality Control of [ 253315-22-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 253315-22-9 ]

CAS No. :	253315-22-9	MDL No. :	MFCD00140749
Formula :	C₉H₇N₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QWFKXYLAKWFQLF-UHFFFAOYSA-N
M.W :	189.17	Pubchem ID :	2763614
Synonyms :

Calculated chemistry of [ 253315-22-9 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	11
Fraction Csp3 :	0.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.32
TPSA :	68.01 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.97 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.44
Log Po/w (XLOGP3) :	0.68
Log Po/w (WLOGP) :	0.97
Log Po/w (MLOGP) :	-0.53
Log Po/w (SILICOS-IT) :	0.36
Consensus Log Po/w :	0.58

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.89
Solubility :	2.43 mg/ml ; 0.0129 mol/l
Class :	Very soluble
Log S (Ali) :	-1.69
Solubility :	3.91 mg/ml ; 0.0207 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.93
Solubility :	2.22 mg/ml ; 0.0117 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.03

Safety of [ 253315-22-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 253315-22-9 ]

* 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.

Upstream synthesis route of [ 253315-22-9 ]
Downstream synthetic route of [ 253315-22-9 ]

[ 253315-22-9 ] Synthesis Path-Upstream 1~2

1
[ 1428929-49-0 ]
[ 253315-22-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium hydroxide In ethanol; water at 20℃;	Compound 1 (8.66g, 40.43mmol, 1 equiv) was dissolved in ethanol (80mL). 3 M NaOH_(aq) (40.40mL, 121.3mmol, 3 equiv) was then added and the mixture stirred overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in water (60mL) and extracted with diethyl ether (40mL) two times. pH of the water phase was adjusted with 2M HCl till 3 where white precipitate was formed (7.42g, 97percent). ¹H NMR (400MHz, DMSO-d6) δ(ppm)=6.65 (dd, J₁=2.7Hz, J₂=1.6Hz, 1H, Ar-H), 7.92 (dd, J₁=1.6Hz, J₂=0.8Hz, 1H, Ar-H), 8.04 (dd, J₁=8.6Hz, J₂=0.8Hz, 1H, Ar-H), 8.44 (dd, J₁=8.6Hz, J₂=2.3Hz, 1H, Ar-H), 8.70 (dd, J₁=2.7Hz, J₂=0.8Hz, 1H, Ar-H), 8.96 (dd, J₁=2.3Hz, J₂=0.8Hz, 1H, Ar-H), 13.44 (s, 1H, COOH).

Reference： [1] European Journal of Medicinal Chemistry, 2018, vol. 154, p. 68 - 90
[2] Patent: WO2014/85210, 2014, A1, . Location in patent: Page/Page column 40

2
[ 321533-62-4 ]
[ 253315-22-9 ]

Reference： [1] Tetrahedron, 2010, vol. 66, # 47, p. 9141 - 9144

[ 253315-22-9 ] Synthesis Path-Downstream 1~71

1
[ 253315-22-9 ]
trans-(+/-)-[2-(piperidin-1-ylmethyl)cyclohexyl]amine hydrochloride [ No CAS ]
trans-(+/-)-N-[2-(piperidin-1-ylmethyl)cyclohexyl]-6-(1H-pyrazol-1-yl)nicotinamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h;	Example 2 trans-(+/-)-N-[2-(piperidin-1-ylmethyl)cyclohexyl]-6-(1H-pyrazol-1-yl)nicotinamide To the solution of trans-(+/-)-[2-(piperidin-1-ylmethyl)cyclohexyl]amine hydrochloride (116 mg, 0.5 mmol) in dry DMF (5 mL) was added <strong>[253315-22-9]6-(1H-pyrazol-1-yl)nicotinic acid</strong> (113 mg, 0.6 mmol) followed by HATU (228 mg, 0.6 mmol) and diisopropylethylamine (0.18 mL, 1.0 mmol). The mixture was stirred at room temperature for 1 h, and the reaction was quenched with water (5 mL). The solvent was removed in vacuo. DCM (15 mL) was added and washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4. The crude product was purified with reverse phase HPLC to yield trans-(+/-)-N-[2-(piperidin-1-ylmethyl)cyclohexyl]-6-(1H-pyrazol-1-yl)nicotinamide (156 mg, 71%) as its HCl salt. MS (M+1): 368.3. 1H NMR (400 MHz, METHANOL-D4): pp 1.20-1.62 (m, 5H), 1.72-1.93 (m, 7H), 1.95-2.15 (m, 3H), 2.76-2.90 (m, 1H), 2.94-3.06 (m, 2H), 3.16-3.24 (m, 1H), 3.39-3.50 (m, 1H), 3.59 (d, J=11.33 Hz, 1H), 3.74-3.85 (m, 1H), 6.55 (d, J=1.76 Hz, 1H), 7.79 (s, 1H), 8.01 (d, J=8.59 Hz, 1H), 8.38 (dd, J=8.59, 2.34 Hz, 1H), 8.64 (d, J=2.54 Hz, 1H), 8.91 (d, J=1.95 Hz, 1H).

Reference： [1]Patent: US2007/259888,2007,A1 .Location in patent: Page/Page column 24

2
[ 253315-22-9 ]
[(1S,2R)-2-(piperidin-1-ylmethyl)cyclohexyl]amine hydrochloride salt [ No CAS ]
N-[(1S,2R)-2-(piperidin-1-ylmethyl)cyclohexyl]-6-(1H-pyrazol-1-yl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 16.6667h;	Step E N-[(1S,2R)-2-(piperidin-1-ylmethyl)cyclohexyl]-6-(1H-pyrazol-1-yl)nicotin-amide A mixture of <strong>[253315-22-9]6-(1H-pyrazol-1-yl)nicotinic acid</strong> (0.0622 g, 0.33 mmol), HATU (0.125 g, 0.33 mmol), and diisopropylethylamine (0.073 mL, 0.42 mmol) in dry DMF (1 mL) was stirred at 0 C. for 10 min. A suspension of crude [(1S,2R)-2-(piperidin-1-ylmethyl)cyclohexyl]amine hydrochloride salt (~0.30 mmol) and diisopropylethylamine (0.14 mL, 0.80 mmol) in DMF (0.5 mL+20.5 mL) was then added to the reaction, and the resulting mixture was stirred at 0 C. for 30 min and then warmed to room temperature and stirred for an additional 16 h. The reaction was concentrated in vacuo, and the residue was taken up into CH2Cl2 (5 mL) and a saturated solution of NaHCO3 in water (5 mL). The mixture was passed through a Varian Chem Elut extraction cartridge, and the cartridge washed with additional CH2Cl2 (35 mL). The organic extract was concentrated in vacuo, and the residue was purified by preparative scale reverse phase LC/MS (gradient 55-75% CH3CN in H2O containing 10 mM NH4HCO3) to provide the title compound as a light yellow solid (0.0574 g, 52% over 3 steps) following lyophilization from CH3CN/H2O. MS (M+1): 368.3. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.00-1.16 (m, 2H), 1.21-1.81 (m, 13H), 2.02-2.25 (m, 3H), 2.38 (dd, J=13.1, 10.0 Hz, 1H), 2.44-2.71 (m, 2H), 3.33-3.46 (m, 1H), 6.48 (dd, J=2.6, 1.7 Hz, 1H), 7.76 (dd, J=1.7, 0.7 Hz, 1H), 8.00 (dd, J=8.6, 0.8 Hz, 1H), 8.25 (dd, J=8.6, 2.3 Hz, 1H), 8.61 (dd, J=2.7, 0.8 Hz, 1H), 8.89 (dd, J=2.3, 0.8 Hz, 1H), 9.41 (s, 1H)

Reference： [1]Patent: US2007/259888,2007,A1 .Location in patent: Page/Page column 104

3
[ 253315-22-9 ]
trans-(+/-)-(2-[(3R)-3-(allyloxy)piperidin-1-yl]methyl}cyclohexyl)amine dihydrochloride [ No CAS ]
N-((1S,2R)-2-[(3R)-3-(allyloxy)piperidin-1-yl]methyl}cyclohexyl)-6-(1H-pyrazol-1-yl)nicotinamide [ No CAS ]
N-((1R,2S)-2-[(3R)-3-(allyloxy)piperidin-1-yl]methyl}cyclohexyl)-6-(1H-pyrazol-1-yl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 14.5h;	Example 203 N-((1S,2R)-2-[(3R)-3-(allyloxy)piperidin-1-yl]methyl}cyclohexyl)-6-(1H-pyrazol-1-yl)nicotinamide A mixture of <strong>[253315-22-9]6-(1H-pyrazol-1-yl)nicotinic acid</strong> (0.146 g, 0.77 mmol), HATU (0.293 g, 0.77 mmol), and diisopropylethylamine (0.17 mL, 0.98 mmol) in dry DMF (2 mL) was stirred at 0 C. for 10 min. A solution of a mixture of crude ((1R,2S)-2-[(3R)-3-(allyloxy)piperidin-1-yl]methyl}cyclohexyl)amine hydrochloride salt and ((1S,2R)-2-[(3R)-3-(allyloxy)piperidin-1-yl]methyl}cyclohexyl)-amine hydrochloride salt (0.228 g, ~0.7 mmol) and diisopropylethylamine (0.32 mL, 1.8 mmol) in DMF (1+21 mL) was then added to the reaction, and the resulting mixture was stirred at 0 C. for 20 min and then warmed to room temperature and stirred for an additional 14 h. The reaction was concentrated in vacuo, and the residue was taken up into CH2Cl2 (8 mL) and a saturated solution of NaHCO3 in water (8 mL). The mixture was passed through a Varian Chem Elut extraction cartridge, and the cartridge washed with additional CH2Cl2 (312 mL). The organic extract was concentrated in vacuo, and the residue was purified by preparative scale reverse phase LC/MS (gradient 55-75% CH3CN in H2O containing 10 mM NH4HCO3). The first stereoisomer of the product to elute, N-((1S,2R)-2-[(3R)-3-(allyloxy)piperidin-1-yl]methyl}cyclohexyl)-6-(1H-pyrazol-1-yl)nicotinamide, was obtained as a slightly orange solid (0.0627 g, 21%) following lyophilization from CH3CN/H2O. MS (M+1): 424.3. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.00-1.48 (m, 6H), 1.52-1.85 (m, 6H), 1.89-2.18 (m, 3H), 2.34-2.53 (m, 2H), 2.62 (d, J=10.7 Hz, 1H), 3.19 (d, J=8.6 Hz, 1H), 3.36-3.53 (m, 2H), 3.86-4.15 (m, 2H), 5.16 (d, J=10.4 Hz, 1H), 5.27 (dd, J=17.1, 1.3 Hz, 1H), 5.80-5.98 (m, J=22.6, 10.7, 5.8 Hz, 1H), 6.42-6.54 (m, 1H), 7.76 (d, J=0.8 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 8.21 (dd, J=8.5, 2.1 Hz, 1H), 8.60 (d, J=2.3 Hz, 1H), 8.84 (d, J=1.6 Hz, 1H), 8.90 (s, 1H). Anal. Calcd for C24H33N5O2.0.1H2O: C, 67.77; H, 7.87; N, 16.46. Found: C, 67.84; H, 7.79; N, 16.43.

Reference： [1]Patent: US2007/259888,2007,A1 .Location in patent: Page/Page column 107

4
[ 253315-22-9 ]
((1S,2R)-2-[(3S)-3-(allyloxy)piperidin-1-yl]methyl}cyclohexyl)amine dihydrochloride [ No CAS ]
N-((1S,2R)-2-[(3S)-3-(allyloxy)piperidin-1-yl]methyl}cyclohexyl)-6-(1H-pyrazol-1-yl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 21.6667h;	Step C N-((1S,2R)-2-[(3S)-3-(allyloxy)piperidin-1-yl]methyl}cyclohexyl)-6-(1H-pyrazol-1-yl)nicotinamide A mixture of <strong>[253315-22-9]6-(1H-pyrazol-1-yl)nicotinic acid</strong> (0.0624 g, 0.33 mmol), HATU (0.126 g, 0.33 mmol), and diisopropylethylamine (0.073 mL, 0.42 mmol) in dry DMF (1 mL) was stirred at 0 C. for 10 min. A solution of crude ((1S,2R)-2-[(3S)-3-(allyloxy)piperidin-1-yl]methyl}cyclohexyl)amine hydrochloride salt (~0.3 mmol) and diisopropylethylamine (0.14 mL, 0.8 mmol) in DMF (0.5+20.5 mL) was then added to the reaction, and the resulting mixture was stirred at 0 C. for 30 min and then warmed to room temperature and stirred for an additional 21 h. The reaction was concentrated in vacuo, and the residue was taken up into CH2Cl2 (4 mL) and a saturated solution of NaHCO3 in water (4 mL). The mixture was passed through a Varian Chem Elut extraction cartridge, and the cartridge washed with additional CH2Cl2 (38 mL). The organic extract was concentrated in vacuo, and the residue was purified by preparative scale reverse phase LC/MS (gradient 55-75% CH3CN in H2O containing 10 mM NH4HCO3) to provide the title compound as a white solid (0.0656 g, 52% over 3 steps) following lyophilization from CH3CN/H2O. MS (M+1): 424.3. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 0.94-1.85 (m, 12H), 1.97-2.79 (m, 7H), 3.17-3.58 (m, 2H), 3.73-4.04 (m, 2H), 4.99 (d, J=10.4 Hz, 1H), 5.13 (d, J=17.4 Hz, 1H), 5.67-5.93 (m, 1H), 6.47 (dd, J=2.6, 1.7 Hz, 1H), 7.75 (d, J=1.0 Hz, 1H), 7.98 (dd, J=8.6, 0.4 Hz, 1H), 8.37 (dd, J=8.7, 1.9 Hz, 1H), 8.60 (dd, J=2.5, 0.6 Hz, 1H), 8.95 (d, J=1.0 Hz, 1H), 9.27 (s, 1H). Anal. Calcd for C24H33N5O2.0.2H2O: C, 67.48; H, 7.88; N, 16.39. Found: C, 67.46; H, 7.65; N, 16.26.

Reference： [1]Patent: US2007/259888,2007,A1 .Location in patent: Page/Page column 108

5
[ 253315-22-9 ]
((1S,2R)-2-[3-cyclohexylpiperidin-1-yl]methyl}cyclohexyl)amine dihydrochloride [ No CAS ]
N-((1S,2R)-2-[3-cyclohexylpiperidin-1-yl]methyl}cyclohexyl)-6-(1H-pyrazol-1-yl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 63.5h;	Step B N-((1S,2R)-2-[3-cyclohexylpiperidin-1-yl]methyl}cyclohexyl)-6-(1H-pyrazol-1-yl)nicotinamide A mixture of crude ((1S,2R)-2-[3-cyclohexylpiperidin-1-yl]methyl}cyclohexyl)amine hydrochloride salt (~0.6 mmol) and <strong>[253315-22-9]6-(1H-pyrazol-1-yl)nicotinic acid</strong> (0.125 g, 0.66 mmol) in dry DMF (5 mL) was cooled to 0 C. HATU (0.251 g, 0.66 mmol) and diisopropylethylamine (0.42 mL, 2.4 mmol) were then added to the reaction, and the resulting mixture was stirred at 0 C. for 30 min and then warmed to room temperature and stirred for an additional 63 h. The reaction was concentrated in vacuo, and the residue was taken up into CH2Cl2 (8 mL) and a saturated solution of NaHCO3 in water (8 mL). The mixture was passed through a Varian Chem Elut extraction cartridge, and the cartridge washed with additional CH2Cl2 (2*12 mL). The organic extract was concentrated in vacuo, and the residue was purified by preparative scale reverse phase LC/MS (gradient 75-100% CH3CN in H2O containing 10 mM NH4HCO3) to provide a mixture of the title compounds as a white solid (0.0414 g, 15% over 3 steps) following lyophilization from CH3CN/H2O. MS (M+1): 450.2. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 0.38-1.91 (m, 26H), 2.05 (d, J=13.3 Hz, 1H), 2.27-2.45 (m, 1H), 2.47-2.73 (m, 2H), 3.03-3.22 (m, 1H), 3.34-3.48 (m, 1H), 6.43-6.50 (m, 1H), 7.72-7.79 (m, 1H), 7.94-8.05 (m, 1H), 8.17-8.29 (m, 1H), 8.56-8.66 (m, 1H), 8.79-8.92 (m, 1H), 9.29-9.47 (m, 1H).

Reference： [1]Patent: US2007/259888,2007,A1 .Location in patent: Page/Page column 127

6
[ 253315-22-9 ]
((1S,2R)-2-[3-phenylpiperidin-1-yl]methyl}cyclohexyl)amine dihydrochloride [ No CAS ]
N-((1S,2R)-2-[(3R)-3-phenylpiperidin-1-yl]methyl}cyclohexyl)-6-(1H-pyrazol-1-yl)nicotinamide [ No CAS ]
N-((1S,2R)-2-[(3S)-3-phenylpiperidin-1-yl]methyl}cyclohexyl)-6-(1H-pyrazol-1-yl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 63.5h;	Step B N-((1S,2R)-2-[3-phenylpiperidin-1-yl]methyl}cyclohexyl)-6-(1H-pyrazol-1-yl)nicotinamide A mixture of crude ((1S,2R)-2-[(3S)-3-phenylpiperidin-1-yl]methyl}cyclohexyl)amine hydrochloride salt and ((1S,2R)-2-[(3R)-3-phenylpiperidin-1-yl]methyl}cyclohexyl)amine hydrochloride salt (~0.6 mmol) and <strong>[253315-22-9]6-(1H-pyrazol-1-yl)nicotinic acid</strong> (0.125 g, 0.66 mmol) in dry DMF (5 mL) was cooled to 0 C. HATU (0.251 g, 0.66 mmol) and diisopropylethylamine (0.42 mL, 2.4 mmol) were then added to the reaction, and the resulting mixture was stirred at 0 C. for 30 min and then warmed to room temperature and stirred for an additional 63 h. The reaction was concentrated in vacuo, and the residue was taken up into CH2Cl2 (8 mL) and a saturated solution of NaHCO3 in water (8 mL). The mixture was passed through a Varian Chem Elut extraction cartridge, and the cartridge washed with additional CH2Cl2 (2*12 mL). The organic extract was concentrated in vacuo, and the residue was purified by preparative scale reverse phase LC/MS (gradient 65-85% CH3CN in H2O containing 10 mM NH4HCO3) to provide a mixture of the title compounds as a white solid (0.131 g, 49% over 3 steps) following lyophilization from CH3CN/H2O. MS (M+1): 444.2. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.00-1.51 (m, 5H), 1.51-2.19 (m, 9H), 2.34-2.53 (m, 2H), 2.56-2.88 (m, 3H), 3.18-3.33 (m, 1H), 3.37-3.51 (m, 1H), 6.45-6.52 (m, J=2.1, 2.1 Hz, 1H), 6.86 (dd, J=7.6, 1.8 Hz, 1H), 7.05-7.16 (m, 2H), 7.20-7.38 (m, 2H), 7.74-7.80 (m, 1H), 8.01-8.09 (m, 1H), 8.22-8.34 (m, J=8.8, 8.8, 2.3 Hz, 1H), 8.63 (d, J=2.7 Hz, 1H), 8.85-8.95 (m, 1H), 9.16 (d, J=3.9 Hz, 1H). Anal. Calcd for C27H33N5O: C, 73.11; H, 7.50; N, 15.79. Found: C, 72.93; H, 7.50; N, 15.89.

Reference： [1]Patent: US2007/259888,2007,A1 .Location in patent: Page/Page column 128

7
[ 253315-22-9 ]
C₂HF₃O₂*C₁₉H₃₀N₂ [ No CAS ]
trans-(+/-)-N-{2-[(4-benzylpiperidin-1-yl)methyl]cyclohexyl}-6-(1H-pyrazol-1-yl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Examples 131-145; Procedure: In a plate format, a 0.30M solution of amine in dichloroethane (0.80 ml, 0.22 mmol) was added to a 0.40M solution of trans-(+/-)-tert-butyl[2-formylcyclohexyl]carbamate in dichloroethane (0.50 ml, 0.20 mmol). Solid sodium triacetoxyborohydride (85 mg, 0.40 mmol) was added to the reaction mixtures. The mixtures were stirred at room temperature for 72 hours. A 1N sodium hydroxide solution (0.45 ml, 0.45 mmol) was added. The mixtures were filtered on Hydromatrix and washed with dichloromethane. The mixtures were concentrated. The crude compounds were dissolved in dichloroethane (0.80 ml) and trifluoroacetic acid (0.15 ml) was added. The reactions were stirred at room temperature for 8 hours and concentrated. A 0.2M solution of 6-(1H-pyrazol-1-yl)-nicotinic acid in dimethylacetamide (1.1 ml, 0.22 mmol) was added to the crude compounds, followed by diisopropylethylamine (0.14 ml, 0.8 mmol) and a 0.55M solution of HATU in dimethylacetamide (0.41 ml, 0.22 mmol). The reactions were stirred at room temperature for 16 hours and concentrated. The crude compounds were dissolved in 0.60 ml dichloromethane. A 1N sodium hydroxide solution (0.20 ml) was added. The mixtures were filtered on Hydromatrix and washed three times with dichloromethane. The mixtures were concentrated. The compounds were purified by high pH reverse phase prep LC-MS.

Reference： [1]Patent: US2007/259888,2007,A1 .Location in patent: Page/Page column 69

Yield	Reaction Conditions	Operation in experiment
	With water; sodium hydroxide; In ethanol; for 20h;Reflux;	General procedure: Intermediate 6A: 5-Iso ropyl-3-methyI-lH-pyrazole-4-carboxylic acidEthyl 5-isopropyl-3-methyl-lH-pyrazole-4-carboxylate (WO2009/013211) (2.1 g, 10.7 mmol) was dissolved in ethanohwater (2:1, 10 mL), to it was added sodium hydroxide (857 mg, 21.4 mmol) and refluxed for 20 h. Volatiles were evaporated under reduced pressure. Aqueous layer was diluted with water (20 mL) and extracted with ethyl acetate (2 X 20 mL). Combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 750 mg (73%) of 5 -isopropyl-3 -methyl- 1H- pyrazole-4-carboxylic acid.? NMR (400 MHz, CDCI3): delta 1.17 (d, J = 6.9 Hz, 6H), 2.32 (s, 3H), 3.45-3.54 (m, 1H), 12.23 (brs, 2H). MS (ES) m/z 169.1 (M+l).
	With sodium hydroxide; In ethanol; water; for 20h;Reflux;	General procedure: Intermediate 6A: 5-Isopropyl-3-methyl-1H-pyrazole-4-carboxylic acid Ethyl 5-isopropyl-3-methyl-1H-pyrazole-4-carboxylate (WO2009/013211) (2.1 g, 10.7 mmol) was dissolved in ethanol:water (2:1, 10 mL), to it was added sodium hydroxide (857 mg, 21.4 mmol) and refluxed for 20 h. Volatiles were evaporated under reduced pressure. Aqueous layer was diluted with water (20 mL) and extracted with ethyl acetate (2*20 mL). Combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 750 mg (73%) of 5-isopropyl-3-methyl-1H-pyrazole-4-carboxylic acid. 1H NMR (400 MHz, CDCl3): delta 1.17 (d, J=6.9 Hz, 6H), 2.32 (s, 3H), 3.45-3.54 (m, 1H), 12.23 (brs, 2H). MS (ES) m/z 169.1 (M+1).

9
[ 253315-22-9 ]
[ 124-40-3 ]
N,N-dimethyl-6-(1 H-pyrazol-1-yl)nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In water; acetonitrile;	EXAMPLE 2 N,N-dimethyl-6-(1 H-pyrazol-1-yl)nicotinamide The desired product was prepared by substituting <strong>[253315-22-9]6-(1H-pyrazol-1-yl)nicotinic acid</strong> for 6-methylnicotinic acid and N,N-dimethylamine for N,N-diethylamine in Example 1 and scaling the reaction to a 1 mmol scale. After workup the crude compound was purified by HPLC on a C-18 column using a solvent system increasing in gradient from 5% to 100% acetonitrile/water containing 0.01% TFA over 50 minutes to provide the desired product as the trifluoroacetate salt. MS m/e 217 (M+H)+; 1H NMR (DMSO-d6) delta 3.01 (d, 6H), 6.61-6.63 (m, 1H), 7.88 (d, 1H), 7.97 (d, 1H), 8.06 (dd, 1H), 8.54 (d, 1H), 8.66 (d, 1H).

Reference： [1]Patent: US2004/116479,2004,A1

10
[ 253315-22-9 ]
[ 1117-97-1 ]
[ 1022154-84-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	Step A: N,O-Dimethylhydroxylamine (1.03 g, 10.6 mmol) was added to an ambient temperature solution of <strong>[253315-22-9]6-(1H-pyrazol-1-yl)nicotinic acid</strong> (2 g, 10.6 mmol), EDC (2.4 g, 12.7 mmol), HOBt (1.94 g, 12.7 mmol) and NMM (5.2 mL, 47.6 mmol) in methylene chloride (100 mL). After stirring at ambient temperature overnight, the reaction mixture was diluted with methylene chloride and washed successively with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded N-methoxy-N-methyl-6-(1H-pyrazol-1-yl)nicotinamide.

Reference： [1]Patent: US2010/22598,2010,A1 .Location in patent: Page/Page column 33

11
[ 321533-62-4 ]
[ 253315-22-9 ]

Reference： [1]Tetrahedron,2010,vol. 66,p. 9141 - 9144

12
[ 1428929-49-0 ]
[ 253315-22-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium hydroxide; In ethanol; water; at 20℃;	Compound 1 (8.66g, 40.43mmol, 1 equiv) was dissolved in ethanol (80mL). 3 M NaOH(aq) (40.40mL, 121.3mmol, 3 equiv) was then added and the mixture stirred overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in water (60mL) and extracted with diethyl ether (40mL) two times. pH of the water phase was adjusted with 2M HCl till 3 where white precipitate was formed (7.42g, 97%). 1H NMR (400MHz, DMSO-d6) delta(ppm)=6.65 (dd, J1=2.7Hz, J2=1.6Hz, 1H, Ar-H), 7.92 (dd, J1=1.6Hz, J2=0.8Hz, 1H, Ar-H), 8.04 (dd, J1=8.6Hz, J2=0.8Hz, 1H, Ar-H), 8.44 (dd, J1=8.6Hz, J2=2.3Hz, 1H, Ar-H), 8.70 (dd, J1=2.7Hz, J2=0.8Hz, 1H, Ar-H), 8.96 (dd, J1=2.3Hz, J2=0.8Hz, 1H, Ar-H), 13.44 (s, 1H, COOH).
	With water; lithium hydroxide; In tetrahydrofuran; at 20℃; for 2h;	To a solution of ethyl 6-(lH-pyrazol-l- yl)pyridine-3-carboxylate (50 mg, 0.23 mmol) in THF (1 mL) was added an aqueous solution of lithium hydroxide (1 N, 230 mu,). The reaction was stirred at ambient temperature for two hours. After two hours, the reaction was further diluted with water and purified by reverse phase HPLC to afford 6-(lH-pyrazol-l -yl)pyridine-3-carboxylic acid. LC-MS (IE, m/z): 190 [M + 1]+

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 154,p. 68 - 90
[2]Patent: WO2014/85210,2014,A1 .Location in patent: Page/Page column 40

13
[ 253315-22-9 ]
[ 57260-71-6 ]
C₁₈H₂₃N₅O₃ [ No CAS ]