[ CAS No. 85230-37-1 ] {[proInfo.proName]}

Name: 85230-37-1|Ethyl 5-hydroxy-1H-pyrazole-3-carboxylate|97%
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SKU: A216637
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Quality Control of [ 85230-37-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 85230-37-1 ]

CAS No. :	85230-37-1	MDL No. :	MFCD09263987
Formula :	C₆H₈N₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FGCPAXRNQIOISG-UHFFFAOYSA-N
M.W :	156.14	Pubchem ID :	12847993
Synonyms :

Calculated chemistry of [ 85230-37-1 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.33
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	36.7
TPSA :	75.21 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) :	-6.72 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.01
Log Po/w (XLOGP3) :	0.75
Log Po/w (WLOGP) :	0.29
Log Po/w (MLOGP) :	-0.18
Log Po/w (SILICOS-IT) :	0.63
Consensus Log Po/w :	0.5

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.42
Solubility :	5.95 mg/ml ; 0.0381 mol/l
Class :	Very soluble
Log S (Ali) :	-1.91
Solubility :	1.93 mg/ml ; 0.0123 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.13
Solubility :	11.7 mg/ml ; 0.0746 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.22

Safety of [ 85230-37-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 85230-37-1 ]

* 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 [ 85230-37-1 ]
Downstream synthetic route of [ 85230-37-1 ]

[ 85230-37-1 ] Synthesis Path-Upstream 1~5

1
[ 40876-98-0 ]
[ 85230-37-1 ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: With acetic acid In toluene at 20℃; for 0.5 h; Stage #2: With hydrazine hydrochloride In toluene at 100℃;	Acetic acid (150 mL) was added drop-wise to a solution of sodium 1 ,4-diethoxy- (0282) 1 ,4-dioxobut-2-en-2-olate (30.0 g, 0.143 mol) in toluene (150 mL), and the mixture was stirred at room temperature for 30 minutes, whereupon hydrazine monohydrochloride (85percent, 17 g, 0.29 mol) was added. The reaction mixture was stirred for an additional 30 minutes at room temperature and subsequently heated at 100 °C overnight. It was then concentrated in vacuo and extracted with ethyl acetate (500 mL); the organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the product as a yellow solid. Yield: 17 g, 0.1 1 mol, 77percent. ¹H NMR (400 MHz, DMSO-cf₆) δ 12.75 (br s, 1 H), 5.91 (br s, 1 H), 4.24 (q, J=7 Hz, 2H), 1 .27 (t, J=7 Hz, 3H).

Reference： [1] Patent: WO2017/145013, 2017, A1, . Location in patent: Page/Page column 54
[2] Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 4, p. 1228 - 1234

2
[ 2644-70-4 ]
[ 88330-76-1 ]
[ 85230-37-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: for 0.333333 h; Stage #2: for 0.5 h; Stage #3: at 100℃; for 24.5 h; Heating / reflux	Diethyloxalacetate, sodium salt (14. 53 g, 69. 15 mmol) was dissolved in 100 mL of benzene and stirred for 20 min. To the solution was added 100 ML of acetic acid and the reaction mixture was stirred for a further 30 min. Hydrazine monohydrochloride (9. 47 g, 138 mmol) was added and the reaction mixture was stirred for an additional 30 min. The reaction was brought to reflux at 100 C for 24 h. The reaction was then removed from heat and cooled to room temperature and extracted with ethyl acetate and washed with 10percent hydrochloric acid, saturated sodium bicarbonate solution, water and then brine. The solvent was removed IN VACUO TO yield an oily solid which was then triturated with a 2 : 1 mixture of diethyl ether : hexanes to yield 3 (10. 00 g, 92percent) as an off-white solid : LRMS (electrospray) ; m/z [M+H1+ = 157.

Reference： [1] Patent: WO2004/74257, 2004, A1, . Location in patent: Page 26; 37; 38

3
[ 64-17-5 ]
[ 687-00-3 ]
[ 85230-37-1 ]

Reference： [1] Synthesis, 2003, # 15, p. 2353 - 2357

4
[ 64-17-5 ]
[ 3702-98-5 ]
[ 85230-37-1 ]

Reference： [1] Synthesis, 2003, # 15, p. 2353 - 2357

5
[ 85230-37-1 ]
[ 109-64-8 ]
[ 153597-59-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium carbonate In acetonitrile for 16 h; Heating / reflux	Step 1: Preparation of ethyl 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2- carboxylate :; To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (10.34 g, 0.66 mol) and 36.62 g of potassium carbonate in 500 mi of acetonitrile was added 14.7 g of 1,3-dibromopropane, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgS04 and evaporated to dryness. 8.80 g of the desired product was obtained (68percent), m. p. 44-46°C (M+H) + 197. 1.
68%	With potassium carbonate In acetonitrile for 16 h; Heating / reflux	To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (10.34 g, 0.66 mol) and 36.62 g of potassium carbonate in 500 ml of acetonitrile was added 14.7 g of 1,3-dibromopropane, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO₄and evaporated to dryness. 8.80 g of the desired product was obtained (68percent), m.p. 44-46° C. (M+H)⁺197.1.
61%	With potassium carbonate In acetonitrile for 16 h; Reflux	Potassium carbonate (48.3 g, 349 mmol) was added to a solution of C1 (13.65 g, 87.42 mmol) in acetonitrile (250 mL). The mixture was stirred at room temperature for 15 minutes, whereupon 1 ,3-dibromopropane (10 mL, 98 mmol) was added drop-wise, and the reaction mixture was heated at reflux for 16 hours. It was then allowed to cool to room temperature and filtered; t e filtered solids were washed with acetonitrile (2 x 100 mL). The filtrate was concentrated in vacuo, and the residue was purified via chromatography on silica gel (Gradient: 50percent to 95percent ethyl acetate in heptane) to afford the product as an orange oil. Yield: 10.48 g, 53.4 mmol, 61 percent. LCMS m/z 197.0 [M+H]⁺. ¹H NMR (400 MHz, CDCI₃) δ 6.03 (s, 1 H), 4.39 (q, J=7.1 Hz, 2H), 4.34-4.30 (m, 2H), 4.26 (t, J=6.2 Hz, 2H), 2.33-2.26 (m, 2H), 1.39 (t, J=7.1 Hz, 3H).

Reference： [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4623 - 4637
[2] Patent: WO2003/93279, 2003, A1, . Location in patent: Page/Page column 137
[3] Patent: US2006/276445, 2006, A1, . Location in patent: Page/Page column 42
[4] Patent: WO2017/145013, 2017, A1, . Location in patent: Page/Page column 54-55
[5] Journal of Heterocyclic Chemistry, 1993, vol. 30, # 4, p. 1097 - 1100
[6] Patent: US2004/132708, 2004, A1,

[ 85230-37-1 ] Synthesis Path-Downstream 1~45

1
[ 110-87-2 ]
[ 85230-37-1 ]
[ 153597-60-5 ]

Reference： [1]Journal of Heterocyclic Chemistry,1993,vol. 30,p. 1097 - 1100

2
[ 110-87-2 ]
[ 85230-37-1 ]
5-Hydroxy-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1993,vol. 30,p. 1097 - 1100

3
[ 104-12-1 ]
[ 85230-37-1 ]
[ 85220-11-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,1982,vol. 19,p. 1389 - 1392

4
[ 3320-83-0 ]
[ 85230-37-1 ]
[ 85220-12-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,1982,vol. 19,p. 1389 - 1392

5
[ 40876-98-0 ]
[ 85230-37-1 ]

Yield	Reaction Conditions	Operation in experiment
77%		Acetic acid (150 mL) was added drop-wise to a solution of sodium 1 ,4-diethoxy- (0282) 1 ,4-dioxobut-2-en-2-olate (30.0 g, 0.143 mol) in toluene (150 mL), and the mixture was stirred at room temperature for 30 minutes, whereupon hydrazine monohydrochloride (85%, 17 g, 0.29 mol) was added. The reaction mixture was stirred for an additional 30 minutes at room temperature and subsequently heated at 100 C overnight. It was then concentrated in vacuo and extracted with ethyl acetate (500 mL); the organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the product as a yellow solid. Yield: 17 g, 0.1 1 mol, 77%. 1H NMR (400 MHz, DMSO-cf6) delta 12.75 (br s, 1 H), 5.91 (br s, 1 H), 4.24 (q, J=7 Hz, 2H), 1 .27 (t, J=7 Hz, 3H).

Reference： [1]Patent: WO2017/145013,2017,A1 .Location in patent: Page/Page column 54
[2]Chemical and Pharmaceutical Bulletin,1983,vol. 31,p. 1228 - 1234

6
[ 85230-37-1 ]
[ 87499-06-7 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1983,vol. 31,p. 1228 - 1234

7
[ 85230-37-1 ]
[ 103-71-9 ]
[ 85220-13-9 ]

Reference： [1]Journal of Heterocyclic Chemistry,1982,vol. 19,p. 1389 - 1392

8
[ 85230-37-1 ]
[ 109-64-8 ]
[ 153597-59-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium carbonate; In acetonitrile; for 16h;Heating / reflux;	Step 1: Preparation of ethyl 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2- carboxylate :; To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (10.34 g, 0.66 mol) and 36.62 g of potassium carbonate in 500 mi of acetonitrile was added 14.7 g of 1,3-dibromopropane, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgS04 and evaporated to dryness. 8.80 g of the desired product was obtained (68%), m. p. 44-46C (M+H) + 197. 1.
68%	With potassium carbonate; In acetonitrile; for 16h;Heating / reflux;	To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (10.34 g, 0.66 mol) and 36.62 g of potassium carbonate in 500 ml of acetonitrile was added 14.7 g of 1,3-dibromopropane, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. 8.80 g of the desired product was obtained (68%), m.p. 44-46 C. (M+H)+197.1.
61%	With potassium carbonate; In acetonitrile; for 16h;Reflux;	Potassium carbonate (48.3 g, 349 mmol) was added to a solution of C1 (13.65 g, 87.42 mmol) in acetonitrile (250 mL). The mixture was stirred at room temperature for 15 minutes, whereupon 1 ,3-dibromopropane (10 mL, 98 mmol) was added drop-wise, and the reaction mixture was heated at reflux for 16 hours. It was then allowed to cool to room temperature and filtered; t e filtered solids were washed with acetonitrile (2 x 100 mL). The filtrate was concentrated in vacuo, and the residue was purified via chromatography on silica gel (Gradient: 50% to 95% ethyl acetate in heptane) to afford the product as an orange oil. Yield: 10.48 g, 53.4 mmol, 61 %. LCMS m/z 197.0 [M+H]+. 1H NMR (400 MHz, CDCI3) delta 6.03 (s, 1 H), 4.39 (q, J=7.1 Hz, 2H), 4.34-4.30 (m, 2H), 4.26 (t, J=6.2 Hz, 2H), 2.33-2.26 (m, 2H), 1.39 (t, J=7.1 Hz, 3H).

With potassium carbonate; In ethyl acetate; acetonitrile;

Step 1 Preparation of ethyl 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate: To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (10.34 g, 0.66 mol) and 36.62 g of potassium carbonate in 500 ml of acetonitrile was added 14.7 g of 1,3-dibromopropane, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. 8.80 g of the desired product was obtained (68%), m.p. 44-46 C. (M+H)+ 197.1.

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 4623 - 4637
[2]Patent: WO2003/93279,2003,A1 .Location in patent: Page/Page column 137
[3]Patent: US2006/276445,2006,A1 .Location in patent: Page/Page column 42
[4]Patent: WO2017/145013,2017,A1 .Location in patent: Page/Page column 54-55
[5]Journal of Heterocyclic Chemistry,1993,vol. 30,p. 1097 - 1100
[6]Patent: US2004/132708,2004,A1

9
[ 85230-37-1 ]
[ 329-01-1 ]
[ 85220-14-0 ]

Reference： [1]Journal of Heterocyclic Chemistry,1982,vol. 19,p. 1389 - 1392

10
[ 85230-37-1 ]
[ 111-36-4 ]
[ 85220-15-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,1982,vol. 19,p. 1389 - 1392

11
[ 64-17-5 ]
[ 687-00-3 ]
[ 85230-37-1 ]

Reference： [1]Synthesis,2003,p. 2353 - 2357

12
[ 64-17-5 ]
[ 3702-98-5 ]
[ 85230-37-1 ]

Reference： [1]Synthesis,2003,p. 2353 - 2357

13
[ 85230-37-1 ]
C₁₅H₂₀N₄O₆ [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1993,vol. 30,p. 1097 - 1100

14
[ 85230-37-1 ]
[ 153597-62-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,1993,vol. 30,p. 1097 - 1100

15
[ 85230-37-1 ]
1-(N-4-chlorophenylcarbamoyl)-4,4-dichloro-3-ethoxycarbonylpyrazolin-5-one [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1982,vol. 19,p. 1389 - 1392

16
[ 85230-37-1 ]
[ 18162-48-6 ]
[ 750636-19-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With 1H-imidazole; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 24h;	A solution of hydroxy pyrazole 3 (1. 00 g, 6. 40 mmol) in 10 mL of dimethylformamide was cooled to 0 C and purged with nitrogen. 12. 8 mL (12. 8 mmol) of BDCS Silylation Reagent (Aldrich) was added and the reaction was stirred for 24 h at room temperature. The reaction was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were further washed with water and brine, dried with MgSO4 and filtered. Excess solvent was removed in vacuo to yield a dark oil. The crude product was purified via silica gel chromatography with hexanes : ethyl acetate (9 : 1) to afford the desired silyl ether 5 (1. 64 g, 94%) : LRMS (electrospray) ; m/z [M+H] + = 271.

Reference： [1]Patent: WO2004/74257,2004,A1 .Location in patent: Page 26; 38

17
[ 24424-99-5 ]
[ 85230-37-1 ]
[ 756752-27-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;	Step 1: A solution of 4.58 g of N-tert-butoxycarbonyl anhydride (Boc2O) in 40 ml of dichloromethane is added to a solution of 3.12 g of <strong>[85230-37-1]ethyl 5-hydroxy-1H-pyrazole-3-carboxylate</strong>, which may be prepared according to Chem. Pharm. Bull. 31(4) 1228 (1983), using toluene instead of benzene, in 40 ml of dichloromethane and 3.1 ml of triethylamine, cooled to 0 C. The reaction medium is stirred for 3 hours at room temperature and then washed with saturated aqueous sodium dihydrogen phosphate solution. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on a column of silica (40-63 mum), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume), 3.26 g of 1-tert-butyl 3-ethyl 5-hydroxypyrazole-1,3-dicarboxylate are obtained in the form of a white solid, the characteristics of which are as follows: Mass spectrum (ES): m/z=257 (MH+)

Reference： [1]Patent: US2005/130989,2005,A1 .Location in patent: Page/Page column 26; 27

18
[ 95629-02-0 ]
[ 85230-37-1 ]
[ 623932-10-5 ]

Yield	Reaction Conditions	Operation in experiment
19%	With potassium carbonate; In acetonitrile; for 16h;Heating / reflux;	Example 33 Preparation of (5R, 6Z)-6-f f6-(ethoxvcarbonvl)-5, 6, 7. 8- tetrahydropyrazolo [5', 1' : 2. 31rl, 31oxazolor5, 4-clpyridin-2-yllmethylene)-7-oxo-4- thia--1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt; Step 1: Preparation of ethyl 3-fr3-ethoxvcarbonyl)-1 H-pyrazol-5-vlloxy}-4- oxopiperidine-1-carboxylate : To the stirred suspension of ethyl 5-hydroxy-1 H-pyrazole-3-carboxylate (19.5 g, 127 mmol) and 50.0 g of potassium carbonate in 500 mi of acetonitrile was added 3-bromo-4-oxo-piperidine-1-carboxylic acid ethyl ester (37.45 g, 149 mmol), and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgS04 and evaporated to dryness. The product was purified by silics-gel column chromatography by eluting it with 1: 1 ethyl acetaet; hexane. 8.5 g (19%) of the desired product was obtained as an yellow oil. (M+H) 326.
19%	With potassium carbonate; In acetonitrile; for 16h;Heating / reflux;	To the stirred suspension of <strong>[85230-37-1]ethyl 5-hydroxy-1H-pyrazole-3-carboxylate</strong> (19.5 g, 127 mmol) and 50.0 g of potassium carbonate in 500 ml of acetonitrile was added 3-bromo-4-oxo-piperidine-1-carboxylic acid ethyl ester (37.45 g, 149 mmol), and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. The product was purified by silics-gel column chromatography by eluding it with 1:1 ethyl acetaet;hexane. 8.5 g (19%) of the desired product was obtained as an yellow oil. (M+H) 326.

Reference： [1]Patent: WO2003/93280,2003,A1 .Location in patent: Page/Page column 165
[2]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 1890 - 1902
[3]Patent: US2006/276446,2006,A1 .Location in patent: Page/Page column 34

19
[ 85230-37-1 ]
[ 74-88-4 ]
[ 180518-75-6 ]

Yield	Reaction Conditions	Operation in experiment
38%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;	5-Methoxy-1H-pyrazole-3-carboxylic acid ethyl ester <strong>[85230-37-1]5-Hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester</strong> (300 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (35 ml) and cesium carbonate (626 mg, 1.92 mmol) was added. The resulting suspension was treated with iodomethane (120 mul, 273 mg, 1.92 mmol) and stirred for 12 h at room temperature. The reaction mixture was quenched with saturated potassium hydrogen sulfate solution and extracted with ethyl acetate (3*100 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml). The extract was dried over sodium sulfate, evaporated and the crude product was purified by column chromatography on silica gel. Elution with ethyl acetate/n-heptane (1:3) yielded 124 mg (38%) of a white solid. MS: M=171.2 (ESI+) 1H-NMR (400 MHz, DMSO): delta (ppm)=1.29 (t, 3H), 3.79 (s, 3H), 4.29 (q, 2H), 6.21 (s, 1H), 13.10 (br, 1H)

Reference： [1]Patent: US2006/69145,2006,A1 .Location in patent: Page/Page column 14

20
[ 85230-37-1 ]
[ 822-87-7 ]
[ 623932-04-7 ]

Yield	Reaction Conditions	Operation in experiment
49%	With potassium carbonate; In acetonitrile; for 16h;Heating / reflux;	Example 32 Preparation of (5R, 6Z)-7-oxo-6-(5678-tetrahvdropvrazolof5, 1- blrl, 31benzoxazol-2-vlmethylene)-4-thia--1-azabicyclor3. 2. Olhept-2-ene-2- carboxylic acid, sodium salt Step 1: Preparation of ethyl-5-f (2-oxocyclohexvl) oxy1-1 H-pyrazole-3- carboxylate : To the stirred suspension of ethyl 5-hydroxy-1 H-pyrazole-3-carboxylate (6. 25 g, 40 mmol) and 22.1 g of potassium carbonate in 500 ml of acetonitrile was added 6.35 g of 2-chlorocyclohexanone, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgS04 and evaporated to dryness. The product was purified by silics-gel column chromatography by eluting it with 1: 1 ethyl acetaet; hexane. 4.92 g (49%) of the desired product was obtained as a white solid. M. Pt. 122-124C ; (M+H) 253.
49%	With potassium carbonate; In acetonitrile; for 16h;Heating / reflux;	To the stirred suspension of <strong>[85230-37-1]ethyl 5-hydroxy-1H-pyrazole-3-carboxylate</strong> (6.25 g, 40 mmol) and 22.1 g of potassium carbonate in 500 ml of acetonitrile was added 6.35 g of 2-chlorocyclohexanone, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. The product was purified by silics-gel column chromatography by eluding it with 1:1 ethyl acetaet;hexane. 4.92 g (49%) of the desired product was obtained as a white solid. M.Pt. 122-124 C.; (M+H) 253.
	With potassium carbonate; In ethyl acetate; acetonitrile;	Step 1 Preparation of ethyl-5-[(2-oxocyclohexyl)oxy]-1H-pyrazole-3-carboxylate: To the stirred suspension of <strong>[85230-37-1]ethyl 5-hydroxy-1H-pyrazole-3-carboxylate</strong> (6.25 g, 40 mmol) and 22.1 g of potassium carbonate in 500 ml of acetonitrile was added 6.35 g of 2-chlorocyclohexanone, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. The product was purified by silics-gel column chromatography by eluding it with 1:1 ethyl acetaet;hexane. 4.92 g (49%) of the desired product was obtained as a white solid. M.Pt. 122-124 C.; (M+H) 253.

Reference： [1]Patent: WO2003/93280,2003,A1 .Location in patent: Page/Page column 162
[2]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 1890 - 1902
[3]Patent: US2006/276446,2006,A1 .Location in patent: Page/Page column 33
[4]Patent: US2004/132708,2004,A1

21
[ 85230-37-1 ]
[ 106-93-4 ]
[ 623565-48-0 ]

Yield	Reaction Conditions	Operation in experiment
48%	With potassium carbonate; In acetonitrile; for 16h;Heating / reflux;	Step 1: Preparation of ethvl2, 3-dihvdropyrazolof5. 1-b1r1, 31oxazole-6- carboxylate :; To the stirred suspension of <strong>[85230-37-1]ethyl 5-hydroxy-1H-pyrazole-3-carboxylate</strong> (10. 34 g, 0.66 mol) and 36.62 g of potassium carbonate in 500 ml of acetonitrile was added 13.68 g of 1,2-dibromoethane, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgS04 and evaporated to dryness. 5.80 g of the desired product was obtained (48%).
48%	With potassium carbonate; In acetonitrile; for 16h;Heating / reflux;	To a solution of morpholine-3-carboxylic acid (6.96 g, 52 mmol) in water (20 ml), at 0 C. under nitrogen, was added concentrated hydrochloric acid (4 ml), followed by sodium nitrite (5.0 g, 72 mmol) in small portions. The mixture was stirred at 0 C. for 1 hr, and then concentrated under vacuum at 30 to 35 C. The residue was stirred with 200 ml of acetone and filtered. The filtrate was evaporated and the residue treated with 50 ml of THF and concentrated. The process was repeated with 2×50 ml of THF to give 11.87 g of light yellow foam; MS (ESI) m/z 159.2 (M-H).

Reference： [1]Patent: WO2003/93279,2003,A1 .Location in patent: Page/Page column 130-131
[2]Patent: US2006/276445,2006,A1 .Location in patent: Page/Page column 40

22
[ 98021-79-5 ]
[ 85230-37-1 ]
[ 623931-97-5 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate; In acetonitrile; for 16h;Heating / reflux;	Example 31 Preparation of (5R, 6Z)-6- (7, 8-dihydro-5H-pyrano [4, 3-d] pyrazolof5, 1- b l, 31oxazol-2-ylmethylene) 7-oxo-4-thia-1-azabicyclor3. 2. 01hept-2-ene-2- carboxylic acid, sodium salt Step 1: Preparation of ethyl-5-[(4-oxotetrahydro-2H-pyran-3-yl)-oxy]-1H- pyrazole-3-carboxylate : To the stirred suspension of ethyl 5-hydroxy-1 H-pyrazole-3-carboxylate (7.0 g, 45 mmol) and 24.9 g g of potassium carbonate in 500 mi of acetonitrile was added 8.0 g of 3-bromo-tetrahydro-pyran-4-one, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. 9.0 g (78%) of the desired product was obtainedas a white solid. M. Pt. 121-123C ; (M+H) 255.
78%	With potassium carbonate; In acetonitrile; for 16h;Heating / reflux;	To the stirred suspension of <strong>[85230-37-1]ethyl 5-hydroxy-1H-pyrazole-3-carboxylate</strong> (7.0 g, 45 mmol) and 24.9 g g of potassium carbonate in 500 ml of acetonitrile was added 8.0 g of 3-bromo-tetrahydro-pyran-4-one, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. 9.0 g (78%) of the desired product was obtained as a white solid. M.Pt. 121-123 C.; (M+H) 255.
	With potassium carbonate; In ethyl acetate; acetonitrile;	Step 1 Preparation of ethyl-5-[(4-oxotetrahydro-2H-pyran-3-yl)oxy]-1H-pyrazole-3-carboxylate: To the stirred suspension of <strong>[85230-37-1]ethyl 5-hydroxy-1H-pyrazole-3-carboxylate</strong> (7.0 g, 45 mmol) and 24.9 g g of potassium carbonate in 500 ml of acetonitrile was added 8.0 g of 3-bromo-tetrahydro-pyran-4-one, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. 9.0 g (78%) of the desired product was obtained as a white solid. M.Pt. 121-123 C.; (M+H) 255.

Reference： [1]Patent: WO2003/93280,2003,A1 .Location in patent: Page/Page column 158
[2]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 1890 - 1902
[3]Patent: US2006/276446,2006,A1 .Location in patent: Page/Page column 32
[4]Patent: US2004/132708,2004,A1

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 1 Synthesis of 3-Ethoxycarbonyl-5-hydroxypyrazole To 400 ml of ethanol were added 20.6 g (0.30 mol) of the hydrazine hydrochloride and 63.0 g (0.30 mol) of sodium diethyloxalacetate. This mixture was stirred at room temperature for 2 hours, and then heated with refluxing and stirring for 3 hours. After the ethanol was distilled off, 100 ml of water was added to the residue. The resulting mixture was stirred at room temperature for 1 hour, and the crystals yielded were taken out by filtration and washed with water. Yield: 30.2 g (65%). Melting point: 180-182 C.
	With hydrazine hydrate; In ethanol; at 0℃; for 0.5h;	General procedure: Step B Ethyl 3-methyl-1H-pyrazole-5-carboxylate (5b)To a stirred solution of 5a (33 g, 208.8 mmol) in ethanol (500 mL) at 0 C, hydrazine hydrate (12.5 g, 250.6 mmol) was added and the reaction mixture was stirred for 30 min. The volatiles were removed under reduced pressure and the crude material thus obtained was suspended in water and the product was extracted with ethyl acetate. The combined organic layer was evaporated to dryness to yield 5b (25 g).

24
propanesultone [ No CAS ]
[ 85230-37-1 ]
[ 180270-37-5 ]

Yield	Reaction Conditions	Operation in experiment
23.3 g (42%)	In methanol; 5,5-dimethyl-1,3-cyclohexadiene;	EXAMPLE 6 Synthesis of 3-(3-Ethoxycarbonyl-5-hydroxypyrazol)-1-yl-propanesulfonic acid A mixture of 31.4 g (0.2 mol) of <strong>[85230-37-1]3-ethoxycarbonyl-5-hydroxypyrazole</strong>, 24.4 g (0.2 mol) of purified propanesultone, and 100 ml of xylene was stirred with heating at 150 C. for 2 hours. After the reaction mixture was allowed to separate into two layers, the supernatant was removed by decantation. To the residual sticky oil was added 50 ml of methanol. The resulting mixture was stirred with heating to be dissolved, and then cooled with ice. At the time when crystals began to precipitate, 40 ml of acetone was added. This mixture was maintained at 5 C. or lower overnight in a refrigerator, and the crystals thus precipitated were taken out by filtration. Yield: 23.3 g (42%). Melting point: 107-109 C.

Reference： [1]Patent: US5556987,1996,A

25
[ 2644-70-4 ]
[ 88330-76-1 ]
[ 85230-37-1 ]

Yield	Reaction Conditions	Operation in experiment
92%		Diethyloxalacetate, sodium salt (14. 53 g, 69. 15 mmol) was dissolved in 100 mL of benzene and stirred for 20 min. To the solution was added 100 ML of acetic acid and the reaction mixture was stirred for a further 30 min. Hydrazine monohydrochloride (9. 47 g, 138 mmol) was added and the reaction mixture was stirred for an additional 30 min. The reaction was brought to reflux at 100 C for 24 h. The reaction was then removed from heat and cooled to room temperature and extracted with ethyl acetate and washed with 10% hydrochloric acid, saturated sodium bicarbonate solution, water and then brine. The solvent was removed IN VACUO TO yield an oily solid which was then triturated with a 2 : 1 mixture of diethyl ether : hexanes to yield 3 (10. 00 g, 92%) as an off-white solid : LRMS (electrospray) ; m/z [M+H1+ = 157.

Reference： [1]Patent: WO2004/74257,2004,A1 .Location in patent: Page 26; 37; 38

26
[ 542-18-7 ]
[ 85230-37-1 ]
[ 1344687-47-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate; In acetonitrile; for 16h;Reflux;	Step 1 : Ethyl 5-(cvclohexyloxy)-1 -/-pyrazole-3-carboxylate (110a) To the stirred suspension of ethyl 5-hydroxy-1 H-pyrazole-3-carboxylate (7.00 g, 45.0 mmol) and K2C03 (24.9 g, 180 mmol) in ACN (500 mL) was added cyclohexyl chloride (5.34 g, 45.0 mmol) and the suspension was refluxed for 16 h, cooled to rt, filtered and the solid was washed with ACN. The combined filtrates were concentrated and purified by CC (PE/EA = 2/1) to give compound 110a (8.36 g, 78%) as a white solid. A NOE between cyclohexyl-H and pyrazole-H was observed by NOE spectrum

Reference： [1]Patent: WO2014/23367,2014,A1 .Location in patent: Page/Page column 113

27
[ 85230-37-1 ]
[ 1561965-85-2 ]

Reference： [1]Patent: WO2014/23367,2014,A1

28
[ 85230-37-1 ]
[ 1561965-90-9 ]

Reference： [1]Patent: WO2014/23367,2014,A1

29
[ 85230-37-1 ]
[ 75-03-6 ]
5-ethoxy-1H-pyrazole-3-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
800 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 15 - 25℃; for 3h;	Step C Ethyl 5-ethoxy-1H-pyrazole-3-carboxylate (11c)To a solution of lib (1 g, 6.5 mmol) in DMF (15 mL) at 0C, potassium carbonate (0.9 g, 6.4 mmol) was added followed by the addition of ethyl iodide (1 g, 6.4 mmol). The reaction mixture was stirred at room temperature for 3h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried over anhydrous Na2S04, and then concentrated under reduced pressure. The crude mass was purified by column chromatography using 15% ethyl acetate in petroleum ether (v/v) to yield 11c (800 mg). 1H NMR (300 MHz, DMSO-d6): delta 13.07 (s, 1H), 6.19 (s, 1H), 4.29-4.15 (m, 2H), 4.08 (q, J=7.05 Hz, 2H), 1.37-1.26 (m, 6H). Molecular Formula: C8H12N2O3; LC-MS purity: 63%; Expected: 184.7; Observed: 185.2 (M+1).

Reference： [1]Patent: WO2015/50798,2015,A1 .Location in patent: Page/Page column 59; 60

30
[ 85230-37-1 ]
ethyl 3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate [ No CAS ]