[ CAS No. 637336-53-9 ] {[proInfo.proName]}

Name: 637336-53-9|Methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate|95%
Brand: Ambeed
SKU: A232991
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Quality Control of [ 637336-53-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 637336-53-9 ]

CAS No. :	637336-53-9	MDL No. :	MFCD04969986
Formula :	C₆H₉N₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UBOGPSNFKMAOPP-UHFFFAOYSA-N
M.W :	155.15	Pubchem ID :	7017722
Synonyms :

Calculated chemistry of [ 637336-53-9 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.33
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	39.17
TPSA :	70.14 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) :	-7.04 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.24
Log Po/w (XLOGP3) :	0.29
Log Po/w (WLOGP) :	-0.2
Log Po/w (MLOGP) :	-0.58
Log Po/w (SILICOS-IT) :	-0.53
Consensus Log Po/w :	0.04

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.19
Solubility :	10.0 mg/ml ; 0.0647 mol/l
Class :	Very soluble
Log S (Ali) :	-1.33
Solubility :	7.34 mg/ml ; 0.0473 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.5
Solubility :	49.1 mg/ml ; 0.316 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.89

Safety of [ 637336-53-9 ]

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 [ 637336-53-9 ]

* 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 [ 637336-53-9 ]
Downstream synthetic route of [ 637336-53-9 ]

[ 637336-53-9 ] Synthesis Path-Upstream 1~3

1
[ 400877-57-8 ]
[ 637336-53-9 ]

Yield	Reaction Conditions	Operation in experiment
96%	With hydrogen In methanol for 24 h;	A mixture of [1-METHYL-4-NITRO-LH-PYRAZOLE-3-CARBOXYLIC] acid methyl ester (500 mg, 2.7 mmol) and 10percent palladium on carbon [(50] mg) in methanol [(25] mL) was subjected to 60 psi pressure of hydrogen gas in a Parr apparatus for 24 h. At this time, the reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated in vacuo to afford [4-AMINO-1-METHYL-LH-PYRAZOLE-3-] carboxylic acid methyl ester (402 mg, 96percent) as an off-white solid
95%	With hydrogen In methanol	240 mg (1.30 mM) of the compound obtained in Preparative Example 7 was dissolved in 5 ml of methanol, to which 24 mg of 10percent palladium/charcoal was added dropwise, and the resulting mixture was stirred under hydrogen pressure of 40 atm for 30 minutes. After the reaction was terminated, the resulting reaction solution was filtered through cellite, and distilled under reduced pressure, to obtain 191 mg (95percent) of the title compound.¹H NMR (300 MHz, CDCl₃) δ 3.86 (s, 3H), 3.92 (s, 3H), 6.91 (s, 1H).Mass: 155 (M⁺)
95%	With palladium on activated charcoal In methanol at 25℃; for 1 h;	A solution of methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (1.0 g, 5.41 mmol) and Pd/C (200 mg) in MeOH (60 mL) was stirred for 1 hour at 25°C. Pd/C was filtered out and the filtrate was concentrated to give desired compound as a white solid (800 mg, 95percent).

95%	With hydrogen In methanol for 0.5 h;	240 mg (1.30 mM) of the compound obtained in Preparative Example 7 was dissolved in 5 ml of methanol, to which 24 mg of 10percent palladium/ EPO <DP n="28"/>charcoal was added dropwise, and the resulting mixture was stirred under hydrogen pressure of 40 atm for 30 minutes. After the reaction was terminated, the resulting reaction solution was filtered through cellite, and distilled under reduced pressure, to obtain 191 mg (95percent) of the title compound.¹H NMR(SOOMHZ, CDCl₃) δ 3.86(s, 3H), 3.92(s, 3H), 6.91(s, IH). Mass : 155(M⁺)
84%	With hydrogen In methanol at 20℃; Inert atmosphere	A solution of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (4.8 g, 25.94 mmol) in dry MeOH (100 ml) was thoroughly purged with argon, treated with 10percent Pd-C (2.7 g, 2.59 mmol), and again purged with argon. Then the reaction mixture was hydrogenated under a balloon pressure of hydrogen at rt for overnight. The reaction mixture was filtered through a bed of celite. The filtrate was concentrated and dried to give the title compound as gray - whitesolid (3.4 g, 84percent), which was used in the next reaction step without further purification.
84%	With hydrogen In methanol at 20℃; Inert atmosphere	A solution of l-methyl-4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (4.8 g, 25.94 mmol) in dry MeOH (100ml) was thoroughly purged with argon, treated with 10percent Pd-C (2.7 g, 2.59 mmol), and again purged with argon. Then the reaction mixture was hydrogenated under a balloon pressure of hydrogen at rt for overnight. The reaction mixture was filtered through a bed of celite. The filtrate was concentrated and dried to give the title compound as gray-white solid (3.4 g, 84percent), which was used in the next reaction step without further purification.
8.57 g	With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 6 h;	B) Methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate To a solution of methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (10 g) in methanol (200 mL), palladium-carbon (10percent) (2 g) was added, and the mixture was stirred at room temperature for 6 hours in a hydrogen atmosphere (45 psi). Palladium-carbon was filtered off, and then, the filtrate was concentrated to obtain the title compound (8.57 g). ¹H NMR (400 MHz, CDCl₃) δ 3.86 (3H, s), 3.92 (3H, s), 4.08 (2H, brs), 6.96 (1H, s).

Reference： [1] Patent: US2004/14766, 2004, A1,
[2] Patent: WO2003/106459, 2003, A1, . Location in patent: Page 162
[3] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 979 - 984
[4] Patent: US2010/63106, 2010, A1, . Location in patent: Page/Page column 11
[5] Patent: WO2017/15449, 2017, A1, . Location in patent: Page/Page column 157
[6] Patent: WO2008/51047, 2008, A1, . Location in patent: Page/Page column 25-26
[7] Patent: US2011/306589, 2011, A1, . Location in patent: Page/Page column 53
[8] Patent: WO2011/154327, 2011, A1, . Location in patent: Page/Page column 137
[9] Tetrahedron Letters, 2009, vol. 50, # 22, p. 2624 - 2627
[10] Patent: CN107235906, 2017, A, . Location in patent: Paragraph 0130-0133
[11] Patent: EP3287441, 2018, A1, . Location in patent: Paragraph 0294

2
[ 138786-86-4 ]
[ 637336-53-9 ]

Reference： [1] Patent: US2011/306589, 2011, A1,
[2] Patent: WO2003/106459, 2003, A1,
[3] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 979 - 984
[4] Patent: CN107235906, 2017, A,
[5] Patent: WO2011/154327, 2011, A1,
[6] Patent: WO2008/51047, 2008, A1,

3
[ 637336-53-9 ]
[ 211738-66-8 ]

Reference： [1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 979 - 984

[ 637336-53-9 ] Synthesis Path-Downstream 1~88

1
[ 637336-53-9 ]
[ 76-83-5 ]
[ 637336-55-1 ]

Yield	Reaction Conditions	Operation in experiment
91.1%	With triethylamine; In aqueous hydrochloric acid; dichloromethane; N,N-dimethyl-formamide;	Step 4 Preparation of 1-methyl-4-(trityl-amino)-1H-pyrazole-3-carboxylic acid methyl ester A solution of <strong>[637336-53-9]4-amino-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester</strong> (160 mg, 1.03 mmol) in N,N-dimethylformamide (1.0 mL) at 25 C. was treated with triethylamine (0.35 mL, 2.6 mmol) and triphenylmethylchloride (316 mg, 1.13 mmol). Additional N,N-dimethylformamide (2.0 mL) was added to the reaction to aid stirring. The reaction was stirred at 25 C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and then was washed with a IN aqueous hydrochloric acid solution (110 mL), a saturated aqueous sodium bicarbonate solution (110 mL), and a saturated aqueous sodium chloride solution (1*10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-methyl-4-(trityl-amino)-1H-pyrazole-3-carboxylic acid methyl ester (373 mg, 91.1%) as an off-white solid: 1H NMR (DMSO-d6, 300 MHz) delta7.25 (m, 16H), 3.74 (s, 3H), 3.53 (s, 3H).
91.1%	With triethylamine; In DMF (N,N-dimethyl-formamide); at 25℃; for 18h;	(160 mg, 1.03 mmol) [IN N, N DIMETHYLFORMAMIDE] (1.0 mL) at [25 oC] was treated with triethylamine (0.35 mL, 2.6 mmol) and triphenylmethylchloride (316 mg, 1.13 mmol). Additional [N, N DIMETHYLFORMAMIDE] (2.0 mL) was added to the reaction to aid stirring. The reaction was stirred at [25 oC] for 18 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and then was washed with a 1N aqueous hydrochloric acid solution [(1 X 10] mL), a saturated aqueous sodium bicarbonate solution [(1 X 10] mL), and a saturated aqueous sodium chloride solution [(1 X 10] mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford [1-METHYL-4- (TRITYL-AMINO)-LH-PYRAZOLE-3-CARBOXYLIC] acid methyl ester (373 mg, 91.1%) as an off-white solid

Reference： [1]Patent: US2004/14766,2004,A1
[2]Patent: WO2003/106459,2003,A1 .Location in patent: Page 163

2
[ 400877-57-8 ]
[ 637336-53-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 4h;	10% palladium/C (2.87 g, 2.7 mmol) was added to a stirred solution of methyl 1 -methyl- 4-nitro-1 H-pyrazole-3-carboxylate (p69, 7.15 g, 38.6 mmol) in methanol (250 ml_) and stirred at RT under H2 atmosphere for 4 hrs. The catalyst was filtered off and the solvent was evaporated under vacuum to afford methyl 4-amino-1 -methyl-1 H-pyrazole- 3-carboxylate (p70, 6 g, y= quant) as purple wax used as such in the next step. MS (/T7/z): 156.1 [MH]+
100%	With palladium on activated charcoal; hydrogen; In methanol; at 20℃; under 775.743 Torr; for 12h;Inert atmosphere;	To a solution of methyl 1-methyl-4-nitro-pyrazole-3-carboxylate (2 g, 10.8 mmol, CAS400877-57-8) in MeOH (20 mL) was added Pd/C (200 mg, 10% wt) under N2 atmosphere. The suspension was degassed and purged with H2 gas 3 times. The mixture was stirred under H2 (15 Psi) at rt for 12 hr. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (1.68 g, 100% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta 6.95 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H).
96%	palladium; In methanol;	Step 3 Preparation of 4-amino-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester A mixture of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (500 mg, 2.7 mmol) and 10% palladium on carbon (50 mg) in methanol (25 mL) was subjected to 60 psi pressure of hydrogen gas in a Parr apparatus for 24 h. At this time, the reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated in vacuo to afford 4-amino-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (402 mg, 96%) as an off-white solid: 1H NMR (DMSO-d6, 300 MHz) delta7.10 (s, 1H), 4.65 (broad s, 2H), 3.73 (s, 3H), 3.72 (s, 3H).

96%	With hydrogen;palladium 10% on activated carbon; In methanol; under 3102.97 Torr; for 24h;	A mixture of [1-METHYL-4-NITRO-LH-PYRAZOLE-3-CARBOXYLIC] acid methyl ester (500 mg, 2.7 mmol) and 10% palladium on carbon [(50] mg) in methanol [(25] mL) was subjected to 60 psi pressure of hydrogen gas in a Parr apparatus for 24 h. At this time, the reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated in vacuo to afford [4-AMINO-1-METHYL-LH-PYRAZOLE-3-] carboxylic acid methyl ester (402 mg, 96%) as an off-white solid
95%	With hydrogen;palladium 10% on activated carbon; In methanol; under 30402.0 Torr;	240 mg (1.30 mM) of the compound obtained in Preparative Example 7 was dissolved in 5 ml of methanol, to which 24 mg of 10% palladium/charcoal was added dropwise, and the resulting mixture was stirred under hydrogen pressure of 40 atm for 30 minutes. After the reaction was terminated, the resulting reaction solution was filtered through cellite, and distilled under reduced pressure, to obtain 191 mg (95%) of the title compound.1H NMR (300 MHz, CDCl3) delta 3.86 (s, 3H), 3.92 (s, 3H), 6.91 (s, 1H).Mass: 155 (M+)
95%	With palladium on activated charcoal; In methanol; at 25℃; for 1h;	A solution of methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (1.0 g, 5.41 mmol) and Pd/C (200 mg) in MeOH (60 mL) was stirred for 1 hour at 25C. Pd/C was filtered out and the filtrate was concentrated to give desired compound as a white solid (800 mg, 95%).
95%	With hydrogen;palladium 10% on activated carbon; In methanol; under 30402.0 Torr; for 0.5h;	240 mg (1.30 mM) of the compound obtained in Preparative Example 7 was dissolved in 5 ml of methanol, to which 24 mg of 10% palladium/ EPO <DP n="28"/>charcoal was added dropwise, and the resulting mixture was stirred under hydrogen pressure of 40 atm for 30 minutes. After the reaction was terminated, the resulting reaction solution was filtered through cellite, and distilled under reduced pressure, to obtain 191 mg (95%) of the title compound.1H NMR(SOOMHZ, CDCl3) delta 3.86(s, 3H), 3.92(s, 3H), 6.91(s, IH). Mass : 155(M+)
84%	With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃;Inert atmosphere;	A solution of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (4.8 g, 25.94 mmol) in dry MeOH (100 ml) was thoroughly purged with argon, treated with 10% Pd-C (2.7 g, 2.59 mmol), and again purged with argon. Then the reaction mixture was hydrogenated under a balloon pressure of hydrogen at rt for overnight. The reaction mixture was filtered through a bed of celite. The filtrate was concentrated and dried to give the title compound as gray - whitesolid (3.4 g, 84%), which was used in the next reaction step without further purification.
84%	With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃;Inert atmosphere;	A solution of l-methyl-4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (4.8 g, 25.94 mmol) in dry MeOH (100ml) was thoroughly purged with argon, treated with 10% Pd-C (2.7 g, 2.59 mmol), and again purged with argon. Then the reaction mixture was hydrogenated under a balloon pressure of hydrogen at rt for overnight. The reaction mixture was filtered through a bed of celite. The filtrate was concentrated and dried to give the title compound as gray-white solid (3.4 g, 84%), which was used in the next reaction step without further purification.
	With palladium 10% on activated carbon; hydrogen; In methanol; under 2068.65 Torr; for 1h;	Methyl-4-nitro-lH-pyrazole-3-carboxylate (5.0 g, 27.01 mmol)Added to a hydrogenation reaction flask containing 50mL of methanol,Pd / C (10%, 0.5 g) was added,40psi hydrogen pressure reaction 1.0h,TLC test showed that the reaction was completed,Suction filtration, Pd / C filtration, and concentrated under reduced pressure to give the crude product (3.72 g, 88.7%),The crude product was used without purification in the next reaction administered.
8.57 g	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 2327.23 Torr; for 6h;	B) Methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate To a solution of methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (10 g) in methanol (200 mL), palladium-carbon (10%) (2 g) was added, and the mixture was stirred at room temperature for 6 hours in a hydrogen atmosphere (45 psi). Palladium-carbon was filtered off, and then, the filtrate was concentrated to obtain the title compound (8.57 g). 1H NMR (400 MHz, CDCl3) delta 3.86 (3H, s), 3.92 (3H, s), 4.08 (2H, brs), 6.96 (1H, s).
	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 4h;	10% palladium/C (2.87 g, 2.7 mmol) was added to a stirred solution of methyl 1-methyl- 4-nitro-1 H-pyrazole-3-carboxylate (p129, 7.15 g, 38.6 mmol) in methanol (250 ml_) and stirred at RT under H2 atmosphere for 4 hrs. The catalyst was filtered off and the solvent was evaporated under vacuum to afford methyl 4-amino-1-methyl-1 H-pyrazole- 3-carboxylate (p130, 6 g, y= quant) as purple wax used as such in the next step. MS (/T7/z): 156.1 [MH]+.

Reference： [1]Patent: WO2019/81939,2019,A1 .Location in patent: Page/Page column 78
[2]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 3146; 3147
[3]Patent: US2004/14766,2004,A1
[4]Patent: WO2003/106459,2003,A1 .Location in patent: Page 162
[5]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 979 - 984
[6]Patent: US2010/63106,2010,A1 .Location in patent: Page/Page column 11
[7]Patent: WO2017/15449,2017,A1 .Location in patent: Page/Page column 157
[8]Patent: WO2008/51047,2008,A1 .Location in patent: Page/Page column 25-26
[9]Patent: US2011/306589,2011,A1 .Location in patent: Page/Page column 53
[10]Patent: WO2011/154327,2011,A1 .Location in patent: Page/Page column 137
[11]Tetrahedron Letters,2009,vol. 50,p. 2624 - 2627
[12]Patent: CN107235906,2017,A .Location in patent: Paragraph 0130-0133
[13]Patent: EP3287441,2018,A1 .Location in patent: Paragraph 0294
[14]Patent: WO2019/43407,2019,A1 .Location in patent: Page/Page column 127

4
[ 637336-53-9 ]
[ 598-21-0 ]
[ 1021498-10-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	With triethylamine; In tetrahydrofuran;Inert atmosphere;	Preparative Example 9 4-(2-bromoacetylamino)-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester 160 mg (1.03 mM) of the compound obtained in Preparative Example 8 was dissolved in 3 ml of tetrahydrofuran, to which 0.11 ml (1.24 mM) of bromo acetylbromide and 0.22 ml (1.55 mM) of triethylamine were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for a day. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=1:1), to obtain 100 mg (69%) of the title compound. 1H NMR (300 MHz, CDCl3) delta 3.79 (s, 3H), 3.99 (s, 3H), 4.03 (s, 2H), 8.20 (s, 1H), 9.95 (br, NH). Mass: 275 (Br79+), 277 (Br81)
69%	With triethylamine; In tetrahydrofuran; for 24h;	160 mg (1.03 mM) of the compound obtained in Preparative Example 8 was dissolved in 3 ml of tetrahydrofuran, to which 0.11 ml (1.24 mM) of bromo acetylbromide and 0.22 ml (1.55 mM) of triethylamine were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for a day. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane : ethyl acetate = 1 : 1), to obtain 100 mg(69%) of the title compound.1H NMR(300MHz, CDCl3) delta 3.79(s, 3H), 3.99(s, 3H), 4.03(s, 2H), 8.20(s, IH), 9.95(br, NH).Mass : 275(Br79+), 277(Br81)

Reference： [1]Patent: US2010/63106,2010,A1 .Location in patent: Page/Page column 11
[2]Patent: WO2008/51047,2008,A1 .Location in patent: Page/Page column 26

5
[ 138786-86-4 ]
[ 637336-53-9 ]

Reference： [1]Patent: US2011/306589,2011,A1
[2]Patent: WO2003/106459,2003,A1
[3]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 979 - 984
[4]Patent: CN107235906,2017,A
[5]Patent: WO2011/154327,2011,A1
[6]Patent: WO2008/51047,2008,A1

6
[ 637336-53-9 ]
[ 1352200-22-6 ]

Reference： [1]Patent: US2011/306589,2011,A1
[2]Patent: WO2011/154327,2011,A1

7
[ 637336-53-9 ]
[ 1352195-40-4 ]

Reference： [1]Patent: US2011/306589,2011,A1
[2]Patent: WO2011/154327,2011,A1

8
[ 637336-53-9 ]
[ 1316122-15-2 ]
[ 1352200-21-5 ]

Yield	Reaction Conditions	Operation in experiment
69%		To a stirred solution of A-2 (600 mg, 2.34 mmol) in DMF (10 ml) was added EDCI (672 mg, 3.51 mmol) and HOBt (538 mg, 3.51 mmol) at 25 C. Stirring was continued for 10 min. 4-Amino-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (362 mg, 2.35 mmol) and triethylamine (0.8 ml, 5.35 mmol) were subsequently added to the above solution. The reaction mixture was stirred at 25 C. overnight, then quenched with water (8 ml), and extracted with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and evaporated. The crude product thus obtained was purified by column chromatography over silica gel (2% MeOH /CH2Cl2) to provide the title compound (642 mg, 69%) as yellow sticky solid.
69%		To a stirred solution of A-2 (600 mg, 2.34 mmol) in DMF (10ml) was added EDCI (672 mg, 3.51 mmol) and HOBt (538 mg, 3.51 mmol) at 25C. Stirring was continued for 10 min. 4- Amino-l-methyl-lH-pyrazole-3-carboxylic acid methyl ester (362 mg, 2.35 mmol) and triethylamine (0.8 ml, 5.35 mmol) were subsequently added to the above solution. The reaction mixture was stirred at 25C overnight, then quenched with water (8 ml), and extracted with CH2C12. The combined organic layers were washed with brine, dried (Na2S04), filtered, and evaporated. The crude product thus obtained was purified by column chromatography over silica gel (2% MeOH/CH2Cl2) to provide the title compound (642 mg, 69%) as yellow sticky solid.

Reference： [1]Patent: US2011/306589,2011,A1 .Location in patent: Page/Page column 53
[2]Patent: WO2011/154327,2011,A1 .Location in patent: Page/Page column 137

9
[ 637336-53-9 ]
[ 1352194-72-9 ]

Reference： [1]Patent: WO2011/154327,2011,A1

10
[ 637336-53-9 ]
[ 637336-52-8 ]

Reference： [1]Patent: WO2003/106459,2003,A1

11
[ 637336-53-9 ]
[ 637336-56-2 ]

Reference： [1]Patent: WO2003/106459,2003,A1

12
[ 637336-53-9 ]
(4-bromo-1-methyl-1H-pyrazol-3-yl)-(3-hydroxy-3-trifluoromethyl-3,3a,4,5,6,7-hexahydroindazol-2-yl)methanone [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 979 - 984

13
[ 637336-53-9 ]
(4-amino-1-methyl-1H-pyrazol-3-yl)-(3-hydroxy-3-trifluoromethyl-3,3a,4,5,6,7-hexahydroindazol-2-yl)methanone [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 979 - 984

14
[ 637336-53-9 ]
(4-ethylamino-1-methyl-1H-pyrazol-3-yl)-(3-hydroxy-3-trifluoromethyl-3,3a,4,5,6,7-hexahydroindazol-2-yl)methanone [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 979 - 984

15
[ 637336-53-9 ]
4-amino-1-methyl-1H-pyrazole-3-carboxylic acid hydrazide [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 979 - 984

16
[ 637336-53-9 ]
C₁₅H₁₈F₃N₅O₂ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 979 - 984

17
[ 637336-53-9 ]
[ 211738-66-8 ]

Yield	Reaction Conditions	Operation in experiment
35%	With copper(I) bromide; copper(ll) bromide; isopentyl nitrite; In acetonitrile; at 80℃; for 2h;	Isoamyl nitrite (1 .3 ml_, 9.67mmol) was added drop-wise to a suspension of methyl 4- amino-1 -methyl-1 H-pyrazole-3-carboxylate (p70, 1 g, 6.45 mmol), CuBr2 (1 .44 g, 6.45 mmol) and CuBr (924 mg, 6.45 mmol) in MeCN (25 ml_). The resulting mixture was stirred at 80 C for 2 hrs. After cooling to RT the volatiles were evaporated under vacuum and the residue was purified by FC on S1O2 column (eluting from cHex to 40% EtOAc) to afford methyl 4-bromo- 1 -methyl- 1 H-pyrazole-3-carboxylate (p71 , 500 mg, y= 35 %) as brown solid. MS (mlz): 220.9 [MH]+
500 mg	With copper(I) bromide; copper(ll) bromide; isopentyl nitrite; In acetonitrile; at 80℃; for 2h;	Isoamyl nitrite (1.3 ml_, 9.67mmol) was added drop-wise to a suspension of methyl 4- amino-1-methyl-1 H-pyrazole-3-carboxylate (p130, 1 g, 6.45 mmol), CuBr2 (1.44 g, 6.45 mmol) and CuBr (924 mg, 6.45 mmol) in MeCN (25 ml_). The resulting mixture was stirred at 80 C for 2 hrs. After cooling to RT the volatiles were evaporated under vacuum and the residue was purified by FC on S1O2 column (eluting from cHex to 40% EtOAc ) to afford methyl 4-bromo- 1 -methyl- 1 H-pyrazole-3-carboxylate (p131 , 500 mg, y= 35 %) as brown solid. MS (/77/z): 220.9 [MH]+

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 979 - 984
[2]Patent: WO2019/81939,2019,A1 .Location in patent: Page/Page column 78
[3]Patent: WO2019/43407,2019,A1 .Location in patent: Page/Page column 127

18
[ 637336-53-9 ]
4-bromo-1-methyl-1H-pyrazole-3-carboxylic acid hydrazide [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 979 - 984

19
[ 637336-53-9 ]
C₂₅H₃₆N₄O₇ [ No CAS ]
C₃₁H₄₃N₇O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;	Synthesis of Compound 32.6 [0287] To a solution of 32.5 (250 mg, 0.5 mmol, 1.0 eq) in DMF (5 mL) were added methyl 4-amino-l-methyl-lH-pyrazole-3-carboxylate (155 mg, 1.0 mmol, 2.0 eq), HBTU (190 mg, 0.5 mmol, 1.0 eq) and DIPEA (130 mg, 1.1 mmol, 2.0 eq). The reaction was stirred at room temperature for 2 h, diluted with EA (100 mL). The mixture was washed with water (30 mL x 3), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (PE : EA = 1 : 1) to give 32.6 (100 mg, yield: 31%) as a red oil. 1H NMR (400 MHz, DMSO- 6) D delta: 10.29 (s, 1H), 9.07 (s, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 7.65 (d, J = 4.8 Hz, 1H), 6.73 (t, J = 5.6 Hz, 1H), 3.96 (s, 3H), 3.93-3.89 (m, 5H), 2.87 (q, J = 6.4 Hz, 2H), 1.60-1.57 (m, 2H), 1.52 (s, 9H), 1.38 (s, 9H), 1.26-1.23 (m, 6H); ESI-MS (M+H) +: 642.0.

Reference： [1]Patent: WO2014/143672,2014,A1 .Location in patent: Paragraph 0287

20
[ 637336-53-9 ]
C₂₄H₃₄N₄O₇ [ No CAS ]
C₃₀H₄₁N₇O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;	Synthesis of Compound 33.3 [0292] To a solution of 33.2 (1.6 g, 3.3 mmol, 1.0 eq) and methyl 4-amino-l -methyl- 1H- pyrazole-3-carboxylate (620 mg, 4.0 mmol, 1.2 eq) in DMF (8 mL) was added HATU (1.9 g, 5.0 mmol, 1.5 eq) and DIPEA (851 mg, 6.6 mmol, 2.0 eq). The mixture was stirred at room temperature for 16 h, diluted with DCM (100 mL), washed with water (20 mL * 3) and brine (20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with pre-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%) to furnish the compound 33.3, 542 mg (Y: 27%), as a yellow oil. 1H NMR (400 MHz, CDC13) delta: 10.43 (s, 1H), 8.53 (d, J = 4.8 Hz, 1H), 8.38 (s, 2H), 8.33 (s, 1H), 7.69-7.67 (m, 1H), 4.58 (bs, 1H), 4.05 (s, 3H), 4.00 (s, 3H), 3.12-3.10 (m, 2H), 1.86- 1.64 (m, 4H), 1.56 (s, 9H), 1.54-1.48 (m, 2H), 1.43 (s, 9H), 1.40-1.32 (m, 2H). LCMS m/z 628.3 [M+H] +;

Reference： [1]Patent: WO2014/143672,2014,A1 .Location in patent: Paragraph 0292

21
[ 637336-53-9 ]
C₁₉H₂₅N₃O₆ [ No CAS ]
C₂₅H₃₂N₆O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 12h;	Synthesis of Compound 37.4 [0328] To a solution of 37.3 (200 mg, 0.51 mmol, 1.0 eq) in DCM (10 mL) were added methyl 4-amino-l-methyl-lH-pyrazole-3-carboxylate (80 mg, 0.51 mmol, 1.0 eq), HATU (194 mg, 0.51 mmol, 1.0 eq) and DIPEA (130 mg, 1.02 mmol, 2.0 eq). After stirred at room temperature for 12 h, the reaction mixture was washed with water (10 mL), brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH = 30 / 1) to give 37.4 (320 mg, yield: 85%) as a white solid. 1H NMR (400 MHz, DMSO- 6) D delta: 10.27 (s, 1H), 9.07 (s, 1H), 8.42 (s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.51 (d, J = 5.6 Hz, 1H), 7.27 (s, 1H), 6.81 (t, J =5.6 Hz, 1H), 4.31 (t, J = 6.4 Hz, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 2.95-2.91 (m, 2H), 1.77-1.71 (m, 2H), 1.43-1.36 (m, 4H), 1.36 (s, 9H); ESI-MS (M+H) +: 529.2.

Reference： [1]Patent: WO2014/143672,2014,A1 .Location in patent: Paragraph 0328

22
[ 637336-53-9 ]
[ 32315-10-9 ]
2,6-difluoro-4-(2-phenylethynyl)phenylamine [ No CAS ]
methyl 4-[[2,6-difluoro-4-(2-phenylethynyl)phenyl]carbamoylamino]-1-methylpyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		Example 33Step 1 : Methyl 4-[[2,6-difluoro-4-(2-phenylethynyl)phenyl]carbamoylamino]-1-methyl- pyrazole-3-carboxylate2,6-Difluoro-4-phenylethynyl-phenylamine (Example 25, step 1) (200 mg, 0.87 mmol) was dissolved in toluene (6.0 ml) and bis(trichloromethyl) carbonate (104 mg, 0.35 mmol, 0.4 equiv.) was added at room temperature. The mixture was stirred for 1 hour at 110 C. The mixture was cooled to room temperature and Et3N (440 mg, 0.61 ml, 4.36 mmol, 5 equiv.) and methyl 4- amino-1 -methyl- lH-pyrazole-3-carboxylate (135 mg, 0.87 mmol, 1.0 equiv.) were added at room temperature. The mixture was stirred for 16 hours at 110 C. The reaction mixture was loaded directly onto a silica gel column. The crude product was purified by flashchromatography eluting with an ethyl acetate:heptane gradient 5:95 to 100:0. The desired methyl 4-[[2,6-difluoro-4-(2-phenylethynyl)phenyl]carbamoylamino]-l-methyl-pyrazole-3-carboxylate (223 mg, 65 % yield) was obtained as a light yellow solid, MS: m/e = 409.4 (M+H+)

Reference： [1]Patent: WO2015/44075,2015,A1 .Location in patent: Page/Page column 48

23
[ 637336-53-9 ]
methyl 4-((4-(3-cyano-4-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)phenyl)-1,3,5-triazin-2-yl)amino)-1-methyl-1H-pyrazole-3-carboxylate [ No CAS ]

Reference： [1]Patent: US2016/96827,2016,A1

24
[ 637336-53-9 ]
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)amino)-1,3,5-triazin-2-yl)benzonitrile [ No CAS ]

Reference： [1]Patent: US2016/96827,2016,A1

25
[ 637336-53-9 ]
2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)amino)-1,3,5-triazin-2-yl)benzonitrile [ No CAS ]

Reference： [1]Patent: US2016/96827,2016,A1

26
[ 637336-53-9 ]
4-{3-[3-(3-aminopropoxy)-6-oxo-6H-pyridazin-1-ylmethyl]benzoylamino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Patent: US2016/229871,2016,A1

27
[ 637336-53-9 ]
4-{3-[3-(3-aminopropoxy)-6-oxo-6H-pyridazin-1-ylmethyl]benzoylamino}-1-methyl-1H-pyrazole-3-carboxylic acid lithium salt [ No CAS ]

Reference： [1]Patent: US2016/229871,2016,A1

28
[ 637336-53-9 ]
(3R,4S)-tert-butyl 4-(2-cyano-4-(4-((3-(methoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)amino)-1,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2016/96827,2016,A1

29
[ 2831-66-5 ]
[ 637336-53-9 ]
methyl 4-((4-chloro-1,3,5-triazin-2-yl)amino)-1-methyl-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 2h;	To a solution of 2,4-dichloro-1,3,5-triazine (667 mg, 4.45 mmol) in dichloromethane (30 mL) at 0 C., <strong>[637336-53-9]methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate</strong> (0.62 g, 4 mmol) in dichloromethane (5 mL+5 mL wash) was added, followed by N,N-Diisopropylethylamine (1.05 mL, 6 mmol). The reaction mixture was stirred at 0 C. for 2 h. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH?8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C9H10ClN6O2: 269.7. found: 269.0.

Reference： [1]Patent: US2016/96827,2016,A1 .Location in patent: Paragraph 1830

30
[ 637336-53-9 ]
3-[3-(3-tert-butoxycarbonylamino-propoxy)-6-oxo-6H-pyridazin-1-ylmethyl]-benzoic acid [ No CAS ]
4-{3-[3-(3-tert-butoxycarbonylaminopropoxy)-6-oxo-6H-pyridazin-1-ylmethyl]benzoylamino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3h;	Synthesis of compound 1d: 4-{3-[3-(3-tert-Butoxycarbonylamino-propoxy)-6-oxo-6H-pyridazin-1-ylmethyl]-benzoylamino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester To a stirred solution of 3-[3-(3-tert-Butoxycarbonylamino-propoxy)-6-oxo-6H-pyridazin-1-ylmethyl]-benzoic acid (300.0 mg; 0.74 mmol; 1.0 eq.) and <strong>[637336-53-9]4-amino-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester</strong> (230.8 mg; 1.49 mmol; 2.0 eq.) in DCM (3 ml), was added ethyldiisopropy-amine (0.26 ml; 1.49 mmol; 2.0 eq.), and then bis(2-oxo-3-oxazolidinyl)phosphinic chloride (397.5 mg; 1.56 mmol; 2.1 eq.). The resulting mixture was stirred at rt for 3 h. The reaction mixture was diluted with ethyl acetate and washed with brine, citric acid solution and brine, dried and concentrated to give the title compound as an off-white solid (400 mg: Yield: 100%), which was used for the next step without further purification. LC-MS (M+Na)+: 563.

Reference： [1]Patent: US2016/229871,2016,A1 .Location in patent: Paragraph 0183

31
[ 637336-53-9 ]
12-methyl-20-oxa-1,9,12,13,16,25-hexaazatetracyclo[19.3.1.1^3,70^10,14]hexacosa-3,5,7⁽²⁶⁾,10,13,21⁽²⁵⁾,22-heptaene-8,15,24-trione [ No CAS ]

Reference： [1]Patent: US2016/229871,2016,A1

32
[ 637336-53-9 ]
3-{3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-pyrazol-4-yl]-6-oxo-6H-pyridazin-1-ylmethyl}benzoic acid [ No CAS ]
4-(3-{3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-pyrazol-4-yl]-6-oxo-6H-pyridazin-1-ylmethyl}benzoylamino)-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;	Synthesis of compound 2d: 4-(3-{3-[1-(2-tert-Butoxycarbonylamino-ethyl)-1H-pyrazol-4-yl]-6-oxo-6H-pyridazin-1-ylmethyl}-benzoylamino)-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester A mixture of 3-{3-[1-(2-tert-Butoxycarbonylamino-ethyl)-1H-pyrazol-4-yl]-6-oxo-6H-pyridazin-1-ylmethyl}-benzoic acid (325.00 mg; 0.74 mmol; 1.0 eq.), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (375.6 mg; 0.89 mmol; 1.2 eq.) and ethyldiisopropylamine (0.20 ml; 1.11 mmol; 1.5 eq.) in DMF (4 ml) was stirred at rt for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate, washed with brine and concentrated to give the crude title compound, which was used for next step without further purification. (400 mg; Yield: 69%). LC-MS (M-Boc+H)+: 477.

Reference： [1]Patent: US2016/229871,2016,A1 .Location in patent: Paragraph 0192

33
[ 637336-53-9 ]
3-{3-[5-(tert-butoxycarbonylaminomethyl)pyridin-3-yl]-6-oxo-6H-pyridazin-1-ylmethyl}benzoic acid lithium salt [ No CAS ]
4-(3-{3-[5-(tert-butoxycarbonylaminomethyl)pyridin-3-yl]-6-oxo-6H-pyridazin-1-ylmethyl}benzoylamino)-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;	Synthesis of compound 3d: 4-(3-{3-[5-(tert-Butoxycarbonylamino-methyl)-pyridin-3-yl]-6-oxo-6H-pyridazin-1-ylmethyl}-benzoylamino)-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester A mixture of 3-{3-[5-(tert-Butoxycarbonylamino-methyl)-pyridin-3-yl]-6-oxo-6H-pyridazin-1-ylmethyl}-benzoic acid lithium salt (240.0 mg; 0.54 mmol; 1.0 eq.), (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (321.5 mg; 0.71 mmol; 1.3 eq.) and ethyldiisopropylamine (0.14 ml; 0.81 mmol; 1.5 eq.) in DMF (3 ml) was stirred at rt for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate, washed with brine and concentrated to yield the crude title compound as off-white solid (310.0 mg; yield: 100%), which was used for next step without further purification. LC-MS (M+H)+: 574.

Reference： [1]Patent: US2016/229871,2016,A1 .Location in patent: Paragraph 0200

34
[ 21190-87-4 ]
[ 637336-53-9 ]
4-[(6-bromo-pyridine-2-carbonyl)-amino]-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	4-[(6-Bromo-pyridine-2-carbonyl)-amino]-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester A mixture of 6-Bromo-pyridine-2-carboxylic acid (3000 mg; 14.85 mmol; 1.00 eq.), 4-Amino-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (2765 mg; 17.82 mmol; 1.20 eq.), Ethyl-diisopropyl-amine (6.57 mL; 37.13 mmol; 2.50 eq.) and 3-[chloro-(2-oxooxazolidin-3-yl)phosphoryl]oxazolidin-2-one (4536 mg; 17.82 mmol; 1.20 eq.) in DCM (20 mL) were stirred at RT for overnight. The reaction was filtered, the solid was washed with water, and then acetonitile, the title compound was obtained as a white solid. The filtrate was washed with water, the organic layer was separated, concentrated, washed with methanol, and collected the title compound (combined portions: gave product 5000 mg, which was quantitative yield). LC-MS (M+1): 339/341.

Reference： [1]Patent: US2016/229856,2016,A1 .Location in patent: Paragraph 0257; 0258

35
[ 637336-53-9 ]
6-(1H-pyrazol-4-yl)-pyridine-2-carboxylic acid (1-methyl-3-pent-4-enylcarbamoyl-1H-pyrazol-4-yl)-amide [ No CAS ]

Reference： [1]Patent: US2016/229856,2016,A1

36
[ 637336-53-9 ]
6-(1-allyl-1H-pyrazol-4-yl)-pyridine-2-carboxylic acid (1-methyl-3-pent-4-enylcarbamoyl-1H-pyrazol-4-yl)-amide [ No CAS ]

Reference： [1]Patent: US2016/229856,2016,A1

37
[ 637336-53-9 ]
(7E)-16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴,¹⁸]hexacosa-1⁽²⁴⁾,2⁽²⁶⁾,3,7,14,17,21⁽²⁵⁾,22-octaene-13,20-dione [ No CAS ]
(7Z)-16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴,¹⁸]hexacosa-1⁽²⁴⁾,2⁽²⁶⁾,3,7,14,17,21⁽²⁵⁾,22-octaene-13,20-dione [ No CAS ]

Reference： [1]Patent: US2016/229856,2016,A1

38
[ 637336-53-9 ]
4-[6-(1-tert-butoxycarbonyl-1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Patent: US2016/229856,2016,A1

39
[ 637336-53-9 ]
lithium 1-methyl-4-[6-(1H-pyrazol-4-yl)-pyridine-2-carbonyl]-amino}-1H-pyrazole-3-carboxylate [ No CAS ]

Reference： [1]Patent: US2016/229856,2016,A1

40
[ 637336-53-9 ]
6-(1H-pyrazol-4-yl)-pyridine-2-carboxylic acid [3-(6-bromo-hexylcarbamoyl)-1-methyl-1H-pyrazol-4-yl]-amide [ No CAS ]

Reference： [1]Patent: US2016/229856,2016,A1

41
[ 637336-53-9 ]
16-methyl-4,5,12,15,16,19,25-heptaazatetracyclo[19.3.1.1²,⁵.0¹⁴,¹⁸]hexacosa-1⁽²⁴⁾,2⁽²⁶⁾,3,14,17,21⁽²⁵⁾,22-heptaene-13,20-dione [ No CAS ]

Reference： [1]Patent: US2016/229856,2016,A1

42
[ 637336-53-9 ]
trans-2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexane-1-carboxylic acid [ No CAS ]
methyl 1-methyl-4-[({2-[4-(1H-pyrazol-3-yl)benzoyl]cyclohexyl}carbonyl)amino]-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 50℃;	Step 1 - Methyl l-methyl-4-r({(lR.2R and 1S.2S) -2-r4-(lH-pyrazol-3-vnbenzovH- cvclohexyl\|carbonyl)amino"\|-lH-pyrazole-3-carboxylate A solution of (R,2R and 15*,2S) -2-(4-(lH-pyrazol-3-yl)benzoyl)cyclohexanecarboxylic acid (Intermediate 1, 200 mg, 0.67 mmol), TBTU (387 mg, 1.21 mmol), methyl 4-amino- 1 -methyl- lH-pyrazole-3-carboxylate (208 mg, 1.34 mmol) and DIPEA (0.351 mL, 2.01 mmol) in NMP (8 mL) was stirred at 50C over night. The reaction was quenched by addition of NaHC03 (sat, aq). The mixture was diluted with EtOAc and the phases were separated. The organic layer was washed with brine, NH4C1 (sat, aq) and finally brine. The organic layer was dried over Na2S04, filtered and evaporated leaving the subtitle compound (292 mg) as a yellow solid.

Reference： [1]Patent: WO2016/177703,2016,A1 .Location in patent: Page/Page column 102-103

43
[ 637336-53-9 ]
(4-amino-1-methyl-1H-pyrazol-3-yl)methanol [ No CAS ]

Reference： [1]Patent: US2016/362408,2016,A1

44
[ 637336-53-9 ]
8-[(2,6-difluorobenzyl)oxy]-N-(1 H-indazol-3-yl)-2-methylimidazo[ 1 ,2-a]pyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: US2016/362408,2016,A1

45
[ 637336-53-9 ]
[ 501-53-1 ]
methyl 4-[(benzyloxy)carbonyl]amino}-1-methyl-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 3.5h;	300mg of methyl 4-amino-i-methyl-1H-pyrazole-3-carboxylate (1.9 mmol, 1 equivalent) were dissolved in 8 ml of dry tetrahydrofuran, and 0.3 ml of benzyl chloroformate (2.12 mmol, 1.1 equivalents), 1.01 ml of diisopropylethylamine (5.8 mmol, 3 equivalents) and 47 mg of N,Ndimethylaminopyridine (0.387 mmol, 0.2 equivalents) were added in succession and the mixture was stirred at RT. To improve solubility, an additional 2 ml of dimethylformamide were added after 30 minutes. After a total of 3.5 h at RT, water was added, the reaction mixture was extracted three times with dichloromethane and the combined organic phases were dried with magnesium sulphate, filtered and concentrated to dryness by rotary evaporation. The residue (491 mg, purity 81%, 73% of theory) was used for the next reaction without thrther purification.10467] LC-MS (Method 1): R=i.22 mm10468] MS (ESpos): mlz=290.1 (M+H)

Reference： [1]Patent: US2016/362408,2016,A1 .Location in patent: Paragraph 0465; 0466; 0467; 0468

46
[ 637336-53-9 ]
[ 501-53-1 ]
benzyl [3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl]carbamate [ No CAS ]

Reference： [1]Patent: US2016/362408,2016,A1

47
[ 637336-53-9 ]
[ 111-44-4 ]
methyl 1-methyl-4-morpholino-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 120℃; for 3h;	A solution of compound from step a (775 mg, 5 mmol), 1-chloro-2-(2-chloroethoxy)ethane(1420 mg, 10 mmol), KI (1660 mg, 10 mmol) and K2C03 (2070 mg,15 mmol) in DMF (60mL) was stirred for 3 hours at 120 C. The solvent was removed and it was purified by reversephase C18 column chromatography (MeCN/H20) to give desired compound as a light yellowsolid. (450 mg, 40%). ESI-MS m/z: 226.0 [M+Hf.
40%	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 120℃; for 3h;	A solution of compound from step a (775 mg, 5 mmol), 1-chloro-2-(2-chloroethoxy)ethane (1420 mg, 10 mmol), KI (1660 mg, 10 mmol) and K2CO3 (2070 mg,15 mmol) in DMF (60 mL) was stirred for 3 hours at 120 oC. The solvent was removed and it was purified by reverse phase C18 column chromatography (MeCN/H2O) to give desired compound as a light yellow solid. (450 mg, 40%). ESI-MS m/z: 226.0 [M+H]+.

Reference： [1]Patent: WO2017/15449,2017,A1 .Location in patent: Page/Page column 157; 158
[2]Patent: WO2019/67864,2019,A1 .Location in patent: Page/Page column 153

48
[ 637336-53-9 ]
methyl 4-[benzyl(3-methoxy-3-oxopropyl)amino]-1-methyl-1H-pyrazole-3-carboxylate [ No CAS ]

Reference： [1]Patent: EP3287441,2018,A1

49
[ 637336-53-9 ]
methyl 4-benzyl-2-methyl-7-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine-6-carboxylate [ No CAS ]

Reference： [1]Patent: EP3287441,2018,A1

50
[ 637336-53-9 ]
4-benzyl-2-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one [ No CAS ]

Reference： [1]Patent: EP3287441,2018,A1

51
[ 637336-53-9 ]
2-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one [ No CAS ]

Reference： [1]Patent: EP3287441,2018,A1

52
[ 637336-53-9 ]
4-(3,4-dimethoxybenzoyl)-2-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one [ No CAS ]

Reference： [1]Patent: EP3287441,2018,A1

53
[ 637336-53-9 ]
(3,4-dimethoxyphenyl)(7-hydroxy-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methanone [ No CAS ]

Reference： [1]Patent: EP3287441,2018,A1

54
[ 637336-53-9 ]
(7-azido-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)(3,4-dimethoxyphenyl)methanone [ No CAS ]

Reference： [1]Patent: EP3287441,2018,A1

55
[ 637336-53-9 ]
(7-amino-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)(3,4-dimethoxyphenyl)methanone [ No CAS ]

Reference： [1]Patent: EP3287441,2018,A1

56
[ 637336-53-9 ]
2-chloro-N-(4-(3,4-dimethoxybenzoyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl)benzamide [ No CAS ]

Reference： [1]Patent: EP3287441,2018,A1

57
[ 637336-53-9 ]
[ 292638-85-8 ]
methyl 4-[(3-methoxy-3-oxopropyl)amino]-1-methyl-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6.76 g	With sodium hydrogencarbonate; acetic acid; at 135℃; for 1h;Microwave irradiation;	C) Methyl 4-[(3-methoxy-3-oxopropyl)amino]-1-methyl-1H-pyrazole-3-carboxylate To a mixture of <strong>[637336-53-9]methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate</strong> (7.67 g) and methyl acrylate (5.45 g), acetic acid (0.77 g) was added, and the resulting mixture was stirred at 135C for 1 hour under irradiation with microwave. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to obtain the title compound (6.76 g). 1H NMR (400 MHz, CDCl3) delta 2.61 (2H, t, J = 6.8 Hz), 3.28-3.35 (2H, m), 3.70 (3H, s), 3.87 (3H, s), 3.89 (3H, s), 5.03 (1H, t, J = 6.4 Hz), 6.88 (1H, s).

Reference： [1]Patent: EP3287441,2018,A1 .Location in patent: Paragraph 0295

58
[ 637336-53-9 ]
6-chloro-N-cyclopropyl-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide [ No CAS ]
4-((3-(cyclopropylcarbamoyl)-8-((4-methoxybenzyl)-(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)amino)-1-methyl-1H-pyrazole-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl acetamide; at 125℃; for 8h;Inert atmosphere; Sealed tube;	A mixture of 6-chloro-N-cyclopropyl-8-((4-methoxybenzyl)(methyl) amino)imidazo [1 ,2-bjpyridazine-3 -carboxamide (id) (125 mg, 0.324 mmol), methyl 4- amino-1-methyl-1H-pyrazole-3-carboxylate (101 mg, 0.648 mmol) [Free based (sodium bicarbonate solutionlEtOAc) from HC1 salt purchased from Art-Chem-BBj, Pd2(dba)3 (29.7 mg, 0.032 mmol), XANTPHOS (37.5 mg, 0.065 mmol) and C52CO3 (422 mg, 1.296mmol) in DMA (2 mL) was degassed by bubbling N2 through the mixture for 5 minutes. The reaction vessel was sealed and heated to 125 C for 8 hr. After cooling to rt, the reaction mixture was partitioned between EtOAc (30 ml) and water (20 ml). The organic layer was extracted with iN NaOH (10 ml) and the combined aqueous layers were washed with EtOAc (20 ml). The aqueous layer was acidified to pH 1 with iN HC1 andthe mixture was transfered to a separatory funnel and the aqueous layer was extracted with EtOAc (3 x 25 ml). The combined organic layers were washed with 10%LiC1 solution (2 x 50 ml) and brine (50 ml). After drying (Na2SO4) and filtration the organic layer was concentrated to afford 4-((3 -(cyclopropylcarbamoyl)-8-((4-methoxybenzyl)- (methyl)amino)imidazo [1 ,2-bj pyridazin-6-yl)amino)- 1-methyl- 1H-pyrazole-3 -carboxylicacid (le) (126 mg, 0.257 mmol, 79 % yield) as a tan solid. LC retention time 2.60 mm [Cj. MS (E+) m/z: 491 (MF-T)

Reference： [1]Patent: WO2018/67432,2018,A1 .Location in patent: Page/Page column 55

59
[ 637336-53-9 ]
[ 2094-72-6 ]
methyl 4-[((adamantan-1-yl)carbonyl)amino]-1-methyl-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane;	General procedure: A solution of the appropriate acyl chloride (adamantane-2-carbonyl chloride or 4-substituted benzoyl chloride, 1.3mmol) in dry dioxane (3mL) was added dropwise to a solution of 7a-m, 15, 16, 17 (1.0mmol) in 10mL of the same solvent, maintained at 70C. After the addition was complete, the mixture was refluxed until the formation of hydrogen chloride stopped (1-18h). The solution was concentrated in vacuo and the residue was dissolved in DCM (30mL), washed with NaHCO3 solution (10mL), dried over anhydrous Na2SO4, and evaporated to dryness. The crude product was purified by recrystallization from MeOH or flash column chromatography on silica gel using the reported eluent system.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 161,p. 239 - 251

60
[ 637336-53-9 ]
[ 1021497-89-1 ]

Reference： [1]Patent: WO2008/51047,2008,A1

61
[ 637336-53-9 ]
[ 1021497-88-0 ]

Reference： [1]Patent: WO2008/51047,2008,A1

62
[ 4598-86-1 ]
[ 637336-53-9 ]

Reference： [1]Patent: WO2019/43407,2019,A1
[2]Patent: WO2019/81939,2019,A1

63
[ 637336-53-9 ]
[ 96256-54-1 ]

Reference： [1]Patent: WO2019/43407,2019,A1
[2]Patent: WO2019/81939,2019,A1

64
[ 637336-53-9 ]
lithium 1-methyl-4-phenyl-1H-pyrazole-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/43407,2019,A1
[2]Patent: WO2019/81939,2019,A1

65
[ 637336-53-9 ]
methyl 1-methyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/43407,2019,A1
[2]Patent: WO2019/81939,2019,A1

66
[ 637336-53-9 ]
lithium 1-methyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/43407,2019,A1
[2]Patent: WO2019/81939,2019,A1

67
[ 637336-53-9 ]
cis-tert-butyl N-[4-methyl-2-(1-methyl-4-phenyl-1H-pyrazole-3-carbonyl)-2-azabicyclo[3.1.1]heptan-3-yl]methyl}carbamate [ No CAS ]

Reference： [1]Patent: WO2019/43407,2019,A1

68
[ 637336-53-9 ]
methyl 7-hydroxy-4-(4-methoxybenzyl)-2-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]-pyridine-6-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/101182,2019,A1
[2]Patent: WO2019/101183,2019,A1

69
[ 637336-53-9 ]
methyl 7-chloro-4-(4-methoxybenzyl)-2-methyl-5-oxo-4,5-dihydro-2H-pyrazolo-[4,3-b]pyridine-6-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/101182,2019,A1
[2]Patent: WO2019/101183,2019,A1

70
[ 637336-53-9 ]
7-chloro-4-(4-methoxybenzyl)-2-methyl-5-oxo-4,5-dihydro-2H-pyrazolo[4,3-b]pyridine-6-carbaldehyde [ No CAS ]

Reference： [1]Patent: WO2019/101182,2019,A1
[2]Patent: WO2019/101183,2019,A1

71
[ 637336-53-9 ]
7-chloro-6-(4-fluoro-6-morpholino-1H-benzo[d]imidazol-2-yl)-4-(4-methoxybenzyl)-2-methyl-2H-pyrazolo[4,3-b]pyridin-5(4H)-one [ No CAS ]

Reference： [1]Patent: WO2019/101182,2019,A1

72
[ 637336-53-9 ]
7-chloro-6-(4-fluoro-6-morpholino-1H-benzo[d]imidazol-2-yl)-2-methyl-2H-pyrazolo-[4,3-b]pyridin-5(4H)-one [ No CAS ]

Reference： [1]Patent: WO2019/101182,2019,A1

73
[ 637336-53-9 ]
(S)-6-(4-fluoro-6-morpholino-1H-benzo[d]imidazol-2-yl)-2-methyl-7-((1-(pyrimidin-2-yl)ethyl)amino)-2H-pyrazolo[4,3-b]pyridin-5(4H)-one [ No CAS ]

Reference： [1]Patent: WO2019/101182,2019,A1

74
[ 637336-53-9 ]
7-chloro-4-(4-methoxybenzyl)-2-methyl-6-(5-methyl-6-(pyrrolidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)-2H-pyrazolo[4,3-b]pyridin-5(4H)-one [ No CAS ]

Reference： [1]Patent: WO2019/101182,2019,A1

75
[ 637336-53-9 ]
7-chloro-2-methyl-6-(5-methyl-6-(pyrrolidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)-2H-pyrazolo[4,3-h]pyridin-5(4H)-one [ No CAS ]

Reference： [1]Patent: WO2019/101182,2019,A1

76
[ 637336-53-9 ]
(S)-2-methyl-6-(5-methyl-6-(pyrrolidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)-7-((1-(pyrimidin-2-yl)ethyl)amino)-2H-pyrazolo[4,3-b]pyridin-5(4H)-one [ No CAS ]

Reference： [1]Patent: WO2019/101182,2019,A1

77
[ 637336-53-9 ]
[ 123-11-5 ]
methyl 4-((4-methoxybenzyl)amino)-1-methyl-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tetrahydroborate; trifluoroacetic acid; In ethyl acetate; at 25 - 35℃; for 0.5h;	To a solution of intermediate 1 (<strong>[637336-53-9]methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate</strong>) (7.50 g, 48.3 mmol) in ethyl acetate (150 mL) was added 4-methoxybenzaldehyde (7.90 g, 58.0 mmol) and trifluoroacetic acid (7.2 mL, 96.7 mmol) . Sodium borohydride (1.83 g, 48.3 mmol) was added to the mixture in portions while keeping the temperature below 35 . After addition, the mixture was stirred at 25 for 30 minutes. The reaction mixture was quenched with water (100 mL) and stirred at 25 for 1 hour. Then the mixture was separated and the aqueous layer was extracted with ethyl acetate (50 mL x 3) . The combined organic layers were washed with brine (100 mL) , dried over anhydrous Na 2SO 4 and filtered. The filtrate was concentrated to give crude product which was purified by flash column chromatography (eluting with: petroleum ether: ethyl acetate from 1: 0 to 5: 4) to give intermediate 2 (7.92 g, 73.9%purity, 73.2%yield) as white solids. LC-MS (ESI) (General Procedure C, Method 9) : R T = 0.66 min, mass calcd. for C 14H 17N 3O 3 275.13, m/z found 275.9 [M+H] +.

Reference： [1]Patent: WO2019/101182,2019,A1 .Location in patent: Page/Page column 74; 76; 77
[2]Patent: WO2019/101183,2019,A1 .Location in patent: Page/Page column 69-70

78
[ 637336-53-9 ]
7-chloro-6- (6-methoxy-1H-benzo[d]imidazol-2-yl)-4-(4-methoxybenzyl)-2-methyl-2H-pyrazolo[4,3-b]pyridin-5(4H)-one [ No CAS ]