[ CAS No. 5334-40-7 ] {[proInfo.proName]}

Name: 5334-40-7|4-Nitro-1H-pyrazole-3-carboxylic acid|98%
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SKU: A118088
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Quality Control of [ 5334-40-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 5334-40-7 ]

CAS No. :	5334-40-7	MDL No. :	MFCD00090899
Formula :	C₄H₃N₃O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZMAXXOYJWZZQBK-UHFFFAOYSA-N
M.W :	157.08	Pubchem ID :	219739
Synonyms :

Calculated chemistry of [ 5334-40-7 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	34.37
TPSA :	111.8 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) :	-7.33 cm/s

Lipophilicity

Log Po/w (iLOGP) :	-0.56
Log Po/w (XLOGP3) :	-0.1
Log Po/w (WLOGP) :	0.02
Log Po/w (MLOGP) :	-1.78
Log Po/w (SILICOS-IT) :	-1.56
Consensus Log Po/w :	-0.8

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-0.96
Solubility :	17.4 mg/ml ; 0.111 mol/l
Class :	Very soluble
Log S (Ali) :	-1.8
Solubility :	2.52 mg/ml ; 0.016 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	0.02
Solubility :	166.0 mg/ml ; 1.05 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.93

Safety of [ 5334-40-7 ]

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 [ 5334-40-7 ]

* 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 [ 5334-40-7 ]
Downstream synthetic route of [ 5334-40-7 ]

[ 5334-40-7 ] Synthesis Path-Upstream 1~13

1
[ 5334-40-7 ]
[ 116008-52-7 ]

Reference： [1] Journal of the American Chemical Society, 1956, vol. 78, p. 2418,2422

2
[ 1453-58-3 ]
[ 5334-40-7 ]

Reference： [1] Russian Chemical Bulletin, 1993, vol. 42, # 11, p. 1861 - 1864[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1993, # 11, p. 1945 - 1948

3
[ 67-56-1 ]
[ 5334-40-7 ]
[ 138786-86-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: at 20℃; for 16 h; Stage #2: With water; sodium hydrogencarbonate In methanol; ethyl acetate	Reference Example 1 Methyl 4-nitro-1H-pyrazole-3-carboxylate Acetyl chloride (9 mL) was added dropwise to methanol (90 mL), 4-nitro-1H-pyrazole-3-carboxylic acid (9.00 g, 57.3 mmol) was added to the mixture. The mixture was stirred at room temperature for 16 hr, and concentrated under reduced pressure. Methanol was added to the residue, and the mixture was concentrated under reduced pressure, the operation was twice repeated. The residue was diluted with methanol and ethyl acetate. 5percent sodium hydrogencarbonate aqueous solution was added, and the pH was adjusted to 8-9. The mixture was extracted with ethyl acetate. The extract was washed with water, brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (9.83 g, yield 100percent). ¹H-NMR (DMSO-d₆, 200 MHz): δ 3.98 (3H, s), 8.28 (1H, s).
100%	Stage #2: With sodium hydrogencarbonate In methanol; water; ethyl acetate	Acetyl chloride (9 mL) was added dropwise to methanol (90 mL), 4-nitro-1H-pyrazole-3-carboxylic acid (9.00 g, 57.3 mmol) was added to the mixture. The mixture was stirred at room temperature for 16 hr, and concentrated under reduced pressure. Methanol was added to the residue, and the mixture was concentrated under reduced pressure, the operation was twice repeated. The residue was diluted with methanol and ethyl acetate. 5percent sodium hydrogencarbonate aqueous solution was added, and the pH was adjusted to 8 - 9. The mixture was extracted with ethyl acetate. The extract was washed with water, brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (9.83 g, yield 100percent). ¹H-NMR (DMSO-d₆, 200 MHz):δ 3.98(3H, s), 8.28(1H, s).
100%	at 20℃; Cooling with ice	Dissolve 4-nitro-1H-pyrazole-3-carboxylic acid in methanol (50 ml) and add thionyl chloride (2.5 ml) dropwise on an ice bath. The reaction is allowed to proceed overnight at room temperature. Concentration under reduced pressure gave 4.36 g of a white solid. Yield: 100percent

99.5%	at 0 - 22℃; for 48 h;	EXAMPLE 1 Synthesis of the methanesulphonic acid salt of 4-{2,6-dichloro-benzoylaminoHH- pyrazole-3-carboxylic acid piperidin-4-ylamide and crystals thereofThe methane sulphonic acid salt of 4-(2,6-dichloro-benzoylamino)-lH-pyrazole-3- carboxylic acid piperidin-4-ylamide may be prepared by the synthetic route shown in the Scheme below. EPO <DP n="73"/>SOCI₂, MeOH Stage 1 ₄H₃N₃O_{4 5}H₅N₃O₄ Stage 2 C₅H_{7 3}O₂ FW: 157.09 FW: 171.11 FW: 141.13C₁₂H₉CI₂N₃O₃ C₁₁H₇CI₂N₃O₃ FW: 314.13 FW: 300.10Stage 5Stage 1 : Preparation of 4-nitro-li7-pyrazole-3-carboxylic acid methyl esterC₄H₃N₃O₄ C₅H₅N₃O₄ FW: 157.09 FW: 171.11 EPO <DP n="74"/>A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-l/7-pyrazole-3-carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5 ⁰C, thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 °C overnight, after which time ¹H NMR analysis (d₆-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 ⁰C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 ⁰C to give 4-nitro-l/f-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5percent).; EXAMPLE I lPreparation of 4-(2,6-dichloro-benzoylamino)-lH-pyrazole-3-carboxylic acid piperidin-4-ylamide hydrochlorideHA. Synthesis of 4-nitro-lH-pyrazole-3-carboxylic acid methyl esterThionyl chloride (2.90 ml, 39.8 mmol) is slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in methanol (100 ml) at ambient temperature and the mixture is stirred for 48 hours. The mixture is reduced in EPO <DP n="98"/>vacuo and dried through azeotrope with toluene to afford the 4-nitro-lH-pyrazole- 3-carboxylic acid methyl ester.
99.5%	at 0 - 22℃;	A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-1H-pyrazole-3- carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5 °C, thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 °C overnight, after which time ¹H NMR analysis (dβ- DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 °C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 °C to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5percent).
99.5%	at 0 - 22℃;	A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-1H-pyrazole-3- carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5 °C, thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 °C overnight, after which time ¹H NMR analysis (dβ- DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 °C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 °C to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5percent).
99.5%	at 0 - 22℃;	A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4- nitro-1/-/-pyrazole-3-carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8 950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to O to 5 ⁰C, thionyl chloride <n="161"/>(0.581 L₁ 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 ⁰C overnight, after which time ¹H NMR analysis (d₆-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 ⁰C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 ⁰C to give 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5percent).
99%	at 0 - 70℃; for 5 h;	To a solution of 4-nitro-3-pyrazolecarboxylic acid (3.14 g,20.0 mmol) in MeOH (50 mL) was slowly added thionyl chloride(7.3 mL, 0.1 mol) at 0 °C. After the completion of the addition, thetemperature of the reaction mixture increased to 70 °C and stirredfor 5 h. Methanol was removed in vacuo, and the resulting residuewas poured into ice water and extracted with EtOAc. The organiclayer was washed with 10percent NaHCO3 solution, brine and dried overNa2SO4. The resulting reaction mixture concentrated in vacuo toafford 1 as a white solid (3.37 g, 99percent). 1H NMR (400 MHz, DMSO-d6)δ 8.93 (s, 1H), 3.89 (s, 3H); 13C NMR (100 MHz, DMSO-d6)δ 161.4,138.0, 133.7, 132.0, 53.3.
99.8%	at 0 - 25℃; for 16 - 24 h; Industry scale	Stage 1: Preparation of 4-nitro-lH-pyrazole-3-carboxylic acid methyl esterC₄H₃N₃O₄ C₅H₅N₃O₄FW: 157.09 FW: 171.114-Nitro-lH-pyrazole-3-carboxylic acid (1.350Kg, 8.59 MoI, 1.0 wt) and methanol (10.80L, 8.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5°C under nitrogen and thionyl chloride (0.702L, 9.62 MoI, 0.52 vol) added at this temperature. The mixture was warmed to 15 to 25⁰C over 16 to 24 hours. Reaction completion was determined by ¹H NMR analysis (d₆-DMSO). The mixture was concentrated under vacuum at 35 to 45⁰C and toluene (2.70L, 2.0 vol) charged to the residue and removed under vacuum at 35 to 45°C. The toluene azeotrope was repeated twice using toluene (2.70L, 2.0 vol) to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl <n="72"/>ester [1.467Kg, 99.8percentth, 108.7percent w/w, ¹H NMR Cd₆-DMSO) concordant with structure, no entrained solvent] as an off-white solid.
98.3%	at 0 - 25℃; for 16 - 24 h;	A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-17f-pyrazole-3-carboxylic acid (1.117Kg, 7.11mol, lwt) and methanol (8.950L₅ 8vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5⁰C, thionyl chloride (0.581L, 8.0mol, 0.52vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22⁰C overnight after which time ¹H NMR analysis (d₆-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45⁰C, the residue treated with toluene and re-concentrated (3x 2.250L, 3x 2vol) under reduced pressure at 40 to 45⁰C to give 4-nitro-l//-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210Kg, 99.5percentth).; 4-Nitro-lH-pyrazole-3-carboxylic acid (1.00kg, 6.37mol, l.Owt) and methanol (8.00L, 8.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5°C under nitrogen and thionyl chloride (0.52L, 7.12mol, 0.52vol) was added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by ¹H NMR analysis (d₆-DMSO). The mixture was concentrated under vacuum at 35 to 45°C. Toluene (2.00L, 2.0vol) was charged to the residue and removed under vacuum at 35 to 45⁰C. The azeotrope was repeated twice using toluene (2.00L, 2.0vol) to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.071Kg, 98.3percent) as an off white solid.
98.3%	at 0 - 25℃; for 16 - 48 h;	A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with A- nitro-1H-pyrazole-3-carboxylic acid (1.117Kg, 7.11mol, 1wt) and methanol (8.950L, δvol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5⁰C, thionyl chloride (0.581 L, δ.Omol, 0.52vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22°C overnight after which time ¹H NMR analysis (d₆-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45⁰C, the residue treated with toluene and re-concentrated (3x 2.250L, 3x 2vol) under reduced pressure at 40 to 45⁰C to give 4-nitro-1 /-/-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210Kg, 99.5percentth).4-Nitro-1H-pyrazole-3-carboxylic acid (1.00kg, 6.37mol, 1.0wt) and methanol (8.00L, δ.Ovol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5°C under nitrogen and thionyl chloride (0.52L, 7.12mol, 0.52vol) was added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by ¹H NMR analysis (d₆- DMSO). The mixture was concentrated under vacuum at 35 to 45°C. Toluene (2.00L, 2.0vol) was charged to the residue and removed under vacuum at 35 to 45⁰C. The azeotrope was repeated twice using toluene (2.00L, 2.0vol) to give 4-nitro-1 H-pyrazole-3- carboxylic acid methyl ester (1.071 Kg, 98.3percent) as an off white solid.Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in MeOH (100 ml) at ambient temperature and the mixture stirred for 48 hours. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 14.4 (s, 1 H), 8.9 (s, 1 H), 3.9 (s, 3H)4-Nitro-1H-pyrazole-3-carboxylic acid (1.350Kg, 8.59 MoI, 1.0 wt) and methanol (10.80L, 8.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to O to 5⁰C under nitrogen and thionyl chloride (0.702L, 9.62 MoI, 0.52 vol) added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by ¹H NMR analysis (d₆- DMSO). The mixture was concentrated under vacuum at 35 to 45°C and toluene (2.70L, 2.0 vol) charged to the residue and removed under vacuum at 35 to 45°C. The toluene azeotrope was repeated twice using toluene (2.70L, 2.0 vol) to give 4-nitro-1 H-pyrazole-3- carboxylic acid methyl ester [1.467Kg, 99.8percentth, 108.7percent w/w, ¹H NMR (d₆-DMSO) concordant with structure, no entrained solvent] as an off-white solid.
98.3%	at 0 - 25℃; for 16 - 24 h;	Stage 4: Synthesis of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester; A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4- nitro-lH-pyrazole-3-carboxylic acid (1.117Kg, 7.11mol, lwt) and methanol (8.950L, 8vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5⁰C, thionyl chloride (0.581L, 8.0mol, 0.52vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22°C overnight after which time ¹H NMR analysis (d₆-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45⁰C, the residue treated with toluene and re-concentrated (3x 2.250L, 3x 2vol) under reduced pressure at 40 to 45°C to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210Kg, 99.5percentth).; Stage 4: Preparation of 4-nitro-lH-pyrazole-3-carboxylic acid methyl; esterC₄H₃N₃O₄ C₅H₅N₃O₄FW: 157.09 FW: 171.114-Nitro-lH-pyrazole-3-carboxylic acid (1.00kg, 6.37mol, l.Owt) and methanol (8.00L, 8.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5°C under nitrogen and thionyl chloride (0.52L, 7.12mol, 0.52vol) was added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by ¹H NMR analysis (dβ-DMSO). The mixture was concentrated under vacuum at 35 to 45°C. Toluene (2.00L, 2.0vol) was charged to the residue and removed under vacuum at 35 to 45°C. The azeotrope was repeated twice using toluene (2.00L, 2.0vol) to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.071Kg, 98.3percent) as an off white solid.
98%	at 20℃; for 24 h;	Step 1. Synthesis of methyl 4-nitro-1 /-/-pyrazole-3-carboxylate (C29). Fuming sulfuric acid (4 mL) was added to a solution of 4-nitro-1 /-/-pyrazole-3-carboxylic acid (16.0 g, 102 mmol) in methanol (200 mL), and the reaction was stirred at RT for 24 hours. The reaction mixture was concentrated, and the resulting solid was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, providing C29 as a white solid. Yield: 17.1 g, 99.9 mmol, 98percent. LCMS m/z 170.0 (M-1 ). H NMR (400 MHz, CDCI₃) δ 4.05 (s, 3H), 8.40 (s, 1 H).
96.9%	at 25℃; for 16 h;	4-nitro-lH-pyrazole-3-carboxylic acid (30.0 g, 191.0 mmol) was dissolved in methanol (300 mL)Sulfoxide (34.1 g, 286.5 mol) was added,25 ° C for 16 hours.The reaction solution was concentrated in vacuo,Saturated sodium bicarbonate solution (400 mL) was added,Ethyl acetate extraction (500 mL x 2),Organic synthesis,Saturated brine (300 mL),Dried over anhydrous sodium sulfate,The product was concentrated in vacuo (31.7 g, 96.9percent yield).
95.8%	at 20℃;	Example 43trans-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexan]-4'-yl]-2-phenyl-2,4-dihydroimidazo[4,5-c]pyrazole(1) Preparation of methyl 4-nitro-1H-pyrazole-3-carboxylate Thionyl chloride (5.1 mL, 70.0 mmol) was added portionwise to a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (10.0g, 63.7 mmol) in methanol (100 mL). After the mixture was stirred overnight at room temperature, the solvent was evaporated in vacuo. After the residue was dissolved in ethyl acetate, the solution was washed with water and saturated aqueous brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title compound (10.43 g, 95.8 percent).
92.1%	at 25 - 60℃; for 4 h;	The 4-nitro-1H-pyrazole-3-carboxylic acid (20.0 g, 0.127 mmol) was dissolved in methanol (100 mL) and thionyl chloride (18.1 g, 0.152 mmol) was added , allowed to react for 2 hours at 25 ° C. , then heated to 60 ° C, and allowed to react for 2 hours. The reaction was concentrated in vacuo and methyl tert-butyl ether (80 mL) was added and filtered to give a white solid which was dried in vacuo to give the product (20.0 g, 92.1percent yield).
91%	at 0 - 20℃; for 2 h;	Reference Example 18 Methyl 4-nitro-1H-pyrazole-3-carboxylate To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (10.0 g, 63.7 mmol) in methanol (100 mL), thionyl chloride (5.1 mL, 70.0 mmol) was added dropwise at 0° C., and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (9.9 g, yield 91percent). ¹H-NMR (CDCl₃): δ 4.06 (3H, s), 8.51 (1H, s).
91%	Stage #1: With thionyl chloride In methanol at 20℃; for 2 h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate	To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (10.0 g, 63.7 mmol) in methanol (100 mL), thionyl chloride (5.1 mL, 70.0 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (9.9 g, yield 91percent). ¹H-NMR (CDCl₃) :δ 4.06(3H, s), 8.51(1H, s).
91.7%	at 20℃; for 16 h;	4-Nitro-1H-pyrazole-3-carboxylic acid (20 g, 127.3 mmol) was dissolved in methanol (200 mL) and thionyl chloride (22.7 g, 190.8 mmol) was added and reacted at 20 ° C for 16 hours. The reaction was completed and concentrated. Methyl tert-butyl ether (200 mL) was added and filtered to give 20 g of the title product in 91.7percent yield.
89%	at 65℃; for 16 h;	To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (5 g, 31.8 mmol) in dry MeOH (60 ml) was added freshly crystallized p-toluenesulphonic acid monohydrate (300 mg, 1.6 mmol). The reaction mixture was heated at 65° C. for 16 hrs. MeOH was removed in vacuo. The residue was taken up with saturated aqueous NaHCO₃solution (15 ml) and extracted with EtOAc. The combined organic layers were washed with water, and then with brine, dried (Na₂SO₄), filtered, and evaporated. The crude product was purified by column chromatography over silica gel using 30percent EtOAc /hexane) to provide the title compound as white solid (4.85 g, 89percent).
89%	Stage #1: at 65℃; for 16 h; Inert atmosphere Stage #2: With sodium hydrogencarbonate In water	To a solution of 4-nitro-lH-pyrazole-3-carboxylic acid (5 g, 31.8 mmol) in dry MeOH (60ml) was added freshly crystallized p-toluenesulphonic acid monohydrate (300 mg, 1.6 mmol). The reaction mixture was heated at 65 °C for 16 hrs. MeOH was removed in vacuo. The residue was taken up with saturated aqueous NaHC0₃ solution (15 ml) and extracted with EtOAc. The combined organic layers were washed with water, and then with brine, dried (Na₂S0₄), filtered, and evaporated. The crude product was purified by column chromatography over silica gel using 30percentEtOAc/hexane) to provide the title compound as white solid (4.85 g, 89percent).
86%	for 3.5 h; Heating / reflux	Reference Example 1 Methyl 4-nitro-1H-pyrazole-3-carboxylate Conc. sulfuric acid(8.2 mL) was added to 4-nitro-1H-pyrazole-3-carboxylic acid(163.8 g) dissolved in methanol(1.64 L) under argon atmosphere and the mixture was heated under reflux for 3.5 hours. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure and the resulted residue was triturated in diisopropyl ether. The precipitate was collected by filtration to give the titled compound(153.2 g, 86percent yield) as a colorless crystalline. mp.115-117°C, MS(ESI)m/z:170 [M-H]^-.
72.7%	at 0 - 20℃; for 16 h;	Acetyl chloride (6.34 ml, 89 mmol) was added to the mixture of 4-nitro-1H-pyrazole-3-carboxylic acid (2, 7 g, 44.6 mmol) in MeOH (223 ml) at 0 °C. The mixture was stirred at rt for 16 h. After concentrated in vacuo, the residue was azeotroped with MeOH two times. The residue was diluted with MeOH and EtOAc, and the mixture was adjusted to a pH of approx. 9 with satd NaHCO₃ aq. The mixture was extracted with EtOAc. The organic layer was washed with H₂O and brine, dried over Na₂SO₄, and concentrated to give the compound 12 (5.545 g, 32.4 mmol, 72.7percent) as a white powder. ¹H NMR (DMSO-d₆) δ 14.39 (br s, 1H), 8.99 (s, 1H), 3.89 (s, 3H); ¹³C NMR (DMSO-d₆) δ 161.1, 138.1, 133.2, 130.9, 52.8; HRMS (ESI) m/z: [M−H]⁻ calcd for C₅H₄N₃O₄: 170.0207, found: 170.0200.
48.8%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 18 h;	A mixture [OF 4-NITRO-LH-PYRAZOLE-3-CARBOXYLIC] acid (2.0 g, 12.7 mmol) in dichloromethane at [25 oC] was treated with 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (2.68 g, 14.0 mmol), methanol (8.2 mL), and 4- dimethylaminopyridine (155 mg, 1.27 mmol). The reaction was stirred at [25 oC] for 18 h. At this time, the reaction was diluted with dichloromethane and was washed with a 1N aqueous hydrochloric acid solution (1 x 50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 45: 55 ethyl acetate/petroleum ether) afforded 4-nitro- [1H-PYRAZOLE-3-CARBOXYLIC] acid methyl ester (1.06 g, 48.8percent) as a white solid: LR-MS for [C5H5N304] [(M-H) + AT M/Z] = 170.

Reference： [1] Patent: US2009/156582, 2009, A1, . Location in patent: Page/Page column 28
[2] Patent: EP1847531, 2007, A1, . Location in patent: Page/Page column 40
[3] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 979 - 984
[4] Patent: CN107652293, 2018, A, . Location in patent: Paragraph 0099; 0100; 0101
[5] Patent: WO2006/77426, 2006, A2, . Location in patent: Page/Page column 71-73; 96-97
[6] Patent: WO2006/77425, 2006, A1, . Location in patent: Page/Page column 210-211
[7] Patent: WO2006/77424, 2006, A1, . Location in patent: Page/Page column 189-190
[8] Patent: WO2006/77428, 2006, A1, . Location in patent: Page/Page column 189-190
[9] Patent: WO2008/7113, 2008, A2, . Location in patent: Page/Page column 159-160
[10] Journal of Medicinal Chemistry, 2014, vol. 57, # 18, p. 7536 - 7549
[11] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 551 - 564
[12] Patent: WO2007/129066, 2007, A1, . Location in patent: Page/Page column 29; 70-71
[13] Patent: WO2006/70195, 2006, A1, . Location in patent: Page/Page column 181; 188
[14] Patent: WO2008/1101, 2008, A2, . Location in patent: Page/Page column 291; 297; 333; 358; 362
[15] Patent: WO2007/77435, 2007, A1, . Location in patent: Page/Page column 237; 243
[16] Patent: WO2012/73143, 2012, A1, . Location in patent: Page/Page column 51
[17] Russian Chemical Bulletin, 1993, vol. 42, # 11, p. 1861 - 1864[18] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1993, # 11, p. 1945 - 1948
[19] Patent: CN107226807, 2017, A, . Location in patent: Paragraph 0239-0241; 0305-0307
[20] Patent: EP1566384, 2005, A1, . Location in patent: Page/Page column 50
[21] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 4, p. 1169 - 1172
[22] Patent: CN107286169, 2017, A, . Location in patent: Paragraph 0155-0157
[23] Patent: US2009/156582, 2009, A1, . Location in patent: Page/Page column 30
[24] Patent: EP1847531, 2007, A1, . Location in patent: Page/Page column 43
[25] Patent: CN107226808, 2017, A, . Location in patent: Paragraph 0327; 0340-0342
[26] Patent: US2011/306589, 2011, A1, . Location in patent: Page/Page column 53
[27] Patent: WO2011/154327, 2011, A1, . Location in patent: Page/Page column 136
[28] Patent: EP1903045, 2008, A1, . Location in patent: Page/Page column 43
[29] MedChemComm, 2013, vol. 4, # 2, p. 456 - 462
[30] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 8, p. 1776 - 1787
[31] Patent: WO2003/106459, 2003, A1, . Location in patent: Page 161
[32] Patent: WO2006/70198, 2006, A1, . Location in patent: Page/Page column 126; 139-140
[33] Patent: WO2006/70198, 2006, A1, . Location in patent: Page/Page column 156
[34] Patent: WO2006/70202, 2006, A1, . Location in patent: Page/Page column 80
[35] Patent: WO2006/3440, 2006, A1, . Location in patent: Page/Page column 154
[36] Patent: WO2007/129062, 2007, A1, . Location in patent: Page/Page column 194-195; 199
[37] Patent: WO2016/144848, 2016, A1, . Location in patent: Page/Page column 36
[38] Patent: WO2016/144846, 2016, A1, . Location in patent: Page/Page column 39; 40
[39] Patent: WO2016/144849, 2016, A1, . Location in patent: Page/Page column 31
[40] Patent: WO2016/144844, 2016, A1, . Location in patent: Page/Page column 32
[41] Patent: WO2016/144847, 2016, A1, . Location in patent: Page/Page column 31
[42] Patent: CN107235906, 2017, A, . Location in patent: Paragraph 0090-0093
[43] Patent: WO2018/64135, 2018, A1, . Location in patent: Paragraph 0454-0457

4
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[ 138786-86-4 ]

Reference： [1] Patent: US2010/21420, 2010, A1,
[2] Patent: US2010/21420, 2010, A1,
[3] Patent: US2010/55094, 2010, A1,
[4] Patent: US2010/55094, 2010, A1,

5
[ 67-56-1 ]
[ 7719-09-7 ]
[ 5334-40-7 ]
[ 138786-86-4 ]

Yield	Reaction Conditions	Operation in experiment
99.5%	at 0 - 25℃; for 16 - 48 h;	A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with A- nitro-1 H-pyrazole-3-carboxylic acid (1.117 Kg, 7.1 1 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to O to 5 ⁰C, thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 ⁰C overnight, after which time ¹H NMR analysis (d₆-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 ⁰C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 ⁰C to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5percent).; Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in MeOH (100 ml) at ambient temperature and the mixture stirred for 48 hours. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as a white solid.; Stage 1 : Preparation of 4-nitro-1 H-pvrazole-3-carboxylic acid methyl ester 4-Nitro-1H-pyrazole-3-carboxylic acid (1.350Kg₁ 8.59 MoI, 1.0 wt) and methanol (10.80L, 8.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to O to 5°C under nitrogen and thionyl chloride (0.702L, 9.62 MoI, 0.52 vol) added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by ¹H NMR analysis (d₆- DMSO). The mixture was concentrated under vacuum at 35 to 45°C and toluene (2.70L, 2.0 vol) charged to the residue and removed under vacuum at 35 to 45°C. The toluene azeotrope was repeated twice using toluene (2.70L, 2.0 vol) to give 4-nitro-1 H-pyrazole-3- carboxylic acid methyl ester [1.467Kg, 99.8percentth, 108.7percent w/w, ¹H NMR (d₆-DMSO) concordant with structure, no entrained solvent] as an off-white solid.

Reference： [1] Patent: WO2008/9954, 2008, A1, . Location in patent: Page/Page column 83-84; 105

6
[ 75-36-5 ]
[ 5334-40-7 ]
[ 138786-86-4 ]

Reference： [1] Journal of Antibiotics, 2015, vol. 68, # 6, p. 361 - 367

7
[ 64-17-5 ]
[ 5334-40-7 ]
[ 55864-87-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	Reflux	A solution of 4-nitro-1H-pyrazole-3-carboxylic acid (2.5 g, 15.9 mmol) in ethanolic HCl (38.3 mL, 1.25M) was refluxed overnight. All volatiles were removed to yield a whitesolid (2.9 g, 98percent) which was used without any further purification. MS: M=186.1 (M+H)⁺
98%	Reflux; Inert atmosphere	A solution of 4-nitro-lH-pyrazole-3-carboxylic acid (2.5 g, 15.9 mmol) in ethanolic HQ (38.3 mL, 1.25M) was refluxed overnight. All volatiles were removed to yield a white solid (2.9 g, 98 percent) which was used without any further purification.MS: M = 186.1 (M+H)⁺
96%	at 20℃; for 48 h;	Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 h. The mixture was reduced in vacuo and EPO <DP n="124"/>dried through azeotrope with toluene to afford 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (¹H NMR (400 MHz, DMSOd₆) δ 14.4 (s, IH), 9.0 (S₅ IH)₃ 4.4 (q, 2H), 1.3 (t, 3H)).

96%	at 20℃; for 48 h;	1A. 4-Nitro-lH-pyrazole-3-carboxylic acid ethyl ester; OEtN-NHThionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3-pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambienttemperature and the mixture stirred for 48 h. The mixture was reduced in vacuaand dried through azeotrope with toluene to afford 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (*H NMR (400 MHz,DMSO-d₆) 8 14.4 (s, 1H), 9.0 (s, 1H), 4.4 (q, 2H), 1.3 (t, 3H)).
96%	at 20℃; for 48 h;	Preparation VIII; Synthesis of 4-ammo-1H-pyrazole-3-carboxylic acid ethyl esterStep 1. 4-Nitro-1H-pyrazole-3-carboxylic acid ethyl esterThionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 hours. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3- carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (¹H NMR (400 MHz, DMSO-d₆) δ 14.4 (s, IH), 9.0 (s, IH), 4.4 (q, 2H), 1.3 (t, 3H)).
96%	at 20℃; for 48 h;	Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3-pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 h. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (¹H NMR (400 MHz, DMSO-d₆) D 14.4 (s, 1 H), 9.0 (s, 1 H), 4.4 (q, 2H), 1.3 (t, 3H)).
96%	at 20℃; for 48 h;	Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3-pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 h. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (¹H NMR (400 MHz, DMSO-d₆) D 14.4 (s, 1 H), 9.0 (s, 1 H), 4.4 (q, 2H), 1.3 (t, 3H)).
96%	at 20℃; for 48 h;	Step 1. 4-Nitro-lH-pyrazole-3-carboxylic acid ethyl ester; Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 hours. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-lH-pyrazole-3- carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (¹H NMR (400 MHz, DMSO-d₆) δ 14.4 (s, IH), 9.0 (s, IH), 4.4 (q, 2H), 1.3 (t, 3H)).

Reference： [1] Patent: US2011/306589, 2011, A1, . Location in patent: Page/Page column 45
[2] Patent: WO2011/154327, 2011, A1, . Location in patent: Page/Page column 118
[3] Patent: WO2006/70198, 2006, A1, . Location in patent: Page/Page column 122-123
[4] Patent: WO2006/3440, 2006, A1, . Location in patent: Page/Page column 147
[5] Patent: WO2006/77414, 2006, A1, . Location in patent: Page/Page column 142
[6] Patent: WO2006/77424, 2006, A1, . Location in patent: Page/Page column 186
[7] Patent: WO2006/77425, 2006, A1, . Location in patent: Page/Page column 186
[8] Patent: WO2006/77428, 2006, A1, . Location in patent: Page/Page column 163
[9] Patent: WO2008/7123, 2008, A2, . Location in patent: Page/Page column 111
[10] Journal of Medicinal Chemistry, 2008, vol. 51, # 16, p. 4986 - 4999
[11] Patent: WO2005/37797, 2005, A1, . Location in patent: Page/Page column 271-272

8
[ 5334-40-7 ]
[ 55864-87-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With thionyl chloride In ethanol at 20℃; for 48 h;	Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 h. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (¹H NMR (400 MHz, DMSO-d₆) δ 14.4 (s, 1H), 9.0 (s, 1H), 4.4 (q, 2H), 1.3 (t, 3H)).

Reference： [1] Patent: WO2005/12256, 2005, A1, . Location in patent: Page/Page column 184
[2] Patent: WO2007/23105, 2007, A1, . Location in patent: Page/Page column 63-64

9
[ 75-36-5 ]
[ 5334-40-7 ]
[ 55864-87-4 ]

Reference： [1] Patent: US2005/197340, 2005, A1, . Location in patent: Page/Page column 68

10
[ 5334-40-7 ]
[ 74-88-4 ]
[ 400877-57-8 ]

Yield	Reaction Conditions	Operation in experiment
19%	Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3 h; Stage #2: at 20℃; for 15 h;	4-Nitropyrazole-3-carboxylic acid (27.5 g, 175 mmol) was dissolved in N,N-dimethylformamide (800 mL) and K₂CO₃ (53.2 g, 385 mmol) was added at room temperature. The reaction was heated to 80°C and stirred for 3 hours. After cooling to room temperature, iodomethane (74.6 g, 525 mmol) was added and the reaction was allowed to react at room temperature for 15 hours. The reaction solution was diluted with water (2.5 L) and extracted with ethyl acetate (1 L x 2). The organic phases were combined, washed with saturated aqueous sodium chloride solution (800 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:1 petroleum ether / ethyl acetate, R_f1 = 0.5, R_f2 = 0.3) to give methyl 2-methyl-4-nitro-2H-pyrazole-3-carboxylate (6.00 g, as a yellow liquid) with a yield of 19percent, and methyl 1-methyl-4-nitro-pyrazole-3-carboxylate (11.0 g, as a white solid) with a yield of 34percent. ¹H NMR: (400 MHz, CDCl₃) δ 8.15(s, 1H), 4.01(s, 3H), 4.00(s, 3H). MS-ESI calcd. [M + H]⁺ 186, found 186.

Reference： [1] Patent: EP3299371, 2018, A1, . Location in patent: Paragraph 0465; 0466; 0467
[2] Patent: WO2017/19804, 2017, A2, . Location in patent: Paragraph 0358

11
[ 77-78-1 ]
[ 5334-40-7 ]
[ 400877-57-8 ]

Yield	Reaction Conditions	Operation in experiment
30 g	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 14 h; Cooling with ice	A) Methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate To a suspension of 4-nitro-1H-pyrazole-3-carboxylic acid (62 g) and potassium carbonate (221 g) in DMF (700 mL), dimethyl sulfate (121 g) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured to water, followed by extraction with ethyl acetate. The extract was 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 (30 g). ¹H NMR (400 MHz, CDCl₃) δ 4.01 (3H, s), 4.03 (3H, s), 8.18 (1H, s).

Reference： [1] Patent: EP3287441, 2018, A1, . Location in patent: Paragraph 0293

12
[ 67-56-1 ]
[ 5334-40-7 ]
[ 74-88-4 ]
[ 400877-57-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 1910 - 1918

13
[ 77-78-1 ]
[ 5334-40-7 ]
[ 309740-49-6 ]

Yield	Reaction Conditions	Operation in experiment
8.62 g	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h; Cooling with ice	A) Methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate To a suspension of 4-nitro-1H-pyrazole-3-carboxylic acid (37 g) and potassium carbonate (97.6 g) in DMF (600 mL), dimethyl sulfate (71.2 g) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured to water, followed by extraction with ethyl acetate. The extract was 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 (8.62 g). ¹H NMR (400 MHz, CDCl₃) δ 4.02 (3H, s), 4.03 (3H, s), 8.01 (1H, s).

Reference： [1] Patent: EP3287441, 2018, A1, . Location in patent: Paragraph 0305

[ 5334-40-7 ] Synthesis Path-Downstream 1~87

1
[ 5334-39-4 ]
[ 5334-40-7 ]

Reference： [1]Gazzetta Chimica Italiana,1945,vol. 75,p. 121,133

2
[ 5334-40-7 ]
[ 116008-52-7 ]

Reference： [1]Journal of the American Chemical Society,1956,vol. 78,p. 2418,2422

3
[ 5334-40-7 ]
1-Amino-4-nitro-1H-pyrazole-3-carboxylic acid [ No CAS ]

Reference： [1]Russian Chemical Bulletin,1993,vol. 42,p. 1369 - 1371
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya,1993,p. 1434 - 1436

4
[ 1453-58-3 ]
[ 5334-40-7 ]

Reference： [1]Russian Chemical Bulletin,1993,vol. 42,p. 1861 - 1864
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya,1993,p. 1945 - 1948

5
[ 67-56-1 ]
[ 5334-40-7 ]
[ 138786-86-4 ]

Yield	Reaction Conditions	Operation in experiment
100%		Reference Example 1 Methyl 4-nitro-1H-pyrazole-3-carboxylate Acetyl chloride (9 mL) was added dropwise to methanol (90 mL), 4-nitro-1H-pyrazole-3-carboxylic acid (9.00 g, 57.3 mmol) was added to the mixture. The mixture was stirred at room temperature for 16 hr, and concentrated under reduced pressure. Methanol was added to the residue, and the mixture was concentrated under reduced pressure, the operation was twice repeated. The residue was diluted with methanol and ethyl acetate. 5% sodium hydrogencarbonate aqueous solution was added, and the pH was adjusted to 8-9. The mixture was extracted with ethyl acetate. The extract was washed with water, brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (9.83 g, yield 100%). 1H-NMR (DMSO-d6, 200 MHz): delta 3.98 (3H, s), 8.28 (1H, s).
100%		Acetyl chloride (9 mL) was added dropwise to methanol (90 mL), 4-nitro-1H-pyrazole-3-carboxylic acid (9.00 g, 57.3 mmol) was added to the mixture. The mixture was stirred at room temperature for 16 hr, and concentrated under reduced pressure. Methanol was added to the residue, and the mixture was concentrated under reduced pressure, the operation was twice repeated. The residue was diluted with methanol and ethyl acetate. 5% sodium hydrogencarbonate aqueous solution was added, and the pH was adjusted to 8 - 9. The mixture was extracted with ethyl acetate. The extract was washed with water, brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (9.83 g, yield 100%). 1H-NMR (DMSO-d6, 200 MHz):delta 3.98(3H, s), 8.28(1H, s).
100%	With thionyl chloride; at 20℃;Cooling with ice;	Dissolve 4-nitro-1H-pyrazole-3-carboxylic acid in methanol (50 ml) and add thionyl chloride (2.5 ml) dropwise on an ice bath. The reaction is allowed to proceed overnight at room temperature. Concentration under reduced pressure gave 4.36 g of a white solid. Yield: 100%

99.5%	With thionyl chloride; at 0 - 22℃; for 48h;Product distribution / selectivity;	EXAMPLE 1 Synthesis of the methanesulphonic acid salt of 4-{2,6-dichloro-benzoylaminoHH- pyrazole-3-carboxylic acid piperidin-4-ylamide and crystals thereofThe methane sulphonic acid salt of 4-(2,6-dichloro-benzoylamino)-lH-pyrazole-3- carboxylic acid piperidin-4-ylamide may be prepared by the synthetic route shown in the Scheme below. EPO <DP n="73"/>SOCI2, MeOH Stage 1 4H3N3O4 5H5N3O4 Stage 2 C5H7 3O2 FW: 157.09 FW: 171.11 FW: 141.13C12H9CI2N3O3 C11H7CI2N3O3 FW: 314.13 FW: 300.10Stage 5Stage 1 : Preparation of 4-nitro-li7-pyrazole-3-carboxylic acid methyl esterC4H3N3O4 C5H5N3O4 FW: 157.09 FW: 171.11 EPO <DP n="74"/>A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-l/7-pyrazole-3-carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5 0C, thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 C overnight, after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 0C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 0C to give 4-nitro-l/f-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5%).; EXAMPLE I lPreparation of 4-(2,6-dichloro-benzoylamino)-lH-pyrazole-3-carboxylic acid piperidin-4-ylamide hydrochlorideHA. Synthesis of 4-nitro-lH-pyrazole-3-carboxylic acid methyl esterThionyl chloride (2.90 ml, 39.8 mmol) is slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in methanol (100 ml) at ambient temperature and the mixture is stirred for 48 hours. The mixture is reduced in EPO <DP n="98"/>vacuo and dried through azeotrope with toluene to afford the 4-nitro-lH-pyrazole- 3-carboxylic acid methyl ester.
99.5%	With thionyl chloride; at 0 - 22℃;	A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-1H-pyrazole-3- carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5 C, thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 C overnight, after which time 1H NMR analysis (dbeta- DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 C to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5%).
99.5%	With thionyl chloride; at 0 - 22℃;	A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-1H-pyrazole-3- carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5 C, thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 C overnight, after which time 1H NMR analysis (dbeta- DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 C to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5%).
99.5%	With thionyl chloride; at 0 - 22℃;	A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4- nitro-1/-/-pyrazole-3-carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8 950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to O to 5 0C, thionyl chloride <n="161"/>(0.581 L1 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 0C overnight, after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 0C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 0C to give 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5%).
99%	With thionyl chloride; at 0 - 70℃; for 5h;	To a solution of 4-nitro-3-pyrazolecarboxylic acid (3.14 g,20.0 mmol) in MeOH (50 mL) was slowly added thionyl chloride(7.3 mL, 0.1 mol) at 0 C. After the completion of the addition, thetemperature of the reaction mixture increased to 70 C and stirredfor 5 h. Methanol was removed in vacuo, and the resulting residuewas poured into ice water and extracted with EtOAc. The organiclayer was washed with 10% NaHCO3 solution, brine and dried overNa2SO4. The resulting reaction mixture concentrated in vacuo toafford 1 as a white solid (3.37 g, 99%). 1H NMR (400 MHz, DMSO-d6)delta 8.93 (s, 1H), 3.89 (s, 3H); 13C NMR (100 MHz, DMSO-d6)delta 161.4,138.0, 133.7, 132.0, 53.3.
99.8%	With thionyl chloride; at 0 - 25℃; for 16 - 24h;Industry scale;	Stage 1: Preparation of 4-nitro-lH-pyrazole-3-carboxylic acid methyl esterC4H3N3O4 C5H5N3O4FW: 157.09 FW: 171.114-Nitro-lH-pyrazole-3-carboxylic acid (1.350Kg, 8.59 MoI, 1.0 wt) and methanol (10.80L, 8.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5C under nitrogen and thionyl chloride (0.702L, 9.62 MoI, 0.52 vol) added at this temperature. The mixture was warmed to 15 to 250C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6-DMSO). The mixture was concentrated under vacuum at 35 to 450C and toluene (2.70L, 2.0 vol) charged to the residue and removed under vacuum at 35 to 45C. The toluene azeotrope was repeated twice using toluene (2.70L, 2.0 vol) to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl <n="72"/>ester [1.467Kg, 99.8%th, 108.7% w/w, 1H NMR Cd6-DMSO) concordant with structure, no entrained solvent] as an off-white solid.
98.3 - 99.5%	With thionyl chloride; at 0 - 25℃; for 16 - 24h;Product distribution / selectivity;	A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-17f-pyrazole-3-carboxylic acid (1.117Kg, 7.11mol, lwt) and methanol (8.950L5 8vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 50C, thionyl chloride (0.581L, 8.0mol, 0.52vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 220C overnight after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 450C, the residue treated with toluene and re-concentrated (3x 2.250L, 3x 2vol) under reduced pressure at 40 to 450C to give 4-nitro-l//-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210Kg, 99.5%th).; 4-Nitro-lH-pyrazole-3-carboxylic acid (1.00kg, 6.37mol, l.Owt) and methanol (8.00L, 8.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5C under nitrogen and thionyl chloride (0.52L, 7.12mol, 0.52vol) was added at this temperature. The mixture was warmed to 15 to 25C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6-DMSO). The mixture was concentrated under vacuum at 35 to 45C. Toluene (2.00L, 2.0vol) was charged to the residue and removed under vacuum at 35 to 450C. The azeotrope was repeated twice using toluene (2.00L, 2.0vol) to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.071Kg, 98.3%) as an off white solid.
98.3 - 99.8%	With thionyl chloride; at 0 - 25℃; for 16 - 48h;Product distribution / selectivity;	A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with A- nitro-1H-pyrazole-3-carboxylic acid (1.117Kg, 7.11mol, 1wt) and methanol (8.950L, deltavol). The reaction mixture was stirred under nitrogen, cooled to 0 to 50C, thionyl chloride (0.581 L, delta.Omol, 0.52vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22C overnight after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 450C, the residue treated with toluene and re-concentrated (3x 2.250L, 3x 2vol) under reduced pressure at 40 to 450C to give 4-nitro-1 /-/-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210Kg, 99.5%th).4-Nitro-1H-pyrazole-3-carboxylic acid (1.00kg, 6.37mol, 1.0wt) and methanol (8.00L, delta.Ovol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5C under nitrogen and thionyl chloride (0.52L, 7.12mol, 0.52vol) was added at this temperature. The mixture was warmed to 15 to 25C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6- DMSO). The mixture was concentrated under vacuum at 35 to 45C. Toluene (2.00L, 2.0vol) was charged to the residue and removed under vacuum at 35 to 450C. The azeotrope was repeated twice using toluene (2.00L, 2.0vol) to give 4-nitro-1 H-pyrazole-3- carboxylic acid methyl ester (1.071 Kg, 98.3%) as an off white solid.Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in MeOH (100 ml) at ambient temperature and the mixture stirred for 48 hours. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester as a white solid.1H NMR (400 MHz, DMSO-d6) delta 14.4 (s, 1 H), 8.9 (s, 1 H), 3.9 (s, 3H)4-Nitro-1H-pyrazole-3-carboxylic acid (1.350Kg, 8.59 MoI, 1.0 wt) and methanol (10.80L, 8.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to O to 50C under nitrogen and thionyl chloride (0.702L, 9.62 MoI, 0.52 vol) added at this temperature. The mixture was warmed to 15 to 25C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6- DMSO). The mixture was concentrated under vacuum at 35 to 45C and toluene (2.70L, 2.0 vol) charged to the residue and removed under vacuum at 35 to 45C. The toluene azeotrope was repeated twice using toluene (2.70L, 2.0 vol) to give 4-nitro-1 H-pyrazole-3- carboxylic acid methyl ester [1.467Kg, 99.8%th, 108.7% w/w, 1H NMR (d6-DMSO) concordant with structure, no entrained solvent] as an off-white solid.
98.3 - 99.5%	With thionyl chloride; at 0 - 25℃; for 16 - 24h;Product distribution / selectivity;	Stage 4: Synthesis of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester; A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with 4- nitro-lH-pyrazole-3-carboxylic acid (1.117Kg, 7.11mol, lwt) and methanol (8.950L, 8vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 50C, thionyl chloride (0.581L, 8.0mol, 0.52vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22C overnight after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 450C, the residue treated with toluene and re-concentrated (3x 2.250L, 3x 2vol) under reduced pressure at 40 to 45C to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210Kg, 99.5%th).; Stage 4: Preparation of 4-nitro-lH-pyrazole-3-carboxylic acid methyl; esterC4H3N3O4 C5H5N3O4FW: 157.09 FW: 171.114-Nitro-lH-pyrazole-3-carboxylic acid (1.00kg, 6.37mol, l.Owt) and methanol (8.00L, 8.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5C under nitrogen and thionyl chloride (0.52L, 7.12mol, 0.52vol) was added at this temperature. The mixture was warmed to 15 to 25C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (dbeta-DMSO). The mixture was concentrated under vacuum at 35 to 45C. Toluene (2.00L, 2.0vol) was charged to the residue and removed under vacuum at 35 to 45C. The azeotrope was repeated twice using toluene (2.00L, 2.0vol) to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.071Kg, 98.3%) as an off white solid.
98%	With sulfuric acid; at 20℃; for 24h;	Step 1. Synthesis of methyl 4-nitro-1 /-/-pyrazole-3-carboxylate (C29). Fuming sulfuric acid (4 mL) was added to a solution of 4-nitro-1 /-/-pyrazole-3-carboxylic acid (16.0 g, 102 mmol) in methanol (200 mL), and the reaction was stirred at RT for 24 hours. The reaction mixture was concentrated, and the resulting solid was partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, providing C29 as a white solid. Yield: 17.1 g, 99.9 mmol, 98%. LCMS m/z 170.0 (M-1 ). H NMR (400 MHz, CDCI3) delta 4.05 (s, 3H), 8.40 (s, 1 H).
98%	With thionyl chloride; at 20℃;Cooling with ice;	Thionyl chloride (6.28ml_, 86.07mmol) was added to an ice cooled solution of 4-nitro-1 H- pyrazole-3-carboxylic acid (10.4 g, 66.21 mmol) in methanol (150 ml_). The resulting solution was stirred at RT O/N. The day after MeOH was removed under vacuum; toluene was added and dried again. The solid was suspended in pentane and filtered under vacuum to afford methyl 4-nitro-1 H-pyrazole-3-carboxylate (p128, 1 1 .15 g, y= 98%) as creamy solid. MS (mlz): 171 .9 [MH]+
98%	With thionyl chloride; at 20℃;	Thionyl chloride (6.28ml_, 86.07mmol) was added to an ice cooled solution of 4-nitro-1 H- pyrazole-3-carboxylic acid (10.4 g, 66.21 mmol) in methanol (150 ml_). The resulting solution was stirred at RT ON. The day after MeOH was removed under vacuum; toluene was added and dried again. The solid was suspended in pentane and filtered under vacuum to afford methyl 4-nitro-1 H-pyrazole-3-carboxylate (p68, 1 1.15 g, y= 98%) as creamy solid. MS (mlz): 171 .9 [MH]+
96.9%	With thionyl chloride; at 25℃; for 16h;	4-nitro-lH-pyrazole-3-carboxylic acid (30.0 g, 191.0 mmol) was dissolved in methanol (300 mL)Sulfoxide (34.1 g, 286.5 mol) was added,25 C for 16 hours.The reaction solution was concentrated in vacuo,Saturated sodium bicarbonate solution (400 mL) was added,Ethyl acetate extraction (500 mL x 2),Organic synthesis,Saturated brine (300 mL),Dried over anhydrous sodium sulfate,The product was concentrated in vacuo (31.7 g, 96.9% yield).
95.8%	With thionyl chloride; at 20℃;	Example 43trans-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1'-cyclohexan]-4'-yl]-2-phenyl-2,4-dihydroimidazo[4,5-c]pyrazole(1) Preparation of methyl 4-nitro-1H-pyrazole-3-carboxylate Thionyl chloride (5.1 mL, 70.0 mmol) was added portionwise to a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (10.0g, 63.7 mmol) in methanol (100 mL). After the mixture was stirred overnight at room temperature, the solvent was evaporated in vacuo. After the residue was dissolved in ethyl acetate, the solution was washed with water and saturated aqueous brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title compound (10.43 g, 95.8 %).
92.1%	With thionyl chloride; at 25 - 60℃; for 4h;	The 4-nitro-1H-pyrazole-3-carboxylic acid (20.0 g, 0.127 mmol) was dissolved in methanol (100 mL) and thionyl chloride (18.1 g, 0.152 mmol) was added , allowed to react for 2 hours at 25 C. , then heated to 60 C, and allowed to react for 2 hours. The reaction was concentrated in vacuo and methyl tert-butyl ether (80 mL) was added and filtered to give a white solid which was dried in vacuo to give the product (20.0 g, 92.1% yield).
91%	With thionyl chloride; at 0 - 20℃; for 2h;Product distribution / selectivity;	Reference Example 18 Methyl 4-nitro-1H-pyrazole-3-carboxylate To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (10.0 g, 63.7 mmol) in methanol (100 mL), thionyl chloride (5.1 mL, 70.0 mmol) was added dropwise at 0 C., and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (9.9 g, yield 91%). 1H-NMR (CDCl3): delta 4.06 (3H, s), 8.51 (1H, s).
91%		To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (10.0 g, 63.7 mmol) in methanol (100 mL), thionyl chloride (5.1 mL, 70.0 mmol) was added dropwise at 0C, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (9.9 g, yield 91%). 1H-NMR (CDCl3) :delta 4.06(3H, s), 8.51(1H, s).
91.7%	With thionyl chloride; at 20℃; for 16h;	4-Nitro-1H-pyrazole-3-carboxylic acid (20 g, 127.3 mmol) was dissolved in methanol (200 mL) and thionyl chloride (22.7 g, 190.8 mmol) was added and reacted at 20 C for 16 hours. The reaction was completed and concentrated. Methyl tert-butyl ether (200 mL) was added and filtered to give 20 g of the title product in 91.7% yield.
89%	With toluene-4-sulfonic acid; at 65℃; for 16h;	To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (5 g, 31.8 mmol) in dry MeOH (60 ml) was added freshly crystallized p-toluenesulphonic acid monohydrate (300 mg, 1.6 mmol). The reaction mixture was heated at 65 C. for 16 hrs. MeOH was removed in vacuo. The residue was taken up with saturated aqueous NaHCO3 solution (15 ml) and extracted with EtOAc. The combined organic layers were washed with water, and then with brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified by column chromatography over silica gel using 30% EtOAc /hexane) to provide the title compound as white solid (4.85 g, 89%).
89%		To a solution of 4-nitro-lH-pyrazole-3-carboxylic acid (5 g, 31.8 mmol) in dry MeOH (60ml) was added freshly crystallized p-toluenesulphonic acid monohydrate (300 mg, 1.6 mmol). The reaction mixture was heated at 65 C for 16 hrs. MeOH was removed in vacuo. The residue was taken up with saturated aqueous NaHC03 solution (15 ml) and extracted with EtOAc. The combined organic layers were washed with water, and then with brine, dried (Na2S04), filtered, and evaporated. The crude product was purified by column chromatography over silica gel using 30%EtOAc/hexane) to provide the title compound as white solid (4.85 g, 89%).
86%	With sulfuric acid; for 3.5h;Heating / reflux;	Reference Example 1 Methyl 4-nitro-1H-pyrazole-3-carboxylate Conc. sulfuric acid(8.2 mL) was added to 4-nitro-1H-pyrazole-3-carboxylic acid(163.8 g) dissolved in methanol(1.64 L) under argon atmosphere and the mixture was heated under reflux for 3.5 hours. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure and the resulted residue was triturated in diisopropyl ether. The precipitate was collected by filtration to give the titled compound(153.2 g, 86% yield) as a colorless crystalline. mp.115-117C, MS(ESI)m/z:170 [M-H]-.
72.7%	With acetyl chloride; at 0 - 20℃; for 16h;	Acetyl chloride (6.34 ml, 89 mmol) was added to the mixture of 4-nitro-1H-pyrazole-3-carboxylic acid (2, 7 g, 44.6 mmol) in MeOH (223 ml) at 0 C. The mixture was stirred at rt for 16 h. After concentrated in vacuo, the residue was azeotroped with MeOH two times. The residue was diluted with MeOH and EtOAc, and the mixture was adjusted to a pH of approx. 9 with satd NaHCO3 aq. The mixture was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated to give the compound 12 (5.545 g, 32.4 mmol, 72.7%) as a white powder. 1H NMR (DMSO-d6) delta 14.39 (br s, 1H), 8.99 (s, 1H), 3.89 (s, 3H); 13C NMR (DMSO-d6) delta 161.1, 138.1, 133.2, 130.9, 52.8; HRMS (ESI) m/z: [M-H]- calcd for C5H4N3O4: 170.0207, found: 170.0200.
48.8%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 18h;	A mixture [OF 4-NITRO-LH-PYRAZOLE-3-CARBOXYLIC] acid (2.0 g, 12.7 mmol) in dichloromethane at [25 oC] was treated with 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (2.68 g, 14.0 mmol), methanol (8.2 mL), and 4- dimethylaminopyridine (155 mg, 1.27 mmol). The reaction was stirred at [25 oC] for 18 h. At this time, the reaction was diluted with dichloromethane and was washed with a 1N aqueous hydrochloric acid solution (1 x 50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60,230-400 mesh, 45: 55 ethyl acetate/petroleum ether) afforded 4-nitro- [1H-PYRAZOLE-3-CARBOXYLIC] acid methyl ester (1.06 g, 48.8%) as a white solid: LR-MS for [C5H5N304] [(M-H) + AT M/Z] = 170.
	With thionyl chloride; at 0 - 20℃; for 4h;Heating / reflux;Product distribution / selectivity;	Thionyl chloride (3.8 ml, 52.5 mmol) was added cautiously to a stirred, ice-cold mixture of 4-nitropyrazole-3-carboxylic acid (7.5 g, 47.7 mmol) in MeOH (150 ml), the mixture stirred at ambient temperature for 1 hour then heated at reflux for 3 hours. The reaction mixture was cooled, evaporated in vacuo then azeotroped with toluene to give 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester (8.8 g).
	With thionyl chloride; at 20℃; for 48h;	4-nitro-lH-pyrazole-3-carboxylic acid was converted to its methyl ester using thionyl chloride and methanol in a method analogous to that used in Example 3A. The nitro group was hydrogenated to the amine and this was then coupled to 2,6- difluorobenzoic acid using EDCI coupling conditions to provide 4-(2,6-Difluoro- benzoylamino)-lH-pyrazole-3-carboxylic acid methyl ester as outlined in Example 3C.
	With thionyl chloride; at 20℃; for 4h;Heating / reflux;	Thionyl chloride (3.8 ml, 52.5 mmol) was added cautiously to a stirred, ice-cold mixture of 4-nitropyrazole-3-carboxylic acid (7.5 g, 47.7 mmol) in MeOH (150 ml), the mixture stirred at ambient temperature for 1 hour then heated at reflux for 3 hours. The reaction mixture was cooled, evaporated in vacuo then azeotroped with toluene to give 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester (8.8 g).
	With thionyl chloride; at 20℃; for 4h;Heating / reflux;	4A. Synthesis of 4-Nitro-lH-pvrazole-3-carboxvlic acid methyl ester; // OMeN-NHThionyl chloride (3.8 ml, 52.5 mmol) was added cautiously to a stirred, ice-coldmixture of 4-nitropyrazole-3-carboxylic acid (7.5 g, 47.7 mmol) in MeOH (150 ml),the mixture stirred at ambient temperature for 1 hour then heated at reflux for 3hours. The reaction mixture was cooled, evaporated in vacuo then azeotroped withtoluene to give 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester (8.8 g).
	With thionyl chloride; at 0 - 25℃; for 16 - 48h;Product distribution / selectivity;	EXAMPLE 11A. 4-Nitro-1H-pyrazole-3-carboxylic acid methyl esterThionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in MeOH (100 ml) at ambient temperature and the mixture stirred for 48 hours. The mixture was reduced in vacuo and dried through <n="196"/>azeotrope with toluene to afford 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester as a white solid.1H NMR (400 MHz, DMSOd6) delta 14.4 (s, 1 H), 8.9 (s, 1 H), 3.9 (s, 3H); Stage 1: Preparation of 4-nitro-1 H-pyrazole-3-carboxylic acid methyl esterC4H3N3O4 C5H5N3O4FW: 157.09 FW: 171.114-Nitro-1H-pyrazole-3-carboxylic acid (1.350Kg, 8.59 MoI, 1.0 wt) and methanol (10.80L, 8.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to O to 5C under nitrogen and thionyl chloride (0.702L, 9.62 MoI, 0.52 vol) added at this temperature. The mixture was warmed to 15 to 25C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6- DMSO). The mixture was concentrated under vacuum at 35 to 45C and toluene (2.70L, 2.0 vol) charged to the residue and removed under vacuum at 35 to 45C. The toluene azeotrope was repeated twice using toluene (2.70L, 2.0 vol) to give 4-nitro-1 H-pyrazole-3- carboxylic acid methyl ester [1.467Kg, 99.8%th, 108.7% w/w, 1H NMR (d6-DMSO) concordant with structure, no entrained solvent] as an off-white solid.
	With sulfuric acid; at 0 - 80℃; for 16h;	Step 1: Into a 250 mL round bottom flask containing a suspension of 4-nitro-1H-pyrazole-3- carboxylic acid (20.0 g, 127 mmol) in methanol (100 mL) was added concentrated sulfuric acid(4 mL) dropwise over 5 mm at 0 C and the resulting slurry was refluxed at 80 C for 16 h. The solvent was removed under reduced pressure and the residual mass was dissolved in ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 100 mL) and brine (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give methyl 4-nitro-1H-pyrazole-3-carboxylate as asolid. The crude product was taken to the next step without further purification. MS calc?d [MHj 170.0, found 170.0.
	With sulfuric acid; In methanol; at 0 - 80℃; for 16h;	Step 1: Into a 250 mL round bottom flask containing a suspension of 4-nitro-1H-pyrazole-3- carboxylic acid (20.0 g, 127 mmol) in methanol (100 mL) was added concentrated sulfuric acid (4 mL) dropwise over 5 mm at 0 C and the resulting slurry was refluxed at 80 C for 16 h. Thesolvent was removed under reduced pressure and the residual mass was dissolved in ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 100 mL) and brine (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give methyl 4-nitro-1H-pyrazole-3-carboxylate as a solid. The crude product was taken to the next step without further purification. MS calc?d [M5 Hj 170.0, found 170.0.
	With sulfuric acid; at 0 - 80℃; for 16h;Reflux;	Stpe 1: Into a 250 mL round bottom flask containing a suspension of 4-nitro-lH-pyrazole-3- carboxylic acid (20.0 g, 127 mmol) in methanol (100 mL) was added concentrated sulfuric acid (4 mL) drop wise over 5 min at 0 C and the resulting slurry was refluxed at 80 C for 16 h. The solvent was removed under reduced pressure and the residual mass was dissolved in ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 100 mL) and brine (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give methyl 4-nitro-lH-pyrazole-3 -carboxylate as a solid. The crude product was taken to the next step without further purification. MS calc'd [M- H]+ 170.0, found 170.0.
	With sulfuric acid; at 0℃;Reflux;	Into a 50 mL round bottom flask containing a solution of 4-nitro-7H-pyrrazole-3-carboxalic acid (5.0 g, 32 mmol) in methanol (50 mL) was added concentrated sulfuric acid (1 mL) at 0 C. The resulting slurry was stirred at reflux temperature overnight. The solvents were evaporated under reduced pressure and the residual mass was dissolved in ethyl acetate and washed with water and brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield methyl 4-nitro-7H-pyrazole-3-carboxylate as a solid which was taken to next step without further purification. 1Eta NMR (CD3OD 300 MHz): delta 8.59 (s, 1H), 3.93 (s, 3H). MS calc'd [M-H]+ 170.0, found 170.1.
	With sulfuric acid; at 0 - 80℃; for 16h;	Step 1: Into a 250 mL round bottom flask containing a suspension of 4-nitro-1H-pyrazole-3- carboxylic acid (20.0 g, 127 mmol) in methanol (100 mL) was added concentrated sulfuric acid (4 mL) dropwise over 5 min at 0 oC and the resulting slurry was refluxed at 80 oC for 16 h. The solvent was removed under reduced pressure and the residual mass was dissolved in ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 100 mL) and brine (100 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give methyl 4-nitro-1H-pyrazole-3-carboxylate as a solid. The crude product was taken to the next step without further purification. MS calc?d [M- H]+ 170.0, found 170.0.
	With thionyl chloride; at 20℃;Cooling with ice;	Nitro-lH-pyrazole-3-carboxylic acid (3.0 g, 19.10 mmol)Add 50mL tomato-shaped bottle containing 15mL of methanol,SOCl 2 (1.8 mL, 24.83 mmol) was slowly added dropwise under ice-cooling,After the transfer was completed and transferred to room temperature reaction overnight,The next day, TLC detection reaction was completed.The reaction solution was concentrated under reduced pressure to remove unreacted methanol and SOCl2 completely,The crude product was homogenized with 30 mL of petroleum ether and the crude product of the target product was filtered off with suction (2.93 g, 89.6%).The crude product was used without purification in the next reaction administered.
	With thionyl chloride; In methanol; at 23℃; for 16h;Cooling with ice;	To a stirred solution of compound I (10 g, 64 mmol, 1 eq) in methanol (100 ml) was added SOCI2 (5.2 ml, 67 mmol, 1.05 eq) drop wise at ice-cold condition and the resulting mixture was stirred at 23 C for 16 h. The reaction mixture was concentrated in vacuo, the residue was diluted with water (25 ml) and the organic components were extracted with ethyl acetate (200 ml). The ethyl acetate layer was removed in vacuo to obtain the desired compound II (10.5 g, 96%) as off white solid which was used in the next step without further purification. (0492) [0456] H NMR (400 MHz, DMSO-cfe) delta 14.41 (br s, 1 H), 8.97 (s, 1 H), 3.88 (s, 3 H); (0493) [0457] LCMS: m/z = 172.0 [M+H], RT = 2.12 minutes; (Program Ql, Column X).
	With thionyl chloride; at 0 - 20℃; for 8h;	In a solution of 4-nitro-1H-pyrazole-3-carboxylic acid 26 (4 g,25.5 mmol) in CH3OH (50 mL) was added SOCl2 (3 g, 25.46 mmol) at0 C. The mixture was stirred at room temperature for 8 h and concentratedin vacuo. The crude product of methyl 4-nitro-1H-pyrazole-3-carboxylate was given as white solid (4.32 g, 99.2%) and could be usedin the next step without further purification.

Reference： [1]Patent: US2009/156582,2009,A1 .Location in patent: Page/Page column 28
[2]Patent: EP1847531,2007,A1 .Location in patent: Page/Page column 40
[3]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 979 - 984
[4]Patent: CN107652293,2018,A .Location in patent: Paragraph 0099; 0100; 0101
[5]Patent: WO2006/77426,2006,A2 .Location in patent: Page/Page column 71-73; 96-97
[6]Patent: WO2006/77425,2006,A1 .Location in patent: Page/Page column 210-211
[7]Patent: WO2006/77424,2006,A1 .Location in patent: Page/Page column 189-190
[8]Patent: WO2008/7113,2008,A2 .Location in patent: Page/Page column 159-160
[9]Journal of Medicinal Chemistry,2014,vol. 57,p. 7536 - 7549
[10]European Journal of Medicinal Chemistry,2017,vol. 125,p. 551 - 564
[11]Patent: WO2007/129066,2007,A1 .Location in patent: Page/Page column 29; 70-71
[12]Patent: WO2006/70195,2006,A1 .Location in patent: Page/Page column 181; 188
[13]Patent: WO2008/1101,2008,A2 .Location in patent: Page/Page column 291; 297; 333; 358; 362
[14]Patent: WO2007/77435,2007,A1 .Location in patent: Page/Page column 237; 243
[15]Patent: WO2012/73143,2012,A1 .Location in patent: Page/Page column 51
[16]Patent: WO2019/43407,2019,A1 .Location in patent: Page/Page column 126
[17]Patent: WO2019/81939,2019,A1 .Location in patent: Page/Page column 77
[18]Russian Chemical Bulletin,1993,vol. 42,p. 1861 - 1864
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya,1993,p. 1945 - 1948
[19]Patent: CN107226807,2017,A .Location in patent: Paragraph 0239-0241; 0305-0307
[20]Patent: EP1566384,2005,A1 .Location in patent: Page/Page column 50
[21]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 1169 - 1172
[22]Patent: CN107286169,2017,A .Location in patent: Paragraph 0155-0157
[23]Patent: US2009/156582,2009,A1 .Location in patent: Page/Page column 30
[24]Patent: EP1847531,2007,A1 .Location in patent: Page/Page column 43
[25]Patent: CN107226808,2017,A .Location in patent: Paragraph 0327; 0340-0342
[26]Patent: US2011/306589,2011,A1 .Location in patent: Page/Page column 53
[27]Patent: WO2011/154327,2011,A1 .Location in patent: Page/Page column 136
[28]Patent: EP1903045,2008,A1 .Location in patent: Page/Page column 43
[29]MedChemComm,2013,vol. 4,p. 456 - 462
[30]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 1776 - 1787
[31]Patent: WO2003/106459,2003,A1 .Location in patent: Page 161
[32]Patent: WO2006/70198,2006,A1 .Location in patent: Page/Page column 126; 139-140
[33]Patent: WO2006/70198,2006,A1 .Location in patent: Page/Page column 156
[34]Patent: WO2006/70202,2006,A1 .Location in patent: Page/Page column 80
[35]Patent: WO2006/3440,2006,A1 .Location in patent: Page/Page column 154
[36]Patent: WO2007/129062,2007,A1 .Location in patent: Page/Page column 194-195; 199
[37]Patent: WO2016/144848,2016,A1 .Location in patent: Page/Page column 36
[38]Patent: WO2016/144846,2016,A1 .Location in patent: Page/Page column 39; 40
[39]Patent: WO2016/144849,2016,A1 .Location in patent: Page/Page column 31
[40]Patent: WO2016/144844,2016,A1 .Location in patent: Page/Page column 32
[41]Patent: WO2016/144847,2016,A1 .Location in patent: Page/Page column 31
[42]Patent: CN107235906,2017,A .Location in patent: Paragraph 0090-0093
[43]Patent: WO2018/64135,2018,A1 .Location in patent: Paragraph 0454-0457
[44]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1211 - 1225

7
[ 108-24-7 ]
[ 5334-40-7 ]
1-acetyl-4-acetylamino-1<i>H</i>-pyrazole-3-carboxylic acid [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2002,vol. 38,p. 269 - 271

8
[ 768-95-6 ]
[ 5334-40-7 ]
1-(1-adamantyl)-3-carboxy-4-nitropyrazole [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2001,vol. 37,p. 1741 - 1746

9
[ 75-31-0 ]
[ 5334-40-7 ]
[ 906087-45-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;	Reference Example 3 N-isopropyl-4-nitro-1H-pyrazole-3-carboxamide To a mixture of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (6.50 g, 41.4 mmol) and N,N-dimethylformamide (100 mL), isopropylamine (4.7 mL, 55 mmol), HOBt (6.71 g, 50 mmol) and (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (9.52 g, 50 mmol) were added, and the mixture was stirred at room temperature for 16 hr. 5percent Aqueous solution of citric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 5percent aqueous solution of citric acid, 5percent sodium hydrogencarbonate aqueous solution, brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.72 g, yield 70percent). 1H-NMR (DMSO-d6, 200 MHz): delta 1.14 (6H, d, J=6.6 Hz), 3.91-4.17 (1H, m), 8.45-8.65 (1H, brm), 8.76 (1H, brs).
70%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a mixture of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (6.50 g, 41.4 mmol) and N,N-dimethylformamide (100 mL), isopropylamine (4.7 mL, 55 mmol), HOBt (6.71 g, 50 mmol) and (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (9.52 g, 50 mmol) were added, and the mixture was stirred at room temperature for 16 hr. 5percent Aqueous solution of citric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 5percent aqueous solution of citric acid, 5percent sodium hydrogencarbonate aqueous solution, brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.72 g, yield 70percent). 1H-NMR (DMSO-d6, 200 MHz) :delta 1.14(6H,d, J=6.6 Hz), 3.91-4.17(1H, m), 8.45-8.65(1H, brm), 8.76(1H, brs).

Reference： [1]Patent: US2009/156582,2009,A1 .Location in patent: Page/Page column 28-29
[2]Patent: EP1847531,2007,A1 .Location in patent: Page/Page column 40

10
[ 5334-40-7 ]
[ 518990-55-1 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 16h;	4-Nitropyrazole-3-carboxylic acid (20.0 g, 127.4 mmol) was suspended in CH2CI2/DMF(99:1 , 400 mL), treated cautiously with oxalyl chloride (11.6 mL, 134 mmol) and then stirred at room temperature for 16 h. The reaction mixture was evaporated then re-evaporated with toluene (x3) to give a yellow solid. The resultant acid chloride was suspended in dioxane (400 mL), treated with triethylamine (26.4 mL, 190 mmol) followed by 4-amino-1- BOC-piperidine (25.0 g, 125 mmol) and stirred at room temperature for 6 h. The reaction mixture was filtered and the solid collected stirred in water (500 mL) and then re-filtered. The solid collected was dried in vacuo, azeotroping with toluene, to give the title compound (37.6 g).
	With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 16h;	4-Nitropyrazole-3-carboxylic acid (20.0 g, 127.4 mmol) was suspended in CH2CI2/DMF(99:1 , 400 mL), treated cautiously with oxaly. chloride (11.6 mL, 134 mmol) and then stirred at room temperature for 16 h. The reaction mixture was evaporated then re-evaporated with toluene (x3) to give a yellow solid. The resultant acid chloride was suspended in dioxane (400 mL), treated with triethylamine (26.4 mL, 190 mmol) followed by 4-amino-1- BOC-piperidine (25.0 g, 125 mmol) and stirred at room temperature for 6 h. The reaction mixture was filtered and the solid collected stirred in water (500 mL) and then re-filtered. The solid collected was dried in vacuo, azeotroping with toluene, to give the title compound (37.6 g). '
	With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 16h;	4-Nitropyrazole-3-carboxylic acid (20.0 g, 127.4 mmol) was suspended in CH2CI2/DMF(99:1 , 400 mL), treated cautiously with oxalyl chloride (11.6 mL, 134 mmol) and then stirred at room temperature for 16 h. The reaction mixture was evaporated then re-evaporated with toluene (x3) to give a yellow solid. The resultant acid chloride was suspended in dioxane (400 mL), treated with triethylamine (26.4 mL, 190 mmol) followed by 4-amino-1- BOC-piperidine (25.0 g, 125 mmol) and stirred at room temperature for 6 h. The reaction mixture was filtered and the solid collected stirred in water (500 mL) and then re-filtered. The solid collected was dried in vacuo, azeotroping with toluene, to give the title compound (37.6 g).

	With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; at 40℃;Inert atmosphere;	A solution of 4-nitro-lH-pyrazole-3-carboxylic acid (1.0 g, 6.4 mmol) in dichloromethane (20 ml) was treated with thionyl chloride (1.4 ml, 19 mmol) and a drop of DMF at ambient temperature. The reaction mixture is stirred at 40°C overnight whereupon another equivalent of thionyl chloride (0.46 ml, 6.4 mmol) was added and stirring was continued at 40°C for another 24h. All volatiles were removed and the acid chloride was suspended in dichloromethane (6 ml) and cooled to 0°C. Triethylamine (4.44 ml, 31.8 mmol) and dimethylamin (4.14 ml, 2M solution in THF) were added. The reaction mixture was allowed to warm-up to ambient temperature and stirring was continued for 3h. The reaction mixture was partitioned between potassium hydrogen sulfate (20 ml, 10percent aqueous solution) and ethyl acetate (40 ml) and extracted. The organic phase was washed with water and brine, dried and the solvent was evaporated. The crude product was triturated with diethylether, sucked off and dried to yield a light brown solid (0.35 g, 30 percent).MS: M = 185.1 (M+H)+
3.33 g	With thionyl chloride; In N,N-dimethyl-formamide; for 3h;Reflux;	Step 1:4-nitropyrazol-3-carbonyl chloride <strong>[5334-40-7]4-nitro-pyrazol-3-formic acid</strong> (3g, 19.1 mmol), thionyl chloride (100mL) and N, N-dimethylformamide (0.1mL) were added to a 250mL reaction flask. The reaction mixture was heated up to reflux and stirred for 3 hours. After completion of the reaction, the reaction solution was concentrated to obtain the title compound (3.33g), the crude product was used directly for the subsequent reaction. (MS: [M+1] none)
	With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 16h;	Step 1: Synthesis of 4-[(4-nitro-lH-pyrazole-3-carbonyl)-amino1-piperidine-l- carboxylic acid tert-butyl ester4-Nitropyrazole-3-carboxylic acid (20.0 g, 127.4 mmol) was suspended in CH2C12/DMF (99:1, 400 mL), treated cautiously with oxalyl chloride (11.6 mL, 134 mmol) and then stirred at room temperature for 16 h. The reaction mixture was evaporated then re-evaporated with toluene (x3) to give a yellow solid. The resultant acid chloride was suspended in dioxane (400 mL), treated with triethylamine (26.4 mL, 190 mmol) followed by 4-amino-l-BOC-piperidine (25.0 <n="79"/>g, 125 mmol) and stirred at room temperature for 6 h. The reaction mixture was filtered and the solid collected stirred in water (500 mL) and then re-filtered. The solid collected was dried in vacuo, azeotroping with toluene, to give the title compound (37.6 g).

Reference： [1]Patent: WO2008/1101,2008,A2 .Location in patent: Page/Page column 368
[2]Patent: WO2007/129062,2007,A1 .Location in patent: Page/Page column 205
[3]Tetrahedron,2008,vol. 64,p. 11249 - 11255
[4]Patent: WO2008/9954,2008,A1 .Location in patent: Page/Page column 111
[5]Patent: WO2011/154327,2011,A1 .Location in patent: Page/Page column 167; 168
[6]Journal of Medicinal Chemistry,2013,vol. 56,p. 796 - 806
[7]Patent: EP3150592,2017,A1 .Location in patent: Paragraph 0378; 0379; 0380
[8]Patent: WO2007/129066,2007,A1 .Location in patent: Page/Page column 77-78

11
[ 67-56-1 ]
[ 7719-09-7 ]
[ 5334-40-7 ]
[ 138786-86-4 ]

Yield	Reaction Conditions	Operation in experiment
99.5%	at 0 - 25℃; for 16 - 48h;Product distribution / selectivity;	A 2OL reaction vessel equipped with a digital thermometer and stirrer was charged with A- nitro-1 H-pyrazole-3-carboxylic acid (1.117 Kg, 7.1 1 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to O to 5 0C, thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 0C overnight, after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 0C, the residue treated with toluene and re-concentrated (3x 2.250 L, 3x 2vol) under reduced pressure at 40 to 45 0C to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5percent).; Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in MeOH (100 ml) at ambient temperature and the mixture stirred for 48 hours. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as a white solid.; Stage 1 : Preparation of 4-nitro-1 H-pvrazole-3-carboxylic acid methyl ester 4-Nitro-1H-pyrazole-3-carboxylic acid (1.350Kg1 8.59 MoI, 1.0 wt) and methanol (10.80L, 8.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to O to 5°C under nitrogen and thionyl chloride (0.702L, 9.62 MoI, 0.52 vol) added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6- DMSO). The mixture was concentrated under vacuum at 35 to 45°C and toluene (2.70L, 2.0 vol) charged to the residue and removed under vacuum at 35 to 45°C. The toluene azeotrope was repeated twice using toluene (2.70L, 2.0 vol) to give 4-nitro-1 H-pyrazole-3- carboxylic acid methyl ester [1.467Kg, 99.8percentth, 108.7percent w/w, 1H NMR (d6-DMSO) concordant with structure, no entrained solvent] as an off-white solid.

Reference： [1]Patent: WO2008/9954,2008,A1 .Location in patent: Page/Page column 83-84; 105

12
[ 64-17-5 ]
[ 5334-40-7 ]
[ 55864-87-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogenchloride;Reflux;	A solution of 4-nitro-1H-pyrazole-3-carboxylic acid (2.5 g, 15.9 mmol) in ethanolic HCl (38.3 mL, 1.25M) was refluxed overnight. All volatiles were removed to yield a whitesolid (2.9 g, 98percent) which was used without any further purification. MS: M=186.1 (M+H)+
98%	With hydrogenchloride;Reflux; Inert atmosphere;	A solution of 4-nitro-lH-pyrazole-3-carboxylic acid (2.5 g, 15.9 mmol) in ethanolic HQ (38.3 mL, 1.25M) was refluxed overnight. All volatiles were removed to yield a white solid (2.9 g, 98 percent) which was used without any further purification.MS: M = 186.1 (M+H)+
98%	With thionyl chloride; at 20℃; for 2h;Cooling with ice;	4-Nitropyrazole-3-carboxylic acid (5.00 g, 31.8 mmol) was added to a 100 mL single-mouth bottle, dissolved in 40 mL of absolute ethanol, and cooled in an ice bath for 10 min.Thionyl chloride (2.78 mL, 38.2 mmol) was added dropwise, and the mixture was transferred to room temperature for 2 h. The reaction was completed by TLC. The solvent was evaporated to dryness to give pale brown solid, 30mL of water, 30 min. The pale yellow solid was obtained. The filtrate was extracted twice with 20 mL of EA.The filtrate was spun and the combined solids were combined to give 5.82 g. Yield 98percent,

96%	With thionyl chloride; at 20℃; for 48h;	Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 h. The mixture was reduced in vacuo and EPO <DP n="124"/>dried through azeotrope with toluene to afford 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (1H NMR (400 MHz, DMSOd6) delta 14.4 (s, IH), 9.0 (S5 IH)3 4.4 (q, 2H), 1.3 (t, 3H)).
96%	With thionyl chloride; at 20℃; for 48h;	1A. 4-Nitro-lH-pyrazole-3-carboxylic acid ethyl ester; OEtN-NHThionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3-pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambienttemperature and the mixture stirred for 48 h. The mixture was reduced in vacuaand dried through azeotrope with toluene to afford 4-nitro-lH-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (*H NMR (400 MHz,DMSO-d6) 8 14.4 (s, 1H), 9.0 (s, 1H), 4.4 (q, 2H), 1.3 (t, 3H)).
96%	With thionyl chloride; at 20℃; for 48h;	Preparation VIII; Synthesis of 4-ammo-1H-pyrazole-3-carboxylic acid ethyl esterStep 1. 4-Nitro-1H-pyrazole-3-carboxylic acid ethyl esterThionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 hours. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3- carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (1H NMR (400 MHz, DMSO-d6) delta 14.4 (s, IH), 9.0 (s, IH), 4.4 (q, 2H), 1.3 (t, 3H)).
96%	With thionyl chloride; at 20℃; for 48h;	Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3-pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 h. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (1H NMR (400 MHz, DMSO-d6) D 14.4 (s, 1 H), 9.0 (s, 1 H), 4.4 (q, 2H), 1.3 (t, 3H)).
96%	With thionyl chloride; at 20℃; for 48h;	Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3-pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 h. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (1H NMR (400 MHz, DMSO-d6) D 14.4 (s, 1 H), 9.0 (s, 1 H), 4.4 (q, 2H), 1.3 (t, 3H)).
96%	With thionyl chloride; at 20℃; for 48h;	Step 1. 4-Nitro-lH-pyrazole-3-carboxylic acid ethyl ester; Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 hours. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-lH-pyrazole-3- carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (1H NMR (400 MHz, DMSO-d6) delta 14.4 (s, IH), 9.0 (s, IH), 4.4 (q, 2H), 1.3 (t, 3H)).
	With sulfuric acid; for 5h;Heating / reflux;	[00842] Example 209: 4- [ (Aminocarbonyl) amino]-l- (3-chloro-4- methoxyphenyl)-1 H-pyrazole-3-carboxamide; [00844] Step 1: Preparation of ethyl 4-nitro-1 H-pyrazole-3-carboxylate [00846] 4-Nitro-1 H-pyrazole-3-carboxylic acid (2 g, 12.73 mmol ; Aldrich) was refluxed in absolute ethanol (25 mL) containing trace sulfuric acid (0. 2. mol) for 5 h. The reaction was evaporated and partitioned between EtOAc and 5percent NaHCO3. The EtOAc layer was separated, dried over MgSO4 and filtered. The EtOAc was removed to give a white solid.'H. NMR (300 MHz, DMSO-d6) : 5 1.28 (t, J=7 Hz, 3 H), 4. 34 (q, J=7 Hz, 2 H), 8.91 (s, 1 H), 14.39 (br s, 1 H); MS (ESI+) for CH N 186. 1 (M+H) +.

Reference： [1]Patent: US2011/306589,2011,A1 .Location in patent: Page/Page column 45
[2]Patent: WO2011/154327,2011,A1 .Location in patent: Page/Page column 118
[3]Patent: CN108948019,2018,A .Location in patent: Paragraph 0497; 0499; 0500
[4]Patent: WO2006/70198,2006,A1 .Location in patent: Page/Page column 122-123
[5]Patent: WO2006/3440,2006,A1 .Location in patent: Page/Page column 147
[6]Patent: WO2006/77414,2006,A1 .Location in patent: Page/Page column 142
[7]Patent: WO2006/77424,2006,A1 .Location in patent: Page/Page column 186
[8]Patent: WO2006/77428,2006,A1 .Location in patent: Page/Page column 163
[9]Patent: WO2008/7123,2008,A2 .Location in patent: Page/Page column 111
[10]Journal of Medicinal Chemistry,2008,vol. 51,p. 4986 - 4999
[11]Patent: WO2005/37797,2005,A1 .Location in patent: Page/Page column 271-272

13
[ 62-53-3 ]
[ 5334-40-7 ]
[ 309740-93-0 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃;	4-Nitropyrazole-3-carboxylic acid (2.5 g; 15.9 mmol) was added to a stirred solution of aniline (1.6 ml; 17.5 mmol), EDC (3.7 g; 19.1 mmol), and HOBt (2.6 g; 19.1 mmol) in N,N-dimethylformamide (DMF) (25 ml), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate / saturated NaHCpsi3 solution. The resultant solid was collected by filtration, washed with water and diethyl ether then dried under vacuum to give 2.85 g of the title compound (sodium salt) as a yellow / brown solid. (LC/MS: Rt 2.78, [M+H]+ 232.95).
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃;	4-Nitropyrazole-3-carboxylic acid (2.5 g; 15.9 mmol) was added to a stirred solution of aniline (1.6 ml; 17.5 mmol), EDC (3.7 g; 19.1 mmol), and HOBt (2.6 g; 19.1 mmol) in N,N-dimethylformamide (DMF) (25 ml), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate / saturated NaHCpsi3 solution. The resultant solid was collected by filtration, washed with water and diethyl ether then dried under vacuum to give 2.85 g of the title compound (sodium salt) as a yellow / brown solid. (LC/MS: Rt 2.78, [M+H]+ 232.95).
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃;	<strong>[5334-40-7]4-nitropyrazole-3-carboxylic acid</strong> (2.5 g; 15.9 mmol) was added to a stirred solution of aniline (1.6 mL; 17.5 mmol), EDC (3.7 g; 19.1 mmol), and HOBt (2.6 g; 19.1 mmol) in N,N-dimetnylformamide (DMF) (25 ml), then stirred at room temperature overnight.The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate/saturated NaHCO3 solution.The resultant solid was collected by filtration, washed with water and diethyl ether then dried under vacuum to give 2.85 g of the t itle compound (sodium salt) as a yellow/brown solid.(LC/MS: Rt 2.78, [M+H]+ 232.95).

Reference： [1]Patent: WO2006/77424,2006,A1 .Location in patent: Page/Page column 135-136
[2]Patent: WO2006/77428,2006,A1 .Location in patent: Page/Page column 113
[3]Patent: WO2005/12256,2005,A1 .Location in patent: Page/Page column 121

14
[ 75-36-5 ]
[ 5334-40-7 ]
[ 55864-87-4 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 0 - 20℃; for 48.5h;	Step 1. Preparation of 4-Nitro-1H-pyrazole-3-carboxylic acid, ethyl ester. Acetyl chloride (50 mL) was added dropwise to ethanol (450 mL) at 0° C. with stirring. After addition was complete, the ice-bath was removed, and the mixture was stirred at room temperature for 30 minutes. To this mixture was added 4-nitro-1H-pyrazole-3-carboxylic acid (Aldrich) (10 g, 63.65 mmol), and the resulting homogeneous mixture was stirred at room temperature for a total of 48 hours. The reaction was monitored by TLC. The solvent was removed under reduced pressure and then co-evaporated with ethyl acetate four times. The residue was concentrated under high vacuum to give the title compound as a white powder (11.426 g, (M-H)+=184, M.P.=128.0-130.1° C.).

Reference： [1]Patent: US2005/197340,2005,A1 .Location in patent: Page/Page column 68

15
[ 6850-65-3 ]
[ 5334-40-7 ]
[ 902152-82-3 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;	A mixture of <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> (4.98 g, 31.7 mmol), trans 4-aminocyclohexanol (3.65 g, 31.7 mmol), EDAC (6. 68 g, 34.8 mmol) and HOBt (4.7 g, 34.8 mmol) in DMF (120 ml) was stirred at ambient temperature for 16 hours.The mixture was reduced in vacuo, the residue taken up in CH2Cl2 and washed successively with 5percent citric acid, saturated aqueous sodium bicarbonate, water and brine.The product was found to be mainly in the citric acid wash, which was basified and extracted with EtOAc.The organic layer was dried over MgS04, filtered and evaporated to give a white solid, which was triturated with CHCl3 to give 1.95 g of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> 4-hydroxy-cyclohexylamide.(LC/MS : Rt 1.62, [M+H] +255).

Reference： [1]Patent: WO2005/12256,2005,A1 .Location in patent: Page/Page column 174-175

16
[ 371-40-4 ]
[ 5334-40-7 ]
[ 844443-71-6 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃;	4-Nitropyrazoie-3-carboxylic acid (10 g; 63.66 mmol) was added to a stirred solution of 4-fluoroaniline (6.7 ml; 70 mmol), EDC (14.6 g; 76.4 mmol), and HOBt (10.3 g; 76.4 mmol) in DMF (25 ml), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate / saturated brine solution. The resultant yellow solid was collected by filtration, washed with 2M hydrochloric acid, then dried under vacuum to give 15.5 g of the title compound. (LC/MS: Rt 2.92 [M+H]+ 250.89 ).
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃;	4-Nitropyrazoie-3-carboxylic acid (10 g; 63.66 mmol) was added to a stirred solution of 4-fluoroaniline (6.7 ml; 70 mmol), EDC (14.6 g; 76.4 mmol), and HOBt (10.3 g; 76.4 mmol) in DMF (25 ml), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate / saturated brine solution. The resultant yellow solid was collected by filtration, washed with 2M hydrochloric acid, then dried under vacuum to give 15.5 g of the title compound. (LC/MS: Rt 2.92 [M+H]+ 250.89 ).
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃;	2A. <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (4-fluorophenyl)amide; <strong>[5334-40-7]4-nitropyrazole-3-carboxylic acid</strong> (10 g; 63.66 mmol) was added to a stirred solution of 4-fluoroaniline (6.7 ml; 70 mmol), EDC (14.6 g; 76.4 mmol), and HOBt (10.3 g; 76.4 mmol) in DMF (25 ml), then stirred at room temperature overnight.The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate/saturated brine solution.The resultant yellow solid was collected by filtration, washed with 2M hydrochloric acid, then dried under vacuum to give 15.5 g of the title compound.(LC/MS: Rt 2.92 [M+H]+ 250.89).

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4986 - 4999
[2]Patent: WO2006/77424,2006,A1 .Location in patent: Page/Page column 136-137
[3]Patent: WO2006/77428,2006,A1 .Location in patent: Page/Page column 114
[4]Patent: WO2005/12256,2005,A1 .Location in patent: Page/Page column 122

17
[ 5334-40-7 ]
[ 55864-87-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With thionyl chloride; In ethanol; at 20℃; for 48h;	Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3- pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in EtOH (100 ml) at ambient temperature and the mixture stirred for 48 h.The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (6.42 g, 96percent). (1H NMR (400 MHz, DMSO-d6) delta 14.4 (s, 1H), 9.0 (s, 1H), 4.4 (q, 2H), 1.3 (t, 3H)).
		Example 17: Synthesis of 3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-methyl-l,4- dihydro-pyrazolo[4,3-b]pyridin-5-one following the procedure of SchemeII; Step 1. Preparation of 4-Nitro-lH-pyrazole-3-carboxylic add, ethyl ester.; Acetyl chloride (50 mL) was added dropwise to ethanol (450 mL) at 00C with stirring. After addition was complete, the ice-bath was removed, and the mixture was stirred at RT for 30 min. To this mixture was added 4-nitro-lH-pyrazole-3-carboxylic acid (10 g, 63.65 mmol), and the resulting homogeneous mixture was stirred at RT for a total of 48 hours. EPO <DP n="65"/>The reaction was monitored by TLC. The solvent was removed under reduced pressure and then co-evaporated with ethyl acetate four times. The residue was concentrated under high vacuum to give the title compound as a white powder (11.426 g, (M-H)+ =184, M.P.= 128.0- 130.1 0C).

Reference： [1]Patent: WO2005/12256,2005,A1 .Location in patent: Page/Page column 184
[2]Patent: WO2007/23105,2007,A1 .Location in patent: Page/Page column 63-64

18
[ 593-51-1 ]
[ 5334-40-7 ]
[ 360573-34-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	General Procedure J; Preparation of a 4-amino-1H-pyrazole-3-carboxylic acid amideStep J (T). Preparation of a <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> amide4-Nitropyrazole-3-carboxylic acid (10 g; 63.66 mmol, 1 equiv.) was added to a stirred solution of an amine RNH2 (70 mmol, 1.1 equiv.), EDC (14.6 g; 76.4 mmol, 1.2 equiv.), and HOBt (10.3 g; 76.4 mmol, 1.2 equiv.) in DMF (250 ml), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate / saturated brine solution. The resultant solid was collected by filtration, washed with 2M hydrochloric acid, then dried under vacuum to give 15.5 g of the amide compound.

Reference： [1]Patent: WO2006/77414,2006,A1 .Location in patent: Page/Page column 160

19
[ 5334-40-7 ]
[ 27489-62-9 ]
4-nitro-1H-pyrazole-3-carboxylic acid 4-hydroxy-cyclohexylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;	General Procedure D; Preparation of Protected 4-amino-pyrazol-3-yl carboxylic acid 4-hydroxy- cyclohexylamideStep D (i): EPO <DP n="157"/>A mixture of <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> (4.98 g, 31.7 mmol), trans 4- aminocyclohexanol (3.65 g, 31.7 mmol), EDAC (6.68 g, 34.8 mmol) and HOBt (4.7 g, 34.8 mmol) in DMF (120 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in CH2Cl2 and washed successively with 5percent citric acid, saturated aqueous sodium bicarbonate, water and brine. The product was found to be mainly in the citric acid wash, which was basified and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated to give a white solid, which was triturated with CHCl3 to give 1.95 g of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> 4-hydroxy-cyclohexylamide. (LC/MS: Rt 1.62, [M+H]+255).

Reference： [1]Patent: WO2006/77414,2006,A1 .Location in patent: Page/Page column 155-156

20
[ 651057-01-1 ]
[ 5334-40-7 ]
[ 902152-87-8 ]

Yield	Reaction Conditions	Operation in experiment
48%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;	A solution of l-methanesulphonyl-piperidin-4-ylamine hydrochloride (2.4 g, 11.1 mmoles), <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (1.8 g, 11.1 mmoles), EDC (2.6 g (13.5 mmoles), HOBt (1.8 g, 13.3 mmoles) and triethylamine (3.4 ml, 24.6 mmoles) in DMF (30 ml) was stirred at room temperature for 24 hours. The reaction mixture was partitioned between EtOAc and a saturated solution of sodium hydrogen carbonate. The organic portion was dried (MgSO4), filtered and evaporated in vacuo to give <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (1-methanesulphonyl- piperidin-4-yl)-amide as a pale orange solid (1.7g, 48percent).

Reference： [1]Patent: WO2006/77414,2006,A1 .Location in patent: Page/Page column 164

21
[ 825619-02-1 ]
[ 5334-40-7 ]
[ 825619-29-2 ]

Yield	Reaction Conditions	Operation in experiment
61%		A mixture of 4-morpholin-4-ylmethyl-benzene-l,2-diamine (2.30 g, 11.1 mmol), 4- nitro-lH-pyrazole-3-carboxylic acid (1.57 g, 10.0 mmol), EDC (2.13 g, 11.1 mmol) and HOBt (1.50 g, 11.1 mmol) in dry DMF (25 ml) was stirred at ambient temperature for 24 hours. The mixture was reduced in vacuo and the crude residue dissolved in AcOH (40 ml) and heated at reflux for 3 h. The solvent was removed EPO <DP n="147"/>in vacuo and the residue was purified by flash column chromatography eluting with 0-20% MeOH in EtOAc to give 5-morpholin-4-ylmethyl-2-(4-nitro-lH-pyrazol-3- yl) IH-benzimidazole as a yellow solid. (1.0 g, 61%). (LC/MS: Rt 1.83, [M + H]+ 329).
61%		ID. Synthesis of 5-morpholin-4-ylmethyl-2-('4-nitro-lH-pyrazol-3-yl') lH-benzimidazole; A mixture of 4-morpholin-4-ylmethyl-benzene-l,2-diamine (2.30 g, 11.1 mmol), 4-nitro-lH- pyrazole-3-carboxylic acid (1.57 g, 10.0 mmol), EDC (2.13 g, 11.1 mmol) and HOBt (1.50 g, 11.1 mmol) in dry DMF (25 ml) was stirred at ambient temperature for 24 hours. The mixture was reduced in vacuo and the crude residue dissolved in AcOH (40 ml) and heated at reflux for 3 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography eluting with 0-20% MeOH in EtOAc to give 5-morpholin-4-yhnethyl-2-(4- nitro-lH-pyrazol-3-yl) IH-benzimidazole as a yellow solid. (1.0 g, 61%). (LC/MS: Rt 1.83, [M + H]+ 329).
52.1%		General procedure: A mixture of compound 4 (55.5mmol), <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (7.85g, 50.0mmol), EDCI (10.65g, 55.5mmol), and HOBt (7.5g, 55.5mmol) in dry DMF (125mL) was stirred at ambient temperature for 24 h. The mixture was reduced in vacuo and the crude residue dissolved in AcOH (200mL) and heated at reflux for 3 h. The solvent was removed in vacuo and the residue was purified by SiO2 column chromatography, eluting with 0-20% MeOH in EtOAc to give nitropyrazole 5.

40%		4-Morpholin-4-ylmethyl-benzene-l,2-diamine (1 mol. eq.) and 4-nitro-lH- pyrazole-3-carboxylic acid (1 mol. eq.) were dissolved in dimethylformamide (DMF) (10 vol.). O-(Benzot?azol-l-yl)-N,N,N',N1-tetramethyluronium tetrafluoroborate (TBTU) (1.2 mol. eq.) was added and the mixture was stirred at ambient temperature for 24 hours. The mixture was concentrated in vacuo until no further solvent was seen to distil. The residue was then dissolved in glacial acetic acid (10 vol.) and heated at 65 0C for ~ 12 hours. The mixture was concentrated in vacuo and then dissolved in water (6 vol.) at 75 0C. The black solution was cooled to 0-5 0C over 2 hours during which time a solid was formed. The solid was removed by filtration and the aqueous filtrate was diluted with ethyl acetate (4 vol.) and tetrahydrofuran (2 vol.). Solid NaHCO3 was added slowly to the stirred mixture until no further effervescence was observed and a pH of 6.8 was reached. The mixture was then stirred until a precipitation was observed. After standing the mixture at 0-5 0C for 2 hours, the solid was collected by filtration and washed with water (2 vol.) and ethyl acetate (2 vol.) and dried to give 5-morpholin-4-ylmethyl-2- (4-nitro-lH-pyrazol-3-yl)lH-benzimidazole as a brown solid (40%). (LC/MS (basic method): Rt 1.93, [M-H+]" 327).
40%		6OD. Synthesis of 5-Morpholin-4-ylmethyl-2-r4-nitro-lH-pyrazol-3-yl)lH-benzimidazole; <n="229"/>4-Mophiholin-4-ylmethyl-benzene-l,2-diamine (1 mol. eq.) and 4-nitro-lH-pyrazole-3- carboxylic acid (1 mol. eq.) were dissolved in dimethylformarnide (DMF) (10 vol.). O- (Benzotriazol-l-y^-N^N^N'-tetrametliyluroniiimtetrafluoroborate (TBTU) (1.2 mol. eq.) was added and the mixture was stirred at ambient temperature for 24 hours. The mixture was concentrated in vacuo until no further solvent was seen to distil. The residue was then dissolved in glacial acetic acid (10 vol.) and heated at 65 0C for ~ 12 hours. The mixture was concentrated in vacuo and then dissolved in water (6 vol.) at 75 0C. The black solution was cooled to 0-5 0C over 2 hours during which time a solid was formed. The solid was removed by filtration and the aqueous filtrate was diluted with ethyl acetate (4 vol.) and tetrahydrofuran (2 vol.). Solid NaHCO3 was added slowly to the stirred mixture until no further effervescence was observed and a pH of 6.8 was reached. The mixture was then stirred until a precipitation was observed. After standing the mixture at 0-5 0C for 2 hours, the solid was collected by filtration and washed with water (2 vol.) and ethyl acetate (2 vol.) and dried to give 5- mophiholin-4-yhnethyl-2-(4-nitro-lH-pyrazol-3-yl)lH-benzimidazole as a brown solid (40%). (LC/MS (basic method): Rt 1.93, [M-H+]" 327).
27%	With benzotriazol-1-ol; acetic acid; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 3h;Reflux;	4-(morpholinomethyl)-phenyl-1,2-diamine (2.3 g, 11.1 mmol), <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (1.57 g, 10 mmol), EDC·HCl (2.13 g, 11.1 mmol) and HOBt (1.5 g, 11.1 mmol) were dissolved in anhydrous DMF (25 mL). The solvent was removed under reduced pressure, was added glacial acetic acid (40 mL), heated to reflux for 3 hours, the solvent was removed under reduced pressure, and purified by column (CH2Cl2 / CH3OH (V / V) = 20/1), and then washed with methanol (30mL) to give a solid (0.9g, 27percent).
27%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	4-(morpholinomethyl)phenyl-1,2-diamine (2.3 g, 1.11 mmol),<strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (1.57 g, 1 mmol),EDCl (2.13 g, 1.11 mmol) and HOBt (1.5 g, 1.11 mmol)Dissolved in dry DMF (25 mL) and stirred at rt overnight.The solvent was removed under reduced pressure, was added glacial acetic acid (40 mL), was heated to reflux for 3 hours.The solvent was removed under reduced pressure and purified by column (dichloromethane/methanol (v/v) = 10/1).Then wash with methanol (10 mL),Methanol-insoluble product as a yellow solid that is, to give the product (0.9g, 27percent).

Reference： [1]Patent: WO2006/70195,2006,A1 .Location in patent: Page/Page column 145-146
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 379 - 388
[3]Patent: WO2007/77435,2007,A1 .Location in patent: Page/Page column 205
[4]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3523 - 3530
[5]Patent: WO2006/70195,2006,A1 .Location in patent: Page/Page column 170-171
[6]Patent: WO2007/77435,2007,A1 .Location in patent: Page/Page column 227-228
[7]Patent: CN104447701,2019,B .Location in patent: Paragraph 0448-0450; 0458-0460
[8]Patent: CN104211692,2019,B .Location in patent: Paragraph 0792; 0802-0804

22
4,5-dimethoxy-1,2-phenylenediamine hydrochloride salt [ No CAS ]
[ 5334-40-7 ]
[ 896466-65-2 ]

Yield	Reaction Conditions	Operation in experiment
36%	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In N,N-dimethyl-formamide; at 20℃;	To a solution of EDC (4.81 g 25 mmol), HOBt (3.40 g, 25 mmol) and triethylamine (4.67 g, 46 mmol) in DMF (100 ml) was added 4-nitro-lH-pyrazole-3-carboxylic acid (3.63 g, 23.09 mmol) and 4,5-dimethoxy-benzene-l,2-diamine dihydrochloride (5.06g, 20.99 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid partitioned between EtOAc (50 ml) and saturated aqueous NaHCO3 (50 ml). A precipitate was formed and removed by filtration. The filtrate was washed with water followed by diethyl ether and then azeotroped with MeOH and toluene to yield 4- nitro-lH-pyrazole-3- carboxylic acid (2-amino-4,5-dimethoxy-phenyl)- amide (2.35 g, 36percent). 4-Nitro- lH-pyrazole-3-carboxylic acid (2-amino-4,5-dimethoxy-phenyl)-amide (2.35g, 7.65 mmol) was dissolved in acetic acid (150 ml) and refluxed at 140° C for 5 hours. The solution was left to cool and the solvent removed in vacuo. The resulting solid was partitioned between EtOAc (25 ml) and brine (25 ml). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to yield 5,6- dimethoxy-2-(4-nitro-lH-pyrazol-3-yl)-lH-benzimidazol (2.08 g, 94percent).
36%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;	15A. Synthesis of 5,6-dimethoxy-2-(4-m'tro-lH-pwazol-3-ylVlH-benzimidazoleTo a solution of EDC (4.81 g 25 mmol), HOBt (3.40 g, 25 mmol) and triethylamine (4.67 g, 46 mmol) in DMF (100 ml) was added 4-nitro-lH-pyrazole-3-carboxylic acid (3.63 g, 23.09 mmol) and 4,5-dimethoxy-benzene-l,2-diamine dihydrochloride (5.06g, 20.99 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid partitioned between EtOAc (50 ml) and saturated aqueous NaHCO3 (50 ml). A precipitate was formed and removed by filtration. The filtrate was washed with water followed by diethyl ether and then azeotroped with MeOH and toluene to yield 4- nitro-lH-pyrazole-3- <n="212"/>carboxylic acid (2-amino-4,5-dimethoxy-phenyl)- amide (2.35 g, 36percent). 4-Nitro-lH-pyrazole- 3-carboxylic acid (2-amino-4,5-dimethoxy-phenyl)-amide (2.35g, 7.65 mmol) was dissolved in acetic acid (150 ml) and refluxed at 140° C for 5 hours. The solution was left to cool and the solvent removed in vacuo. The resulting solid was partitioned between EtOAc (25 ml) and brine (25 ml). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to yield 5,6-dimethoxy-2-(4-nitro-lH-pyrazol-3-yl)-lH-benzimidazol (2.08 ft 94percent).

Reference： [1]Patent: WO2006/70195,2006,A1 .Location in patent: Page/Page column 151-152
[2]Patent: WO2007/77435,2007,A1 .Location in patent: Page/Page column 210-211

23
trans-4-methoxymethoxy-cyclohexylamine [ No CAS ]
[ 5334-40-7 ]
4-nitro-1H-pyrazole-3-carboxylic acid (trans-4-methoxymethoxy-cyclohexyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;	Step 2. Synthesis of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (trans-4- methoxymethoxy-cvclohexyl)-amideA mixture of <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> (2.32 g, 14.8 mmol), trans 4- aminocyclohexanol (2.95 g, 18.5 mmol), EDAC (3.55 g, 18.5 mmol) and HOBt (2.50 g, 18.5 mmol) in DMF (75 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was washed (water, brine) dried (MgSO4), and reduced in vacuo to give a yellow oil (3.25 g), which was purified by column chromatography, eluting 0-100 percent EtOAc in petroleum ether, then 1-25 percent MeOH in EtOAc to give <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (trans- 4-methoxymethoxy-cyclohexyl)-amide as a pale yellow solid (1.25 g). (LC/MS: Rt 2.11 [M+H]+ 297.25).

Reference： [1]Patent: WO2006/77414,2006,A1 .Location in patent: Page/Page column 153

24
[ 100-44-7 ]
[ 5334-40-7 ]
[ 407623-75-0 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; potassium carbonate; In methanol; ethyl acetate; N,N-dimethyl-formamide;	Step 1 Synthesis of Methyl 1-benzyl-<strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylate</strong>: 10 g (63.7 mmol) of <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> was dissolved in 100 ml of methanol. 5.7 ml (76.4 mmol) of thionyl chloride was added dropwise to the obtained solution under cooling with ice. The temperature was elevated to room temperature and the obtained mixture was stirred for 2 days. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the solvent was evaporated. The obtained crude product was dissolved in 150 ml of DMF. 9.5 g (68.8 mmol) of potassium carbonate and 7.5 ml (65.0 mmol) of benzyl chloride were added to the obtained solution, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound. Yield: 10.5 g (40.2 mmol) (63percent) H-NMR (CDCl3) delta 3.99 (3H, s), 5.34 (2H, s), 7.28-7.33 (2H, m), 7.39-7.45 (3H, m), 8.00 (1H, s)

Reference： [1]Patent: US2003/186969,2003,A1

25
[ 5334-40-7 ]
[ 521300-01-6 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 16 4-Nitro-1H-pyrazol-3-carboxylic Acid Amide The title product was prepared by an analogous method to Preparation 5 starting from <strong>[5334-40-7]4-nitro-1H-pyrazol-3-carboxylic acid</strong> (Sigma-Aldrich Chemical Co.)

Reference： [1]Patent: US2003/195205,2003,A1

26
[ 27489-62-9 ]
[ 5334-40-7 ]
[ 844443-75-0 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃; for 16h;	A mixture of <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> (4.98 g, 31.7 mmol), trans 4-aminocyclohexanol (3.65 g, 31.7 mmol), EDAC (6.68 g, 34.8 mmol) and HOBt (4.7 g, 34.8 mmol) in DMF (120 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in CH2CI2 and washed successively with 5percent citric acid, saturated aqueous sodium bicarbonate, water and brine. The product was found to be mainly in the citric acid wash, which was basified and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated to give a white solid, which was triturated with CHCI3 to give 1.95 g of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> 4-hydroxy-cyclohexylamide. (LC/MS: Rt 1.62, [M+H]+255).
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃; for 16h;	A mixture of <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> (4.98 g, 31.7 mmol), trans 4-aminocyclohexanol (3.65 g, 31.7 mmol), EDAC (6.68 g, 34.8 mmol) and HOBt (4.7 g, 34.8 mmol) in DMF (120 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in CH2CI2 and washed successively with 5percent citric acid, saturated aqueous sodium bicarbonate, water and brine. The product was found to be mainly in the citric acid wash, which was basified and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated to give a white solid, which was triturated with CHCI3 to give 1.95 g of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> 4-hydroxy-cyclohexylamide. (LC/MS: Rt 1.62, [M+H]+255).

Reference： [1]Patent: WO2006/77424,2006,A1 .Location in patent: Page/Page column 179-180
[2]Patent: WO2006/77428,2006,A1 .Location in patent: Page/Page column 157

27
[ 87120-72-7 ]
[ 5334-40-7 ]
[ 844443-80-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃;	4-Nitropyrazole-3-carboxylic acid (7.3 g; 15.9 mmol) was added to a stirred solution of 4-amino-1-Boc- piperidine (10.2 mg; 51 mmol), EDC (10.7 g; 55.8 mmol), and HOAt (55.8 g; 19.1 mmol) in DMF (100 ml), and then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with water (250ml). The resultant cream solid was collected by filtration, washed with water then dried under vacuum to give 13.05 g of 4-[(4-nitro-1H-pyrazole-3-carbonyl)-amino]-piperidine-1- carboxylic acid tert-butyl ester (LC/MS: Rt 2.50, [M+H]+ 340).
	With 1-hydroxy-7-aza-benzotriazole; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃;	4-Nitropyrazole-3-carboxylic acid (7.3 g; 15.9 mmol) was added to a stirred solution of 4-amino-1-Boc- piperidine (10.2 mg; 51 mmol), EDC (10.7 g; 55.8 mmol), and HOAt (55.8 g; 19.1 mmol) in DMF (100 ml), and then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with water (250ml). The resultant cream solid was collected by filtration, washed with water then dried under vacuum to give 13.05 g of 4-[(4-nitro-1H-pyrazole-3-carbonyl)-amino]-piperidine-1- carboxylic acid tert-butyl ester (LC/MS: Rt 2.50, [M+H]+ 340).
		Add 6.31 kg of raw material to a 100 L reactor, N,N-dimethylformamide (45 L), carbodiimide (6.59 kg), 1-hydroxybenzotriazole (4.65 kg), stirred for 0.5 h, The ice water bath was cooled to 0 to 10 C, and the starting material 1 (4.5 kg) was added in portions, and then the temperature was raised to 20-25 C, and the reaction was stirred for 16 hours. The reaction solution was added to 270 L of water, and a solid was precipitated, suction filtered, washed, and separated, and the organic phases were combined and dried

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4986 - 4999
[2]Patent: WO2006/77424,2006,A1 .Location in patent: Page/Page column 184
[3]Patent: WO2006/77428,2006,A1 .Location in patent: Page/Page column 161-162
[4]Patent: CN109705090,2019,A .Location in patent: Paragraph 0106-0109

28
[ 67-56-1 ]
[ 5334-40-7 ]
[ 138786-86-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; at 0 - 20℃; for 16.5h;	SOCI2 (4.62 mL, 63.66 mmol) was added dropwise over 5 min approximately to a solution of 4-Nitro-lH-pyrazole-3-carboxylic acid (5.00 g, 31.83 mmol) in MeOH (50 mL) at 0 C. The resulting clear solution was stirred at 0 C for 30 min, followed by rt for 16 h. Solvent was evaporated under reduced pressure to obtain 5.4 of intermediate 487 (99% yield, white solid).
82%	With thionyl chloride; at 0 - 20℃;	Step 1 Thionyl chloride (9.2 mL) was added dropwise to a solution of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (19.77 g, 125.9 mmol) in methanol (200 mL) at 0C. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried and concentrated. The obtained crude crystals were washed with diisopropyl ether to give methyl 4-nitro-1H-pyrazole-5-carboxylate (17.8 g, 82%). 1H-NMR (300MHz, CDCl3) delta: 4.06 (3H, s), 8.50 (1H, s).
82%	With thionyl chloride; at 0 - 35℃;	(Step 1) Thionyl chloride (9.2 mL) was added dropwise to a solution of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (19.77 g, 125.9 mmol) in methanol (200 mL) at 0 C. The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated. The obtained crude crystal was washed with diisopropyl ether to give methyl 4-nitro-1H-pyrazole-5-carboxylate (17.77 g, 82%). 1H NMR (300 MHz, CDCl3) delta: 4.06 (3H, s), 8.50 (1H, s).

Reference： [1]Patent: WO2018/2217,2018,A1 .Location in patent: Page/Page column 317
[2]Patent: EP1953148,2008,A1 .Location in patent: Page/Page column 136
[3]Patent: US2015/329556,2015,A1 .Location in patent: Paragraph 1813

29
[ 39226-95-4 ]
[ 5334-40-7 ]
[ 915371-83-4 ]

Reference： [1]Heterocycles,2009,vol. 78,p. 71 - 91

30
[ 75-36-5 ]
[ 5334-40-7 ]
[ 138786-86-4 ]

Reference： [1]Journal of Antibiotics,2015,vol. 68,p. 361 - 367

31
[ 5334-40-7 ]
[ 138786-86-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; In methanol; at 70℃; for 5h;	To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (50.0 g, 318 mmol, CAS5334-40-7) in MeOH (250 mL) was added SOCl2 (56.8 g, 477 mmol). The mixture was stirred at 70 C. for 5 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (54.0 g, 99% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) delta 14.40 (s, 1H), 9.98 (s, 1H), 3.89 (s, 3H).
	With thionyl chloride; In methanol; toluene;	Preparation of 4-nitro-1H-Pyrazole-3-carboxylic acid methyl ester A 20 L reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-1H-pyrazole-3-carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5 C., thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 C. overnight, after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 C., the residue treated with toluene and re-concentrated (32.250 L, 32 vol) under reduced pressure at 40 to 45 C. to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5%).
	With thionyl chloride; In methanol;	Example 1 1A.4-Nitro-1H-pyrazole-3-carboxylic acid methyl ester Thionyl chloride (2.90 ml, 39.8 mmol) was slowly added to a mixture of 4-nitro-3-pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in MeOH (100 ml) at ambient temperature and the mixture stirred for 48 hours. The mixture was reduced in vacuo and dried through azeotrope with toluene to afford 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 14.4 (s, 1H), 8.9 (s, 1H), 3.9 (s, 3H)

	With thionyl chloride; In methanol; toluene;	Synthesis of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester A 20 L reaction vessel equipped with a digital thermometer and stirrer was charged with 4-nitro-1H-pyrazole-3-carboxylic acid (1.117 Kg, 7.11 mol, 1 wt) and methanol (8.950 L, 8 vol). The reaction mixture was stirred under nitrogen, cooled to 0 to 5 C., thionyl chloride (0.581 L, 8.0 mol, 0.52 vol) added over 180 minutes and the resultant mixture allowed to warm to and stir at 18 to 22 C. overnight after which time 1H NMR analysis (d6-DMSO) indicated reaction completion. The reaction mixture was concentrated under reduced pressure at 40 to 45 C., the residue treated with toluene and re-concentrated (32.250 L, 32 vol) under reduced pressure at 40 to 45 C. to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid (1.210 Kg, 99.5% th).
	In methanol; toluene;	Preparation of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester 4-Nitro-1H-pyrazole-3-carboxylic acid (1.00 kg, 6.37 mol, 1.0 wt) and methanol (8.00 L, 8.0 vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5 C. under nitrogen and thionyl chloride (0.52 L, 7.12 mol, 0.52 vol) was added at this temperature. The mixture was warmed to 15 to 25 C. over 16 to 24 hours. Reaction completion was determined by 1H NMR analysis (d6-DMSO). The mixture was concentrated under vacuum at 35 to 45 C. Toluene (2.00 L, 2.0 vol) was charged to the residue and removed under vacuum at 35 to 45 C. The azeotrope was repeated twice using toluene (2.00 L, 2.0 vol) to give 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.071 Kg, 98.3%) as an off white solid.

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2867; 2868
[2]Patent: US2010/21420,2010,A1
[3]Patent: US2010/21420,2010,A1
[4]Patent: US2010/55094,2010,A1
[5]Patent: US2010/55094,2010,A1

32
[ 95-54-5 ]
[ 5334-40-7 ]
[ 825615-90-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 27h;Reflux;	A mixture of4-nitro-1H-pyrazole-3-carboxyiic acid (5.0 g, 31.8 mmol), 1,2-phenyienediamine (3.79 g, 35.0 mmol), EDC (7.30 g, 38.2 mmol) and HOBt (5.16 g, 38.2 mmol) in DMF (65 rnL) was stirred at room temperature for 24 h. After which the solvent was reduced to a third of its original volume, and the remaining mixture was diiuted with AcOH (60 mL) and refluxed for 3 h.Upon cooling, the solvents were removed under reduced pressure and water was added to the residue. The resultant precipitate was collected by filtration and washed thoroughly with water.A mixture of4-nitro-1H-pyrazole-3-carboxyiic acid (5.0 g, 31.8 mmol), 1,2-phenyienediamine (3.79 g, 35.0 mmol), EDC (7.30 g, 38.2 mmol) and HOBt (5.16 g, 38.2 mmol) in DMF (65 rnL) was stirred at room temperature for 24 h. After which the solvent was reduced to a third of its original volume, and the remaining mixture was diiuted with AcOH (60 mL) and refluxed for 3 h.Upon cooling, the solvents were removed under reduced pressure and water was added to the residue. The resultant precipitate was collected by filtration and washed thoroughly with water.

Reference： [1]Patent: WO2014/64134,2014,A1 .Location in patent: Page/Page column 86; 87
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 379 - 388

33
[ 20781-20-8 ]
[ 5334-40-7 ]
[ 850727-60-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 20h;	4-Nitro-1H-pyrazole-3-carboxylic acid 2,4-dimethoxybenzylamide is obtained in the following manner:23 g of 2,4-dimethoxybenzylamine and then 20.04 g of 98percent <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> are added to a solution of 28.76 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 20.27 g of 1-hydroxybenzotriazole in 100 ml of dimethylformamide. The reaction medium is stirred for at room temperature for 20 hours. The clear yellow solution obtained is then poured into 1000 ml of distilled water. A white suspension is obtained, which is left at room temperature for 1 hour. The suspension is filtered and the filter cake is washed with three times 250 ml of distilled water. The solid obtained is drained by suction and dried in air and then in a Heraeus oven under vacuum (temp. 40° C. P: 0.2 mbar). 40.65 g of a white solid are obtained, which product is triturated in 750 ml of refluxing isopropanol for 20 minutes. The suspension obtained is cooled in a bath of water+ice for 2 hours, and then filtered off. The filter cake is washed with twice 100 ml of isopropanol and then twice 100 ml of isopropyl ether. The solid obtained is dried in air and then in a Heraeus oven (temp. 40° C. P: 0.2 mbar). 32.16 g of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> 2,4-dimethoxybenzylamide are obtained in the form of a white solid melting at 204° C. ([M+H]+): 307). RT: 3.12 min Example 35: 4-(ethyl{3-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]benzyl}amino)-1H-pyrazole-3-carboxamide
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃; for 16h;	4-Nitro-1H-pyrazole-3-(2,4-dimethoxybenzylamide) A solution of 14.65 g (76.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide dihydrate and 10.32 g (76.4 mmol) of 1-hydroxybenzotriazole in 50 ml of dimethylformamide is stirred at ambient temperature. 11.7 g (70.03 mmol) of 2,4-dimethoxybenzylamine are added, then 10.2 g of 4-nitro-3-pyrazole carboxylic acid are added in small portions. After 16 hours of stirring at ambient temperature, the reaction medium is poured into 500 ml of water. The suspension is filtered, then washed with 2.x.250 ml of water. The solid obtained is dried in an oven under vacuum at 40° C. in order to give 18.58 g of 4-nitro-1H-pyrazole-3-(2,4-dimethoxybenzylamide) in the form of a white solid.1H NMR (400 MHz, DMSO-d) delta ppm 3.75 (s, 3H) 3.80 (s, 3H) 4.35 (d, J=5.9 Hz, 2H) 6.50 (dd, J=8.3, 2.4 Hz, 1H) 6.56 (d, J=2.4 Hz, 1H) 7.21 (d, J=8.3 Hz, 1H) 8.71 (broad s, 1 H) 8.88 (broad t, J=5.9 Hz, 1H) 14.13 (broad unresolved m, 1H)MS (ES+/-) Retention time Tr (min)=3.23; [M+H]+ m/z=307; [M-H]- m/z=305Melting point (Kofler): 192° C.

Reference： [1]Patent: US2009/291984,2009,A1 .Location in patent: Page/Page column 22-23
[2]Patent: US2012/270918,2012,A1 .Location in patent: Page/Page column 6

34
Fmoc-Rink Amide resin [ No CAS ]
[ 5334-40-7 ]
C₅H₇N₄OPol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of the Resin (ii):30 g of Rink resin (PolymerLab; 0.99 mmol/g) is swollen in 150 ml of DMF. After stirring for 10 minutes, the DMF is filtered off and replaced with 150 ml of a solution of piperidine in DMF (50/50, v/v). The mixture is stirred for 1 hour and then filtered. The resin is washed successively with five times 150 ml of DMF, twice 150 ml of methanol and three times 150 ml of DMF. Next, a solution of 14.1 g of <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> (90 mmol, 3 eq.) and 13.8 g of HOBt (90 mmol, 3 eq.) in 150 ml of DMF is added to the resin, immediately followed by 13.8 ml of DIC (90 mmol; 3 eq.). The mixture is stirred for 16 hours at room temperature. The solution is filtered and the resin is washed successively with five times 150 ml of DMF, twice 150 ml of methanol, three times 150 ml of DMF and then with 150 ml of a 1 M SnCl2 solution (33 g in 150 ml). The mixture is stirred at room temperature for 24 hours and is then filtered, and the resin is washed with five times 150 ml of DMF, twice 150 ml of methanol, three times 150 ml of DCM and twice 150 ml of ethyl ether. After drying under vacuum, 31 g of intermediate resin (ii) are isolated.

Reference： [1]Patent: US2009/291984,2009,A1 .Location in patent: Page/Page column 9

35
[ 79-37-8 ]
[ 87120-72-7 ]
[ 5334-40-7 ]
[ 844443-80-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1,4-dioxane; water;	Step 1: Synthesis of 4-[(4-nitro-1H-pyrazole-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester 4-Nitropyrazole-3-carboxylic acid (20.0 g, 127.4 mmol) was suspended in CH2Cl2/DMF (99:1, 400 mL), treated cautiously with oxalyl chloride (11.6 mL, 134 mmol) and then stirred at room temperature for 16 h. The reaction mixture was evaporated then re-evaporated with toluene (*3) to give a yellow solid. The resultant acid chloride was suspended in dioxane (400 mL), treated with triethylamine (26.4 mL, 190 mmol) followed by 4-amino-1-BOC-piperidine (25.0 g, 125 mmol) and stirred at room temperature for 6 h. The reaction mixture was filtered and the solid collected stirred in water (500 mL) and then re-filtered. The solid collected was dried in vacuo, azeotroping with toluene, to give the title compound (37.6 g).

Reference： [1]Patent: US2010/21420,2010,A1

36
[ 5334-40-7 ]
[ 75-65-0 ]
[ 1207877-93-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a 1 L R.B. flask containing <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> (40 g, 0.255 mol), and t-BuOH (94 g, 122 mL, 1.275 mol, 5 eq.) was added conc. H2SO4 (25 g, 13.5 mL, 0.255 mol); and the reaction mixture was stirred at 100° C. for 2 h. After cooling to rt, the reaction mixture was diluted with EtOAc and water. Then added saturated aq NaHCO3 solution until pH was around 3-4. The aqueous layer was extracted with excess ethyl acetate. The combined ethyl acetate part was dried over any Na2SO4, filtered and distilled off to give 28 g of 1-tert-butyl-<strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> as solid.To a vial containing 1-tert-butyl-<strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong>, (214 mg, 1.0 mmol, 1 eq.) was added PCl5 (240 mg, 1.15 mmol, 1.5 eq.) in chilled toluene (2 mL). The mixture was stirred until all solids dissolved (ca. 5-10 min.). The pre-formed acid chloride solution was then added to 3,3-dimethylpiperazine-2-one (141 mg, 1.10 mmol, 1.1 eq.) and TEA (0.300 mL, 2.15 mmol, 2.15 eq) in DCM (4 mL) and stirred for 45 min. at room temperature. The reaction was quenched with NaHCO3, and the organics extracted with EtOAc, washed with water, and brine. The aqueous portions were back-extracted and the combined organics were dried over MgSO4, filtered and concentrated to an off-white solid, 4-(1-tert-butyl-4-nitro-1H-pyrazole-3-carbonyl)-3,3-dimethylpiperazine-2-one, 310.4 mg.To a rb flask containing 4-(1-tert-butyl-4-nitro-1H-pyrazole-3-carbonyl)-3,3-dimethylpiperazine-2-one (303 mg, 0.937 mmol, 1 eq.) in MeOH (9 mL) was added Pd/C (105 mg, 0.1 eq.). A balloon filled with H2 was attached and the atmosphere of the vessel purged with H2. The contents of the flask were stirred at r.t. overnight. Themixture was filtered through Celite.(R)., eluting with MeOH. The solvent was removed in vacuo to give 4-(4-amino-1-tert-butyl-1H-pyrazole-3-carbonyl)-3,3-dimethylpiperazine-2-one 259.7 mg, as a purple solid.The urea was formed from 4-(4-Amino-1-tert-butyl-1H-pyrazole-3-carbonyl)-3,3-dimethylpiperazine-2-one and 3-(6-isopropylpyridin-3-yl)-4-methylaniline to give 1-(1-tert-butyl-3-(2,2-dimethyl-3-oxopiperazine-1-carbonyl)-1H-pyrazol-4-yl)-3-(3-(6-isopropylpyridin-3-yl)-4-methylphenyl)urea.
	With sulfuric acid; at 100℃; for 16h;	Step 1: Into a 50 mL round bottom flask containing a solution of 4-nitro-1H-pyrazole-3- carboxylic acid (5.0 g, 32 mmol) in tert-butanol (25 mL) was added sulfuric acid (2 mL, 32mmol) and the mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and neutralized with saturated solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (50-70percent) to afford 1-(tert-butyl)-<strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> as asolid. ?HNMR(DMSO-d6,400 MHz): oe 13.90 (brs, 1H), 8.96 (s, 1H), 1.55 (s, 9H).
	With sulfuric acid; at 100℃; for 16h;	Step 1: Into a 50 mL round bottom flask containing a solution of 4-nitro-1H-pyrazole-3- carboxylic acid (5.0 g, 32 mmol) in tert-butanol (25 mL) was added sulfuric acid (2 mL, 32 mmol) and the mixture was heated at 100 oC for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and neutralized with saturated solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (50-70percent) to afford 1-(tert-butyl)-<strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> as a solid. 1H NMR (DMSO-d6, 400 MHz): delta 13.90 (brs, 1H), 8.96 (s, 1H), 1.55 (s, 9H).

Reference： [1]Patent: US2010/41642,2010,A1 .Location in patent: Page/Page column 23
[2]Patent: WO2016/144846,2016,A1 .Location in patent: Page/Page column 48; 49
[3]Patent: WO2016/144847,2016,A1 .Location in patent: Page/Page column 33

37
[ 67-56-1 ]
[ 5334-40-7 ]
[ 1166981-47-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With acetyl chloride;	20 g of 4-nitropyrazolo-l-carboxylic acid (1) (127.32 mM) as a starting material was drop wisely added to the reaction solution dissolving 11.10 ml of acetyl chloride (381.96 mM) in 350 ml of methanol to react together and finally 23.69 g of methyl- 4-nitro-lH-pyrazole-3-carboxylate hydrochloride was obtained (yield: 90percent).
	With thionyl chloride; at 20℃;Cooling with ice;	Synthesis of 123-A. To a solution of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (8.00 g, 50.1 mmol) in MeOH (160 mL) was added SOCl2 (11.92 g, 100.2 mmol) dropwise under ice bath. Then the solution was stirred at room temperature overnight. The solution was concentrated in vacuo to give 123-A (8.70 g, 84percent) as a white solid.

Reference： [1]Patent: WO2010/74480,2010,A2 .Location in patent: Page/Page column 20
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6053 - 6058
[3]Patent: WO2017/7756,2017,A1 .Location in patent: Paragraph 288

38
[ 67-56-1 ]
[ 824-94-2 ]
[ 5334-40-7 ]
[ 896467-74-6 ]

Reference： [1]Molecules,2010,vol. 15,p. 4382 - 4400

39
[ 124-40-3 ]
[ 5334-40-7 ]
[ 1352200-35-1 ]

Yield	Reaction Conditions	Operation in experiment
30%		A solution of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (1.0 g, 6.4 mmol) in dichloromethane (20 ml) was treated with thionyl chloride (1.4 ml, 19 mmol) and a drop of DMF at ambient temperature. The reaction mixture is stirred at 40° C. overnight whereupon another equivalent of thionyl chloride (0.46 ml, 6.4 mmol) was added and stirring was continued at 40° C. for another 24 h. All volatiles were removed and the acid chloride was suspended in dichloromethane (6 ml) and cooled to 0° C. Triethylamine (4.44 ml, 31.8 mmol) and dimethylamin (4.14 ml, 2M solution in THF) were added. The reaction mixture was allowed to warm-up to ambient temperature and stirring was continued for 3 h. The reaction mixture was partitioned between potassium hydrogen sulfate (20 ml, 10percent aqueous solution) and ethyl acetate (40 ml) and extracted. The organic phase was washed with water and brine, dried and the solvent was evaporated. The crude product was triturated with diethylether, sucked off and dried to yield a light brownsolid (0.35 g, 30percent). MS: M=185.1 (M+H)+

Reference： [1]Patent: US2011/306589,2011,A1 .Location in patent: Page/Page column 67

40
[ 100-39-0 ]
[ 5334-40-7 ]
[ 1355011-61-8 ]

Yield	Reaction Conditions	Operation in experiment
51%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1.5h;	Synthesis of benzyl l-benzyl-4-nitro-lH-pyrazole-3-carboxylate[00227] To a solution of 4-nitro-lH-pyrazole-3-carboxylic acid (1.0 equiv.) in DMF (0.3 M) was added BENZYL BROMIDE (2.0 equiv.) and Cs2C03 (4.0 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. After quenched with H20, The reaction mixture was extracted with EtOAc. The combined organic layer was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The benzyl 1 -benzyl- lH-pyrazole-3- carboxylate was obtained as a colorless oil by flash column chromatography ( 20percent EtOAc in Hexanes) in 51percent yield. LCMS (m/z): 338.2 (MH+), R, = 1.02 min. 1H NMR (400 M Hz, CHLOROFORM-d) delta ppm 7.98 (s, 1H), 7.49-7.34 (m, 8H), 7.31 (dd, J=6.7, 2.7 Hz, 2H), 5.43 (s, 2H), 5.33 (s, 2H).

Reference： [1]Patent: WO2012/4217,2012,A1 .Location in patent: Page/Page column 105-106

41
[ 144-82-1 ]
[ 5334-40-7 ]
C₁₃H₁₁N₇O₅S₂ [ No CAS ]

Reference： [1]Chemical Science,2013,vol. 4,p. 1229 - 1233

42
[ 1254229-46-3 ]
[ 5334-40-7 ]
[ 1254229-48-5 ]

Yield	Reaction Conditions	Operation in experiment
49.6%		General procedure: A mixture of compound 4 (55.5mmol), <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (7.85g, 50.0mmol), EDCI (10.65g, 55.5mmol), and HOBt (7.5g, 55.5mmol) in dry DMF (125mL) was stirred at ambient temperature for 24 h. The mixture was reduced in vacuo and the crude residue dissolved in AcOH (200mL) and heated at reflux for 3 h. The solvent was removed in vacuo and the residue was purified by SiO2 column chromatography, eluting with 0-20percent MeOH in EtOAc to give nitropyrazole 5.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3523 - 3530

43
[ 1254229-47-4 ]
[ 5334-40-7 ]
[ 1254229-50-9 ]

Yield	Reaction Conditions	Operation in experiment
57.8%		General procedure: A mixture of compound 4 (55.5mmol), <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (7.85g, 50.0mmol), EDCI (10.65g, 55.5mmol), and HOBt (7.5g, 55.5mmol) in dry DMF (125mL) was stirred at ambient temperature for 24 h. The mixture was reduced in vacuo and the crude residue dissolved in AcOH (200mL) and heated at reflux for 3 h. The solvent was removed in vacuo and the residue was purified by SiO2 column chromatography, eluting with 0-20percent MeOH in EtOAc to give nitropyrazole 5.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3523 - 3530

44
[ 496-72-0 ]
[ 5334-40-7 ]
[ 1254229-49-6 ]

Yield	Reaction Conditions	Operation in experiment
57.3%		General procedure: A mixture of compound 4 (55.5mmol), <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (7.85g, 50.0mmol), EDCI (10.65g, 55.5mmol), and HOBt (7.5g, 55.5mmol) in dry DMF (125mL) was stirred at ambient temperature for 24 h. The mixture was reduced in vacuo and the crude residue dissolved in AcOH (200mL) and heated at reflux for 3 h. The solvent was removed in vacuo and the residue was purified by SiO2 column chromatography, eluting with 0-20percent MeOH in EtOAc to give nitropyrazole 5.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3523 - 3530

45
[ 137-07-5 ]
[ 5334-40-7 ]
[ 1607441-38-2 ]

Yield	Reaction Conditions	Operation in experiment
61%		Step 12-(4-Nitro- 1 H-pvrazo 1-3 -yl)-benzothiazoleTo a solution of<strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (5 g, 31.8 mmol) in THF (40 mL) was added DMF (0.25 mL, 3.19 mmol) and oxalyl chloride (4.1 mL, 47.8 mmol). The mixture wasstirred at room temperature for 1 h and then concentrated under reduced pressure. The crude material was redissolved in NMP (40 mL) and 2-amino-beiizenethiol (4.0 mL, 31.8 mmol) was added. This mixture was heated at 100 °C for 1 h, at which point water (100 mL) was added and the aqueous phase extracted with ethyl acetate (3 x 25 mL). The combined organic layers were 42dried (Na2SO4), concentrated under reduced pressure, and purified by chromatography (silica, EtOAc / hexanes) to give 2-(4-nitro- 1 H-pyrazol-3 -yl)-benzothiazo le as a light yellow solid (4.8 g, 61 percent). MS (El/Cl) m/z: 245.0 [M - H].

Reference： [1]Patent: WO2014/64134,2014,A1 .Location in patent: Page/Page column 41; 42

46
[ 70261-82-4 ]
[ 5334-40-7 ]
[ 1308400-19-2 ]

Yield	Reaction Conditions	Operation in experiment
88.2%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;	In a 250 mL round bottom flask, 7.5 g (36.6 mmol) of crude I-a' and 6.3 g (40.1 mmol) of 4-nitro-1H-pyrazole-3-carboxylic acid were added. EDC HCl 8.4 g (44.0 mmol), HOBt 6.0 g (44.4 mmol) and anhydrous DMF 100 mL were stirred at room temperature for 24 hr. The disappearance of the starting material by TLC (methanol: chloroform = 1:10). The reaction solution was poured into 200 mL of ice water to precipitate a large amount of pale yellow solid, which was allowed to stand, and a yellow solid was obtained. The obtained crude product was recrystallized from a mixed solvent of ethyl acetate and methanol to give (I-e) 11.1 g. The yield was 88.2 %.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;	4-Amino-N-[4-[(4-methylpiperazin-1-yl) methyl] phenyl]-1Hpyrazole-3-carboxamide (5): The mixture of N-methylpiperazine (4.9 mL, 44.2 mmol) and triethylamine (12 mL,86.3 mmol) in dichloromethane (20 mL) was added dropwiseto a stirred solution of Nitro-benzyl bromide 1 (10.0 mg,46.3 mmol) in dichloromethane (100 mL) under the ice-waterbath and was refluxed for 1 h. The reaction mixture was extractedwith chloroform (100 mL×3), washed with water andsaturated sodium chloride each time (100 mL×1). The organicphase was dried with anhydrous magnesium sulfate, filtered,evaporated under vacuum to give pale yellow solid 2. Withoutfurther purification, 2 mixed with FeO(OH)/C (catalyst 2.0 g)and 95% ethanol (100 mL) were kept refluxing and dropwiseadded the mixture of hydrazine hydrate (25 mL) and 95%ethanol (20 mL), then filtrated when the solution was hot. Theresidue was washed with hot ethanol (30 mL×2). The solventwas distilled under vacuum to give white solid 3 (6.7 g), thenmixed with 4-nitro-1H-pyrazole-3-acid (6.3 g, 40.0 mmol),EDCI (8.4 g, 43.8 mmol) and HOBT (6.0 g, 44.4 mmol) in anhydrousDMF (100 mL), stirred for 24 h at room temperature.The reaction mixture was poured into ice water (200 mL).A large amount of yellow solid precipitation was acquired.The pure product 4 was got from recrystallizing with mixedsolvent of methanol and ethyl acetate, then the same processof hydrazine hydrate reduction was done with the catalyst ofFeO(OH)/C. The solvent was distilled under vacuum to give white solid 5 (3.5 g). Yield= 63.9%; mp 199-201C; IR (KBr)cm-1: 3369, 3227 (NH2), 1346 (C= C), 1456 (C= N) pyrazole,646 (ArH); 1H-NMR (300 MHz, DMSO-d6) delta (ppm): 2.1 (3H,s, -CH3), 2.3-2.5 (8H, m, -CH2-), 3.3 (2H, s, -CH2-), 4.7(1H, s, -NH2), 7.1-7.2 (3H, m, ArH), 7.7 (2H, d, J=10.5 Hz,ArH), 9.7 (1H, s, -NHCO-), 12.7 (1H, s, Pyrazole); MS m/z:315.82 (M+); Anal. Calcd for C16H22N6O: C, 61.13; H, 7.05; N,26.73; O, 5.09. Found: C, 61.31; H, 6.84; N, 26.52.
11.1 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;	EXAMPLE 5 N(4-((4-methyl-1-piperazinyl)methyl)phenyl)-4-nitro-1H-3-pyrazolecarboxamide (I-e) Crude I-c (7.5g 36.6mmol), 4-nitro-1H-pyrazole-3-carboxylic acid (6.3 g, 40.1 mmol), EDC·HCl (8.4 g, 44.0 mmol), HOBT (6.0 g, 44.4 mmol) and anhydrous DMF (100 ml) were added into a 250 mL round bottom flask, which was stirred for 24 hours at room temperature. The depletion of the starting materials was confirmed by TLC (methanol: chloroform = 1:10). The reaction mixture was poured into 200 mL ice water and a large amount of yellowish solid precipitation was acquired, which was allowed to stand and suction filtered to give yellow solid. The crude was recrystallized from the mixed solvents of ethyl acetate and methanol to give 11.1 g (I-e); Yield: 88.2%; mp: 194-196 C; MS [M+H]+ 345.3. 1H-NMR[300MHz, DMSO-d6]: delta2.2 (3H, s, -CH3), 2.3-2.4 (8H, m, -CH2-*4), 3.4 (2H, s, -CH2-), 7.3 (2H, d, J = 8.4 Hz, ArH), 7.6 (2H, d, J = 8.4 Hz, ArH), 8.8 (1H, s, ArH), 10.6 (1H, s, -NHCO-), 14.2(1H, s, -NH-, Pyrazole).

11.1 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;	To a 250 mL round bottom flask was added 7.5 g (36.6 mmol) of crude I-a '4-nitro-1H-pyrazole-3-carboxylic acid 6.3 g(40.1 mmol),EDC · HCl 8.4 g (44.0 mmol)HOBt 6.0 g (44.4 mmol) and dry DMF 100 mL,Stir at room temperature for 24 h TLC detects the disappearance of the starting material (methanol: chloroform = 1:10).The reaction solution was poured into 200 mL of ice water,Precipitation of a large number of light yellow solid, standing, take the yellow solid,The crude product was recrystallized from a mixed solvent of ethyl acetate and methanol to give 11.1 g of (I-e)Yield 88.2%.
	With benzotriazol-1-ol; 1,2-dichloro-ethane; In N,N-dimethyl-formamide; for 24h;	General procedure: 4-Nitrobenzyl bromide (46.3mmol) was dissolved in dichloromethane (100mL). The solution was added to the mixture of relative amine (47.0mmol) and triethylamine (70.3mmol) in dichloromethane (20ml). The reaction mixture was stirred at r. t. for 24 h and was extracted with dichloromethane (100ml×3). After removal of the solvent, the residue was crystallized from ethanol, giving yellow powder. Compounds 1 and 2 were used for further reaction without purification. To a suspension of compounds 1-2 (36.2mmol) in 95% ethanol (100ml), 85% NH2NH2·H2O (362mmol), 95% ethanol (100ml) and iron (III) oxide hydroxide (FeO(OH)/C, 2.0g) were added and heated to reflux. When TLC analysis showed complete conversion of the starting material, the reaction mixture was filtrate through Cellit and the filtrate was concentrated in vacuum. The crude product was purified by silica gel colum chromatography (DCM/MeOH) to yield the title compound (3 and 4) as white solid. The mixture of compound 4 (1eq, 18.5mmol), 4-Nitro-1H-pyrazole-3-acid (1.1equiv, 20.4mmol), EDC (1.2equiv, 22.2mmol), HOBT (1.2equiv, 22.2mmol) in DMF (50ml) was stirred for 24h. The ice water (100ml) was added to the reaction mixture. A large amount of yellow solid precipitation (compound 8) was acquired. Compound 8 was used without further purification. Compounds 8 was reduced by the same process as compound 4, and then the resulting compound 12 was purified by column chromatography on silica gel, eluted with the appropriate solvent.
11.1 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;	In a 250 mL round bottom flask, 7.5 g (36.6 mmol) of crude I-b' was added. 4-nitro-1H-pyrazole-3-carboxylic acid 6.3 g (40.1 mmol), EDC·HCl 8.4 g (44.0 mmol), HOBt 6.0g (44.4mmol) and anhydrous DMF 100mL, Stir at room temperature for 24 h. The disappearance of the starting material by TLC (methanol: chloroform = 1:10). The reaction solution was poured into 200 mL of ice water. A large amount of pale yellow solid is precipitated, Rest, Thinking about a yellow solid, The obtained crude product was recrystallized from ethyl acetate and methanol to give (I-e) 11.1 g. The yield was 88.2%.

Reference： [1]Patent: CN104592251,2019,B .Location in patent: Paragraph 0254-0256
[2]Chemical and Pharmaceutical Bulletin,2014,vol. 62,p. 238 - 246
[3]Patent: EP2955185,2015,A1 .Location in patent: Paragraph 0083
[4]Patent: CN107245073,2017,A .Location in patent: Paragraph 0127; 0128; 0129
[5]Journal of Medicinal Chemistry,2018,vol. 61,p. 1499 - 1518
[6]European Journal of Medicinal Chemistry,2018,vol. 155,p. 303 - 315
[7]Patent: CN109970717,2019,A .Location in patent: Paragraph 0090; 0113-0115

47
[ 51013-67-3 ]
[ 5334-40-7 ]
[ 1308400-44-3 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;	5-(3-Cyclopropylureido)-N-[4-(morpholinomethyl) phenyl]-1H-pyrazole-3-carboxamide (pyz-5): The preparation processof pyz-5 which began with morphine was the same as pym-5.Yield= 56.1%; mp 121-123C; IR (KBr) cm-1: 3335 (NH),1344 (C= C), 1454 (C= N) pyrazole, 2995 (CH2) cycloproyl,1666 (O= C-NH), 1533, 1265 (amide), 1066 (C-O) ether 1H-NMR (300 MHz, DMSO-d6) delta: 0.7-1.0 (4H, m, -CH2-),2.5 (4H, m, -NCH2-), 2.7 (1H, m, -CH-), 3.3 (2H, s, -CH2-),3.6 (4H, m, -OCH2-), 7.0 (1H, m, ArH), 7.2 (2H, d, J=8.7 Hz,ArH), 7.7 (2H, d, J=8.7 Hz, ArH), 10.0 (1H, s, -NHCO-), 11.3(1H, s, -NHCONH-), 12.0 (1H, s, -NHCONH-), 14.0 (1H, s,pyrazole); MS m/z: 383.90 (M-); Anal. Calcd for C19H24N6O3:C, 59.36; H, 6.29; N, 21.86; O, 12.49%. Found: C, 59.65; H,6.63; N, 21.55.
11.6 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;	EXAMPLE 6 N-(4-((4-morpholinyl)methyl)phenyl)-4-nitro-1H-3-pyrazolecarboxamide (I-f) Crude I-d (7.5 g, 39.0 mmol), 4-nitro-1H-pyrazole-3-carboxylic acid (6.3 g, 40.1 mmol), EDC·HCl (8.4 g, 44.0 mmol), HOBT (6.0 g, 44.4 mmol) and anhydrous DMF (100 ml) were added into a 250 mL round bottom flask, which was stirred for 24 hours at room temperature. The depletion of the starting materials was confirmed by TLC (methanol: chloroform = 1:20). The reaction mixture was poured into 200 mL ice water and a large amount of yellowish solid precipitation was acquired, which was allowed to stand and suction filtered to give yellow solid. The crude was recrystallized from the mixed solvents of ethyl acetate and methanol to give 11.6 g (I-f); Yield: 89.7%; mp: 208-210 C; MS [M+H]+332.4. 1H-NMR[300MHz, DMSO-d6]: delta2.4 (4H, t, J = 4.1 Hz, -NCH2-2), 3.4 (2H, s, -CH2-), 3.6 (4H, t, J = 4.1 Hz, -OCH2-2), 7.3 (2H, d, J = 8.4 Hz, ArH), 7.6 (2H, d, J = 8.4 Hz, ArH), 8.9 (1H, s, ArH), 10.7 (1H, s, -NHCO-), 14.2 (1H, s, Pyrazole).
	With benzotriazol-1-ol; 1,2-dichloro-ethane; In N,N-dimethyl-formamide; for 24h;	General procedure: 4-Nitrobenzyl bromide (46.3mmol) was dissolved in dichloromethane (100mL). The solution was added to the mixture of relative amine (47.0mmol) and triethylamine (70.3mmol) in dichloromethane (20ml). The reaction mixture was stirred at r. t. for 24 h and was extracted with dichloromethane (100ml×3). After removal of the solvent, the residue was crystallized from ethanol, giving yellow powder. Compounds 1 and 2 were used for further reaction without purification. To a suspension of compounds 1-2 (36.2mmol) in 95% ethanol (100ml), 85% NH2NH2·H2O (362mmol), 95% ethanol (100ml) and iron (III) oxide hydroxide (FeO(OH)/C, 2.0g) were added and heated to reflux. When TLC analysis showed complete conversion of the starting material, the reaction mixture was filtrate through Cellit and the filtrate was concentrated in vacuum. The crude product was purified by silica gel colum chromatography (DCM/MeOH) to yield the title compound (3 and 4) as white solid. The mixture of compound 4 (1eq, 18.5mmol), 4-Nitro-1H-pyrazole-3-acid (1.1equiv, 20.4mmol), EDC (1.2equiv, 22.2mmol), HOBT (1.2equiv, 22.2mmol) in DMF (50ml) was stirred for 24h. The ice water (100ml) was added to the reaction mixture. A large amount of yellow solid precipitation (compound 8) was acquired. Compound 8 was used without further purification. Compounds 8 was reduced by the same process as compound 4, and then the resulting compound 12 was purified by column chromatography on silica gel, eluted with the appropriate solvent.

8.6 g

With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;

In a 250 mL round bottom flask, 7.0 g (36.6 mmol) of crude I-f was added. 4-nitro-1H-pyrazole-3-carboxylic acid 6.3 g (40.1 mmol), EDC·HCl 8.4 g (44.0 mmol), HOBt 6.0g (44.4mmol) and anhydrous DMF 100mL, Stir at room temperature for 24 h. The disappearance of the starting material by TLC (methanol: chloroform = 1:10). The reaction solution was poured into 200 mL of ice water to precipitate a large amount of pale yellow solid, which was allowed to stand, and a yellow solid was obtained. The obtained crude product was recrystallized from a mixed solvent of ethyl acetate and methanol to give (I-g) 8.6 g (yield: 71.0%).

Reference： [1]Chemical and Pharmaceutical Bulletin,2014,vol. 62,p. 238 - 246
[2]Patent: EP2955185,2015,A1 .Location in patent: Paragraph 0084
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 1499 - 1518
[4]European Journal of Medicinal Chemistry,2018,vol. 155,p. 303 - 315
[5]Patent: CN109970717,2019,A .Location in patent: Paragraph 0088; 0125-0127

48
[ 121588-79-2 ]
[ 5334-40-7 ]
N-((1r,4r)-4-methoxycyclohexyl)-4-nitro-1H-pyrazole-3-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 7536 - 7549

49
[ 57011-48-0 ]
[ 5334-40-7 ]
1,3-diazidopropan-2-yl 4-nitro-1H-pyrazole-3-carboxylate [ No CAS ]

Reference： [1]RSC Advances,2014,vol. 4,p. 39924 - 39933

50
[ 75-03-6 ]
[ 5334-40-7 ]
[ 1352200-79-3 ]
ethyl 1-ethyl-4-nitro-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20.7%; 34.4%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;	4-Nitro-1H-pyrazole-3-carboxylic acid (1) (300mg, 1.91mmol) was added to a stirred solution of ethyl iodide (324mul, 4.01mmol) and K2CO3 (660mg, 4.77mmol) in DMF (9ml). The reaction mixture was stirred at rt for 3h, and then the mixture was filtrated and concentrated. The residue was suspended in H2O and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give 3A (140mg, 0.656mmol, 34.4percent) as a pale brown oil and 3B (84mg, 0.395mmol, 20.7percent) as a pale brown oil. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give 3A (140 mg, 0.656 mmol, 34.4percent) as a pale brown oil and 3B (84 mg, 0.395 mmol, 20.7percent) as a pale brown oil. Compound 3A: 1H NMR (CDCl3) delta 8.16 (s, 1H), 4.47 (q, J = 7.2 Hz, 2H), 4.26 (q, J = 7.3 Hz, 2H), 1.57 (t, J = 7.3 Hz, 3H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3) delta 160.3, 138.8, 134.1, 129.1, 62.5, 48.9, 14.9, 14.0; HRMS (ESI) m/z: [M+Na]+ calcd for C8H11N3O4Na: 236.0642, found: 236.0643. Compound 3B: 1H NMR (CDCl3) delta 8.03 (s, 1H), 4.50 (q, J = 7.2 Hz, 2H), 4.31 (q, J = 7.3 Hz, 2H), 1.50 (t, J = 7.3 Hz, 3H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3) delta 158.6, 135.2, 134.4, 131.2, 63.4, 47.7, 15.3, 13.8; HRMS (ESI) m/z: [M+Na]+ calcd for C8H11N3O4Na: 236.0642, found: 236.0639.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 1776 - 1787

51
[ 2106-02-7 ]
[ 5334-40-7 ]
C₁₀H₆ClFN₄O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3024 - 3029

52
[ 67-56-1 ]
[ 5334-40-7 ]
[ 74-88-4 ]
[ 400877-57-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 1910 - 1918

53
[ 5334-40-7 ]
[ 65190-36-5 ]

Yield	Reaction Conditions	Operation in experiment
96%		Compound 3.1 (15.7 g, 99.95 mmol, 1.00 eq.) was placed into a 500-mL 3-necked round-bottom flask and then THF (250 mL) and oxalyl chloride (13.9 g, 109.51 mmol, 1.00 eq.) were added. The reaction was stirred for 0.5 h at 25 °C. Then the reaction was cooled in an ice bath and aqueous ammonium hydroxide (36 mL, 5.00 eq.) was added and the reaction was stirred for 3 hr at 25 °C. The resulting mixture was concentrated in vacuo. The crude material was washed with H20 to furnish 15 g (96 percent) of compound 3.2 as a white solid.

Reference： [1]Patent: WO2017/4133,2017,A1 .Location in patent: Paragraph 00323
[2]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 1910 - 1918

54
[ 1087782-00-0 ]
[ 5334-40-7 ]
5-(4-nitro-1H-pyrazole-3-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,2,4-oxadiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%		5-(4-Nitro-l/ -pyrazole-3-yl)-3-(4-(4-(trifluoromethyl)phenoxy)phenyl)-l,2,4-oxadiazole (63b). 4-Nitropyrazole-3-carboxylic acid (34, 0.24 g, 1.50 mmol) was dissolved in SOCI2 (2.2 mL, 30.548 mmol) and the solution was stirred at reflux for 2 h. The excess SOCI2 was evaporated to dryness in vacuo and the residue was taken up in toluene (15 mL) and pyridine (0.61 mL, 7.0 mmol), followed by the addition of (Z)-A^-hydroxy-4-(4-(trifluoromethyl)phenoxy)benzimidamide (6b, 0.30 g, 1.0 mmol). The resultant mixture was stirred at reflux overnight. The solvent was evaporated to dryness in vacuo and the residue was purified by silica-gel chromatography (CH2Cl2/MeOH, 100:1) to afford the title compound as a yellow powder (0.20 g, 48.0percent). mp 204-206 °C; FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDCb) delta 7.15-7.18 (m, 4H), 7.65 (d, J= 8.4 Hz, 2H), 8.18-8.20 (m, 2H), 8.55 (s, 1H); 13C NM (100 MHz, CDCU) delta 120.0, 120.5, 122.2, 123.5, 125.0, 125.3, 126.2, 128.3 (q, J = 3.5 Hz), 130.2, 133.1, 134.8, 159.2, 159.8, 168.4, 169.3; HRMS (ESI): calcd for CisHioFsNsNaC [M+Na]+ 440.0577, found 440.0579.

Reference： [1]Patent: WO2016/49586,2016,A2 .Location in patent: Page/Page column 44

55
[ 75-30-9 ]
[ 5334-40-7 ]
[ 923283-85-6 ]
[ 923283-86-7 ]

Yield	Reaction Conditions	Operation in experiment
35%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;	Step 1: Into a 100 mL round bottom flask containing a solution of methyl 4-nitro-1H-pyrazole- 3-carboxylate (5.0 g, 29 mmol) in dimethylformamide (50 mL) were added anhydrous potassium carbonate (8.0 g, 58 mmol) and 2-iodopropane (5.8 mL, 58 mmol) at 0 oC and the mixture was stirred at room temperature for 16 h. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified flash chromatography eluting with ethyl acetate in petroleum ether (10-20percent) to afford a mixture of regioisomers, methyl 1-isopropyl-4-nitro-1H-pyrazole-5-carboxylate (2.2 g, 35percent yield) as a colorless oil and methyl 1-isopropyl-<strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylate</strong> as an oil. For methyl 1- isopropyl-4-nitro-1H-pyrazole-5-carboxylate; 1H NMR (CD3OD, 400 MHz): delta 8.16 (s, 1H), 4.75-4.71 (m, 1H), 4.04 (s, 3H), 1.52 (d, J = 6.6 Hz, 6H). For methyl 1-isopropyl-4-nitro-1H- pyrazole-3-carboxylate; 1H NMR (CD3OD, 400 MHz): delta 8.68 (s, 1H), 4.66-4.59 (m, 1H), 3.95 (s, 3H), 1.55 (d, J = 6.7 Hz, 6H).

Reference： [1]Patent: WO2016/144847,2016,A1 .Location in patent: Page/Page column 34

56
[ 5334-40-7 ]
[ 74-88-4 ]
[ 400877-57-8 ]

Yield	Reaction Conditions	Operation in experiment
19%		4-Nitropyrazole-3-carboxylic acid (27.5 g, 175 mmol) was dissolved in N,N-dimethylformamide (800 mL) and K2CO3 (53.2 g, 385 mmol) was added at room temperature. The reaction was heated to 80°C and stirred for 3 hours. After cooling to room temperature, iodomethane (74.6 g, 525 mmol) was added and the reaction was allowed to react at room temperature for 15 hours. The reaction solution was diluted with water (2.5 L) and extracted with ethyl acetate (1 L x 2). The organic phases were combined, washed with saturated aqueous sodium chloride solution (800 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:1 petroleum ether / ethyl acetate, Rf1 = 0.5, Rf2 = 0.3) to give methyl 2-methyl-4-nitro-2H-pyrazole-3-carboxylate (6.00 g, as a yellow liquid) with a yield of 19percent, and methyl 1-methyl-4-nitro-pyrazole-3-carboxylate (11.0 g, as a white solid) with a yield of 34percent. 1H NMR: (400 MHz, CDCl3) delta 8.15(s, 1H), 4.01(s, 3H), 4.00(s, 3H). MS-ESI calcd. [M + H]+ 186, found 186.
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (1.00 g, 6.37 mmol) in DMF (20 mL) were added K2C03 (1.93 g, 14.01 mmol) and iodomethane (1.99 g, 14.01 mmol), and the mixture was stirred at rt overnight under nitrogen. Water (50 mL) was added and the mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether EtOAc (8: ito 1:2) to afford methyl 1- methyl-4-nitro- 1H-pyrazole-3-carboxylate.

Reference： [1]Patent: EP3299371,2018,A1 .Location in patent: Paragraph 0465; 0466; 0467
[2]Patent: WO2017/19804,2017,A2 .Location in patent: Paragraph 0358

57
[ 5334-40-7 ]
[ 75-65-0 ]
C₈H₁₂N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%		A stirred solution of S-83 (1.00 g, 6.36 mmol) in THF (10 mL) taken in a round- bottom flask was charged with Et3N (1.3 mL, 9.55 mmol) and DPPA (2.62 g, 9.55 mmol) at room temperature. The reaction mixture was stirred for 6 h at room temperature under nitrogen atmosphere. At this time, t-butanol (10 mL) was added and refluxed for 6 h under nitrogen atmosphere. When TLC showed complete consumption of starting material, the reaction mixture was diluted with the water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (10 mL). The organic layers were dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 0? 50percent EtOAc in hexanes as eluent to afford S-91 (0.20 g, 14percent, AMRI lot IN-SKY-C-110) as an off-white solid. The compound was characterized by UPLC analysis. MS-UPLC (MM) m/z 127.2 [M? ]-

Reference： [1]Patent: WO2017/106771,2017,A1 .Location in patent: Paragraph 00431

58
[ 5334-40-7 ]
[ 170911-92-9 ]
4-(4-(4-nitro-1H-pyrazole-3-carboxamido)phenyl)piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4.7 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;	To a 250 mL round bottom flask was added 5 g (18.1 mmol) of crude I-f,Nitro-lH-pyrazole-3-carboxylic acid (3.1 g, 19.9 mmol)EDC · HCl 4.1 g (21.7 mmol),HOBt 2.9 g (21.7 mmol) and anhydrous DMF 50 mL,Stir at room temperature for 24 hTLC detects the disappearance of the starting material (methanol: chloroform = 1:10).The reaction solution was poured into 200 mL of ice water,Precipitation of a large number of light yellow solid, standing,Consider the yellow solid,The crude product was recrystallized from a mixed solvent of ethyl acetate and methanol to give 4.7 g of (I-g)Yield 62.4%.
	With benzotriazol-1-ol; 1,2-dichloro-ethane; In N,N-dimethyl-formamide; for 24h;	General procedure: 4-Nitrobenzyl bromide (46.3mmol) was dissolved in dichloromethane (100mL). The solution was added to the mixture of relative amine (47.0mmol) and triethylamine (70.3mmol) in dichloromethane (20ml). The reaction mixture was stirred at r. t. for 24 h and was extracted with dichloromethane (100ml×3). After removal of the solvent, the residue was crystallized from ethanol, giving yellow powder. Compounds 1 and 2 were used for further reaction without purification. To a suspension of compounds 1-2 (36.2mmol) in 95% ethanol (100ml), 85% NH2NH2·H2O (362mmol), 95% ethanol (100ml) and iron (III) oxide hydroxide (FeO(OH)/C, 2.0g) were added and heated to reflux. When TLC analysis showed complete conversion of the starting material, the reaction mixture was filtrate through Cellit and the filtrate was concentrated in vacuum. The crude product was purified by silica gel colum chromatography (DCM/MeOH) to yield the title compound (3 and 4) as white solid. The mixture of compound 4 (1eq, 18.5mmol), 4-Nitro-1H-pyrazole-3-acid (1.1equiv, 20.4mmol), EDC (1.2equiv, 22.2mmol), HOBT (1.2equiv, 22.2mmol) in DMF (50ml) was stirred for 24h. The ice water (100ml) was added to the reaction mixture. A large amount of yellow solid precipitation (compound 8) was acquired. Compound 8 was used without further purification. Compounds 8 was reduced by the same process as compound 4, and then the resulting compound 12 was purified by column chromatography on silica gel, eluted with the appropriate solvent.
4.7 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;	In a 250 mL round bottom flask, 5 g of crude I-j (18.1 mmol) was added. <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> 3.1 g (19.9 mmol), EDC·HCl 4.1g (21.7mmol), HOBt 2.9g (21.7mmol) and anhydrous DMF 50mL, Stir at room temperature for 24 h. The disappearance of the starting material by TLC (methanol: chloroform = 1:10). The reaction solution was poured into 200 mL of ice water. A large amount of pale yellow solid is precipitated, Rest, Thinking about a yellow solid, The obtained crude product was recrystallized from ethyl acetate and methanol to give (I-k) 4.7 g. The yield was 62.4%.

Reference： [1]Patent: CN107245073,2017,A .Location in patent: Paragraph 0139; 0140; 0141
[2]European Journal of Medicinal Chemistry,2018,vol. 155,p. 303 - 315
[3]Patent: CN109970717,2019,A .Location in patent: Paragraph 0092; 0137-0139

59
[ 109-83-1 ]
[ 5334-40-7 ]
5-methyl-3-nitro-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With thionyl chloride; triethylamine; N,N-dimethyl-formamide; In toluene; at 15 - 70℃; for 30.1667h;	2-(methylamino)ethanol (2.00 g, 26.63 mmol) and <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (3.54 g, 22.52 mmol) in toluene (24.44 mL) were stirred at 15 °C. SOd2 (4.52 mL, 62.28 mmol) was slowly added followed by DMF (171.44 jiL, 2.21 mmol). The reaction mixturewas stirred at 55 °C for 10 minutes then 70 °C for 18 h. Solvents were evaporated. The residue was taken up into DMF (20.62 mL) and TEA (16.66 mL) was added slowly. The reaction mixture was stirred at rt for 12 h. Water was added and the mixture was extracted twice with EtOAc, dried over Mg504, filtered and evaporated. The crude residue was purified via silica gel chromatography (Stationary phase: irregular SiOH 15-40 jim, 80 g,mobile phase gradient: from 100percent DCM to 97percent DCM, 3percent MeOH (+ 10percent NH4OH)) to give 1.96 g of intermediate 14b (38percent yield).

Reference： [1]Patent: WO2018/2219,2018,A1 .Location in patent: Page/Page column 211

60
[ 5334-40-7 ]
[ 104-63-2 ]
C₁₃H₁₂N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%		N-Benzylthanolamine (2.147 mL, 1.06 g/mL, 15.052 mmol) and 4-nitro-1H-pyrazole-3- carboxylic acid (2 g, 12.732 mmol) in toluene (13.8 14 mL) were stirred at 15°C. SOC12 (2.554 mL, 1.64 g/mL, 35.206 mmol) was slowly added followed by DMF (96.907 jiL,0.944 g/mL, 1.252 mmol). The reaction mixture was stirred at 55°C for 10 minutes then70°C for 1 8h. The reaction was allowed to cool to room temperature and then the solvents were evaporated in vacuo. The residue was taken up into DMF (11.655 mL) and triethylamine (9.4 15 mL, 0.728 g/mL, 67.732 mmol) was added slowly. The reaction mixture was stirred at rt for 1 2h. Water was added. The mixture was extracted twice withEtOAc, dried over MgSO4, filtered and concentrated in vacuo to give 4.4g of crude material. A purification was performed via preparative LC (Stationary phase: irregular SiOH 15-40jim 120g Grace, Mobile phase: gradient from 100percent DCM to 97percent DCM, 3percent MeOH, 0.3percentNH4OH) to give 1.7g of intermediate 133b (41percent).

Reference： [1]Patent: WO2018/2219,2018,A1 .Location in patent: Page/Page column 303

61
[ 5334-40-7 ]
[ 304897-49-2 ]
C₂₀H₂₆N₆O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1499 - 1518

62
4-((4-methyl-1,4-diazepan-1-yl)methyl)aniline [ No CAS ]
[ 5334-40-7 ]
C₁₇H₂₂N₆O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1499 - 1518

63
[ 6406-73-1 ]
[ 5334-40-7 ]
C₁₅H₁₉N₅O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1499 - 1518

64
4-((cyclopropylamino)methyl)aniline [ No CAS ]
[ 5334-40-7 ]
C₁₄H₁₅N₅O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1499 - 1518

65
[ 109-01-3 ]
[ 5334-40-7 ]
C₉H₁₃N₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%		To a suspension of 4-nitro-3-pyrazole carboxylic acid (6 g, 38.196 mmol) and DMF (73.938 mu, 0.944 g/mL, 0.955 mmol) in DCM (48.93 mL) at 0 °C was added dropwise a solution of oxalyl chloride 2M in DCM (36 mL, 2 M, 72 mmol) and the reaction mixture was stirred at ambient temperature for 18h. The reaction mixture was concentrated in vacuo and the residue was dissolved in 20 mL of DCM and 1- methylpiperazine (6.355 mL, 0.903 g/mL, 57.294 mmol) was added slowly at 0°C. The reaction mixture was then allowed to warm to rt and stirred at rt overnight. DCM was removed in vacuo and the resulting slurry was diluted with DCM and a little MeOH. The insoluble residue was filtered off to give 5g (54 percent) of intermediate 582. (1737) The filtrate was concentrated in vacuo and purified by Normal phase flash (1738) chromatography (Irregular SiOH 40muiotaeta 40g GRACE). Mobile phase 98percent DCM, 2percent MeOH, 0.2percent NH4OH to 90percent DCM, 10percent MeOH, 1 percent NH4OH. The pure fractions were combined and the solvent was evaporated to give a further 2.7g (30 percent) of intermediate 582.

Reference： [1]Patent: WO2018/2217,2018,A1 .Location in patent: Page/Page column 328; 329

66
[ 77-78-1 ]
[ 5334-40-7 ]
[ 400877-57-8 ]

Yield	Reaction Conditions	Operation in experiment
30 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 14h;Cooling with ice;	A) Methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate To a suspension of 4-nitro-1H-pyrazole-3-carboxylic acid (62 g) and potassium carbonate (221 g) in DMF (700 mL), dimethyl sulfate (121 g) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured to water, followed by extraction with ethyl acetate. The extract was 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 (30 g). 1H NMR (400 MHz, CDCl3) delta 4.01 (3H, s), 4.03 (3H, s), 8.18 (1H, s).

Reference： [1]Patent: EP3287441,2018,A1 .Location in patent: Paragraph 0293

67
[ 77-78-1 ]
[ 5334-40-7 ]
[ 309740-49-6 ]

Yield	Reaction Conditions	Operation in experiment
8.62 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;Cooling with ice;	A) Methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate To a suspension of 4-nitro-1H-pyrazole-3-carboxylic acid (37 g) and potassium carbonate (97.6 g) in DMF (600 mL), dimethyl sulfate (71.2 g) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured to water, followed by extraction with ethyl acetate. The extract was 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 (8.62 g). 1H NMR (400 MHz, CDCl3) delta 4.02 (3H, s), 4.03 (3H, s), 8.01 (1H, s).

Reference： [1]Patent: EP3287441,2018,A1 .Location in patent: Paragraph 0305

68
[ 16153-81-4 ]
[ 5334-40-7 ]
C₁₅H₁₈N₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1,2-dichloro-ethane; In N,N-dimethyl-formamide; for 24h;	General procedure: 4-Nitrobenzyl bromide (46.3mmol) was dissolved in dichloromethane (100mL). The solution was added to the mixture of relative amine (47.0mmol) and triethylamine (70.3mmol) in dichloromethane (20ml). The reaction mixture was stirred at r. t. for 24 h and was extracted with dichloromethane (100ml×3). After removal of the solvent, the residue was crystallized from ethanol, giving yellow powder. Compounds 1 and 2 were used for further reaction without purification. To a suspension of compounds 1?2 (36.2mmol) in 95percent ethanol (100ml), 85percent NH2NH2·H2O (362mmol), 95percent ethanol (100ml) and iron (III) oxide hydroxide (FeO(OH)/C, 2.0g) were added and heated to reflux. When TLC analysis showed complete conversion of the starting material, the reaction mixture was filtrate through Cellit and the filtrate was concentrated in vacuum. The crude product was purified by silica gel colum chromatography (DCM/MeOH) to yield the title compound (3 and 4) as white solid. The mixture of compound 4 (1eq, 18.5mmol), 4-Nitro-1H-pyrazole-3-acid (1.1equiv, 20.4mmol), EDC (1.2equiv, 22.2mmol), HOBT (1.2equiv, 22.2mmol) in DMF (50ml) was stirred for 24h. The ice water (100ml) was added to the reaction mixture. A large amount of yellow solid precipitation (compound 8) was acquired. Compound 8 was used without further purification. Compounds 8 was reduced by the same process as compound 4, and then the resulting compound 12 was purified by column chromatography on silica gel, eluted with the appropriate solvent.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 155,p. 303 - 315

69
[ 2524-67-6 ]
[ 5334-40-7 ]
C₁₄H₁₅N₅O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1,2-dichloro-ethane; In N,N-dimethyl-formamide; for 24h;	General procedure: 4-Nitrobenzyl bromide (46.3mmol) was dissolved in dichloromethane (100mL). The solution was added to the mixture of relative amine (47.0mmol) and triethylamine (70.3mmol) in dichloromethane (20ml). The reaction mixture was stirred at r. t. for 24 h and was extracted with dichloromethane (100ml×3). After removal of the solvent, the residue was crystallized from ethanol, giving yellow powder. Compounds 1 and 2 were used for further reaction without purification. To a suspension of compounds 1?2 (36.2mmol) in 95percent ethanol (100ml), 85percent NH2NH2·H2O (362mmol), 95percent ethanol (100ml) and iron (III) oxide hydroxide (FeO(OH)/C, 2.0g) were added and heated to reflux. When TLC analysis showed complete conversion of the starting material, the reaction mixture was filtrate through Cellit and the filtrate was concentrated in vacuum. The crude product was purified by silica gel colum chromatography (DCM/MeOH) to yield the title compound (3 and 4) as white solid. The mixture of compound 4 (1eq, 18.5mmol), 4-Nitro-1H-pyrazole-3-acid (1.1equiv, 20.4mmol), EDC (1.2equiv, 22.2mmol), HOBT (1.2equiv, 22.2mmol) in DMF (50ml) was stirred for 24h. The ice water (100ml) was added to the reaction mixture. A large amount of yellow solid precipitation (compound 8) was acquired. Compound 8 was used without further purification. Compounds 8 was reduced by the same process as compound 4, and then the resulting compound 12 was purified by column chromatography on silica gel, eluted with the appropriate solvent.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 155,p. 303 - 315

70
copper(II) choride dihydrate [ No CAS ]
[ 5334-40-7 ]
Cu(4-nitro-3-pyrazolecarboxylic acid(-H))₂*8H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; for 48h;	Complex CuL28H2O was synthesized in the reaction on the warm ethanolic solutions of CuCl22H2O and <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> ligand (L) mixed in molar ratio 1:2. After 2 days, the microcrystalline product was filtered off and washed with ethanol.

Reference： [1]Journal of Thermal Analysis and Calorimetry,2018,vol. 133,p. 813 - 821

71
[ 373-02-4 ]
[ 5334-40-7 ]
Ni(4-nitro-3-pyrazolecarboxylic acid(-H))₂*4H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; for 6h;	Complex NiL2*4H2O was synthesized in the reaction on the warm ethanolic solutions of Ni(CH3COO)2 and <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> ligand (L) mixed in molar ratio 1:2. After 6 h, the microcrystalline product was filtered off and washed with ethanol.

Reference： [1]Journal of Thermal Analysis and Calorimetry,2018,vol. 133,p. 813 - 821

72
cobalt(II) chloride hexahydrate [ No CAS ]
[ 5334-40-7 ]
Co(4-nitro-3-pyrazolecarboxylic acid(-H))₂*H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; for 8h;	Complex CoL2H2O was synthesized in the reaction on the warm ethanolic solutions of CoCl26H2O and <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> ligand (L) mixed in molar ratio 1:2. After 8 h, the microcrystal product was filtered off and washed with ethanol.

Reference： [1]Journal of Thermal Analysis and Calorimetry,2018,vol. 133,p. 813 - 821

73
[ 557-34-6 ]
[ 5334-40-7 ]
Zn(4-nitro-3-pyrazolecarboxylic acid(-H))₂*1.5H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; for 24h;	Complex ZnL2*1.5H2O was synthesized in the reaction on the warm ethanolic solutions of Zn(CH3COO)2 and <strong>[5334-40-7]4-nitro-3-pyrazolecarboxylic acid</strong> ligand (L) mixed in molar ratio 1:2. After 1 day, the microcrystal product was filtered off and washed with ethanol.

Reference： [1]Journal of Thermal Analysis and Calorimetry,2018,vol. 133,p. 813 - 821

74
[ 6638-79-5 ]
[ 5334-40-7 ]
N-methoxy-N-methyl-4-nitro-1H-pyrazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
926 mg	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0.1 - 0.35℃; for 14h;	To a mixture of <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (1.02 g), N,O-dimethylhydroxylamine hydrochloride (689 mg), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (3.39 g) and DMF (10 mL) was added N,N-diisopropylethylamine (2.80 mL). After being stirred at room temperature for 14 hr, the mixture was poured into aqueous saturated ammonium chloride and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane and NH, MeOH) to give the title compound (926 mg). MS m/z 201.1 [M+1]+.

Reference： [1]Patent: US2018/280389,2018,A1 .Location in patent: Paragraph 3468; 3819; 3820

75
[ 5334-40-7 ]
C₄H₃N₃O₄*H₃N [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With zinc diacetate; ammonium thiocyanate; In ethanol;	Single crystals of NH4Lwere obtained from the ethanolic solution of Zn(OAc)2(0.25 mmol) and <strong>[5334-40-7]4-nitropyrazole-3-carboxylic acid</strong> (0.5 mmol)in the presence of NH4SCN (0.5 mmol).

Reference： [1]Acta Crystallographica Section C: Structural Chemistry,2019,vol. 75,p. 255 - 264

76
copper(II) nitrate [ No CAS ]
[ 5334-40-7 ]
bis(μ-4-nitro-1H-imidazol-1-ide-5-carboxylato)-κ³N¹,O:N²;κ³N²:N¹,O-bis[aqua(dimethylformamide-κO)copper(II)] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.3%	In N,N-dimethyl-formamide; at 20℃; under 760.051 Torr; for 240h;Heating;	warm dimethylformamide(DMF) solution (5 ml) of <strong>[5334-40-7]4-nitropyrazole-3-carboxylic acid</strong> (0.5 mmol) and a warm DMF solution (6 ml) of Cu(NO3)2(0.25 mmol) were mixed in a 2:1 ratio. The resulting solutionwas allowed to concentrate under ambient conditions for 10 d.Blue single crystals of (II) were filtered off and washed withDMF (yield 32.3%).

Reference： [1]Acta Crystallographica Section C: Structural Chemistry,2019,vol. 75,p. 255 - 264

77
cobalt(II) chloride hexahydrate [ No CAS ]
[ 5334-40-7 ]
bis(μ-4-nitro-1H-imidazol-1-ide-5-carboxylato)-κ²N¹,O:N²;κ²N²:N¹,O-bis[triaquacobalt(II)] dihydrate [ No CAS ]

Reference： [1]Acta Crystallographica Section C: Structural Chemistry,2019,vol. 75,p. 255 - 264

78
4-(((4aR,7aR)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)methyl)benzene-1,2-diamine [ No CAS ]
[ 5334-40-7 ]
(4aR,7aR)-6-((2-(4-nitro-1H-pyrazol-3-yl)-1H-benzo[d]imidazol-5-yl)methyl)hexahydro-2H-[1,4] dioxino[2,3-c]pyrrole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃;	4-Nitro-1H-pyrrole-3-carboxylic acid (0.65 g, 4.12 mmol), EDCI (0.87 g, 4.53 mmol) and HOBt (0.61 g, 4, 53 mmol) were added to the reaction mixture.Stir at room temperature overnight.The solvent was removed under reduced pressure and ethyl acetate (20 mL) was evaporated. The solvent was removed under reduced pressure and purified by column to afford product (1.10 g, 54percent).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃;	4-Nitro-1H-pyrrole-3-carboxylic acid (0.65 g, 4.12 mmol), EDCI (0.87 g, 4.53 mmol) and HOBt (0.61 g, 4.53 mmol) were added to the reaction mixture.Stir at room temperature overnight. The solvent was removed under reduced pressure.AcOH (20 mL) was added to the residue, and the mixture was refluxed for 3 hr.The solvent was removed under reduced pressure and purified by column (dichloromethane/methanol (v/v) = 10/1).The product was obtained (2.10g, >100percent).

Reference： [1]Patent: CN104447701,2019,B .Location in patent: Paragraph 0426-0428; 0439-0441
[2]Patent: CN104211692,2019,B .Location in patent: Paragraph 0668; 0693-0695

79
4-(octahydrocyclopentane[c]pyrrolylmethyl)-phenyl-1,2-diamine [ No CAS ]
[ 5334-40-7 ]
4-((2-(4-nitro-1H-pyrazol-3-yl)-1H-benzo[d]imidazol-5-yl)methyl)octahydrocyclopentane[c]pyrrole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23.94%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	4-(octahydrocyclopentane[c]pyrrolylmethyl)-phenyl-1,2-diamine (4.0 g, 17.32 mmol), <strong>[5334-40-7]4-nitro-1H-pyrazole-3-carboxylic acid</strong> (2.47 g) , 17.32mmol), EDC · HCl (4.98g, 19.05mmol) and HOBt (3.4g, 19.05mmol) was dissolved in dry DMF (25mL) are stirred at room temperature overnight. The solvent was removed under reduced pressure, was added glacial acetic acid (40 mL), heated to reflux for 3h, the solvent was removed under reduced pressure, purified through the column, and then washed with methanol, methanol-insoluble product as a yellow solid that is, to give a yellow solid (0.90 g, 23.94percent).

Reference： [1]Patent: CN104447701,2019,B .Location in patent: Paragraph 0508-0510; 0520-0522

80
C₁₂H₁₇N₃O [ No CAS ]
[ 5334-40-7 ]
C₁₆H₁₆N₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	4-(2-oxa-5-heterobicyclo[2.2.1]-heptan-5-ylmethyl)phenyl-1,2-diamine(0.85g, 3.88mmol), 4-nitro-1H-pyrrole-3-carboxylic acid (0.58g, 3.69mmol), EDCl (0.78g, 4.06mmol) and HOBt (0.55g, 4.06mmol)DMF (10 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure.AcOH (16 mL) was added to the residue and heated to reflux for 3.5 hr.The solvent was removed under reduced pressure and purified by column (dichloromethane/methanol (v/v) = 10/1).A yellow solid (0.79 g, 63percent) was obtained.

Reference： [1]Patent: CN104211692,2019,B .Location in patent: Paragraph 0572; 0600-0602

81
4-(2-thia-5-azabicyclo[2.2.1]heptane-5-ylmethyl)benzene-1,2-diamine [ No CAS ]
[ 5334-40-7 ]
C₁₆H₁₆N₆O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;	4-(2-Thio-5-azabicyclo[2.2.1]heptane-5-ylmethyl)benzene-1,2-diamine (0.7 g, 3 mmol), 4-nitro-1 hydrogen -pyrazole-3-carboxylic acid (0.47 g, 3 mmol)Dissolved in DMF (15 mL) followed by EDCI (0.63 g, 3.3 mmol)HOBt (0.45 g, 3.3 mmol) was stirred at room temperature for 24 hours.The solvent was removed under reduced pressure, and acetic acid (20 mL) was evaporated.After completion of the reaction, concentration and purification by column (dichloromethane/methanol (v/v) = 10/1),The product was obtained (0.5 g, 50percent).

Reference： [1]Patent: CN104211692,2019,B .Location in patent: Paragraph 0612; 0637-0639

82
2-amino-4-(morpholinomethyl)phenol [ No CAS ]
[ 5334-40-7 ]
N-(2-hydroxy-5-(morpholinomethyl)phenyl)-4-nitro-1H-pyrazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	The compound 2-amino-4-(morpholinomethyl)phenol (2.54 g, 16 mmol) was dissolved.In DMF (15mL),Add 4-nitro-1 hydrogen-pyrazole-3-carboxylic acid (3.4 g, 16 mmol)With HATU (7.4 g, 19.6 mmol), react at room temperature overnight.After the reaction was completed, the solvent was evaporated and ethyl acetate (3×50 mL).Washed with water (2 × 50 mL), dried over anhydrous sodium sulfate (10 g),Dry to give the crude product (1.5 g), which was used directly to the next step.

Reference： [1]Patent: CN104211692,2019,B .Location in patent: Paragraph 0647; 0658; 0659

83
4-((tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrole-6(3H)-yl)methyl)benzene-1,2-diamine [ No CAS ]
[ 5334-40-7 ]
6-((2-(4-nitro-1H-pyrazol-3-yl)-1H-benzo[d]imidazol-5-yl)methyl)hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	4-((tetrahydro-2H-[1,4]dioxo[2,3-c]pyrrole-6(3H)-yl)methyl)benzene-1,2-diamine (2.19 g,8.78 mmol), 4-nitro-1H-pyrrole-3-carboxylic acid (1.24 g, 7.91 mmol), EDCl (1.68 g, 8.78 mmol) and HOBt (1.19 g, 8.78 mmol)It was stirred at room temperature overnight in DMF (22 mL). The solvent was removed under reduced pressure.AcOH (35 mL) was added to the residue and heated to reflux for 3.5 hr.The solvent was removed under reduced pressure and purified by column chromatography (dichloromethane/methanol (v/v) = 10/1).The product was obtained (1.65 g, 51percent).

Reference： [1]Patent: CN104211692,2019,B .Location in patent: Paragraph 0545; 0559-0561

84
[ 51207-86-4 ]
[ 5334-40-7 ]
N-(4-(morpholine-4-carbonyl)phenyl)-4-nitro-1H-pyrazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.6 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;	In a 250 mL round bottom flask, 7.0 g (36.6 mmol) of crude I-n was added. 4-nitro-1H-pyrazole-3-carboxylic acid 6.3 g (40.1 mmol), EDC·HCl 8.4 g (44.0 mmol), HOBt 6.0g (44.4mmol) and anhydrous DMF 100mL, Stir at room temperature for 24 h. The disappearance of the starting material by TLC (methanol: chloroform = 1:10). The reaction solution was poured into 200 mL of ice water, and a large amount of pale yellow solid was precipitated and allowed to stand. Thinking about a yellow solid, The obtained crude product was recrystallized from ethyl acetate and methanol to give (I-o) 8.6 g. The yield was 72.0%.

Reference： [1]Patent: CN109970717,2019,A .Location in patent: Paragraph 0149-0151

85
[ 55121-99-8 ]
[ 5334-40-7 ]
C₁₆H₁₈N₆O₄ [ No CAS ]

Reference： [1]International Journal of Molecular Sciences,2019,vol. 20

86
[ 5334-40-7 ]
[ 116008-52-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With iron(III) chloride hexahydrate; pyrographite; hydrazine hydrate; In water; for 30.0h;Reflux;	General procedure: Reduction of the nitrogroup was carried out according to a published method.21The corresponding nitro acid 1, 3 (0.032 mol) wassuspended in H2O (30 ml). Activated carbon (0.8 g),N2H4·H2O (95%, rho 1.023 g/cm3) (6.55 ml, 6.71 g, 0.134 mol),and FeCl3·6H2O (64 mg) were added to the suspension withstirring. The reaction mixture was heated under reflux for30 h. The hot solution was filtered, the filtrate wasevaporated to dryness under reduced pressure. Theresulting dry residue was dissolved in H2O (20 ml) andcarefully acidified with 2 M aqueous HCl to pH 4-5. Theformed precipitate was filtered off and washed with a smallamount of H2O. The product was dried in a vacuumdesiccator over P2O5 to constant weight.

Reference： [1]Chemistry of Heterocyclic Compounds,2020,vol. 56,p. 180 - 191

87
[ 6232-11-7 ]
[ 5334-40-7 ]
methyl 4-((4-nitro-1H-pyrazole-3-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h;	4.1.1. Methyl 4-((4-nitro-1H-pyrazole-3-carboxamido)methyl)benzoate (4) 4-nitro-1H-pyrazole-3-carboxylic acid (3.18 mmol, 1.1equiv),methyl 4-(aminomethyl)benzoate hydrochloride (2.89 mmol,1equiv), EDCI (3.47 mmol, 1.2equiv), HOBt (3.47 mmol, 1.2equiv),DIEA (6.94 mmol, 2.4equiv) were mixed in DMF (20 mL). The reactionwasstirred for 12 h at room temperature. TLC analysis, usingpetroleum ether: ethyl acetate (1:2) as the eluent, indicated thecomplete reaction. The mixture was diluted with a large amount ofwater and then extracted with ethyl acetate. The organic layer wascollected and dried by anhydrous sodium sulfate. The solvent wasconcentrated to obtain 4 as a light purple solid. 1H NMR (400 MHz DMSO-d6): d 7.91(3H, m), 7.50(2H, m), 4.50(2H, s), 3.84(3H, s);HRMS (ESI) (M H) Calc’d for C13H12N4O5: 305.0887Found:305.0884.

Reference： [1]Cheng, Chunhui; Ullah, Sadeeq; Yuan, Qipeng; Yun, Fan [European Journal of Medicinal Chemistry, 2020, vol. 189]

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H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 5334-40-7 ] {[proInfo.proName]}

Quality Control of [ 5334-40-7 ]

Related Doc. of [ 5334-40-7 ]

Product Details of [ 5334-40-7 ]

Calculated chemistry of [ 5334-40-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 5334-40-7 ]

Application In Synthesis of [ 5334-40-7 ]

[ 5334-40-7 ] Synthesis Path-Upstream 1~13

[ 5334-40-7 ] Synthesis Path-Downstream 1~87

Related Functional Groups of [ 5334-40-7 ]

Carboxylic Acids

Nitroes

Related Parent Nucleus of [ 5334-40-7 ]

Pyrazoles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 5334-40-7 ]

Related Parent Nucleus of
[ 5334-40-7 ]