Name: 2075-46-9 | 4-Nitropyrazole
Brand: Ambeed
SKU: A191546
Rating: 4.3 (59 reviews)

1
[ 7119-95-1 ]
[ 2075-46-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at -10 - 20℃;	4-Nitro-lJH-pyrazoIe=N; [547] [Ref: Huettel, R. and Buechele, F., Chem. Ber. 1955, 88, 1586-1590] 1-Nitro-l/Z'-pyrazole (2.2g, 0.019 mol) was dissolved in sulfuric acid (lOmL) at-10°C, and theresulting mixture was slowly warmed to rt overnight. The solution was added to ice (lOOg)dropwise, and the resulting white solid was collected by filtration and washed with water.The aqueous phase was extracted with EtOAc (3x30mL), the combined organic phases werewashed with brine (2x30mL), and dried over anhydrous sodium sulfate. Evaporation underreduced pressure provided an off-white solid, which was combined with the first solid anddried in vacua to provide the title compound. LC-MS (ES, Pos.): 1 14 [MH+]. 'H NMR(DMSO-d6, 400 MHz): 8 = 8.27 (s, 1H), 8.90 (s, 1H), 13.96 (br s, 1H).
		Concentrated sulphuric acid (80 ml) was added dropwise to a stirred sample of <strong>[7119-95-1]<strong>[7119-95-1]1-nitropyrazol</strong>e</strong> (20.3 g) that was cooled in an ice-bath. The resultant mixture was stirred for20 16 hours and allowed to warm to ambient temperature. The mixture was poured onto ice and stirred for 20 minutes. The resultant solid was isolated and washed with water. The filtrate was neutralised by the addition of potassium carbonate and extracted with diethyl ether. The recovered solid was added to the diethyl ether solution and the resultant solution was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered.25 Petroleum ether (b.p. 60-80°C) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. There was thus obtained 4-<strong>[7119-95-1]nitropyrazole</strong> (16 g); 1HNMR: (DMSOd6 + CF3CO2H) 8.57 (s, 2H).
	With sulfuric acid; at 0℃; for 16h;	Concentrated sulphuric acid (80 ml) was added dropwise to a stirred sample of <strong>[7119-95-1]<strong>[7119-95-1]1-nitropyrazol</strong>e</strong> (20.3 g) that was cooled in an ice-bath. The resultant mixture was stirred for 16 hours and allowed to warm to ambient temperature. The mixture was poured onto ice and 0 stirred for 20 minutes. The resultant solid was isolated and washed with water. The filtrate was neutralised by the addition of potassium carbonate and extracted with diethyl ether. The <n="105"/>recovered solid was added to the diethyl ether solution and the resultant solution was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered.Petroleum ether (b.p. 60-80°C) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. There was thus obtained 4-<strong>[7119-95-1]nitropyrazole</strong> (16 g); 1HNMR: (DMSOd6 + CF3CO2H) 8.57 (s,2H).

	With sulfuric acid; at 0 - 25℃; for 16h;	Concentrated sulphuric acid (80 ml) was added dropwise to a stirred sample of <strong>[7119-95-1]<strong>[7119-95-1]1-nitropyrazol</strong>e</strong> (20.3 g) that was cooled in an ice-bath. The resultant mixture was stirred for 16 hours and allowed to warm to ambient temperature. The mixture was poured onto ice and stirred for 20 minutes. The resultant solid was isolated and washed with water. The filtrate was neutralised by the addition of potassium carbonate and extracted with diethyl ether. The recovered solid was added to the diethyl ether solution and the resultant solution was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered. Petroleum ether (b.p. 60-800C) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. There was thus obtained 4-<strong>[7119-95-1]nitropyrazole</strong> (16 g); 1H NMR: (DMSOd6 + CF3CO2H) 8.57 (s, 2H).
		Concentrated sulphuric acid (80 ml) was added dropwise to a stirred sample of <strong>[7119-95-1]<strong>[7119-95-1]1-nitropyrazol</strong>e</strong> (20.3 g) that was cooled in an ice-bath. The resultant mixture was stirred for 16 hours and allowed to warm to ambient temperature. The mixture was poured onto ice and stirred for 20 minutes. The resultant solid was isolated and washed with water. The filtrate was neutralised by the addition of potassium carbonate and extracted with diethyl ether. The recovered solid was added to the diethyl ether solution and the resultant solution was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered. Petroleum ether (b.p. 60-80°C) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. <n="96"/>There was thus obtained 4-<strong>[7119-95-1]nitropyrazole</strong> (16 g); 1H NMR: (DMSOd6 + CF3CO2H) 8.57 (s, 2H).
		Concentrated sulphuric acid (80 ml) was added dropwise to a stirred sample of <strong>[7119-95-1]<strong>[7119-95-1]1-nitropyrazol</strong>e</strong> (20.3 g) that was cooled in an ice-bath. The resultant mixture was stirred for 16 hours and allowed to warm to ambient temperature. The mixture was poured onto ice and stirred for 20 minutes. The resultant solid was isolated and washed with water. The filtrate was neutralised by the addition of potassium carbonate and extracted with diethyl ether. The recovered solid was added to the diethyl ether solution and the resultant solution was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered. Petroleum ether (b.p. 60-80° C.) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. There was thus obtained 4-<strong>[7119-95-1]nitropyrazole</strong> (16 g); 1H NMR: (DMSOd6+CF3CO2H) 8.57 (s, 2H).
0.97 g	With sulfuric acid; at 25℃;	1-Nitropyrazole (1 g) was slowly added to a round-bottomed flask containing H2SO4 (98percent, 5 mL) and stirred for 20 h at room temperature. The reaction mixture was slowly transferred to a beaker containing ice with stirring. The solution was extracted with ether. The organic layer was dried with Na2SO4 then evaporated to afford 4-<strong>[7119-95-1]nitropyrazole</strong> as a colorless solid (0.97 g, 96percent). The solid was recrystallized from ether/hexane to get white crystalline compound. m.p. 163?165 °C; FT-IR (KBr, cm?1) 3186 (N?H), 1526 and 1353 cm?1 (NO2). 1H NMR (DMSO-d6) delta: 8.26 (d, 1, 5-H), 6.76 (d, 1, 3-H). EI-MS: m/z 113 (M+·). Anal. Calcd for C3H3N3O2: C, 27.54; H, 3.88; N, 32.42. Found: C, 28.31; H, 3.21; N, 31.38.
		The compound may be explosive and should be handled cautiously.Concentrated sulphuric acid (80 ml) was added dropwise to a stirred sample of <strong>[7119-95-1]<strong>[7119-95-1]1-nitropyrazol</strong>e</strong> (20.3 g) that was cooled in an ice-bath. The resultant mixture was stirred for 16 hours and allowed to warm to ambient temperature. The mixture was poured onto ice and stirred for 20 minutes. The resultant solid was isolated and washed with water. The filtrate was neutralised by the addition of potassium carbonate and extracted with diethyl ether. The recovered solid was added to the diethyl ether solution and the resultant solution was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered. Petroleum ether (b.p. 60-80°C) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. There was thus obtained 4-<strong>[7119-95-1]nitropyrazole</strong> (16 g); 1H NMR Spectrum: (DMSOd6 + CF3CO2H) 8.57 (s, 2H).
		Concentrated sulphuric acid (80 ml) was added dropwise to a stirred sample of <strong>[7119-95-1]<strong>[7119-95-1]1-nitropyrazol</strong>e</strong> (20.3 g) that was cooled in an ice-bath. The resultant mixture was stirred for <n="95"/>16 hours and allowed to warm to ambient temperature. The mixture was poured onto ice and stirred for 20 minutes. The resultant solid was isolated and washed with water. The filtrate was neutralised by the addition of potassium carbonate and extracted with diethyl ether. The recovered solid was added to the diethyl ether solution and the resultant solution was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered. Petroleum ether (b.p. 60-80°C) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. There was thus obtained 4-<strong>[7119-95-1]nitropyrazole</strong> (16 g); 1H NMR Spectrum: (DMSOd6 + CF3CO2H) 8.57 (s, 2H).

References: [1]Chemische Berichte,1955,vol. 88,p. 1586,1590.
[2]Patent: WO2006/17443,2006,A2 .Location in patent: Page/Page column 126.
[3]Patent: WO2006/40520,2006,A1 .Location in patent: Page/Page column 122.
[4]Patent: WO2007/99326,2007,A1 .Location in patent: Page/Page column 103-104.
[5]Patent: WO2007/99317,2007,A1 .Location in patent: Page/Page column 101.
[6]Patent: WO2007/99335,2007,A1 .Location in patent: Page/Page column 94-95.
[7]Patent: US2009/76075,2009,A1 .Location in patent: Page/Page column 36.
[8]Journal of Molecular Structure,2013,vol. 1043,p. 121 - 131.
[9]Patent: WO2007/113548,2007,A1 .Location in patent: Page/Page column 142.
[10]Patent: WO2007/113565,2007,A1 .Location in patent: Page/Page column 93-94.

2
[ 2075-46-9 ]
[ 28466-26-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium 10% on activated carbon; hydrogen; In methanol; at 25℃; under 760.051 Torr; for 12h;	Under hydrogen (1 atm), to a solution of 4-nitropyrazole (1.13 g, 10 mmol) in methanol (10 mL) was added 10% Pd-C (0.1 g). The mixture was stirred at 25 C. for 12 hours, and then filtrated, the filtrate was concentrated under reduced pressure to give compound 31-a (860 mg, yield: 100%), which was used directly for the next step without purification.
100%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃;	5.0g 4-nitropyrazole was dissolved in 160mL of ethanol and 0.8g of 10% Pd/C was added. The reaction was subjected to hydrogen and reacted overnight at room temperature. TLC was used to monitor reaction completion. By celite was filtered off Pd/C. Ethanol solvent was evaporated to give 3.6g of the pure intermediate 8 as a red solid, quantitative reaction.
99%	With palladium 10% on activated carbon; hydrogen; In methanol; for 16h;	A suspension of 4-nitro-1H-pyrazole (2.05 g, 18.13 mmol), and Pd/C (10% w/w palladium on activated carbon, 0.96 g, 0.90 mmol) in MeOH (20 mL) was stirred under H2 atmosphere (balloon) for 16 h. The reaction mixture was filtered through Celite, rinsed with MeOH (3x 30 mL) and concentrated, affording 1.50 g of 1H-pyrazol-4- amine (pale pink solid, 99% yield). HPLC-MS (Method H): Ret, 1.16 min; ESI+-MS m/z: 84 (M+1).

95%	With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 2068.65 Torr; for 3h;	Compound Ia (15.0 g, 133 mmol) was added to a suspension of palladium on carbon 10% (7.0 g, 6.65 mmol) in ethanol (100 mL). The mixture was shaken for 3 hours under hydrogen pressure (40 psi) at room temperature. The catalyst was removed by filtration through a pad of Celite and the solvent was evaporated. Compound Ib was obtained as a burgundy oil (10.5 g, 126 mmol, 95%) which was used in the following step without purification; GC/MS: m/z = 83 (100%).
49%	With hydrogen;1% Pd/C; In ethanol; under 1034.32 - 1551.49 Torr;	A mixture of 4-nitro-l/f-pyrazole (1.13 g, 10 mmol), Pd/C (10%, 57 mg) in ethanol (20 mL) was hydrogenated at 20-30 psi on a parr apparatu overnight. The reaction mixture was filtered through celite, washed with ethanol (10 mL). The filtrate was concentrated to get desired compound 0113-42 (404 mg, 49%) as a brown solid. LC-MS: 84 [M+l]+; 1H-NMR (400 MHz, DMSO-d6) delta 3.11 (br s, 2H), 6.99 (s, 2H), 11.92 (s, IH).
	palladium; In ethanol;	4-aminopyrazole (10) The 4-nitropyrazole (9) (15.0 g, 133 mmol) was added to a suspension of palladium on carbon 10% (7.0 g, 6.65 mmol, 5% mmol) in ethanol (100 ml). The mixture was shaken for 3 hours under hydrogen pressure (40 psi) at room temperature. The end of reaction checked by TLC (Ethylacetate/Hexane 1/1, 4-nitropyrazole Rf=0.6, UV active, 4-aminopyrazole Rf 0.1, UV active). The catalyst was removed by filtration through a pad of Celite and the solvent was evaporated. The product (10) was obtained as a burgundy oil (10.5 g, 126 mmol, 95%), which was used in the following step without purification. GC/MS: m/z=83 (100%).
	With hydrogen;platinum(IV) oxide; In ethanol; ethyl acetate; under 2280.15 Torr; for 2h;	The 4-amino-l/i-pyrazole used as a starting material was prepared as follows :-A mixture of 4-nitro-l/J-pyrazole (0.7 g), platinum oxide (0.05 g), ethyl acetate (5 ml) <n="110"/>and ethanol (15 ml) was stirred under 3 atmospheres pressure of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. There was thus obtained the required starting material (0.5 g).
	With iron; ammonium chloride; In ethanol; water; at 80℃; for 2h;	Step2:[00394] To a stirred mixture of iron (1.68g, 30 mmol), ammonium chloride (540mg, 10 mmol), water (2ml_) and ethanol (8ml_) at 800C was added 4-nitro-1 H-pyrazol (1 .13g, lOmmol) in portions. After completion of addition, the mixture was stirred at 800C for additional 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, and the resultant mixture was filtered through a pad of celite. The filtrate was concentrated to afford the crude title compound which was used at next step without further purification. MS (ES) [M+H]+ expected 84.0, found 84.0.
	With hydrogen;palladium 10% on activated carbon; In ethanol; under 760.051 Torr; for 22h;	Intermediate (1e), 4-nitro-1 H-pyrazole (2.8g, 24.8mmol), was stirred in ethanol (20OmL) and the flask was evacuated and then flushed with nitrogen. Palladium, 10wt. % on activated carbon (300mg, catalytic amount) was added and after two vacuum / H2 cycles to replace the nitrogen inside with hydrogen, the mixture was shaken for 18 hours under ordinary hydrogen pressure (1atm). Palladium, 10wt. % on activated carbon (300mg) was added and after two vacuum / H2 cycles to replace the nitrogen inside with hydrogen, the mixture was shaken for a further 4 hours. The reaction mixture was filtered through celite and the filter cake was washed through with ethanol (2x50ml_). The combined washings and the filtrate were concentrated in vacuo. The residue obtained was triturated with ethyl acetate to yield a light pink solid, 1.48g, 72%. The filtrate subsequently obtained was concentrated in vacuo to yield another batch of sufficiently pure material, 0.54g, 26%, as a dark pink solid.
		4-Nitro-1 /-/-pyrazole (Manchester organics; 1.13 g, 9.99 mmol) was dissolved in ethanol (50 ml). This solution was added carefully to 10% palladium on carbon (Aldrich; 102 mg) under a nitrogen atmosphere. The atmosphere was exchanged to hydrogen, and the mixture was stirred vigorously at room temperature under a hydrogen atmosphere. After 45 min, ca. 700 ml of hydrogen had been taken up, and no further hydrogen was taken up over the next 30 min. Stirring was stopped and the atmosphere was exchanged to nitrogen. The solution was filtered through cellite (10 g cartridge) and washed with further ethanol (150 ml). Relevant fractions (as verified by TLC) were combined and concentrated in vacuo to give a red oil. Trituration with DCM gave the title compound (815 mg) as a red solid; 1 H NMR (MeOH-d4, 400 MHz) delta (ppm) 7.20 (2 H, s).
	With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 1.25h;Inert atmosphere;	Intermediate 5: 1 H-Pyrazol-4-amine. 4-Nitro-1H-pyrazole (Manchester organics; 1.13 g, 9.99 mmol) was dissolved in ethanol (50 ml). This solution was added carefully to 10% palladium on carbon (Aldrich; 102 mg) under a nitrogen atmosphere. The atmosphere was exchanged to hydrogen, and the mixture was stirred vigorously at room temperature under a hydrogen atmosphere. After 45 min, ca. 700 ml of hydrogen had been taken up, and no further hydrogen was taken up over the next 30 min. Stirring was stopped and the atmosphere was exchanged to nitrogen. The solution was filtered through cellite (10 g cartridge) and washed with further ethanol (150 ml). Relevant fractions (as verified by TLC) were combined and concentrated in vacuo to give a red oil. Trituration with DCM gave the title compound (815 mg) as a red solid; 1 H NMR (MeOH-d4, 400 MHz) delta (ppm) 7.20 (2 H, s).
	With hydrogen;palladium on activated charcoal; In ethanol; at 20℃; for 18h;	A -(1H-Pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide Step 1 : To a round bottom flask, 4-nitro-1 /-/-pyrazole (2.0 g, 17.68 mmol), Pd/C (200 mg, 1.89 mmol) and EtOH (15.0 mL, degassed) was added. The flask was evacuated and backfilled with H2 and the reaction mixture was stirred under H2-atmosphere at rt for 18 h. The reaction mixture was filtered over celite, washed with MeOH and the solvent was removed under reduced pressure to yield 1 H-pyrazol-4-amine as a red oil which was used without further purification. 1 H-NMR (400 MHz, DMSO) delta 3.72 (brs, 2H), 6.99 (s, 2H), 1 1.9 (brs, 1 H).
	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 1h;	Synthesis of compound 96.2[00605] A solution of 4-nitro-lH-pyrazole (200 mg, 1.77 mmol, 1.00 equiv) and 10% Palladium on carbon (40 mg) in methanol (5 mL) was degassed with H2 three times and the reaction mixture was stirred for 1 h at room temperature. The catalyst was filtered out and the filtrate was concentrated under vacuum to give 120 mg (crude) of compound 96.2 as a light yellow solid.
3.6 g	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃;	Dissolving 5.0 g of 4-nitropyrazole in 160 mL of ethanol, and then adding 0.8 g of 10 wt% Pd/C to the above solution; Hydrogen was introduced into the reaction solution and allowed to react overnight at room temperature; after the TLC detection reaction was completed, the insoluble matter was filtered off with diatomaceous earth; Evaporation of the ethanol solvent gave pure intermediate 2 as a red solid 3.6 g.

References: [1]Patent: US2015/336982,2015,A1 .Location in patent: Paragraph 0252; 0253.
[2]ChemMedChem,2016,p. 1695 - 1699.
[3]Patent: CN105418616,2016,A .Location in patent: Paragraph 0118; 0119.
[4]Organic and Biomolecular Chemistry,2013,vol. 11,p. 395 - 399.
[5]Patent: WO2017/178510,2017,A1 .Location in patent: Page/Page column 297.
[6]Patent: WO2006/44821,2006,A1 .Location in patent: Page/Page column 23.
[7]Journal of Medicinal Chemistry,2019,vol. 62,p. 3898 - 3923.
[8]Patent: WO2010/75542,2010,A1 .Location in patent: Page/Page column 73.
[9]Chemische Berichte,1904,vol. 37,p. 3501.
[10]Journal of the Chemical Society,1945,p. 114.
[11]Journal of the Chemical Society,1925,vol. 127,p. 2939.
[12]Journal of Medicinal Chemistry,2005,vol. 48,p. 5780 - 5793.
[13]Patent: US6531475,2003,B1 .
[14]Patent: WO2007/99326,2007,A1 .Location in patent: Page/Page column 108-109.
[15]Patent: WO2008/8375,2008,A2 .Location in patent: Page/Page column 83.
[16]Patent: WO2009/93012,2009,A1 .Location in patent: Page/Page column 20; 35.
[17]Journal of Medicinal Chemistry,2011,vol. 54,p. 4350 - 4364.
[18]Patent: WO2012/52459,2012,A1 .Location in patent: Page/Page column 38-39.
[19]Patent: WO2012/52458,2012,A1 .Location in patent: Page/Page column 34.
[20]Patent: WO2012/110986,2012,A1 .Location in patent: Page/Page column 52-53.
[21]Patent: WO2014/194242,2014,A2 .Location in patent: Paragraph 00603-0605.
[22]Patent: CN108864057,2018,A .Location in patent: Paragraph 0105; 0206-0208.

3
[ 2075-46-9 ]
[ 105-36-2 ]
[ 39753-81-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate In acetone at 65℃; for 3h;	3.1 Example 3 Step 1 : ethyl 2-(4-nitro-1 H-pyrazol-1 -yl)acetate A mixture of 4-nitro-1 H-pyrazole (11.3 g, 0.1 mol), ethyl 2-bromoacetate (20.0 g, 0.12 mol) and K2CC>3 (20.7 g, 0.15 mol) in acetone (100 ml.) was stirred for 3 h at 65 °C. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (PE/EA 2:1) to give the desired product (18.5 g, 93%) as a yellow solid LCMS (acidic 5 min): 0.86 min [MH]+=200.0
90%	With potassium hydroxide In methanol; water
90%	With nitrogen; potassium carbonate	38.1 Step 1: Step 1: Synthesis of ethyl 2-(4-nitro-1H-pyrazol-1-yl)acetate (38c). 4-Nitro-1H-pyrazole (10.0 g, 88.0 mmol) and potassium carbonate (24.0 g, 88.0 mmol) were added to a solution of ethyl 2-bromoacetate in N,N-dimethylformamide (200 mL) at room temperature. The mixture was replaced with nitrogen three times and stirred at 90°C overnight. Water was added to the reaction system. The mixture was extracted with EA (100 mL∗3). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residues were purified by flash column chromatography (mobile phase: petroleum ether/ethyl acetate = 100/1 to 4/1) to give 16.0 g of the title compound as a yellow solid, yield: 90.0% LC-MS: m/z 200[M+H]+

90%	With potassium carbonate In N,N-dimethyl-formamide at 90℃; Inert atmosphere;	38.1 Step 1: Synthesis of ethyl 2-(4-nitro-1H-pyrazol-1-yl)acetate (38c). 4-Nitro-1H-pyrazole (10.0 g, 88.0 mmol) and potassium carbonate (24.0 g, 88.0 mmol) were added to a solution of ethyl 2-bromoacetate in N,N-dimethylformamide (200 mL) at room temperature. The mixture was replaced with nitrogen three times and stirred at 90°C overnight. Water was added to the reaction system. The mixture was extracted with EA (100 mL 3). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residues were purified by flash column chromatography (mobile phase: petroleum ether/ethyl acetate = 100/1 to 4/1) to give 16.0 g of the title compound as a yellow solid, yield: 90.0% LC-MS: m/z 200[M+H]+
89%	With potassium hydroxide In water; acetone for 15h;
84%	With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 12h;	33 Preparation of Compound 33-b Ethyl bromoacetate (1.67 g, 10 mmol) and potassium carbonate (2.76 g, 20 mmol) were added to a solution of 4-nitropyrazole (1.13 g, 10 mmol) in DMF (15 mL), the mixture was heated to 90° C. and stirred for 12 hours. After the mixture was cooled to room temperature, water (60 mL) was added, then the mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined, washed with water (10 mL) and saturated brine (10 mL) in sequence, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=5:1) to give compound 33-b (1.68 g, yield: 84%). LC-MS (ESI): m/z=200 [M+H]+.
83%	Stage #1: 4-nitro-1H-pyrazole With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: ethyl bromoacetate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	B Synthesis of 4-a To a solution of 4-nitropyrazole (1.13 g, 1.0 eq) in dry DMF (15 mL) was added CS2CO3 (8.13 g, 2.5 eq). The mixture was stirred at RT for 30 mins under N2, and then bromoacetate (2 g, 1.2 eq) was added into reaction. The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with 50 mL ethyl acetate and 10 mL hexane. The inorganic was removed by filtration. The filtrate was washed with 3x3 OmL water and brine. The crude was purified on ISCO silica gel to afford 6 (1.65 g, yield 83%) white solid.
83%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	B Synthesis of 4-a [00161] To a solution of 4-nitropyrazole (1.13 g, 1.0 eq) in dry DMF (15 mL) was added CS2CO3 (8.13 g, 2.5 eq). The mixture was stirred at RT for 30 mins under N2, and then bromoacetate (2 g, 1.2 eq) was added into reaction. The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with 50 mL ethyl acetate and 10 mL hexane. The inorganic was removed by filtration. The filtrate was washed with 3x3 OmL water and brine. The crude was purified on ISCO silica gel to afford 6 (1.65 g, yield 83%) as a white solid.
31.28%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 5h;	Intermediate 179: Ethyl 2-(4-amino-1H-pyrazol-1-yl)acetate To a stirred solution of 4-nitro-1H-pyrazole (5.00 g; 43.33 mmol; 1.00 eq.) in DMF (60.00 ml; 733.07 mmol; 16.92 eq.) were added K2CO3 (18.91 g; 130.00 mmol; 3.00 eq.) and ethyl 2-bromoacetate (9.14 g; 52.00 mmol; 1.20 eq.) at 0-5 . The reaction mixture was stirred 5 h at room temperature and then concentrated under reduced pressure. The residue was purified by chromatography, eluted with PE/EA (10:1) to afford ethyl 2-(4-nitro-1H-pyrazol-1-yl)acetate (3.00 g; 31.28%) as light brown oil. LC/MS: Method H. [M+H]+ 200.15, Rt.: 0.66 min.

References: [1]Current Patent Assignee: ANAXIS PHARMA - WO2021/168521, 2021, A1 Location in patent: Page/Page column 35; 36.
[2]Kanishchev, M. I.; Kral, V.; Arnold, Z.; Semenov, V. V.; Shevelev, S. A.; Fainzil'berg, A. A. [Bulletin of the Academy of Sciences of the USSR Division of Chemical Science, 1986, vol. 35, # 10, p. 2191][Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1986, # 10, p. 2392].
[3]Current Patent Assignee: CHINA MEDICINE RESEARCH AND DEVELOPMENT CENTER - EP4011865, 2022, A1.
[4]Current Patent Assignee: CHINA MEDICINE RESEARCH AND DEVELOPMENT CENTER - EP4011865, 2022, A1 Location in patent: Paragraph 0377-0379.
[5]Kral, Vladimir; Semenov, Viktor Vladimirovich; Kanishchev, Mikhail Ivanovich; Arnold, Zdenek; Shevelev, Svyatoslav Arkadievich; Fainzilberg, Albert Aleksandrovich [Collection of Czechoslovak Chemical Communications, 1988, vol. 53, # 7, p. 1519 - 1528].
[6]Current Patent Assignee: GUANGZHOU MAXINOVEL PHARMACEUTICALS - US2015/336982, 2015, A1 Location in patent: Paragraph 0259; 0260.
[7]Current Patent Assignee: VIMALAN BIOSCIENCES - WO2020/227563, 2020, A1 Location in patent: Paragraph 00194.
[8]Current Patent Assignee: VIMALAN BIOSCIENCES - WO2021/26465, 2021, A1 Location in patent: Paragraph 00161.
[9]Current Patent Assignee: MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG - WO2025/163390, 2025, A2 Location in patent: Paragraph 001063-001064.

4
[ 7119-95-1 ]
[ 7664-93-9 ]
[ 2075-46-9 ]

References: [1]Chemische Berichte,1955,vol. 88,p. 1586,1590.

5
[ 2075-46-9 ]
[ 64-19-7 ]
zinc dust [ No CAS ]
[ 28466-26-4 ]

References: [1]Chemische Berichte,1904,vol. 37,p. 3501.

6
[ 75-30-9 ]
[ 2075-46-9 ]
[ 97421-21-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h;	53 Synthesis of intermediate 53.2. A 100 mL round-bottom flask, was charged withsolution of 4-nitro-1H-pyrazole (2 g, 17.69 mmol, 1.00 equiv) in N,N-dimethylformamide (60 mL), 2-iodopropane (4 mL) and K2C03 (4.88 g, 35.05 mmol, 2.00 equiv). The reaction was stirred for 2 h at 70 °C in an oil bath. The resulting solution was extracted with 5 x 100 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 2.65 g (97%) of intermediate 53.2 as a yellow solid.
91%	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	6 Synthesis of Compound 6.1. Synthesis of Compound 6.1. Into a 250-mL round-bottom flask, was placed 4- nitro-lH-pyrazole (2 g, 17.69 mmol, 1.00 equiv), potassium carbonate (7.33 g, 53.04 mmol, 3.00 equiv), N,N-dimethylformamide (50 mL), and 2-iodopropane (6 g, 35.30 mmol, 2.00 equiv). The reaction was stirred overnight at room temperature. The resulting solution was extracted with 3 x 500 mL of ethyl acetate and the organic layers were combined and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 : 10). This afforded 2.5 g (91%) of 6.1 as a white solid.
90%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 0.5h;	12.1 Step 1: Preparation of 1-isopropyl-4-nitro-1H-pyrazole (Int-12-b) To a solution of 4-nitropyrazole (5 g, 44.22 mmol) in DMF (50 mL) was added potassium carbonate (12.20 g, 88.44 mmol)And isopropyl iodide (11.28g, 66.33mmol).The reaction mixture was heated to 50 ° C, and the reaction was stirred for 30 minutes.The reaction mixture was allowed to stand, cooled to room temperature, suction filtered, and the obtained filtrate was poured into water.It was extracted three times with ethyl acetate, the organic phases were combined, and the organic phases were washed three times with saturated brine.The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.The obtained residue was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3/1) to obtain the title compound (6.2 g, yield: 90.0%) in this step.

81%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 3h;	41 Preparation of Compound 41-b 2-Iodopropane (2.3 g, 13.27 mmol) and potassium carbonate (1.81 g, 13.27 mmol) were added to a solution of 4-nitropyrazole (1.0 g, 8.85 mmol) in DMF (10 mL) in sequence, the mixture was heated to 60° C. and stirred for 3 hours. The mixture was poured into ice water (100 mL), extracted with ethyl acetate (100 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure to give yellow oil 41-b (1.1 g, yield: 81%), which was used for the next step without purification.
80%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h;	108.1 Step 1: preparation of 1-isopropyl-4-nitro-1H-pyrazole Step 1: preparation of 1-isopropyl-4-nitro-1H-pyrazole (0296) (0297) 4-Nitro-1H-pyrazole (226 mg, 2 mmol) and 2-iodopropane (340 mg, 2 mmol) were dissolved in N,N-dimethylformamide (5 mL), followed by the addition of potassium carbonate (276 mg, 2 mmol). The reaction solution was reacted at 70°C for 2 hours, then poured into water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 : 1) to give a white solid (250 mg). Yield: 80.0%. MS (ESI, m/z): [M+H]+: 155.8; 1H-NMR (300 MHz, CDCl3) δ: 8.16 (s, 1H), 8.08 (s, 1H), 4.48-4.57 (m, 1H), 1.57 (s, 3H), 1.55 (s, 3H).
65%	Stage #1: 4-nitro-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 2-iodo-propane In N,N-dimethyl-formamide for 3h; Reflux;	34.1 Step 1: Synthesis of 1-isopropyl-4-nitro-1H-pyrazole 4-Nitro-1H-pyrazole (0.30 g, 2.65 mmol) and DMF (30 ml) were added and stirred for 10 minutes in an ice bath. NaH (0.17 g, 3.97 mmol) was added thereto, followed by stirring thereof for 30 minutes. 2-Iodopropane (0.58 g, 3.44 mmol) was then added thereto, followed by refluxing thereof for 3 hours. Upon termination of the reaction, it was evaporated under reduced pressure and extracted with ethyl acetate. It was dried over MgSO4 and evaporated under reduced pressure. It was subjected to column chromatography (Hep:EA = 1:1) to obtain 0.26 g of the target compound in liquid phase (yield: 65%). 1H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H), 8.09 (s, 1H), 4.58-4.49 (m, 1H), 1.56 (s, 6H).
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h;	9 The 4-amino-l-isopropyl-lH-pyrazole used as a starting material was prepared as follows :-A mixture of 4-nitropyrazole (1.13 g), isopropyl iodide (1 ml), potassium carbonate (1.38 g) and DMF (30 ml) was stirred and heated to 7O0C for 2 hours. The resultant mixture was poured into water and the precipitate was isolated, washed with water and dried under vacuum. There was thus obtained l-isopropyl-4-nitro-lH-pyrazole (0.845 g); 1H NMR: (DMSOd6) 1.44 (d, 6H), 4.59 (m, IH), 8.26 (s, IH), 8.93 (s, IH).
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h;	4.8 The 4-amino-l-isopropyl-l/f-pyrazole used as a starting material was prepared as follows :- A mixture of 4-nitropyrazole (1.13 g), isopropyl iodide (1 ml), potassium carbonate(1.38 g) and DMF (30 ml) was stirred and heated to 700C for 2 hours. The resultant mixture was poured into water and the precipitate was isolated, washed with water and dried under vacuum. There was thus obtained l-isopropyl-4-nitro-lH-pyrazole (0.845 g); H NMR: (DMSOd6) 1.44 (d, 6H), 4.59 (m, IH), 8.26 (s, IH), 8.93 (s, IH).
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h;	2 A mixture of 4-nitropyrazole (1.13 g), isopropyl iodide (1 ml), potassium carbonate (1.38 g) and DMF (30 ml) was stirred and heated to 700C for 2 hours. The resultant mixture was poured into water and the precipitate was isolated, washed with water and dried under vacuum. There was thus obtained l-isopropyl-4-nitro-lH-pyrazole (0.845 g); 1H NMR: (DMSOd6) 1.44 (d, 6H), 4.59 (m, IH), 8.26 (s, IH), 8.93 (s, IH).
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h;	4.1 The 4-amino-l-isopropyl-lH-pyrazole used as a starting material was prepared as follows :-A mixture of 4-nitropyrazole (1.13 g), isopropyl iodide (1 ml), potassium carbonate (1.38 g) and DMF (30 ml) was stirred and heated to 70° C for 2 hours. The resultant mixture was poured into water and the precipitate was isolated, washed with water and dried under vacuum. There was thus obtained l-isopropyl-4-nitro-lH-pyrazole (0.845 g); 1H NMR:(DMSOd6) 1.44 (d, 6H), 4.59 (m, IH), 8.26 (s, IH), 8.93 (s, IH).
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h;	2 EXAMPLE 2 The 4-amino-1-isopropyl-1H-pyrazole used as a starting material was prepared as follows:- A mixture of 4-nitropyrazole (1.13 g), isopropyl iodide (1 ml), potassium carbonate (1.38 g) and DMF (30 ml) was stirred and heated to 70° C. for 2 hours. The resultant mixture was poured into water and the precipitate was isolated, washed with water and dried under vacuum. There was thus obtained 1-isopropyl-4-nitro-1H-pyrazole (0.845 g); 1H NMR: (DMSOd6) 1.44 (d, 6H), 4.59 (m, 1H), 8.26 (s, 1H), 8.93 (s, 1H).
	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 3h;	14 Synthesis of Compound 14-b 2-Iodopropane (2.3 g, 13.27 mmol) and potassium carbonate (1.81 g, 13.27 mmol) were sequentially added to a solution of 4-nitropyrazole (1.0 g, 8.85 mmol) in N,N-dimethylformamide (10 mL) and the mixture was heated to 60° C. for 3 hours. The mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 14-b as a yellow oil (1.1 g, yield 81%), which was directly used for the next reaction without purification.
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h;	10.1 The 4-amino-l-isopropyl-lH-pyrazole used as a starting material was prepared as follows :-A mixture of 4-nitropyrazole (1.13 g), isopropyl iodide (1 ml), potassium carbonate (1.38 g) and DMF (30 ml) was stirred and heated to 70°C for 2 hours. The resultant mixture was poured into water and the precipitate was isolated, washed with water and dried under vacuum. There was thus obtained l-isopropyl-4-nitro-lH-pyrazole (0.845 g); 1H NMR Spectrum: (DMSOd6) 1.44 (d, 6H), 4.59 (m, IH), 8.26 (s, IH), 8.93 (s, IH).
	With potassium carbonate	35.A A) A) 4-nitro-1-(propan-2-yl)-1H-pyrazole To a mixture of 4-nitro-1H-pyrazole (10 g), potassium carbonate (13.6 g) and DMSO (90 ml) was added 2-iodopropane (9.8 ml), and the mixture was stirred at 40° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with a mixture of ethyl acetate and hexane. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.5 g). 1H NMR (300 MHz, DMSO-d6) δ 1.45 (6H, d, J=6.4 Hz), 4.50-4.67 (1H, m), 8.25 (1H, s), 8.92 (1H, s).
12.5 g	With potassium carbonate In dimethyl sulfoxide at 40℃;	35.A A) 4-nitro-1-(propan-2-yl)-1H-pyrazole To a mixture of 4-nitro-1H-pyrazole (10 g), potassium carbonate (13.6 g) and DMSO (90 ml) was added 2-iodopropane (9.8 ml), and the mixture was stirred at 40° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with a mixture of ethyl acetate and hexane. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.5 g).1H NMR (300 MHz, DMSO-d6) δ 1.45 (6H, d, J=6.4 Hz), 4.50-4.67 (1H, m), 8.25 (1H, s), 8.92 (1H, s).
12.5 g	With potassium carbonate In dimethyl sulfoxide at 40℃;	35.A A) 4-nitro-1-(propan-2-yl)-1H-pyrazole To a mixture of 4-nitro-1H-pyrazole (10 g), potassium carbonate (13.6 g) and DMSO (90 ml) was added 2-iodopropane (9.8 ml), and the mixture was stirred at 40° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with a mixture of ethyl acetate and hexane. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.5 g).1H NMR (300 MHz, DMSO-d6) δ 1.45 (6H, d, J=6.4 Hz), 4.50-4.67 (1H, m), 8.25 (1H, s), 8.92 (1H, s).
97.6 %	With potassium carbonate In N,N-dimethyl acetamide at 70℃;

References: [1]Current Patent Assignee: NIMBUS IRIS - WO2015/48281, 2015, A1 Location in patent: Paragraph 00510; 00511.
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[6]Current Patent Assignee: OSCOTEC - EP3722298, 2020, A1 Location in patent: Paragraph 0160.
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7
[ 2075-46-9 ]
[ 6482-24-2 ]
[ 948570-75-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In acetonitrile at 80℃; for 4h;	39 Synthesis ofl-(2-methoxyethyl)-4-nitro-1H-pyrazole [0223j To a mixture of 4-nitro-1H-pyrazole (113 mg, 1 mmol, 1.0 eq) in CH3CN (5 mL), 1-bromo-2-methoxyethane (138 mg, 1 mmol, 1.0 equiv) and K2C03 (276 mg, 2 mmol, 2.0 equiv) was added. The mixture was stirred at 80 °C for 4 h. After diluted with EtOAc (100 mL), the mixture was washed with water (50 mL x 2). The organic layer was concentrated and purified by silica gel column (petroleum ether/EtOAc = 10 : 1) to give 1-(2-methoxyethyl)-4-nitro-1H- pyrazole (170 mg, yield: 100%) as a colorless oil. ESI-MS (M+H): 172.1. ‘H NMR (400 MHz, CDC13) (5: 8.23 (s, 1H), 8.07 (s, 1H), 4.31 (t, J= 5.2 Hz, 2H), 3.74 (t, J= 5.2 Hz, 2H), 3.35 (s, 3H).
98%	With potassium carbonate In acetonitrile for 6h; Reflux;	5.1.57. 1-methyl-4-nitro-1H-pyrazole (17a) General procedure: To a stirred solution of 4-nitro-1H-pyrazole (2 g, 17.7 mmol) inacetonitrile (15 mL) was added potassium carbonate (2.7 g, 19.5 mmol)and iodomethane (2.76 g, 19.5 mmol). The reaction mixture was stirredat reflux temperature for 6 h. And it was evaporated to dryness. Thecrude mass was purified by silica gel column chromatography (PE:EA=10:1) to afford compound 15c (2.2 g, 98%) as a white solid. MS(ESI) m/z 128 [M+H]+.
98%	With potassium iodide In acetonitrile at 82℃; for 10h;	4.1.60. 1-(2-Methoxyethyl)-4-nitro-1H-pyrazole (19c) General procedure: To a solution of compound 18 (1.1 g, 10.0 mmol) and K2CO3 (2.1 g,15.0 mmol) in MeCN (20 mL) was added iodomethane (1.6 g,11.0 mmol) at room temperature. The reaction mixture was stirredovernight at 82 °C. TLC showed the completion of the reactin. The resultingmixture was removed under vacuum. Water (20 mL) was addedto the residue, and the resultant mixture was extracted with EtOAc(2 × 50 mL). The organic layers were then washed with water followed by brine. The organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated to provide 19a as a yellow solid(1.2 g,9.8 mmol, 98%) without further purification. MS (ESI) m/z: 128.1 [M+H]+

97%	With potassium carbonate In acetonitrile at 90℃; for 5h;	Synthesis of 1-(2-methoxyethyl)-4-nitro-1H-pyrazole (16) To a solution of 4-nitro-1H-pyrazole 12 (1.70 g, 15.03 mmol) in CH3CN (50 mL) was added K2C03 (3.11 g, 22.53 mmol) followed by addition of 1-bromo-2- methoxy-ethane (2.5 g, 18.0 mmol) at room temperature. The reaction mixture was heated to 90°C for 5 h. After completion of reaction (monitored by TLC), the solvent was evaporated, added water and extracted with EtOAc (3 x 200 mL). the combined organics was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2.50 g (97% yield) of the title compound 16 as colorless liquid. 1H NMR (400 MHz, DMDO-d6): 3 8.85 (s, 1H), 8.27 (s, 1H), 4.36-4.33 (t, 2H), 3.77-3.72 (t, 2H), 3.23 (s, 3H). MS: 172.11 (M+H).
79%	With potassium carbonate In acetonitrile at 80℃; for 12h;	29.1 Step 1: l-(2-methoxyethyl)-4-nitro-pyrazole. To a solution of 4-nitro- 1 H-pyrazole (5.0 g, 44.2 mmol) in CH3CN (100 ml) was added 1 -bromo-2-methoxyethane (4.15 ml, 44.2 mmol, 4.15 mL) and K2C03 (12.22 g, 88.4 mmol). The mixture was stirred at 80 °C for 12 h. The solvent was removed under reduced pressure. The residue was diluted with water (30 ml) and extracted with EtOAc (3 x 50 ml), the organic layers were combined and washed with brine (20 ml), dried over Na2S04, and concentrated. The resulting residue was purified by FCC (10 - 25 % petroleum ether in ethyl acetate) to give the title compound as a colourless oil (Y = 79 %). H NMR (400 MHz, chlorofomwf) d ppm 8.24 (s, 1H), 8.08 (s, 1H), 4.32 (t, J= 5 Hz, 2H), 3.75 (t, J= 5 Hz, 2H), 3.36 (s, 3H).
76%	With potassium carbonate In acetonitrile at 60℃; for 6h;	23 1-(2-Methoxyethyl)-4-nitro-1H-pyrazole A mixture of 4-nitro-1H-pyrazole (1 equiv), 1-bromo-2-methoxyethane (1.05 equiv), potassium carbonate (1.5 equiv) and acetonitrile (0.44 M) was stirred and heated to 60° C. for 6 h. The resultant mixture was evaporated and the residue was purified by flash chromatography (2.5% MeOH in DCM) to afford the desired product as a yellow solid (76% yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm 8.25 (s, 1H), 8.08 (s, 1H), 4.34-4.31 (t, J=4.8 Hz, 2H), 3.77-3.74 (t, J=4.8 Hz, 2H), 3.37 (s, 3H)
66%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 16h;	1.1 Step 1): 1 - (2 - methoxy ethyl) -4 - nitro - 1H - pyrazole of preparation: The 4 - nitro - 1H - pyrazole (5 g, 44.21 mmol) dissolved in DMF (20 ml), add K2CO3(9.1 G, 65 . 85 mmol) and 1 - bromo -2 - methoxy ethane (7.4 g, 53 . 24 mmol), 50 °C reaction 16 hours. The reaction solution is poured into ice water, ethyl acetate extraction, anhydrous sodium sulfate drying, filtering steams the main column chromatography (petroleum ether: ethyl acetate=3:1), to obtain brown oil of 5 g, yield 66%.
66%	With potassium carbonate In acetonitrile at 60℃; for 72h;
45%	With potassium carbonate In acetonitrile at 0 - 90℃; for 20h; Inert atmosphere;	5.2 Step 2: l-(2-Methoxyethyl)-4-nitro-1H-pyrazole (5): To a stirred solution of 4-nitro- 1H-pyrazole 4 (50 g, 442.47 mmol) in acetonitrile (600 mL) under inert atmosphere were added potassium carbonate (183 g, 1.32 mol) and 1-bromo -2 -methoxy ethane 5 (146 g, 884.95 mmol) at 0 °C. The reaction mixture was heated to 90 °C for 20 h. After consumption of starting material (by TLC); the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica-gel flash column chromatography to afford 1 -(2-methoxyethyl)-4-nitro-1H-pyrazole 5 (40 g, 201.0 mmol, 45%) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6): δ 8.87 (s, 1H), 8.27 (s, lH), 5.18 (s, 2H), 4.18 (t, J = 5.2 Hz, 2H), 1.20 (t, J= 5.2 Hz, 3H).
	With potassium carbonate In acetonitrile at 60℃; for 6h;	2 A mixture of 4-nitropyrazole (0.8 g), 2-methoxyethyl bromide (0.73 ml), potassium carbonate (1.46 g) and acetonitrile (15 ml) was stirred and heated to 600C for 6 hours. The resultant mixture was evaporated and the residue was purified by column chromatography on silica using a 99:1 mixture of methylene chloride and ethyl acetate as eluent. There was thus obtained l-(2-methoxyethyl)-4-nitro-lF-pyrazole (0.98 g); 1H NMR: (CDCl3) 3.36 (s, 3H),3.75 (t, 2H), 4.32 (t, 2H), 8.07 (s, IH), 8.23 (s, IH).
	With potassium carbonate; potassium iodide In acetonitrile Reflux;	3 1-(2-methoxyethyl)-4-nitro-1H-pyrazole Add 4-nitropyrazole (5g), K2CO3 (9.17g) to a 100mL eggplant-shaped bottle,2-bromoethyl methyl ether (7.38g),KI (1.47g) and 63mL CH3CN, reflux overnight.At the end of the reaction, spin dry under reduced pressure, add H2O 75mL, EA 50mL × 3, combine the organic layers, wash with saturated brine, and dry the organic phase with anhydrous Na2SO4.Dry under reduced pressure to give an oily product.
	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 4h;	S100.1 Step-1: Synthesis of 1-(2-methoxyethyl)-4-nitro-1H-pyrazole: To a stirred solution of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol, 1 equiv) in DMF (5 mL), was added K2CO3 (1220 mg, 8.84 mmol, 2 equiv) and 1-bromo-2-methoxyethane (915 mg, 6.63 mmol, 1.5 equiv). The resultant reaction mixture was allowed to stir at 100 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, diluted with water (50 mL) and extracted with ethyl acetate (150 mL). Organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain desired product. LCMS: 172 [M+H]
92 %	With potassium carbonate In acetonitrile at 80℃;	Preparation of 1-(2-methoxyethyl)-4-nitro-1H-pyrazole (1d). In a similar fashion to the method described in WO 2015/089337 (p125-6), a mixture of 4-nitro-1H- pyrazole 1c (2.00g, 17.6mmol) and 1-bromo-2-methoxyethane (1.66ml, 17.6mmol) and K2CO3 (5.47g, 39.6mmol) in MeCN (50ml) was heated to 80°C for 18h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated then purified by column chromatography on SiO2 (Puriflash) eluting with 0-5% EtOH in DCM to afford 1d as a clear oil (2.77g,92%).1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.26 (s, 1H), 4.34 (t, J = 5.2 Hz, 2H), 3.79 - 3.64 (m, 2H), 3.23 (s, 3H)
92 %	With potassium carbonate In acetonitrile at 80℃;	Preparation of 1-(2-methoxyethyl)-4-nitro-1H-pyrazole (1d). In a similar fashion to the method described in WO 2015/089337 (p125-6), a mixture of 4-nitro-1H- pyrazole 1c (2.00g, 17.6mmol) and 1-bromo-2-methoxyethane (1.66ml, 17.6mmol) and K2CO3 (5.47g, 39.6mmol) in MeCN (50ml) was heated to 80°C for 18h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated then purified by column chromatography on SiO2 (Puriflash) eluting with 0-5% EtOH in DCM to afford 1d as a clear oil (2.77g,92%).1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.26 (s, 1H), 4.34 (t, J = 5.2 Hz, 2H), 3.79 - 3.64 (m, 2H), 3.23 (s, 3H)
92 %	With potassium carbonate In acetonitrile at 80℃;	1-2 Preparation of 1-(2-methoxyethyl)-4-nitro-1H-pyrazole (1d). In a similar fashion to the method described in WO 2015/089337 (p125-6), a mixture of 4-nitro-1H- pyrazole 1c (2.00g, 17.6mmol) and 1-bromo-2-methoxyethane (1.66ml, 17.6mmol) and K2CO3 (5.47g, 39.6mmol) in MeCN (50ml) was heated to 80°C for 18h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated then purified by column chromatography on SiO2 (Puriflash) eluting with 0-5% EtOH in DCM to afford 1d as a clear oil (2.77g,92%).1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.26 (s, 1H), 4.34 (t, J = 5.2 Hz, 2H), 3.79 - 3.64 (m, 2H), 3.23 (s, 3H)

References: [1]Current Patent Assignee: BIOGEN MA - WO2015/89337, 2015, A1 Location in patent: Paragraph 0223.
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[4]Current Patent Assignee: JUBILANT THERAPEUTICS INDIA - WO2015/25197, 2015, A1 Location in patent: Paragraph 00078.
[5]Current Patent Assignee: NODTHERA - WO2019/121691, 2019, A1 Location in patent: Paragraph 0881.
[6]Current Patent Assignee: SIGNAL PHARMACEUTICALS - US2014/200206, 2014, A1 Location in patent: Paragraph 0339.
[7]Current Patent Assignee: BEIJING SCITECH MINGQIANG PHARMACEUTICAL TECH - CN109535132, 2019, A Location in patent: Paragraph 0085-0088.
[8]Current Patent Assignee: BLUEPRINT MEDICINES - WO2021/62327, 2021, A1 Location in patent: Paragraph 0214.
[9]Current Patent Assignee: VIMALAN BIOSCIENCES - WO2021/62036, 2021, A1 Location in patent: Paragraph 00180.
[10]Current Patent Assignee: ASTRAZENECA - WO2007/99326, 2007, A1 Location in patent: Page/Page column 104.
[11]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN110885331, 2020, A Location in patent: Paragraph 0258-0262.
[12]Current Patent Assignee: NUVATION BIO - WO2021/3314, 2021, A1 Location in patent: Paragraph 0442.
[13]Current Patent Assignee: AB SCIENCE - WO2024/146923, 2024, A1 Location in patent: Paragraph 0088; 0090.
[14]Current Patent Assignee: AB SCIENCE - WO2024/146923, 2024, A1 Location in patent: Paragraph 0088; 0090.
[15]Current Patent Assignee: AB SCIENCE - WO2024/146923, 2024, A1 Location in patent: Paragraph 0086; 0090.

8
[ 2075-46-9 ]
[ 359-13-7 ]
[ 1006442-51-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere;	35.1 Step 1: l-(2,2-difluoroethyl)-4-nitropyrazole. To a solution of 4-nitro- 1 H-pyrazole (5.0 g, 44.2 mmol) in THF (100 ml) was added 2,2-difluoroethanol (4.35 g, 53.1 mmol) and triphenylphosphine (17.40 g, 66.3 mmol) at rt under N2 atmosphere. The RM was cooled to 0 °C and diisopropyl azodicarboxylate (10.3 ml, 53.1 mmol) was added. The RM was allowed to warm to rt and then stirred for 12 h. The solvent was removed under reduced pressure. The residue was purified by FCC (5 - 20 % EtOAc in petroleum ether) to give the title compound as a white solid (Y = 83 %). XH NMR (400 MHz, chloroform-* d ppm 8.25 (s, 1H), 8.14 (s, 1H), 6.31 - 5.99 (m, 1H), 4.57 - 4.49 (m, 2H).
81%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;
	With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;

	With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere;	Preparation of 1H-pyrazol-4-ylamine derivatives General Procedure: General procedure: 4-Nitro-1H-pyrazole (4.422 mmol; 500.00 mg), 1 equivalent of the primary alcohol and 1.77 g of triphenylphosphine are dissolved in 20 ml of dried THF in a 100 ml three-necked flask with drying tube under N2. Di-tert-butyl azodicarboxylate (5.748 mmol; 1.35 g) is subsequently added in portions. The yellow solution is stirred at RT for 2 h. [0265] For work-up, the triphenylphosphine oxide is filtered off with suction, and the filtrate is evaporated in a rotary evaporator. The 4-nitro-1H-pyrazole derivative is, if necessary, chromatographed over silica gel in ethyl acetate/ petroleum ether. The 4-nitro-1H-pyrazole derivative is dissolved in methanol, 5% Pd/C is added, and the mixture is hydrogenated at room temperature using hydrogen. The 1H-pyrazol-4-ylamine derivative is obtained after filtration and evaporation of the solution.
	With triphenylphosphine In tetrahydrofuran at 25℃;	5.1.9 General procedure for the synthesis of intermediates 30a-d. General procedure: 4-nitro-1H-pyrazole (1 equiv), triphenylphosphine (1.5 equiv) and corresponding alcohols (1 equiv) were dissolved in THF, and di-tert-butyl azodicarboxylate (1.5 equiv) was added over approximately 15min. The resulting mixture was stirred at 25°C. Upon completion, the residue was concentrated to dryness and purified by column chromatography to give intermediates 29a-c. A solution of 4-nitro-1H-pyrazole (1 equiv), bromo(methoxy)methane (1.1eq) and potassium carbonate (1 equiv) in acetonitrile was heated at 60°C for 6h. The mixture was diluted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by chromatography to give intermediates 29d.Intermediates 29a-d (1 equiv) were dissolved in ethanol, and Pd/C (0.1 equiv) was added. The flask was flushed with H2and stirred for 6h at 40°C. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to dryness, yielding intermediates 30a-d.

References: [1]Current Patent Assignee: NODTHERA - WO2019/121691, 2019, A1 Location in patent: Paragraph 0899.
[2]Kawahata, Wataru; Asami, Tokiko; Irie, Takayuki; Sawa, Masaaki [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 2, p. 145 - 151].
[3]Zabierek, Anna A.; Konrad, Kaleen M.; Haidle, Andrew M. [Tetrahedron Letters, 2008, vol. 49, # 18, p. 2996 - 2998].
[4]Current Patent Assignee: MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG - US2014/228340, 2014, A1 Location in patent: Paragraph 0264-0265; 0266-0267.
[5]Wang, Ruifeng; Zhao, Xiangxin; Yu, Sijia; Chen, Yixuan; Cui, Hengxian; Wu, Tianxiao; Hao, Chenzhou; Zhao, Dongmei; Cheng, Maosheng [Bioorganic Chemistry, 2020, vol. 102].

9
[ 2075-46-9 ]
[ 67-63-0 ]
[ 97421-21-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 16.05h;	I Preparation of 1-isopropyl-4-nitro-1H-pyrazole (1) Di-tert-butyl azodicarboxylate (1.59 g, 6.91 mmol) was added to a solution of 4-nitro-1H-pyrazole (601 mg, 5.32 mmol), 2-propanol (319 mg, 5.32 mmol) and triphenylphosphine (1.67 g, 6.36 mmol) in tetrahydrofuran (25 mL) over 3 minutes and the mixture was stirred at room temperature for 16 h. After this time, the reaction was concentrated under reduced pressure and the resulting residue purified by chromatography (silica, gradient, 1:4 ethyl acetate/heptane to 7:3 ethyl acetate/heptane) to afford 1-isopropyl-4-nitro-1H-pyrazole (1) (1.23 g, >100%) as an impure off-white solid, which was used without further purification: 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.24 (s, 1H), 4.58 (m, 1H), 1.42 (d, J=6.6 Hz, 6H).
99%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 12h;	1 Step 1. 4-Nitro-1-(propan-2-yl)-1H-pyrazole To a solution of 4-nitro-1H-pyrazole (15 g, 133 mmol) in THF (300 ml) cooled to 0° C was added propan-2-ol (12.2 ml, 159 mmol), PPh3 (52.2 g, 199 mmol) and DIAD (31.0 ml, 159 mmol). The resulting mixture was stirred at rt for 12 h. The solution was concentrated under reduced pressure and the resulting residue purified by column chromatography (silica, 9- 33 % EtOAc in petrol) to give the title compound as a white solid. Y = 99 %. 1H NMR (400 MHz, chloroform-d) d 8.17 (s, 1H), 8.08 (s, 1H), 4.61 - 4.46 (m, 1H), 1.56 (d, J = 7 Hz, 6H).
58%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere;	56.1 Step 1: l-isopropyI-4-nitro-pyrazole. To a solution of 4-nitro- 1 H-pyrazole (10.0 g, 88.44 mmol) in THF (200 ml) was added propan-2-ol (8.12 ml, 106.1 mmol) and PPh3 (32.5 g, 123.8 mmol) at rt under N2. The RM was cooled to 0 °C then DIAD (20.6 ml, 106.1 mmol) was added. The RM was stirred at rt for 12 h then the solvent was removed under reduced pressure. The residue was purified by FCC (9 - 20 % EtOAc in petroleum ether) to give the title compound as a white solid (Y = 58 %).

With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;

References: [1]Current Patent Assignee: KRONOS BIO - US2010/152159, 2010, A1 Location in patent: Page/Page column 12-13.
[2]Current Patent Assignee: NODTHERA - WO2020/249664, 2020, A1 Location in patent: Paragraph 01275-01276.
[3]Current Patent Assignee: NODTHERA - WO2019/121691, 2019, A1 Location in patent: Paragraph 0963.
[4]Zabierek, Anna A.; Konrad, Kaleen M.; Haidle, Andrew M. [Tetrahedron Letters, 2008, vol. 49, # 18, p. 2996 - 2998].

10
[ 2075-46-9 ]
[ 141699-55-0 ]
[ 1314987-79-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 16h; Inert atmosphere;	42 Synthesis of tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate [0229j DIAD (3.92 mL, 19.9 mmmol, 1.5 equiv) was added dropwise to a stirred solution of 4-nitro-1H-pyrazole (1.5 g, 13.27 mmol), 1-Boc-3-Hydroxyazetidine (2.3 g, 13.27 mmol, 1 equiv) and triphenyiphosphine (5.22 g, 19.9 mmol, 1.5 equiv) in THF (30 mL) placed an ice-bath under N2. The mixture was stirred at 0 °C for 10 mm and allowed to warm to rt and stirred for 16 h. After diluted with EA (100 mL), the mixture was washed with water (40 mL), brine (30 mL x 2). The combined organic layer was dried, concentrated. The crude was purified through silica gel column chromatography (petroleum ether/EtOAc = 1/10) to give tert-butyl 3-(4-nitro-1H- pyrazol-1-yl)azetidine-1-carboxylate as light yellow solid (3 g, yield: 85%). ESI-MS (M+H-56) : 213.1. ‘H NMR (400 MHz, CDC13)(5: 8.28 (s, 1H), 8.16 (s, 1H), 5.07-5.04 (m, 1H), 4.44-4.40 (m, 2H), 4.34-4.30 (m, 2H), 1.47 (s, 9H).
60%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	4.1 Step 1 : tert-butyl 3-(4-nitro-1 H-pyrazol-1-yl)azetidine-1-carboxylate To a solution of 4-nitro-1 H-pyrazole (2.26 g, 20 mmol) and tert-butyl 3-hydroxyazetidine-1- carboxylate (3.56 g, 20 mmol) in THF (35 ml.) were added triphenylphosphine (6.28 g, 24 mmol) and DIAD (5.3 g, 26 mmol) dropwise at 0 °C. The mixture was stirred under nitrogen at room temperature overnight, then partitioned between water and EtOAc. The organic was separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (PE/EA 10:1) to give the desired product (3.2 g, 60%) as the white solid. LCMS (acidic 5 min): 2.42 min [M-55]+=213.1 , [MNa]+=291 .1 .
	With Di-tert-butyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;

5.3 g	With di-tert-butyl (E)-azodicarboxylate; triphenylphosphine In tetrahydrofuran at 10 - 35℃;	131.A A) tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate A) tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate To a solution of 4-nitro-1H-pyrazole (2.0 g), tert-butyl 3-hydroxyazetidine-1-carboxylate (3.1 g) and triphenylphosphine (5.6 g) in tetrahydrofuran (20 mL) was added di-tert-butyl (E)-diazene-1,2-dicarboxylate (5.3 g) at room temperature, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.3 g). 1H NMR(300 MHz, CDCl3)δ1.47 (9H, s), 4.28-4.37 (2H, m), 4.38-4.47 (2H, m), 5.05 (1H, tt, J = 7.9, 5.1 Hz), 8.16 (1H, s), 8.27 (1H, s).
5.6 g	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at 20℃;	29 Production Example 29 A 1.9 N diisopropyl azodicarboxylate-toluene solution (8.7 mL) was added to a mixture containing 4-nitro-1H-pyrazole (1.5 g), tert-butyl 3-hydroxyazetidine-1-carboxylate (commercially available from Tokyo Chemical Industry Co., Ltd., 2.3 g), triphenyl phosphine (4.35 g)and THF (50 mL), and the mixture was stirred at room temperature overnight. Magnesium chloride (3.15 g) was added to the reaction mixture, and the mixture was then stirred at 60° C. for 2 hours, cooled, and filtered. The filtrate was concentrated, and the obtained residue was distributed in water and ethyl acetate. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate, and then concentrated under a reduced pressure. The obtained residue was purified through silica gel column chromatography (elution solvent: hexane-ethyl acetate), and thereby tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate (5.6 g)as a solid was obtained.
	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 16h;	71.1 Step 1. Tert-butyl 3- (4-nitro-1H-pyrazol-1-yl) azetidine-1-carboxylate (71b) A mixture of 4a (2.0 g, 17.7 mmol) , tert-butyl 3-hydroxyazetidine-1-carboxylate (3.1 g, 17.7 mmol) and PPh3(7.0 g, 26.5 mmol) in THF (50 mL) was stirred at 0 for 5 min. Then DIAD (5.4 g, 26.5 mmol) was added to the reaction mixture. After stirring for 16 hours at RT, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (300 mL) . The separated organic layer was concentrated to dryness. The residue was purified by column chromatography on silica gel (PE: EtOAc = 10: 1) to afford the crude product (4.7 g, 100%yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H) , 8.16 (s, 1H) , 5.09 -5.06 (m, 1H) , 4.45 -4.41 (m, 2H) , 4.35 -4.31 (m, 2H) , 1.47 (s, 9H) .
5 g	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;	Step 1: Tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (3 g, 17.32 mmol) and 4- nitropyrazole (1.96 g, 17.32 mmol) in THF (20 mL) was added PPh3 (6.81 g, 25.98 mmol) in portions at 0 °C and DIAD (5.25 g, 25.98 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography (PE/EA, 5:1) to afford tert-butyl 3- (4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate (5 g). LCMS (ESI-MS) m/z = 269.1[M+H]+.
5 g	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;	Step 1: Tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (3 g, 17.32 mmol) and 4- nitropyrazole (1.96 g, 17.32 mmol) in THF (20 mL) was added PPh3 (6.81 g, 25.98 mmol) in portions at 0 °C and DIAD (5.25 g, 25.98 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography (PE/EA, 5:1) to afford tert-butyl 3- (4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate (5 g). LCMS (ESI-MS) m/z = 269.1[M+H]+.
	Stage #1: 4-nitro-1H-pyrazole; tert-butyl 3-hydroxyazetidine-1-carboxylate With triphenylphosphine In tetrahydrofuran at 20℃; Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 0 - 20℃;
5 g	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;	Step 1: Tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (3 g, 17.32 mmol) and 4- nitropyrazole (1.96 g, 17.32 mmol) in THF (20 mL) was added PPh3 (6.81 g, 25.98 mmol) in portions at 0 °C and DIAD (5.25 g, 25.98 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography (PE/EA, 5:1) to afford tert-butyl 3- (4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate (5 g). LCMS (ESI-MS) m/z = 269.1[M+H]+.
	With diisopropyl (E)-azodicarboxylate	1 Step 1: Step 1: Tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (3 g, 17.32 mmol) and 4-nitropyrazole (1.96 g, 17.32 mmol) in THF (20 mL) was added PPh3 (6.81 g, 25.98 mmol) in portions at 0° C. and DIAD (5.25 g, 25.98 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum and purified by silica gel column chromatography (PE/EA, 5:1) to afford tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate (5 g).

References: [1]Current Patent Assignee: BIOGEN MA - WO2015/89337, 2015, A1 Location in patent: Paragraph 0229.
[2]Current Patent Assignee: ANAXIS PHARMA - WO2021/168521, 2021, A1 Location in patent: Page/Page column 37; 38.
[3]Zabierek, Anna A.; Konrad, Kaleen M.; Haidle, Andrew M. [Tetrahedron Letters, 2008, vol. 49, # 18, p. 2996 - 2998].
[4]Current Patent Assignee: TAKEDA PHARMACEUTICAL - EP2832734, 2015, A1 Location in patent: Paragraph 0520.
[5]Current Patent Assignee: THE UNIVERSITY OF TOKYO - US2019/337926, 2019, A1 Location in patent: Paragraph 0587.
[6]Current Patent Assignee: XIAODONG LI - WO2020/119819, 2020, A1 Location in patent: Paragraph 00362.
[7]Current Patent Assignee: IAMBIC THERAPEUTICS - WO2024/20419, 2024, A1 Location in patent: Paragraph 0615.
[8]Current Patent Assignee: IAMBIC THERAPEUTICS - WO2024/20419, 2024, A1 Location in patent: Paragraph 0615.
[9]Huang, Junli; Ma, Zeli; Peng, Xiaopeng; Yang, Zichao; Wu, Yuhao; Zhong, Guanghong; Ouyang, Tianfeng; Chen, Zhen; Liu, Yao; Wang, Qirui; Chen, Jianjun; Chen, Ting; Zeng, Zhenhua [Journal of Medicinal Chemistry, 2024, vol. 67, # 4, p. 2438 - 2465].
[10]Current Patent Assignee: IAMBIC THERAPEUTICS - WO2024/20419, 2024, A1 Location in patent: Paragraph 0615.
[11]Current Patent Assignee: IAMBIC THERAPEUTICS - US2025/235456, 2025, A1.

11
[ 2075-46-9 ]
[ 3647-69-6 ]
[ 957479-10-6 ]

Yield	Reaction Conditions	Operation in experiment
49%	With potassium hydroxide In ethanol for 2h; Reflux;	N-(2-chloroethyl)morpholine HCI salt (2.1 g, 11.06 mmol) was added portionwise to a stirred mixture of 4-nitro-1 H-pyrazole (1.0 g, 8.85 mmol) and KOH (1.24 g, 22.12 mmol) in EtOH (20 ml_). The mixture was heated under reflux for 2 h and allowed to cool to rt.After dilution with EtOAc and water the organic phase was washed with brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel(100 g) eluting with 50:1 DCM-MeOH to provide an orange oil (987 mg, 49 %). 1H NMR (400 MHz, DMSO-Cf6) δH ppm 2.30 - 2.49 (m, 4 H), 2.73 (t, J=6.2 Hz, 2 H), 3.42 - 3.61(m, 4 H), 4.30 (t, J=6.2 Hz, 2 H), 8.26 (s, 1 H), 8.88 (s, 1 H); m/z (ESMPCI)+ : 227[M+Hf.
49%	With potassium hydroxide In ethanol Reflux;	50 N-(2-chloroethyl)morpholine HCl salt (2.1 g, 11.06 mmol) was added portionwise to a stirred mixture of 4-nitro-lH-pyrazole (1.0 g, 8.85 mmol) and KOH (1.24 g, 22.12 mmol) in EtOH (20 ml). The mixture was heated under reflux for 2 h and allowed to cool to rt. After dilution with EtOAc and water the organic phase was washed with brine, dried and concentrated. The residue was purified by flash column chromatography on silica gel (100 g) eluting with 50:1 DCM-MeOH to provide an orange oil (987 mg, 49 %). 1H NMR (400 MHz, DMSO-J6) δ ppm 2.30 - 2.49 (m, 4 H), 2.73 (t, /=6.18 Hz, 2 H), 3.42 - 3.61 (m, 4 H), 4.30 (t, /=6.18 Hz, 2 H), 8.26 (s, 1 H), 8.88 (s, 1 H); m/z (ES+APCI)+ : 227 [M+H]+.
44%	With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 2h; Sealed tube;	A18 Example A18 (1338) Preparation of intermediate 56 and intermediate 56' General procedure: Bromo-3-methoxypropane (1.20 mL, 10.51 mmol) was added at rt to a mixture of 5 - nitro-lH-pyrazole (1.00 g, 8.84 mmol), K2C03 (2.35 g, 17.00 mmol) in DMF (10 mL). This reaction was stirred in a sealed tube at 120 °C using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 min. Then, water was added and this mixture was extracted twice with EtOAc. The organic layers were mixed, dried over MgS04, filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography on silica gel (Irregular SiOH, 40 μιη, 80 g, mobile phase: gradient from 70% heptane, 29% EtOAc, 1% MeOH (+10% NH4OH) to 40% heptane, 52% EtOAc, 8% MeOH (+10% NH4OH)). The pure fractions were collected and the solvent was evaporated until dryness to give 1.39 g of intermediate 56 (85% yield) and 267 mg of intermediate 56' (16% yield). These intermediates were used as it in the next step

30%

With potassium hydroxide In ethanol at 80℃; for 3h;

50 Preparation of Compound 50-b N-(2-chloroethyl)morpholine hydrochloride (2.1 g, 11.06 mmol) and potassium hydroxide (1.24 g, 22.12 mmol) were added to a solution of 4-nitropyrazole (1.0 g, 8.85 mmol) in ethanol (20 mL) in sequence, the mixture was heated to 80° C. and stirred for 3 hours. The mixture was then concentrated under reduced pressure, the residue was treated with water (50 mL), extracted with ethyl acetate (50 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=1:1) to give compound 50-b (600 mg, yield: 30%). LC-MS (ESI): m/z=227 [M+H]+.

References: [1]Current Patent Assignee: CHEMICAL BIOPHARMACEUTICAL LABORATORIES OF PATRA - WO2010/100431, 2010, A1 Location in patent: Page/Page column 53.
[2]Current Patent Assignee: LIFEARC - WO2009/122180, 2009, A1 Location in patent: Page/Page column 97.
[3]Current Patent Assignee: JANSSEN PHARMACEUTICA - WO2018/2217, 2018, A1 Location in patent: Page/Page column 261; 267.
[4]Current Patent Assignee: GUANGZHOU MAXINOVEL PHARMACEUTICALS - US2015/336982, 2015, A1 Location in patent: Paragraph 0337; 0338.

12
[ 2075-46-9 ]
[ 24424-99-5 ]
[ 1018446-95-1 ]

Yield	Reaction Conditions	Operation in experiment
0.9 g	With dmap In dichloromethane at 20℃; for 2h;	4-Nitro-1H-pyrazole (1.1 g, 10 mmol) was dissolved in dichloromethane, and BocO (2.2 g, 10 mmol) and DMAP (110 mg, 1 mmol) were added, respectively.The mixture was stirred at room temperature for 2 hours. After completion, the reaction was quenched by the addition of ammonium chloride solution. The organic phase was concentrated and purified by flash column chromatography to afford tert-butyl 4-nitro-1H-pyrazole-1-carboxylate (1.7 g, 8 mmol). This intermediate was dissolved in methanol, purged with nitrogen, and then palladium on carbon was added. A hydrogen balloon was added, and the atmosphere was replaced with hydrogen three times. The reaction was allowed to proceed overnight. After completion, the mixture was filtered through a pad of Celite, and the filtrate was concentrated to afford BIOS-A1-2 (0.9 g, 5 mmol) as a pale yellow solid

References: [1]Current Patent Assignee: HANGHZOU BIO SINCERITY PHARMA TECH COP - CN120020131, 2025, A Location in patent: Paragraph 0186-0188.

13
[ 2075-46-9 ]
[ 24211-54-9 ]
[ 1201935-66-1 ]

Yield	Reaction Conditions	Operation in experiment
77%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 25℃; Inert atmosphere;	4.13.a a) A solution of DIAD (2.95 mL, 15.00 mmol) in THF (5 mL) was added over a period of 60 minutes to a stirred solution of (S)-5-hydroxypiperidin-2-one (1.382 g, 12.00 mmol), triphenylphosphine (3.93 g, 15.00 mmol) and 4-nitro-lH-pyrazole (1.131 g, 10 mmol) in THF (15 mL) cooled to O0C, under an atmosphere of nitrogen. The resulting solution was stirred at 00C for 1 hour and was then allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and a mixture of 20% EtOAc in isohexane (60 mL) was added with rapid stirring. The mixture was stirred10 for 20 minutes and then filtered. The solid was washed first with EtOAc and then with Et2O and then dried in air to afford (5R)-5-(4-nitropyrazol-l-yl)piperidin-2-one (1.623 g, 77% yield); 1H NMR spectrum (300 MHz, DMSO): δ 2.29 (4H, m), 3.56 (2H, dd), 4.75 (IH, m), 7.59 (IH, s), 8.31 (IH, s), 8.96 (IH, s); Mass spectrum: m/z (ESI+) (M+H)+ = 211.41.

References: [1]Current Patent Assignee: ASTRAZENECA - WO2009/153589, 2009, A1 Location in patent: Page/Page column 161.

14
[ 2075-46-9 ]
[ 75-45-6 ]
[ 956477-64-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 95℃; for 2h;	ClCHF2 is added to a solution of 4-nitro-lH-pyrazole and K2CO3 in DMF. The reaction is heated at 95°C for 2hrs. The reaction mixture is allowed to cool to room temperature. EtOAc and water were added to the reaction. The organic phase is separated, dried over MgSO4, evaporated under reduced pressure. The crude is used without further purification.

References: [1]Current Patent Assignee: GALAPAGOS - WO2010/10184, 2010, A1 Location in patent: Page/Page column 60.

15
[ 2075-46-9 ]
[ 100-39-0 ]
[ 88095-61-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate In N,N-dimethyl-formamide at 20℃;
95%	Stage #1: 4-nitro-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 12h; Inert atmosphere;	21.a a) 1-Benzyl-4-nitro-1H-pyrazole To a solution of 4-nitro-1H-pyrazole (283 mg, 2.5 mmol) in dry DMF (5 ml) under an argon atmosphere was added NaH (120 mg, 2.75 mmol) in small portions at 0° C. The reaction mixture was stirred at rt for 1 hour, cooled again to 0° C. before benzyl bromide (300 μl, 2.5 mmol) was added and stirred at rt for 12 h. The mixture was diluted with water, extracted with ethyl acetate and the product was purified by chromatography on silica gel using heptane/ethyl acetate as eluent. The title compound was obtained as light yellow oil (484 mg, 95%). MS ISP (m/e): 226.3 (100) [(M+Na)+].
78%	Stage #1: 4-nitro-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 15℃; for 1h; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 15℃; for 15h;	5.1; 76.1 Step 1: Step 1: Preparation of 1-benzyl-4-nitro-pyrazole To a stirred solution of 4-nitro-1H-pyrazole (2.00 g, 17.7 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (0.778 g, 19.0 mmol, 60% purity in mineral oil) at 0° C. The reaction mixture was stirred at 15° C. for 1 h and then cooled to 0° C. before benzyl bromide (2.10 mL, 17.7 mmol) was added. The reaction mixture was warmed to 15° C. and stirred for 15 h then quenched by adding ice water (5 mL) and extracted with ethyl acetate (15 mL3). The combined organic layers were washed with water (10 mL2) and brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO, 20 g silica, 0-30% ethyl acetate in petroleum ether, gradient over 20 min) to give 1-benzyl-4-nitro-pyrazole (2.80 g, 13.8 mmol, 78%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 8.10 (s, 1H), 8.04 (s, 1H), 7.45-7.39 (m, 3H), 7.32-7.28 (m, 2H), 5.31 (s, 2H); LCMS (ESI) m/z: 204.1 [M+H]+.

References: [1]Burch, Jason D.; Lau, Kevin; Barker, John J.; Brookfield, Fred; Chen, Yong; Chen, Yuan; Eigenbrot, Charles; Ellebrandt, Claire; Ismaili, M. Hicham A.; Johnson, Adam; Kordt, Daniel; Mackinnon, Colin H.; McEwan, Paul A.; Ortwine, Daniel F.; Stein, Daniel B.; Wang, Xiaolu; Winkler, Dirk; Yuen, Po-Wai; Zhang, Yamin; Zarrin, Ali A.; Pei, Zhonghua [Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5714 - 5727].
[2]Current Patent Assignee: HOFFMANN LA ROCHE - US2010/120874, 2010, A1 Location in patent: Page/Page column 27-28.
[3]Current Patent Assignee: JANSSEN PHARMACEUTICA - US2019/330198, 2019, A1 Location in patent: Paragraph 0853; 1110.

16
[ 2075-46-9 ]
[ 10226-29-6 ]
[ 1163253-71-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetonitrile; at 80℃; for 2h;Inert atmosphere;	6-(4-Nitro-pyrazol-1-yl)-hexan-2-oneIn a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 4-nitro-1H-pyrazole (8.29 g, 64.99 mmol) and Cs2CO3 (31.87 g, 71.49 mmol) in AcCN (75.0 mL) was treated with a solution of 6-bromo-hexan-2-one (12.80 g, 71.49 mmol) in AcCN (58.0 mL). The reaction mixture was stirred at 80 C. for 2 h. Water (270 mL) and EA (400 mL) were added to the cooled reaction mixture. The aq. layer was extracted with EA (400 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound. TLC: rf (50:50 hept-EA)=0.29. LC-MS-conditions 02: tR=0.82 min; [M+H]+=212.18.

References: [1]Patent: US2011/34516,2011,A1 .Location in patent: Page/Page column 34-35.

17
[ 22633-44-9 ]
[ 2075-46-9 ]
[ 1296309-91-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In acetonitrile at 60℃; for 16h; Inert atmosphere;	234.i Example 234: N-(l-((3-((Dimethylamino)methyl)oxetan-3-yl)methyl)-1H-pyrazol-4-yl)-1-(3- morpholinobenzyl)-1H-pyrazol -d]pyrimidin-6-amineStep (i)4-nitro-1H-pyrazole (0.5g, 4.42mmol) and K2CO3 (1.22g, 8.84mmol) were suspended in acetonitrile (30mL) in a 2-necked flask under Nitrogen and (3-(bromomethyl)oxetan-3- yl)methanol (1.36g, 7.52mmol) was added dropwise. The reaction was heated at 60°C for 16h and the solution was concentrated to about 1/3 of the volume under vacuum and then partitioned between DCM (50mL) and water (50mL). The organics were dried over Na2S04, filtered and the solvent evaporated to give (3-((4-nitro-1H-pyrazol-1-yl)methyl)oxetan-3- yl)methanol as a transparent oil (0.94g, quantitative yield).

References: [1]Current Patent Assignee: CELLZOME - WO2011/48082, 2011, A1 Location in patent: Page/Page column 198.

18
[ 2075-46-9 ]
[ 124-63-0 ]
[ 1206641-28-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: 4-nitro-1H-pyrazole; methanesulfonyl chloride With triethylamine In dichloromethane at 20℃; for 1h; Stage #2: With hydrogen In methanol at 20℃; Inert atmosphere;	96.i Example 96 : 1 -(2-Fluorobenzyl)-N-( 1 -(methylsulfonyl)- 1 H-pyrazo 1-4-yl)- 1 H-pyrazolo [3 ,4- d]pyrimidin-6-amineStep (i)To a solution of 4-nitro-1H-pyrazole (250mg, 2.2mmol) in DCM (5mL) were added triethylamine (0.46mL, 1.5eq) and methanesulfonyl chloride (0.20mL, 1.2eq). After stirring for lh at rt, water was added and the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in 5mL methanol and palladium on carbon added under an inert atmosphere. The reaction mixture was stirred overnight at rt under an hydrogen atmosphere. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give 1- (methylsulfonyl)- 1 H-pyrazo 1-4-amine as a brown oil (0.34g, 2. lmmol, 96%).

References: [1]Current Patent Assignee: CELLZOME - WO2011/48082, 2011, A1 Location in patent: Page/Page column 114.

19
[ 2075-46-9 ]
[ 75-03-6 ]
[ 876343-24-7 ]

Yield	Reaction Conditions	Operation in experiment
		Procedure A:General Procedure for the Synthesis of 4-Amino-l-N-alkylated-pyrazolesA solution of 4-nitropyrazole (300mg, 2.65mmol), potassium carbonate (2eq) and the alkylating reagent (l .leq) in acetonitrile (lOmL) was heated at 60°C for 18h. After cooling to rt the mixture was diluted with EtOAc and washed with water. The organic phase was collected, dried (MgS04) and concentrated in vacuo. The crude residue was dissolved in methanol (lOmL), palladium on carbon (50mg) was added and the reaction was stirred under a balloon of hydrogen for 18h. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give the desired product. Procedure B:Example 11: 2-((6-( 1 -Ethyl- 1 H-pyrazo 1-4-ylamino)- 1 H-pyrazo lo [3 ,4-d]pyrimidin- 1 -yl) methyl)benzonitrileThe following compound was made according to the procedure in Example 1, using 1-ethyl- lH-pyrazo 1-4-amine. 1 -ethyl- lH-pyrazol-4-amine was prepared by Procedure A using ethyl iodide as alkylating agent: 1H NMR (d6-DMSO) delta 9.94 (s, 1H), 8.94 (s, 1H), 8.10 (s, 2H), 7.91 (dd, 1H), 7.66 (td, 1H), 7.49-7.53 (m, 2H), 7.35-7.37 (m, 1H), 5.76 (s, 2H), 4.11 (q, 2H), 1.35 (t, 3H); LC-MS method B, (ES+) 345.1, RT = 8.58min.

References: [1]Patent: WO2011/48082,2011,A1 .Location in patent: Page/Page column 63; 64; 69; 70.

20
[ 2075-46-9 ]
[ 598-39-0 ]
[ 1006442-51-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 12h;	347 Intermediate 347A: 1-(2,2-Difluoroethyl)-4-nitro-1H-pyrazole Intermediate 347A: 1-(2,2-Difluoroethyl)-4-nitro-1H-pyrazole [0590] 4-nitro-1H-pyrazole (5 g, 44.2 mmol) in DMF (60 mL) was added K2CO3 (12.22 g, 88 mmol) over a period of 5 minutes. The reaction mixture was stirred at ambient temperature for 10 minutes. Next, 1,1-difluoro-2-iodoethane (11.03 g, 57.5 mmol) was added and the reaction mixture was stirred for 12 h at 90° C. The reaction mixture was then partitioned between water (150 mL) and EtOAc (150 mL) and the aqueous layer was extracted with EtOAc (2×100 mL). The combined EtOAc layer was washed with water (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to give crude product. The product was purified via column chromatography to afford 1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (5.2 g, 60% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.35 (s, 1H), 6.45 (m, 1H), 4.75 (td, J=15, 3.5 Hz, 2H).
60%	Stage #1: 4-nitro-1H-pyrazole With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 1,1-difluoro-2-iodoethane In N,N-dimethyl-formamide at 90℃; for 12h;	Intermediate I-i 5A: 1 -(2,2-difluoroethyl)-4-nitro- 1 H-pyrazole To a stirred solution of 4-nitro-1H-pyrazole (5g, 44.2 mmol) in DMF (60 mL) was added K2C03 (12.22 g, 88 mmol) over a period of 5 minutes. The reaction mixture wasstirred at ambient temperature for 10 minutes. 1,1 -difluoro-2-iodoethane (11.03 g, 57.5 mmol) was added and the reaction mixture was stirred for 12 hrs at 90 °C. The reaction mixture was then partitioned between water (150 mL) and EtOAc (150 mL) and the aqueous layer was extracted with EtOAc (2x100 mL). The combined EtOAc extracts were washed with water (2x 100 mL) and brine (100 mL), dried over sodium sulfate,filtered and concentrated in vacuo. The cmde product was purified via columnchromatography to afford 1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (5.2 g, 60 % yield) asa tan solid. ‘H NMR (400 MHz, DMSO-d6) 8.95 (s, 1H), 8.35 (s, 1H), 6.45 (m, 1H),4.75 (td, J15, 3.5 Hz, 2H).

References: [1]Current Patent Assignee: BRISTOL MYERS SQUIBB - US2015/191464, 2015, A1 Location in patent: Paragraph 0591.
[2]Current Patent Assignee: BRISTOL MYERS SQUIBB - WO2016/210036, 2016, A1 Location in patent: Page/Page column 125.

21
[ 2075-46-9 ]
[ 163035-65-2 ]
[ 1006333-08-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-nitro-1H-pyrazole; 2,2-difluoroethyl methanesulfonate With potassium carbonate In acetonitrile at 60℃; for 18h; Stage #2: With hydrogen In methanol for 18h;	4 A solution of 4-nitropyrazole (300mg, 2.65mmol), potassium carbonate (2eq) and 2,2- difluoromethane sulfonate (l . leq) in acetonitrile (lOmL) was heated at 60°C for 18h. After cooling to rt the mixture was diluted with EtOAc and washed with H20. The organic phase was collected, dried (MgS04) and concentrated in vacuo. The crude residue was dissolved in methanol (lOmL), palladium on carbon (50mg, 10%wt) was added and the reaction was stirred under a balloon of hydrogen for 18h. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give l-(2,2-difluoroethyl)-lH-pyrazol-4-amine.

References: [1]Current Patent Assignee: CELLZOME - WO2011/134831, 2011, A1 Location in patent: Page/Page column 40.

22
[ 2075-46-9 ]
[ 411235-57-9 ]
[ 1240568-16-4 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium carbonate; copper(II) sulfate; 4,4'-di-tert-butyl-2,2'-bipyridine In 1,2-dichloro-ethane at 70℃; for 16h; Inert atmosphere;	76 Preparation of Compound 76-b Under nitrogen, 4-nitropyrazole (1.0 g, 8.45 mmol) was added to a solution of cyclopropyl boronic acid (1.45 g, 16.9 mmol), anhydrous CuSO4 (1.55 g, 8.45 mmol), 4,4′-di-tert-butyl-2,2′-dipyridyl (2.26 g, 8.45 mmol) and Na2CO3 (1.87 g, 16.9 mmol) in 1,2-dichloroethane (30 mL). The mixture was stirred at 70° C. for 16 hours, then cooled to room temperature, concentrated under reduced pressure to remove there solvent, the residue was purified by silica column chromatography (petroleum ether:ethyl acetate=8:1) to give compound 76-b (740 mg, yield: 55%). LC-MS (ESI): m/z=154 [M+H]+.
55%	With copper diacetate; sodium carbonate; 4,4'-di-tert-butyl-2,2'-bipyridine In 1,2-dichloro-ethane at 70℃; for 16h; Inert atmosphere;	1.1 Preparation of key intermediate A-2 (1) 1.45g of cyclopropylboronic acid, 1.55g of anhydrous copper acetate, 2.26g of 4,4'-di-tert-butyl bipyridine and 1.87g of sodium carbonate were sequentially added to 30mL of 1,2-dichloroethane to obtain In the mixed solution, under a nitrogen atmosphere, 1.0 g of 4-nitropyrazole was added to the above mixed solution, and reacted at 70°C for 16 hours; after the reaction, cooled to room temperature, concentrated under reduced pressure to remove the solvent to obtain the crude product. The crude product was purified by silica gel column chromatography with a volume ratio of petroleum ether/ethyl acetate = 8/1 to obtain 740 mg of Intermediate A-1 with a yield of 55%.
47.5%	With [2,2]bipyridinyl; copper diacetate; sodium carbonate In 1,2-dichloro-ethane for 6h; Inert atmosphere; Heating;	Preparation of l-cyclopropyl-4-nitro-lH-pyrazole DCE (66 ml) was added to 4-nitro-lH-pyrazole (1.5 g, 13.3 mmol), cyclopropylboronic acid (2.28 g, 26.5 mmol), 2,2'-bipyridine (2.1 g, 13.3 mmol), and Na2C03 (2.81 g, 26.5 mmol) in a 250 mL RBF. It was purged with Ar (3x). Cu(OAc)2 (2.41 g, 13.3 mmol) was added followed purging with Ar. The reaction was then heated under Ar for 6 h. Upon the completion of reaction, the mixture was filtered through CELITE and concentrated. Purification with silica gel chromatography yielded 1- cyclopropyl-4-nitro-lH-pyrazole (0.965 g, 47.5%) as a white solid. Intermediate 8

46%	With sodium carbonate; copper(II) sulfate; 4,4'-di-tert-butyl-2,2'-bipyridine In 1,2-dichloro-ethane at 70℃; for 12h; Inert atmosphere;	1 Step 1. 1-Cyclopropyl-4-nitro-1H-pyrazole To a solution of 4-nitro-1H-pyrazole (8.0 g, 71 mmol) in DCE (6 ml) under N2 were added cyclopropylboronic acid (12.2 g, 142 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl) pyridine (18.0 g, 67 mmol), CuSO4 (12.4 g, 78 mmol) and Na2CO3 (15.0 g, 142 mmol). The RM was heated at 70° C for 12 h. The solution was concentrated in vacuo and the resulting residue purified by silica gel chromatography (5- 9 % EtOAc in petrol) to give the title compound as a yellow solid. Y = 46 %.
45%	With [2,2]bipyridinyl; copper diacetate; sodium carbonate In 1,2-dichloro-ethane at 70℃; for 3h; Inert atmosphere;	116.1 Step 1. 1-Cyclopropyl-4-nitro-1H-pyrazole (116b) To a mixture of 4a (50 g, 0.44 mol) , cyclopropylboronic acid (76 g, 0.688 mol) , Na 2CO 3 (94 g, 0.88 mol) , copper (II) acetate (80 g, 0.88 mol) in 1 L of 1, 2-dichloroethane was added 2, 2'-bipyridine (69 g, 0.44 mol) . The mixture was stirred at 70 for 3 hours under N 2 atmosphere. After cooling down to RT, the mixture was filtered and filtrate was diluted with DCM (3 L) . The mixture was washed with 2M aq. HCl. The organic layer was dried and concentrated to afford the desired product (30 g, 45%yield) as a yellow solid. 1H NMR (400 MHz, CDCl 3) δ 8.20 (s, 1H) , 8.03 (s, 1H) , 3.69 -3.67 (m, 1H) , 1.21 -1.12 (m, 4H) .
45%	With [2,2]bipyridinyl; copper diacetate; sodium carbonate In 1,2-dichloro-ethane at 70℃; for 18h;	36.1 Step 1: Synthesis of 1-cyclopropyl-4-nitro-1H-pyrazole A suction flask was charged with 4-nitro-1H-pyrazole (0.5 g, 4.42 mmol), cyclopropylboronic acid (0.75 g, 8.84 mmol), 2,2'-bipyridine (0.69 g, 4.42 mmol), and Na2CO3 (0.93 g, 8.84 mmol). Dichloroethane (22 ml) was added thereto, and nitrogen (N2) was bubbled for 10 minutes. Cu(OAc)2 (0.80 g, 4.42 mmol) was added thereto, and N2 was bubbled for 1 minute, followed by stirring thereof at 70°C for 18 hours. The temperature was lowered to room temperature, and it was filtered with ethyl acetate and then concentrated. It was extracted with ethyl acetate and a 1 N aqueous hydrochloric acid solution, dried over MgSO4, filtered under reduced pressure, and concentrated to obtain 0.67 g of the target compound (yield: 45%). 1H NMR (300 MHz, CDCl3) δ 8.20 (s, 1H), 3.69 (p, J = 1.8 Hz, 1H), 1.27-1.16 (m, 4H).
44%	With [2,2]bipyridinyl; copper diacetate; sodium carbonate at 65℃; for 16h;	Preparation of 1-cyclopropyl-4-nitro-1H-pyrazole To a stirred solution of 4-nitro-1H-pyrazole (5 g, 44.20 mmol) in dichloroethane (200 mL) were added cyclopropyl boronic acid (7.59 g, 88 mmol), 2,2-bipyridyl (7.59 g, 48.63 mmol) and sodium carbonate (13.37 g, 137 mmol) under oxygen atmosphere. Finally, copper acetate (8.86 g, 48.63 mmol) was added to the reaction mixture. Resulting mixture was heated to 65° C. for 16 h. Reaction mixture was filtered through a pad of celite bed, washed with methanol and concentrated under reduced pressure. The crude residue was extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. Crude product was purified by combi-flash chromatography (silica gel; 10% ethyl acetate-hexane) to afford 1-cyclopropyl-4-nitro-1H-pyrazole (3 g, 44% yield) as colourless liquid. LCMS Condition: A; Rt=1.68 min·m/z 153.1 [M+H]+
41%	With pyridine; copper diacetate; sodium carbonate In dichloromethane at 70℃; for 4h; Inert atmosphere;	23.1 Step 1): 1 - cyclopropyl -4 - nitro - 1H - pyrazole of preparation The 4 - nitro - 1H - pyrazole (200 mg, 1 . 77 mmol) dissolved in anhydrous dichloromethane (15 ml) in, adding the cyclopropyl-boronic acid (320 mg, 3 . 72 mmol), copper acetate (326 mg, 1 . 79 mmol), pyridine (144 mg, 1 . 82 mmol), sodium carbonate (432 mg, 4 . 08 mmol), 70 °C under the protective conditions, reaction 4 hours. The reaction solution concentration column chromatography (petroleum ether: ethyl acetate=4:1), to obtain yellow oil of 110 mg, yield 41%.
41%	With sodium carbonate; copper(II) sulfate; 4,4'-di-tert-butyl-2,2'-bipyridine In 1,2-dichloro-ethane at 70℃; for 16h;	39.1 Step 1: l-eyciopropyl-4-uitro-pyrazoIe. To a solution of 4-nitro- 1 H-pyrazole (2.0 g, 17.7 mmol) in DCE (50 ml) was added cyclopropylboronic acid (3.04 g, 35.4 mmol), 4-tert- butyl-2-(4-tert-butyl-2-pyridyl)pyridine (4.75 g, 17.7 mmol), Na2C03 (3.75 g, 35.4 mmol) and CuS04 (2.71 ml, 17.7 mmol). The RM was heated at 70 °C for 16 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (50 ml) and H20 (50 ml). The aqueous phase was extracted with EtOAc (3 x 50 ml) and the combined organics washed with brine (50 ml), dried over Na2S04 and concentrated. The residue was purified by FCC (5 - 33 % EtOAc in petroleum ether) to give the title compound as a white solid (Y = 41 %). H NMR (400 MHz, chloroform-* d = 8.20 (d, J= 4 Hz, 1H), 8.04 (d, /= 4 Hz, 1H), 3.71 - 3.66 (m, 1H), 1.21 - 1.13 (m, 4H).
41%	With [2,2]bipyridinyl; oxygen; copper diacetate; sodium carbonate In 1,2-dichloro-ethane at 80℃; for 6.4h;	1.1 Step 1: 1-cyclopropyl-4-nitro-1H-pyrazole (26) 4-nitro-1H-pyrrazole (24, 2.0 g, 18 mmol), cyclopropyl boronic acid (25, 3.0 g, 35 mmol), 2,2’-bipyridine (2.8 g, 18 mmol) and sodium carbonate (3.8 g, 35 mmol) were mixed in round bottom flask containing 1,2-dichloroethane (80 mL). The mixture was purged with oxygen gas for 10 min, copper (II) acetate (3.2 g, 18 mmol) was added, purged further for 15 min and heated at 80 °C for 6 h under oxygen atmosphere. The mixture was then passed through a celite pad, the filtrate was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude mass. The crude mass was purified by flash column chromatography on silica gel (using 12 g SNAP column, and 8% ethyl acetate in hexane on a Biotage chromatography system) to give 1- cyclopropyl-4-nitro-1H-pyrazole (26, 41% yield) as a white solid.1H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 7.97 (s, 1H), 3.70-3.64 (m, 1H), 1.03-1.02 (m, 2H), 0.88-0.86 (m, 2H).
37%	Stage #1: 4-nitro-1H-pyrazole; cyclopropylboronic acid With [2,2]bipyridinyl; sodium carbonate In 1,2-dichloro-ethane for 0.5h; Inert atmosphere; Reflux; Stage #2: In 1,2-dichloro-ethane at 70℃; for 6h;	109a l-Cyclopropyl-4-nitro-lH-pyrazole 109aA 100-mL three-neck round-bottomed flask equipped with a reflux condenser and magnetic stirrer was purged with nitrogen and charged with 4-nitropyrazole (500 mg, 4.42 CGIPHARM60WO mmol), cyclopropylboronic acid (760 mg, 8.84 mmol), sodium carbonate (937 mg, 8.84 mmol), 2, 2'-bipryidyl (690 mg, 4.42 mmol), and dichloroethane (45 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper (II) acetate (802 mg, 4.42 mmol) was added, and the reaction mixture was heated at 70 °C (oil bath temperature) for 6 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 50% ethyl acetate/hexanes) to afford a 37% yield (185 mg) of 109a as an off-white solid: mp 44-45 °C; ]H NMR (500 MHz, CDC13) δ 8.18 (s, 1H), 8.03 (s, 1H), 3.67 (s, 1H), 1.16 (m, 4H); MS (APCI+) mJz 154.1 (M+H).
1.0 g	With pyridine; dmap; copper diacetate In 1,4-dioxane at 100℃; for 16h;	1 Step 1 : 1 -Cyclopropyl -4-nitro- 1 /7-pyrazolc To a mixture of 4-nitro- lH-pyrazole (5.0 g, 44.2 mmol), cyclopropylboronic acid (11.3 g, 132 mmol), copper (II) acetate (12.0 g, 66.3 mmol) and DMAP (16.2 g, 132 mmol) in l,4-dioxane (100 mL) was added pyridine (5.3 mL, 65.7 mmol) at RT. The mixture was heated at 100 °C for 16 h. The mixture was cooled to RT and diluted with ethyl acetate. The organic solution was washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 1.0 g of the desired product. NMR (400 MHz, DMSO-
41.5 %	With [2,2]bipyridinyl; copper diacetate; sodium carbonate In 1,2-dichloro-ethane at 70℃;	5.1.3.1 1-Cyclopropyl-4-nitro-1H-pyrazole (16) To a flask charged with 4-nitro-1H-pyrazole (15, 4.00g, 35.37mmol) and cyclopropylboronic acid (6.08g, 70.75mmol) was added 1,2-dichloroethane (100mL), Cu(OAc)2 (6.43g, 35.37mmol), 2,2′-bipyridine (5.53g, 35.37mmol) and Na2CO3 (7.50g, 70.75mmol) in turn. The system was evacuated and purged with argon for three times, then the mixture was heated to 70°C and stirred for 10h. Upon completion, the reaction mixture was filtered through Celite, concentrated, and partitioned between DCM (150mL) and 0.5N aq. HCl (50mL). The separated organic phase was washed with brine (50mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EA, 20:1-10:1, v/v) to give the desired intermediate as a white amorphous solid (2.25g, 41.5%). 1H NMR (400MHz, CDCl3) δ 8.18 (s, 1H), 8.01 (s, 1H), 3.67 (tt, J=7.3, 3.9Hz, 1H), 1.22-1.16 (m, 2H), 1.15-1.08 (m, 2H).
41.5 %	With [2,2]bipyridinyl; copper diacetate; sodium carbonate In 1,2-dichloro-ethane at 70℃;	5.1.3.1 1-Cyclopropyl-4-nitro-1H-pyrazole (16) To a flask charged with 4-nitro-1H-pyrazole (15, 4.00g, 35.37mmol) and cyclopropylboronic acid (6.08g, 70.75mmol) was added 1,2-dichloroethane (100mL), Cu(OAc)2 (6.43g, 35.37mmol), 2,2′-bipyridine (5.53g, 35.37mmol) and Na2CO3 (7.50g, 70.75mmol) in turn. The system was evacuated and purged with argon for three times, then the mixture was heated to 70°C and stirred for 10h. Upon completion, the reaction mixture was filtered through Celite, concentrated, and partitioned between DCM (150mL) and 0.5N aq. HCl (50mL). The separated organic phase was washed with brine (50mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EA, 20:1-10:1, v/v) to give the desired intermediate as a white amorphous solid (2.25g, 41.5%). 1H NMR (400MHz, CDCl3) δ 8.18 (s, 1H), 8.01 (s, 1H), 3.67 (tt, J=7.3, 3.9Hz, 1H), 1.22-1.16 (m, 2H), 1.15-1.08 (m, 2H).

References: [1]Current Patent Assignee: GUANGZHOU MAXINOVEL PHARMACEUTICALS - US2015/336982, 2015, A1 Location in patent: Paragraph 0470; 0471.
[2]Current Patent Assignee: SHANGHAI ZAIJI MEDICINE TECH - CN111943959, 2020, A Location in patent: Paragraph 0030-0032; 0034.
[3]Current Patent Assignee: BRISTOL MYERS SQUIBB - WO2015/116882, 2015, A1 Location in patent: Page/Page column 81.
[4]Current Patent Assignee: NODTHERA - WO2020/249664, 2020, A1 Location in patent: Paragraph 01449-01450.
[5]Current Patent Assignee: XIAODONG LI - WO2020/119819, 2020, A1 Location in patent: Paragraph 00497.
[6]Current Patent Assignee: OSCOTEC - EP3722298, 2020, A1 Location in patent: Paragraph 0165.
[7]Current Patent Assignee: MUNA THERAPEUTICS APS - US2025/223293, 2025, A1 Location in patent: Paragraph 0294-0295.
[8]Current Patent Assignee: BEIJING SCITECH MINGQIANG PHARMACEUTICAL TECH - CN109535132, 2019, A Location in patent: Paragraph 0102-0105.
[9]Current Patent Assignee: NODTHERA - WO2019/121691, 2019, A1 Location in patent: Paragraph 0911.
[10]Current Patent Assignee: BLUEPRINT MEDICINES - WO2021/62327, 2021, A1 Location in patent: Paragraph 0208.
[11]Current Patent Assignee: GENENTECH - WO2012/31004, 2012, A1 Location in patent: Page/Page column 81-82.
[12]Current Patent Assignee: ICHNOS SCIENCES - WO2020/70331, 2020, A1 Location in patent: Page/Page column 71-72.
[13]Shi, Huanyu; Tang, Haotian; Li, Yan; Chen, Danqi; Liu, Tongchao; Chen, Yuting; Wang, Xin; Chen, Lin; Wang, Ying; Xie, Hua; Xiong, Bing [European Journal of Medicinal Chemistry, 2023, vol. 248].
[14]Shi, Huanyu; Tang, Haotian; Li, Yan; Chen, Danqi; Liu, Tongchao; Chen, Yuting; Wang, Xin; Chen, Lin; Wang, Ying; Xie, Hua; Xiong, Bing [European Journal of Medicinal Chemistry, 2023, vol. 248].

23
[ 5344-27-4 ]
[ 2075-46-9 ]
[ 1383705-77-8 ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	Step a) Formation of 4-[2-(4-nitro-1 H-pyrazol-1 -yl)ethyl]pyridine D IAD (7.27 m L; 37.2 m mol ; 1 . 1 eq . ) was added slowly i nto a sol ution of 4-(2- hydroxyethyl)pyridine (4.2 g; 34.1 mmol; 1.0 eq.) , 4-nitro-1 H-pyrazole (3.86 g; 34.1 mmol; 1.0 eq.) and triphenylphosphine (9.84 g; 37.5 mmol; 1.1 eq.) in THF (120 mL) maintained under nitrogen at 0C. The reaction mixture was allowed to warm to RT and left O/N. THF was removed under reduced pressure and the crude was purified by flash chromatography on silica (EtOAc:heptane, gradient from 50:50 to 100:0) to afford the title compound in quantitative yield. MS(ESI+): 219.0, (ESI-) 272.1 (purity 92.2%). 1 H NMR (400 Mz, DMSO-d6) delta 8.80 (s, 1 H), 8.44-8.43( m, 2H), 8.24 (s, 1 H), 7.18-7.17 (m, 2H), 4.50-4.48 (t, J = 7.04 Hz, 2H), 3.19-3.17 (t, J = 7.0 Hz, 2H).

References: [1]Patent: WO2012/84704,2012,A1 .Location in patent: Page/Page column 110-111.

24
[ 2075-46-9 ]
[ 3245-45-2 ]
[ 1394161-99-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In acetonitrile at 80℃; for 1.5h;	1 1 -[2-(3-Methoxy-phenoxy)-ethyl]-1H-pyrazol-4-ylamineStep 1 : To a solution of 4-nitro-1 H-pyrazole (220 mg, 1.90 mmol) in MeCN (9.5 mL), 1-(2- bromoethoxy)-3-methoxybenzene (495 mg, 2.14 mmol) dissolved in MeCN (1.5 mL) and Cs2C03 (697 mg, 2.14 mmol) was added. The resulting mixture was refluxed (80 °C) for 1 .5 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo to obtain 1 -(2-(3-methoxyphenoxy)ethyl)-4-nitro-1 /-/-pyrazole which was used in the next step without further purification. LC-MS conditions A: tR = 0.85 min, [M+H]+= no ionization.

References: [1]Current Patent Assignee: IDORSIA PHARMACEUTICALS - WO2012/110986, 2012, A1 Location in patent: Page/Page column 42-43.

25
[ 2075-46-9 ]
[ 18334-96-8 ]
[ 1394162-27-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide; acetonitrile at 100℃; for 0.166667h; Microwave;	1 1 -[2-(5-Methoxy-1 H-indol-3-yl)-ethyl]-1H-pyrazol-4-ylamineStep 1 : A microwave vial was charged with 4-nitro-1 H-pyrazole (1.0 g, 8.84 mmol), 3-(2- bromoethyl)-5-methoxy-1 H-indole (2.25 g, 8.84 mmol), Cs2C03 (5.76 g, 17.69 mmol), MeCN (75.0 mL) and DMF (5.0 mL). The tube was sealed and the reaction mixture was irradiated in the microwave to 100 °C for 10 min with cooling. The reaction mixture was diluted with water and DCM, then the org. layer was separated and the aq. layer was extracted with DCM. The combined org. layers were dried (MgS04), filtered and the solvent was removed under reduced pressure. Purification was performed by FC (EtOAc /hex 1 :4) to yield 5-methoxy-3- (2-(4-nitro-1 H-pyrazol-1-yl)ethyl)-1 /-/-indole as a yellow solid, which was used in the next step without further purification. LC-MS conditions B: tR = 0.70 min, [M+H]+= 287.13.
53 %	Stage #1: 4-nitro-1H-pyrazole; 3-(2-bromoethyl)-5-methoxy-1H-indole With caesium carbonate In N,N-dimethyl-formamide; acetonitrile at 20℃; Stage #2: In N,N-dimethyl-formamide; acetonitrile at 100℃; Microbiological reaction; Cooling;

References: [1]Current Patent Assignee: IDORSIA PHARMACEUTICALS - WO2012/110986, 2012, A1 Location in patent: Page/Page column 51-52.
[2]Brotschi, Christine; Bolli, Martin H.; Gatfield, John; Roch, Catherine; Sifferlen, Thierry; Treiber, Alexander; Williams, Jodi T.; Boss, Christoph [RSC Medicinal Chemistry, 2023, vol. 15, # 1, p. 344 - 354].

26
[ 2075-46-9 ]
[ 540-51-2 ]
[ 948571-47-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 8h;	1.1 Step 1) Synthesis of (2-hydroxylethyl)-1H-pyrazole-4-amine In a 50 mL round bottom flask, 4-nitroguanidine was added to 1 · 13 g (10 mmol), 2-bromoethanol 1 · 88 g (15 mmol), anhydrous potassium carbonate 2.76 g (20 mmol), DMF 50 ml, 50. (: stirring for 8 hours, cooling, suction filtration, followed by concentration of DMF, ethyl acetate (100 ml X 3), ethyl acetate was evaporated to give the title compound 1.35 g, yield: 86.0%, without purification, directly in palladium carbon Catalytic hydrogenation under conditions gave reduction to the oily product (2-hydroxyethyl)-1H-pyrazole-4-amine.
	Stage #1: 4-nitro-1H-pyrazole; 2-bromoethanol With potassium carbonate In acetonitrile at 60℃; for 18h; Stage #2: With palladium on activated charcoal; hydrogen In methanol; acetonitrile for 18h;	Procedure A:General Procedure for the Synthesis of 4-Amino-l-N-alkylated-pyrazolesA solution of 4-nitropyrazole (300mg, 2.65mmol), potassium carbonate (2eq) and the alkylating reagent (l . leq) in acetonitrile (lOmL) was heated at 60°C for 18h. After cooling to rt the mixture was diluted with EtOAc and washed with water. The organic phase was collected, dried (MgSC^) and concentrated in vacuo. The crude residue was dissolved in methanol (lOmL), palladium on carbon (50mg) was added and the reaction was stirred under a balloon of hydrogen for 18h. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give the desired product.

References: [1]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN108929309, 2018, A Location in patent: Paragraph 0063-0066.
[2]Current Patent Assignee: CELLZOME - WO2012/143320, 2012, A1 Location in patent: Page/Page column 39.

27
[ 2075-46-9 ]
[ 74-88-4 ]
[ 54210-32-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile at 60℃; for 18h;	3 A solution of 4-nitro-lH-pyrazole (lg, 8.84mmol), potassium carbonate (2.2eq) and iodomethane (l . leq) in acetonitrile (60mL) was heated at 60°C for 18h. After cooling to rt the mixture was diluted with EtOAc and washed with H20 and then brine. The organic phase was collected, dried (MgSC^) and concentrated in vacuo. The crude residue was dissolved in ethanol (60mL), palladium on carbon (50mg) was added and the reaction was stirred under a balloon of hydrogen for 18h. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give 1 -methyl- lH-pyrazol-4-amine.

References: [1]Current Patent Assignee: CELLZOME - WO2013/17479, 2013, A1 Location in patent: Page/Page column 45.

28
[ 2075-46-9 ]
[ 96-34-4 ]
[ 6715-84-0 ]

Yield	Reaction Conditions	Operation in experiment
95.8%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 12h;	4.1.1. 2-(4-nitro-1H-pyrazol-1-yl)ethanol (2a) General procedure: To a solution of 4-nitro-1H-pyrazole (1.13 g, 10 mmol) in DMF (20 ml) was added K2CO3 (1.38 g, 10 mmol) and 2-Bromoethanol(1.50 g, 12 mmol). Then the mixture was stirred at 60 °C for 12 h. DMF was removed at reduced pressure and add water (100 ml), extractedwith ethyl acetate (3×100 ml), dried with Na2SO4 and evaporated to give compound 2a as a white solid.
92%	With potassium carbonate In acetonitrile at 60℃; for 5h;	1 Step 1 Step 1 To a solution of 4-nitro-lH-pyrazole (100 g, 0.88 mol) in ACN (2L) was added K2C03 (183.2 g, 1.33 mol) and methyl 2-chloroacetate (95.6 g, 0.88 mol). The mixture was warmed to 60°C and stirred for 5h. The mixture was then filtered and solvent removed to give methyl 2-(4- nitro-lH-pyrazol-l-yl)acetate as a white solid (150 g, 92%). 1H NMR (400 MHz CDC13): δ 8.28 (s, 1H), 8.11 (s, 1H), 4.98 (s, 2H), 3.84 (s, 3H),
	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 12h;	1.4.1 (1) Synthesis of methyl 2-(4-nitro-1H-pyrazol-1-yl)acetate In a 50mL round bottom flask, add 0.11g (1mmol) of 4-nitropyrazole, add 10mL DMF, add 30.28g (2mmol) of K2CO3, add 0.13g (1.2mmol) of methyl chloroacetate, and stir for 12h at 60°C. When poured into water, a white solid precipitated out, filtered with suction to obtain a white solid, and dried to obtain methyl 2-(4-nitro-1H-pyrazol-1-yl)acetate product.

References: [1]Ding, Huai-Wei; Wang, Shu; Qin, Xiao-Chun; Wang, Jian; Song, Hong-Rui; Zhao, Qing-Chun; Song, Shao-Jiang [Bioorganic and Medicinal Chemistry, 2019, vol. 27, # 13, p. 2729 - 2740].
[2]Current Patent Assignee: CELLZOME - WO2013/14162, 2013, A1 Location in patent: Page/Page column 99.
[3]Current Patent Assignee: SHENYANG PHARMACEUTICAL UNIVERSITY - CN113135913, 2021, A Location in patent: Paragraph 0062; 0081-0086.

29
[ 2075-46-9 ]
[ 78385-26-9 ]
[ 1428574-89-3 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium formate; In methanol; acetonitrile;	Example 42 1-((3-Methyloxetan-3-yl)methyl)-1H-pyrazol-4-amine A mixture of 4-nitropyrazole (1.13 g, 10 mmol) and K2CO3 (3.4 g, 25 mmol) in MeCN (50 mL) was stirred at room temperature for 15 min prior to addition of <strong>[78385-26-9]3-(bromomethyl)-3-methyloxetane</strong> (1.8 g, 11 mmol). The reaction mixture was stirred at room temperature for 18 hr, filtered and the filter cake washed with MeCN. The filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) gradient to afford 1-((3-methyloxetan-3-yl)methyl)-4-nitro-1H-pyrazole as a colorless solid (1.43 g, 73%). A portion of this solid (206 mg, 1.04 mmol) dissolved in MeOH (20 mL) was treated with ammonium formate (260 mg, 4.13 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 80 C. for 1.5 hr, cooled, filtered through Celite and the filtrate concentrated under reduced pressure to afford 1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-amine as a pale pink gum (160 mg, 92%). 1H NMR (400 MHz, CDCl3) delta 7.15 (s, 1H), 6.97 (s, 1H), 4.66 (d, J=6.1 Hz, 2H), 4.37 (d, J=6.1 Hz, 2H), 4.19 (s, 2H), 2.91 (s, 2H), 1.23 (s, 3H).

References: [1]Patent: US2014/88117,2014,A1 .Location in patent: Page/Page column.

30
[ 2075-46-9 ]
[ 79-08-3 ]
[ 6645-69-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: 4-nitro-1H-pyrazole With potassium hydroxide In water; acetone at 20℃; for 0.5h; Stage #2: bromoacetic acid In water; acetone at 20℃;	G2.i Step (i) 2-(4-nitro-lH-pyrazol-l-yl)acetic acid A solution of potassium hydroxide (32.7 g, 0.58 mol) in water (100 mL) was added to a stirred mixture of 4-nitro-lH-pyrazole (30 g, 0.27 mol) in acetone (500 mL) at room temperature. After 30 min, a solution of 2-bromoacetic acid (38.7 g, 0.27 mol) in acetone (100 mL) was added and the reaction was stirred overnight. The solvent was removed in vacuo, the residue was diluted with water then extracted three times with ethyl acetate and the combined organic layer was concentrated in vacuo. The residue was further extracted with dichloromethane and methanol and the combined organic layer was concentrated in vacuo to afford 2-(4-nitro-lH-pyrazol-l-yl)acetic acid (40 g, 88%).

References: [1]Current Patent Assignee: CELLZOME - WO2013/174895, 2013, A1 Location in patent: Page/Page column 70.

31
[ 51333-90-5 ]
[ 2075-46-9 ]
[ 1497207-40-5 ]

Yield	Reaction Conditions	Operation in experiment
0.21 g	With potassium carbonate In acetonitrile at 60℃;	G3.i Step (i) l-(2-( 4-nitro- lH-pyrazol- 1 -yl) ethyl) pyrrolidin-2-one l-(2-Chloroethyl)pyrrolidin-2-one (0.72 g, 4.8 mmol) was added to a solution of potassium carbonate (1.2 g, 8.7 mmol), 4-nitro-lH-pyrazole (0.5 g, 4.4 mmol) in dry acetonitrile (4 mL) and the reaction was stirred at 60°C overnight. The solvent was concentrated in vacuo, then the residue was slurried in water, collected by filtration and dried in vacuo to afford l-(2-(4- nitro-lH-pyrazol-l-yl)ethyl)pyrrolidin-2-one (0.21 g, 0.9 mmol). LC-MS (Method H), RT = 1.23 min. (ES+) 225.

References: [1]Current Patent Assignee: CELLZOME - WO2013/174895, 2013, A1 Location in patent: Page/Page column 71.

32
[ 2075-46-9 ]
[ 6482-24-2 ]
[ 948570-74-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-nitro-1H-pyrazole; 2-Bromoethyl methyl ether With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 1h; Stage #2: With 10% Pd/C; hydrogen In methanol at 20℃; for 2h;	174.1 Step 1: 1-(2-methoxyethyl)-JH-pyrazol-4-amine Example 1743-(2,6-difluoro-3,5-dimethoxyphenyl)-1- j1-(2-methoxyethyl)-1H-pyrazol-4-ylj -1,3,4,7-tetrahydro-2H-pyrazolo j4’,3’ : 5,6j pyrido j4,3-dj pyrimidin-2-one Step 1: 1-(2-methoxyethyl)-JH-pyrazol-4-amine A mixture of 4-nitro-1H-pyrazole (0.5 g, 4 mmol), Ethane, 1-bromo-2-methoxy (0.84mL, 8.8 mmol), and potassium carbonate (1.2 g, 8.8 mmol) in N,N-dimethylformamide (8mL, 100 mmol) was stirred at 70 °C for 1 hour. After cooling to room temperature, the mixture was diluted with water then extracted with EtOAc. The combined extracts were washed with water and brine. The organic layer was dried over Na2SO4, filtered then concentrated. The residue was dissolved in methanol (10 ml) then a catalytic amount ofpalladium (10 wt % on activated carbon) was added. The suspension was stirred under a balloon of H2 at room temperature for 2 hours then filtered and concentrated. The residue was used in the next step without further purification.

References: [1]Current Patent Assignee: INCYTE - WO2014/7951, 2014, A2 Location in patent: Page/Page column 241.

33
[ 2075-46-9 ]
[ 598-39-0 ]
[ 1006333-08-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-nitro-1H-pyrazole; 1,1-difluoro-2-iodoethane With potassium carbonate In acetonitrile at 70℃; for 1h; Stage #2: With 10% Pd/C; hydrogen In methanol at 20℃; for 2h;	175.1 Step 1: 1-(2, 2-difluoroethyl)-JH-pyrazol-4-amine Example 175 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-j1-(2,2-difluoroethyl)-1H-pyrazol-4-ylj -1,3,4,7- tetrahydro-2H-pyrazolo j4’,3’ : 5,6j pyrido j4,3-dj pyrimidin-2-one Step 1: 1-(2, 2-difluoroethyl)-JH-pyrazol-4-amine A mixture of 4-nitro-1H-pyrazole (0.25 g, 2.2 mmol), 1,1-difluoro-2-iodoethane (0.23 mL, 2.4 mmol), and potassium carbonate (0.61 g, 4.4 mmol) in acetonitrile (8 mL, 200 mmol) was stirred at 70 °C for 1 hour. After cooling to room temperature, the mixture was diluted with water then extracted with EtOAc. The combined extracts were washed withwater and brine. The organic layer was dried over Na2SO4 then concentrated. The residue was dissolved in methanol (8 mL) then palladium (10 wt % on activated carbon, 50 mg) was added. The suspension was stirred under H2 atmosphere (balloon) at room temperature for 2 hours then filtered and concentrated. The residue was used in the next step without further purification.

References: [1]Current Patent Assignee: INCYTE - WO2014/7951, 2014, A2 Location in patent: Page/Page column 241; 242.

34
[ 2075-46-9 ]
[ 4773-33-5 ]
[ 220535-36-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With caesium carbonate In N,N-dimethyl-formamide at 20℃;	A11 Example Al l: methyl -(4-amino-lH-pyrazol-l-yl)-2-phenylacetate Example Al l: methyl -(4-amino-lH-pyrazol-l-yl)-2-phenylacetate To a solution of ethyl 2-chloro-2-phenyl-acetate (501 mg, 2.52 mmol) and 4-nitro-lH- pyrazole (1.1 equiv., 2.77 mmol, 313 mg) in dimethylformamide (5 mL) was added cesium carbonate (1.1 equiv., 2.77 mmol, 904 mg) and the mixture was stirred overnight at rt. The mixture was diluted with 50 mL EtOAc, and washed with 2 x 50 mL 1 :1 H20:brine. The organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by CombiFlash (40 g; dry load; 100:0 to 50:50 heptane:EtOAc over 20 minutes) provided ethyl 2-(4-nitropyrazol-l- yl)-2- phenyl-acetate (694 mg, 2.52 mmol, 99% yield). Nitropyrazole reduction is accomplished using palladium on carbon as outlined in Example A3.

References: [1]Current Patent Assignee: GENENTECH - WO2014/23258, 2014, A1 Location in patent: Page/Page column 61.

35
[ 2075-46-9 ]
[ 269740-46-7 ]
[ 1557243-00-1 ]

Yield	Reaction Conditions	Operation in experiment
51%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃;

References: [1]Burch, Jason D.; Lau, Kevin; Barker, John J.; Brookfield, Fred; Chen, Yong; Chen, Yuan; Eigenbrot, Charles; Ellebrandt, Claire; Ismaili, M. Hicham A.; Johnson, Adam; Kordt, Daniel; Mackinnon, Colin H.; McEwan, Paul A.; Ortwine, Daniel F.; Stein, Daniel B.; Wang, Xiaolu; Winkler, Dirk; Yuen, Po-Wai; Zhang, Yamin; Zarrin, Ali A.; Pei, Zhonghua [Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5714 - 5727].

36
[ 2075-46-9 ]
[ 96-32-2 ]
[ 6715-84-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetone for 5h; Reflux;	765A Example 765A methyl 2-(4-nitro- 1 H-pyrazol- 1 -yl)acetate A suspension of 4-nitro- lH-pyrazole (1 g, 8.84 mmol), methyl 2-bromoacetate (1.556 g, 10.17 mmol), and potassium carbonate (1.833 g, 13.27 mmol) in acetone (44 ml) was heated at reflux for 5 hours. The cooled reaction was filtered with acetone washes. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (AnaLogix IntelliFlash 280 system) eluting with a gradient of from 5% to 35% ethyl acetate in heptanes to afford the title compound. MS (DCI+) m/z 185.9 (M+H)+.
89 %	Stage #1: 4-nitro-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide Inert atmosphere; Cooling with ice; Stage #2: bromoacetic acid methyl ester In N,N-dimethyl-formamide Cooling with ice;	2.1 Step 1 Under nitrogen protection, compound 2a (6.00 g, 53.10 mmol) was dissolved in N,N-dimethylformamide (50 mL), and 60% sodium hydride (2.50 g, 63.72 mmol) was added in batches under an ice bath. Methyl bromoacetate (6.00 mL, 63.72 mmol) was added after reacting for 30 minutes, and the reaction was continued for 2 hours under an ice bath. The reaction system was quenched by adding water (200 mL) under an ice bath, and extracted with ethyl acetate (200 mL 3 2). The organic phase was successively washed with saturated brine (200 mL 3 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether=0-100%) to obtain compound 2b (8.80 g), yield: 89%. MS-ESI calculated value [M+H] + 186, found 186.
89 %	Stage #1: 4-nitro-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide Inert atmosphere; Cooling with ice; Stage #2: bromoacetic acid methyl ester In N,N-dimethyl-formamide Cooling with ice;	2.1 Step 1 Under nitrogen protection, compound 2a (6.00 g, 53.10 mmol) was dissolved in N,N-dimethylformamide (50 mL), and 60% sodium hydride (2.50 g, 63.72 mmol) was added in batches under an ice bath. Methyl bromoacetate (6.00 mL, 63.72 mmol) was added after reacting for 30 minutes, and the reaction was continued for 2 hours under an ice bath. The reaction system was quenched by adding water (200 mL) under an ice bath, and extracted with ethyl acetate (200 mL 3 2). The organic phase was successively washed with saturated brine (200 mL 3 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether=0-100%) to obtain compound 2b (8.80 g), yield: 89%. MS-ESI calculated value [M+H] + 186, found 186.

89 %	Stage #1: 4-nitro-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide Inert atmosphere; Cooling with ice; Stage #2: bromoacetic acid methyl ester In N,N-dimethyl-formamide Cooling with ice;	2.1 Step 1 Under nitrogen protection, compound 2a (6.00 g, 53.10 mmol) was dissolved in N,N-dimethylformamide (50 mL), and 60% sodium hydride (2.50 g, 63.72 mmol) was added in batches under an ice bath. Methyl bromoacetate (6.00 mL, 63.72 mmol) was added after reacting for 30 minutes, and the reaction was continued for 2 hours under an ice bath. The reaction system was quenched by adding water (200 mL) under an ice bath, and extracted with ethyl acetate (200 mL 3 2). The organic phase was successively washed with saturated brine (200 mL 3 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether=0-100%) to obtain compound 2b (8.80 g), yield: 89%. MS-ESI calculated value [M+H] + 186, found 186.
89 %	Stage #1: 4-nitro-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide Inert atmosphere; Cooling with ice; Stage #2: bromoacetic acid methyl ester In N,N-dimethyl-formamide Cooling with ice;	2.1 Step 1 Under nitrogen protection, compound 2a (6.00 g, 53.10 mmol) was dissolved in N,N-dimethylformamide (50 mL), and 60% sodium hydride (2.50 g, 63.72 mmol) was added in batches under an ice bath. Methyl bromoacetate (6.00 mL, 63.72 mmol) was added after reacting for 30 minutes, and the reaction was continued for 2 hours under an ice bath. The reaction system was quenched by adding water (200 mL) under an ice bath, and extracted with ethyl acetate (200 mL 3 2). The organic phase was successively washed with saturated brine (200 mL 3 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate:petroleum ether=0-100%) to obtain compound 2b (8.80 g), yield: 89%. MS-ESI calculated value [M+H] + 186, found 186.
89 %	With sodium hydride In N,N-dimethyl-formamide Cooling with ice;	1.1 Step 1 Under nitrogen protection, compound 1a (6.00 g, 53.10 mmol) was dissolved in N,N-dimethylformamide (50 mL), 60% sodium hydride (2.50 g, 63.72 mmol) was added in batches under an ice bath, methyl bromoacetate (6.00 mL, 63.72 mmol) was added after 30 minutes of reaction, and the reaction was continued under an ice bath for 2 hours. Under the ice bath, the reaction system was quenched with water (200mL), ethyl acetate (200mL x 2) was extracted, and the organic phase was successively dried by saturated brine (200mL x 1), anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain compound 1b (8.80g), yield: 89%.

References: [1]Current Patent Assignee: ABBVIE - WO2014/139328, 2014, A1 Location in patent: Page/Page column 658A.
[2]Current Patent Assignee: MINGHUI PHARMACEUTICAL HANGZHOU LIMITED - EP4119565, 2023, A1 Location in patent: Paragraph 0072-0074.
[3]Current Patent Assignee: MINGHUI PHARMACEUTICAL HANGZHOU LIMITED - EP4119565, 2023, A1 Location in patent: Paragraph 0072-0074.
[4]Current Patent Assignee: MINGHUI PHARMACEUTICAL HANGZHOU LIMITED - EP4119565, 2023, A1 Location in patent: Paragraph 0072-0074.
[5]Current Patent Assignee: MINGHUI PHARMACEUTICAL HANGZHOU LIMITED - EP4119565, 2023, A1 Location in patent: Paragraph 0072-0074.
[6]Current Patent Assignee: MINGHUI PHARMACEUTICAL HANGZHOU - WO2024/32569, 2024, A1 Location in patent: Page/Page column 26-27.

37
[ 2075-46-9 ]
[ 620-05-3 ]
[ 88095-61-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 16h;	General Procedures for the Preparation of 1-Alkyl-4-nitroazoles General procedure: To a stirred solution of 4-nitroimidazole or 4-nitropyrazole (1.00 g, 8.84 mmol) in DMF (6.00 mL) at 25°C were added K2CO3 (1.47 g, 10.6 mmol) and alkyl iodide(10.6 mmol). After stirring for 16 h at 25 °C, the reactionmixture was treated with water (15 mL) and EtOAc (20 mL)and transferred to a 125 mL separatory funnel. The organiclayer was collected and the aqueous layer was extracted withEtOAc (25 mL × 2). The combined organic layers werewashed with brine (20 mL), dried over sodium sulfate andfiltered. The filtrate was concentrated, and the residue waspurified by flash column chromatography to provide thecorresponding alkyl azole.
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	1.2.2 General procedure for the synthesis of compounds (2a-g) General procedure: A mixture of methyliodide (12 mmol), 1a (6 mmol) and K2CO3 (9 mmol) in DMF (6 mL) was stirred overnight at room temperature. Then the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL × 3). The organic layer was washed with aqueous saturated sodium bicarbonate, dried by sodium sulfate, ltered and concentrated in vacuum. Purication by ash column chromatography gave the desired product 2a (2a-2c).A mixture of iodobenzene (6.82 mmol), 1a (0.70 g, 6.20 mmol), 8-hydroxyquinoline (0.09 g, 0.62 mmol), cuprous iodide (0.18 g, 0.62 mmol) and potassium carbonate (1.73 g, 12.40 mmol) in DMSO (10 mL) was heated at 135 oC for 20 h. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate, dried by sodium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography gave the desired products 2d (2d-2g).
	With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 16h;

References: [1]Jung, Haeun; Bae, Seri; Jang, Ha-Lim; Joo, Jung Min [Bulletin of the Korean Chemical Society, 2014, vol. 35, # 10, p. 3009 - 3014].
[2]Wang, Chen-Ru; Wang, Ze-Feng; Shi, Lu; Wang, Zhong-Chang; Zhu, Hai-Liang [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 14, p. 2382 - 2390].
[3]Wang, Peng-Fei; Wang, Ze-Feng; Qiu, Han-Yue; Huang, Yue; Hu, Hui-Min; Wang, Zhong-Chang; Zhu, Hai-Liang [ChemMedChem, 2018, vol. 13, # 23, p. 2558 - 2566].

38
[ 2075-46-9 ]
[ 281204-90-8 ]
[ 1639350-76-7 ]

Yield	Reaction Conditions	Operation in experiment
18%	With caesium carbonate In N,N-dimethyl-formamide at 85℃; for 3h; Inert atmosphere;	117 Synthesis of compound 117.4. [00685] Synthesis of compound 117.4. To a solution of compound 117.3 (1.0 g, crude) and 4-nitro-lH-pyrazole (582 mg, 5.15 mmol, 1.00 equiv) in anhydrous DMF (20 mL) was added Cs2C03 (5.07 g, 3.00 equiv). Reaction was stirred for 3 hours at 85 °C under nitrogen. The resulting solution was diluted with H20, extracted with 3 x 80 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. Crude was purified using flash column chromatography to give 200 mg (18%) of compound 117.4 as a white solid.

References: [1]Current Patent Assignee: NIMBUS IRIS - WO2014/194242, 2014, A2 Location in patent: Paragraph 00682; 00685.

39
[ 2075-46-9 ]
[ 23233-33-2 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; caesium carbonate; trans-N,N'-dimethyl-1,2-cyclohexanediamine In N,N-dimethyl-formamide at 90 - 100℃;

References: [1]Zheng, Ke; Iqbal, Sarah; Hernandez, Pamela; Park, Hajeung; Lograsso, Philip V.; Feng, Yangbo [Journal of Medicinal Chemistry, 2014, vol. 57, # 23, p. 10013 - 10030].

40
[ 2075-46-9 ]
[ 612835-53-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; caesium carbonate; trans-N,N'-dimethyl-1,2-cyclohexanediamine In N,N-dimethyl-formamide at 90 - 100℃;

References: [1]Zheng, Ke; Iqbal, Sarah; Hernandez, Pamela; Park, Hajeung; Lograsso, Philip V.; Feng, Yangbo [Journal of Medicinal Chemistry, 2014, vol. 57, # 23, p. 10013 - 10030].

41
[ 2075-46-9 ]
[ 558-42-9 ]
[ 1182917-01-6 ]

Yield	Reaction Conditions	Operation in experiment
78%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;	Synthesis of 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol A mixture of 4-nitro-1H-pyrazole (1.6 g, 13.9 mmol), 1-chloro-2-methylpropan-2-ol (1.5 g, 13.9 mmol) and Cs2CO3 (9.1 g, 27.8 mmol) in DMF (20 mL) was stirred at 80° C. for 5 h. The reaction mixture was cooled to RT and diluted with EA (200 ml). The organic phase was washed by water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol as a yellow oil (2.0 g, 78percent), which was used for the next step without further purification. MS (ES+) C7H11N3O3 requires: 185, found: 186 [M+H]+.
64%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 14h;	To a strried solution of 4-nitro-1H-pyrazole 12 (5.0 g, 44.0 mmol) and 1- chloro-2-methylpropan-2-ol 12a (9.5 g, 88.0 mmol) in DMF (60 mL), cesium carbonate (26 g, 88.0 mmol) was charged at room temperature. The reaction contents were heated at 100°C for 14 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (120 mL) and washed with water (2 x 100 mL). The organic layer was dried (Na2SO4), filtered and concentrated to give 2-methyl-i -(4-nitro- I H-pyrazol- 1 -yl)propan2-ol 18 (5.2 g, 64percent yield). ?HNMR (400 MHz, DMSO-d6): oe 8.6 (s, 1H), 8.25 (s, 1H),4.83 (s, 1H), 4.09 (s, 2H), 1.08 (s, 6H).

References: [1]Patent: US2015/111857,2015,A1 .Location in patent: Paragraph 0223; 0224.
[2]Patent: WO2015/25197,2015,A1 .Location in patent: Paragraph 00082.

42
[ 2075-46-9 ]
[ 476014-76-3 ]
4-(4-nitro-1H-pyrazol-1-yl)piperidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 27℃; for 16.16h;	A solution of DIAD (5.3 g, 26.4 mmol) in dry THF (20 mL) was added to a solution of (<strong>[476014-76-3]4-hydroxypiperidin-2-one</strong> 41 (2.20 g, 19.4 mmol), 4-nitro-1H-pyrazole (2.0 g, 17.6 mmol) and triphenyiphosphine (6.9 g, 26.4 mmol) in dry THF (80 mL) drop-wise at 0°C over a period of 10 mm. The mixture was then stirred at room temperature for 16h. Solvents evaporated under reduced pressure to obtain a crude solid, which was purified by flash chromatography on silica gel using ethyl acetate as eluent to obtain 3 4-(4-nitro- 1H-pyrazol-1-yl)piperidin-2-one 42 (1.8 g, 48percent yield) as a white solid. ?H NMR (400 MHz, DMSO-d6): 8.96 (s, 1H), 8.31 (s, 1H), 7.71 (s, 1H), 4.83-4.79 (m, 1H), 3.25-3.15 (m, 2H), 2.69-2.67 (m, 2H), 2.20-2.17 (m, 1H), 2.13-2.06 (m, 1H).

References: [1]Patent: WO2015/25197,2015,A1 .Location in patent: Paragraph 000112.

43
[ 2075-46-9 ]
[ 15205-66-0 ]
[ 1677706-50-1 ]

Yield	Reaction Conditions	Operation in experiment
41%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃;	39 Synthesis of compound 39.2. Into a 100 mL round-bottom flask, was placed a solution of compound 39.1 (1 g, 8.84 mmol, 1.00 equiv) in THF (20 mL), triphenylphosphine (4.6 g, 17.54 mmol, 1.98 equiv) and 2-methanesulfonylethan-1-ol (1.1 g, 8.86 mmol, 1.00 equiv). This was followed by the addition of DEAD (2.7 g, 15.50 mmol, 1.75 equiv) dropwise with stirring. The reaction was stirred overnight at room temperature. The resulting solution was diluted with 50 mL of H20 and extracted with 2 x 50 mL of ethyl acetate . The organic layers were combined and washed with 2 x 100 mL of brine, then dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified using flash column chromatography to furnish 0.8 g (4 1%) of intermediate 39.2 as a yellow solid.

References: [1]Current Patent Assignee: NIMBUS IRIS - WO2015/48281, 2015, A1 Location in patent: Paragraph 00449; 00450.

44
[ 2075-46-9 ]
[ 28466-26-4 ]
[ 63680-90-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triethylsilane; 5% palladium on Al2O3; In ethanol; water; at 15℃; for 72h;Inert atmosphere;	Example 1 3-chloro-1H-pyrazol-4-amine hydrochloride (1a) A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with a mechanical stirrer, temperature probe and nitrogen (N2) inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37 wt %, 180 mL). The reaction was cooled to 15 C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15 C. The reaction was stirred at 15 C. for 72 hours, after which the reaction mixture was filtered through a Celite pad and the pad was rinsed with warm ethanol (40 C., 2100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was stirred at 20 C. for 1 hour and filtered. The filter cake was rinsed with acetonitrile (2100 mL) and dried under vacuum at 20 C. to afford a white solid (?10:1 mixture of 1a and 1H-pyrazole-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-d6) delta 10.52 (bs, 3H), 8.03 (s, 1H) EIMS m/z 117 ([M]+).
	With hydrogenchloride; triethylsilane; 5% palladium on Al2O3; In ethanol; water; at 15℃; for 73h;Inert atmosphere;	Example 1 3-chloro-1H-pyrazol-4-amine hydrochloride (1a) [0019] nitrogen (N2) inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 weight %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37%, 180 mL). The reaction was cooled to 15 C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15 C. The reaction was stirred at 15 C. for 72 hours, after which the reaction mixture was filtered through a Celite pad and the pad was rinsed with warm ethanol (40 C., 2×100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to 100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to 100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to 100 mL. Acetonitrile (200 mL) was added and the resulting suspension was stirred at 20 C. for 1 hour and filtered. The filter cake was rinsed with acetonitrile (2×100 mL) and dried under vacuum at 20 C. to afford a white solid (10:1 mixture of 1a and 1H-pyrazol-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-d6) delta 10.52 (bs, 3H), 8.03 (s, 1H) EIMS: m/z 117.
	With hydrogenchloride; triethylsilane; Pd/Al2O3; In ethanol; water; at 15℃; for 73h;	Example 1 3-Chloro-1H-pyrazol-4-amine hydrochloride (1a) A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with a mechanical stirrer, temperature probe and nitrogen (N2) inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37 wt %, 180 mL). The reaction was cooled to 15 C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15 C. The reaction was stirred at 15 C. for 72 hours, after which the reaction mixture was filtered through a Celite pad and the pad was rinsed with warm ethanol (40 C., 2100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was stirred at 20 C. for 1 hour and filtered. The filter cake was rinsed with acetonitrile (2100 mL) and dried under vacuum at 20 C. to afford a white solid (?10:1 mixture of 1a and 1H-pyrazol-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-d6) delta 10.52 (bs, 3H), 8.03 (s, 1H); EIMS m/z 117 ([M]+).

References: [1]Patent: US2015/111938,2015,A1 .Location in patent: Paragraph 0018; 0019.
[2]Patent: US2015/112073,2015,A1 .Location in patent: Paragraph 0019-0020.
[3]Patent: US2015/112074,2015,A1 .Location in patent: Paragraph 0020; 0021.

45
[ 2075-46-9 ]
[ 63680-90-0 ]
[ 4331-28-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triethylsilane; Pd/Al2O3; In ethanol; water; at 15.0℃; for 73h;Inert atmosphere;	A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with a mechanical stirrer, temperature probe and nitrogen inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37 wt %, 180 mL). The reaction was cooled to 15 C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15 C. The reaction was stirred at 15 C. for 72 hours, after which the reaction mixture was filtered through a Celite pad and the pad was rinsed with warm ethanol (40 C., 2×100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to 100 mL. Acetonitrile (200 mL) was added and the resulting suspension was stirred at 20 C. for 1 hour and filtered. The filter cake was rinsed with acetonitrile (2×100 mL) and dried under vacuum at 20 C. to afford a white solid (10:1 mixture of 1a and 1H-pyrazol-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-d6) delta 10.52 (bs, 3H), 8.03 (s, 1H); EIMS m/z 117 ([M]+).

References: [1]Patent: US2015/112075,2015,A1 .Location in patent: Paragraph 0019; 0020.

46
[ 2075-46-9 ]
[ 28466-26-4 ]
3-chloro-1H-pyrazol-4-amine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triethylsilane; palladium/alumina; In ethanol; water; at 15℃; for 73h;	A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with a mechanical stirrer, temperature probe and nitrogen (N2) inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37 wt %, 180 mL). The reaction was cooled to 15 C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15 C. The reaction was stirred at 15 C. for 72 hours, after which the reaction mixture was filtered through a Celite pad and the pad was rinsed with warm ethanol (40 C., 2100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to ?100 mL. Acetonitrile (200 mL) was added and the resulting suspension was concentrated to ?100 mL. Acetonitrile (200 mL) was added a second time and the resulting suspension was concentrated to ?100 mL. Acetonitrile (200 mL) was added a third time and the resulting suspension was stirred at 20 C. for 1 hour and filtered. The filter cake was rinsed with Acetonitrile (2100 mL) and dried under vacuum at 20 C. to afford a white solid (?10:1 mixture of 1a and 1H-pyrazol-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-d6) delta 10.52 (bs, 3H), 8.03 (s, 1H); EIMS m/z 117 ([M]+).

References: [1]Patent: US2015/112076,2015,A1 .Location in patent: Paragraph 0008; 0020; 0021.

47
[ 2075-46-9 ]
[ 371240-55-0 ]
[ 1798793-15-3 ]

Yield	Reaction Conditions	Operation in experiment
47%	With caesium carbonate In 1-methyl-pyrrolidin-2-one at 90℃; for 12h;	121 Synthesis of (R)-tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [0408j To a mixture of (S)-tert-butyl 3 -(tosyloxy)pyrrolidine- 1 -carboxylate (1.3 g, 3.8mmol, 1.0 equiv) inNMP (10 mL), 4-nitro-1H-pyrazole (429 mg, 3.8 mmol, 1.0 equiv) andCs2CO3 (2.47 g, 7.6 mmol, 2.0 equiv) were added. The mixture was stirred at 90 °C for 12 h.After cooling down to rt, the mixture was diluted with EtOAc (150 mL) and washed with water(50 mL x 4). The organic layer was concentrated and purified by silica gel column (PE : EA = 31) to give (R)-tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (500 mg, yield:47%) as a yellow solid. ESI-MS (M+Na):3O5.1. ‘H NMR (400 MHz, CDC13) 5: 8.17 (s, 1H),8.09 (s, 1H), 4.91-4.89 (m, 1H), 3.89-3.85 (m, 2H), 3.56-3.50 (m, 2H), 2.43-2.41 (m, 2H), 1.48(s, 9H).

References: [1]Current Patent Assignee: BIOGEN MA - WO2015/89337, 2015, A1 Location in patent: Paragraph 0408.

48
[ 2075-46-9 ]
[ 373604-28-5 ]
[ 1798794-05-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere;	213.2 2. Synthesis of tert-butyl 3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate [0601j To a solution of 4-nitro-1H-pyrazole (1.13 g, 10 mmol), tert-butyl 3-fluoro-4- hydroxypiperidine-1-carboxylate (2.19 g, 10 mmol) and PPh3 (2.88 g, 11 mmol) in THF (25 mL) was added DIAD (2.22 g, 11 mmol) under nitrogen. The mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc (150 mL) and washed with water (50 mL x 2). The organic phase was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether: EtOAc =3:1) to give the title product tert-butyl 3 -fluoro-4-(4-nitro- 1H- pyrazol-1-yl)piperidine-1-carboxylate (1.3 g, yield: 91%) as a yellow solid. ESI-MS (M+H) :315.1. ‘H NMR (400 MHz, CDC13) 5: 8.70 (s, 1H), 8.19 (s, 1H), 4.91-4.88 (m, 2H), 4.72-4.61 (m, 1H), 4.48-4.47 (m, 2H), 4.11-4.10 (m, 1H), 2.10-2.09 (m, 2H), 1.49 (s, 9H).

References: [1]Current Patent Assignee: BIOGEN MA - WO2015/89337, 2015, A1 Location in patent: Paragraph 0601.

49
[ 2075-46-9 ]
[ 109431-87-0 ]
tert-butyl (S)-3-(4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	To a solution of 4-nitro-IH-pyrazole (1 g, 8.84 mmol), triphenylphosphine (2.78 g, 10.61 mmol) and <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (1.656 g, 8.84 mmol) in THF (50 mL) was added dropwise DIAD (2.264 mL, 11.50 mmol) at 0 C under nitrogen. The mixture was then slowly warmed to room temperature and stirred overnight. Solvent was evaporated and the crude product was directly purified by column chromatography on silica gel (PE:EA2: 1) to give the title compound D132 (2.23 g, 7.90 mmol, 89 % yield) as yellow oil.LCMS: 227 [M-t-Bu+H]. tR =2.295 mins. (LCMS condition 1)1H NMR (400 MHz, CHLOROFORM-cl): 68.20 (s, 1H), 8.10 (s, 1H), 3.50-3.94(m, 5H), 2.43(d, J=6.36 Hz, 2H), 1.49 (s, 9H).

References: [1]Patent: WO2015/113452,2015,A1 .Location in patent: Page/Page column 103.

50
[ 2075-46-9 ]
[ 1174020-40-6 ]
[ 1802989-18-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;	D209 (3S,4S)-tert-butyl 3-fluoro-4-(4-nitro-I H-pyrazol-1 -yl) piperidi ne-I -carboxylate (0209) To a solution of (3S, 4R)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (3.40 g, 15.5mmol), 4-nitro-1H-pyrazole (1.75 g, 15.5 mmol), PPh3 (6.10 g, 23.3 mmol) in THE (100 mL)was added slowly DIAD (4.71 g, 23.3 mmol) at 000. The mixture was stirred overnight at room temperature. The mixture was concentrated, the residue was dissolved in EtOAc (50 mL) and then n-hexane (100 mL) was added. The suspension was stirred vigorously for 1 hour and then filtered. The filtrate was concentrated and the crude was purified by columnchromatography on C18 (MeCN/water: 20% to 80%) to give the title compound 0209 (4.05 g,83% yield) as yellow oil.1H NMR (300 MHz, CHLOROFORM-d): 58.22 (s, 1H), 8.12 (s, 1H), 4.86-4.57 (m, 2H), 4.29-4.18 (m, 2H), 2.85 (brs, 2H), 2.28-2.12 (m, 2H), 1.48 (s, 9H).
83%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;
69.78 %	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;	123.1 Step 1: Synthesis of /c/V-butyl (3S,4S)-3-fluoro-4-(4-nitropyrazol-l-yl)piperidine-l- carboxylate (X35b) To a stirred mixture of /c/V-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-l- carboxylate (X35a) (1 g, 4.561 mmol, 1 equiv), 4-nitropyrazole (X33b) (515.73 mg, 4.561 mmol, 1 equiv) and PPh3 (1.44 g, 5.473 mmol, 1.2 equiv) in THF (10 mL) were added DIAD (1.20 g, 5.929 mmol, 1.3 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1) to afford tert- butyl (3S,4S)-3-fluoro-4-(4-nitropyrazol-l-yl)piperidine-l-carboxylate (X35b) (1 g, 69.78%) as a yellow oil.

69.78 %	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;	123.1 Step 1: Synthesis of /c/V-butyl (3S,4S)-3-fluoro-4-(4-nitropyrazol-l-yl)piperidine-l- carboxylate (X35b) To a stirred mixture of /c/V-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-l- carboxylate (X35a) (1 g, 4.561 mmol, 1 equiv), 4-nitropyrazole (X33b) (515.73 mg, 4.561 mmol, 1 equiv) and PPh3 (1.44 g, 5.473 mmol, 1.2 equiv) in THF (10 mL) were added DIAD (1.20 g, 5.929 mmol, 1.3 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1) to afford tert- butyl (3S,4S)-3-fluoro-4-(4-nitropyrazol-l-yl)piperidine-l-carboxylate (X35b) (1 g, 69.78%) as a yellow oil.
83 %	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	S13.1 Synthesis of tert-butyl (3S,4S)-4-(4-amino-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate (Int. D-2i) Step 1: A solution of 4-nitro-1H-pyrazole (414 mg, 3.66 mmol), tert-butyl (3S,4R)-3-fluoro-4-hydroxy-piperidine-1-carboxylate (375 mg, 1.71 mmol) and triphenylphosphine polymer bound (1.31 g, 3.93 mmol) in dry THF (18 mL) was prepared and cooled to at 0 °C under nitrogen. A solution of diisopropyl azodicarboxylate (0.66 mL, 3.34 mmol) in dry THF (18 mL) was added slowly. After 18 h at rt, the reaction mixture was filtered, concentrated, and purified by reverse phase column chromatography (5% to 100% MeOH in water w/0.1% formic acid) affording tert-butyl (3S,4S)-3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (452 mg, 1.42 mmol, 83% yield) as a yellow solid. [00443] LCMS: [M-tBu+H]+ = 259.2. [00444] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 - 1.25 (m, 1 H), 1.43 (s, 9 H), 1.88 - 2.04 (m, 1 H), 2.08 - 2.13 (m, 1 H), 3.98 (br d, J = 12.6 Hz, 1 H), 4.22 - 4.39 (m, 1 H), 4.62 - 4.74 (m, 1 H), 4.75 - 4.83 (m, 1 H), 4.84 - 4.96 (m, 1 H), 8.35 (s, 1 H), 9.09 (s, 1 H). [00445] 19F NMR (377 MHz, DMSO-d6) δ ppm -188.02 (br dd, J = 49.0, 5.5 Hz, 1 F).
86 %	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 35℃; Inert atmosphere;	28.1 first stepPreparation of (3S,4S)-3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester Combine (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester Cpd-42A (2.0g, 91mmol), 4-nitro-1H-pyrazole (1.1g, 10mmol), tris Phenylphosphorus (3.6g, 14mmol) was dissolved in tetrahydrofuran (100mL), under nitrogen protection, and diisopropyl azodicarboxylate (2.8g, 14mmol) was added dropwise at 0°C. After the dropwise addition was completed, stir at 35°C overnight. After the reaction is completed, concentrate under reduced pressure, add methylene chloride (100 mL) to the residue, wash once with water, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain compound (3S, 4S)-3-fluoro-4-(4-nitro-1H-pyrazol-1-yl) Piperidine-1-carboxylic acid tert-butyl ester Cpd-42B (2.6g, light yellow oil), yield: 86%.

References: [1]Current Patent Assignee: GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT - WO2015/113452, 2015, A1 Location in patent: Page/Page column 131.
[2]Axten, Jeffrey M.; Ding, Xiao; Stasi, Luigi Piero; Zhao, Baowei; Sang, Yingxia; Ho, Ming-Hsun; Wang, Lizhen; Zhang, Minhua; Guo, Xianjun; Tan, Chengfang; Feng, Xu; Edge, Colin; Valko, Klara; Li, Yi; Dong, Kelly; Guan, Xiaoming; Zinn, Nico; David Tattersall; Ren, Feng; Su, Dai-Shi; Reith, Alastair D. [RSC Medicinal Chemistry, 2026, vol. 17, # 1, p. 676 - 685].
[3]Current Patent Assignee: NURIX THERAPEUTICS - WO2022/235715, 2022, A1 Location in patent: Paragraph 000459.
[4]Current Patent Assignee: NURIX THERAPEUTICS - WO2022/235715, 2022, A1 Location in patent: Paragraph 000459.
[5]Current Patent Assignee: CELGENE - WO2024/137743, 2024, A1 Location in patent: Paragraph 00441-00445.
[6]Current Patent Assignee: CHANGCHUN GENESCIENCE PHARMACEUTICAL - CN116891437, 2023, A Location in patent: Paragraph 0466-0472.

51
[ 2075-46-9 ]
[ 1174020-42-8 ]
[ 2858742-76-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; Cooling with ice;	D214 (3R,4R)-tert-butyl 3-fl uoro-4-(4-n itro- I H-pyrazol-I -yl)piperid i ne-I -carboxylate (D2 14) To a solution of (3R, 4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (2.2 g, 10.04mmcl), 4-nitro-1H-pyrazole (1.19 g, 10.5 mmol), PPh3 (3.94g, 15.06 mmcl) in THE (50 mL)was added slowly DIAD (3.04 g, 15.06 rnmol) under ice cooling. The mixture was stirred overnight at room temperature. Solvent was removed and the residue was dissolved in Et20 (50 mL). The suspension was stirred vigorously for 30 mm and then filtered. The filtrate was concentrated and the crude was purified by flash column chromatography on 018 (30-60%ACN in water) to give the title compound D214 (2.7 g, 85% yield) as yellow oil.LCMS: 313 [M-H]. tR =1.80 mins. (LCMS condition 3)1H NMR (300 MHz, CHLOROFORM-d): 58.23 (s, 1H), 8.13 (s, 1H), 4.87-4.62 (m, 2H), 4.29-4.17 (m, 2H), 2.93-2.80 (m, 2H), 2.33-2.12 (m, 2H), 1.47 (s, 9H).
85%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; Cooling with ice;
47 %	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	S13.1 Synthesis of tert-butyl (3R,4R)-4-(4-amino-1H-pyrazol-1-yl)-3-fluoropiperidine-1-carboxylate (Int. D-2e) Step 1: To a solution of 4-nitro-1H-pyrazole (618.9 mg, 5.47 mmol, 2 eq.), diisopropyl azodicarboxylate (1.1 mL, 5.47 mmol, 2 eq.) and triphenylphosphine polymer bound (1.82 g, 5.47 mmol, 2 eq.) in dry THF (7 mL, 0.2 M) at 0 °C under nitrogen was slowly added a solution of tert-butyl (3R,4S)-3-fluoro-4-hydroxy-piperidine-1-carboxylate (600 mg, 2.74 mmol, 1 eq.) in dry THF (7 mL, 0.2 M). After 19 h at room temperature, the reaction mixture was filtered and concentrated in vacuo and the crude residue was purified by reverse phase column chromatography (5% to 100% MeOH in water w/ 0.1% formic acid). The fractions were combined and concentrated to afford tert-butyl (3R,4R)-3-fluoro-4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (404 mg, 47 % yield) as a yellow oil. [00416] LCMS: [M-tBu+H]+ = 259.2. [00417] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (d, J = 6.4 Hz, 2 H), 1.43 (s, 9 H), 1.95 (qd, J = 12.4, 4.4 Hz, 1 H), 2.04 - 2.14 (m, 1 H), 3.98 (br d, J = 13.2 Hz, 1 H), 4.22 - 4.39 (m, 1 H), 4.68 (qd, J = 10.7, 4.6 Hz, 1 H), 4.74 - 4.95 (m, 1 H), 8.35 (s, 1 H), 9.09 (s, 1 H). [00418] 19F NMR (377 MHz, DMSO-d6) δ ppm -188.01 (br dd, J = 50.4, 5.4 Hz, 1 F).

References: [1]Current Patent Assignee: GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT - WO2015/113452, 2015, A1 Location in patent: Page/Page column 133; 134.
[2]Axten, Jeffrey M.; Ding, Xiao; Stasi, Luigi Piero; Zhao, Baowei; Sang, Yingxia; Ho, Ming-Hsun; Wang, Lizhen; Zhang, Minhua; Guo, Xianjun; Tan, Chengfang; Feng, Xu; Edge, Colin; Valko, Klara; Li, Yi; Dong, Kelly; Guan, Xiaoming; Zinn, Nico; David Tattersall; Ren, Feng; Su, Dai-Shi; Reith, Alastair D. [RSC Medicinal Chemistry, 2025].
[3]Current Patent Assignee: CELGENE - WO2024/137743, 2024, A1 Location in patent: Paragraph 00414-00418.

52
[ 2075-46-9 ]
[ 188869-05-8 ]
tert-butyl (±)-3-(4-nitro-1H-pyrazol-1-yl)-4-oxopiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	To a solution of <strong>[188869-05-8]tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate</strong> (10.0 g, 35.9 mmol) and 4-nitro-1 H-pyrazole (4.47 g, 39.5 mmol) in DMF (50 mL) was added K2C03 (9.92 g, 71.9mmcl). The reaction was stirred overnight at room temperature. The mixture was poured into500 mL of water and extracted with EA (300 mLx2). The extracts were concentrated and theresidue was purified by column 018 (ACN/H20 = 35-57%) to give the title compound D246(4.Og, 36%) as a yellow oil.LCMS: 211 [M+H-100]. tR =1.92 mins. (LCMS condition 3)1H NMR (300 MHz, CHLOROFORM-d): 58.22 (s, 1H), 8.12 (s, 1H), 4.93-4.97 (m, 1H), 4.74(br s, 1 H), 4.43 (br s, 1 H), 3.63 (t, J = 11.4 Hz, 1 H), 3.23-3.33 (m, 1 H), 2.68-2.64 (m, 2H),1.51 (s, 9H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;	To a solution of tert-butyl3-bromo-4-oxo-piperidine-1-carboxylate (20 g, 71.91 mmol) and 4-nitro-1H-pyrazole (8.94 g, 79.10 mmol) in DMF (100 mL) was added K2CO3 (19.88 g, 143.81 mmol) at 20 C. under N2. The mixture was stirred at 20 C. for 16 h. The mixture was poured into ice-water (300 mL) and extracted with EtOAc (3100 mL). The combined organic phase was washed with brine (3100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=1:0 to 3:1) to give tert-butyl 3-(4-nitropyrazol-1-yl)-4-oxo-piperidine-1-carboxylate as a yellow oil. LCMS: RT 1.306 min, m/z=255.2 [M-56]+. 1H NMR (400 MHz, CDCl3): delta 8.22-8.27 (m, 1 H), 8.12 (s, 1 H), 4.97 (dd, J=10.85, 6.34 Hz, 1 H), 4.75 (br s, 1 H), 4.43 (br s, 1 H), 3.64 (br t, J=11.86 Hz, 1 H), 3.30 (br d, J=5.77 Hz, 1 H), 1.41-1.58 (m, 9 H), 1.41-1.58 (m, 2 H).

References: [1]Patent: WO2015/113452,2015,A1 .Location in patent: Page/Page column 144; 145.
[2]Patent: US2017/362206,2017,A1 .Location in patent: Paragraph 0404.

53
[ 2075-46-9 ]
[ CAS Unavailable ]
[ 956477-64-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: 4-nitro-1H-pyrazole With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.0833333h; Stage #2: sodium chlorodifluoroacetate In N,N-dimethyl-formamide for 0.5h;	30A 3 OA. Preparation of 1 -(difluoromethyl)-4-nitro- 1H-pyrazole Cs2CO3 (14.41 g, 44.2 mmol) was suspended in a solution of 4-nitro-1H-pyrazole(5.00 g, 44.2 mmol) and DMF (40 mL). After heating to 120 °C for 5 mm, solid sodium2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was added in 10 equal portions over 20 mm. The reaction was complete after 10 mm of additional heating. The mixture wasadded to a separatory funnel containing 100 mL water and extracted with Et20 (2 x 50 mL). The combined organic layers were concentrated. Purification by normal-phasechromatography eluting with a gradient of hexanes/EtOAc yielded 1 -(difluoromethyl)-4- nitro-1H-pyrazole (6.99 g, 42.9 mmol, 97% yield) as a clear, colorless oil. ‘H NMR(500MHz, CDC13) ö 8.58 (s, 1H), 8.22 (s, 1H), 7.39-7.05 (t,J= 60Hz, 1H).
97%	Stage #1: 4-nitro-1H-pyrazole With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.0833333h; Stage #2: sodium chlorodifluoroacetate In N,N-dimethyl-formamide at 120℃; for 0.5h;	19A Preparation of l-(difluoromethyl)-4-nitro-lH-pyrazole CS2CO3 (14.41 g, 44.2 mmol) was suspended in a solution of 4-nitro-lH-pyrazole (5.00 g, 44.2 mmol) and DMF (40 mL). After heating to 120 °C for 5 min, solid sodium 2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was added in 10 equal portions over 20 min. The reaction was complete after 10 min of additional heating. The mixture was added to a separatory funnel containing 100 mL water and extracted with Et20 (2 x 50 mL). The combined organic layers were concentrated. Purification by normal-phase chromatography eluting with a gradient of hexanes/EtOAc yielded 1 -(difluoromethyl)-4- nitro-lH-pyrazole (6.99 g, 42.9 mmol, 97% yield) as a clear, colorless oil. 'H NMR (500MHz, CDCI3) δ 8.58 (s, 1H), 8.22 (s, 1H), 7.39 - 7.05 (t, J= 60 Hz, 1H).
97%	With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.5h;

97%	Stage #1: 4-nitro-1H-pyrazole With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.0833333h; Stage #2: sodium chlorodifluoroacetate In N,N-dimethyl-formamide for 0.5h;	1.1A IA. Preparation of 1 -(difluoromethyl)-4-nitro- 1 H-pyra/ole CS2CO3 (14.41 g, 44.2 mmol) was suspended in a solution of 4-nitro-l H- pyra/ole (5.00 g, 44.2 mmol) and DMF (40 mL). After heating to 120 °C for 5 min, solid sodium 2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was added in 10 equal portions over 20 min. The reaction was complete after 10 min of additional heating. The mixture was added to a separatory funnel containing 100 mL water and extracted with Et20 (2 x 50 mL). The combined organic layers were concentrated. Purification by normal-phase chromatography eluting with a gradient of hexanes/EtO Ac yielded 1 -(difluoromethyl)-4- nitro-1H-pyrazole (6.99 g, 42.9 mmol, 97% yield) as a clear, colorless oil. 'H NMR (500MHz, CDCh) d 8.58 (s, 1H), 8.22 (s, 1H), 7.39 - 7.05 (t, J= 60 Hz, 1H).
97%	Stage #1: 4-nitro-1H-pyrazole With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.0833333h; Stage #2: sodium chlorodifluoroacetate In N,N-dimethyl-formamide for 0.5h;	1.1A IA. Preparation of 1 -(difluoromethyl)-4-nitro- 1 H-pyra/ole CS2CO3 (14.41 g, 44.2 mmol) was suspended in a solution of 4-nitro-l H- pyra/ole (5.00 g, 44.2 mmol) and DMF (40 mL). After heating to 120 °C for 5 min, solid sodium 2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was added in 10 equal portions over 20 min. The reaction was complete after 10 min of additional heating. The mixture was added to a separatory funnel containing 100 mL water and extracted with Et20 (2 x 50 mL). The combined organic layers were concentrated. Purification by normal-phase chromatography eluting with a gradient of hexanes/EtO Ac yielded 1 -(difluoromethyl)-4- nitro-1H-pyrazole (6.99 g, 42.9 mmol, 97% yield) as a clear, colorless oil. 'H NMR (500MHz, CDCh) d 8.58 (s, 1H), 8.22 (s, 1H), 7.39 - 7.05 (t, J= 60 Hz, 1H).
79.2%	With caesium carbonate	24.1 Step 1: Step 1: Synthesis of 1-(difluoromethyl)-4-nitro-1H-pyrazole (24b) Sodium difluorochloroacetate (13.5 g, 88.4 mmol) was added in portions to a mixture of 4-nitro-1H-pyrazole (5.00 g, 44.2 mmol) and cesium carbonate (14.4 g, 44.2 mmol) in N,N-dimethylformamide (40 mL) at room temperature. The mixture was stirred and heated in an oil bath at 120°C for 30 minutes. The reaction solution was cooled, diluted with ethyl acetate (300 mL) and washed with water (200 mL∗3). The organic phase was washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residues were separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-10:1) to give 5.7 g of the title compound as a colorless oil. Yield: 79.2%. LC-MS: m/z 164 [M+H]+.
79.2%	With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.5h;	24.1 Step 1: Synthesis of 1-(difluoromethyl)-4-nitro-1H-pyrazole (24b) Sodium difluorochloroacetate (13.5 g, 88.4 mmol) was added in portions to a mixture of 4-nitro-1H-pyrazole (5.00 g, 44.2 mmol) and cesium carbonate (14.4 g, 44.2 mmol) in N,N-dimethylformamide (40 mL) at room temperature. The mixture was stirred and heated in an oil bath at 120°C for 30 minutes. The reaction solution was cooled, diluted with ethyl acetate (300 mL) and washed with water (200 mL 3). The organic phase was washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residues were separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-10:1) to give 5.7 g of the title compound as a colorless oil. Yield: 79.2%. LC-MS: m/z 164 [M+H]+.
77%	Stage #1: 4-nitro-1H-pyrazole With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.0833333h; Stage #2: sodium chlorodifluoroacetate In N,N-dimethyl-formamide at 120℃; for 0.5h;	34.1 Step 1: l-(difluoromethyl)-4-nitro-pyrazole. To a solution of 4-nitro- 1 H-pyrazole (9.0 g, 79.6 mmol) in DMF (90 ml) was added Cs2C03 (25.9 g, 79.6 mmol). The mixture was stirred at 120 °C for 5 min then (2 -chloro-2 ,2 -difluoro-acetyl)oxysodium (24.3 g, 159.2 mmol) was added to the mixture portionwise over 20 min. The mixture was stirred at 120 °C for 10 min. The solvent was removed under reduced pressure. The residue was diluted with water (50 ml) and extracted with EtOAc (3 x 60 ml). The combined organic layers were washed with brine (30 ml) and dried over Na2S04. The residue was purified by FCC (5 - 20 % petroleum ether in ethyl acetate) to give the title compound as a light yellow oil (Y = 77 %).‘H NMR (400 MHz, chloroform-;/) d ppm 8.59 (s, 1H), 8.21 (s, 1H), 7.27 (t, J= 60 Hz, 1H).
41%	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 100℃;	Intermediate 56a: I -(diluoromethyl)-4-nitro-pyrazole [00559] Intermediate 56a: I -(diluoromethyl)-4-nitro-pyrazole[00560] Sodium chiorodifluoroacetate (2.7g, 17.6gmmol) was added to a solution of 4- nitropyrazole (1 .OOg, 8.84mmol) and NaHCO3 (1 .49g, 1 7.6gmmol) in DMF (8mL) and the solution heated to 100°C overnight. More NaHCO3 (1.49g, 17.6gmmol) and 4-nitropyrazole (1.OOg, 8.84mmol) were added and stirring was continued overnight. More NaHCO3 (1 .49g, 1 7.6gmmol) and 4-nitropyrazole (1 .Og, 8.84mmol) were added and stirring was continued overnight. The solutionwas then cooled to room temperature and the mixture was diluted with water (5OmL) and EtOAc (5OmL). The insoluble precipitate was filtered off and the organic layer separated. The aqueous was extracted with EtOAc (3 x 5OmL) and the combined organic layers were washed with brine (5OmL), dried over Na2504 and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 50% EtOAc in heptane to give 1-(difluoromethyl)-4-nitro-pyrazole (0.58g,3.S9mmol, 41% yield) as a pale yellow oil.1H NMR (CDCI3, 400MHz) O/ppm: 8.59 (1H, 5), 8.24 (1H, 5), 7.23 (1H, t, J= 60.0Hz). MS Method 2: RT: 1.16 mi mlz 164.0 [M+H]
	With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 2h; Inert atmosphere;	165.165A; 165-a.165A; 165-b.165A EXAMPLE 165, 465-a, 165-b 5-(5-CHLORO-2-(4-(TRIFLUOROMETHYL)-1H-1,2,3-TRIAZOL-1-YL)PHENYL)-2-(1¹- (DIFLUOROMETHYL)-8-OXO-1¹H-9-AZA-1(5,4)-PYRAZOLA-2(1,3)- BENZENACYCLONONAPHANE-3-YL)PYRIDINE 1-OXIDE 165A: 1-(Difluoromethyl)-4-nitro-1H-pyrazole: A mixture of 4-nitro-1H-pyrazole (2 g, 17.69 mmol), Cs2CO3 (5.76 g, 17.69 mmol) and sodium 2-chloro-2,2-difluoroacetate (5.39 g, 35.4 mmol) in DMF (10 mL) was stirred at 120°C under nitrogen for 2 h. It was cooled to rt and diluted with water (20 mL). The mixture was extracted with EtOAc (70 mL x 3). The combined organic layers were washed with water (40 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash column chromatography on silica gel (eluting with petroleum ether:ethyl acetate = 100:1 to 10:1, gradient) to give the title compound
11.4 g	Stage #1: 4-nitro-1H-pyrazole With caesium carbonate In N,N-dimethyl-formamide at 120℃; Inert atmosphere; Stage #2: sodium chlorodifluoroacetate In N,N-dimethyl-formamide at 120℃; Inert atmosphere;	Synthesis of Intermediate A3 At room temperature, cesium carbonate (28.8g, 88.5mmol) was added to a solution of intermediate A3-1 (10.0g, 88.5mmol) in DMF (80mL), and after the reaction was carried out at 120°C for 5min, A3-2 (26.9 g, 177.0 mmol) was added to the reaction liquid in batches, and the reaction was continued at 120°C for 10 min. After the reaction, the reaction solution was naturally cooled to room temperature and poured into water (300mL), extracted with ethyl acetate (100mL×3); the extract was dried with anhydrous Na2SO4 and filtered, the filtrate was concentrated under reduced pressure, and the crude product was Purification by silica gel column chromatography (PE:EA=5:1) gave intermediate A3 (11.4 g).
	With caesium carbonate	13.A A) A) 1-(difluoromethyl)-4-nitro-1H-pyrazole A mixture of 4-nitro-1H-pyrazole (5 g), cesium carbonate (14.5 g) and DMF (40 ml) was stirred at 120° C. for 5 min. Sodium 2-chloro-2,2-difluoroacetate (13.5 g) was added thereto at 120° C., and the mixture was stirred for 10 min. To the reaction mixture was added water, and the mixture was extracted with Et2O. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.48 g). 1H NMR (300 MHz, DMSO-d6) δ 7.64-8.11 (1H, m), 8.59 (1H, s), 9.43 (1H, s).
6.48 g	Stage #1: 4-nitro-1H-pyrazole With caesium carbonate In N,N-dimethyl-formamide at 120℃; Stage #2: sodium chlorodifluoroacetate In N,N-dimethyl-formamide at 120℃;	13.A A) 1-(difluoromethyl)-4-nitro-1H-pyrazole A mixture of 4-nitro-1H-pyrazole (5 g), cesium carbonate (14.5 g) and DMF (40 ml) was stirred at 120° C. for 5 min. Sodium 2-chloro-2,2-difluoroacetate (13.5 g) was added thereto at 120° C., and the mixture was stirred for 10 min. To the reaction mixture was added water, and the mixture was extracted with Et2O. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.48 g).1H NMR (300 MHz, DMSO-d6) δ 7.64-8.11 (1H, m), 8.59 (1H, s), 9.43 (1H, s).
6.48 g	Stage #1: 4-nitro-1H-pyrazole With caesium carbonate In N,N-dimethyl-formamide at 120℃; Stage #2: sodium chlorodifluoroacetate In N,N-dimethyl-formamide at 120℃;	13.A A) 1-(difluoromethyl)-4-nitro-1H-pyrazole A mixture of 4-nitro-1H-pyrazole (5 g), cesium carbonate (14.5 g) and DMF (40 ml) was stirred at 120° C. for 5 min. Sodium 2-chloro-2,2-difluoroacetate (13.5 g) was added thereto at 120° C., and the mixture was stirred for 10 min. To the reaction mixture was added water, and the mixture was extracted with Et2O. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.48 g).1H NMR (300 MHz, DMSO-d6) δ 7.64-8.11 (1H, m), 8.59 (1H, s), 9.43 (1H, s).
	Stage #1: sodium chlorodifluoroacetate Heating; Stage #2: 4-nitro-1H-pyrazole Alkaline conditions;

References: [1]Current Patent Assignee: BRISTOL MYERS SQUIBB - WO2015/116886, 2015, A1 Location in patent: Page/Page column 200.
[2]Current Patent Assignee: BRISTOL MYERS SQUIBB - WO2015/116882, 2015, A1 Location in patent: Page/Page column 84; 88.
[3]Dilger, Andrew K.; Pabbisetty, Kumar B.; Corte, James R.; De Lucca, Indawati; Fang, Tianan; Yang, Wu; Pinto, Donald J. P.; Wang, Yufeng; Zhu, Yeheng; Mathur, Arvind; Li, Jianqing; Hou, Xiaoping; Smith, Daniel; Sun, Dawn; Zhang, Huiping; Krishnananthan, Subramaniam; Wu, Dauh-Rurng; Myers, Joseph E.; Sheriff, Steven; Rossi, Karen A.; Chacko, Silvi; Zheng, Joanna J.; Galella, Michael A.; Ziemba, Theresa; Dierks, Elizabeth A.; Bozarth, Jeffrey M.; Wu, Yiming; Crain, Earl; Wong, Pancras C.; Luettgen, Joseph M.; Wexler, Ruth R.; Ewing, William R. [Journal of Medicinal Chemistry, 2022, vol. 65, # 3, p. 1770 - 1785].
[4]Current Patent Assignee: BRISTOL MYERS SQUIBB - WO2021/207659, 2021, A1 Location in patent: Page/Page column 47; 48.
[5]Current Patent Assignee: BRISTOL MYERS SQUIBB - WO2021/207659, 2021, A1 Location in patent: Page/Page column 47; 48.
[6]Current Patent Assignee: CHINA MEDICINE RESEARCH AND DEVELOPMENT CENTER - EP4011865, 2022, A1.
[7]Current Patent Assignee: CHINA MEDICINE RESEARCH AND DEVELOPMENT CENTER - EP4011865, 2022, A1 Location in patent: Paragraph 0270-0272.
[8]Current Patent Assignee: NODTHERA - WO2019/121691, 2019, A1 Location in patent: Paragraph 0895.
[9]Current Patent Assignee: REDX PHARMA - WO2016/51193, 2016, A1 Location in patent: Paragraph 00558; 00559; 00560.
[10]Current Patent Assignee: MERCK SHARP DOHME - WO2017/74832, 2017, A1 Location in patent: Page/Page column 202.
[11]Current Patent Assignee: SHANGHAI MEIYUE BIO TECH DEV - WO2022/222960, 2022, A1 Location in patent: Page/Page column 18; 20.
[12]Current Patent Assignee: TAKEDA PHARMACEUTICAL - US2023/322683, 2023, A1.
[13]Current Patent Assignee: TAKEDA PHARMACEUTICAL - US2023/322683, 2023, A1 Location in patent: Paragraph 0614-0615.
[14]Current Patent Assignee: TAKEDA PHARMACEUTICAL - US2023/322683, 2023, A1 Location in patent: Paragraph 0614-0615.
[15]Hands, Allison T.; Walters, Zachary G.; Sorrentino, Jacob P.; Garg, Neil K. [Organic Syntheses, 2024, vol. 101, p. 164 - 180].

54
[ 2075-46-9 ]
[ 74427-22-8 ]
[ 1006442-51-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-nitro-1H-pyrazole With sodium hydride In tetrahydrofuran at 20℃; for 0.0833333h; Stage #2: 2,2-difluoroethyl triflate In tetrahydrofuran at 20℃;	Preparation of 1 -(2,2-difluoroethyl)-4-nitro- 1 H-pyrazole General procedure: To a solution of 4-nitro-lH-pyrazole (2.5 g, 22.11 mmol) in THF (50 mL) was added NaH (0.973 g, 24.32 mmol) and the mixture was stirred at rt for 5 min. To this suspension was then added Mel (1.382 mL, 22.11 mmol) and stirred at rt overnight. The reaction mixture was then diluted with EtOAc and washed with brine. The organic layer was concentrated, followed by purification using normal phase chromatography to yield l-methyl-4-nitro-lH-pyrazole a as white solid (1.9 g, 80%). NMR (400 MHz, CDC13) 5 ppm 8.12 (s, 1H), 8.06 (s, 1H), 3.97 (s, 3H).1-(2,2-Difluoroethyl)-4-nitro-1H-pyrazole was prepared in the same manner as that used for the preparation of 1-methyl-4-nitro-1H-pyrazole described in Example 1D by substituting 2,2-difluoroethyl trifluoromethanesulfonate for Mel. ‘H NMR (400MHz,15 CDC13) 5 8.24 (s, 1H), 8.13 (s, 1H), 6.34 - 5.97 (m, 1H), 4.52 (td, J=13.5, 4.1 Hz, 2H).

References: [1]Current Patent Assignee: BRISTOL MYERS SQUIBB - WO2015/116882, 2015, A1 Location in patent: Page/Page column 82; 93; 94.

55
[ 2075-46-9 ]
[ 605655-08-1 ]
[ 1314987-79-5 ]

Yield	Reaction Conditions	Operation in experiment
41%	With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 12h;	54 Preparation of Compound 54-b Compound 54-c (4.9 g, 15 mmol) and cesium carbonate (6.5 g, 2 mmol) were added to a solution of 4-nitropyrazole (1.13 g, 10 mmol) in DMF (15 mL) in sequence, and then the mixture was heated to 120° C. and stirred for 12 hours. After cooled to room temperature, the mixture was treated with water (60 mL), extracted with ethyl acetate (30 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=5:1) to give compound 54-b (1.1 g, yield: 41%). LC-MS (ESI): m/z=291 [M+Na]+.

References: [1]Current Patent Assignee: GUANGZHOU MAXINOVEL PHARMACEUTICALS - US2015/336982, 2015, A1 Location in patent: Paragraph 0353; 0356.

56
[ 2075-46-9 ]
[ 109-86-4 ]
[ 948570-75-0 ]

Yield	Reaction Conditions	Operation in experiment
76.1%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 3h;	70 Preparation of Compound 70-b At 0° C., DEAD (4.1 g, 19.91 mmol) was added slowly to a solution of 4-nitropyrazole (1.5 g, 13.27 mmol), 2-methoxyethanol (1.5 g, 19.91 mmol) and PPh3 (5.2 g, 19.91 mmol) in anhydrous TH-IF (25 mL). The mixture was warmed to room temperature and stirred for 3 hours, then concentrated under reduced pressure, the residue was purified by silica column chromatography (petroleum ether:ethyl acetate=5:1) to give white solid 70-b (1.72 g, yield: 76.1%). LC-MS (ESI): m/z=198 [M+H
93 %	With Di-tert-butyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	2 General Procedure for the Mitsunobu Reaction with 4-nitro-lH-pyrazole (a) General procedure: Synthesis was performed in a dried flask in an argon atmosphere. Di-/m-butyl azodicarboxylate (9.20 mmol, 1.30 eq.) dissolved in THF (10 ml) was added dropwise to a solution of 4-nitro- lH-pyrazole (7.08 mmol, 1.00 eq.), alcohol (7.08 mmol, 1.00 eq.) and triphenylphosphine (8.49 mmol, 1.20 eq.) in anhydrous THF (25 ml) at 0 °C. Afterwards the mixture was stirred for 4-16 h at room temperature, was concentrated under reduced pressure and purified by flash chromatography (SiCh, gradient 0-50 % ethyl acetate in cyclohexane). Further purification was achieved by recrystallization from cyclohexane/ethyl acetate.
93 %	With Di-tert-butyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	2 General Procedure for the Mitsunobu Reaction with 4-nitro-lH-pyrazole (a) General procedure: Synthesis was performed in a dried flask in an argon atmosphere. Di-/m-butyl azodicarboxylate (9.20 mmol, 1.30 eq.) dissolved in THF (10 ml) was added dropwise to a solution of 4-nitro- lH-pyrazole (7.08 mmol, 1.00 eq.), alcohol (7.08 mmol, 1.00 eq.) and triphenylphosphine (8.49 mmol, 1.20 eq.) in anhydrous THF (25 ml) at 0 °C. Afterwards the mixture was stirred for 4-16 h at room temperature, was concentrated under reduced pressure and purified by flash chromatography (SiCh, gradient 0-50 % ethyl acetate in cyclohexane). Further purification was achieved by recrystallization from cyclohexane/ethyl acetate.

93 %

With Di-tert-butyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;

2 General Procedure for the Mitsunobu Reaction with 4-nitro-lH-pyrazole (a) General procedure: Synthesis was performed in a dried flask in an argon atmosphere. Di-/m-butyl azodicarboxylate (9.20 mmol, 1.30 eq.) dissolved in THF (10 ml) was added dropwise to a solution of 4-nitro- lH-pyrazole (7.08 mmol, 1.00 eq.), alcohol (7.08 mmol, 1.00 eq.) and triphenylphosphine (8.49 mmol, 1.20 eq.) in anhydrous THF (25 ml) at 0 °C. Afterwards the mixture was stirred for 4-16 h at room temperature, was concentrated under reduced pressure and purified by flash chromatography (SiCh, gradient 0-50 % ethyl acetate in cyclohexane). Further purification was achieved by recrystallization from cyclohexane/ethyl acetate.

References: [1]Current Patent Assignee: GUANGZHOU MAXINOVEL PHARMACEUTICALS - US2015/336982, 2015, A1 Location in patent: Paragraph 0436; 0437.
[2]Current Patent Assignee: UNIVERSITY OF LAUSANNE - WO2022/194953, 2022, A1 Location in patent: Page/Page column 53-54; 61.
[3]Current Patent Assignee: UNIVERSITY OF LAUSANNE - WO2022/194953, 2022, A1 Location in patent: Page/Page column 53-54; 61.
[4]Current Patent Assignee: UNIVERSITY OF LAUSANNE - WO2022/194953, 2022, A1 Location in patent: Page/Page column 53-54; 61.

57
[ 2075-46-9 ]
[ 78385-26-9 ]
1-((3-methyloxetan-3-yl)methyl)-4-nitro-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		A mixture of 4-nitropyrazole (1.13 g, 10 mmol) and K2C03 (3.4 g, 25 mmol) in MeCN (50 mL) was stirred at room temperature for 15 min prior to addition of 3- (bromomethyl)-3-methyloxetane (1.8 g, 11 mmol). The reaction mixture was stirred at room temperature for 18 hr, filtered and the filter cake washed with MeCN. The filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) gradient to afford l-((3-methyloxetan-3- yl)methyl)-4-nitro-lH-pyrazole as a colorless solid (1.43 g, 73%). A portion of this solid (206 mg, 1.04 mmol) dissolved in MeOH (20 mL) was treated with ammonium formate (260 mg, 4.13 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 80 C for 1.5 hr, cooled, filtered through Celite and the filtrate concentrated under reduced pressure to afford l-((3-methyloxetan-3-yl)methyl)-lH-pyrazol-4-amine as a pale pink gum (160 mg, 92%). NMR (400 MHz, CDC13) delta 7.15 (s, 1H), 6.97 (s, 1H), 4.66 (d, / = 6.1 Hz, 2H), 4.37 (d, / = 6.1 Hz, 2H), 4.19 (s, 2H), 2.91 (s, 2H), 1.23 (s, 3H).

References: [1]Patent: WO2015/140189,2015,A1 .Location in patent: Page/Page column 65-66.

58
[ 2075-46-9 ]
[ 28466-26-4 ]
N-(1H-pyrazol-4-yl)hydroxylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate; In tetrahydrofuran; for 4h;	General procedure: Into a 2 dram vial was placed 5-nitro-8-hydroxyquinonline (63 mg, 0.33 mmol), Ru/PS nanoparticle catalyst (8.0 mg, 0.477 mmol Ru/gram catalyst, 1.2 mol%), and hydrazine monohydrate (42 muL, 2.5 equiv) in 4 ml of THF. The reaction mixture was stirred for 2 hr, at which point the solvent was removed under reduced pressure. The product was extracted from the solid mixture with 3x 2 ml EtOH. The combined ethanol extracts were then passed through a short silica plug in a pipet and the silica plug was washed 2 times with 1 ml ethanol. The EtOH was then removed on a rotary evaporator under reduced pressure. The product 5-(hydroxyamino)quinolin-8-ol was isolated as an orange solid (51 mg, 0.29 mmol, 87% yield). For some of the more complex substrates, the reaction results are highly temperature sensitive, the reactions can be forced to completion by adding extra equivalents of hydrazine, and by raising the temperature to 27 C.

References: [1]Tetrahedron Letters,2017,vol. 58,p. 82 - 86.

59
[ 2075-46-9 ]
[ 101691-94-5 ]
[ 1683576-41-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 5h;	D.319 Example D-319: Synthesis of 5-[(2R,3R)-3-(4-cyclopropylbenzamido)-2-methylpiperidin-1-yl]- 3-[1-(oxan-4-ylmethyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide (D-319) 4-Nitropyrazole (300 mg, 2.65 mmol) and 4-(iodomethyl)tetrahydro-2H-pyran (600 mg, 2.65 mmol) were dissolved in 10 mL of DMF with 1,7 g (5.3 mmol) of Cs2CO3, then the mixture so obtained was stirred at 80C 5 h. The mixture was cooled to room temperature, then it was extracted with DCM. The organic phase was dried over Na2SO4, filtered and evaporated to give a crude which was purified by silica flash chromatography with 30% to 80% ethyl acetate in cyclohexane to obtain 4-nitro-1-(oxan-4-ylmethyl)-1H-pyrazole (488.4 mg, 87% yield) as a colorless oil. MS found for C9H13N3O3 as (M+H)+ 212.1.

References: [1]Current Patent Assignee: PHARMACYCLICS - WO2016/196776, 2016, A2 Location in patent: Paragraph 001254.

60
[ 2075-46-9 ]
[ 123640-41-5 ]
[ 2101641-01-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: 4-nitro-1H-pyrazole With sodium hydride In diethylene glycol dimethyl ether Stage #2: 2-bromo-6-(1H-pyrazol-1-yl)pyridine In diethylene glycol dimethyl ether at 120℃; for 96h; Inert atmosphere; Glovebox;

References: [1]Strohecker; Lynch; Holliday; Jones [Dalton Transactions, 2017, vol. 46, # 24, p. 7733 - 7742].

61
[ 2075-46-9 ]
[ 118684-32-5 ]
[ 2127171-81-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate In acetone for 3h; Reflux;	16.A A. A solution of 4-nitropyrazole (compound 16a,0.27 g, 2.45 mmol) and tert-butyl (3-(bromomethyl)phenyl)carbamate (compound 16b, 0.586 g, 2.04 mmol) in acetone (10 mE) was treated with potassium carbonate (0.563 g, 4.08 mmol) and heated to reflux temperature for 3 hours. Thereaction was brought to room temperature and solvent wasevaporated on rotavapot The reaction was diluted with theaddition of water (30 mE) and product was extracted intoethyl acetate (2x25 mE). The combined ethyl acetate layerwas washed with water (2x25 mE) and dried (Na2504).Solvent was evaporated and crude product was purifiedthrough column using 10-30% ethyl acetate in hexanes and obtained tert-butyl (3-((4-nitro-1 H-pyrazol-1 -yl)methyl) phenyl)carbamate, compound 16c, (0.56 g, 95%) as off- white solid, which was used directly in the next step.

References: [1]Current Patent Assignee: PHOENIX MOLECULAR DESIGNS CA - US2017/240549, 2017, A1 Location in patent: Paragraph 0723; 0724.

62
[ 2075-46-9 ]
[ 239074-27-2 ]
[ 2127171-85-9 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate In acetone for 3h; Reflux;	18.A A. A solution of 4-nitropyrazole (compound 16a, 0.236 g, 2.09 mmol) and tert-butyl (4-(bromomethyl)phenyl)carbamate (compound 18a, 0.5 g, 1.74 mmol) in acetone (10 mL) was treated with potassium carbonate (0.48 g, 3.48 mmol) and heated to reflux temperature for 3 hours. The reaction was brought to room temperature and solvent was evaporated on rotavapor. The reaction was diluted with the addition of water (30 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer was washed with water (2×25 mL) and dried (Na2SO4). Solvent was evaporated and crude product was purified through column using 10-30% ethyl acetate in hexanes and obtained tert-butyl (4-((4-nitro-1H-pyrazol-1-yl)methyl)phenyl)carbamate, compound 18b, (0.46 g, 91%) as pale yellow thick liquid, which was used directly in the next step.

References: [1]Current Patent Assignee: PHOENIX MOLECULAR DESIGNS CA - US2017/240549, 2017, A1 Location in patent: Paragraph 0733; 0734.

63
[ 2075-46-9 ]
[ 75-26-3 ]
[ 97421-21-1 ]

Yield	Reaction Conditions	Operation in experiment
96.09%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 6h;	1.vii (vii): Synthesis of Intermediate 9 4-Nitropyrazole (100.00 g), potassium carbonate (146.67 g), and 1000 mL of N,N-dimethylformamide were placed in a reaction flask, and 2-bromopropane (130.52 g) was added in batches. The reaction was carried out at 50°C for 6 h. The organic phases were combined and extracted with ethyl acetate, then washed three times with saturated NaCl water, dehydrated with a desiccant, and concentrated by column chromatography (petroleum ether:ethyl acetate = 97:3) to obtain 131.85 g of intermediate 9 as a white solid in a yield of 96.09%.
92%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 0.5h;

References: [1]Current Patent Assignee: ANHUI SENFON BIOCHEMICAL - CN119999690, 2025, A Location in patent: Paragraph 0050; 0054-0055; 0082-0085.
[2]Zhang, Yanmin; Chen, Yadong; Zhang, Danfeng; Wang, Lu; Lu, Tao; Jiao, Yu [Journal of Medicinal Chemistry, 2018, vol. 61, # 1, p. 140 - 157].

64
[ 622-40-2 ]
[ 2075-46-9 ]
[ 957479-10-6 ]

Yield	Reaction Conditions	Operation in experiment
51%	With cyanomethylenetributyl-phosphorane In toluene at 60℃; for 36h; Sealed tube;	A35 Example A35 (1559) (1560) Preparation of intermediate 303: General procedure: The reaction was performed in 2 batches. In a sealed tube, cyanomethylenetributyl phosphorane (9.28 mL, 35.40 mmol) was added to a solution of 3-methyl-5-nitro-lH- pyrazole (1.50 g, 1 1.80 mmol) and 3-hydroxymethyl-3-methyloxethane (3.53 mL, 35.40 mmol) in toluene (100 mL). The solution was heated at 60 °C for 18 h. The 2 batches were combined and the solvent was evaporated in vacuo. The residue (black oil) was purified by column chromatography on silica gel (irregular SiOH, 15-40 μιη, 330 g, liquid loading on DCM, mobile phase: heptane/EtOAc, gradient from 90: 10 to 50:50). The fractions containing the product were combined and evaporated to dryness to give 3.95 g of intermediate 303 (79% yield, orange oil) directly used as it in the next step.
	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 16h;	S3-7.1 [271] Step 1: Synthesis of 4-(2-(4-nitro-lH-pyrazol-l-yl)ethyl)morpholine. To a stirred solution ofPPh3 (2.98 g, 0.0114 mol, 1.5 equiv), DIAD (2.30 g, 0.0114 mol, 1.5 equiv.) in THF (10 mL) atRT was added 2-morpholinoethan-l-ol (1 g, 0.0076 mol, 1 equiv.) and 4-nitro-lH-pyrazole (0.86 g, 0.0076 mol, 1 equiv.) The reaction mixture was stirred at RT for 16 hr. Reaction progress was monitored by TLC and LCMS. After the reaction completion, the reaction mixture was extracted with ethyl acetate and water 2 times. Organic layer was separated and evaporated under reduced pressure to give crude product which was further purified by using combiflash chromatography to yield 4-(2-(4-nitro-lH-pyrazol-l- yl)ethyl)morpholine. 1HNMR (400 MHz, DMSO-rie) d ppm 8.88 (s, 1H) 8.26 (s, 1H) 4.29 (t, 7=6.14 Hz, 2 H) 3.46 - 3.58 (m, 4 H) 2.73 (t, 7=6.36 Hz, 2 H) 2.40 (d, 7=3.95 Hz, 4 H).

References: [1]Current Patent Assignee: JANSSEN PHARMACEUTICA - WO2018/2217, 2018, A1 Location in patent: Page/Page column 299; 305.
[2]Current Patent Assignee: ALTOS LABS - WO2021/69721, 2021, A1 Location in patent: Paragraph 271.

65
[ 2075-46-9 ]
[ 1699727-68-8 ]
[ 2181001-88-5 ]

Yield	Reaction Conditions	Operation in experiment
88.7%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	1.3 Synthesis of 1.3(3R)-3-(4-nitro-1H-pyrazol-1-yl)-cyclopentylpropionitrile (IV) Under a nitrogen atmosphere, compound III (26.72 g, 192 mmol) was added to a 3L three-necked flask.4-Nitropyrazole (87.29 g, 772 mmol), triphenylphosphine (200.92 g, 766 mmol) and THF (1.5 L). Diethyl azodicarboxylate (DEAD, 121 ml, 770 mmol) was slowly added dropwise at about 0-5° C. After the addition was completed, the mixture was warmed to room temperature and stirred at room temperature for 12-15 h. The reaction solution was concentrated to dryness and 500 ml of ethyl acetate was added. Stir for 30 min, filter, and concentrate the filtrate to dryness. The solid was propelled with 30 ml of acetone solvent, cooled, filtered and dried to give 39.88 g of a pale yellow solid in a yield of 88.7%. The ee value is 99.3%.

References: [1]Current Patent Assignee: XIAMEN HALOSYNTECH - CN107674026, 2018, A Location in patent: Paragraph 0062; 0063; 0079; 0080; 0090; 0091.

66
[ 108-85-0 ]
[ 2075-46-9 ]
[ 97421-23-3 ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: 1-bromocyclohexane; 4-nitro-1H-pyrazole With potassium carbonate In N,N-dimethyl-formamide at 18 - 25℃; Stage #2: With 10% Pd/C; hydrogen In ethanol for 2h;	45.3 Step 3: preparation of 1-cyclohexyl-1H-pyrazol-4-ylamine 4-Nitro-1H-pyrazole (220 mg, 2 mmol), 39 bromocyclohexane (650 mg, 4 mmol), and 40 potassium carbonate (276 mg, 2 mmol) were added into 41 N,N-dimethylformamide (5 mL), and stirred overnight at room temperature. The reaction liquid was diluted with water (50 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was collected, concentrated, and separated by flash column chromatography (eluent: n-hexane: ethyl acetate = 2: 1) to give 190 mg of a pale yellow solid. The resulting 42 solid was dissolved in ethanol (10 mL), added with 10% palladium on carbon (10 mg), and stirred under hydrogen atmosphere for two hours, followed by filtration and concentration to give 160 mg of a pale yellow solid. Yield: 50%. MS (ESI, m/z): [M+H]+: 166.3.

References: [1]Current Patent Assignee: BEIJING HANMI PHARMACEUTICAL - EP3336090, 2018, A1 Location in patent: Paragraph 0163; 0164.

67
[ 2075-46-9 ]
[ 624-75-9 ]
[ 1001500-47-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h;

References: [1]Come, Jon H.; Collier, Philip N.; Henderson, James A.; Pierce, Albert C.; Davies, Robert J.; Le Tiran, Arnaud; O'Dowd, Hardwin; Bandarage, Upul K.; Cao, Jingrong; Deininger, David; Grey, Ron; Krueger, Elaine B.; Lowe, Derek B.; Liang, Jianglin; Liao, Yusheng; Messersmith, David; Nanthakumar, Suganthi; Sizensky, Emmanuelle; Wang, Jian; Xu, Jinwang; Chin, Elaine Y.; Damagnez, Veronique; Doran, John D.; Dworakowski, Wojciech; Griffith, James P.; Jacobs, Marc D.; Khare-Pandit, Suvarna; Mahajan, Sudipta; Moody, Cameron S.; Aronov, Alex M. [Journal of Medicinal Chemistry, 2018, vol. 61, # 12, p. 5245 - 5256].

68
[ 2075-46-9 ]
[ 65094-22-6 ]
[ 956477-64-8 ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium fluoride In acetonitrile at 20℃; for 12h; Schlenk technique; Inert atmosphere; Green chemistry;	General Procedure For the N-Difluoromethylation of Imidazoles and Pyrazoles. General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added Imidazoles/Pyrazoles (0.4 mmol, 1.0 equiv) and KF (46.4 mg, 2.0 equiv) under Ar, followed by MeCN (3 mL) with stirring. 2 (0.40 mmol, 1.0 equiv) were added subsequently. After stirring for 12 h, the reaction mixture was concentrated. The residue was purified with silica gel chromatography to provide pure product.

References: [1]Mao, Ting; Zhao, Liang; Huang, Yang; Lou, Yue-Guang; Yao, Qiuli; Li, Xiao-Fei; He, Chun-Yang [Tetrahedron Letters, 2018, vol. 59, # 28, p. 2752 - 2754].

69
[ 2075-46-9 ]
[ 627-42-9 ]
[ 948570-75-0 ]

Yield	Reaction Conditions	Operation in experiment
49.5%	With potassium carbonate In acetonitrile for 18h; Reflux;	20.1 (1) Preparation of 1-(2-methoxyethyl)-4-nitro-1H-pyrazole 4-Nitropyrazole (2.0 g, 17.68 mmol),The solution obtained by dissolving 2-chloroethyl methyl ether (2.01 g, 21.26 mmol) and potassium carbonate (4.88 g, 35.31 mmol) in 40 mL of acetonitrile was refluxed for 18 h.Spin dry,A silica gel column (PE/EA = 4:1) gave 1.5 g of a pale yellow solid.Yield: 49.5%.

References: [1]Current Patent Assignee: KBP BIOSCIENCES - CN104583195, 2018, B Location in patent: Paragraph 0633; 0634; 0635; 0636; 0637.

70
[ 2075-46-9 ]
[ 23511-05-9 ]
[ 1802990-36-8 ]

Yield	Reaction Conditions	Operation in experiment
77%	With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 2h;	4-Nitro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole (28). A flask was charged with1,4-dioxaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate (176 g, 562 mmol) and DMF (700mL). 4-Nitro-1H-pyrazole (60.5 g, 535 mmol) and Cs2CO3 (209 g, 642 mmol) were added and the mixture was heated to 100 °C for 2 h. The reaction mixture was cooled to ambient temperatureand poured into water (800 mL). The suspension was stirred at 0C for 30 min and filtered.The precipitate was washed with water (500 mL) and dried to give the title compound(104 g, 77%); MS m/z: 254(M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.92±8.82 (m, 1H), 8.24(d, J = 0.7 Hz, 1H), 4.42±4.27 (m, 1H), 3.92±3.79 (m, 4H), 2.00 (ddt, J = 8.8, 5.1, 3.4 Hz, 4H),1.76 (ddt, J = 11.2, 3.8, 2.0 Hz, 2H), 1.72±1.58 (m, 2H).

References: [1]George, Dawn M.; Huntley, Raymond J.; Cusack, Kevin; Duignan, David B.; Hoemann, Michael; Loud, Jacqueline; Mario, Regina; Melim, Terry; Mullen, Kelly; Somal, Gagandeep; Wang, Lu; Edmunds, Jeremy J. [PLoS ONE, 2018, vol. 13, # 9].

71
[ 2075-46-9 ]
[ 96-35-5 ]
[ 6715-84-0 ]

Yield	Reaction Conditions	Operation in experiment
76%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; Inert atmosphere;

References: [1]Pettersen, Daniel; Broddefalk, Johan; Emtenäs, Hans; Hayes, Martin A.; Lemurell, Malin; Swanson, Marianne; Ulander, Johan; Whatling, Carl; Amilon, Carl; Ericsson, Hans; Westin Eriksson, Annika; Granberg, Kenneth; Plowright, Alleyn T.; Shamovsky, Igor; Dellsèn, Anita; Sundqvist, Monica; Någård, Mats; Lindstedt, Eva-Lotte [Journal of Medicinal Chemistry, 2019, vol. 62, # 9, p. 4312 - 4324].

72
[ 2075-46-9 ]
[ 590-17-0 ]
[ 1001500-47-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 2h;	40.1 Step 1. 2- (4-Nitro-1H-pyrazol-1-yl) acetonitrile (40a) A mixture of 4-nitro-1H-pyrazole (10.0 g, 88.5 mmol) , 2-bromoacetonitrile (21.0 g, 177 mmol) and K2CO3(37.0 g, 266 mmol) in DMF (50 mL) was stirred at 50 for 2 hrs. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (150 mL) . The separated organic layer was concentrated to afford 40a (13.5 g, 100%yield) as brown oil.1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H) , 8.16 (s, 1H) , 5.18 (s, 2H) .
89%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 5h;	30.1 Step 1: 2-(4-nitropyrazol-l-yl)acetomtrile. To a solution of 4-nitro- lH-pyrazole (5.0 g, 44.2 mmol) in DMF (50 ml) was added 2-bromoacetonitrile (5.89 ml, 88.4 mmol) and K2CO3 (18.3 g, 133 mmol), then the mixture was stirred at 80 °C for 5 h. The solvent was removed under reduced pressure. The residue was diluted with water (30 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (20 ml), dried over Na2S04 and concentrated in vacuo. The residue was purified by FCC (9 - 25 % EtOAc in petroleum ether) to give the title compound as a light brown solid (Y = 89 %). NMR (400 MHz, chloroform-* d ppm 8.36 (s, 1H), 8.17 (s, 1H), 5.15 (s, 2H).
65%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;	Step 5: Dissolve 4-nitropyrazole (2.5 g, 22.1 mmol) in DMF of 50 mL, add potassium carbonate (6.1 g, 44.2 mmol) and 2-bromoacetonitrile (4.0 g, 33.2 mmol) and stir at room temperature for 12 h, TLC monitoring the reaction completely. Saturated sodium bicarbonate was added to the reaction solution to be weakly alkaline, and the organic phase was separated. The aqueous phase is extracted three times using dichloromethane. Combined organic phase and washed with saturated saline, anhydrous sodium sulfate dried and then concentrated in vacuo, giving 3- (4-nitro-1H-pyrazole-1-yl) acetonitrile as a pale yellow solid (2.2g, 65%) The product can be used directly for the next step without further purification.

65%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;	Dissolve 4-nitropyrazole (2.5 g, 22.1 mmol) in 50 mL of DMF, add potassium carbonate (6.1 g, 44.2 mmol) and 2-bromoacetonitrile (4.0 g, 33.2 mmol) and stir at room temperature for 12 h. The completion of the reaction is monitored by TLC. Saturated sodium bicarbonate is then added until the reaction solution is weakly basic, and the organic phase is separated. Extract the aqueous phase three times using dichloromethane. Combine the organic phases and wash with saturated NaCl solution, dry over anhydrous sodium sulfate and concentrate under vacuum to yield 3-(4-nitro-1H-pyrazol-1-yl)acetonitrile as a pale yellow solid (2.2 g, 65%) The product can be used directly in the next step without further purification. HRMS (ESI): m/z [M+H]+ .C5H5N4O2 calculated value 153.0407, measured value 153.0411.
63%	With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 4h; Sealed tube;	33.1 2-(4-nitro-1H-pyrazol-1-yl)acetonitrile 4-Nitro-1H-pyrazole 16a (1.13g, 10mmol) was dissolved in N,N-dimethylformamide (12mL), and cesium carbonate (9.75g, 30mmol) was added. After cooling to 0°C, 2-bromoacetonitrile (2.4 g, 20 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour, diluted with water (150 mL), and then extracted with ethyl acetate (3×100 mL). The combined organic phase extracts were washed with water (3×100 mL) and then dried over anhydrous sodium sulfate. After filtration, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100/0 to 1/1) to obtain the target product 2-(4-nitro-1H-pyridine). Azol-1-yl)acetonitrile 33a (960mg), yield: 63%.
63%	With caesium carbonate In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere;	33.1 Step 1. 2- (4-Nitro-1H-pyrazol-1-yl) acetonitrile (33a) To a solution of 4-nitro-1H-pyrazol 16a (1.13 g, 10 mmol) in DMF (12 mL) was added cesium carbonate (9.75 g, 30 mmol). After cooling to 0°C, the mixture was added with 2-bromoacetonitrile (2.4 g, 20 mmol) dropwise. The mixture was stirred for 1 h, diluted with water (150 mL) and extracted with ethyl acetate (3100 mL). The combined organic phase was washed with water (3100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 100/0 to 1/1) to give the title compound 33a (960 mg, 63%). MS m/z (ESI) : 153 [M+1] 1H NMR (400 MHz, CDCl 3) δ 8.36 (s, 1H), 8.16 (s, 1H), 5.15 (s, 2H).

References: [1]Current Patent Assignee: XIAODONG LI - WO2020/119819, 2020, A1 Location in patent: Paragraph 00272.
[2]Current Patent Assignee: NODTHERA - WO2019/121691, 2019, A1 Location in patent: Paragraph 0885.
[3]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN114149428, 2022, A Location in patent: Paragraph 0307-0308; 0313.
[4]Current Patent Assignee: YIYOU BIO TECH SHANGHAI - EP4393923, 2024, A1 Location in patent: Paragraph 0229; 0234.
[5]Current Patent Assignee: GUANGZHOU INNOCARE PHARMA TECH - CN112142743, 2020, A Location in patent: Paragraph 0415-0422.
[6]Current Patent Assignee: GUANGZHOU INNOCARE PHARMA TECH - WO2020/259584, 2020, A1 Location in patent: Page/Page column 64; 65.

73
[ 430430-57-2 ]
[ 2075-46-9 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 130℃; for 2h;	1 Step 1-Tert-butyl N-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethyl]carbamate To a solution of 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate (2.08 g, 6.37 mmol, synthesized via Step 1 of Intermediate AM) and 4-nitro-1H-pyrazole (0.600 g, 5.31 mmol, CAS2075-46-9) in DMF (40 mL) was added Cs2CO3 (3.46 g, 10.6 mmol). The mixture was stirred at 130° C. for 2 hours. On completion, after cooling to 25° C., the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (1.50 g, 82% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.00 (s, 1H), 4.90 (s, 1H), 4.28 (t, J=4.8 Hz, 2H), 3.84-3.77 (m, 2H), 3.56-3.50 (m, 4H), 3.46 (t, J=5.2 Hz, 2H), 3.30-3.21 (m, 2H), 1.37 (s, 9H). LC-MS (ESI+) m/z 367.2 (M+Na)+.

References: [1]Current Patent Assignee: KYMERA THERAPEUTICS - US2019/192668, 2019, A1 Location in patent: Paragraph 3962; 3963.

74
[ 2075-46-9 ]
[ 1447797-72-9 ]
[ 2357117-28-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 130℃; for 2h;	1 Step 1-Tert-butyl N-[2-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethyl]carbamate To a solution of 2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (3 g, 8.08 mmol, Intermediate AO) and 4-nitro-1H-pyrazole (608 mg, 5.38 mmol) in DMF (40 mL) was added Cs2CO3 (3.51 g, 10.7 mmol). The reaction mixture was stirred at 130° C. for 2 hours. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (1.20 g, 57% yield) as yellow oil. LC-MS (ESI+) m/z 411.2 (M+Na)+.

References: [1]Current Patent Assignee: KYMERA THERAPEUTICS - US2019/192668, 2019, A1 Location in patent: Paragraph 3943; 3944.

75
[ 2075-46-9 ]
[ 1462286-01-6 ]
[ 2432058-66-5 ]

Yield	Reaction Conditions	Operation in experiment
54%	With caesium carbonate In N,N-dimethyl-formamide at 110℃; for 5h;	21.1 Step 1: Example 143bN- (1-methyl-1H-pyrazol-4-yl) -4- (4-nitro-1H-pyrazol-1-yl) pyrimidin-2-amine A mixture of compound B0 (326 mg, 1.56 mmol), compound 143a (264 mg, 2.34 mmol) and Cs2CO3 (1.27 g, 3.9 mmol) in DMF (12 mL) was heated to 110 ° C and reacted for 5 hours. The mixture was poured into H2O (20 mL) and the precipitated solid was collected by filtration. The obtained solid was slurried with ethyl acetate / petroleum ether (1: 2), filtered, and dried. Compound 143b was obtained as a yellow solid (240 mg, 54% yield).

References: [1]Current Patent Assignee: JIAXING TEKELUO BIOTECHNOLOGY - CN110734428, 2020, A Location in patent: Paragraph 0309; 0310; 0311-0314.

76
[ 2075-46-9 ]
[ 26825-94-5 ]
[ 2561415-63-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 1.5h; Sealed tube;	Methyl 10-(4-nitro-1H-pyrazol-1-yl)decanoate 4-Nitro-1H-pyrazole (1 g, 8.84 mmol), methyl 10-bromodecanoate (3.09 mL, 13.27 mmol) andpotassium carbonate (1.833 g, 13.27 mmol) were sealed within a vessel and DMF (10 mL) was added.The reaction mixture was heated at 50 °C for 1.5 h. The reaction mixture was diluted with water (30mL) and extracted with DCM (3 x 30 mL). The organic layers were combined, passed through ahydrophobic frit and the solvent was removed in vacuo. The residue was purified by normal phasecolumn chromatography (0 - 100 % EtOAc in cyclohexane, 80 g SiO2) to afford methyl 10-(4-nitro-1Hpyrazol-1-yl)decanoate (2.2 g, 7.40 mmol, 84 % yield) as a white solid. M.pt.: 69 - 71 °C; νmax (neat):3151, 3123, 2928, 2855, 1722, 1533 cm1; 1H NMR (400 MHz, DMSO-d6) δ = 8.89 (1H, s), 8.24 (1H, s),4.16 (2H, t, J = 7.1 Hz), 3.58 (3H, s), 2.27 (2H, t, J = 7.3 Hz), 1.80 (2H, quin, J = 7.0 Hz), 1.45 - 1.54 (2H,m), 1.23 (10H, br s); 13C NMR (101 MHz, DMSO-d6) δ = 173.8, 135.9, 135.2, 130.8, 52.8, 51.6, 33.7, 3729.5, 29.1, 29.0, 28.9, 28.7, 26.1, 24.9; LCMS (Method A): tR = 1.28 min, [M+H]+ 298, (100 % purity);HRMS: (C14H24N3O4) [M+H]+ requires 298.1767, found [M+H]+ 298.1767.

References: [1]Shah, Rishi R.; Redmond, Joanna M.; Mihut, Andrei; Menon, Malini; Evans, John P.; Murphy, John A.; Bartholomew, Michelle A.; Coe, Diane M. [Bioorganic and Medicinal Chemistry, 2020, vol. 28, # 5].

77
[ 2075-46-9 ]
[ 24424-99-5 ]
[ 130106-42-2 ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: 4-nitro-1H-pyrazole With sodium dithionite; ammonia In methanol at 20℃; for 1h; Stage #2: di-<i>tert</i>-butyl dicarbonate With triethylamine In methanol at 20℃; for 16h;	9 Preparation of Compound 49 To a solution of 4-nitropyrazole (1 g, 6.13 mmol) in methanol (20 mL) were added ammonia solution (28-30% ammonia, 2.2 mL) and sodium hydrosulfite (7.7 g). After stirring at room temperature for 1 hour, the reaction solution was filtered through Celite and the filtrate was evaporated under reduced pressure. Methanol (15 mL) was added to the concentrated filtrate and then di-t-butyl dicarbonate (2.24 mL, 9.73 mmol) and triethylamine (1.86 mL, 13.27 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 16 hours and then diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The reduced was purified by column chromatography to afford Compound 49 (0.7 g, 43%). 1H-NMR (400 MHZ, DMSO-d6) 8 9.05 (s, 1H), 7.44 (s, 1H), 1.42 (s, 9H)
43%	Stage #1: 4-nitro-1H-pyrazole With ammonium hydroxide; sodium dithionite In methanol at 20℃; for 1h; Stage #2: di-<i>tert</i>-butyl dicarbonate With triethylamine In methanol at 20℃; for 16h;	9 Preparation of Compound 49 To a solution of 4-nitropyrazole (1 g, 6.13 mmol) in methanol (20 mL) were added ammonia solution (28-30% ammonia, 2.2 mL) and sodium hydrosulfite (7.7 g). After stirring at room temperature for 1 hour, the reaction solution was filtered through Celite and the filtrate was evaporated under reduced pressure. Methanol (15 mL) was added to the concentrated filtrate and then di-t-butyl dicarbonate (2.24 mL, 9.73 mmol) and triethylamine (1.86 mL, 13.27 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 16 hours and then diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The reduced was purified by column chromatography to afford Compound 49 (0.7 g, 43%).’H-NMR (400 MHz, DMSO-d6), δ 9.05 (s, 1H), 7.44 (s, 1H), 1.42 (s, 9H).
6.07 g	With 10% Pd/C; hydrogen In tetrahydrofuran at 20℃;	4.i Process (i): A mixture of Compound I (4.53 g), THF (80 mL), (Boc) 2 O (13.21 g) and 10% Pd-carbon (2.04 g, 53% water) at room temperature under a hydrogen atmosphere of 0.2 MPa. Stir overnight. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to obtain compound II (6.07 g).

43 %	Stage #1: 4-nitro-1H-pyrazole With sodium dithionite; ammonia In methanol at 20℃; Stage #2: di-<i>tert</i>-butyl dicarbonate With triethylamine In methanol at 20℃;	9 Preparation of Intermediate Compound 49 To a solution of 4-nitropyrazole (1 g, 6.13 mmol) in methanol (20 mL) were added ammonia solution (28-30% ammonia, 2.2 mL) and sodium hydrosulfite (7.7 g). After stirred at room temperature for 1 hour, the reaction solution was filtered through Celite and the filtrate was evaporated under reduced pressure. Methanol (15 mL) was added to the concentrated filtrate and then di-t-butyl dicarbonate (2.24 mL, 9.73 mmol) and triethylamine (1.86 mL, 13.27 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 16 hours and then diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The reduced was purified by column chromatography to afford Intermediate compound 49 (0.7 g, 43%).1H-NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.44 (s, 1H), 1.42 (s, 9H).
43 %	Stage #1: 4-nitro-1H-pyrazole With sodium dithionite; ammonia In methanol at 20℃; Stage #2: di-<i>tert</i>-butyl dicarbonate With triethylamine In methanol at 20℃;	9 Preparation of Intermediate Compound 49 To a solution of 4-nitropyrazole (1 g, 6.13 mmol) in methanol (20 mL) were added ammonia solution (28-30% ammonia, 2.2 mL) and sodium hydrosulfite (7.7 g). After stirred at room temperature for 1 hour, the reaction solution was filtered through Celite and the filtrate was evaporated under reduced pressure. Methanol (15 mL) was added to the concentrated filtrate and then di-t-butyl dicarbonate (2.24 mL, 9.73 mmol) and triethylamine (1.86 mL, 13.27 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 16 hours and then diluted with ethyl acetate (50 mL) and washed with distilled water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The reduced was purified by column chromatography to afford Intermediate compound 49 (0.7 g, 43%).1H-NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.44 (s, 1H), 1.42 (s, 9H).

References: [1]Current Patent Assignee: LIGACHEM BIOSCIENCES - WO2025/233679, 2025, A1 Location in patent: Page/Page column 147.
[2]Current Patent Assignee: LIGACHEM BIOSCIENCES - WO2025/233676, 2025, A1 Location in patent: Page/Page column 128.
[3]Current Patent Assignee: SUMITOMO DAINIPPON PHARMA - JP2015/129094, 2015, A Location in patent: Paragraph 0189-0191.
[4]Current Patent Assignee: LEGOCHEM BIOSCIENCES - WO2024/100452, 2024, A2 Location in patent: Page/Page column 93-95.
[5]Current Patent Assignee: LEGOCHEM BIOSCIENCES - WO2024/100452, 2024, A2 Location in patent: Page/Page column 93-95.

78
[ 2075-46-9 ]
[ 957062-72-5 ]
[ 2489612-17-9 ]

Yield	Reaction Conditions	Operation in experiment
	With [2,2]bipyridinyl; oxygen; copper diacetate; sodium carbonate In 1,2-dichloro-ethane at 75℃; for 24h;	89.2 Step 2 Synthesis of methyl 4-(4-nitro-1H-pyrazol-1-yl)picolinate 2,2'-bipyridine (1.56g, 10mmol),Copper acetate (1.8g, 10mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)picolinate(2.4g, 9.13mmol),Sodium carbonate (1.94g, 18.26mmol) and4-nitropyrazole(1g, 9.13mmol) placed in the reaction flask, add 30mL 1,2-dichloroethane,Under an oxygen atmosphere, the reaction was stirred at 75°C for 24h. Cool to room temperature,Saturated brine and dichloromethane were added, extracted, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.

References: [1]Current Patent Assignee: NANJING SANHOME PHARMACEUTICAL - CN111196804, 2020, A Location in patent: Paragraph 0891; 0896-0898.

79
[ 2075-46-9 ]
[ 83197-70-0 ]
[ 2460687-71-0 ]

Yield	Reaction Conditions	Operation in experiment
75.7%	With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;	1.S3; 2.S3; 3.S3 S3,Synthesis of (S)-1-(4'-nitropyrazole)-2-propylbenzyloxyamide In a 3L reaction bottle, dissolve 451.6g (S)-2-benzyloxyamido-1-methanesulfonate in 1.5L DMF, add 325g sodium carbonate and 177.7g 4-nitropyrazole under mechanical stirring ,React at 80 for 2h. TLC analysis of the raw materials is complete, cool to room temperature,Add 3L of ice water to the system, a large amount of solids are generated,Filtration, washing, drying,(S)-1-(4’-nitropyrazole)-2-propylbenzyloxyamide362g, 75.7% yield.

References: [1]Current Patent Assignee: NANTONG UNIVERSITY - CN111233770, 2020, A Location in patent: Paragraph 0027; 0032-0033; 0040; 0045-0046; 0053; 0058-0059.

80
[ 2075-46-9 ]
[ CAS Unavailable ]
[ 1002243-79-9 ]

Yield	Reaction Conditions	Operation in experiment
12%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃; for 24h;	216.1 Step 1. 3- (4-Nitro-1H-pyrazol-1-yl) propanenitrile (216a) 4-Nitro-1H-pyrazole (10 g, 88.5 mmol) , acrylonitrile (9.85 g, 185.8 mmol) and DBU (53.8 g, 354.0 mmol) were dissolved in CH 3CN (50 mL) . The above reaction mixture was stirred at 80 for 24 hours. After cooling to RT, the mixture was concentrated to dryness. The residue was diluted with H 2O (100 mL) and extracted with EtOAc (100 mL*2) . The combined organic layers were dried over Na 2SO 4 and filtered. The filtrate was concentrated to dryness. The residue was purified by chromatography on silica gel (elute: PE: EtOAc = 5: 1) to afford the desired product (1.8 g, 12%yield) as a yellow solid. 1H NMR (400 MHz, CDCl 3) δ 8.27 (s, 1H) , 8.14 (s, 1H) , 4.44 (t, J = 6.4 Hz, 2H) , 3.04 (t, J = 6.8 Hz, 2H) .
	With sodium carbonate In water at 50℃; for 12h; Inert atmosphere;	1 Step 1: 3-(4-nitro- 1/7-pvrazol- 1 -vDpropanenitrile A mixture of 4-nitro- 1/7-pyrazole (1.0 eq), acrylonitrile (1.0 eq) and NazCCb (2.0 eq) in HzO (0.9 M) was stirred at 50 °C for 12 h under Ar. The reaction mixture was extracted with DCM/i- PrOH = 5:1 (100 mL x 3) and HzO (100 mL). The combined organic layer was washed with brine, and then dried overNazSCN. The cmde product was purified by flash chromatography on silica gel (elute: petroleum ether/EtOAc = 4:1 to 1 :1) to give the title compound as a white solid. LC-MS {m/z): [M+H]+=167.3.

References: [1]Current Patent Assignee: XIAODONG LI - WO2020/119819, 2020, A1 Location in patent: Paragraph 00748.
[2]Current Patent Assignee: NEXYS THERAPEUTICS - WO2020/139636, 2020, A1 Location in patent: Paragraph 00369.

81
[ 2075-46-9 ]
[ 121138-01-0 ]
[ 1428776-15-1 ]

References: [1]Patent: WO2020/211839,2020,A1 .Location in patent: Page/Page column 46; 88-89.

82
[ 2075-46-9 ]
[ 148430-81-3 ]
[ 1393100-37-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 18h;	18.1 Step 1: Synthesis of 4-nitro-1-(oxetan-3-yl)-1H-pyrazole 4-Nitro-1H-pyrazole (0.66 g, 5.88 mmol) and oxetan-3-yl methane sulfonate (0.94 g, 6.17 mmol) were dissolved in DMF. Cs2CO3 (3.80 g, 11.67 mmol) was added thereto, followed by stirring thereof at 90°C for 18 hours. The temperature was lowered to room temperature, and the reaction was then terminated with water. It was extracted with acetate and then dried over MgSO4. It was filtered under reduced pressure, concentrated, and subjected to column chromatography to obtain 0.83 g of the target compound (yield: 84%). MS (ESI) m/z 170.0 [M+H]+
56.7%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 60h;

References: [1]Current Patent Assignee: OSCOTEC - EP3722298, 2020, A1 Location in patent: Paragraph 0112.
[2]Axten, Jeffrey M.; Ding, Xiao; Stasi, Luigi Piero; Zhao, Baowei; Sang, Yingxia; Ho, Ming-Hsun; Wang, Lizhen; Zhang, Minhua; Guo, Xianjun; Tan, Chengfang; Feng, Xu; Edge, Colin; Valko, Klara; Li, Yi; Dong, Kelly; Guan, Xiaoming; Zinn, Nico; David Tattersall; Ren, Feng; Su, Dai-Shi; Reith, Alastair D. [RSC Medicinal Chemistry, 2026, vol. 17, # 1, p. 676 - 685].

83
[ 2075-46-9 ]
[ 141699-58-3 ]
[ 1314987-79-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 12h;	30.1 Step 1: Synthesis of tert-butyl-3-(4-nitro-1H-pyrazol-1-yl)azetidin-1-carboxylate 4-Nitro-1H-pyrazole (2.9 g, 25.77 mmol) was dissolved in DMF (30 ml). Cs2CO3 (17.6 g, 2.0 eq.) and tert-butyl-3-(methylsulfonyloxy)azetidin-1-carboxylate (6.8 g, 1.05 eq., Intermediate 21) were added thereto, followed by stirring thereof at 90°C for 12 hours. Water was added thereto to terminate the reaction. It was extracted three times with ethyl acetate, dried over MgSO4, and concentrated. It was subjected to column chromatography (MeOH:MC = 1:40) to obtain 6.45 g of the target compound in yellow color (yield: 93%). MS (ESI) m/z : 268.9 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 8.14 (s, 1H), 5.09-5.03 (m, 1H), 4.44-4.29 (m, 4H), 1.46 (s, 9H).
87.6%	With caesium carbonate In N,N-dimethyl-formamide at 100℃;	21 Synthesis Intermediate 21-1: tert-Butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate Dissolve 4-nitro-1H-pyrazole (230mg, 2.04mmol) in 4ml DMF, add cesium carbonate (1.33g, 4.08mmol), 3-((methylsulfonyl)oxy) nitrogen to the reaction solution Etidine-1-carboxylate tert-butyl ester (614.4 mg, 2.45 mmol), heated to 100 degrees and reacted overnight. After the reaction was completed, 50ml of water was added to the system, ethyl acetate was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 480mg of intermediate 21-1 with a yield of 87.6%.
290 mg	With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 100℃; Inert atmosphere;	S3-3.2 [254] Step 2: Synthesis of tert-butyl 3-(4-nitro-lH-pyrazol-l-yl) azetidine-l- carboxylate. To a stirred solution 4-nitro-lH-Pyrazole (225 mg, 1.99 mmol, 1 equiv.) in DMF (10 mL) under nitrogen atmosphere was added CS2CO3 (980 mg, 2.98 mmol, 1.5 equiv.) and TBAI(1.10 g, 2.98 mmol, 1.5 equiv.) followed by the addition of tert-butyl 3- ((methylsulfonyl)oxy)azetidine-l-carboxylate (500 mg, 1.99mmol, 1.0 equiv.). The reaction mixture was heated at 100 °C for overnight. After completion of reaction, ice-water was added to the reaction mixture and was extracted with ethyl acetate (2 X 25 mL). Organic layers were combined, washed with cold water, collected, dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain tert-butyl 3-(4-nitro-lH-pyrazol-l-yl) azetidine-l-carboxylate which was purified by flash column chromatography (290 mg), LCMS: 269 [M+H+]

References: [1]Current Patent Assignee: OSCOTEC - EP3722298, 2020, A1 Location in patent: Paragraph 0147.
[2]Current Patent Assignee: HENAN MEDINNO PHARMACEUTICAL TECH - CN113666911, 2021, A Location in patent: Paragraph 0487; 0490; 0492-0494.
[3]Current Patent Assignee: ALTOS LABS - WO2021/69721, 2021, A1 Location in patent: Paragraph 254.

84
[ 2075-46-9 ]
[ 1153949-11-1 ]
[ 2763672-47-3 ]

Yield	Reaction Conditions	Operation in experiment
50%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h;	Step 2: Add DBU (11.8 g, 77.4 mmol) to the acetonitrile (30 mL) solution of 3-(cyanomer)azetidine-1-carboxylate (5.0 g, 25.8 mmol) and 4-nitropyrazole (3.2 g, 28.7 mmol). The mixture is then stirred at room temperature for 16 h. After the end of the reaction, an appropriate amount of water is added, and the aqueous phase is extracted twice with EA. The organic layer was combined and washed with brine, the sodium sulfate was dried and concentrated under vacuum, and the residue was purified using a silica gel column (petroleum ether: ethyl acetate = 4:1) to give 3-(cyanomethyl)-3-(4-nitro-1H-pyrazole-1-yl) azetidine-1-carboxylate tert-butyl ester as a white oil (4.0g, 50%).
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h;	4.1.1 Tert-butyl 3-(cyanomethylene) azetidine-1-carboxylate (11) 2-Diethoxyphosphorylacetonitrile (5.7g, 32.1mmol) in THF (50mL) was added to a stirred solution of NaH (1.2g, 30.7mmol) in THF (50mL) at 0°C. The mixture was stirred at ambient temperature for 1h then tert-butyl 3-oxoazetidine-1-carboxylate (10; 5.0g, 29.2mmol) in THF was added at 0°C in 1h. The mixture was then stirred at ambient temperature for 16h. The aqueous phase was extracted twice with EA. The combined extracts were washed with brine, dried with sodium sulfate and concentrated under vacuum, the residue was dissolved in CH3CN (30mL) and DBU (11.8g, 77.4mmol) together with 4-nitropyrazole (3.2g, 28.7mmol) were added. The mixture was then stirred at ambient temperature for 16h. Water was added and aqueous phase was extracted twice with EA. The combined extracts were washed with brine, dried with sodium sulfate and concentrated under vacuum give the crude product, which was then dissolved in methanol and purged with argon, palladium on carbon (10% Pd content, 1.4g, 1.3mmol) was added, and the reaction mixture stirred under an atmosphere of hydrogen for 12h. The solids were removed by filtration, washed with methanol and the filtrate concentrated under vacuum to afford 3.5g (43% for three steps) of 11 as a clear oil.

References: [1]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN114149428, 2022, A Location in patent: Paragraph 0271-0272; 0274.
[2]Xu, Pengfei; Shen, Pei; Wang, Hai; Qin, Lian; Ren, Jie; Sun, Qiushuang; Ge, Raoling; Bian, Jinlei; Zhong, Yi; Li, Zhiyu; Wang, JuBo; Qiu, Zhixia [European Journal of Medicinal Chemistry, 2021, vol. 218].

85
[ 2075-46-9 ]
[ 40557-20-8 ]
[ 2636104-80-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 4-nitro-1H-pyrazole With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: 3-bromopyrrolidin-2-one In N,N-dimethyl-formamide at 20℃;	8 Example 8: To a solution of 4-nitropyrazole 1 (0.23g, l.Oeq) in 5 mL dry DMF was added K2CO3 (0.54g,2.0eq). The mixture was stirred at RT for 5 mins under N2, and then compound 2 (0.33g, 1 ,0eq) was added into reaction. The resulting mixture was RT overnight. The reaction mixture was diluted with30mL acetate and lOmL Hexane. The inorganic was removed by fdtration. The filtrate was washed with3x30mL water and brine. The crude was purified on ISCO silica gel to afford intermediate 3 (0.305g, yield 75%).

References: [1]Current Patent Assignee: VIMALAN BIOSCIENCES - WO2021/62036, 2021, A1 Location in patent: Paragraph 00187.

86
[ 2075-46-9 ]
[ 1250113-83-7 ]
[ 2639533-88-1 ]

Yield	Reaction Conditions	Operation in experiment
1.2 g	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	S1-13.2 Step 2: Synthesis of 4-nitro-1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazole To a solution of 1-(2,4,6-trifluorophenyl)ethan-1-ol ( 1.00 g, 5.68 mmol, 1 eq ) & 4-nitro- lH-pyrazole (642 mg, 5.68 mmol, 1.0 eq ), in THF (15 ml) was added TPP (2.23 gm 8.522 mmol 1.5 eq) was cooled to 0 deg C & DIAD (1.72 ml, 8.522 mmol, 1.5 eq.) was added drop wise under inert condition . After addition Reaction mixture was stir at RT, Reaction progress was monitored by TLC and LCMS. After reaction completion, Workup done by water 10 ml & extracted with ethyl acetate (2 X 20 ml) times, Organic layer was separated and evaporated under reduced pressure to give crude which was purified by combiflash chromatography to obtain pure product 4-nitro-1-(1-(2,4,6-trifluorophenyl)ethyl)- lH-pyrazole (1.2 g)

References: [1]Current Patent Assignee: ALTOS LABS - WO2021/69701, 2021, A1 Location in patent: Paragraph 229; 230.

87
[ 2075-46-9 ]
[ 1512718-16-9 ]
[ 2130521-01-4 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 2h;	Step 3: Synthesis of compound B20-3 Compound B20-2 (2 g, 7.34 mmol, 1 eq), 4-nitropyrrole (1.25 g) and cesium carbonate (4.79 g) were added toN,N-dimethylformamide (20 mL) and the mixture was incubated at 70 °C for 2 hours. The resulting solution was addedinto water (100 mL) and extracted with ethyl acetate (180 mL). The resulting organic phase was dehydrate using anhydroussodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on a silica gel column(petroleum ether: ethyl acetate = 100:0 to 4:1) to give compound B20-3. LCMS (ESI) m/z: 214.0 [M+H]+

References: [1]Current Patent Assignee: CHIA TAI TIANQING PHARMACEUTICAL GROUP - EP3816164, 2021, A1 Location in patent: Paragraph 0118; 0121.

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

CAS No. :	2075-46-9
Formula :	C₃H₃N₃O₂
M.W :	113.08
SMILES Code :	C1=N[NH]C=C1[N+]([O-])=O
English Name :	4-Nitro-1H-pyrazole
MDL No. :	MFCD00159626
InChI Key :	XORHNJQEWQGXCN-UHFFFAOYSA-N
Pubchem ID :	16376

GHS Pictogram:
Signal Word:
Hazard Statements:
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Class:
UN#:
Packing Group:

Num. heavy atoms	8
Num. arom. heavy atoms	5
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	27.41
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	74.5 Å²

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.16
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.04
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.32
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	-1.62
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.86
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	-0.39

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CAS No.: 2075-46-9

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Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.96
Solubility	12.3 mg/ml ; 0.109 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.16
Solubility	7.87 mg/ml ; 0.0696 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.56
Solubility	31.2 mg/ml ; 0.276 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.96 cm/s

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	2.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.66

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P378
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P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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CAS No.: 2075-46-9

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CAS No.: 2075-46-9

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[ 2075-46-9 ] Synthesis Path-Downstream 1~87

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