Name: 4598-86-1|1-Methyl-4-nitro-1H-pyrazole-3-carboxylic acid|97%
Brand: Ambeed
SKU: A272205
Rating: 96 (40 reviews)

1
[ 25016-20-0 ]
[ 4598-86-1 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1983,vol. 19,p. 1326 - 1330
Khimiya Geterotsiklicheskikh Soedinenii,1983,vol. 19,p. 1676 - 1679

2
[ 6647-98-9 ]
[ 4598-86-1 ]

Yield	Reaction Conditions	Operation in experiment
58.3%	With sulfuric acid; nitric acid at 55℃; for 6h;

Reference： [1]Tret'yakov; Vasilevsky [Russian Chemical Bulletin, 1996, vol. 45, # 11, p. 2581 - 2584]

Yield	Reaction Conditions	Operation in experiment
	1,3-Dimethyl-4-nitro-pyrazol, Chromschwefelsaeure;

4
[ 400877-57-8 ]
[ 4598-86-1 ]

Yield	Reaction Conditions	Operation in experiment
91.6%	With lithium hydroxide; In tetrahydrofuran; water; at 20℃; for 8h;	In a solution of compound 34 (1.3 g, 7.02 mol) in tetrahydrofuran(10 mL) was added 5 mL LiOH aqueous solution (0.336 g, 14 mmol).The mixture was stirred at room temperature for 8 h and was dilutedwith water (100 mL). The pH was adjusted to 2-3 and the aqueous layerwas extracted with EtOAc (20 mL×3). The combined organic phasewas dried over Na2SO4, filtered and concentrated in vacuo to affordcompound 35 (1.1 g, 92%) as white solid.
79%		Reference Example 21 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid To a mixture of <strong>[400877-57-8]methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate</strong> obtained in Reference Example 19 (0.95 g, 5.1 mmol) and THF (25 mL)-methanol (5 mL), 1N aqueous sodium hydroxide solution (8.0 mL) was added, and the mixture was stirred at room temperature for 2 hr. The mixture was acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.69 g, yield 79%). 1H-NMR (CDCl3): delta 4.08 (3H, s), 8.28 (1H, s).
79%		To a mixture of methyl -1-methyl-4-nitro-1H-pyrazole-3-carboxylate obtained in Reference Example 19 (0.95 g, 5.1 mmol) and THF (25 mL)-methanol (5 mL), 1N aqueous sodium hydroxide solution (8.0 mL) was added, and the mixture was stirred at room temperature for 2 hr. The mixture was acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.69 g, yield 79%). 1H-NMR (CDCl3) :delta 4.08(3H, s), 8.28 (1H, s).

With water; lithium hydroxide; In tetrahydrofuran; methanol; at 0 - 20℃; for 3h;

To a solution of <strong>[400877-57-8]methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate</strong> (GM g,32.4 mmoi) in a mixture of THE (30 mU and MeOH (20 mL) at 0 C was added a solution of LiOH (2.6 g, 64.8 mmol) in water (12 mL), and the mixture was stirred at it for 3 h. The mixture was concentrated and subsequently diluted with water. The aqueous layer was acidified with concentrated HCI to pH?2-3 and the solid was collected by filtration to afford 1-methyl-4-nitro- 1H-pyrazole-3-carboxylic acid.

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 2624 - 2627
[2]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1211 - 1225
[3]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 1910 - 1918
[4]Patent: US2009/156582,2009,A1 .Location in patent: Page/Page column 30
[5]Patent: EP1847531,2007,A1 .Location in patent: Page/Page column 43
[6]Patent: WO2017/19804,2017,A2 .Location in patent: Paragraph 0359

5
[ 4598-86-1 ]
[ 1003-03-8 ]
[ 514217-41-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 4h;	22 N-cyclopentyl-1-methyl-4-nitro-1H-pyrazole-3-carboxamide Reference Example 22 N-cyclopentyl-1-methyl-4-nitro-1H-pyrazole-3-carboxamide A solution of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid obtained in Reference Example 21 (0.56 g, 3.3 mmol), cyclopentylamine (0.31 g, 3.6 mmol), HOBt (0.53 g, 3.9 mmol) and WSC (0.75 g, 3.9 mmol) in DMF (10 mL) was stirred at room temperature for 4 hr. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 1:1) to give the title compound (0.71 g, yield 91%). melting point 176-177° C. (ethyl acetate-hexane). 1H-NMR (CDCl3): δ 1.56-1.75 (6H, m), 2.04-2.08 (2H, m), 4.00 (3H, s), 4.42-4.48 (1H, m), 8.22 (1H, s).
91%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 4h;	22 A solution of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid obtained in Reference Example 21 (0.56 g, 3.3 mmol), cyclopentylamine (0.31 g, 3.6 mmol), HOBt (0.53 g, 3.9 mmol) and WSC (0.75 g, 3.9 mmol) in DMF (10 mL) was stirred at room temperature for 4 hr. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 1:1) to give the title compound (0.71 g, yield 91%). melting point 176-177°C (ethyl acetate-hexane). 1H-NMR (CDCl3): δ 1.56-1.75(6H, m), 2.04-2.08(2H, m), 4.00(3H, s), 4.42-4.48(1H, m), 8.22(1H, s).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2009/156582, 2009, A1 Location in patent: Page/Page column 30
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1847531, 2007, A1 Location in patent: Page/Page column 43

6
dipotassium salt of 4-nitro-3⁽⁵⁾-pyrazolecarboxylic acid [ No CAS ]
[ 3185-99-7 ]
[ 400877-57-8 ]
[ 309740-49-6 ]
[ 92534-69-5 ]
[ 4598-86-1 ]

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 2624 - 2627

7
dipotassium salt of 4-nitro-3⁽⁵⁾-pyrazolecarboxylic acid [ No CAS ]
[ 74-88-4 ]
[ 92534-69-5 ]
[ 4598-86-1 ]

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 2624 - 2627

8
[ 4598-86-1 ]
[ 74-89-5 ]
[ 405279-32-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine; HATU at 0℃;
	Stage #1: 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 17 - 25℃; for 1h; Stage #2: methylamine In tetrahydrofuran at 0℃; for 1h;	To l-methyl-4-nitropyrazole-3-carboxylic acid (2.0 g) in THF (30 ml) was charged carbonyl-1 , 1 '-diimidazole (1.9 g) over 1 hour at room temperature. The reaction was stirred overnight before cooling to O0C. A solution of methylamine in THF (12 ml of a 2M solution) was added and the reaction stirred for 1 hour. The THF layer was separated and concentrated in vacuo. The crude oil was purified by column chromatography on silica (25 g), eluting with 100% EtOAc (500 ml) to give N,l-dimethyl-4-nitropyrazole-3- carboxamide, 976mg.

Reference： [1]Zhang, Peilong; Dong, Jiaqiang; Zhong, Boyu; Zhang, Deyi; Yuan, Hongbin; Jin, Can; Xu, Xiangyuan; Li, Hailong; Zhou, Yong; Liang, Zhi; Ji, Minghua; Xu, Tao; Song, Guowei; Zhang, Ling; Chen, Gang; Meng, Xuejing; Sun, Desheng; Shih, Joe; Zhang, Ruihao; Hou, Guojun; Wang, Chengcheng; Jin, Ying; Yang, Qiong [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 1910 - 1918]
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2009/153589, 2009, A1 Location in patent: Page/Page column 202

9
[ 4598-86-1 ]
[ 74-89-5 ]
[ 1201935-78-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 17 - 25℃; for 1h; Stage #2: methylamine In tetrahydrofuran at 0℃; for 1h;	To l-methyl-4-nitropyrazole-3-carboxylic acid (2.0 g) in THF (30 ml) was charged carbonyl-1 , 1 '-diimidazole (1.9 g) over 1 hour at room temperature. The reaction was stirred overnight before cooling to O0C. A solution of dimethylamine in THF (12 ml of a 2M solution) was added and the reaction stirred for 1 hour. The THF layer was separated and concentrated in vacuo. The crude product was purified by column chromatography on silica (30 g), eluting with 100% EtOAc (300 ml) to give N,N,l-trimethyl-4-nitropyrazole- 3-carboxamide, 1235mg.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2009/153589, 2009, A1 Location in patent: Page/Page column 203

10
[ 67-56-1 ]
[ 4598-86-1 ]
[ 400877-57-8 ]

Yield	Reaction Conditions	Operation in experiment
	sulfuric acid; for 4h;Heating; Reflux;	Concentrated H2SO4 (0.4 ml) was added to l-methyl-4-nitropyrazole-3-carboxylic acid (2.02 g) in MeOH (40 ml) and the mixture heated to reflux for 4 hours. After cooling <n="207"/>to room temperature, the reaction was concentrated in vacuo. The crude material was dissolved in EtOAc (60 ml) then washed with water (10 ml) and brine (10 ml). The organic layer was dried, filtered and concentrated to give methyl l-methyl-4-nitropyrazole-3- carboxylate, 1.96g
8.15 g	With sulfuric acid;Reflux;	1-methyl-4-nitropyrazole-3-carboxylic acid (Int A, 20 g, 64.29 mmol) was suspended in methanol (200 ml_), sulfuric acid (2.4 ml_, 45mmol) was added dropwise and the resulting suspension was refluxed O/N. The day after it was cooled, diluted with water, and then MeOH was removed under vacuum. The aqueous phase was extracted several times with EtOAc, the organic phase was dried and evaporated. The residue was triturated with pentane, and then with ether to afford methyl 1-methyl-4-nitro-1 H-pyrazole-3-carboxylate (p129, 8.15 g, y=68%) as yellow-orange solid. MS (/T7/z): 186.0 [MH]+
8.15 g	With sulfuric acid;Reflux;	1 -methyl-4-nitropyrazole-3-carboxylic acid (Int A, 20 g, 64.29 mmol) was suspended in methanol (200 ml_), sulfuric acid (2.4 ml_, 45mmol) was added dropwise and the resulting suspension was refluxed ON. The day after it was cooled, diluted with water, and then MeOH was removed under vacuum. The aqueous phase was extracted several times with EtOAc, the organic phase was dried and evaporated. The residue was triturated with pentane, and then with ether to afford methyl 1 -methyl-4-nitro-1 H-pyrazole-3-carboxylate (p69, 8.15 g, y=68%) as yellow-orange solid. MS (/T7/z): 186.0 [MH]+

Reference： [1]Patent: WO2009/153589,2009,A1 .Location in patent: Page/Page column 205-206
[2]Patent: WO2019/43407,2019,A1 .Location in patent: Page/Page column 126; 127
[3]Patent: WO2019/81939,2019,A1 .Location in patent: Page/Page column 77; 78

11
[ 506-59-2 ]
[ 4598-86-1 ]
[ 1201935-78-5 ]

Yield	Reaction Conditions	Operation in experiment
40%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 4h; Inert atmosphere;	1.1 A solution of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (500 mg, 2.92 mmol) in DMF (5 ml) under inert gas atmosphere was treated with TBTU (1030 mg, 3.2 mmol), dimethylamine hydrochloride (262 mg, 3.2 mmol) and N,N-diisopropylethylamine (2.0 ml, 11.7 mmol) and stirring was continued for 4 h. All volatiles were removed and the crude product was extracted with water and ethyl acetate. The organic phase was washed with sodium bicarbonate and the aqueous phases were back-extracted with ethyl acetate and dichloromethane. The combined organic phases were dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a dichloromethane /methanol gradient as white solid (230 mg, 40%). MS: M=199.3 (M+H)+
40%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 4h; Inert atmosphere;	B.1.1 A solution of l-methyl-4-nitro-lH-pyrazole-3-carboxylic acid (500 mg, 2.92 mmol) in DMF (5 ml) under inert gas atmosphere was treated with TBTU (1030 mg, 3.2 mmol), dimethylamine hydrochloride (262 mg, 3.2 mmol) and N,N-diisopropylethylamine (2.0 ml, 11.7 mmol) and stirring was continued for 4 h. All volatiles were removed and the crude product was extracted with water and ethyl acetate. The organic phase was washed with sodium bicarbonate and the aqueous phases were back-extracted with ethyl acetate and dichloromethane. The combined organic phases were dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a dichloromethane/methanol gradient as white solid (230 mg, 40 %).MS: M = 199.3 (M+H)+

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/306589, 2011, A1 Location in patent: Page/Page column 44
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2011/154327, 2011, A1 Location in patent: Page/Page column 115

12
[ 4598-86-1 ]
[ 1201935-77-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 4 h / Inert atmosphere 2: hydrogen / 5%-palladium/activated carbon / ethanol / Inert atmosphere
	Multi-step reaction with 2 steps 1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / Inert atmosphere 2: hydrogen / 5%-palladium/activated carbon / ethanol / 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/306589, 2011, A1
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2011/154327, 2011, A1

13
[ 4598-86-1 ]
[ 1352193-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 4 h / Inert atmosphere 2.1: hydrogen / 5%-palladium/activated carbon / ethanol / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 3.2: 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / Inert atmosphere 2.1: hydrogen / 5%-palladium/activated carbon / ethanol / 20 °C 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 0.08 h / 20 °C / Inert atmosphere 3.2: 0.17 h 3.3: 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/306589, 2011, A1
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2011/154327, 2011, A1

14
[ 4598-86-1 ]
[ 1352200-55-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate; tetrahydrofuran / 16 h / 0 - 70 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 16 h / 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; diisopropylamine / tetrahydrofuran; ethyl acetate / 16 h / 70 °C / Inert atmosphere 2: hydrogen / palladium 10% on activated carbon / ethanol / 16 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/306589, 2011, A1
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2011/154327, 2011, A1

15
[ 67622-86-0 ]
[ 4598-86-1 ]
[ 1352200-71-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 4-methyl-morpholine; HATU; In tetrahydrofuran; at 70℃; for 16h;	To a suspension of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (639 mg, 3.7 mmol) and <strong>[67622-86-0]2-methyl-1-(methylamino)propan-2-ol</strong> (500 mg, 4.85 mmol) in THF (15 mL) were added HATU (1.57 g, 4.12 mmol) and N-methylmorpholine (2.13 mL, 19.4 mmol) at ambient temperature. The mixture was heated to 70 C. and stirred for 16 h. After cooling down to ambient temperature, the reaction mixture was poured into 20 mL HCl (2N aqueous solution) and extracted with ethyl acetate (2×100 mL). The organic layers were washed with water, brine and the solvent was evaporated. The aqueous layer was back-extracted with dichloromethane, dried and concentrated in vacuo. Both residues were combined to give 2.75 g of a semi-solid yellow material. The crude material was purified by silica gel chromatography using a methanol /ethyl acetate gradient to yield the product (1.2 g, 90%) as colorless oil.MS: M=257.3 (M+H)+
90%	With 4-methyl-morpholine; HATU; In tetrahydrofuran; at 70℃; for 16h;Inert atmosphere;	To a suspension of l-methyl-4-nitro-lH-pyrazole-3-carboxylic acid (639 mg, 3.7 mmol) and 2- methyl-l-(methylamino)propan-2-ol (500 mg, 4.85 mmol) in THF (15 mL) were added HATU (1.57 g, 4.12 mmol) and N-methylmorpholine (2.13 mL, 19.4 mmol) at ambient temperature. The mixture was heated to 70 C and stirred for 16 h. After cooling down to ambient temperature, the reaction mixture was poured into 20 mL HC1 (2N aqueous solution) and extracted with ethyl acetate (2 x 100 mL).The organic layers were washed with water, brine and the solvent was evaporated. The aqueous layer was back-extracted with dichloromethane, dried and concentrated in vacuo. Both residues were combined to give 2.75 g of a semi-solid yellow material. The crude material was purified by silica gel chromatography using a methanol/ethyl acetate gradient to yield the product (1.2 g, 90 %) as colorless oil.MS: M = 257.3 (M+H)+

Reference： [1]Patent: US2011/306589,2011,A1 .Location in patent: Page/Page column 78
[2]Patent: WO2011/154327,2011,A1 .Location in patent: Page/Page column 191

16
[ 2854-16-2 ]
[ 4598-86-1 ]
[ 1352200-53-3 ]

Yield	Reaction Conditions	Operation in experiment
31%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; diisopropylamine In tetrahydrofuran; ethyl acetate at 0 - 70℃; for 16h;	95.1 To a suspension of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (0.9 g, 5.26 mmol) and 1-amino-2-methylpropan-2-ol (469 mg, 5.26 mmol) in THF (20 mL) cooled to 0-5° C. were added N,N-diisopropylamine (3.67 mL, 21.0 mmol) and 1-propanephosphonic acid cyclic anhydride (8.37 mL, 13.1 mmol, 50% solution in ethyl acetate). The mixture was stirred at 70° C. for 16 hours, cooled to ambient temperature, poured into ethyl acetate (50 mL) and extracted with HCl (1 M, 20 mL). The organic phase was washed with water and brine. The aqueous layers were back-extracted separately with ethyl acetate and dichloromethane. The combined organic layers were dried and concentrated in vacuo to give 1.4 g crude product. The crude material was purified by silica gel chromatography using a methanol /ethyl acetate gradient to give the title compound as colorless foam (391 mg, 31% yield). MS: M=243.2 (M+H)+
31%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; diisopropylamine In tetrahydrofuran; ethyl acetate at 70℃; for 16h; Inert atmosphere;	B.95.1 To a suspension of l-methyl-4-nitro-lH-pyrazole-3-carboxylic acid (0.9 g, 5.26 mmol) and 1- amino-2-methylpropan-2-ol (469 mg, 5.26 mmol) in THF (20 mL) cooled to 0-5 °C were added N,N-diisopropylamine (3.67 mL, 21.0 mmol) and 1-propanephosphonic acid cyclic anhydride (8.37 mL, 13.1 mmol, 50% solution in ethyl acetate). The mixture was stirred at 70 °C for 16 hours, cooled to ambient temperature, poured into ethyl acetate (50 mL) and extracted with HCl (1 M , 20 mL). The organic phase was washed with water and brine. The aqueous layers were back-extracted separately with ethyl acetate and dichloromethane. The combined organic layers were dried and concentrated in vacuo to give 1.4 g crude product. The crude material was purified by silica gel chromatography using a methanol/ethyl acetate gradient to give the title compound as colorless foam (391 mg, 31 % yield).MS: M=243.2 (M+H)+

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2011/306589, 2011, A1 Location in patent: Page/Page column 73
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2011/154327, 2011, A1 Location in patent: Page/Page column 180; 181

17
[ 67622-86-0 ]
[ 4598-86-1 ]
[ 1352200-73-7 ]

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

18
[ 4598-86-1 ]
[ 1005588-05-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 24 h / 0 - 20 °C / Inert atmosphere 2: acetic acid / 3 h / Reflux

Reference： [1]Moore, Terry W.; Sana, Kasinath; Yan, Dan; Krumm, Stefanie A.; Thepchatri, Pahk; Snyder, James P.; Marengo, Jose; Arrendale, Richard F.; Prussia, Andrew J.; Natchus, Michael G.; Liotta, Dennis C.; Plemper, Richard K.; Sun, Aiming [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 762 - 767]

19
[ 4598-86-1 ]
[ 1005694-00-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 24 h / 0 - 20 °C / Inert atmosphere 2: acetic acid / 3 h / Reflux 3: palladium 10% on activated carbon; hydrogen / methanol; ethyl acetate / 2 h / 2068.65 Torr

Reference： [1]Moore, Terry W.; Sana, Kasinath; Yan, Dan; Krumm, Stefanie A.; Thepchatri, Pahk; Snyder, James P.; Marengo, Jose; Arrendale, Richard F.; Prussia, Andrew J.; Natchus, Michael G.; Liotta, Dennis C.; Plemper, Richard K.; Sun, Aiming [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 762 - 767]

20
[ 4598-86-1 ]
[ 1443114-19-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 24 h / 0 - 20 °C / Inert atmosphere 2.1: acetic acid / 3 h / Reflux 3.1: palladium 10% on activated carbon; hydrogen / methanol; ethyl acetate / 2 h / 2068.65 Torr 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 4 h / 0 - 20 °C / Inert atmosphere 4.2: 12 h / 20 °C / Inert atmosphere

Reference： [1]Moore, Terry W.; Sana, Kasinath; Yan, Dan; Krumm, Stefanie A.; Thepchatri, Pahk; Snyder, James P.; Marengo, Jose; Arrendale, Richard F.; Prussia, Andrew J.; Natchus, Michael G.; Liotta, Dennis C.; Plemper, Richard K.; Sun, Aiming [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 762 - 767]

21
[ 4598-86-1 ]
[ 95-54-5 ]
C₁₁H₁₁N₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 24h; Inert atmosphere;

Reference： [1]Moore, Terry W.; Sana, Kasinath; Yan, Dan; Krumm, Stefanie A.; Thepchatri, Pahk; Snyder, James P.; Marengo, Jose; Arrendale, Richard F.; Prussia, Andrew J.; Natchus, Michael G.; Liotta, Dennis C.; Plemper, Richard K.; Sun, Aiming [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 8, p. 762 - 767]

22
[ 4598-86-1 ]
C₁₀H₁₆N₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C 2: iron; ammonium chloride / ethanol; water / 12 h / 80 °C

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1

23
[ 4598-86-1 ]
C₂₉H₃₇N₇O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C 2: iron; ammonium chloride / ethanol; water / 12 h / 80 °C 3: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1

24
[ 4598-86-1 ]
C₂₇H₃₅N₇O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C 2: iron; ammonium chloride / ethanol; water / 12 h / 80 °C 3: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C 4: tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride / toluene / 16 h / 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1

25
[ 4598-86-1 ]
C₂₂H₂₇N₇O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C 2.1: iron; ammonium chloride / ethanol; water / 12 h / 80 °C 3.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 2 h / 20 °C 4.1: tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride / toluene / 16 h / 80 °C / Inert atmosphere 5.1: hydrogen; palladium 10% on activated carbon / dichloromethane; ethyl acetate / 12 h / 20 °C 5.2: 12 h / 20 °C

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1

26
[ 4598-86-1 ]
C₁₈H₁₈N₆O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 12 h / 20 °C 2: lithium hydroxide monohydrate; water / methanol / 4 h / 60 °C

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1

27
[ 4598-86-1 ]
C₁₈H₂₀N₆O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 12 h / 20 °C 2: lithium hydroxide monohydrate; water / methanol / 4 h / 60 °C 3: hydrogen / tetrahydrofuran / 12 h / 20 °C

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1

28
[ 4598-86-1 ]
C₁₈H₁₈N₆O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 12 h / 20 °C 2: lithium hydroxide monohydrate; water / methanol / 4 h / 60 °C 3: hydrogen / tetrahydrofuran / 12 h / 20 °C 4: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 4 h / 20 °C

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1

29
[ 22537-07-1 ]
[ 4598-86-1 ]
C₁₀H₁₄N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;	28 Syntheis of Compound 28.1 [0266] To a solution of l-methyl-4-nitro-lH-pyrazole-3-carboxylic acid (1.63 g, 9.5 mmol, 1.0 eq) in DMF (10 mL) were added pent-4-en-l -amine (1.5 g, 14.3 mmol, 1.5 eq), HBTU (5.4 g, 14.3 mmol, 1.5 eq) and DIPEA (6.2 g, 48 mmol, 5.0 eq). The mixture was stirred at room temperature for 2 h, diluted with EA (100 mL). The mixture was washed with water (50 mL x 4) and brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography column (PE : EA = 2 : 3) to give 28.1 (1.6 g, yield: 72%) as a yellow oil. 1H NMR (400MHz, DMSO- 6) D δ: 8.84 (s, 1H), 8.61 (t, J = 5.6 Hz, 1H), 5.88-5.78 (m, 1H), 5.07-4.96 (m, 2H), 3.90 (s, 3H), 3.22 (q, J = 6.8 Hz, 2H), 2.07 (q, J = 6.8 Hz, 2H), 1.61-1.54 (m, 2H); ESI-MS (M+H) +: 239.1.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1 Location in patent: Paragraph 0266

30
C₁₉H₂₆N₄O₅ [ No CAS ]
[ 4598-86-1 ]
C₂₄H₂₉N₇O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 5h;	30 Synthesis of Compound 30.4 [0276] To a solution of 30.3 (350 mg, 0.9 mmol) in DMF (5 mL) were added l-methyl-4- nitro-lH-pyrazole-3-carboxylic acid (190 mg, 1.1 mmol, 1.2 eq), HATU (513 mg, 1.4 mmol, 1.5 eq) and DIPEA (232 mg, 1.8 mmol, 2.0 eq). The mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with DCM (20 mL) and washed with water (5 mL x 3). The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether/ethyl acetate = 1/10) to afford 30.4 as a yellow solid (250 mg, yield: 50%). 1HNMR (400 MHz, DMSO- 6) D δ: 8.47 (d, J = 4.8 Hz, 1H), 8.35 (s, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 7.69 (d, J = 4.8 Hz, 1H), 4.12 (t, J = 6.8 Hz, 2H), 4.05 (s, 3H), 4.04 (s, 3H), 3.55-3.51 (m, 2H), 1.77-1.75 (m, 2H), 1.70-1.66 (m, 2H), 1.54 (s, 9H); ESI-MS (M+H)+: 544.1.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1 Location in patent: Paragraph 0276

31
C₁₄H₁₇N₃O₄ [ No CAS ]
[ 4598-86-1 ]
C₁₉H₂₀N₆O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 16h;	34 Synthesis of Compound 34.9 [0304] To a solution of 34.8 (300 mg, 1.03 mmol, 1.0 eq) in DMF (8 mL) was added HATU (587 mg, 1.55 mmol, 1.5 eq) and DIPEA (398 mg, 3.09 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 16 h, diluted with EtOAc (50 mL) and washed with water (5 mL x 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by pre-HPLC (MeOH/H20 with 0.05% TFA as mobile phase; from 20% to 95%) to furnish the compound 34.9 (128 mg, Y: 28%) as a yellow oil; ESI-MS (M+H)+: 445.1.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1 Location in patent: Paragraph 0304

32
C₁₅H₁₉N₃O₅ [ No CAS ]
[ 4598-86-1 ]
C₂₀H₂₂N₆O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With triethylamine; HATU In dichloromethane at 20℃; for 14h;	35 Synthesis of Compound 35.8 [0315] To a solution of 35.7 (2.0 g, 6.3 mmol, 1.0 eq) in DCM (150 mL) were added 1- methyl-4-nitro-lH-pyrazole-3-carboxylic acid (1.1 g, 6.3 mmol, 1.0 eq), HATU (3.6 g, 9.5 mmol, 1.5 eq) and Et N (3.2 g, 31.5 mmol, 5.0 eq). After stirred at room temperature for 14 h, the resulting mixture was washed with brine (30 mL x 3), dried over anhydrous Na2S04, concentrated under reduced pressure. The residue was purified by chromatography column (PE : EA = 5 : 1) to give 35.8 (1.0 g, yield: 32%) as a white solid. 1H NMR (400 MHz, DMSO- ) S: 9.07 (s, 1H), 8.84 (s, 1H), 8.68 (t, J = 5.2 Hz, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.54 (dd, J = 5.2 Hz, 5.2 Ηζ,ΙΗ), 7.28 (s, 1H), 4.47 (t, J = 4.4 Hz, 2H), 4.36 (q, J = 1.2 Hz, 7.2 Hz, 2H), 3.90 (s, 3H), 3.81 (t, J = 4.4 Hz, 2H), 3.61 (t, J = 6.0 Hz, 2H), 3.43 (q, J = 6.0 Hz, 5.6 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); ESI-MS (M+H)+: 475.1

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1 Location in patent: Paragraph 0315

33
C₁₆H₁₇N₃O₃ [ No CAS ]
[ 4598-86-1 ]
C₂₁H₂₀N₆O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With triethylamine; HATU In N,N-dimethyl-formamide at 20℃; for 5h;	39 Synthesis of Compound 39.4 [0339] To a solution of 39.3 (800 mg, 2.7 mmol) and in DMF (10 mL) were added HATU (2.0 g, 5.4 mmol, 2.0 eq), l-methyl-4-nitro-lH-pyrazole-3-carboxylic acid (1.2 eq) and TEA (545 mg, 5.4 mmol, 2.0 eq). After stirred at room temperature for 5 h, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (5 mL x 6). The organic layer was dried over Na2S04 and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA = 1 / 2) to afford 39.4 (500 mg, yield: 45%) as a yellow solid; ESI-MS (M+H) +: 453.1.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1 Location in patent: Paragraph 0339

34
C₁₃H₁₈N₄O₃ [ No CAS ]
[ 4598-86-1 ]
C₁₈H₂₁N₇O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With triethylamine; HATU In dichloromethane at 20℃; for 2h;	41 Synthesis of Compound 41.6 [0352] To a solution of 41.5 (330 mg, 1.15 mmol, 1.0 eq) in DCM (15 mL) were added 1- methyl-4-nitro-lH-pyrazole-3-carboxylic acid (197 mg, 1.15 mmol, 1.0 eq), HATU (655 mg, 1.72 mmol, 1.5 eq) and Et N (232 mg, 2.30 mmol, 2.0 eq). After stirred at room temperature for 2 h, the reaction mixture was diluted with DCM (50 mL), washed with water (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (PE / EA = 1 / 2) to give 41.6 (140 mg, yield: 27%) as a white solid; ESI-MS (M+H) +: 454.1.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1 Location in patent: Paragraph 0352

35
C₁₇H₂₃N₃O₄S [ No CAS ]
[ 4598-86-1 ]
C₂₂H₂₆N₆O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 12h;	43 Synthesis of Compound 43.4 [0363] To a mixture of 43.3 (1.0 g, 2.7 mmol, 1.0 eq) and l-methyl-4-nitro-lH-pyrazole-3- carboxylic acid (460 mg, 2.7 mmol, 1.0 eq) in CH2C12 (50 ml), DIPEA (880 mg, 6.8 mmol, 2.5 eq) and HATU (1.56 g, 4.1 mmol, 1.5 eq) were added. The reaction mixture was stirred at room temperature for 12 h. After concentrated under reduced pressure, the residue was purified by pre-TLC (MeOH / DCM = 1 / 100) to give 43.4 (800 mg, yield: 56%) as a yellow oil; ESI-MS (M+H) +: 519.1

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1 Location in patent: Paragraph 0363

36
C₁₇H₂₄N₄O₃S [ No CAS ]
[ 4598-86-1 ]
C₂₂H₂₇N₇O₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 4h;	45 Synthesis of Compound 45. [0377] To a mixture of 45.6 (500 mg, 1.4 mmol, 1.0 eq) and l-methyl-4-nitro-lH-pyrazole-3- carboxylic acid (240 mg, 1.4 mmol, 1.0 eq) in CH2C12 (50 ml), DIPEA (440 mg, 3.4 mmol, 2.5 eq) and HATU (780 mg, 2.1 mmol, 1.5 eq) were added. After stirred at room temperature for 4 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by pre-TLC (MeOH / DCM = 1 / 100) to give 45.7 (500 mg, yield: 70%) as a yellow solid. 1H NMR (400 MHz, CDC13) δ: 8.23 (s, 1H), 8.15 (s, 1H), 8.11 (d, J = 5.6 Hz, 1H), 7.24 (s, 1H), 7.17-7.15 (m, 1H), 3.97 (s, 3H), 3.78-3.76 (m, 2H), 3.73-3.72 (m, 4H), 3.66-3.65 (m, 2H), 1.63 (s, 9H); ESI-MS (M+H) +: 517.8.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1 Location in patent: Paragraph 0377

37
C₁₅H₁₉N₃O₄ [ No CAS ]
[ 4598-86-1 ]
C₂₀H₂₂N₆O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With triethylamine; HATU In dichloromethane at 20℃; for 16h;	62 Syntheis of Compound 62.3 [0438] To a solution of l-methyl-4-nitro-lH-pyrazole-3-carboxylic acid (404 mg, 2.36 mmol, 1.2 eq) in DCM (100 mL), HATU (1.12 g, 2.96 mmol, 1.5 eq), Et N (388 mg, 3.94 mmol, 2.0 eq) and 62.2 (600 mg, 1.97 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for 16 h. After concentrated under reduced pressure, the residue was purified by pre-TLC (EA) to give 62.3 (500 mg, Y: 55%) as a white solid. 1H NMR (400 MHz, DMSO- de) δ: 8.99 (s, 1H), 8.83 (s, 1H), 8.65 (s, 1H), 8.63 (t, J = 5.6 Hz, 1H), 8.36 (d, J = 4.8 Hz, 1H), 7.84 (d, J = 4.8 Hz, 1H), 4.34-4.29 (m, 4H), 3.89 (s, 3H), 3.34 (t, J = 5.2 Hz, 2H), 1.86- 1.83 (m, 2H), 1.76-1.73 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H); ESI-MS (M+H) +: 459.1.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1 Location in patent: Paragraph 0438

38
C₁₅H₂₀N₄O₄*ClH [ No CAS ]
[ 4598-86-1 ]
C₂₀H₂₃N₇O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 2h;	202 Synthesis of 202.4 To a solution of 202.3 (500 mg, 1.4 mmol, 1.0 eq) and l-methyl-4-nitro-lH-pyrazole-3- carboxylic acid (291 mg, 1.7 mmol, 1.2 eq) in CH2C12 (80 mL), DIPEA (362 mg, 2.8 mmol, 2.0 eq) and HATU (798 mg, 2.1 mmol, 1.5 eq) were added. The reaction mixture was stirred at room temperature for 2 h and washed with H20 (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by pre-TLC (MeOH / DCM = 1 / 20) to give 202.4 (490 mg, yield: 75%) as a yellow oil; ESI-MS (M+H)+: 474.2.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1 Location in patent: Page/Page column 174

39
C₁₅H₂₀N₄O₄*ClH [ No CAS ]
[ 4598-86-1 ]
C₁₈H₁₉N₇O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 2 h / 20 °C 2.1: palladium on activated charcoal; hydrogen / ethyl acetate / 2 h / 20 °C 2.2: 2 h / 60 °C 2.3: 2 h / 20 °C

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1

40
C₁₉H₂₇N₃O₃S [ No CAS ]
[ 4598-86-1 ]
C₂₄H₃₀N₆O₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 2h;	215 Synthesis of 215.11 To a solution of 215.10 (450 mg, 1.2 mmol, 1.0 eq) and l-methyl-4-nitro-lH-pyrazole-3- carboxylic acid (205 mg, 1.2 mmol, 1.0 eq) in CH2C12 (30 mL), DIPEA (387 mg, 3.0 mmol, 2.5 eq) and HATU (680 mg, 1.8 mmol, 1.5 eq) were added. The mixture was stirred at room temperature for 2 h and then washed with H20 (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by pre-TLC (MeOH / DCM = 1 / 20) to give 215.11 (400 mg, yield: 63%) as a yellow oil; ESI-MS (M+H)+: 531.0.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/143672, 2014, A1 Location in patent: Page/Page column 183

41
[ 4598-86-1 ]
(4-amino-1-methyl-1H-pyrazol-3-yl)(4-chlorophenyl)ketone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: thionyl chloride / 3.5 h / Reflux 2: aluminum (III) chloride / 18 h / 25 - 120 °C 3: iron; ammonium chloride / ethanol; water / 1 h / 90 °C
	Multi-step reaction with 3 steps 1: thionyl chloride / 3.5 h / Reflux 2: aluminum (III) chloride / chlorobenzene / 18 h / 25 - 120 °C 3: ammonium chloride / ethanol; water / 1 h / 90 °C

Reference： [1]Current Patent Assignee: BAYER AG - US2016/9725, 2016, A1
[2]Current Patent Assignee: BAYER AG - US2015/376196, 2015, A1

42
[ 4598-86-1 ]
(4-chlorophenyl)(1-methyl-4-nitro-1H-pyrazol-3-yl)ketone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: thionyl chloride / 3.5 h / Reflux 2: aluminum (III) chloride / 18 h / 25 - 120 °C
	Multi-step reaction with 2 steps 1: thionyl chloride / 3.5 h / Reflux 2: aluminum (III) chloride / chlorobenzene / 18 h / 25 - 120 °C

Reference： [1]Current Patent Assignee: BAYER AG - US2016/9725, 2016, A1
[2]Current Patent Assignee: BAYER AG - US2015/376196, 2015, A1

43
[ 4598-86-1 ]
methyl N-[3-(4-chlorobenzoyl)-1-methyl-1H-pyrazol-4-yl]-N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-aspartate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: thionyl chloride / 3.5 h / Reflux 2: aluminum (III) chloride / 18 h / 25 - 120 °C 3: iron; ammonium chloride / ethanol; water / 1 h / 90 °C 4: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 19 h / 40 °C

Reference： [1]Current Patent Assignee: BAYER AG - US2016/9725, 2016, A1

44
[ 4598-86-1 ]
2-[(6S)-8-(4-chlorophenyl)-2-methyl-5-oxo-2,4,5,6-tetrahydropyrazolo[4,3-e][1,4]diazepin-6-yl]acetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: thionyl chloride / 3.5 h / Reflux 2.1: aluminum (III) chloride / 18 h / 25 - 120 °C 3.1: iron; ammonium chloride / ethanol; water / 1 h / 90 °C 4.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 19 h / 40 °C 5.1: piperidine / tetrahydrofuran / 1 h / 25 °C 5.2: 21 h / 25 °C
	Multi-step reaction with 5 steps 1.1: thionyl chloride / 3.5 h / Reflux 2.1: aluminum (III) chloride / chlorobenzene / 18 h / 25 - 120 °C 3.1: ammonium chloride / ethanol; water / 1 h / 90 °C 4.1: N-ethyl-N,N-diisopropylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / tetrahydrofuran / 16 h / 40 °C 5.1: piperidine / tetrahydrofuran / 1 h / 25 °C 5.2: 21 h / 25 °C

Reference： [1]Current Patent Assignee: BAYER AG - US2016/9725, 2016, A1
[2]Current Patent Assignee: BAYER AG - US2015/376196, 2015, A1

45
[ 4598-86-1 ]
2-[(4S)-6-(4-chlorophenyl)-1,8-dimethyl-4,8-dihydropyrazolo[3,4-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]acetic acid, sodium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: thionyl chloride / 3.5 h / Reflux 2.1: aluminum (III) chloride / 18 h / 25 - 120 °C 3.1: iron; ammonium chloride / ethanol; water / 1 h / 90 °C 4.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 19 h / 40 °C 5.1: piperidine / tetrahydrofuran / 1 h / 25 °C 5.2: 21 h / 25 °C 6.1: sodium hydride / tetrahydrofuran; mineral oil / 0.33 h / -70 - 0 °C / Inert atmosphere 6.2: 0.5 h / -70 - 0 °C / Inert atmosphere 7.1: sodium hydroxide; water / methanol / 4 h / 25 °C
	Multi-step reaction with 7 steps 1.1: thionyl chloride / 3.5 h / Reflux 2.1: aluminum (III) chloride / chlorobenzene / 18 h / 25 - 120 °C 3.1: ammonium chloride / ethanol; water / 1 h / 90 °C 4.1: N-ethyl-N,N-diisopropylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / tetrahydrofuran / 16 h / 40 °C 5.1: piperidine / tetrahydrofuran / 1 h / 25 °C 5.2: 21 h / 25 °C 6.1: sodium hydride / tetrahydrofuran; mineral oil / 0.33 h / -70 - 0 °C / Inert atmosphere 6.2: 1 h / -70 - 0 °C 6.3: 1 h / 25 °C 7.1: sodium hydroxide / methanol / 4 h / 25 °C

Reference： [1]Current Patent Assignee: BAYER AG - US2016/9725, 2016, A1
[2]Current Patent Assignee: BAYER AG - US2015/376196, 2015, A1

46
[ 4598-86-1 ]
2-[(4S)-6-(4-chlorophenyl)-1,8-dimethyl-4,8-dihydropyrazolo[3,4-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: thionyl chloride / 3.5 h / Reflux 2.1: aluminum (III) chloride / 18 h / 25 - 120 °C 3.1: iron; ammonium chloride / ethanol; water / 1 h / 90 °C 4.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 19 h / 40 °C 5.1: piperidine / tetrahydrofuran / 1 h / 25 °C 5.2: 21 h / 25 °C 6.1: sodium hydride / tetrahydrofuran; mineral oil / 0.33 h / -70 - 0 °C / Inert atmosphere 6.2: 0.5 h / -70 - 0 °C / Inert atmosphere 7.1: sodium hydroxide; water / methanol / 4 h / 25 °C 8.1: triethylamine; HATU / N,N-dimethyl-formamide / 48 h / 25 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: BAYER AG - US2016/9725, 2016, A1

47
[ 4598-86-1 ]
2-[(4S)-6-(4-chlorophenyl)-1,8-dimethyl-4,8-dihydropyrazolo[3,4-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]-1-(1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: thionyl chloride / 3.5 h / Reflux 2.1: aluminum (III) chloride / 18 h / 25 - 120 °C 3.1: iron; ammonium chloride / ethanol; water / 1 h / 90 °C 4.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 19 h / 40 °C 5.1: piperidine / tetrahydrofuran / 1 h / 25 °C 5.2: 21 h / 25 °C 6.1: sodium hydride / tetrahydrofuran; mineral oil / 0.33 h / -70 - 0 °C / Inert atmosphere 6.2: 0.5 h / -70 - 0 °C / Inert atmosphere 7.1: sodium hydroxide; water / methanol / 4 h / 25 °C 8.1: triethylamine; HATU / N,N-dimethyl-formamide / 20 °C

Reference： [1]Current Patent Assignee: BAYER AG - US2016/9725, 2016, A1

48
[ 4598-86-1 ]
2-[(4S)-6-(4-chlorophenyl)-1,8-dimethyl-4,8-dihydropyrazolo[3,4-f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl]acetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: thionyl chloride / 3.5 h / Reflux 2.1: aluminum (III) chloride / 18 h / 25 - 120 °C 3.1: iron; ammonium chloride / ethanol; water / 1 h / 90 °C 4.1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 19 h / 40 °C 5.1: piperidine / tetrahydrofuran / 1 h / 25 °C 5.2: 21 h / 25 °C 6.1: sodium hydride / tetrahydrofuran; mineral oil / 0.33 h / -70 - 0 °C / Inert atmosphere 6.2: 0.5 h / -70 - 0 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: thionyl chloride / 3.5 h / Reflux 2.1: aluminum (III) chloride / chlorobenzene / 18 h / 25 - 120 °C 3.1: ammonium chloride / ethanol; water / 1 h / 90 °C 4.1: N-ethyl-N,N-diisopropylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / tetrahydrofuran / 16 h / 40 °C 5.1: piperidine / tetrahydrofuran / 1 h / 25 °C 5.2: 21 h / 25 °C 6.1: sodium hydride / tetrahydrofuran; mineral oil / 0.33 h / -70 - 0 °C / Inert atmosphere 6.2: 1 h / -70 - 0 °C 6.3: 1 h / 25 °C

Reference： [1]Current Patent Assignee: BAYER AG - US2016/9725, 2016, A1
[2]Current Patent Assignee: BAYER AG - US2015/376196, 2015, A1

49
[ 4598-86-1 ]
[ 1006433-28-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With thionyl chloride In N,N-dimethyl-formamide at 76℃; for 1h;
	With thionyl chloride for 3.5h; Reflux;	Intermediate 4A 4-Chlorophenyl 1-methyl-4-nitro-1H-pyrazol-3-yl ketone 11.45 g of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (CAS 4598-86-1) were added carefully to 52.1 ml of thionyl chloride, and the mixture was then heated at reflux with stirring for 3.5 h. After cooling, the mixture was concentrated under reduced pressure and dried further under oil pump vacuum. This gave 12.75 g of 1-methyl-4-nitro-1H-pyrazole-3-carbonyl chloride which were used for the next step without further purification. (0543) A solution of 12.68 g of the acid chloride prepared beforehand in 200 ml of chlorobenzene was added to a suspension of 8.92 g of aluminium trichloride in 53 ml of chlorobenzene. (0544) Subsequently, the mixture was stirred at 120° C. for 2 h and then at 25° C. for 16 h. The reaction mixture was diluted with 250 ml of ethyl acetate and extracted with 150 ml of water. After phase separation, the aqueous phase was extracted three times with in each case 150 ml of ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by chromatography on silica gel (hexane/ethyl acetate gradient). This gave 14.7 g of 4-chlorophenyl 1-methyl-4-nitro-1H-pyrazol-3-yl ketone. (0545) 1H NMR (400 MHz, DMSO-d6) δ=3.95 (s, 3Hδ) 7.59-7.64 (m, 2H) 7.85-7.91 (m, 2H) 9.01 (s, 1H).
12.75 g	With thionyl chloride for 3.5h; Reflux;	11.45 g of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (CAS 4598-86-1) were added carefully to 52.1 ml of thionyl chloride, and the mixture was then heated at reflux with stirring for 3.5 h. After cooling, the mixture was concentrated under reduced pressure and dried further under oil pump vacuum. This gave 12.75 g of 1-methyl-4-nitro-1H-pyrazole-3-carbonyl chloride which were used in the next step without further purification.

Reference： [1]Current Patent Assignee: BIOARDIS LLC - WO2020/177067, 2020, A1 Location in patent: Paragraph 0218-0219
[2]Current Patent Assignee: BAYER AG - US2016/9725, 2016, A1 Location in patent: Paragraph 0541-0545
[3]Current Patent Assignee: BAYER AG - US2015/376196, 2015, A1 Location in patent: Paragraph 0616; 0617

50
[ 4598-86-1 ]
N-[3-(4-chlorobenzoyl)-1-methyl-1H-pyrazol-4-yl]-N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-aspartic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: thionyl chloride / 3.5 h / Reflux 2: aluminum (III) chloride / chlorobenzene / 18 h / 25 - 120 °C 3: ammonium chloride / ethanol; water / 1 h / 90 °C 4: N-ethyl-N,N-diisopropylamine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / tetrahydrofuran / 16 h / 40 °C

Reference： [1]Current Patent Assignee: BAYER AG - US2015/376196, 2015, A1

51
[ 138786-86-4 ]
[ 74-88-4 ]
[ 4598-86-1 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: Into a 1 L round bottom flask containing a suspension of sodium hydride (60% in paraffin oil, 4.7 g, 116 mmol) in tetrahydrofuran (400 mL) at 0 C was added methyl 4-nitro-1H- pyrazole-3-carboxylate (16.5 g, 96 mmol) in tetrahydrofuran (50 mL) dropwise and the reactionmixture was stirred for 1 h. To the reaction mixture was added methyl iodide (9 mL, 145 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0C and treated with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (4 x 200 mL). The combined organic fractions were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography eluting with ethyl acetate in petroleum ether (15-25%) to afford methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate as a solid. ?H NMR (CDC13, 400 MHz): 8.17 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H).
		NaH 60% dispersion in oil (3.13 g, 78.2 mmol) was added portionwise to an ice cooled suspension of methyl 4-nitro-1 H-pyrazole-3-carboxylate (p128, 1 1.15 g, 65.16 mmol) in THF (100 ml_) and the resulting mixture was stirred for 30min. lodomethane (6.09 ml_, 97.74mmol) was added to the mixture and the reaction was stirred at RT O/N. The day after UPLC showed mainly hydrolysis of the methyl ester and presence of the corresponding carboxilic acid. The reaction was quenced with water and diluted with EtOAc, but no product was present in the organic phase so the organic phase was discarded. The water phase was acidified until pH 4 with 6N HCI, then extracted several times with EtOAc, but only traces of product were detected in organic phase. The water phase was then dried under vacuum, the orange residue was triturated with Et20/MeOH 9/1 to afford 1 -methyl-4-nitropyrazole-3-carboxylic acid (Int A, 20 g, 1 16.88 mmol) as pale yellow solid in mixture with inorganic salts that was used as such.
		NaH 60% dispersion in oil (3.13 g, 78.2 mmol) was added portionwise to an ice cooled suspension of methyl 4-nitro-1 H-pyrazole-3-carboxylate (p68, 1 1.15 g, 65.16 mmol) in THF (100 ml_) and the resulting mixture was stirred for 30min. lodomethane (6.09 ml_, 97.74mmol) was added to the mixture and the reaction was stirred at RT ON. The day after UPLC showed mainly hydrolysis of the methyl ester and presence of the corresponding carboxilic acid. The reaction was quenced with water and diluted with EtOAc, but no product was present in the organic phase so the organic phase was discarded. The water phase was acidified until pH 4 with 6N HCI, then extracted several times with EtOAc, but only traces of product were detected in organic phase. The water phase was then dried under vacuum, the orange residue was triturated with Et20/MeOH 9/1 to afford 1 -methyl-4-nitropyrazole-3-carboxylic acid (Int A, 20 g, 1 16.88 mmol) as pale yellow solid in mixture with inorganic salts that was used as such.

Reference： [1]Patent: WO2016/144848,2016,A1 .Location in patent: Page/Page column 36; 37
[2]Patent: WO2019/43407,2019,A1 .Location in patent: Page/Page column 126
[3]Patent: WO2019/81939,2019,A1 .Location in patent: Page/Page column 77

52
[ 4598-86-1 ]
[ 3920-39-6 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia In methanol at -60 - 80℃; for 4h; Sealed tube;	4.3 Step 3: Into a 250 mL sealed tube were added methyl 1-methyl-4-nitro-1H-pyrazole-3- carboxylate (2.5 g, 13.5 mmol) and methanol (60 mL) and the reaction mixture was cooled to -60°C and ammonia gas was purged for 15 mm and then heated at 80 °C for 4 h. The reaction mixture was cooled to -15 °C and the excess ammonia gas was carefully removed by bubbling nitrogen and concentrated under reduced pressure to afford 1 -methyl-4-nitro- 1H-pyrazole-3 - carboxamide as a solid. ‘H NMR (CD3OD, 300 MHz): 8.56 (s, 1H), 3.94 (s, 3H). MS calc’d [M+Hj 171.0, found 171.2.
	Stage #1: 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid With thionyl chloride; N,N-dimethyl-formamide for 2h; Reflux; Stage #2: With ammonia In N,N-dimethyl-formamide at 0℃; for 0.5h;	17.3 Step 3: To a solution of imethyi-4-nitro-lH-pyrazole-3carboxylic acid (1.0 g, 5.85 mrnoi) in SOC12 (10 mE) at 0°C was added catalytic amount of DMF (0.lmL), and the mixture was heated at reflux for 2 h. The mixture was concentrated under reduced pressure and the residue was diluted with DMF and cooled to 0 °C. Ammonia (0.50g. l5mmoi) was added dropwise and the mixture was kept at 0 CC for 30 mm. The solid was collected by filtration to afford 1-methyl-4-nitro- 1H-pyrazole-3-carboxamide.

Reference： [1]Current Patent Assignee: MERCK & CO INC; BRUBAKER JASON - WO2016/144848, 2016, A1 Location in patent: Page/Page column 37
[2]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - WO2017/19804, 2017, A2 Location in patent: Paragraph 0360

53
[ 4598-86-1 ]
1-methyl-4-nitro-1H-pyrazole-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: ammonia / methanol / 4 h / -60 - 80 °C / Sealed tube 2: trichlorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 0 - 25 °C / Sealed tube
	Multi-step reaction with 2 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / 2 h / Reflux 1.2: 0.5 h / 0 °C 2.1: pyridine; trichlorophosphate / 1 h / -5 - 20 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC; BRUBAKER JASON - WO2016/144848, 2016, A1
[2]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - WO2017/19804, 2017, A2

54
[ 4598-86-1 ]
[ 1201935-84-3 ]

Reference： [1]Patent: WO2016/144848,2016,A1
[2]Patent: WO2017/19804,2017,A2

55
[ 4598-86-1 ]
[ 20055-00-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With trifluoroacetic acid In dichloromethane Cooling with ice;	2 second step: 1-Methyl-4-nitro-3-tert-butoxycarbonylamino-pyrazole (2 g, 7.8 mmol) was dissolved in dichloromethane(10 mL), trifluoroacetic acid (6 mL) was slowly added dropwise thereto under ice cooling.After the dropwise addition was completed, the reaction solution was stirred at room temperature overnight. The reaction is completed and concentrated under reduced pressure.1-Methyl-4-nitro-3-amino-pyrazole (1 g, 80%) was obtained.
	Stage #1: 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid With diphenylphosphoranyl azide; triethylamine In 1,4-dioxane; <i>tert</i>-butyl alcohol at 100℃; for 16h; Stage #2: With trifluoroacetic acid In dichloromethane at 25℃; for 2h;	1; 2 Step 1 & 2: Into a 250 mL round bottom flask containing a solution of 1-methyl-4-nitro-1H- pyrazole-3-carboxylic acid (5.0 g, 29 mmol) in 1,4-dioxane (75 mL) and tert-butanol (50 mL)were added triethylamine (9.8 mL, 45 mmol) and diphenylphosphoryl azide (9.8 mL, 45 mmol) and the reaction was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To a stirred solution of the residue in dichloromethane (50 mL) was added trifluoroacetic acid (25 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reducedpressure and triturated with diethyl ether to afford 1-methyl-4-nitro-1H-pyrazol-3-amine as a solid. ‘H NMR (DM50-c/6, 300 MHz): 8.44 (s, 1H), 7.31 (s, 1H), 3.65 (s, 3H). MS calc’d [M+Hj 143.0, found 143.4.

Reference： [1]Current Patent Assignee: RUDONG RINGENE PHARMACEUTICALS; RUDONG LINGDA BIOMEDICAL TECH - CN109721600, 2019, A Location in patent: Paragraph 0221; 0222; 0224
[2]Current Patent Assignee: MERCK & CO INC - WO2016/144846, 2016, A1 Location in patent: Page/Page column 53

56
[ 4598-86-1 ]
5-methyl-2-(1-methyl-4-nitro-1H-pyrazol-3-yl)oxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0 - 25 °C 2: trifluoromethylsulfonic anhydride / 1,4-dioxane / 90 °C / Sealed tube

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2016/144846, 2016, A1

57
[ 4598-86-1 ]
1-methyl-3-(5-methyloxazol-2-yl)-1H-pyrazol-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0 - 25 °C 2: trifluoromethylsulfonic anhydride / 1,4-dioxane / 90 °C / Sealed tube 3: hydrogen; palladium on carbon / methanol / 6 h / 25 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2016/144846, 2016, A1

58
[ 4598-86-1 ]
[ 2450-71-7 ]
1-methyl-4-nitro-N-(prop-2-yn-1-yl)-1H-pyrazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 25℃;	1 Step 1: Into a 50 mL round bottom flask containing a solution of 1-methyl-4-nitro-1H-pyrazole- 3-carboxylic acid (500 mg, 2.9 mmol) in dimethylformamide (20 mL) were added propargylamine (0.2 mL, 2.9 mmol) and diisopropylethylamine (1.4 mL). To the resulting solution cooled to 0 °C were added N-(3-dimethylaminopropyl)-N’-ethylcarbodiimidehydrochloride (850 mg, 4.4 mmol) and hydroxybenzotriazole (200 mg, 1.46 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was treated with water (50 mL) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate inpetroleum ether (25-40%) to afford 1 -methyl-4-nitro-N-(prop-2-yn- 1 -yl)- 1H-pyrazole-3 -+carboxamide as a solid. MS calc d [M+Hj 209.1, found 209.2.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2016/144846, 2016, A1 Location in patent: Page/Page column 41

59
N₄-(3-aminobenzyl)-8-isopropyl-N₂-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine [ No CAS ]
[ 4598-86-1 ]
N-(3-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-1-methyl-4-nitro-1H-pyrazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 1h;	14.1 Step-1 : Synthesis of N-(3-(((8-isopropyl-2-((tetrahvdro-2H-pyran-4-yl)amino)pyrazolo[l,5- al [ 1 ,3,51triazin-4-yl)amino)methyl)phenyl)- l-methyl-4-nitro- lH-pyrazole-3-carboxamide. Step-1 : Synthesis of N-(3-(((8-isopropyl-2-((tetrahvdro-2H-pyran-4-yl)amino)pyrazolo[l,5- al [ 1 ,3,51triazin-4-yl)amino)methyl)phenyl)- l-methyl-4-nitro- lH-pyrazole-3-carboxamide. To a cooled solution of l-methyl-4-nitro-lH-pyrazole-3-carboxylic acid (0.108g, 0.62mmol; US 2009/156582A1) in DMF (lOmL) at 0 °C was added HATU (0.3g, 0.78mmol) followed by DIPEA (0.2mL, 1.04mmol) and finally added N4-(3-aminobenzyl)-8-isopropyl-N2- (tetrahydro-2H-pyran-4-yl)pyrazolo[l,5-a][l,3,5]triazine-2,4-diamine (0.2g, 0.52mmol; intermediate-33). The reaction mixture was stirred for lh at room temperature. The reaction mixture was quenched with ice-water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (2x25mL). The combined organic phase was washed with brine, dried over Na2S04, filtered and concentrated the crude residue was purified by 100- 200 silica gel column chromatography to afford the title compound (0.23g, 82%). LCMS: m/z = 535.1 (M+H)+.

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2016/142855, 2016, A2 Location in patent: Page/Page column 101

60
[ 4598-86-1 ]
2-{4-[2-(3-cyano-1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-5-yl]-2-fluoro-phenyl}-N-[5-(1-trifluoromethyl-cyclopropyl)-isoxazol-3-yl]-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / 2 h / Reflux 1.2: 0.5 h / 0 °C 2.1: pyridine; trichlorophosphate / 1 h / -5 - 20 °C 3.1: ammonium chloride; iron / water; ethanol / 1 h / 60 °C 4.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 2 h / 120 °C / Inert atmosphere 5.1: sodium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / water; acetonitrile / 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - WO2017/19804, 2017, A2

61
[ 4598-86-1 ]
4-((5-bromopyrimidin-2-yl)amino)-1-methyl-1H-pyrazole-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / 2 h / Reflux 1.2: 0.5 h / 0 °C 2.1: pyridine; trichlorophosphate / 1 h / -5 - 20 °C 3.1: ammonium chloride; iron / water; ethanol / 1 h / 60 °C 4.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 2 h / 120 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - WO2017/19804, 2017, A2

62
[ 4598-86-1 ]
[ 70261-82-4 ]
C₁₇H₂₂N₆O₃ [ No CAS ]

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

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

63
[ 4598-86-1 ]
[ 1201935-81-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sulfuric acid / 4 h / Heating; Reflux 2.1: diisobutylaluminium hydride / tetrahydrofuran; toluene / -20 - 25 °C 3.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 5 °C 3.2: 5 - 50 °C 4.1: hydrogen / palladium on activated charcoal / methanol / Inert atmosphere

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2009/153589, 2009, A1

64
[ 4598-86-1 ]
[ 1201935-83-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sulfuric acid / 4 h / Heating; Reflux 2.1: diisobutylaluminium hydride / tetrahydrofuran; toluene / -20 - 25 °C 3.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 5 °C 3.2: 5 - 50 °C

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2009/153589, 2009, A1

65
[ 4598-86-1 ]
[ 1201935-82-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sulfuric acid / 4 h / Heating; Reflux 2: diisobutylaluminium hydride / tetrahydrofuran; toluene / -20 - 25 °C

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2009/153589, 2009, A1

66
[ 4598-86-1 ]
[ 1001500-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 17 - 25 °C 1.2: 1 h / 0 °C 2.1: hydrogen / palladium on activated charcoal / methanol / Inert atmosphere

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2009/153589, 2009, A1

67
[ 4598-86-1 ]
[ 1201934-94-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 17 - 25 °C 1.2: 1 h / 0 °C 2.1: hydrogen / palladium on activated charcoal / methanol / Inert atmosphere 3.1: caesium carbonate / palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2009/153589, 2009, A1

68
[ 4598-86-1 ]
[ 75-65-0 ]
(1-methyl-4-nitro-1H-pyrazole-3-yl)-bis-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.6%	Stage #1: 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid With diphenyl phosphoryl azide; trimethylamine In 1,4-dioxane at 20℃; for 0.5h; Inert atmosphere; Stage #2: <i>tert</i>-butyl alcohol In 1,4-dioxane at 80℃; for 8h; Inert atmosphere;	4.1.22. Synthesis of (1-methyl-4-nitro-1H-pyrazole-3-yl)-bis-carbamic acidtert-butyl ester (36) In a solution of compound 35 (1 g, 5.78 mmol) in 1,4-dioxane(15 mL) was added diphenylphosphoryl azide (2.41 g, 8.77 mmol) andtrimethylamine (1.18 g, 11.7 mmol). The mixture was stirred at roomtemperature under nitrogen for 0.5 h. The reaction was added with t-BuOH (7.5 mL) and heated at 80 °C under nitrogen for 8 h. The mixturewas concentrated in vacuo and added with EtOAc (100 mL). After washedwith water (50 mL×3), the organic phase was dried over Na2SO4,filtered and concentrated in vacuo and the residue was purified by flashcolumn chromatography (silica gel, petroleum ether/EtOAc=5/1) toafford compound 36 (1.1 g, 56%) as white liquid. 1H NMR (300 MHz,DMSO-d6) δ (ppm): 8.94 (s, 1H), 3.91 (s, 3H), 1.38 (s, 18H).

Reference： [1]Yuan, Xinrui; Wu, Hanshu; Bu, Hong; Zheng, Peiyuan; Zhou, Jinpei; Zhang, Huibin [Bioorganic and Medicinal Chemistry, 2019, vol. 27, # 7, p. 1211 - 1225]

69
[ 4598-86-1 ]
[ 637336-53-9 ]

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

70
[ 4598-86-1 ]
[ 211738-66-8 ]

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

71
[ 4598-86-1 ]
[ 96256-54-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: sulfuric acid / Reflux 2: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C 3: isopentyl nitrite; copper(ll) bromide; copper(I) bromide / acetonitrile / 2 h / 80 °C 4: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / water; 1,4-dioxane / 3 h / 120 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: sulfuric acid / Reflux 2: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C 3: isopentyl nitrite; copper(I) bromide; copper(ll) bromide / acetonitrile / 2 h / 80 °C 4: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / water; 1,4-dioxane / 3 h / 120 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2019/43407, 2019, A1
[2]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2019/81939, 2019, A1

72
[ 4598-86-1 ]
lithium 1-methyl-4-phenyl-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: sulfuric acid / Reflux 2: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C 3: isopentyl nitrite; copper(ll) bromide; copper(I) bromide / acetonitrile / 2 h / 80 °C 4: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / water; 1,4-dioxane / 3 h / 120 °C / Inert atmosphere 5: lithium hydroxide monohydrate / tetrahydrofuran; water / 20 °C
	Multi-step reaction with 5 steps 1: sulfuric acid / Reflux 2: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C 3: isopentyl nitrite; copper(I) bromide; copper(ll) bromide / acetonitrile / 2 h / 80 °C 4: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / water; 1,4-dioxane / 3 h / 120 °C / Inert atmosphere 5: lithium hydroxide monohydrate / water; tetrahydrofuran / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2019/43407, 2019, A1
[2]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2019/81939, 2019, A1

73
[ 4598-86-1 ]
methyl 1-methyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sulfuric acid / Reflux 2.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C 3.1: isopentyl nitrite; copper(ll) bromide; copper(I) bromide / acetonitrile / 2 h / 80 °C 4.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; copper(l) iodide / N,N-dimethyl-formamide / 0.33 h / Inert atmosphere 4.2: 4 h / 110 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: sulfuric acid / Reflux 2.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C 3.1: isopentyl nitrite; copper(I) bromide; copper(ll) bromide / acetonitrile / 2 h / 80 °C 4.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; copper(l) iodide / N,N-dimethyl-formamide / 0.33 h / Inert atmosphere 4.2: 4 h / 110 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2019/43407, 2019, A1
[2]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2019/81939, 2019, A1

74
[ 4598-86-1 ]
lithium 1-methyl-4-(pyrimidin-2-yl)-1H-pyrazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sulfuric acid / Reflux 2.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C 3.1: isopentyl nitrite; copper(ll) bromide; copper(I) bromide / acetonitrile / 2 h / 80 °C 4.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; copper(l) iodide / N,N-dimethyl-formamide / 0.33 h / Inert atmosphere 4.2: 4 h / 110 °C / Inert atmosphere 5.1: lithium hydroxide monohydrate / tetrahydrofuran; water / 20 °C
	Multi-step reaction with 5 steps 1.1: sulfuric acid / Reflux 2.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C 3.1: isopentyl nitrite; copper(I) bromide; copper(ll) bromide / acetonitrile / 2 h / 80 °C 4.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; copper(l) iodide / N,N-dimethyl-formamide / 0.33 h / Inert atmosphere 4.2: 4 h / 110 °C 5.1: water; lithium hydroxide monohydrate / tetrahydrofuran / 20 °C

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2019/43407, 2019, A1
[2]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2019/81939, 2019, A1

75
[ 4598-86-1 ]
cis-tert-butyl N-[4-methyl-2-(1-methyl-4-phenyl-1H-pyrazole-3-carbonyl)-2-azabicyclo[3.1.1]heptan-3-yl]methyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sulfuric acid / Reflux 2.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C 3.1: isopentyl nitrite; copper(ll) bromide; copper(I) bromide / acetonitrile / 2 h / 80 °C 4.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / water; 1,4-dioxane / 3 h / 120 °C / Inert atmosphere 5.1: lithium hydroxide monohydrate / tetrahydrofuran; water / 20 °C 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 6.2: 3 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: CHRONOS THERAPEUTICS LIMITED - WO2019/43407, 2019, A1

76
[ 4598-86-1 ]
[ 75-65-0 ]
1-methyl-4-nitro-3-tert-butoxycarbonylaminopyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With diphenyl phosphoryl azide; triethylamine In N,N-dimethyl-formamide at 80℃; for 4h;	1 first step: Add triethylamine (2.5 mL, 17.3 mmol) to the ice bath for cooling1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (1.6 g, 8.64 mmol)In a solution with N,N-dimethylformamide (15 mL) and tert-butanol (5 mL),Subsequent addition of diphenylphosphoryl DPPA (3.6 g, 12.97 mmol),The reaction solution was heated to 80 ° C and stirred for 4 h. The reaction is completed,A part of the solvent was removed under reduced pressure and then diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfatePurification by column chromatography gave 1-methyl-4-nitro-3-tert-butoxycarbonylamino-pyrazole (2 g, 90%).
90%	With diphenyl phosphoryl azide; triethylamine In N,N-dimethyl-formamide at 80℃; for 4h; Cooling with ice;	1 Step 1: Add triethylamine (2.5 mL, 17.3 mmol) to the ice bath for cooling1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (1.6 g, 8.64 mmol) in a solution of DMF (15 mL) and tert-butanol (5 mL), followed by DPPA (3.6 g,12.97 mmol). The reaction solution was heated to 80 ° C and stirred for 4 h. After completion of the reaction, some solvent was removed under reduced pressure and then diluted with ethyl acetate.The organic phase was washed with water and brine, dried over anhydrous sodium sulfatePurification by column chromatography gave 1-methyl-4-nitro-3-tert-butoxycarbonylamino-pyrazole (2 g, 90%).
90%	With diphenylphosphoranyl azide; triethylamine In N,N-dimethyl-formamide at 80℃; for 4h; Cooling with ice;	1 Intermediate 5: 1-methyl-4-nitro-3-amino-pyrazole Step 1: Add triethylamine (2.5mL, 17.3mmol) to 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (1.6g, 8.64mmol) and DMF under cooling in an ice bath. (15 mL) and tert-butanol (5 mL), followed by the addition of DPPA (3.6 g, 12.97 mmol),The reaction was heated to 80 ° C and stirred for 4h. After completion of the reaction, some solvents were removed under reduced pressure and diluted with ethyl acetate. The organic phase was washed with water and saturated brine,It was dried over anhydrous sodium sulfate, concentrated by filtration, and purified by column chromatography to obtain 1-methyl-4-nitro-3-tert-butoxycarbonylamino-pyrazole (2g, 90%).

57%

With diphenyl phosphoryl azide; triethylamine at 90℃; for 4h; Inert atmosphere;

Reference： [1]Current Patent Assignee: RUDONG RINGENE PHARMACEUTICALS; RUDONG LINGDA BIOMEDICAL TECH - CN109721600, 2019, A Location in patent: Paragraph 0222; 0223
[2]Current Patent Assignee: RUDONG LINGDA BIOMEDICAL TECH - CN109721589, 2019, A Location in patent: Paragraph 0066
[3]Current Patent Assignee: RUDONG RINGENE PHARMACEUTICALS; RUDONG LINGDA BIOMEDICAL TECH - CN110857300, 2020, A Location in patent: Paragraph 0317-0319
[4]Shao, Min; Chen, Xiaojuan; Yang, Fang; Song, Xiaojuan; Zhou, Yang; Lin, Qianmeng; Fu, Ying; Ortega, Raquel; Lin, Xiaojing; Tu, Zhengchao; Patterson, Adam V.; Smaill, Jeff B.; Chen, Yongheng; Lu, Xiaoyun [Journal of Medicinal Chemistry, 2022, vol. 65, # 6, p. 5113 - 5133]

77
[ 4598-86-1 ]
6-(3,5-dimethoxyphenyl)-2-(1-methyl-4-nitro-1H-pyrazole-3-carbonyl) cycloheptan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 1 h / 76 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / -78 - -40 °C 2.2: -78 °C

Reference： [1]Current Patent Assignee: BIOARDIS LLC - WO2020/177067, 2020, A1

78
[ 4598-86-1 ]
7-(3,5-dimethoxyphenyl)-3-(1-methyl-4-nitro-1H-pyrazol-3-yl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 1 h / 76 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / -78 - -40 °C 2.2: -78 °C 3.1: hydrazine hydrate; acetic acid / ethanol

Reference： [1]Current Patent Assignee: BIOARDIS LLC - WO2020/177067, 2020, A1

79
[ 4598-86-1 ]
7-(2,6-difluoro-3,5-dimethoxyphenyl)-3-(1-methyl-4-nitro-1H-pyrazol-3-yl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole [ No CAS ]
7-(2-fluoro-3,5-dimethoxyphenyl)-3-(1-methyl-4-nitro-1H-pyrazol-3-yl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 1 h / 76 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / -78 - -40 °C 2.2: -78 °C 3.1: hydrazine hydrate; acetic acid / ethanol 4.1: Selectfluor / acetonitrile / 2 h / 20 °C

Reference： [1]Current Patent Assignee: BIOARDIS LLC - WO2020/177067, 2020, A1

80
[ 4598-86-1 ]
3-(7-(2,6-difluoro-3 ,5-dimethoxyphenyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-3-yl)-1-methyl-1H-pyrazol-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 1 h / 76 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / -78 - -40 °C 2.2: -78 °C 3.1: hydrazine hydrate; acetic acid / ethanol 4.1: Selectfluor / acetonitrile / 2 h / 20 °C 5.1: palladium on activated charcoal; hydrogen / ethyl acetate / 8 h / 20 °C

Reference： [1]Current Patent Assignee: BIOARDIS LLC - WO2020/177067, 2020, A1

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CAS No. :	4598-86-1	MDL No. :	MFCD00464004
Formula :	C₅H₅N₃O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OMMBYRSUPXNTEK-UHFFFAOYSA-N
M.W :	171.11	Pubchem ID :	535976
Synonyms :

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

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Code	Phrase
H400	Very toxic to aquatic life
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H402	Harmful to aquatic life
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H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 4598-86-1 ] {[proInfo.proName]}

Quality Control of [ 4598-86-1 ]

Related Doc. of [ 4598-86-1 ]

Product Details of [ 4598-86-1 ]

Safety of [ 4598-86-1 ]

Application In Synthesis of [ 4598-86-1 ]

[ 4598-86-1 ] Synthesis Path-Upstream 1~5

[ 4598-86-1 ] Synthesis Path-Downstream 1~80

Related Functional Groups of
[ 4598-86-1 ]

Carboxylic Acids

Nitroes

Related Parent Nucleus of
[ 4598-86-1 ]

Pyrazoles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

[ CAS No. 4598-86-1 ] {[proInfo.proName]}

Quality Control of [ 4598-86-1 ]

Related Doc. of [ 4598-86-1 ]

Product Details of [ 4598-86-1 ]

Safety of [ 4598-86-1 ]

Application In Synthesis of [ 4598-86-1 ]

[ 4598-86-1 ] Synthesis Path-Upstream 1~5

[ 4598-86-1 ] Synthesis Path-Downstream 1~80

Related Functional Groups of [ 4598-86-1 ]

Carboxylic Acids

Nitroes

Related Parent Nucleus of [ 4598-86-1 ]

Pyrazoles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 4598-86-1 ]

Related Parent Nucleus of
[ 4598-86-1 ]