[ CAS No. 84547-84-2 ] {[proInfo.proName]}

Name: 84547-84-2|4-Bromo-1-methyl-1H-pyrazole-5-carboxylic acid|95%
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Quality Control of [ 84547-84-2 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 84547-84-2 ]

CAS No. :	84547-84-2	MDL No. :	MFCD00463982
Formula :	C₅H₅BrN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YXIJCAVZGBGUKM-UHFFFAOYSA-N
M.W :	205.01	Pubchem ID :	673686
Synonyms :

Calculated chemistry of [ 84547-84-2 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.2
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	38.15
TPSA :	55.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.0 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.18
Log Po/w (XLOGP3) :	0.78
Log Po/w (WLOGP) :	0.88
Log Po/w (MLOGP) :	0.43
Log Po/w (SILICOS-IT) :	0.45
Consensus Log Po/w :	0.74

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.91
Solubility :	2.54 mg/ml ; 0.0124 mol/l
Class :	Very soluble
Log S (Ali) :	-1.52
Solubility :	6.22 mg/ml ; 0.0303 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.03
Solubility :	19.2 mg/ml ; 0.0935 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.55

Safety of [ 84547-84-2 ]

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

Application In Synthesis of [ 84547-84-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 84547-84-2 ]
Downstream synthetic route of [ 84547-84-2 ]

[ 84547-84-2 ] Synthesis Path-Upstream 1~6

1
[ 15803-02-8 ]
[ 124-38-9 ]
[ 84547-84-2 ]

Yield	Reaction Conditions	Operation in experiment
77.3 g	With n-butyllithium; diisopropylamine In tetrahydrofuran; acetone at -78 - 0℃; for 1 h; Inert atmosphere	tHF (anhydrous) 600 ml was added to a 2 L reaction flask.Diisopropylamine 65.4g,Argon replacement protection,Dry ice acetone was cooled to -78 °C. Add 2.5M n-butyl lithium 258ml,The temperature is raised at 0 ° C for 0.5 h, and the temperature is lowered to -78 ° C.80.0 g of 1-methyl-4-bromopyrazole was added dropwise, and the reaction was maintained at -78 ° C for 1 h.Pass dry carbon dioxide gas until the reaction is complete.TLC showed the reaction was complete, and 1N HCl was added dropwise to adjust pH = 2-3.A large amount of white solid precipitated. After cooling at 0 ° C for 3 h, filter.Drying at 40 ° C for 16 h gave a white solid compound 22 (77.3 g).

Reference： [1] Patent: CN108264520, 2018, A, . Location in patent: Paragraph 0261; 0262; 0263; 0264; 0265

2
[ 5775-86-0 ]
[ 84547-84-2 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1982, vol. 52, # 11, p. 2291 - 2296[2] Zhurnal Obshchei Khimii, 1982, vol. 52, # 11, p. 2592 - 2598

3
[ 16034-46-1 ]
[ 84547-84-2 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1982, vol. 52, # 11, p. 2291 - 2296[2] Zhurnal Obshchei Khimii, 1982, vol. 52, # 11, p. 2592 - 2598

4
[ 13808-64-5 ]
[ 84547-84-2 ]

Reference： [1] Patent: WO2005/66147, 2005, A1, . Location in patent: Page/Page column 183

5
[ 694-31-5 ]
[ 84547-84-2 ]

Reference： [1] J. Gen. Chem. USSR (Engl. Transl.), 1982, vol. 52, # 11, p. 2291 - 2296[2] Zhurnal Obshchei Khimii, 1982, vol. 52, # 11, p. 2592 - 2598

6
[ 15803-02-8 ]
[ 591-51-5 ]
[ 84547-84-2 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1959, vol. 625, p. 55,60

[ 84547-84-2 ] Synthesis Path-Downstream 1~88

1
[ 15803-02-8 ]
[ 591-51-5 ]
[ 84547-84-2 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1959,vol. 625,p. 55,60

2
[ 5775-86-0 ]
[ 84547-84-2 ]

Reference： [1]Journal of general chemistry of the USSR,1982,vol. 52,p. 2291 - 2296
Zhurnal Obshchei Khimii,1982,vol. 52,p. 2592 - 2598

3
[ 16034-46-1 ]
[ 84547-84-2 ]

Reference： [1]Journal of general chemistry of the USSR,1982,vol. 52,p. 2291 - 2296
Zhurnal Obshchei Khimii,1982,vol. 52,p. 2592 - 2598

4
[ 84547-84-2 ]
[ 90-04-0 ]
[ 93703-04-9 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1984,vol. 20,p. 918 - 920
Khimiya Geterotsiklicheskikh Soedinenii,1984,p. 1123 - 1125

5
[ 84547-84-2 ]
[ 106-49-0 ]
[ 93703-00-5 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1984,vol. 20,p. 918 - 920
Khimiya Geterotsiklicheskikh Soedinenii,1984,p. 1123 - 1125

6
[ 84547-84-2 ]
[ 106-47-8 ]
[ 93703-01-6 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1984,vol. 20,p. 918 - 920
Khimiya Geterotsiklicheskikh Soedinenii,1984,p. 1123 - 1125

7
[ 84547-84-2 ]
[ 104-94-9 ]
[ 93703-02-7 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1984,vol. 20,p. 918 - 920
Khimiya Geterotsiklicheskikh Soedinenii,1984,p. 1123 - 1125

8
[ 84547-84-2 ]
[ 100-01-6 ]
[ 93703-03-8 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1984,vol. 20,p. 918 - 920
Khimiya Geterotsiklicheskikh Soedinenii,1984,p. 1123 - 1125

9
[ 84547-84-2 ]
[ 88-74-4 ]
[ 93703-05-0 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1984,vol. 20,p. 918 - 920
Khimiya Geterotsiklicheskikh Soedinenii,1984,p. 1123 - 1125

10
[ 84547-84-2 ]
[ 62-53-3 ]
[ 93702-99-9 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1984,vol. 20,p. 918 - 920
Khimiya Geterotsiklicheskikh Soedinenii,1984,p. 1123 - 1125

11
[ 84547-84-2 ]
[ 84547-89-7 ]

Yield	Reaction Conditions	Operation in experiment
15 g	With sulfuric acid; nitric acid; at 20 - 50℃; for 32.0h;Cooling with ice;	Compound 22 (20 g) was dissolved in 100 mL of concentrated sulfuric acid.33 mL of concentrated nitric acid was slowly added dropwise in an ice water bath.After reacting for 16 h at room temperature, TLC showed a large amount of substrate remaining.After heating to 50 ° C for 16 h, the substrate substantially disappeared.After cooling, the reaction solution was slowly added dropwise to 1 L of ice water.Extract with ethyl acetate and wash the organic phase several times with water until pH = 7.After concentration, column chromatography gave yellowSolid 23 (15 g).

Reference： [1]Chemistry of Heterocyclic Compounds,1983,vol. 19,p. 1326 - 1330
Khimiya Geterotsiklicheskikh Soedinenii,1983,vol. 19,p. 1676 - 1679
[2]Patent: CN108264520,2018,A .Location in patent: Paragraph 0261; 0262; 0266; 0267; 0268

12
[ 84547-84-2 ]
[ 32683-45-7 ]

Reference： [1]Journal of general chemistry of the USSR,1982,vol. 52,p. 2291 - 2296
Zhurnal Obshchei Khimii,1982,vol. 52,p. 2592 - 2598

13
[ 84547-84-2 ]
[ 84547-89-7 ]
[ 32683-45-7 ]

Reference： [1]Journal of general chemistry of the USSR,1982,vol. 52,p. 2291 - 2296
Zhurnal Obshchei Khimii,1982,vol. 52,p. 2592 - 2598
[2]Journal of general chemistry of the USSR,1982,vol. 52,p. 2291 - 2296
Zhurnal Obshchei Khimii,1982,vol. 52,p. 2592 - 2598

Yield	Reaction Conditions	Operation in experiment
		N-methyl-4-bromopyrazole-3-carboxylic acid was prepared according to known methods, see: Yu. A. M.; Andreeva, M. A.; Perevalov, V. P.; Stepanov, V. I.; Dubrovskaya, V. A.; and Seraya, V. I. in Zh. Obs. Khim. (Journal of General Chemistry of the USSR) 1982, 52, 2592, and refs cited therein.

15
[ 84547-84-2 ]
[ 124-40-3 ]
[ 473732-07-9 ]

Yield	Reaction Conditions	Operation in experiment
48%	With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 25℃; for 26.0h;	To a solution of N-METHYL4-BRORNOPYRAZOLE-3-CARBOXYLIC ACID (2.0 g), available from step A, in 65 mL of anhydrous DMF was added BROMOTRIPYRROLIDINOPHOSPHONIUM HEXAFLUOROPHOSPHATE (PyBrop, 4.60 g), dimethyl amine (10 mL, 2.0 M in THF) and DIISOPROPYLETHYL amine (5.2 mL) at 25 C. The mixture was stirred for 26 h, and concentrated under reduced pressure to an oily residue. This residue was treated with a 1.0 M NAOH aqueous solution, and extracted with ethyl acetate (50 mL x 4). The organic extracts were combined, washed with brine, and dried with anhydrous NA2SO4. Removal of solvents yielded an oil, which was purified by preparative thin layer chromatography, eluting with CH2CI2-MeOH (20: 1), to give 1.09 g of the amide product (48%, MH+ = 232.0).
48%		To a solution of N-methyl-4-bromopyrazole-3-car-boxylic acid (2.0 g), available from step A, in 65 mL of anhydrous DMF was added bromotripyrrolidinophospho-nium hexafluorophosphate (PyBrop, 4.60 g), dimethyl amine (10 mL, 2.0 M in THF) and diisopropylethyl amine (5.2 mL) at 25 C. The mixture was stirred for 26 h, and concentrated under reduced pressure to an oily residue. This residue was treated with a 1.0 M NaOH aqueous solution, and extracted with ethyl acetate (50 mLx4). The organic extracts were combined, washed with brine, and dried with anhydrous Na2SO4. Removal of solvents yielded an oil, which was purified by preparative thin layer chromatogra-phy, eluting with CH2Cl2-MeOH (20:1), to give 1.09 g of the amide product (48%, MH+=232.0).
48%		Step B; To a solution of <strong>[84547-84-2]N-methyl-4-bromopyrazole-3-carboxylic acid</strong> (2.0 g), available from step A, in 65 mL of anhydrous DMF was added bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop, 4.60 g), dimethyl amine (10 mL, 2.0 M in THF) and diisopropylethyl amine (5.2 mL) at 25 C. The mixture was stirred for 26 h, and concentrated under reduced pressure to an oily residue. This residue was treated with a 1.0 M NaOH aqueous solution, and extracted with ethyl acetate (50 mL x 4). The organic extracts were combined, washed with brine, and dried with anhydrous Na2SO4. Removal of solvents yielded an oil, which was purified by preparative thin layer chromatography, eluting with CH2CI2-MeOH (20: 1), to give 1.09 g of the amide product (48%, MH+ = 232.0).

48%

With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 25℃; for 26.0h;

To a solution of <strong>[84547-84-2]N-methyl-4-bromopyrazole-3-carboxylic acid</strong> (2.0 g), available from step A, in 65 mL of anhydrous DMF was added bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop, 4.60 g), dimethyl amine (10 mL, 2.0 M in THF) and diisopropylethyl amine (5.2 mL) at 25 C. The mixture was stirred for 26 h, and concentrated under reduced pressure to an oily residue. This residue was treated with a 1.0 M NaOH aqueous solution, and extracted with ethyl acetate (50 mL x 4). The organic extracts were combined, washed with brine, and dried with anhydrous Na2SO4. Removal of solvents yielded an oil, which was purified by preparative thin layer chromatography, eluting with CH2CI2-MeOH (20: 1), to give 1.09 g of the amide product (48%, MH+ = 232.0).

Reference： [1]Patent: WO2004/33440,2004,A1 .Location in patent: Page 212
[2]Patent: US2004/147559,2004,A1 .Location in patent: Page 104
[3]Patent: WO2005/66147,2005,A1 .Location in patent: Page/Page column 183
[4]Patent: WO2005/68460,2005,A1 .Location in patent: Page/Page column 186

16
[ 84547-84-2 ]
[ 473732-07-9 ]

Yield	Reaction Conditions	Operation in experiment
48%	With bromotripyrrolidinophosphonium hexafluorophosphate; dimethyl amine; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 25℃; for 26.0h;	To a solution of <strong>[84547-84-2]N-methyl-4-bromopyrazole-3-carboxylic acid</strong> (2.0 g), available from step A, in 65 mL of anhydrous DMF was added bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop, 4.60 g), dimethyl amine (10 mL, 2.0 M in THF) and diisopropylethyl amine (5.2 mL) at 25 C. The mixture was stirred for 26 h, and concentrated under reduced pressure to an oily residue. This residue was treated with a 1.0 M NaOH aqueous solution, and extracted with ethyl acetate (50 mL?4). The organic extracts were combined, washed with brine, and dried with anhydrous Na2SO4. Removal of solvents yielded an oil, which was purified by preparative thin layer chromatography, eluting with CH2Cl2-MeOH (20:1), to give 1.09 g of the amide product (48%, MH+=232.0).

Reference： [1]Patent: US2004/106794,2004,A1 .Location in patent: Page 106

17
[ 67-56-1 ]
[ 84547-84-2 ]
[ 514816-42-3 ]

Yield	Reaction Conditions	Operation in experiment
65.4%	With thionyl chloride; for 18.0h;Reflux;	<strong>[84547-84-2]4-Bromo-2-methyl-2H-pyrazole-3-carboxylic acid</strong> (6 g, 29.3 mmol) was added to 150 mL of methanol treated with thionyl chloride (3.5 g, 29.3 mmol). The mixture was refluxed for 18 firs. Solvents were evaporated and the residue was extracted with dichloromethane and 0.5N sodium hydroxide solution. The organic layer was washed with brine and dried. After the evaporation of solvents, a white solid (4.19 g, 65.4percent yield) was obtained as the desired compound 4-bromo-2- methyl-2H-pyrazole-3-carboxylic acid methyl ester. 1H NMR (400 MHz, CDC13) delta ppm 3.97 (s, 3H), 4.19 (s, 3H), 7.51 (s, 1H). The aqueous extraction was filtered and neutralized with IN hydrochloric acid. The white solid was filtered and dried to give the unreacted starting material carboxylic acid (1.51 g).
63%		Part A. <strong>[84547-84-2]4-bromo-2-methyl-2H-pyrazole-3-carboxylic acid</strong> methyl ester To the suspension of <strong>[84547-84-2]4-Bromo-2-methyl-2H-pyrazole-3-carboxylic acid</strong> (0.205 g, 1 mmol) in methanol (2 mL) was added thionyl chloride (0.29 mL, 4 mmol). The suspension was heated at 90° C. for 18 h to give a clear solution. The solution was cooled to rt and then concentrated. The residue was dissolved in EtOAc (10 mL), and washed with sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give 0.137 g (63percent) of the methyl ester as a white solid. 1H NMR (400 MHz, CDCl3) delta: 3.95 (s, 3H), 4.17 (s, 3H), 7.53 (s, 1H). HRMS calc'd for C6H8BrN2O2: 218.9769. Found: 218.9770.

Reference： [1]Patent: WO2013/189862,2013,A1 .Location in patent: Page/Page column 17
[2]Patent: US2005/228000,2005,A1 .Location in patent: Page/Page column 30

18
[ 84547-84-2 ]
[ 1350323-53-3 ]

Reference： [1]Patent: US2011/281888,2011,A1

19
[ 84547-84-2 ]
[ 1350323-54-4 ]

Reference： [1]Patent: US2011/281888,2011,A1

20
[ 84547-84-2 ]
C₅H₆BrN₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.166667h;	Example 434-{3-[(1S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-methyl-1H-pyrazole-5-carboxamideA mixture of <strong>[84547-84-2]4-bromo-2-methyl-2H-pyrazole-3-carboxylic acid</strong> (20.0 mg, 0.0976 mmol), NH4Cl (52.2 mg, 0.976 mmol), TBTU (62.6 mg, 0.195 mmol), DIPEA (0.170 mL, 0.976 mmol) and DMF (2 mL, 20 mmol) was stirred at rt for 10 min.The material was extracted with EtOAc, and washed with sat. NaHCO3 (3*) to remove carboxylic acid starting material.The organic layer was concentrated in vacuo. 3-[(S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (15.0 mg, 0.0348 mmol), (1,1'bis-(diphenylphosphino)-ferrocene) palladium dichloride (3.57 mg, 0.00488 mmol), K2CO3 (20.2 mg, 0.146 mmol) and 4:1 dioxane:H2O (1 mL, 10 mmol) were added, and the mixture was heated to 95° C. for 30 min.The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): delta=1.79 (d, J=7.3 Hz, 3H), 3.70 (br. s., 3H), 3.99 (s, 3H), 5.09-5.16 (m, 1H), 6.90 (dd, J=9.2, 4.2 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H), 7.34 (s, 1H), 7.50 (s, 1H), 7.59 (br. s., 1H), 8.20 (br. s., 1H). MS (ES+): m/z=428.11/430.12 (100/50) [MH+]. HPLC: tR=1.34 min (polar-3 min, UPLC-ACQUITY).

Reference： [1]Patent: US2011/281888,2011,A1 .Location in patent: Page/Page column 42

21
[ 84547-84-2 ]
[ 1276056-83-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	With borane-THF; In tetrahydrofuran; at 80℃; for 12.0h;Inert atmosphere;	A mixture of 4-bromo- 1 -methyl - 1 //-pyrazole-5-carboxylic acid (4.80 g, 23.4 mmol, CAS 84547-84-2) in THF (40.00 mL) was added BH3/THF (93.60 mL, 1 M). The mixture was stirred at 80 C for 12 hours under N2 atmosphere. To the mixture was added EtOAc (200 mL). The mixture was washed with saturated NaHCO, (200 mL x 3). The organic layer was dried over anhydrous Na2S04, filtered and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether : ethyl acetate = 100 : 0 to 100 : 10) to give (4-bromo-l -methyl- li-pyrazol-5-yl)methanol (4.10 g, 92% yield) as a white solid. 1HNMR (400 MHz, DMSO-6): d 7.26 (s, 1H), 4.62 (s, 2H), 3.86 (s, 3H).
77%	With borane-THF; In tetrahydrofuran; at 50℃; for 48.0h;	A mixture of 4-bromo- 1 -methyl- 1 H-pyrazole-5-carboxylic acid (5.0 g, 24.4 mmol) and BH3.THF (36.6 mL of a 1 M solution in THF, 36.6 mmol) in THF (50 mL) was stirred at 50 C for 2 days; at this point LCMS showed the completion of the reaction. The reaction was cooled to RT and cautiously quenched with aq. 1N HC1 and stirred at RT for 1 h, after which the mixture was extracted with EtOAc (3 X 50 mL). The combined organic extracts were concentrated in vacuo. The residue was chromato graphed (80 g Si02; continuous gradient from 0% to 100% EtOAc in hexanes, 25 min) to give the title compound (3.60 g, 18.9 mmol, 77 % yield) as a white solid. LCMS, [M+H]+ = 193.0.
77%	With borane-THF; In tetrahydrofuran; at 50℃; for 48.0h;Inert atmosphere;	A mixture of 4-bromo- 1 -methyl- 1 H-pyrazole-5-carboxylic acid (5.0 g, 24.4 mmol) and BH3.THF (36.6 mL of a 1 M solution in THF, 36.6 mmol) in THF (50 mL) was stirred at 50 C for 2 days; at this point LCMS showed the completion of the reaction. The reaction was cooled to RT and cautiously quenched with aq. IN HC1 and stirred at RT for 1 h, after which the mixture was extracted with EtOAc (3 X 50 mL). The combined organic extracts were concentrated in vacuo. The residue was chromatographed (80 g Si02; continuous gradient from 0% to 100% EtOAc in hexanes, 25 min) to give the title compound (3.60 g, 18.9 mmol, 77 % yield) as a white solid. LCMS, [M+H]+ = 193.0.

77%	With borane-THF; In tetrahydrofuran; at 50℃; for 48.0h;	A mixture of 4-bromo-l-methyl-lH-pyrazole-5-carboxylic acid (5.0 g, 24.4 mmol) and BH3.THF (36.6 mL of a 1 M solution in THF, 36.6 mmol) in THF (50 mL) was stirred at 50 C for 2 days; at this point LCMS showed the completion of the reaction. The reaction was cooled to RT and cautiously quenched with aq. 1N F1C1 and stirred at RT for 1 h, after which the mixture was extracted with EtOAc (3 X 50 mL). The combined organic extracts were concentrated in vacuo. The residue was (0667) chromatographed (80 g S1O2; continuous gradient from 0% to 100% EtOAc in hexanes, 25 min) to give the title compound (3.60 g, 18.9 mmol, 77 % yield) as a white solid. LCMS, [M+H]+ = 193.0.
		Example 44 (4-{3-[(1S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-methyl-1H-pyrazol-5-yl)methanol To a solution of <strong>[84547-84-2]4-bromo-2-methyl-2H-pyrazole-3-carboxylic acid</strong> (20.0 mg, 0.0976 mmol) in THF (3 mL, 40 mmol) was added 1.0 M of BH3.THF in THF (0.49 mL, 0.49 mmol), and the resulting solution was heated to 60 C. overnight. The material was extracted with EtOAc, and washed with sat. NaHCO3 (3*) to remove carboxylic acid starting material. The organic layer was concentrated in vacuo. 3-[(S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (15.0 mg, 0.0348 mmol), (1,1'bis-(diphenylphosphino)-ferrocene) palladium dichloride (3.57 mg, 0.00488 mmol), K2CO3 (20.2 mg, 0.146 mmol) and 4:1 dioxane:H2O (1 mL, 10 mmol) were added, and the mixture was heated to 95 C. for 30 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): delta=1.80 (d, J=7.1 Hz, 3H), 3.67 (br. s., 3H), 3.96 (s, 3H), 4.55 (s, 2H), 5.08-5.17 (m, 1H), 6.90 (dd, J=9.1, 4.3 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H), 7.34 (d, J=1.3 Hz, 1H), 7.46 (s, 1H), 7.53 (s, 1H), 8.15-8.22 (m, 1H). MS (ES+): m/z=415.13/417.13 (100/50) [MH+]. HPLC: tR=1.37 min (polar-3 min, UPLC-ACQUITY).
	With borane-THF; In tetrahydrofuran; at 20 - 50℃; for 73.0h;	To a RT solution of 4-bromo-l -methyl- lH-pyrazole-5-carboxylic acid (2.0 g, 9.8 mmol) in THF (24.4 ml) was added BH3.THF complex (19.5 mL of a 1M solution in TFIF, 19.5 mmol) and the reaction was stirred at RT for 1 h, then was heated to 50 C and stirred at 50 C for 3 days, then was cooled to RT. The reaction was quenched slowly by dropwise addition of 1M aq. HC1 (10 mL) at RT, then was partitioned between CH2Cl2 (30 mL) and water (30 mL). The aqueous phase was extracted with CFLCh (2 X 30 mL) and the combined organic extracts were dried (MgS04) and filtered through a pad of Si02 to give the crude title compound (1.86 g, 100 % yield) as a white solid. LCMS, [M + H]+ = 191.0, 193.0.

Reference： [1]Patent: WO2019/183367,2019,A1 .Location in patent: Paragraph 0261
[2]Patent: WO2019/126089,2019,A1 .Location in patent: Page/Page column 91; 92
[3]Patent: WO2019/126085,2019,A1 .Location in patent: Page/Page column 83; 89; 98
[4]Patent: WO2019/126103,2019,A1 .Location in patent: Page/Page column 92
[5]Patent: US2011/281888,2011,A1 .Location in patent: Page/Page column 43
[6]Patent: WO2019/126098,2019,A1 .Location in patent: Page/Page column 84; 85; 110

22
[ 84547-84-2 ]
[ 75-65-0 ]
[ 1380587-83-6 ]

Yield	Reaction Conditions	Operation in experiment
		<strong>[84547-84-2]4-Bromo-2-methyl-2H-pyrazole-3-carboxylic acid</strong> (2 g, 9.76 mmol) and triethylamine (1.50 mL, 10.73 mmol) were combined in toluene (10 mL).Diphenylphosphoryl azide (2.31 mL, 10.73 mmol) was added and the reaction stirred at room temperature for 3 hours . tert-Butanol (1.12 mL, 11.71 mmol) was added and the reaction was stirred at 60 °C overnight. After cooling the ?-BuOH was removed under vacuum and the reaction was submitted to EtOAc/ELO workup. The crude material was purified via silica gel chromatography (0-100percent EtOAc in hexanes) to give the title compound.

Reference： [1]Patent: WO2012/78593,2012,A2 .Location in patent: Page/Page column 148

23
[ 84547-84-2 ]
[ 1517-69-7 ]
[ 1396007-83-2 ]

Yield	Reaction Conditions	Operation in experiment
	With diphenyl phosphoryl azide; triethylamine; In toluene; at 80℃; for 1.0h;	<strong>[84547-84-2]4-Bromo-2-methyl-2H-pyrazole-3-carboxylic acid</strong> (787.2 mg, 3.84 mmol), DPPA (1.16 g, 4.22 mmol), (R)-l-phenylethanol (491 mg, 4.02 mmol) and TEA (1.10 mL, 7.68 mmol) were combined in 15 mL of toluene to give a clear solution. The mixture was heated to 80 °C and stirred for 1 fir. Solvents were evaporated and the residue was extracted with ethyl acetate and sodium bicarbonate solution. The organic layer was dried and evaporated to give an oily material (1.38 g). TLC indicated no UV absorption. 1H-NMR of the crude material indicated 75percent desired compound as 4-bromo-2-methyl-2H-pyrazol-3-yl-carbamic acid (R)-l-phenyl-ethyl ester. LRMS calcd for Ci3Hi4BrN302 (m/e) 324.0, obsd 323.0 (M-H, ES-).

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 7920 - 7939,20
[2]Patent: WO2013/189862,2013,A1 .Location in patent: Page/Page column 18; 19

24
[ 84547-84-2 ]
[ 142598-53-6 ]

Reference： [1]Patent: WO2013/189862,2013,A1

25
[ 84547-84-2 ]
4-(4-fluorophenyl)-2-methyl-2H-pyrazol-3-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Patent: WO2013/189862,2013,A1

26
[ 84547-84-2 ]
[ 483315-65-7 ]

Reference： [1]Patent: WO2013/189862,2013,A1

27
[ 84547-84-2 ]
[ 23097-85-0 ]

Reference： [1]Patent: WO2013/189862,2013,A1

28
[ 15803-02-8 ]
[ 124-38-9 ]
[ 84547-84-2 ]

Yield	Reaction Conditions	Operation in experiment
77.3 g	With n-butyllithium; diisopropylamine; In tetrahydrofuran; acetone; at -78 - 0℃; for 1.0h;Inert atmosphere;	tHF (anhydrous) 600 ml was added to a 2 L reaction flask.Diisopropylamine 65.4g,Argon replacement protection,Dry ice acetone was cooled to -78 °C. Add 2.5M n-butyl lithium 258ml,The temperature is raised at 0 ° C for 0.5 h, and the temperature is lowered to -78 ° C.80.0 g of 1-methyl-4-bromopyrazole was added dropwise, and the reaction was maintained at -78 ° C for 1 h.Pass dry carbon dioxide gas until the reaction is complete.TLC showed the reaction was complete, and 1N HCl was added dropwise to adjust pH = 2-3.A large amount of white solid precipitated. After cooling at 0 ° C for 3 h, filter.Drying at 40 ° C for 16 h gave a white solid compound 22 (77.3 g).

Reference： [1]Patent: CN108264520,2018,A .Location in patent: Paragraph 0261; 0262; 0263; 0264; 0265

29
[ 84547-84-2 ]
C₆H₆BrN₃O₄ [ No CAS ]

Reference： [1]Patent: CN108264520,2018,A

30
[ 84547-84-2 ]
C₈H₉N₃O₄ [ No CAS ]

Reference： [1]Patent: CN108264520,2018,A

31
[ 84547-84-2 ]
C₈H₁₁N₃O₂ [ No CAS ]

Reference： [1]Patent: CN108264520,2018,A

32
[ 84547-84-2 ]
C₈H₁₁N₃O₅S [ No CAS ]

Reference： [1]Patent: CN108264520,2018,A

33
[ 84547-84-2 ]
C₈H₁₀ClN₃O₄S [ No CAS ]

Reference： [1]Patent: CN108264520,2018,A

34
[ 84547-84-2 ]
C₁₁H₁₆N₄O₄S [ No CAS ]

Reference： [1]Patent: CN108264520,2018,A

35
[ 84547-84-2 ]
C₉H₁₂N₄O₄S [ No CAS ]

Reference： [1]Patent: CN108264520,2018,A

36
[ 84547-84-2 ]
C₈H₁₀N₄O₄S [ No CAS ]

Reference： [1]Patent: CN108264520,2018,A

37
[ 84547-84-2 ]
C₁₅H₁₃FN₆O₃S [ No CAS ]

Reference： [1]Patent: CN108264520,2018,A

38
[ 84547-84-2 ]
4-methyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H- pyrazol-4-yl)pyrimidin-5-ol [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1
[2]Patent: WO2019/126098,2019,A1
[3]Patent: WO2019/126089,2019,A1
[4]Patent: WO2019/126103,2019,A1

39
[ 84547-84-2 ]
isopropyl (1S,3S)-3-((4-methyl-2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrimidin-5-yl)oxy)cyclohexane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1
[2]Patent: WO2019/126089,2019,A1
[3]Patent: WO2019/126103,2019,A1
[4]Patent: WO2019/126103,2019,A1

40
[ 84547-84-2 ]
isopropyl (1S,3S)-3-((2-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1
[2]Patent: WO2019/126089,2019,A1
[3]Patent: WO2019/126103,2019,A1
[4]Patent: WO2019/126103,2019,A1

41
[ 84547-84-2 ]
isopropyl (1S,3S)-3-((2-(5-(bromomethyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1
[2]Patent: WO2019/126089,2019,A1
[3]Patent: WO2019/126103,2019,A1
[4]Patent: WO2019/126103,2019,A1

42
[ 84547-84-2 ]
isopropyl (1S,3S)-3-((2-(5-(azidomethyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1
[2]Patent: WO2019/126089,2019,A1
[3]Patent: WO2019/126103,2019,A1
[4]Patent: WO2019/126103,2019,A1

43
[ 84547-84-2 ]
(1S,3S)-3-((6-(5-(((butoxycarbonyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1

44
[ 84547-84-2 ]
2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyridin-3-ol [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1

45
[ 84547-84-2 ]
(1S,3S)-isopropyl 3-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1

46
[ 84547-84-2 ]
isopropyl trans-3-((6-(5-(bromomethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1
[2]Patent: WO2019/126089,2019,A1
[3]Patent: WO2019/126103,2019,A1

47
[ 84547-84-2 ]
(1S,3S)-isopropyl 3-((6-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1

48
[ 84547-84-2 ]
(1S,3S)-isopropyl 3-((6-(5-(bromomethyl)-1-methyl-1H-pyrazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1

49
[ 84547-84-2 ]
(1S,3S)-isopropyl 3-((6-(5-(azidomethyl)-1-methyl-1H-pyrazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1

50
[ 84547-84-2 ]
(1S,3S)-isopropyl 3-((6-(5-(aminomethyl)-1-methyl-1H-pyrazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1

51
[ 84547-84-2 ]
(1S,3S)-isopropyl 3-((6-(5-(((butoxycarbonyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1

52
[ 84547-84-2 ]
(1S,3S)-3-((6-(5-(((butoxycarbonyl)(methyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylic acid [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1

53
[ 84547-84-2 ]
4-bromo-1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1
[2]Patent: WO2019/126098,2019,A1
[3]Patent: WO2019/126089,2019,A1
[4]Patent: WO2019/126103,2019,A1

54
[ 84547-84-2 ]
1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1
[2]Patent: WO2019/126098,2019,A1
[3]Patent: WO2019/126089,2019,A1
[4]Patent: WO2019/126103,2019,A1

55
[ 84547-84-2 ]
C₂₃H₃₃N₅O₅*C₂HF₃O₂ [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1

56
[ 84547-84-2 ]
isopropyl trans-3-((6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)- 1H-pyrazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1
[2]Patent: WO2019/126089,2019,A1
[3]Patent: WO2019/126103,2019,A1

57
[ 84547-84-2 ]
C₂HF₃O₂*C₂₅H₂₉N₅O₅ [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1

58
[ 84547-84-2 ]
isopropyl trans-3-((6-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1
[2]Patent: WO2019/126089,2019,A1
[3]Patent: WO2019/126103,2019,A1

59
[ 84547-84-2 ]
isopropyl (1S,3S)-3-((2-(5-(aminomethyl)-1-methyl-1H-pyrazol-4-yl)-4-methylpyrimidin-5-yl)oxy)cyclohexane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/126085,2019,A1
[2]Patent: WO2019/126089,2019,A1
[3]Patent: WO2019/126103,2019,A1
[4]Patent: WO2019/126103,2019,A1

60
[ 84547-84-2 ]
6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyridin-3-ol [ No CAS ]

Reference： [1]Patent: WO2019/126098,2019,A1

61
[ 84547-84-2 ]
C₃₀H₃₄N₆O₃ [ No CAS ]