[ CAS No. 1040377-08-9 ]

Name: 1040377-08-9|2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol|97%
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SKU: A273098
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Quality Control of [ 1040377-08-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1040377-08-9 ]

Product Details of [ 1040377-08-9 ]

CAS No. :	1040377-08-9	MDL No. :	MFCD12033564
Formula :	C₁₁H₁₉BN₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QEHDAUWYRNEWBF-UHFFFAOYSA-N
M.W :	238.09	Pubchem ID :	45788855
Synonyms :

Calculated chemistry of [ 1040377-08-9 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.73
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	65.93
TPSA :	56.51 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.42 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.47
Log Po/w (WLOGP) :	0.17
Log Po/w (MLOGP) :	-0.24
Log Po/w (SILICOS-IT) :	0.03
Consensus Log Po/w :	0.09

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.63
Solubility :	5.56 mg/ml ; 0.0233 mol/l
Class :	Very soluble
Log S (Ali) :	-1.23
Solubility :	14.2 mg/ml ; 0.0595 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.25
Solubility :	1.34 mg/ml ; 0.00561 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.1

Safety of [ 1040377-08-9 ]

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 [ 1040377-08-9 ]

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

Upstream synthesis route of [ 1040377-08-9 ]
Downstream synthetic route of [ 1040377-08-9 ]

[ 1040377-08-9 ] Synthesis Path-Upstream 1~3

1
[ 96-49-1 ]
[ 269410-08-4 ]
[ 1040377-08-9 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydroxide In N,N-dimethyl-formamide at 140℃; for 16 h;	Intermediate 1182-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxa H-pyrazol-1 -yl]ethanolA solution of 1 ,3-dioxolan-2-one (2.496 g, 28.3 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (5 g, 25.8 mmol) and sodium hydroxide (0.103 g, 2.58 mmol) in N,N-Dimethylformamide (DMF) (18 mL) was stirred at 140°C for 16 h. then cooled to room temperature and treated with activated charcoal (200mg). The resulting mixture was stirred at room temperature for 1 h then filtered through celite (10 g). The insoluble were washed with EtOAc (50 mL) and EtOH (50ml_). The combined filtrate and washings were concentrated in vacuo. Purification of the residue by flash chromatography on silica gel using a 50 G silica cartyridge (gradient: 0 to 40percent MeOH in DCM) gave a residue which was further purified by SP4 using a 100 G silica cartridge (eluant: 0 to 20percent MeOH in DCM) to give 2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1 - yl]ethanol (5.58 g, 23.44 mmol, 91 percent yield) as a colourless oil which was used in the next step without further purification.LCMS (method A): Retention time 0.68 min, [M+H]+ = 239.13
85%	With sodium hydroxide In N,N-dimethyl-formamide for 2.5 h; Heating / reflux	INTERMEDIATE 34; 2-[4-f4.4.5.5-Tetramethyl-ri.3.21dioxaborolan-2-ylVρyrazol-l-yl1-ethanol; 4-Pyrazoleboronic acid pinacol ester (0.25 g, 1.29 mmol), ethylene carbonate(0.125 g, 1.42 mmol) and sodium hydroxide (5 mg, 0.13 mmol) were dissolved in DMF (1 mL) and the reaction mixture was heated to reflux for 2 Vi h. It was cooled to r.t. before addition of activated charcoal (25 mg). The resulting suspension was stirred at r.t. for Ih and then filtered through celite, washed with DMF (6 mL) and concentrated in vacuo to give the title compound (0.26g, 85percent) as a yellow oil. LCMS (ES+) 239.18 (M+H)⁺.
76%	With caesium carbonate In N,N-dimethyl-formamide at 140℃; for 0.5 h;	100 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 91 mg of 1,3-dioxolan-2-one weredissloved in 2 ml of dimethylformamide. 336 mg of cesium carbonate was heated to 140 °C, stirred for 0.5 h and thencooled to room temperature and concentrated. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 30: 70) to give 93 mg of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol aspale yellow oil. Yield: 76percent.1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.25 (s, 12H), 3.71 (q, J= 5.4 Hz, 2H), 4.15 (t, J = 5.4 Hz, 2H), 4.87 (t, J = 5.4Hz, 1H), 7.57 (s, 1H), 7.88 (s, 1H).

7.53 g

With sodium hydroxide In N,N-dimethyl-formamide at 140℃;

A solution of I ,3-dioxolan-2-one (1 .902 mL, 28.5 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-IH-pyrazole (5.0239 g, 25.9 mmol) and sodium hydroxide (0.0998 g, 2.495 mmol) in N,Ndimethylformamide (DMF) (20 mL) was heated to 140 °C overnight. The mixture was cooled down to rt and then activated charcoal (200 mg) was added and this was stirred for 4 h before filtering through celite cartridge (10 g). The mixture was washed with EtOAc (50 mL) and EtCH (50 mL andthe combined filtrate was concentrated in vacuo to afford 7.53 g of brown oil. This was used crude in further reactions. LCMS: Not recorded.

Reference： [1] Patent: WO2011/54841, 2011, A1, . Location in patent: Page/Page column 107
[2] Patent: WO2008/44022, 2008, A1, . Location in patent: Page/Page column 35
[3] Patent: EP3112351, 2017, A1, . Location in patent: Paragraph 0041
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3208 - 3212
[5] Patent: WO2010/19899, 2010, A1, . Location in patent: Page/Page column 155
[6] Patent: US2010/144783, 2010, A1, . Location in patent: Page/Page column 15
[7] Patent: US2011/281842, 2011, A1, . Location in patent: Page/Page column 45
[8] Patent: US2011/281868, 2011, A1, . Location in patent: Page/Page column 21
[9] Patent: US2012/208798, 2012, A1, . Location in patent: Page/Page column 48
[10] Patent: WO2014/140076, 2014, A1, . Location in patent: Page/Page column 208

2
[ 214614-81-0 ]
[ 1040377-08-9 ]

Yield	Reaction Conditions	Operation in experiment
26.6%	Stage #1: With potassium acetate In N,N-dimethyl-formamide for 0.166667 h; Stage #2: at 80℃;	To a solution of 22b (0.45g, 2.36mmol) and bis(pinacolato)diboron (0.718g, 2.83mmol) in DMF (2OmL), was added KOAc (0.694g, 7.08mmol). The mixture was 0 degassed with N₂, stirred for 1 Omin and added Pd(dppf)Cl₂ (58mg, 0.071 mmol). The mixture was degassed with N₂ and stirred at 8O⁰C overnight. DMF was removed and the residue was purified by column chromatography (EA:PE=1 :10) to afford of 22c (149mg, 26.6percent yield).

Reference： [1] Patent: WO2008/88881, 2008, A1, . Location in patent: Page/Page column 47
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6804 - 6820

3
[ 269410-08-4 ]
[ 540-51-2 ]
[ 1040377-08-9 ]

Yield	Reaction Conditions	Operation in experiment
63%	With caesium carbonate In N,N-dimethyl-formamide at 70℃;	4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (1 .00 g, 5.15 mmol) and cesium carbonate (5.04 g, 15.47 mmol) were suspended in 10 mL of dimethylformamide. 2-Bromoethanol (0.73 mL, 10.30 mmol) was added and the mixture was stirred at 70 °C for 3 hours. Additional amounts of cesium carbonate (5.04 g, 15.47 mmol) and 2-bromoethanol (0.73 mL, 10.30 mmol) were added and the mixture was left at 70 °C overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated to give 770 mg (63percent yield) of a yellowish oil that was used in the next step without further purification.LRMS (m/z): 239 (M+1 )⁺.
31.47%	With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 48 h; Inert atmosphere; Sealed	Step A: Preparation of 2-(4-(4 A5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H- pyrazol- 1 -yDethanol : To a flask charged with 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-lH-pyrazole (1.000 g, 5.154 mmol), Cs₂C0₃ (2.687 g, 8.246 mmol), and 2-bromoethanol (0.5479 mL, 7.730 mmol) was added 10 mL of DMF and the flask was sealed under nitrogen and heated to 100 °C for 48 hours. The reaction was diluted with ethyl acetate (100 mL) and stirred for 30 minutes before it was passed through a glass microfiber filter and the cake was washed with ethyl acetate. The organic was concentrated under reduced pressure. The crude was then purified by silica gel chromatography eluting with a gradient of 75-100percent ethyl acetate in Hexanes to afford 2-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazol- l-yl)ethanol (0.4290 g, 1.622 mmol, 31.47percent yield). MS (apci) m/z = 239.2 (M+H).

Reference： [1] Patent: WO2014/60432, 2014, A1, . Location in patent: Page/Page column 129
[2] Patent: WO2011/130146, 2011, A1, . Location in patent: Page/Page column 82-83
[3] Patent: US2014/121200, 2014, A1, . Location in patent: Paragraph 0281; 0282; 0283

[ 1040377-08-9 ] Synthesis Path-Downstream 1~62

1
[ 96-49-1 ]
[ 269410-08-4 ]
[ 1040377-08-9 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydroxide; In N,N-dimethyl-formamide; at 140℃; for 16h;	Intermediate 1182-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxa H-pyrazol-1 -yl]ethanolA solution of 1 ,3-dioxolan-2-one (2.496 g, 28.3 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (5 g, 25.8 mmol) and sodium hydroxide (0.103 g, 2.58 mmol) in N,N-Dimethylformamide (DMF) (18 mL) was stirred at 140C for 16 h. then cooled to room temperature and treated with activated charcoal (200mg). The resulting mixture was stirred at room temperature for 1 h then filtered through celite (10 g). The insoluble were washed with EtOAc (50 mL) and EtOH (50ml_). The combined filtrate and washings were concentrated in vacuo. Purification of the residue by flash chromatography on silica gel using a 50 G silica cartyridge (gradient: 0 to 40% MeOH in DCM) gave a residue which was further purified by SP4 using a 100 G silica cartridge (eluant: 0 to 20% MeOH in DCM) to give 2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1 - yl]ethanol (5.58 g, 23.44 mmol, 91 % yield) as a colourless oil which was used in the next step without further purification.LCMS (method A): Retention time 0.68 min, [M+H]+ = 239.13
85%	With sodium hydroxide; In N,N-dimethyl-formamide; for 2.5h;Heating / reflux;	INTERMEDIATE 34; 2-[4-f4.4.5.5-Tetramethyl-ri.3.21dioxaborolan-2-ylVrhoyrazol-l-yl1-ethanol; 4-Pyrazoleboronic acid pinacol ester (0.25 g, 1.29 mmol), ethylene carbonate(0.125 g, 1.42 mmol) and sodium hydroxide (5 mg, 0.13 mmol) were dissolved in DMF (1 mL) and the reaction mixture was heated to reflux for 2 Vi h. It was cooled to r.t. before addition of activated charcoal (25 mg). The resulting suspension was stirred at r.t. for Ih and then filtered through celite, washed with DMF (6 mL) and concentrated in vacuo to give the title compound (0.26g, 85%) as a yellow oil. LCMS (ES+) 239.18 (M+H)+.
76%	With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 0.5h;	100 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 91 mg of 1,3-dioxolan-2-one weredissloved in 2 ml of dimethylformamide. 336 mg of cesium carbonate was heated to 140 C, stirred for 0.5 h and thencooled to room temperature and concentrated. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 30: 70) to give 93 mg of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol aspale yellow oil. Yield: 76%.1H NMR (300 MHz, DMSO-d6) delta (ppm): 1.25 (s, 12H), 3.71 (q, J= 5.4 Hz, 2H), 4.15 (t, J = 5.4 Hz, 2H), 4.87 (t, J = 5.4Hz, 1H), 7.57 (s, 1H), 7.88 (s, 1H).

	With sodium hydroxide; In N,N-dimethyl-formamide; for 2h;Reflux;	2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)ethanol was synthesized according to the procedure in PCT Publication No. WO 2008/44022, which is incorporated herein in its entirety. Specifically, 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l/f-pyrazole (5.0 g, 25.8 mmol), l,3-dioxolan-2-one (2.5 g, 28.3 mmol), and sodium hydroxide (pellets, 1.0 g, 25.8 mmol) were dissolved in DMF (206 mL). The reaction mixture was heated to reflux for 2 hours. Activated charcoal was added after reaction was cooled to ambient temperature and the reaction was stirred for 1 hr and then filtered through Celite. The filter cake was then rinsed with DMF (120 mL), and the filtrate was concentrated to provide 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)ethanol as a yellow oil (6 g). The resulting material was used without further purification. ESI-MS :m/z 239.3 (M+H)+.
	With caesium carbonate; at 20 - 100℃;	4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.66 g, 49.8 mmol), 1,3-dioxolan-2-one (21 g, 238 mmol) and cesium carbonate (16 g, 49.1 mmol) were combined in a 100 mL round bottom flask. The reaction was warmed from room temperature to 100 C. in an oil bath, by which time the carbonate had melted and served as the solvent for the reaction, which remained a slurry. After heating for 3.5 hours, the reaction was cooled to room temperature and diluted with ethyl acetate, then filtered through Celite washing repeatedly with ethyl acetate. The filtrate was concentrated, then purified by chromatography on an Analogix Intelliflash purification system using a SF60-200 g column at a flow rate of 80 mL/min, eluding as follows: 5 minutes at 20% ethyl acetate/hexanes, then ramped from 40% to 90% ethyl acetate/hexanes over 35 minutes, then 100% ethyl acetate for another 20 minutes, to provide the title compound.
	With caesium carbonate; at 100℃; for 0.583333h;oil bath;	Example 39A 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.66 g, 49.8 mmol), 1,3-dioxolan-2-one (21 g, 238 mmol) and cesium carbonate (16 g, 49.1 mmol) were combined in a 100 mL round bottom flask. The reaction was warmed from room temperature to 100 C. in an oil bath, by which time the carbonate had melted and served as the solvent for the reaction, which remained a slurry. After heating for 3.5 hours, the reaction was cooled to room temperature and was diluted with ethyl acetate, then filtered through diatomaceous earth washing repeatedly with ethyl acetate. The filtrate was concentrated, then purified by chromatography on an Analogix(R) Intelliflash(TM) purification system using a SF60-200 g column at a flow rate of 80 mL/minute, eluting as follows: 5 minutes at 20% ethyl acetate/hexanes, then ramped from 40% to 90% ethyl acetate/hexanes over 35 minutes, then 100% ethyl acetate for another 20 minutes, to provide the title compound. MS ESI(+) m/z 239.0 (M+H)+.
	With caesium carbonate; at 100℃; for 3.5h;	Example 10A2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol; 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.66 g, 49.8 mmol), 1,3-dioxolan-2-one (21 g, 238 mmol), and cesium carbonate (16 g, 49.1 mmol) were combined in a 100 mL round bottom flask At room temperature all reagents were solids. The reaction was warmed from room temperature to 100 C. in an oil bath, at which time the carbonate had melted and served as the solvent for the reaction, which then remained a slurry. After heating for 3.5 hours, the reaction was cooled to room temperature, diluted with ethyl acetate, and filtered through Celite (diatomaceous earth) washing repeatedly with ethyl acetate. The filtrate was concentrated, and the residue was purified by chromatography on an Analogix Intelliflash purification system using a SF60-200 g column at a flow rate of 80 mL/minute, eluting as follows: 5 minutes at 20% ethyl acetate/hexane, then ramped from 40% to 90% ethyl acetate/hexanes over 35 minutes, and then 100% ethyl acetate for another 20 minutes, to afford the title compound.
	In N,N-dimethyl-formamide; at 140℃; for 16h;	A solution of 1,3-dioxolan-2-one (2.496 g, 28.3 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5 g, 25.8 mmol) and sodium hydroxide (0.103 g, 2.58 mmol) in N,N-Dimethylformamide (DMF) (18 mL) was stirred at 140 C. for 16 h. then cooled to room temperature and treated with activated charcoal (200 mg). The resulting mixture was stirred at room temperature for 1 h then filtered through celite (10 g). The insoluble were washed with EtOAc (50 mL) and EtOH (50 mL). The combined filtrate and washings were concentrated in vacuo. Purification of the residue by flash chromatography on silica gel using a 50 G silica cartyridge (gradient: 0 to 40% MeOH in DCM) gave a residue which was further purified by SP4 using a 100 G silica cartridge (eluant: 0 to 20% MeOH in DCM) to give 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanol (5.58 g, 23.44 mmol, 91% yield) as a colourless oil which was used in the next step without further purification.LCMS (method A): Retention time 0.68 min, [M+H]+=239.13
7.53 g	With sodium hydroxide; In N,N-dimethyl-formamide; at 140℃;	A solution of I ,3-dioxolan-2-one (1 .902 mL, 28.5 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-IH-pyrazole (5.0239 g, 25.9 mmol) and sodium hydroxide (0.0998 g, 2.495 mmol) in N,Ndimethylformamide (DMF) (20 mL) was heated to 140 C overnight. The mixture was cooled down to rt and then activated charcoal (200 mg) was added and this was stirred for 4 h before filtering through celite cartridge (10 g). The mixture was washed with EtOAc (50 mL) and EtCH (50 mL andthe combined filtrate was concentrated in vacuo to afford 7.53 g of brown oil. This was used crude in further reactions. LCMS: Not recorded.

Reference： [1]Patent: WO2011/54841,2011,A1 .Location in patent: Page/Page column 107
[2]Patent: WO2008/44022,2008,A1 .Location in patent: Page/Page column 35
[3]Patent: EP3112351,2017,A1 .Location in patent: Paragraph 0041
[4]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3208 - 3212
[5]Patent: WO2010/19899,2010,A1 .Location in patent: Page/Page column 155
[6]Patent: US2010/144783,2010,A1 .Location in patent: Page/Page column 15
[7]Patent: US2011/281842,2011,A1 .Location in patent: Page/Page column 45
[8]Patent: US2011/281868,2011,A1 .Location in patent: Page/Page column 21
[9]Patent: US2012/208798,2012,A1 .Location in patent: Page/Page column 48
[10]Patent: WO2014/140076,2014,A1 .Location in patent: Page/Page column 208

2
[ 105679-24-1 ]
[ 1040377-08-9 ]
2-[4-(7-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-pyrazol-1-yl]-ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium acetate;bis(tri-t-butylphosphine)palladium(0); In N,N-dimethyl-formamide; at 140℃; for 1h;	INTERMEDIATE 44; 2-r4-(7-Methyl-3,4-dihvdro-2H-benzori.41oxazm-6-ylVpyrazol-l-yll-ethanol; A mixture of Intermediate 41 (0.304 g, 1.33 mmol), Intermediate 34 (0.476 g, 2 mmol), potassium acetate (0.157 g, 1.6 mmol) and bis(tris-tert- butylrhohosphino)palladium(O) (0.041 g, 0.08 mmol) in DMF (3 mL) was heated to 14O0C for 1 h. After cooling to r.t. activated charcoal (47 mg) was added, and the resulting suspension stirred at r.t. for 2h. It was filtered through celite, washed with DMF (5 mL) and then concentrated in vacuo. The residue was purified by prep etaPLC then dissolved in DCM (15 mL), washed with aqueous potassium carbonate and the organic fraction concentrated in vacuo to give the title compound (73 mg, 21%) as a yellow oil. 5eta (CDCl3) 2.24 (3eta, s), 3.39-3.43 (2H, m), 3.91-3.95 (IH, m), 4.01-4.06 (2H, m), 4.22-4.30 <n="40"/>(4H, m), 6.58 (IH, s), 6.68 (IH5 s), 7.44 (IH, s), 7.57 (IH, d, J 0.4 Hz). LCMS (ES+) 260.16 (M+H)+.

Reference： [1]Patent: WO2008/44022,2008,A1 .Location in patent: Page/Page column 38-39

3
[ 1067172-02-4 ]
[ 1040377-08-9 ]
2-{6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2,3-dihydro-4H-1,4-benzoxazin-4-yl}-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With potassium acetate;bis(tri-t-butylphosphine)palladium(0); In N,N-dimethyl-formamide; at 140℃; for 1h;Microwave irradiation;	EXAMPLE 85; 2-{6-ri-(2-HvdroxyethylVlijr-pyrazol-4-yll-2.3-dihvdro-4H-l,4-benzoxazin-4-vU-5,5- dimethyl-5 ,6-dihydro- 1 ,3 -benzothiazol-7(4H)-one; A mixture of Example 1 (0.275 g, 0.7 mmol), Intermediate 34 (0.25 g, 1.049 mmol), potassium acetate (82 mg, 0.84 mmol) and bis{tris-tert- butylphosphino)palladium(O) (32 mg, 0.063 mmol) in DMF (2 mL) was heated to 14O0C under microwave irradiation for 1 h. After cooling to r.t.. activated charcoal (25 mg) was added and the resulting suspension stirred for 2h. It was filtered through celite, washed with DMF (3 mL) and concentrated in vacuo. The residue was purified by prep etaPLC then dissolved in DCM (15 mL), washed with aqueous potassium carbonate solution (0.7 M) and the organic fraction was concentrated in vacuo to give the title compound (113 mg, 38%) as a pale yellow solid. deltaeta (CDCl3) 1.16 (6H, s), 2.43 (2H, s), 2.77 (2H, s), 3.06 (IH, t, J 6.0 Hz), 4.02-4.08 (2H, m), 4.22-4.36 (6H, m), 6.96 (IH, d, J 8.3 Hz), 7.19 (IH, dd, J8.5, 2.1 Hz), 7.64 (IH, s), 7.74 (IH, d, J0.6 Hz), 7.99 (IH, d, J 1.9 Hz). LCMS (ES+) 425.17 (M+H)+.

Reference： [1]Patent: WO2008/44022,2008,A1 .Location in patent: Page/Page column 75

4
[ 214614-81-0 ]
[ 73183-34-3 ]
[ 1040377-08-9 ]

Yield	Reaction Conditions	Operation in experiment
26.6%		To a solution of 22b (0.45g, 2.36mmol) and bis(pinacolato)diboron (0.718g, 2.83mmol) in DMF (2OmL), was added KOAc (0.694g, 7.08mmol). The mixture was 0 degassed with N2, stirred for 1 Omin and added Pd(dppf)Cl2 (58mg, 0.071 mmol). The mixture was degassed with N2 and stirred at 8O0C overnight. DMF was removed and the residue was purified by column chromatography (EA:PE=1 :10) to afford of 22c (149mg, 26.6% yield).
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 10h;Inert atmosphere;	General procedure: To a solution of 4-bromo-1-(oxan-4-yl)-1H-pyrazole 26a (1.00 g, 4.33 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.32 g, 5.19 mmol) in 10 mL of DMF was added potassium acetate (1.27 g, 12.98 mmol), followed by 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (177 mg, 0.22 mmol) under argon. The resulting mixture was stirred at 80 C for 10 h and then diluted with 40 mL of water. The mixture was extracted with EA (3 × 30 mL). The combined organic phase was washed with water (3 × 30 mL), brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EA/PE, 1:4) to afford 25c as white solid in 68% yield.

Reference： [1]Patent: WO2008/88881,2008,A1 .Location in patent: Page/Page column 47
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 6804 - 6820

5
[ 1040377-08-9 ]
[ 1040376-44-0 ]
[ 1040376-73-5 ]

Yield	Reaction Conditions	Operation in experiment
74%		To a solution of 22c (149mg, 0.63mmol) and D (120mg, 0.32mmol) in DMF (15mL) was added Pd(Ph3P)2Cl2 (22mg, 0.032mmol) under the protection of N2. The mixture was degassed with N2, stirred for lOmin and added IN Na2CO3 solution dropwise. The mixture was degassed with N2 and stirred overnight at 8O0C. After the reaction was complete, DMF was evaporated and the residue was purified by column 0 chromatography (EA:PE=3:1) to give the title compound (96mg, 74% yield). 1H- NMR (300MHz, CDCl3): 5=8.1 1-8.12 (d, IH), 7.59-7.60 (d, IH), 7.641-7.644 (d, <n="49"/>IH), 7.26-7.32 (m, IH), 7.01-7.06 (dd, IH), 6.94-6.95 (d, IH), 5.99-6.05 (m, IH), 4.24-4.27 (m, 2H), 4.01-4.04 (m, 2H), 2.55 (s, 3H), 1.84-1.86 (ds, 3H). LC/MS [M+H]+ : 410.0.

Reference： [1]Patent: WO2008/88881,2008,A1 .Location in patent: Page/Page column 47-48

6
[ 1000793-42-9 ]
[ 1040377-08-9 ]
[ 1000796-48-4 ]

Yield	Reaction Conditions	Operation in experiment
22%	With potassium acetate;bis(tri-t-butylphosphine)palladium(0); In N,N-dimethyl-formamide; at 140℃; for 1.5h;	INTERMEDIATE 212-(6-ri-(2-HvdroxyethylVlH-pyrazol-4-yl1-2.3-dihvdro-4H-1.4-benzoxazin-4-vU-6,6- dimemyl-6,7-dihydro[l,31thiazolor5.4-c1pyridin-4f5H)-one A mixture of Intermediate 14 (2.7 g, 6.86 mmol), 2-[4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)pyrazol-l-yl]ethanol (3.67 g, 10.3 mmol), potassium acetate (807 mg, 8.2 mmol) and bis(tri-tert-butylphosphine)palladium(0) (306 mg, 0.60 mmol) in DMF (14 mL) was heated to 1400C for 1.5 h. Purification by preparative etaPLC {Method <n="104"/>6) gave the title compound (640 mg, 22%) as a pale yellow solid. deltaH (CDCl3) 7.99 (IH, d,J 1.9 Hz), 7.72 (IH, s), 7.65 (IH, s), 7.16 (IH, dd, J8.3, 1.9 Hz), 6.95 (IH, d, J8.3 Hz), 5.52 (IH, s), 4.37-4.31 (2H, m), 4.31-4.25 (2H, m), 4.21-4.15 (2H, m), 4.07-4.01 (2H, m), 2.87 (2H, s), 1.40 (6H, s). One exchangeable proton was not observed. LCMS (ES+) 426.0 (M+H)+, RT 2.59 minutes {Method 1).

Reference： [1]Patent: WO2009/71895,2009,A1 .Location in patent: Page/Page column 102-103

7
[ 1040377-08-9 ]
[ 1208247-67-9 ]
N-(6-(6-(1-(2-hydroxyoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of Lambda/-(6-(6-bromo-[l,2,4]triazolo[4,3-alpha]pyridin-3-ylthio)imidazo[l,2- delta]pyridazin-2-yl)cyclopropanecarboxamide (500 mg, 1.2 mmol), 2-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)ethanol (1.4 g, 5.8 mmol), cesium carbonate (1.14 mL, 3 M solution), and [l,r-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (85 mg, 0.12 mmol) in DME (5 mL) was heated in a microwave for 30 min at 1000C. The reaction mixture was then concentrated to dryness via rotary evaporation. The resulting crude material was reconstituted in DMSO (Volume: 1.0 mL) and purified via preparative mass trigger LCMS using a gradient eluant of 10-35% ACN:0.05% TFA (aq). The collected fractions were combined and the ACN was removed via rotary evaporation. The resulting mixture was lyophilized and reconstituted in water: ACN (1 : 10, 5.0 mL) Two drops of concentrated HCl were added and the resulting solution was lyophilized to provide the HCl salt of the title compound 1H NMR (400MHz ,DMSO-d6) delta ppm 11.16 (s, 1 H) 8.69 (s, 1 H) 8.38 (s, 1 H) 8.04 - 8.08 (m, 1 H) 8.02 (d, J=LOl Hz, 1 H) 7.91 - 7.95 (m, 1 H) 7.88 - 7.91 (m, 2 H) 6.99 - 7.05 (m, 1 H) 4.10 - 4.16 (m, 2 H) 3.73 (t, J=5.56 Hz, 2 H) 1.90 (quin, J=6.19 Hz, 1 H) 0.74 - 0.84 (m, 4 H) ESI-MS:m/z 462.3 (M+H)+. MP 182 - 184C.

Reference： [1]Patent: WO2010/19899,2010,A1 .Location in patent: Page/Page column 155-156

8
[ 832695-09-7 ]
[ 1040377-08-9 ]
[ 1227939-87-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; methanol; water; at 80℃;Inert atmosphere;	EXAMPLE 1A (6 g, 16.34 mmol), EXAMPLE 1B (4.8 g, 20.16 mmol), PdCl2(dppf) (1.2 g, 1.640 mmol) and sodium carbonate (4.6 g, 43.4 mmol) were combined in tetrahydrofuran (400 mL), methanol (80 mL) and water (80 mL), and the reaction was degassed by bubbling N2 through the mixture for 1 hour. The reaction was then heated to 80 C. for 2 hours, then allowed to cool and diluted with 300 mL ethyl acetate. The mixture was partitioned with H2O (500 mL) and the aqueous layer was extracted with ethyl acetate (2*300 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered through a pad of Celite, concentrated to a total volume of about 200 mL, then left standing overnight. The solid that formed was collected by filtration, providing the title compound.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3208 - 3212
[2]Patent: US2010/144783,2010,A1 .Location in patent: Page/Page column 15

9
[ 1040377-08-9 ]
[ 865-50-9 ]
1-(2-trideuteromethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a 20 mL pressure via. was 2-(4-(4,4,5,5-tetramethy.-1 ,3,2-dioxaborolan-2-y.)-1 H- pyrazol-1-yl)ethanol (2.1 1 mmol) and DMF (10 mL). NaH (60% w/w in mineral oil, 4.22 mmol, 169 mg) was added portion-wise and the resulting soiution was allowed to stir at room temperature for 10 minutes. At 10 minutes, iodomethane-d3 (4.22 mmoi, 263 muL) was added dropwise. The vial was sealed and the reaction was stirred at 80 C for 48 hours. At 48 hours, the solvent was removed in vacuo. The residue was taken up in DCM and filtered through celite. The title compound was then purified via fiash chromatography.

Reference： [1]Patent: WO2010/118207,2010,A1 .Location in patent: Page/Page column 360-361

10
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl acetate [ No CAS ]
[ 1040377-08-9 ]

Yield	Reaction Conditions	Operation in experiment
		To a 50 mL roundbottom flask was charged 2-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yI)-1 H-pyrazol-1-y.)ethyl acetate (2.11 mmol, 591 mg), a solution of 2:1 THFiH2O (15 mL), and 1 N LiOH(aq) (4.82 mmol, 4.82 mL). The resulting solution was stirred at room temperature for 48 hours. At 48 hours, the reaction was quenched with 1 N HCI(aq) (4.82 mmol, 4.82 mL) and the solvent removed in vacuo. The product was taken forward without further purification.

Reference： [1]Patent: WO2010/118207,2010,A1 .Location in patent: Page/Page column 359-360

11
[ 1040377-08-9 ]
[ 1300031-98-4 ]
[ 1301197-84-1 ]

Yield	Reaction Conditions	Operation in experiment
15%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃; for 18h;Inert atmosphere;	Example 1081 -Methylethyl {(2S,4 ?)-1 -acetyl-6-[1 -(2-hydroxyethyl)-1 H-pyrazol-4-yl]-2-methyl- 1 ,2,3,4-tetrahydro-4-quinolinyl}carbamate A flask was charged with 1 -methylethyl [(2S,4/?)-1 -acetyl-6-bromo-2-methyl-1 ,2,3,4- tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (0.185 g, 0.500 mmol), 2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazol-1 -yl]ethanol (for a preparation see Intermediate 1 18) (143 mg, 0.600 mmol), K2C03 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80C for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2S04 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave an oil which was dissolved in 1 ,4-dioxane, freezed using an acetone bath cooled with solid C02 and left on a freeze drier for 16 h to give 1 - methylethyl {(2S,4R)-1 -acetyl-6-[1 -(2-hydroxyethyl)-1 H-pyrazol-4-yl]-2-methyl-1 ,2,3,4- tetrahydro-4-quinolinyl}carbamate (33.3 mg, 0.083 mmol, 15%) as a white solid.LCMS (method A): Retention time 0.73 min, [M+H]+ = 401 .15
15%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃; for 18h;	A flask was charged with 1-methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (0.185 g, 0.500 mmol), <strong>[1040377-08-9]2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanol</strong> (for a preparation see Intermediate 118) (143 mg, 0.600 mmol), K2CO3 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80 C. for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave an oil which was dissolved in 1,4-dioxane, freezed using an acetone bath cooled with solid CO2 and left on a freeze drier for 16 h to give 1-methylethyl {(2S,4R)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (33.3 mg, 0.083 mmol, 15%) as a white solid.LCMS (method A): Retention time 0.73 min, [M+H]+=401.15

Reference： [1]Patent: WO2011/54841,2011,A1 .Location in patent: Page/Page column 176-177
[2]Patent: US2012/208798,2012,A1 .Location in patent: Page/Page column 83

12
[ 269410-08-4 ]
[ 540-51-2 ]
[ 1040377-08-9 ]

Yield	Reaction Conditions	Operation in experiment
63%	With caesium carbonate; In N,N-dimethyl-formamide; at 70℃;	4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (1 .00 g, 5.15 mmol) and cesium carbonate (5.04 g, 15.47 mmol) were suspended in 10 mL of dimethylformamide. 2-Bromoethanol (0.73 mL, 10.30 mmol) was added and the mixture was stirred at 70 C for 3 hours. Additional amounts of cesium carbonate (5.04 g, 15.47 mmol) and 2-bromoethanol (0.73 mL, 10.30 mmol) were added and the mixture was left at 70 C overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulphate, filtered and the solvent was evaporated to give 770 mg (63% yield) of a yellowish oil that was used in the next step without further purification.LRMS (m/z): 239 (M+1 )+.
31.47%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 48h;Inert atmosphere; Sealed;	Step A: Preparation of 2-(4-(4 A5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H- pyrazol- 1 -yDethanol : To a flask charged with 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-lH-pyrazole (1.000 g, 5.154 mmol), Cs2C03 (2.687 g, 8.246 mmol), and 2-bromoethanol (0.5479 mL, 7.730 mmol) was added 10 mL of DMF and the flask was sealed under nitrogen and heated to 100 C for 48 hours. The reaction was diluted with ethyl acetate (100 mL) and stirred for 30 minutes before it was passed through a glass microfiber filter and the cake was washed with ethyl acetate. The organic was concentrated under reduced pressure. The crude was then purified by silica gel chromatography eluting with a gradient of 75-100% ethyl acetate in Hexanes to afford 2-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazol- l-yl)ethanol (0.4290 g, 1.622 mmol, 31.47% yield). MS (apci) m/z = 239.2 (M+H).
24%	With caesium carbonate; In N,N-dimethyl-formamide; at 85℃;	To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.58 mmol) in DMF (7 mL) was added 2-bromoethanol (645 mg, 5.16 mmol) and cesium carbonate (2.52 g, 7.74 mmol) and the mixture was heated at 85C for 3 h. More cesium carbonate (2.52 g, 7.74 mmol) and 2-bromoethanol (645 mg, 5.16 mmol) were added and the mixture was again heated at 85C overnight. The solvent was removed and the residue was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated to give the desired product (150 mg, 24% yield) as a yellow oil. LCMS (ES-API): Rt2.0 min; m/z 239.1 [M+H]+.

With potassium carbonate; In acetonitrile; at 60℃;

General procedure: To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine hydrochloride (500 mg, 1.54 mmol) and potassium carbonate (430 mg, 3.1 mmol) in acetonitrile (20 mL) was added 2-bromoethanol (388 mg, 3.1 mmol), then the mixture was heated at 60 C. overnight under an atmosphere of nitrogen. Then the mixture was filtered over celite and washed with DCM, concentrated to give product as a light brown solid. 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol The title compound was prepared according to the procedures of Intermediate 52 using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (m/z): 239 (M+H)+.

Reference： [1]Patent: WO2014/60432,2014,A1 .Location in patent: Page/Page column 129
[2]Patent: WO2011/130146,2011,A1 .Location in patent: Page/Page column 82-83
[3]Patent: WO2019/43139,2019,A1 .Location in patent: Page/Page column 113
[4]Patent: US2014/121200,2014,A1 .Location in patent: Paragraph 0281; 0282; 0283

13
[ 1040377-08-9 ]
[ 124-63-0 ]
[ 1339891-05-2 ]

Yield	Reaction Conditions	Operation in experiment
81.4%	With triethylamine; In dichloromethane; at 0℃; for 0.5h;	Step B: Preparation of 2-( 4-Gamma4.4.5 ,5 -tetramethyl- 1.3 ,2-dioxaborolan-2-vn- 1 H- pyrazol- 1 -vDethyl methanesulfonate: To a solution of 2-(4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)ethanol (0.150 g, 0.630 mmol) and TEA (0.132 mL, 0.945 mmol) in 5 mL of DCM was added methansulfonyl chloride (0.0536 mL, 0.693 mmol) with stirring at 0 C. The reaction was allowed to proceed at 0 C for 30 minutes. The reaction was loaded directly onto a silica gel column pre-pre-wetted with and eluted with 50% ethyl acetate in hexanes to afford 2-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)ethyl methanesulfonate (0.169 g, 0.513 mmol, 81.4% yield) MS (apci) m/z = 317.1 (M+H).

Reference： [1]Patent: WO2011/130146,2011,A1 .Location in patent: Page/Page column 83

14
[ 1040377-08-9 ]
[ 1339891-02-9 ]

Reference： [1]Patent: WO2011/130146,2011,A1

15
[ 832695-09-7 ]
[ 1040377-08-9 ]
[ 1227939-82-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3208 - 3212

16
[ 1040377-08-9 ]
[ 1382619-94-4 ]
[ 1382620-02-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4044 - 4048

17
[ 1040377-08-9 ]
[ 1382619-94-4 ]
(x)C₂HF₃O₂*C₂₂H₁₈N₆O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4044 - 4048

18
[ 1040377-08-9 ]
[ 1407496-23-4 ]
[ 1407496-18-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; for 8h;Reflux; Inert atmosphere;	General procedure: To a solution of 3-bromo pyrido[2,3]pyrimidines 11 or 14a-c (1.0 mmol), piperidinyl-pyrazo-4-ylboranes (1 mmol) and Cs2CO3 (1.6 mmol) in 1,4-dioxane (4 mL) containing water (1 mL), was added PdCl2(dppf)·CH2Cl2 (3.2 mmol %). The mixture was stirred at reflux for 8 h under nitrogen atmosphere, and then quenched with 20 mL of water. The mixture was extracted with 20 mL of CH2Cl2 (3x25 mL). The combined organic phases were washed with brine, dried with anhydrous Na2SO4, and then filtered and concentrated. The resulting residue was absorbed into silica gel and purified on column chromatography (CHCl3/MeOH = 20:1) to give the corresponding pyrido[2,3-d]pyrimidines 13a-c and 15a-c.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 6368 - 6372

19
[ 1040377-08-9 ]
5-bromo-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]sulfanyl}pyridin-2-amine [ No CAS ]
2-[4-(6-amino-5-[1-(2,6-dichloro-3-fluorophenyl)ethyl]sulfanyl}pyridin-3-yl)-1H-pyrazol-1-yl]ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	With tetrakis(triphenylphosphine) palladium(0); potassium fluoride dihydrate; In 1,2-dimethoxyethane; ethanol; water; at 110℃; for 0.833333h;Microwave irradiation;	General procedure: A vial was charged with 10a (200 mg, 0.50 mmol), 25c (140 mg, 0.50 mmol), KF·2H2O (143 mg, 1.51 mmol), Pd(PPh3)4 (29 mg, 0.25 mmol) and 5 mL of DME/H2O/EtOH (v/v/v, 7:3;2). Then the vial was capped and heated at 110 C for 50 min under microwave irradiation. The reaction mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by flash column chromatography (0-3% MeOH/CH2Cl2 gradient) and further separated by reverse HPLC (75-80% MeOH/H2O gradient) to afford compound 10c in 30% yield.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 6804 - 6820

Yield	Reaction Conditions	Operation in experiment
49%	With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 18h;Inert atmosphere;	General procedure: Intermediate 10: Methyl [4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yI)-1 Hpyrazol-1 -yI]acetate Methyl [4-(4,4, 5, 5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 -yl]acetate was prepared according to the synthetic route shown in Scheme 5. To a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (560 mg, 2.9 mmol) in anhydrous DMF (10 mL) was added 052003 (1.03 g, 3.16 mmol) and methyl bromoacetate (0.30 mL, 3.16 mmol) and the reaction was stirred at 9000 under a nitrogen atmosphere for 18 hrs. The reaction was cooled, diluted with EtOAc (50 mL), washed with water (2 x 25 mL), brine (25 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography (50% EtOAc/heptane) to give the title compound as a colourless oil (360 mg, 47%).
		General procedure: To 1-methyl-4-iodopyrazole (1.0 g) and 10 mL of THF,Under the protection of nitrogen, slowly add isopropylmagnesium chloride/lithium chloride solution (3.97mL), the temperature during the dropwise addition does not exceed 0 C,After the addition, stir for 1 h, then at 0 C,Slowly add isopropyl pinacol borate (1.11g) to control the temperature not to exceed 0 C, and then stir at room temperature for 1.5 h after the addition.After the reaction was completed, 10 mL of a saturated ammonium chloride solution was added dropwise.Quenched.Then add 50 mL of ethyl acetate and 10 mL of saturated ammonium chloride solution.The organic layer was separated, and the aqueous layer was extracted twice with 50 mL of ethyl acetate. The organic layer was combined and dried over anhydrous Na2SO?Dry under reduced pressure,The title product (1 g) was obtained.

21
[ 1040377-08-9 ]
di-tert-butyl {5-bromo-3-[(tert-butoxycarbonyl)(2,6-dichlorobenzyl)amino]pyrazin-2-yl}imidodicarbonate [ No CAS ]
di-tert-butyl {3-[(tert-butoxycarbonyl)(2,6-dichlorobenzyl)amino]-5-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]pyrazin-2-yl}imidodicarbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%		Stage 1. Di-teit-butyl {3-[(teit-butoxycarbonyl) (2,6-dichlorobenzyl)am ino]-5-[1 -(2- hydroxyethyl)- 1 H-pyrazol-4-yI]pyrazin-2-yI}imidodicarbonate To a solution of Intermediate 4 (951 mg, 1.46 mmol) in DME (20 mL), was added Intermediate 11(524 mg, 2.20 mmol) and 2N Na2003 (1.8 mL, 3.65 mmol) and the solution was degassed by bubbling nitrogen through the reaction mixture for 20 mins. Dichlorobis (triphenylphosphine) palladium (II) (270 mg, 0.4 mmol) was added and the reaction was stirred at 8000 under nitrogen for 5 hrs. The reaction mixture was cooled to RT and diluted was EtOAc (100 mL). The reaction was filtered through Celite and the filter cake was washed with EtOAc (50 mL). The filtrated was washed with brine (100 mL), dried over MgSO4, filtered, concentrated in vacuo and purified by automated column chromatography using EtOAc in heptane (gradient 10- 100%) to give the title compound as an off white solid (920 mg, 93%).LCMS: m/z 579/581/583 [M-Boc].

Reference： [1]Patent: WO2014/1802,2014,A1 .Location in patent: Page/Page column 117; 118

22
[ 1040377-08-9 ]
[ 1513858-93-9 ]
[ 1513856-65-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 7h;Inert atmosphere;	Step 2: 3-(2-chloro-3, 5-dimethoxyphenyl)-8-[1-(2-hydroxyethyl)-JH-pyrazol-4-ylJ-1-methyl- 1,3,4, 7-tetrahydro-2H-pyrrolo[3 ?,2 ?:5, 6Jpyrido[4 , 3-dJpyrimidin-2-oneA mixture of the crude product from Step 1, 2-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)- 1 H-pyrazol- 1 -yl]ethanol (12 mg, 0.051 mmol), [1,1?-bis(diphenylphosphino) ferrocene] dichloropalladium(II) complexed with dichloromethane (1:1) (2 mg, 0.002 mmol), and potassium carbonate (10 mg, 0.076 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). The reaction mixture was degassed then back-filled with nitrogen three times. The resulting solution was heated to 90 C. After stirring for 7 h, the reaction mixture was cooled to room temperature and diluted with MeOH, then filteredand purified by RP-HPLC (pH = 10) to afford the product as a yellow solid. LC-MS calculated for C23H24C1N604 [M+H] mlz: 483.2; found: 483.2.

Reference： [1]Patent: WO2014/7951,2014,A2 .Location in patent: Page/Page column 93

23
[ 1040377-08-9 ]
[ 1605328-62-8 ]
[ 1605326-17-7 ]

Yield	Reaction Conditions	Operation in experiment
48%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 42h;Inert atmosphere;	The title compound was prepared following the experimental procedure described in Example 3 from 100 mg (0.21 mmol) of (S)-2-(1 -((6-amino-5-iodopyrimidin-4- yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1 -/][1 ,2,4]triazin-4(3H)-one and 76 mg (0.32 mmol) of 2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1 -yl)ethanol. After 18 hours heating, an excess of 2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 /-/-pyrazol-1 -yl)ethanol (76 mg), palladium catalyst (19 mg) and aqueous sodium carbonate solution (317 muIota) were added and the reaction mixture was stirred at 80 C for 24 hours more. The product was purified by flash chromatography (0% to 15%, dichloromethane-methanol) to obtain 46 mg (48% yield) of the title compound.LRMS (m/z): 458 (M+1 )+.1H NMR (400 MHz, DMSO-d6) delta 7.79 (s, 1 H), 7.76 (s, 1 H), 7.60 (dd, 1 H), 7.53 - 7.38 (m, 6H), 6.91 (dd, 1 H), 6.58 (dd, 1 H), 5.69 (d, 3H), 4.86 (t, 1 H), 4.79 - 4.68(m, 1 H), 4.19 (t, 2H), 3.79 (q, 2H), 1.25 (d, 3H).

Reference： [1]Patent: WO2014/60432,2014,A1 .Location in patent: Page/Page column 264; 265

24
[ 1040377-08-9 ]
[ 18162-48-6 ]
[ 1233526-53-8 ]

Yield	Reaction Conditions	Operation in experiment
46%	With dmap; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of 2-(4-(4 ,4,5,5-tetramethyl- I ,3,2-dioxaborolan-2-yl)- I H-pyrazol- I -yl)ethanol (for a preparation see Intermediate 351, 1 .057 g, 4.44 mmol) in N,N-dimethylformamide (DMF) (5 mL) was added imidazole (3 g, 44.1 mmol) and TBDMSCI (3.35 g, 22.20 mmol) and rection mixture stirred at rt. After 2 h a catalytic amount of DMAP was added and reaction mixture was continued to stir at rtovernight. The reaction mixture diluted with water and diethyl ether. The organic layer was separated and the aqueous layer extracted with further portions of diethyl ether (2x50 mL). The combined organic layers were dried (Na2SO4) and concentrated to give 2.82 g of crude pale yellow oil. This was further purified by chromatography on SiC2 (100 g cartridge, eluting with 0-100% ethyl actetate/cyclohexane over 1320 mL, collecting all fracations and visualising with KMnC4) to give theproduct(712 mg, 2.021 mmol, 46%) as a colourless oilLCMS: (2 mm Formic): Rt = 1 .40 mi [MH] = 353.

Reference： [1]Patent: WO2014/140076,2014,A1 .Location in patent: Page/Page column 209

25
[ 1040377-08-9 ]
1-((2S,3R,4R)-4-amino-6-bromo-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]
1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 1h;Microwave irradiation;	I -((2S,3R,4R)-4-amino-6-bromo-2-cyclopropyl-3-methyl-3,4-dihyd roquinolin- I (2H)-yl)ethanone (for apreparation see Intermediate 344, 860 mg, 2.66 mmol), 2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-IH-pyrazol-1-yl)ethanol (for a preparation see Intermedaite 351, 950 mg, 3.99 mmol), potassium carbonate (1103 mg, 7.98 mmol) and Pd(PPh3)2C12 (374 mg, 0.532 mmol) were combined in a mixture of I ,4-dioxane (12 mL) and water (4 mL) and heated in the microwave reactor at 120 C for I h. The reaction mixture was diluted with ethyl acetate and water and combined with thereaction mixture from the same reaction carried out on 200 mg of starting THQ. The organic layer was separated, dried and evaporated in vacuo to give -2.3g of crude orange oil. This was dissolved in the minimum amount of MeOH (-5 mL) and loaded onto a 50 g SCX catridge (pre-conditioned with MeOH). This was then eluted with MeOH (200 mL) followed by 2M NH3 in MeOH (300 mL). Ammonia fractions containing desired product by TLC were combined and concentrated in vacuo togive 1.29 g of yellow oil. This was further purified by chromatography on SiC2 (100 g cartridge, eluting with 0-20% methanol/DCM over 1300 mL) to give the product (645 mg, 1.820 mmol, 68%) as a pale yellow foamy solid. LCMS (2 mm Formic): Rt = 0.51 mi [M-NH2] = 338.

Reference： [1]Patent: WO2014/140076,2014,A1 .Location in patent: Page/Page column 209

26
[ 1040377-08-9 ]
1-((2,.3R,4R)-2-cyclopropyl-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]

Reference： [1]Patent: WO2014/140076,2014,A1

27
[ 1040377-08-9 ]
1-((2S,3R,4R)-4-amino-6-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]

Reference： [1]Patent: WO2014/140076,2014,A1

28
[ 1040377-08-9 ]
1-((2S,3R,4R)-6-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-2-cyclopropyl-3-methyl-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]

Reference： [1]Patent: WO2014/140076,2014,A1

29
[ 1040377-08-9 ]
(S)-3-(1-((4-(5-bromopyrimidin-2-yl)morpholin-2-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile [ No CAS ]
(S)-3-(1-((4-(5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)morpholin-2-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; caesium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 5h;	General procedure: To a solution of 6-(4-(benzyloxy)phenyl)-2-((4-(5-bromopyrimidin-2-yl)morpholin-2-yl)methyl)pyridazin-3(2H)-one (100 mg, 0.18 mmol) in DME:H2O (3:1, 4 mL) was added 1-methylpyrazole-4-boronic acid pinacol ester (58 mg, 0.28 mmol), Cs2CO3 (201 mg, 0.61 mmol), PdCl2(dppf)2 ((18 mg, 0.022 mmol).The mixture was stirred at 80C for 5 h, and extracted with EtOAc (30 mL).Purification by column chromatography (SiO2) afforded 6-(4-(benzyloxy)phenyl)-2-((4-(5-bromopyrimidin-2-yl)morpholin-2-yl)methyl)pyridazin-3(2H)-one (50 mg, 50%)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 5093 - 5097

30
[ 1040377-08-9 ]
C₁₂H₈BrN₇ [ No CAS ]
[ 1313722-93-8 ]