[ CAS No. 638218-78-7 ] {[proInfo.proName]}

Name: 638218-78-7|2-(6-Bromopyridin-2-yl)propan-2-ol|97%
Brand: Ambeed
SKU: A995634
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Quality Control of [ 638218-78-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 638218-78-7 ]

Product Details of [ 638218-78-7 ]

CAS No. :	638218-78-7	MDL No. :	MFCD16657880
Formula :	C₈H₁₀BrNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OXSDDDKLMCHNHF-UHFFFAOYSA-N
M.W :	216.08	Pubchem ID :	22714301
Synonyms :

Calculated chemistry of [ 638218-78-7 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.38
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	47.56
TPSA :	33.12 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) :	-6.47 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.8
Log Po/w (XLOGP3) :	1.62
Log Po/w (WLOGP) :	1.96
Log Po/w (MLOGP) :	1.29
Log Po/w (SILICOS-IT) :	2.17
Consensus Log Po/w :	1.77

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.54
Solubility :	0.626 mg/ml ; 0.0029 mol/l
Class :	Soluble
Log S (Ali) :	-1.93
Solubility :	2.55 mg/ml ; 0.0118 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.13
Solubility :	0.159 mg/ml ; 0.000738 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.96

Safety of [ 638218-78-7 ]

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 [ 638218-78-7 ]

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

Upstream synthesis route of [ 638218-78-7 ]
Downstream synthetic route of [ 638218-78-7 ]

[ 638218-78-7 ] Synthesis Path-Upstream 1~6

1
[ 638218-78-7 ]
[ 955365-80-7 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694

2
[ 626-05-1 ]
[ 67-64-1 ]
[ 638218-78-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -76 - -60℃; Stage #2: at 20℃; Cooling with dry ice Stage #3: With ammonium chloride In tetrahydrofuran; hexane; water	Place a 1.6 M solution of n-butyl lithium in hexane (31.2 niL, 50 mmol) in a dry 250 rnL round bottomed flask fitted with a stir bar, septum and temperature probe. Cool in a dry- ice acetone bath to -76 ⁰C. Add THF (30 mL) to the solution, then add a solution of 2,6- dibromopyridine (11.5 g, 50 mmol) in THF (60 mL) slowly via syringe maintaining the temperature under -60⁰C. Stir the dark yellow-brown solution for 30 minutes in the dry- ice bath, then add acetone (6 mL, 80 mmol). Stir the deep green solution in the dry-ice bath for 15 minutes then allow the reaction to warm to room temperature. After an hour add a 5percent aqueous solution of ammonium chloride (50 mL) carefully. Extract with dichloromethane, evaporate to give 2-(6-bromo-pyridin-2-yl)-propan-2-ol (10.6 g, 98percent) as an orange oil. MS (m/z): 216 and 218 (M+H) ⁺.
94.3%	With n-butyllithium In tetrahydrofuran; hexane at -76 - 20℃; for 1.25 h; Cooling with ice	Step 1 2-(6-Bromopyridin-2-yl)propan-2-ol A dry 250 mL round bottomed flask fitted with a stir bar and septum was charged with n-buthyllithium 1.6 M in hexane (30.3 mL, 48.5 mmol), the flask was cooled in a dry-ice acetone bath to -76° C. and added THF (30 mL) to the solution, then added a solution of 2,6-dibromopyridine (11.5 g, 48.5 mmol) in THF (60 mL) slowly via cannula over 15 min. The dark yellow-brown solution was stirred for 30 minutes in the dry-ice bath, then added propan-2-one (4.75 g, 6 mL, 81.7 mmol). The deep green solution was stirred in the dry-ice bath for 15 minutes and then allowed to warm to room temperature. After an hour, added carefully a saturated aqueous solution of ammonium chloride (100 mL) and product extracted with dichloromethane (3*200), combined organics dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (silica gel 50 μm, 150 g, Analogix) eluting with 0 to 50percent over 20 min dichloromethane/hexanes, obtained 2-(6-bromopyridin-2-yl)propan-2-ol (9.9 g, 94.3percent yield) as a light yellow clear liquid. ¹H NMR (CHLOROFORM-d) δ: 7.52-7.59 (m, 1H), 7.33-7.40 (m, 2H), 4.05 (br. s., 1H), 1.55 (s, 6H); LC-MS 216.1, 218.1 [M+H]⁺.
94%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -76℃; for 0.75 h; Cooling with acetone-dry ice Stage #2: at 20℃; for 1.25 h; Cooling with acetone-dry ice	Step 1 2-(6-Bromopyridin-2-yl)propan-2-ol A dry 250 mL round bottomed flask fitted with a stir bar and septum was charged with n- buthyllithium 1.6 M in hexane (30.3 mL, 48.5 mmol), the flask was cooled in a dry- ice acetone bath to -76 °C then THF (30 mL) was added followed by a solution of 2,6-dibromopyridine (11.5 g, 48.5 mmol) in THF (60 mL) slowly via cannula over 15 min. The dark yellow-brown solution was stirred for 30 minutes in the dry- ice bath, then propan-2-one (4.75 g, 6 mL, 81.7 mmol) was added. The deep green solution was stirred in the dry- ice bath for 15 minutes then was warmed to room temperature over 1 hour. A saturated aqueous solution of ammonium chloride (100 mL) was carefully added and the mixture extracted with dichloromethane (3 x 200 mL). The combined organic extracts were dried over magnesium sulfate then concentrated in vacuo and purified by chromatography (silica gel 50 μιη, 150g, Analogix, eluting with 0 to 50percent dichloromethane in hexanes) to obtain 2-(6-bromopyridin-2-yl)propan-2-ol (9.9 g, 94 percent) as a light yellow, clear liquid. 1H NMR (CHLOROFORM-d) δ: 7.52 - 7.59 (m, 1H), 7.33 - 7.40 (m, 2H), 4.05 (br. s., 1H), 1.55 (s, 6H); MS (EI/CI) m/z: 216.1, 218.1 [M + H].

Reference： [1] Patent: WO2009/131814, 2009, A2, . Location in patent: Page/Page column 40
[2] Patent: US2013/178478, 2013, A1, . Location in patent: Paragraph 0461; 0462
[3] Patent: WO2014/60371, 2014, A1, . Location in patent: Page/Page column 76
[4] Chemical Communications, 2016, vol. 52, # 74, p. 11056 - 11059
[5] Patent: WO2004/814, 2003, A1, . Location in patent: Page 50
[6] Patent: WO2014/99695, 2014, A1, . Location in patent: Page/Page column 41
[7] Patent: WO2014/99694, 2014, A1, . Location in patent: Page/Page column 67

3
[ 49669-13-8 ]
[ 75-16-1 ]
[ 638218-78-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: at 0℃; Stage #2: With water In tetrahydrofuran; ethyl acetate	Preparation 31 Synthesis of 2-(6-bromo-pyridin-2-yl)-propan-2-ol Add a solution of methyl magnesium bromide (3.0 M, 9.7 mL, 29.09 mmol) in tetrahydrofuran dropwise over 20 min to a cooled solution of 1-(6-bromo-pyridin-2-yl)-ethanone (5 g, 24.25 mmol) in anhydrous tetrahydrofuran (48.5 mL) at 0° C. Upon completion of the reaction, add water (exothermic), dilute with ethyl acetate (50 mL) and separate the layers. Extract the aqueous layer once with ethyl acetate (50 mL). Dry the combined organic layers over sodium sulfate, filter and concentrate to give the title compound as a pale yellow liquid (5.69 g, 98percent) that is used without further purification. ¹H NMR (CDCl₃) δ 1.55 (s, 6H), 4.07 (s, 1H), 6.59 (t, 1H), 7.37 (t, 2H), 7.55 (t, 1H).
98%	at 20℃; for 16 h;	To a solution of l-(6-bromo-pyridin-2-yl)-ethanone (4.0 g, 20 mmol) in anhydrous THF (50 mL) at 0 °C was added a solution of methyl magnesium bromide (3.0 M, 8.0 mL, 24 mmol, 1.2 eq) in THF dropwise over 20 min. The mixture was stirred at rt for 16 h, quenched with H₂0 (30 mL) and extracted by EA (4 x 30 mL). The organic phase was washed with brine (30 mL) and dried over Na₂S0₄. After filtration and concentration, the residue was directly used for next step without further purification. 4.2 g, Y: 98percent. ESI-MS (M+H)⁺: 216.

Reference： [1] Patent: US2009/253750, 2009, A1, . Location in patent: Page/Page column 10
[2] Patent: WO2016/11390, 2016, A1, . Location in patent: Page/Page column 209
[3] Patent: WO2010/11375, 2010, A2, . Location in patent: Page/Page column 40
[4] Patent: WO2008/156726, 2008, A1, . Location in patent: Page/Page column 111

4
[ 917-64-6 ]
[ 26218-75-7 ]
[ 638218-78-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	at 20℃; for 0.0833333 h; Inert atmosphere	Methylmagnesium iodide (3M in Et20, 1.50 ml, 4.48 mmol) was added to a solution of methyl 6-bromopyridine-2- carboxylate (0.430 g, 1.99 mmol) in dry Et20 (1 5 ml) under N2. After 5 min at RT the reaction was quenched with 1 M HCI (10 ml) and extracted with EtOAc (15 ml). The organic extract was washed with sat. NaHC03 solution (1 5 ml) and brine (10 ml), dried (MgS04) and concentrated in vacuo. The desired product was obtained as a yellow oil (0.365 g, 1.69 mmol, 85percent). Rf 0.60 (1 :1 Hexane:EtOAc); I R (cm-1 ) 3420, 2975, 2930, 1731 , 1701 , 1 580, 1 553; 1 H NMR (400 MHz, DMSO-d6) 1.42 (6H, s, C(CH2)2), 5.33 (1 H, s, OH), 7.47 (1 H, dd, J = 7.7, 0.9 Hz, H-5), 7.67 (1 H, dd, J = 7.7, 0.9 Hz, H-3), 7.73 (1 H, dd, J = 7.7, 7.7 Hz, H-4); 13C N MR (125 MHz, DMSO-d6) 30.9 (C(CH2)2), 72.6 (C(CH2)2), 1 18.5 (Ar-C), 126.0 (Ar-C), 140.4 (Ar-C), 140.5 (Ar-C), 170.8 (Ar-C).

Reference： [1] Patent: WO2017/75629, 2017, A2, . Location in patent: Page/Page column 34
[2] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694
[3] Patent: US2007/254892, 2007, A1, . Location in patent: Page/Page column 51
[4] Patent: WO2008/133866, 2008, A1, . Location in patent: Page/Page column 29
[5] Patent: WO2013/39854, 2013, A1, . Location in patent: Page/Page column 27
[6] Patent: WO2014/62454, 2014, A1, . Location in patent: Page/Page column 31
[7] Patent: US2016/8361, 2016, A1, . Location in patent: Paragraph 0162

5
[ 626-05-1 ]
[ 638218-78-7 ]

Reference： [1] Patent: US2003/114478, 2003, A1,

6
[ 638218-78-7 ]
[ 955368-90-8 ]
[ 955369-56-9 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 16, p. 1681 - 1694
[2] Patent: US2016/8361, 2016, A1, . Location in patent: Paragraph 0163
[3] ACS Chemical Biology, 2016, vol. 11, # 4, p. 921 - 930
[4] Patent: WO2017/75629, 2017, A2, . Location in patent: Page/Page column 34; 35

[ 638218-78-7 ] Synthesis Path-Downstream 1~78

1
[ 917-64-6 ]
[ 26218-75-7 ]
[ 638218-78-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	In diethyl ether; at 20℃; for 0.5h;Inert atmosphere;	Dissolve methyl 6-bromopicolinate (Int-1-a) (5 g, 23.1 mmol) in diethyl ether (100 mL),Methyl magnesium iodide (17 mL, 50.8 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 0.5 hours.Water and 2N hydrochloric acid were added to the reaction solution, and extracted three times with ethyl acetate.The organic layers were combined and washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution.It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (5 g, yield: 100%) in this step.
85%	In diethyl ether; at 20℃; for 0.0833333h;Inert atmosphere;	Methylmagnesium iodide (3M in Et20, 1.50 ml, 4.48 mmol) was added to a solution of methyl 6-bromopyridine-2- carboxylate (0.430 g, 1.99 mmol) in dry Et20 (1 5 ml) under N2. After 5 min at RT the reaction was quenched with 1 M HCI (10 ml) and extracted with EtOAc (15 ml). The organic extract was washed with sat. NaHC03 solution (1 5 ml) and brine (10 ml), dried (MgS04) and concentrated in vacuo. The desired product was obtained as a yellow oil (0.365 g, 1.69 mmol, 85%). Rf 0.60 (1 :1 Hexane:EtOAc); I R (cm-1 ) 3420, 2975, 2930, 1731 , 1701 , 1 580, 1 553; 1 H NMR (400 MHz, DMSO-d6) 1.42 (6H, s, C(CH2)2), 5.33 (1 H, s, OH), 7.47 (1 H, dd, J = 7.7, 0.9 Hz, H-5), 7.67 (1 H, dd, J = 7.7, 0.9 Hz, H-3), 7.73 (1 H, dd, J = 7.7, 7.7 Hz, H-4); 13C N MR (125 MHz, DMSO-d6) 30.9 (C(CH2)2), 72.6 (C(CH2)2), 1 18.5 (Ar-C), 126.0 (Ar-C), 140.4 (Ar-C), 140.5 (Ar-C), 170.8 (Ar-C).
85%	In diethyl ether; at 20℃; for 0.0833333h;Inert atmosphere;	(0223) Synthesis of 2-(6-bromopyridin-2-yl)propan-2-ol. Methylmagnesium iodide (3M in Et20, 1.50 ml, 4.48 mmol) was added to a solution of methyl 6-bromopyridine-2- carboxylate (0.430 g, 1.99 mmol) in dry Et20 (15 ml) under N2. After 5 min at RT the reaction was quenched with 1 M HCI (10 ml) and extracted with EtOAc (15 ml). The organic extract was washed with sat. NaHC03 solution (15 ml) and brine (10 ml), dried (MgS04) and concentrated in vacuo. The desired product was obtained as a yellow oil (0.365 g,1.69 mmol, 85%). Rf 0.60 (1 :1Hexane:EtOAc); IR (cm 1) 3420, 2975, 2930, 1731, 1701, 1580, 1553; 1H NMR (400 MHz, DMSO-d6) 1.42 (6H, s, C(CH2)2), 5.33 (1H, s, OH), 7.47 (1H, dd, J = 7.7, 0.9 Hz, H-5), 7.67 (1H, dd, J = 7.7, 0.9 Hz, H-3), 7.73 (1H, dd, J = 7.7, 7.7 Hz, H-4); 13C NMR (100 MHz, DMSO- 6) 30.9 (C(CH2)2), 72.6 (C(CH2)2), 1 18.5 (Ar-C), 126.0 (Ar-C), 140.4 (Ar-C), 140.5 (Ar-C), 170.8 (Ar-C).

	With hydrogenchloride; In diethyl ether; water;	1) Production of 2-(6-bromo-2-pyridinyl)-2-propanol In a nitrogen atmosphere, 30 mL of 3 M methylmagnesium iodide/diethyl ether was added to 300 mL of diethyl ether solution of 8.72 g of methyl 6-bromopyridine-2-carboxylate. Water and 2 N hydrochloric acid were added to the reaction liquid, and extracted with ethyl acetate. This was washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain 8.51 g of crude 2-(6-bromo-2-pyridinyl)-2-propanol as a yellow oily substance. 1H-NMR (400 MHz, CDCl3) delta: 7.56 (1H, t, J=7.8 Hz), 7.38 (1H, dd, J=7.8, 1.0 Hz), 7.36 (1H, dd, J=7.8, 1.0 Hz), 1.55(6H, s). ESI-MS Found: m/z[M+H]+ 216, 218.
		Reference Example 2:Production of 2-allyl-l -[6-(I -hydroxy- 1 -methyl ethyl)pyridin-2-yl] -6-{ [4-(4-methylpiperazin- 1- yl)phenyl]ammo>-l,2-dihvdro-3H-pyrazolo[3,4-dlpyrimidin-3-one1) Production of 2-(6-bromo-2-pyridinyl)-2-propanol:In a nitrogen atmosphere, 30 mL of 3 M methylmagnesium iodide/diethyl ether was added to 300 mL of diethyl ether solution of 8.72 g of methyl 6-bromopyridine-2- carboxylate. Water and 2 N hydrochloric acid were added to the reaction liquid, and extracted with ethyl acetate. This was washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain 8.51 g of crude 2-(6-bromo-2-pyridinyl)-2- propanol as a yellow oily substance. iH-NMR (400 MHz, CDC13) 6: 7.56 (IH, t, J=7.8 Hz), 7.38 (IH, dd, J=7.8, 1.0 Hz), 7.36 (IH, dd, J=7.8, 1.0 Hz), 1.55(6H, s). ESI-MS Found: m/z[M+H]+ 216, 218.
		In a nitrogen atmosphere, 30 mL of 3 M methylmagnesium iodide/diethyl ether was added to 300 mL of diethyl ether solution of 8.72 g of methyl 6-bromopyridine-2- carboxylate. Water and 2N hydrochloric acid were added to the reaction liquid, and extracted with ethyl acetate. This was washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain 8.51 g of crude 2-(6-bromo-2-pyridinyl)-2- propanol as a yellow oily substance. iH-NMR (400 MHz, CDC13) delta: 7.56 (IH, t, J=7.8 Hz), 7.38 (IH, dd, J=7.8, 1.0 Hz), 7.36 (IH, dd, J=7.8, 1.0 Hz), 1.55(6H, s). ESI-MS Found: m/z[M+H]+ 216, 218.
	With hydrogenchloride; In diethyl ether; water;Inert atmosphere;	Step 1) Production of 2-(6-bromo-2-pyridinyl)-2-propanol: In a nitrogen atmosphere, 30 mL of 3 M methylmagnesium iodide/diethyl ether was added to 300 mL of diethyl ether solution of 8.72 g of methyl 6-bromopyridine-2- carboxylate. Water and 2 N hydrochloric acid were added to the reaction liquid, and extracted with ethyl acetate. This was washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain 8.51 g of crude 2-(6-bromo-2-pyridinyl)-2- propanol as a yellow oily substance. iH-NMR (400 MHz, CDC13) delta: 7.56 (1H, t, J=7.8 Hz), 7.38 (1H, dd, J=7.8, 1.0 Hz), 7.36 (1H, dd, J=7.8, 1.0 Hz), 1.55(6H, s). ESI-MS Found: m/z[M+H]+ 216, 218.
	In diethyl ether;Inert atmosphere;	In a nitrogen atmosphere, 30 mL of 3 M methylmagnesium iodide/diethyl ether was added to 300 mL of diethyl ether solution of 8.72 g of methyl 6-bromopyridine-2-carboxylate. Water and 2 N hydrochloric acid were added to the reaction liquid, and extracted with ethyl acetate. This was washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain crude 2-(6-bromo-2-pyridinyl)-2-propanol as a yellow oily substance. 1H-NMR (400 MHz, CDCl3) delta: 7.56 (1H, t, J=7.8 Hz), 7.38 (1H, dd, J=7.8, 1.0 Hz), 7.36 (1H, dd, J=7.8, 1.0 Hz), 1.55 (6H, s). ESI-MS Found: m/z[M+H]+ 216, 218.

Reference： [1]Patent: CN110467615,2019,A .Location in patent: Paragraph 0176-0180
[2]Patent: WO2017/75629,2017,A2 .Location in patent: Page/Page column 34
[3]ChemMedChem,2018,vol. 13,p. 1681 - 1694
[4]Patent: WO2019/169065,2019,A2 .Location in patent: Page/Page column 43
[5]Patent: US2007/254892,2007,A1 .Location in patent: Page/Page column 51
[6]Patent: WO2008/133866,2008,A1 .Location in patent: Page/Page column 29
[7]Patent: WO2013/39854,2013,A1 .Location in patent: Page/Page column 27
[8]Patent: WO2014/62454,2014,A1 .Location in patent: Page/Page column 31
[9]Patent: US2016/8361,2016,A1 .Location in patent: Paragraph 0162

2
[ 638218-78-7 ]
[ 638218-62-9 ]
[ 638218-76-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;palladium diacetate; triphenylphosphine; In propan-1-ol; water; at 80℃; for 0.25h;	[ A MIXTURE OF QUINOLINE 4 (L. OEQ. ), 2- (6-BROMO-PYRIDIN-2-YL)-PROPAN-2- OL (1. 2EQ. ), NA2CO3 (3.5EQ. ; 2M IN H20), PD (OAC) 2 (0.05EQ.) AND PPH3 (0. 15EQ.) IN N-] propanol [(0.] 1M) was stirred at [80C] for [15MIN.] The mixture was cooled to rt, poured in water and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over [NA2SO4,] filtered and concentrated. Flash chromatography (Tol: Ace; 9: 1) afforded the title compound as a white [SOLID. 1H] NMR (500 MHz, acetone-d6) : [8] 8.95 (dd, 1H), 8.53 (t, 1H), 8.48 (dd, 1H), 8.32 (d, 1H), 8.26 (d, 1H), 8.20 (dt, 1H), 7.92-7. 81 (m, 3H), 7.65-7. 58 (m, 3H), 4.83 (s, OH), 2.76 (s, 3H), 2.03 (s, 6H), 1.58 (s, 6H).

Reference： [1]Patent: WO2004/814,2003,A1 .Location in patent: Page 50; 51

3
[ 626-05-1 ]
[ 638218-78-7 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: 2-Bromo-6-(1-hydroxy-1-methylethyl)pyridine. Following the procedure of Step 1 of EXAMPLE 27, but substituting 2,6-dibromopyridine for 2,5-dibromopyridine, the 2-Bromo-6-(1-hydroxy-1-methylethyl)pyridine compound was obtained as a solid.

Reference： [1]Patent: US2003/114478,2003,A1

4
[ 626-05-1 ]
[ 67-64-1 ]
[ 638218-78-7 ]

Yield	Reaction Conditions	Operation in experiment
98%		Place a 1.6 M solution of n-butyl lithium in hexane (31.2 niL, 50 mmol) in a dry 250 rnL round bottomed flask fitted with a stir bar, septum and temperature probe. Cool in a dry- ice acetone bath to -76 0C. Add THF (30 mL) to the solution, then add a solution of 2,6- dibromopyridine (11.5 g, 50 mmol) in THF (60 mL) slowly via syringe maintaining the temperature under -600C. Stir the dark yellow-brown solution for 30 minutes in the dry- ice bath, then add acetone (6 mL, 80 mmol). Stir the deep green solution in the dry-ice bath for 15 minutes then allow the reaction to warm to room temperature. After an hour add a 5% aqueous solution of ammonium chloride (50 mL) carefully. Extract with dichloromethane, evaporate to give 2-(6-bromo-pyridin-2-yl)-propan-2-ol (10.6 g, 98%) as an orange oil. MS (m/z): 216 and 218 (M+H) +.
94.3%	With n-butyllithium; In tetrahydrofuran; hexane; at -76 - 20℃; for 1.25h;Cooling with ice;	Step 1 2-(6-Bromopyridin-2-yl)propan-2-ol A dry 250 mL round bottomed flask fitted with a stir bar and septum was charged with n-buthyllithium 1.6 M in hexane (30.3 mL, 48.5 mmol), the flask was cooled in a dry-ice acetone bath to -76 C. and added THF (30 mL) to the solution, then added a solution of 2,6-dibromopyridine (11.5 g, 48.5 mmol) in THF (60 mL) slowly via cannula over 15 min. The dark yellow-brown solution was stirred for 30 minutes in the dry-ice bath, then added propan-2-one (4.75 g, 6 mL, 81.7 mmol). The deep green solution was stirred in the dry-ice bath for 15 minutes and then allowed to warm to room temperature. After an hour, added carefully a saturated aqueous solution of ammonium chloride (100 mL) and product extracted with dichloromethane (3*200), combined organics dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (silica gel 50 mum, 150 g, Analogix) eluting with 0 to 50% over 20 min dichloromethane/hexanes, obtained 2-(6-bromopyridin-2-yl)propan-2-ol (9.9 g, 94.3% yield) as a light yellow clear liquid. 1H NMR (CHLOROFORM-d) delta: 7.52-7.59 (m, 1H), 7.33-7.40 (m, 2H), 4.05 (br. s., 1H), 1.55 (s, 6H); LC-MS 216.1, 218.1 [M+H]+.
94%		Step 1 2-(6-Bromopyridin-2-yl)propan-2-ol A dry 250 mL round bottomed flask fitted with a stir bar and septum was charged with n- buthyllithium 1.6 M in hexane (30.3 mL, 48.5 mmol), the flask was cooled in a dry- ice acetone bath to -76 C then THF (30 mL) was added followed by a solution of 2,6-dibromopyridine (11.5 g, 48.5 mmol) in THF (60 mL) slowly via cannula over 15 min. The dark yellow-brown solution was stirred for 30 minutes in the dry- ice bath, then propan-2-one (4.75 g, 6 mL, 81.7 mmol) was added. The deep green solution was stirred in the dry- ice bath for 15 minutes then was warmed to room temperature over 1 hour. A saturated aqueous solution of ammonium chloride (100 mL) was carefully added and the mixture extracted with dichloromethane (3 x 200 mL). The combined organic extracts were dried over magnesium sulfate then concentrated in vacuo and purified by chromatography (silica gel 50 muiotaeta, 150g, Analogix, eluting with 0 to 50% dichloromethane in hexanes) to obtain 2-(6-bromopyridin-2-yl)propan-2-ol (9.9 g, 94 %) as a light yellow, clear liquid. 1H NMR (CHLOROFORM-d) delta: 7.52 - 7.59 (m, 1H), 7.33 - 7.40 (m, 2H), 4.05 (br. s., 1H), 1.55 (s, 6H); MS (EI/CI) m/z: 216.1, 218.1 [M + H].

		To a suspension of 2,6-dibromopyridine [(L.] Oeq. ) in Et20 (0.2M) at -78C was added dropwise n-BuLi [(1.] [05EQ.).] The mixture was stirred at-78C for [45MIN] then acetone [(1.] 5eq.) was added. The final mixture was stirred for an extra [15MIN] at-78C and quenched with saturated aqueous NaHCO3,. The mixture was extracted with EtOAc (2x). The combined organic extracts were washed with, brine, dried over [MGS04,] filtered and concentrated to afford the title compound as a white solid which was used as such.
		Place a 1.6 M solution ofn-BuLi in hexane (5.2 mL) in a dry 100 mL roundbottomed flask fitted with a stir bar, septum and temperature probe. Cool in adry- ice acetone bath to -76 C. Add THF (5 mL) to the solution, then add asolution of2,6- dibromopyridine (2.0 g) in THF (10 mL) slowly via syringemaintaining the temperature below -60 C. Stir the solution for 30 min in thedry- ice bath, then add acetone (13.5 mL). Stir the solution in the dry-ice bathfor 15 min then allow the reaction to warm to room temperature. After 1 h thereaction mixture was quenched with a 5% aqueous solution ofNH4Cl, andextracted with EtOAc. The combined organic layer was washed with brine anddried over Na2S04? It was filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (Heptane:CH2Cb=70:30 toCH2Cb) to obtain compound 4-1 as an orange oil.
		Place a 1.6 M solution of n-BuLi in hexane (5.2 mL) in a dry 100 rnL round bottomed flask fitted with a stir bar, septum and temperature probe. Cool in a dry- ice acetone bath to -76 C. Add THF (5 mL) to the solution, then add a solution of 2,6- dibromopyridine (2.0 g) in THF (10 mL) slowly via syringe maintaining the temperature under -60 C. Stir the solution for 30 min in the dry- ice bath, then add acetone (13.5 mL). Stir the solution in the dry-ice bath for 15 min then allow the reaction to warm to room temperature. After an h the reaction mixture was quenched with a 5% aqueous solution of NH4C1, and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2S04. It was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (Heptane:CH2Cl2=70:30 to 0:100) to obtain compound 21-1 as a orange solid.

Reference： [1]Patent: WO2009/131814,2009,A2 .Location in patent: Page/Page column 40
[2]Patent: US2013/178478,2013,A1 .Location in patent: Paragraph 0461; 0462
[3]Patent: WO2014/60371,2014,A1 .Location in patent: Page/Page column 76
[4]Chemical Communications,2016,vol. 52,p. 11056 - 11059
[5]Patent: WO2004/814,2003,A1 .Location in patent: Page 50
[6]Patent: WO2014/99695,2014,A1 .Location in patent: Page/Page column 41
[7]Patent: WO2014/99694,2014,A1 .Location in patent: Page/Page column 67

5
[ 49669-13-8 ]
[ 75-16-1 ]
[ 638218-78-7 ]

Yield	Reaction Conditions	Operation in experiment
98%		Preparation 31 Synthesis of 2-(6-bromo-pyridin-2-yl)-propan-2-ol Add a solution of methyl magnesium bromide (3.0 M, 9.7 mL, 29.09 mmol) in tetrahydrofuran dropwise over 20 min to a cooled solution of 1-(6-bromo-pyridin-2-yl)-ethanone (5 g, 24.25 mmol) in anhydrous tetrahydrofuran (48.5 mL) at 0 C. Upon completion of the reaction, add water (exothermic), dilute with ethyl acetate (50 mL) and separate the layers. Extract the aqueous layer once with ethyl acetate (50 mL). Dry the combined organic layers over sodium sulfate, filter and concentrate to give the title compound as a pale yellow liquid (5.69 g, 98%) that is used without further purification. 1H NMR (CDCl3) delta 1.55 (s, 6H), 4.07 (s, 1H), 6.59 (t, 1H), 7.37 (t, 2H), 7.55 (t, 1H).
98%	In tetrahydrofuran; at 20℃; for 16h;	To a solution of l-(6-bromo-pyridin-2-yl)-ethanone (4.0 g, 20 mmol) in anhydrous THF (50 mL) at 0 C was added a solution of methyl magnesium bromide (3.0 M, 8.0 mL, 24 mmol, 1.2 eq) in THF dropwise over 20 min. The mixture was stirred at rt for 16 h, quenched with H20 (30 mL) and extracted by EA (4 x 30 mL). The organic phase was washed with brine (30 mL) and dried over Na2S04. After filtration and concentration, the residue was directly used for next step without further purification. 4.2 g, Y: 98%. ESI-MS (M+H)+: 216.
		A solution of l-(6~bromorhoyridin-2-yl)ethanone (5 g, 25.0 mmol) in diethyl ether (77 ml) at 00C was treated with methyl magnesium bromide (8.33 ml, 25.0 mmol). After 3 hours, water was added to quench excess methyl magnesium bromide, and then concentrated aqueous hydrogen chloride solution was added until two layers were obtained. The layers were separated and the aqueous layer was extracted with diethyl ether (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield the title compound. LRMS (APCI) calc'd for C8H1 jBrNO [M+H]+: 216, Found: 216.

In diethyl ether; at 0℃; for 3h;

A solution of l-(6-bromopyridin-2-yl)ethanone (5 g, 25.0 mmol) in diethyl ether (77 mL) at 0C was treated with methyl magnesium bromide (8.33 mL, 25.0 mmol). After 3 hours, water was added to quench the excess methyl magnesium bromide, and then concentrated aqueous hydrogen chloride solution was added until two layers were obtained. The layers were separated and the aqueous layer was extracted with diethyl ether (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield the title compound.Calc'd for C8HnBrNO [M+H]+: 216, Found: 216.

Reference： [1]Patent: US2009/253750,2009,A1 .Location in patent: Page/Page column 10
[2]Patent: WO2016/11390,2016,A1 .Location in patent: Page/Page column 209
[3]Patent: WO2010/11375,2010,A2 .Location in patent: Page/Page column 40
[4]Patent: WO2008/156726,2008,A1 .Location in patent: Page/Page column 111

6
[ 638218-78-7 ]
[ 1189746-38-0 ]

Yield	Reaction Conditions	Operation in experiment
71%	With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at -78 - 20℃;	Preparation 32 Synthesis of 2-bromo-6-(1-fluoro-1-methyl-ethyl)-pyridine Add (bis(2-methoxyethyl)amino)sulfur trifluoride (2.05 mL, 11.11 mmol) dropwise to a cooled solution of <strong>[638218-78-7]2-(6-bromo-pyridin-2-yl)-propan-2-ol</strong> (2 g, 9.26 mmol) in dichloromethane (46.3 mL) at -78 C. Upon addition, warm to room temperature and stir overnight. Add a saturated aqueous solution of sodium bicarbonate and stir until gas evolution stops. Filter through a 50 mL hydrophobic IST Phase Separator Frit, concentrate and purify by silica gel chromatography, gradient eluding from 3:97 to 5:95 and then to 10:90 using dichloromethane:iso-hexane to give the title compound as a colorless liquid (5.13 g, 71%). 1H NMR (CDCl3) delta 1.66 (s, 3H), 1.73 (s, 3H), 7.37 (dd, 2H), 7.53 (m, 2H). 19F NMR (CDCl3) delta-143.37 (s, 1F).
70.43%	With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 12h;	Step)-1: Synthesis of 2-bromo-6-(2-fluoropropan-2-yl)pyridine To a stirred solution of 2-(6-bromo-pyridine-2-yl)-propane-2-ol (0.500 g, 2.313 mmol, 1.0 eq) in DCM (10 mL), DAST (0.36 mL, 2.545 mmol, 1.1 eq) was added at -78 C. The reaction mixture was stirred at rt for 12 h. After completion of reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and was extracted with EtOAc (50 mL*2). The combined organic layer was washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography [silica gel 100-200 mesh; elution 0-10% EtOAc in hexane] to afford the desired compound, tert-butyl 6-((2-cyclopropyl-1-(6-(2-fluoropropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (355 mg, 70.43%) as colorless liquid. LCMS: 217.99 [M+1]+
33.69%	With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃;Inert atmosphere;	Into a lOO-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[638218-78-7]2-(6-bromopyridin-2-yl)propan-2-ol</strong> (500.00 mg, 2.3l4mmol, l.OOequiv), DCM (20.00 mL). This was followed by the addition of DAST (1118.96 mg, 6.942mmol, 3.00equiv) dropwise with stirring at -78 degrees C .The resulting solution was stirred for overnight at room temperature. The reaction was then quenched by the addition of 20 mL of NaHC03 (5mol/L). The resulting solution was extracted with 3x20 mL of dichloromethane concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl (0330) acetate/petroleum ether (1:20). The collected fractions were combined and concentrated. This resulted in 170 mg (33.69%) of 2-bromo-6-(2-fluoropropan-2-yl)pyridine as light yellow oil. LC-MS-l (ES, m/z): 218[M+1] +

Reference： [1]Patent: US2009/253750,2009,A1 .Location in patent: Page/Page column 10
[2]Patent: US2019/106427,2019,A1 .Location in patent: Paragraph 0589; 0590; 0633-0635
[3]Patent: WO2019/165204,2019,A1 .Location in patent: Page/Page column 54-55

7
[ 638218-78-7 ]
[ 75-05-8 ]
[ 776297-29-1 ]

Yield	Reaction Conditions	Operation in experiment
36%	With boron trifluoride diethyl etherate; for 16h;Reflux;	To a solution of <strong>[638218-78-7]2-(6-bromopyridin-2-yl)propan-2-ol</strong> (2.0 g, 9.26 mmol) in MeCN (30 mL) was added BF3-Et20 (3.7 mL, 23.1 mmol, 2.5 eq) at rt. The mixture was refluxed for 16 h. After cooling to rt, the mixture was neutralized with 5 N NaOH and extracted with DCM (100 mL). The organic phase was washed with brine (30 mL) and dried over Na2S04. After filtration and concentration, the residue was purified by column chromatography (silica gel, PE/EA = 1/1) to afford the compound N-(2-(6-bromopyridin-2-yl)propan-2-yl)acetamide (860 mg, Y: 36%). ESI-MS (M+H)+: 257.0
26%		Dissolve <strong>[638218-78-7]2-(6-bromo-pyridin-2-yl)-propan-2-ol</strong> (10.6 g, 50 mmol) in acetonitrile (40 mL). Add BFs-Et2O (20 mL, 125 mmol) and reflux for 3 days. Cool to room temperature, add ice and neutralize the reaction with 5N NaOH and extract with dichloromethane. Purify over silica (120 g) eluting with 0 to 100% EtOAc:hexanes to give N-[l-(6-bromo-pyridin- 2-yl)-l-methyl-ethyl]-acetamide (3.3 g, 26%), MS (m/z): 257 and 259 (M+H) + and recovered <strong>[638218-78-7]2-(6-bromo-pyridin-2-yl)-propan-2-ol</strong> (3.7 g, 34%).

Reference： [1]Patent: WO2016/11390,2016,A1 .Location in patent: Page/Page column 210
[2]Patent: WO2009/131814,2009,A2 .Location in patent: Page/Page column 40

8
[ 638218-78-7 ]
2-bromo-6-isopropenylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; Methanesulfonic anhydride; In dichloromethane; for 3h;	A solution of 2-(6-bromorhoyridin-2~yI)propan-2-ol (2.44 g, 1 1.29 mmol) and methansulfonic anhydride (5.90 g, 33.9 mmol) in dichloromethane (35 mL) was charged with triethylamine (6.26 ml, 45.2 mmol). After three hours, the reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (25 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (25 mL) and brine (2 x 25 mL), dried over sodium sulfate, filtered, and concentrated. The resulting yellow liquid was purified by silica gel chromatography (2-20% ethyl acetate / hexanes) to afford the title compound. 1H NMR (600 MHz, LambdaS-DMSO): delta 7.70 (t, 1 H), 7.61 (d, 1 H), 7.49 (d, 1 H), 5.89 (s, 1 H), 5.33 (s, 1 H), 2.06 (s, 3 H).

Reference： [1]Chemical Communications,2016,vol. 52,p. 11056 - 11059
[2]Patent: WO2010/11375,2010,A2 .Location in patent: Page/Page column 40-41

9
[ 638218-78-7 ]
[ 955405-38-6 ]
C₄₀H₄₀N₂O₆ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 13168 - 13172

10
[ 638218-78-7 ]
C₃₆H₃₂N₂O₄ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 13168 - 13172

11
[ 638218-78-7 ]
C₃₆H₂₈Mo₂N₂O₈ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 13168 - 13172

12
[ 638218-78-7 ]
[ 1446793-30-1 ]

Reference： [1]Patent: US2013/178478,2013,A1
[2]Patent: WO2014/60371,2014,A1

13
[ 638218-78-7 ]
[ 1446793-32-3 ]

Reference： [1]Patent: US2013/178478,2013,A1
[2]Patent: WO2014/60371,2014,A1

14
[ 638218-78-7 ]
[ 1446793-34-5 ]

Reference： [1]Patent: US2013/178478,2013,A1

15
[ 638218-78-7 ]
[ 1446791-07-6 ]

Reference： [1]Patent: US2013/178478,2013,A1

16
[ 638218-78-7 ]
[ 1446793-28-7 ]

Yield	Reaction Conditions	Operation in experiment
56%	With copper(I) oxide; ammonium hydroxide; potassium carbonate; N,N-dimethylethylenediamine; In 1,2-dimethoxyethane; at 60℃; for 6h;Inert atmosphere;	Step 2 2-(6-Aminopyridin-2-yl)propan-2-ol A heavy walled sealable tube was loaded under an argon atmosphere with copper (I) oxide (53.0 mg, 370 muiotaetaomicron), <strong>[638218-78-7]2-(6-bromopyridin-2-yl)propan-2-ol</strong> (1600 mg, 7.4 mmol), ammonium hydroxide 28% solution (16.5 M, 9.0 mL, 148 mmol), K2C03 (205 mg, 1.48 mmol), N,N- dimethylethylenediamine (65 mg, 81 mu^, 740 muiotaetaomicron) and ethyleneglycol (14.8 mL). The reaction was stirred for 6 h at 60 C, then cooled to room temperature and extracted with dichloromethane (3x25mL). The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and then purified by chromatography (spherical silica 20-45 muMu, 23g, Versaflash Supelco, eluting with 0 to 5 % of a 1 :9 ammonium hydroxide: methanol solution in dichloromethane, 20 min) to obtain 2-(6-aminopyridin-2-yl)propan-2-ol (626 mg, 56 %) as a light yellow liquid. 1H NMR (CHLOROFORM-d) delta: 7.44 (t, J = 7.7 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.38 (d, J = 7.9 Hz, 1H), 5.12 (s, 1H), 4.38 - 4.55 (m, 2H), 1.49 (s, 6H); MS (EI/CI) m/z: 153.1, 155.1 [M + H].
55.5%	With copper(I) oxide; ammonium hydroxide; potassium carbonate; N,N-dimethylethylenediamine; In ethylene glycol; at 60℃; for 6h;Sealed tube; Inert atmosphere;	Step 2 2-(6-Aminopyridin-2-yl)propan-2-ol A heavy walled resealable tube was loaded under an argon atmosphere with copper (I) oxide (53.0 mg, 370 mumol), <strong>[638218-78-7]2-(6-bromopyridin-2-yl)propan-2-ol</strong> (1600 mg, 7.4 mmol), ammonium hydroxide 28% solution (16.5 M) (8.98 mL, 148 mmol), K2CO3 (205 mg, 1.48 mmol), N,N-dimethylethylenediamine (65.3 mg, 81.3 muA, 740 mumol) and ethyleneglycol (14.8 mL). The reaction was stirred for 6 h at 60 C. After cooling to room temperature, the reaction mixture was extracted with dichloromethane (3*25 mL), combined organics dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (spherical silica 20-45 muM, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (10% ammonium hydroxide in methanol)/dichloromethane to give 2-(6-aminopyridin-2-yl)propan-2-ol (626 mg, 55.5% yield) as a light yellow liquid. 1H NMR (CHLOROFORM-d) delta: 7.44 (t, J=7.7 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 6.38 (d, J=7.9 Hz, 1H), 5.12 (s, 1H), 4.38-4.55 (m, 2H), 1.49 (s, 6H); LC-MS 153.1, 155.1 [M+H]+.

Reference： [1]Patent: WO2014/60371,2014,A1 .Location in patent: Page/Page column 76-77
[2]Patent: US2013/178478,2013,A1 .Location in patent: Paragraph 0463; 0464

17
[ 638218-78-7 ]
[ 1602681-02-6 ]

Reference： [1]Patent: WO2014/60371,2014,A1

18
[ 638218-78-7 ]
[ 1602682-12-1 ]

Reference： [1]Patent: WO2014/60371,2014,A1

19
[ 638218-78-7 ]
[ 1602682-10-9 ]

Reference： [1]Patent: WO2014/60371,2014,A1

20
[ 638218-78-7 ]
[ 1602682-15-4 ]

Reference： [1]Patent: WO2014/60371,2014,A1

21
[ 638218-78-7 ]
[ 1602681-13-9 ]

Reference： [1]Patent: WO2014/60371,2014,A1

22
[ 638218-78-7 ]
[ 74-88-4 ]
[ 1602682-09-6 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃;	Step 1 2-Bromo-6-(2-methoxypropan-2-yl)pyridine A dry flask fitted with a stir bar and septum was charged with 2-(6-bromopyridin-2-yl)propan-2- ol (1.66 g, 7.68 mmol), Mel (3.27 g, 1.44 mL, 23.0 mmol) and THF (40 mL). NaH (60% in mineral oil, 922 mg, 23.0 mmol) was added portion wise over 10 min and the reaction then stirred at room temperature overnight. Saturated aqueous ammonium chloride (20 mL) was added and the mixture extracted with dichloro methane (3 x 75 mL). The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo, and purified by a chromatography (silica gel 50 muiotaeta, 80g, Analogix, eluting with dichloromethane) to give 2- bromo-6-(2-methoxypropan-2-yl)pyridine (1.473 g, 81 %) as a clear liquid1 NMR (CHLOROFORM-d) delta: 7.49 - 7.57 (m, 2H), 7.34 (dd, J = 6.6, 2.1 Hz, 1H), 3.19 (s, 3H), 1.54 (s, 6H); . MS (EI/CI) m/z: 230.0, 232.0 [M + H].

Reference： [1]Patent: WO2014/60371,2014,A1 .Location in patent: Page/Page column 89-90

23
[ 638218-78-7 ]
[ 955365-80-7 ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

24
[ 638218-78-7 ]
[ 955368-90-8 ]
[ 955369-56-9 ]

Yield	Reaction Conditions	Operation in experiment
74%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 80℃;	Step-3: Synthesis of 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-methylsulfanyl-pyrazolo[3,4-d]pyrimidin-3-one To a stirred solution of 2-allyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-3-one (200 mg, 0.90 mmol, 1.0 eq) and <strong>[638218-78-7]2-(6-bromo-2-pyridyl)propan-2-ol</strong> (233 mg, 1.08 mmol, 1.20 eq) in 10 mL of dioxane were added copper iodide (171 mg, 0.90 mmol, 1.0 eq), potassium carbonate (186 mg, 1.35 mmol, 1.5 eq) and N,N'-dimethylethylenediamine (87 mg, 0.99 mmol, 1.1 eq) and stirred at 80 C. for overnight. After completion of reaction, solvent was removed under reduced pressure; residue was diluted with water and extracted with ethyl acetate (30 mL*3). Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography to afford 240 mg (74%) of 2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-methylsulfanyl-pyrazolo[3,4-d]pyrimidin-3-one.
47%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃;	Into a lOOO-mL 3-necked round-bottom flask, was placed 6-(methylsulfanyl)-2-(prop-2-en-l-yl)-lH,2H,3H- pyrazolo[3,4-d]pyrimidin-3-one (20 g, 89.98 mmol, 1.00 equiv), <strong>[638218-78-7]2-(6-bromopyridin-2- yl)propan-2-ol</strong> (24 g, 111.07 mmol, 1.23 equiv), 1,4-dioxane (500 mL), iodocopper (17.1 g, 89.79 mmol, 1.0 equiv), K2C03 (17.1 g, 122.83 mmol, 1.37 equiv). This was followed by the addition of methyl [2-(methylamino) ethyl] amine (10.8 mL) dropwise with stirring. The resulting solution was stirred overnight at 95C in an oil bath. The resulting mixture was cooled to room temperature. The mixture was then quenched by the addition of 100 mL of water. The resulting mixture was concentrated under vacuum. The residue was extracted with 3x500 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5- 1:3). This resulted in 15 g (47%) of l-[6-(2-hydroxypropan-2-yl) pyridin-2-yl]-6-(methylsulfanyl)-2-(prop-2-en-l-yl)-lH,2H,3H- pyrazolo[3,4-d]pyrimidin-3-one as a white solid. LC-MS(ES, m/z) M+l=358
	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃;	General procedure: 2.4 mL of N,N?-dimethylethylenediamine was added to 1,4-dioxane (50 mL) solution of 4.44 g of 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, 3.80 g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.80 g of potassium carbonate, and stirred overnight at 95 C. The reaction liquid was cooled, aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and crystallized with ethyl acetate to obtain the entitled compound as a white solid Step 2) Production of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one The entitled compound was obtained in the same manner as in Preparative Example 1-1, for which, however, the compound obtained in the above reaction was used in place of 2-iodopyridine used in Preparative Example 1-1. 1H-NMR (400 MHz, CDCl3) delta: 8.95 (1H, s), 7.91 (1H, t, J=8.0 Hz), 7.76 (1H, d, J=7.3 Hz), 7.40 (1H, dd, J=7.8, 1.0 Hz), 5.70 (1H, ddt, J=17.1, 10.2, 6.3 Hz), 5.06 (1H, dd, J=10.2, 1.0 Hz), 4.93 (1H, dd, J=17.1, 1.2 Hz), 4.81 (2H, d, J=6.3 Hz), 2.59 (4H, s), 1.59 (6H, s). ESI-MS Found: m/z[M+H]+:358.

	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 80 - 95℃; for 18h;	General method for the preparation of pyridyl pyrazolopyrimidinones (9a-c). Nu,Nu'- Dimethylethylenediamine (4.47 mmol) was added to a solution of pyrazolopyrimidine 7 (2.25 mmol), bromopyridine (8a-c; 2.93 mmol), copper iodide (2.25 mmol) and K2C03 (3.1 5 mmol) in 1 ,4-dioxane (5 ml) at 80 C. The resultant suspension was heated at 95 C for 18 h, over which time a colour change of orange to dark green occurred. The reaction mixture was cooled to RT and diluted with NH40H (10 ml) before being extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with brine (20 ml), dried 33 (MgS04) and evaporated to dryness. The crude material was purified via silica gel chromatography (19:1 DCM:MeOH) to afford the target pyridyl pyrazolopyrimidinones (69-84%). 2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H- pyrazolo[3,4- d]pyrimidin-3-one (9a). Rf 0.63 (9:1 DCM:MeOH); M.p.108-111 C; IR (cm-1) 3337, 3081, 2966, 2924, 1663, 1601, 1559; 1H NMR(400 MHz, CDCI3) 1.61 (6H, s, C(CH3)2), 2.61 (3H, s, S-CH3), 3.77 (1H, s, -OH), 4.82 (2H, dapp, J = 5.9 Hz, N2-CH2), 4.95 (1H, dapp, J = 16.9 Hz, allyl C-Htrans), 5.08 (1H, dapp, J = 10.3 Hz, allyl C-Hcis), 5.72 (1H, dd = 16.9, 10.3, 5.9 Hz, allyl C-H), 7.42 (1H, d, J = 7.7 Hz, H-5'), 7.78 (1H, d,J = 8.0 Hz, H-3'), 7.93 (1H, dd,J = 8.0, 7.7 Hz, H-4'), 8.96 (1H, s, H-4); 13C NMR(125 MHz, CDCI3) 14.5 (SCH3), 30.5 (C(CH3)2), 47.5 (N2-CH2), 72.5 (C(CH3)2), 116.4 (Ar-C), 116.6 (Ar-C), 119.3 (allyl-CH2), 131.2, 139.2, 147.0 (Ar-C), 154.3 (Ar-C), 159.2 (C=0), 161.0 (Ar-C), 166.1 (Ar-C), 177.0 (Ar-C); MS [M + H]+ m/z 359.3.
1.8 g	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere;	Compound N1, N2-dimethylethane-1,2-diamine (872 mg) was added to compound S-4 (2g), and 2- (6-bromopyridin-2-yl) propan-2-ol ( 2.3 g), CuI (1.7 g) and potassium carbonate (2.5 g) in 1,4-dioxane (25 mL). Heat to 100 C under nitrogen and stir for 12 hours. After cooling to room temperature, a saturated ammonium chloride solution (50 mL) was added to the reaction system, and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH, 45: 1, v / v) to give the target product Int-1 (1.8 g) as a pale yellow solid

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694
[2]Patent: US2019/106427,2019,A1 .Location in patent: Paragraph 0252; 0258; 0259
[3]Patent: WO2019/165204,2019,A1 .Location in patent: Page/Page column 31-32
[4]Patent: US2016/8361,2016,A1 .Location in patent: Paragraph 0163
[5]ACS Chemical Biology,2016,vol. 11,p. 921 - 930
[6]Patent: WO2017/75629,2017,A2 .Location in patent: Page/Page column 34; 35
[7]Patent: CN110872296,2020,A .Location in patent: Paragraph 0140; 0146-0147

25
[ 638218-78-7 ]
N-(2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-2-yl)acetamide [ No CAS ]

Reference： [1]Patent: WO2016/11390,2016,A1

26
[ 638218-78-7 ]
2-(6-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)propan-2-amine [ No CAS ]

Reference： [1]Patent: WO2016/11390,2016,A1

27
[ 638218-78-7 ]
methyl 5-([6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/174183,2016,A1
[2]Patent: WO2017/157792,2017,A1
[3]Patent: US2017/349570,2017,A1
[4]Patent: WO2017/207481,2017,A1

28
[ 638218-78-7 ]
methyl 5-([6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-2-(4,4,4-trifluorobutyl)-2H-indazole-6-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/174183,2016,A1
[2]Patent: WO2017/157792,2017,A1
[3]Patent: US2017/349570,2017,A1
[4]Patent: WO2017/207481,2017,A1

29
[ 638218-78-7 ]
potassium 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/174183,2016,A1
[2]Patent: WO2017/157792,2017,A1
[3]Patent: US2017/349570,2017,A1
[4]Patent: WO2017/207481,2017,A1
[5]Patent: US2019/71432,2019,A1

30
[ 67-56-1 ]
[ 638218-78-7 ]
[ 201230-82-2 ]
methyl 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine; In dimethyl sulfoxide; at 20 - 100℃; under 9750.98 - 10501.1 Torr; for 24.5h;Autoclave;	2.00 g (9.26 mmol) of <strong>[638218-78-7]2-(6-bromopyridin-2-yl)propan-2-ol</strong> (CAS 638218-78-7) were dissolved in 20 ml of methanol and 20 ml of DMSO. Subsequently, 250 mg of 1,3- bis(diphenylphosphino)propane, 130 mg of palladium(ll) acetate and 3 ml of triethylamine were added. The reaction mixture was purged three times with carbon monoxide at room temperature and stirred under a 13 bar carbon monoxide atmosphere for 30 min. The carbon monoxide atmosphere was removed by applying a vacuum and the mixture was stirred under a 14 bar carbon monoxide atmosphere at 100C for 24 h. The autoclave was decompressed, water was added to the reaction mixture, and the reaction mixture was extracted three times with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and sodium chloride solution, filtered through a hydrophobic filter and concentrated. This gave 1.60 g of a crude product. UPLC-MS (Method Al): Rt = 0.76 min (UV detector: TIC), mass found 195.00.
	With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine; In dimethyl sulfoxide; at 100℃; under 9750.98 - 10501.1 Torr; for 24.5h;Autoclave;	2.00 g (9.26 mmol) of <strong>[638218-78-7]2-(6-bromopyridin-2-yl)propan-2-ol</strong> (CAS 638218-78-7) were dissolved in 20 ml of methanol and 20 ml of DMSO. Subsequently, 250 mg of 1,3- bis(diphenylphosphino)propane, 130 mg of palladium(ll) acetate and 3 ml of triethylamine were added. The reaction mixture was purged three times with carbon monoxide at room temperature and stirred under a 13 bar carbon monoxide atmosphere for 30 min. The carbon monoxide atmosphere was removed by applying a vacuum and the mixture was stirred under a 14 bar carbon monoxide atmosphere at 100C for 24 h . The autoclave was decompressed, water was added to the reaction mixture, and the reaction mixture was extracted three times with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and sodium ch loride solution, filtered through a hydrophobic filter and concentrated. This gave 1.60 g of a crude product. UPLC-MS (Method Al): t = 0.76 min (UV detector: TIC), mass found 195.00.
	With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine; In dimethyl sulfoxide; at 20 - 100℃; under 9750.98 - 10501.1 Torr; for 24.5h;Autoclave;	Starting Materials Intermediate V2-1 RRN 5758 Methyl 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate (0232) (0233) 2.00 g (9.26 mmol) of 59 <strong>[638218-78-7]2-(6-bromopyridin-2-yl)propan-2-ol</strong> (CAS 638218-78-7) were dissolved in ml of 35 methanol and 20 ml of 60 DMSO. Subsequently, 250 mg of 61 1,3-bis(diphenylphosphino)propane, 130 mg of 62 palladium(II) acetate and 3 ml of 63 triethylamine were added. The reaction mixture was purged three times with carbon monoxide at room temperature and stirred under a 13 bar carbon monoxide atmosphere for 30 min. The carbon monoxide atmosphere was removed by applying a vacuum and the mixture was stirred under a 14 bar carbon monoxide atmosphere at 100 C. for 24 h. The autoclave was decompressed, 64 water was added to the reaction mixture, and the reaction mixture was extracted three times with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and sodium chloride solution, filtered through a hydrophobic filter and concentrated. This gave 1.60 g of a crude product. (0234) UPLC-MS (Method A1): Rt=0.76 min (UV detector: TIC), mass found 195.00.

	With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine; In dimethyl sulfoxide; at 20 - 100℃; under 9750.98 Torr; for 24.5h;	2.00 g (9.26 mmol) of <strong>[638218-78-7]2-(6-bromopyridin-2-yl)propan-2-ol</strong> (CAS 638218-78-7) were dissolved in20 ml of methanol and 20 ml of DMSO. Subsequently, 250 mg of 1,3- bis(diphenylphosphino)propane, 130 mg of palladium(II) acetate and 3 ml of triethylamine were added. The reaction mixture was purged three times with carbon monoxide at room temperature and stirred under a 13 bar carbon monoxide atmosphere for 30 mm. The carbon monoxideatmosphere was removed by applying a vacuum and the mixture was stirred under a 14 bar carbon monoxide atmosphere at 100C for 24 h. The autoclave was decompressed, water was added to the reaction mixture, and the reaction mixture was extracted three times with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and sodium chloride solution, filtered through a hydrophobic filter and concentrated. This gave 1.60 g of a crude product.UPLC-MS (Method Al): R = 0.76 mm (UV detector: TIC), mass found 195.00.
	With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine; In methanol; dimethyl sulfoxide; at 20 - 100℃; under 9750.98 - 10501.1 Torr; for 24.5h;	2.00 g (9.26 mmol) of 2-(6-bromopyridin-2-yl) propan-2-ol (CAS 6382 18-78-7) were dissolved in 20 ml of methanol and 20 ml of DMSO. Subsequently, 250 mg of 1,3-bis(diphenylphosphino)propane, 130 mg of palladium (II) acetate and 3 ml of triethylamine were added. The reaction mixture was purged three times with carbon monoxide at room temperature and stirred under a 13 bar carbon monoxide atmosphere for 30 mm. The carbon monoxide atmosphere was removed by applying a vacuum and the mixture was stirred under a 14 bar carbon monoxide atmosphere at 100C. for 24 h. The autoclave was decompressed, water was added to the reaction mixture, and the reaction mixture was extracted three times with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and sodium chloride solution, filtered through a hydrophobic filter and concentrated. This gave 1.60 g of a crude product. 10395] UPLC-MS (Method C): R=0.76 mm (UV detector:TIC), mass found 195.00.

Reference： [1]Patent: WO2016/174183,2016,A1 .Location in patent: Page/Page column 47; 48
[2]Patent: WO2017/157792,2017,A1 .Location in patent: Page/Page column 52-53
[3]Patent: US2017/349570,2017,A1 .Location in patent: Paragraph 0232; 0233; 0234
[4]Patent: WO2017/207481,2017,A1 .Location in patent: Page/Page column 36
[5]Patent: US2019/71432,2019,A1 .Location in patent: Paragraph 0393; 0394; 0395

31
[ 638218-78-7 ]
C₂₅H₃₅NO₂ [ No CAS ]

Reference： [1]Chemical Communications,2016,vol. 52,p. 11056 - 11059

32
[ 638218-78-7 ]
C₂₂H₂₉NO [ No CAS ]

Reference： [1]Chemical Communications,2016,vol. 52,p. 11056 - 11059

33
[ 638218-78-7 ]
6-(2-hydroxypropan-2-yl)-N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)-2H-indazol-5-yl] pyridine-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2017/157792,2017,A1
[2]Patent: US2017/349570,2017,A1
[3]Patent: WO2017/207481,2017,A1

34
[ 638218-78-7 ]
[ 500874-32-8 ]
1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-2-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 80 - 95℃; for 18h;	General procedure: (0225) General procedure for the preparation of pyridyl pyrazolopyrimidinones. N,N'- Dimethylethylenediamine (2.0 equiv.) was added to a solution of the relevant pyrazolopyrimidine (1.0 equiv.), the relevant bromopyridine (1.3 equiv.), copper iodide (1.0 equiv.) and K2C03 (1.4 equiv.) in 1,4-dioxane (2 mL/mmol) at 80 C. The resultant suspension was heated at 95 C for 18 h, over which time a color change of orange to dark green occurred. The reaction mixture was cooled to RT and diluted with NH4OH (10 ml) before being extracted with EtOAc (2 x 10 mL/mmol). The combined organic extracts were washed with brine (10 mL/mmol), dried (MgS04) and evaporated to dryness before the crude material was purified via chromatography on silica. Synthesis of 1 -(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-2-methyl-6-(methylthio)-1,2- dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one. 1-(6-(2-Hydroxypropan-2-yl)pyridin-2-yl)-2-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (0.177 g, 0.90 mmol), <strong>[638218-78-7]2-(6-bromopyridin-2-yl)propan-2-ol</strong> (0.253 g, 1.17 mmol), copper iodide (0.172 g, 0.90 mmol), K2C03 (0.174 g, 1.26 mmol) and L/,L/'-dimethylethylenediamine (194 pL, 1.80 mmol) were reacted in 1,4-dioxane (2 mL) according to the described general procedure. Purification on silica gel (19:1 DCM:MeOH) gave the desired compound as a white solid (0.215 g, 0.65 mmol, 72%). Rf 0.34 (19:1 DCM:MeOH); M.p. 155-158 C; IR (cm 1) 3432, 2973, 2928, 1683, 1604, 1562; 1H NMR (400 MHz, DMSO-d6) 1.46 (6H, s, C(CH3)2), 2.56 (3H, s, SCH3), 3.49 (3H, s, N2-CH3), 5.35 (1 H, s, OH), 7.67 (1 H, dapp, J = 7.7 Hz, H-5'), 7.79 (1 H, dapp, J = 8.2 Hz, H-3'), 8.06 (1 H, ddapp, J = 8.2, 7.7 Hz, H-4'), 9.00 (1 H, s, H-4); 13C NMR (100 MHz, DMSO- e) 14.4 (SCH3), 30.9 (C(CH3)2), 32.8 (N2-CH3), 72.8 (C(CH3)2), 104.8, 1 16.6, 1 17.5, 139.7, 146.8, 154.7, 158.3, 160.4, 168.4, 175.9; MS [M + H]+ m/z 332.6.

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694
[2]Patent: WO2019/169065,2019,A2 .Location in patent: Page/Page column 43-44

35
[ 638218-78-7 ]
[ 500874-32-8 ]
1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-2-methyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

36
[ 638218-78-7 ]
2-(4-methoxybenzyl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]
1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-2-(4-methoxybenzyl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

37
[ 638218-78-7 ]
2-allyl-6-amino-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

38
[ 638218-78-7 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-methoxybenzyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

39
[ 638218-78-7 ]
2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(phenylamino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

40
[ 638218-78-7 ]
2-allyl-6-((3-(dimethylamino)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

41
[ 638218-78-7 ]
2-allyl-6-((3-((dimethylamino)methyl)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

42
[ 638218-78-7 ]
3-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N,N-dimethylbenzamide [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

43
[ 638218-78-7 ]
2-allyl-6-((4-(2-(dimethylamino)ethyl)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

44
[ 638218-78-7 ]
2-allyl-6-((4-(2-(dimethylamino)ethoxy)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

45
[ 638218-78-7 ]
1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-2-(4-methoxybenzyl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

46
[ 638218-78-7 ]
6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(6-(prop-1-en-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

47
[ 638218-78-7 ]
1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1681 - 1694

48
[ 638218-78-7 ]
[ 15243-33-1 ]
C₁₇H₉BrNO₁₀Ru₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.9%	In tetrahydrofuran;Reflux; Inert atmosphere;	Add 2-(6-bromopyridinyl)-isopropanol to a 100 mL flask(0.20 g, 0.94 mmol) and Ru3(CO)12 (0.30 g, 0.47 mmol),Then, 30 mL of anhydrous tetrahydrofuran was added, and the mixture was heated under reflux for 24 hours under nitrogen. After the reaction was completed, it was cooled to room temperature, and the solvent was removed under reduced pressure.Neutral alumina was passed through the column to finally obtain a yellow solid of 0.30 g.The yield was 81.9%.

Reference： [1]New Journal of Chemistry,2018,vol. 42,p. 15472 - 15478
[2]Patent: CN108794541,2018,A .Location in patent: Paragraph 0039; 0040; 0041

49
[ 638218-78-7 ]
[ 955368-90-8 ]
2-allyl-6-((4-(dimethylamino)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3Hpyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: WO2017/75629,2017,A2

50
[ 638218-78-7 ]
[ 1192356-15-2 ]

Reference： [1]Patent: WO2009/131814,2009,A2

51
[ 638218-78-7 ]
[ 1192356-18-5 ]

Reference： [1]Patent: WO2009/131814,2009,A2

52
[ 638218-78-7 ]
[ 1192356-16-3 ]

Reference： [1]Patent: WO2009/131814,2009,A2

53
[ 638218-78-7 ]
[ 1192356-17-4 ]

Reference： [1]Patent: WO2009/131814,2009,A2

54
[ 638218-78-7 ]
N-[6-chloro-2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-yl]-6-(2-hydroxypropan-2-yl)pyridine-2-carboxamide [ No CAS ]

Reference： [1]Patent: US2019/71432,2019,A1

55
[ 638218-78-7 ]
[ 955368-93-1 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-(methylsulfanyl)-2-(propan-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31.2%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 95℃; for 12h;	Into a lOO-mL round-bottom flask, was placed <strong>[638218-78-7]2-(6-bromopyridin-2-yl)propan-2-ol</strong> (5.78 g, 26.750 mmol, 3.00 equiv), 6- (methylsulfanyl)-2-(propan-2-yl)-lH,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one (2 g, 8.917 mmol, 1 equiv), methyl[2-(methylamino)ethyl]amine (0.79 g, 8.917 mmol, 1 equiv), Cul (1.70 g, 8.917 mmol, 1 equiv), K2C03 (3.70 g, 26.752 mmol, 3 equiv), Dioxane (30 mL). The resulting solution was stirred for 12 hr at 95C. The solids were filtered out. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0: 1-2: 1). This resulted in 1 g (31.20%) of l-[6-(2-hydroxypropan-2- yl)pyridin-2-yl]-6-(methylsulfanyl)-2-(propan-2-yl)-lH,2H,3H-pyrazolo[3,4-d]pyrimidin-3- one as a white solid. LC-MS-5: [M+l]=360, 1H-NMR-5: (300MHz, CDCl3, ppm): d 8.89(s, 1H), 7.96-7.9l(m, 1H), 7.72-7.70(m, 1H), 7.74-7.42(m, 1H), 4.35-4.30(m, 1H), 2.57(s, 3H), l.64(s, 6H), l.54-l.52(m, 6H).
55 mg	With copper(l) iodide; potassium carbonate; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 80℃; for 12h;	Step-6: Synthesis of 1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-2-isopropyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one To a stirred solution of 2-isopropyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (0.26 g, 1.16 mmol, 1.0 eq) and <strong>[638218-78-7]2-(6-bromo-2-pyridyl)propan-2-ol</strong> (0.3 g, 1.39 mmol, 1.20 eq) in dioxane (10 mL) were added CuI (0.044 g, 0.23 mmol, 1.0 eq), K2CO3 (0.32 g, 2.32 mmol, 2 eq) and DIPEA (0.041 g, 0.46 mmol, 0.4 eq) and stirred at 80 C. 12 h. After completion of reaction, solvent was removed under reduced pressure; residue was diluted with water and extracted with ethyl acetate (10 mL*3). Combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography to afford 1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-2-isopropyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (55 mg, 13+%) as yellow oil.

Reference： [1]Patent: WO2019/165204,2019,A1 .Location in patent: Page/Page column 47
[2]Patent: US2019/106427,2019,A1 .Location in patent: Paragraph 0315; 0326; 0327; 0400-0402

56
[ 638218-78-7 ]
2-(cyclopropylmethyl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]
2-(cyclopropylmethyl)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31.84%	With copper(l) iodide; potassium carbonate; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 90℃; for 12h;	Step-5: Synthesis of 2-(cyclopropylmethyl)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one To a stirred solution of 2-(cyclopropylmethyl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (1.0 g, 4.23 mmol, 1.0 eq) and <strong>[638218-78-7]2-(6-bromo-2-pyridyl)propan-2-ol</strong> (1.09 g, 5.07 mmol, 1.20 eq) in dioxane (10 mL) were added K2CO3 (1.16 g, 8.46 mmol, 2.0 eq) and the resulting mixture was purged with nitrogen for 10 min followed by addition of CuI (161 mg, 0.84 mmol, 0.2 eq), and DIPEA (149 mg, 1.69 mmol, 0.4 eq) and again purged with nitrogen for 10 min, stirred at 90 C. for 12 h. After completion of reaction, the reaction mixture was diluted with water and extracted with EtOAc (50 mL*2). Combined organic layer was washed with water (50 mL) and brine solution (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography to afford the desired compound, 2-(cyclopropylmethyl)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (500 mg, 31.84%) as an off white solid.

Reference： [1]Patent: US2019/106427,2019,A1 .Location in patent: Paragraph 0333; 0342; 0343

57
[ 638218-78-7 ]
1-[6-(2-fluoropropan-2-yl)pyridin-2-yl]-6-(methylsulfanyl)-2-(propan-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: US2019/106427,2019,A1
[2]Patent: WO2019/165204,2019,A1

58
[ 638218-78-7 ]
2-cyclopropyl-1-(6-(2-fluoropropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-on [ No CAS ]

Reference： [1]Patent: US2019/106427,2019,A1
[2]Patent: WO2019/165204,2019,A1

59
[ 638218-78-7 ]
[ 955370-02-2 ]
2-ethyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40.24%	With copper(l) iodide; potassium carbonate; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 90℃; for 12h;	Step-5: Synthesis of 2-ethyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one To a stirred solution of 2-ethyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (250 mg, 1.189 mmol, 1.0 eq) and <strong>[638218-78-7]2-(6-bromo-2-pyridyl)propan-2-ol</strong> (308 mg, 1.426 mmol, 1.20 eq) in dioxane (10 mL) were added K2CO3 (328 mg, 2.378 mmol, 2.0 eq) and the resulting mixture was purged with nitrogen for 10 min followed by addition of CuI (45 mg, 0.237 mmol, 0.2 eq), and DIPEA (42 mg, 0.475 mmol, 0.4 eq) and again purged with nitrogen for 10 min, stirred at 90 C. for 12 h. After completion of reaction, the reaction mixture was diluted with water and extracted with EtOAc (50 mL*2). Combined organic layer was washed with water (50 mL) brine solution (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography to afford the desired compound, 2-ethyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (170 mg, 40.24%) as off white viscous.

Reference： [1]Patent: US2019/106427,2019,A1 .Location in patent: Paragraph 0289; 0298; 0299

60
[ 638218-78-7 ]
2-(cyclopropylmethyl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]
2-cyclopropyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37.5%	With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; for 12h;	Step-5: Synthesis of 2-cyclopropyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one To a stirred solution of 2-(cyclopropylmethyl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (1.0 g, 4.49 mmol, 1.0 eq) and <strong>[638218-78-7]2-(6-bromo-2-pyridyl)propan-2-ol</strong> (1.16 g, 5.39 mmol, 1.20 eq) in (10 mL) of dioxane were added Potassium carbonate (1.24 g, 8.98 mmol, 2.0 eq) and the resulting mixture was purged with nitrogen for 10 min, followed by addition of copper iodide (171 mg, 0.89 mmol, 0.2 eq), and N,N'-dimethylethylenediamine (DMEDA) (158 mg, 1.79 mmol, 0.4 eq) and again purged with nitrogen for 10 min, stirred at 90 C. for overnight. After completion of reaction, the reaction mixture was diluted with water and extracted with EtOAc (50 mL*2). The combined organic layers were washed with water (50 mL), brine solution (50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography to afford the desired compound, 2-cyclopropyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (600 mg, 37.50%) as an off white solid.

Reference： [1]Patent: US2019/106427,2019,A1 .Location in patent: Paragraph 0422; 0431; 0432

61
[ 638218-78-7 ]
6-(methylthio)-2-propyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-(methylsulfanyl)-2-(propan-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With copper(l) iodide; potassium carbonate; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 80℃; for 12h;	Step-2: Synthesis of 1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-2-propyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one To a stirred solution of 6-(methylthio)-2-propyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (1.318 g, 5.88 mmol, 1.0 eq) and <strong>[638218-78-7]2-(6-bromo-2-pyridyl)propan-2-ol</strong> (1.525 g, 7.06 mmol, 1.20 eq) in dioxane (50 mL) were added CuI (224 mg, 1.17 mmol, 0.2 eq), K2CO3 (1.626 g, 11.76 mmol, 2 eq) and DIPEA (2.35 g, 2.35 mmol, 0.4 eq) and stirred at 80 C. 12 h. The reaction was monitored by LCMS. After completion of reaction, solvent was removed under reduced pressure; residue was diluted with water and extracted with ethyl acetate (30 mL*3). The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography (elution: 0-10% MeOH in CH2Cl2) to afford 1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-2-isopropyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (1.035 g, 49%) as yellow solid.

Reference： [1]Patent: US2019/106427,2019,A1 .Location in patent: Paragraph 0365; 0368; 0369

62
[ 638218-78-7 ]
1-[6-(2-fluoropropan-2-yl)pyridin-2-yl]-6-methanesulfinyl-2-(propan-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

63
[ 638218-78-7 ]
1-(6-(2-fluoropropan-2-yl)pyridin-2-yl)-2-isopropyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

64
[ 638218-78-7 ]
2-cyclopropyl-1-[6-(2-fluoropropan-2-yl)pyridin-2-yl]-6-[[4-(4-methylpiperazin-1-yl)phenyl]amino]-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

65
[ 638218-78-7 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-[[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]amino]-2-(prop-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

66
[ 638218-78-7 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-methanesulfinyl-2-(prop-2-en-1-yl)-1H,2H,3H-pyrazolo [3,4-d] pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

67
[ 638218-78-7 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-1-yl)-6-([1-[1-(propan-2-yl)piperidin-4-yl]-1H-pyrazol-4-yl]amino)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

68
[ 638218-78-7 ]
6-[(1-[4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-1H- pyrazol-4-yl)amino]-1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

69
[ 638218-78-7 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-1-yl)-6-([1-[1'-(propan-2-yl)-[1,4-bipiperidin]-4-yl]-1H-pyrazol-4-yl]amino)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

70
[ 638218-78-7 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-1-yl)-6-[[1-(propan-2-yl)-1H-pyrazol-4-yl]amino]-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

71
[ 638218-78-7 ]
6-[(1-cyclopentyl-1H-pyrazol-4-yl)amino]-1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one hydrochloride: [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

72
[ 638218-78-7 ]
6-[(1-cyclohexyl-1H-pyrazol-4-yl)amino]-1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-2-(prop-2-en-1-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

73
[ 638218-78-7 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-methanesulfinyl-2-(propan-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

74
[ 638218-78-7 ]
1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-[[4-(4-methylpiperazin-1-yl)phenyl]amino]-2-(propan-2-yl)-1H,2H,3H-pyrazolo[3,4-d]pyrimidin-3-one [ No CAS ]

Reference： [1]Patent: WO2019/165204,2019,A1

75
[ 26218-75-7 ]
[ 75-16-1 ]
[ 638218-78-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	Into a 2000-mL 4-necked round- bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 6-bromopyridine-2-carboxylate (43.2 g, 199.97 mmol, 1.00 equiv), tetrahydrofuran (700 mL). This was followed by the addition of bromo(methyl)magnesium (150 mL) dropwise with stirring at 0C. The resulting solution was stirred overnight at room temperature. The mixture was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 35 g (81%) of 2-(6-bromopyridin-2-yl)propan-2- ol as yellow oil.

Reference： [1]Patent: WO2019/165204,2019,A1 .Location in patent: Page/Page column 32

76
[ 638218-78-7 ]
2-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]
2-(6-(2-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)propan-2-ol [ No CAS ]

Reference： [1]Patent: CN110467615,2019,A

77
[ 638218-78-7 ]
2-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]
2-(6-(2-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50.9%	With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In 1,4-dioxane; at 95℃;Inert atmosphere;	Compound (Int-2-a) (2.2 g, 12.82 mmol) was dissolved in 1,4-dioxane (60 mL),Then add compound (Int-1-b) (3.05 g, 14.11 mmol),Cuprous iodide (1.22g, 6.41mmol),Potassium carbonate (2.66g, 19.24mmol) and (1S, 2S) -N, N'-dimethylcyclohexane-1,2-diamine (910.47mg, 6.41mmol),Reaction at 95 C overnight under nitrogen.The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3/1).The title compound (2 g, yield: 50.9%) was obtained.

Reference： [1]Patent: CN110467615,2019,A .Location in patent: Paragraph 0184-0185; 0189-0191

78
[ 67-51-6 ]
[ 638218-78-7 ]
2-(6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With copper(l) iodide; potassium carbonate In dimethyl sulfoxide at 110℃; for 6h; Inert atmosphere;	1 Synthesis of 2-(6-(3,5-Dimethyl-1H-pyrazol-1-yl)pyridin-2-yl)propan-2-ol (L4H) Load 6-BrPyC(CH3)2OH (1.08g, 5.0mmol), 3,5-dimethylpyrazole (1.16g, 5.0mmol), CuI (0.19g, 1mmol), K2CO3 (2.48 g, 15mmol) and DMSO (40mL) under N2 atmosphere. The mixture was stirred at 110°C for 12 h. After cooling to room temperature, 10 mL brine was added, and the resulting solution was extracted with dichloromethane (3×15 mL). The combined organic phase was dried with anhydrous Na2SO4 and filtered. After the solvent was removed in vacuo, the residue was purified by Al2O3 column chromatography (petroleum ether and ethyl acetate as eluents) to give L4H as a yellow oil (0.82 g, 71%).
	With copper(l) iodide; potassium carbonate In dimethyl sulfoxide at 110℃; for 6h; Inert atmosphere;	2.3. Synthesis of ligand L1H General procedure: A 100 mL reaction vessel was charged with 2-(6-bromopyridin-2-yl)propan-2-ol (1.08 g, 5.0 mmol), pyrazole (0.34 g, 5.0 mmol), CuI(0.19 g, 1.0 mmol), K2CO3 (2.48 g, 15 mmol) and DMSO (40 mL) under aN2 atmosphere. The mixture was stirred at 110 C for 6 h. After coolingto ambient temperature, 10 mL of brine was added and the resultingsolution was extracted with dichloromethane (3 × 15 mL). The combinedorganic phases were dried over anhydrous Na2SO4 and filtered.After removal of the solvent under vacuum, the residue was subjected topurification by neutral Al2O3 column chromatography (petroleum ether:ethyl acetate 15~40: 1, v/v) to afford L1H as a yellow oil (0.86 g, 85%).

Reference： [1]Current Patent Assignee: HEBEI NORMAL UNIVERSITY - CN112209916, 2021, A Location in patent: Paragraph 0040; 0050-0052
[2]Huo, Shuaicong; Kong, Siqi; Zeng, Guang; Feng, Qi; Hao, Zhiqiang; Han, Zhangang; Lin, Jin; Lu, Guo-Liang [Molecular catalysis, 2021, vol. 514]

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P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 638218-78-7 ] {[proInfo.proName]}

Quality Control of [ 638218-78-7 ]

Related Doc. of [ 638218-78-7 ]

Product Details of [ 638218-78-7 ]

Calculated chemistry of [ 638218-78-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 638218-78-7 ]

Application In Synthesis of [ 638218-78-7 ]

[ 638218-78-7 ] Synthesis Path-Upstream 1~6

[ 638218-78-7 ] Synthesis Path-Downstream 1~78

Related Functional Groups of [ 638218-78-7 ]

Bromides

Alcohols

Related Parent Nucleus of [ 638218-78-7 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 638218-78-7 ]

Related Parent Nucleus of
[ 638218-78-7 ]