638218-78-7|2-(6-Bromopyridin-2-yl)propan-2-ol| Ambeed

Structure of 638218-78-7

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Quality Control of [ 638218-78-7 ] Purity: 97% SDS Specification

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Product Details of [ 638218-78-7 ]

CAS No. :	638218-78-7
Formula :	C₈H₁₀BrNO
M.W :	216.08
SMILES Code :	CC(C)(O)C1=NC(Br)=CC=C1
MDL No. :	MFCD16657880
InChI Key :	OXSDDDKLMCHNHF-UHFFFAOYSA-N
Pubchem ID :	22714301

Safety of [ 638218-78-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 638218-78-7 ] Show Less

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 ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	33.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.8
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.62
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.96
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.29
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.17
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.77

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.54
Solubility	0.626 mg/ml ; 0.0029 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.93
Solubility	2.55 mg/ml ; 0.0118 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.13
Solubility	0.159 mg/ml ; 0.000738 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.47 cm/s

Druglikeness

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

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.96

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.

Downstream synthetic route of [ 638218-78-7 ]

[ 638218-78-7 ] Synthesis Path-Downstream 1~35

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.

References: [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).

References: [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.

References: [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.

References: [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.

References: [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] +

References: [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%).

References: [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).

References: [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 ]

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

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

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

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

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

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

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

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

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

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

References: [1]Patent: US2013/178478,2013,A1 .

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

References: [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]+.

References: [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 ]