[ CAS No. 101990-70-9 ] {[proInfo.proName]}

Name: 101990-70-9|5-(Chloromethyl)-2-methoxypyridine|95%
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SKU: A296992
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Quality Control of [ 101990-70-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 101990-70-9 ]

CAS No. :	101990-70-9	MDL No. :	MFCD10697570
Formula :	C₇H₈ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YNCJGPOTUFPVTB-UHFFFAOYSA-N
M.W :	157.60	Pubchem ID :	13752891
Synonyms :

Calculated chemistry of [ 101990-70-9 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.29
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	40.49
TPSA :	22.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.16 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.05
Log Po/w (XLOGP3) :	1.55
Log Po/w (WLOGP) :	1.68
Log Po/w (MLOGP) :	1.23
Log Po/w (SILICOS-IT) :	2.29
Consensus Log Po/w :	1.76

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.11
Solubility :	1.24 mg/ml ; 0.00784 mol/l
Class :	Soluble
Log S (Ali) :	-1.62
Solubility :	3.74 mg/ml ; 0.0238 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.16
Solubility :	0.109 mg/ml ; 0.000692 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.65

Safety of [ 101990-70-9 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P260-P264-P270-P280-P301+P312+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P362+P364-P405-P501	UN#:	3261
Hazard Statements:	H302+H312-H314	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 101990-70-9 ]

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

Upstream synthesis route of [ 101990-70-9 ]
Downstream synthetic route of [ 101990-70-9 ]

[ 101990-70-9 ] Synthesis Path-Upstream 1~5

1
[ 58584-63-7 ]
[ 101990-70-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With methanesulfonyl chloride; triethylamine In dichloromethane at 20℃; for 1 h; Inert atmosphere	j0259j To a stirred solution of (6-methoxypyridin-3-yl)methanol (75 mg, 0.54 mmol) in dichloromethane (2 mL) under nitrogen was added triethylamine (0.083 mL, 0.59 mmol) followed by methanesulfonyl chloride (0.044 mL, 0.57 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between dichioromethane (10 mL) and water (10 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the title compound 88 mg (quantitative yield) as a yellow oil.Tr(METCR1278) = 1.63 mm, (ESj (M-J-H) 1581160.
96%	With thionyl chloride In toluene at 20℃; for 1 h; Inert atmosphere	Under nitrogen, thionyl chloride (2.05mL, 3.34g, 28.09mmol) was added to a solution of (6-methoxy-pyridin-3-yl)methanol 2c (3.56g, 25.60mmol) in dry toluene (10.6mL) and the solution was stirred at room temperature for 1h before NaOH (2M, 10mL) was added. The solution was stirred for 10min before extraction with toluene (2×20mL). The organic extracts were washed water and concentrated under reduced pressure to give the product 24 (3.85g, 24.52mmol, 96percent yield) as a yellow oil; δ_H (400MHz, CDCl₃) 8.15 (1H, d, J 2.7, H₃), 7.62 (1H, dd, J 8.5, 2.7, H₂), 6.75 (1H, d, J 8.5, H₁), 4.55 (2H, s, H₄), 3.94 (3H, s, CH₃); δ_C (101MHz, CDCl₃) 163.6, 146.7, 139.2, 126.1, 111.3, 53.6, 43.3.
91.4%	With thionyl chloride In N,N-dimethyl-formamide at 0℃; for 2.3 h;	Preparation Example 2 Synthesis of 5-chloromethyl-2-methoxypyridine (3) To a solution of (6-methoxypyridin-3-yl)methanol (2) (537.8 g, 3.86 mol) obtained in Preparation Example 1 in dimethylformamide (1.6 L) was added dropwise thionyl chloride (310 mL, 4.25 mol) over a period of 1.3 hours while cooling in an ice bath under a nitrogen atmosphere. After stirring for 1 hour while cooling in an ice bath, toluene (5.4 L) and a 2N aqueous solution of sodium hydroxide (5.4 L) were added successively to the reaction mixture at 23° C. or below. The reaction mixture was stirred for about 10 minutes and then the aqueous layer was separated, the organic layer was washed with water (2.7 L). The organic layer was concentrated under reduced pressure to dryness, and then toluene (1.0 L) was added to the residue and azeotropic distillation was carried out to give 618.8 g of the title compound as a pale yellow oil (content 556.3 g, yield 91.4percent). ¹H-NMR (CDCl₃) δ (ppm): 8.15 (1H, d, J=2.4 Hz), 7.63 (1H, dd, J=2.4 Hz, 8.4 Hz), 6.75 (1H, d, J=8.4 Hz), 4.55 (2H, s), 3.94 (3H, s)

88%	Stage #1: With thionyl chloride In dichloromethane at 20℃; Stage #2: With water; sodium hydrogencarbonate In dichloromethane	Step 2: 5-Chloromethyl-2-methoxy-pyridine Thionyl chloride (9.2 mL, 126 mmol) was added dropwise to a solution of (6-methoxy-pyridin-3-yl)-methanol (1.00 g, 7.2 mmol) in dichloromethane (38 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was washed with saturated aqueous sodium hydrogen carbonate (this resulted in bubbling). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2*100 mL). The combined organic layers were washed with brine (150 mL), dried (sodium sulfate), filtered, and evaporated to give 5-chloromethyl-2-methoxy-pyridine (995 mg, 88percent) as a clear oil.
88%	Stage #1: With thionyl chloride In dichloromethane at 0 - 20℃; for 2 h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water	Step B: Preparation of 5-(Chloromethyl)-2-methoxypyridine. Thionyl chloride (0.23 ml, 3.23 mmol) was added to a solution of (6-methoxypyridin-3-yl)methanol (1.10 g, 8.41 mmol) in DCM at 0° C. and the reaction mixture was stirred for 2 h at room temperature. After completion of reaction, the volatiles were evaporated and the reaction mixture was basified with saturated sodium bicarbonate solution. The compound was extracted with DCM (2.x.30 ml) and washed with brine (15 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and dried to afford 1.1 g (88percent) of 5-(chloromethyl)-2-methoxypyridine as a colorless liquid. This compound was directly taken to the next step.
0.58 g	With thionyl chloride In dichloromethane at 0 - 30℃; for 2 h; Inert atmosphere	To a solution of 2-methoxy-5-hydroxymethylpyridine (0.71 g, 0.005mole) in DCM (5 mL) at 0 °C under N₂, was added thionyl chloride (0.7 mL, 0.009 mole) drop wise. The reaction mixture was warmed to RT and stirred for 2 hours. The reaction mixture was diluted with DCM (50 mL) and treated with saturated aqueous sodium bicarbonate (10 mL). Organic layer was washed with water (20 mL), brine solution (20 mL), dried over Na₂SC>4 and concentrated under vacuum to obtain the title compound. Yield: 0.58 g; ^lH - NMR (CDC1₃, 400 MHz) δ ppm: 3.94 (s, 3H), 4.55 (s, 2H), 6.75 - 6.77 (d, J = 8.5 Hz, 1H), 7.61 - 7.64 (dd, J = 2.2, 8.5 Hz, 1H), 8.14 (s, 1H); Mass (m/z): 158.0 - 160.0 (M+H) ⁺.

Reference： [1] Patent: WO2016/33445, 2016, A1, . Location in patent: Paragraph 0259
[2] Tetrahedron, 2014, vol. 70, # 40, p. 7207 - 7220
[3] Patent: US2006/235225, 2006, A1, . Location in patent: Page/Page column 4
[4] Patent: US2007/49632, 2007, A1, . Location in patent: Page/Page column 38
[5] Patent: US2011/224225, 2011, A1, . Location in patent: Page/Page column 23
[6] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4636 - 4645
[7] Patent: US2010/179321, 2010, A1, . Location in patent: Page/Page column 4
[8] Organic Letters, 2010, vol. 12, # 21, p. 5004 - 5007
[9] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4721 - 4734
[10] Journal of Organic Chemistry, 2011, vol. 76, # 20, p. 8336 - 8346
[11] Patent: WO2011/159554, 2011, A1, . Location in patent: Page/Page column 31
[12] Patent: WO2011/159553, 2011, A1, . Location in patent: Page/Page column 28
[13] Patent: WO2011/84368, 2011, A1, . Location in patent: Page/Page column 55
[14] Organic Letters, 2017, vol. 19, # 14, p. 3895 - 3898
[15] Patent: WO2018/42362, 2018, A1, . Location in patent: Page/Page column 41

2
[ 65873-72-5 ]
[ 101990-70-9 ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: With sodium tetrahydroborate In methanol at 0℃; for 1 h; Stage #2: With ammonium chloride In methanol; water	Reference Example 28Step 15-chloromethyl-2-methoxypyridine (Compound A80)2-methoxy-5-pyridinecarbaldehyde (137 mg, 0.999 mmol) was dissolved in methanol (5.0mL). To this, sodium borohydride (37.8 mg, 0.999 mmol) was added at 0°C, and the mixture was stirred for 1 hour. To the reaction mixture, a saturated ammonium chloride aqueous solution was added, and extraction with ethyl acetate was performed twice. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was dissolved in dichloromethane (5.0 mL). To this, triethylamine (278 μL, 2.00 mmol) and methanesulfonyl chloride (116 μL, 1.50 mmol) were added, and the mixture was stirred overnight. After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, extraction with chloroform was performed twice. The organic layer was dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography to give Compound A80 (116 mg, yield: 74percent). ESI-MS: m/z 158 [M + H]⁺; ¹H NMR (CDCl₃)δ(ppm): 3.94 (s, 3H), 4.55 (s, 2H), 6.76 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 2.4, 8.4 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H).

Reference： [1] Patent: EP2308880, 2011, A1, . Location in patent: Page/Page column 56
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4721 - 4734

3
[ 26218-80-4 ]
[ 101990-70-9 ]

Reference： [1] Patent: US2011/224225, 2011, A1,
[2] Journal of Organic Chemistry, 2011, vol. 76, # 20, p. 8336 - 8346
[3] Patent: WO2011/159554, 2011, A1,
[4] Patent: WO2011/159553, 2011, A1,
[5] Patent: WO2011/84368, 2011, A1,
[6] Organic Letters, 2017, vol. 19, # 14, p. 3895 - 3898
[7] Tetrahedron, 2014, vol. 70, # 40, p. 7207 - 7220

4
[ 66572-55-2 ]
[ 101990-70-9 ]

Reference： [1] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4636 - 4645
[2] Tetrahedron, 2014, vol. 70, # 40, p. 7207 - 7220

5
[ 5006-66-6 ]
[ 101990-70-9 ]

Reference： [1] Journal of Organic Chemistry, 1991, vol. 56, # 15, p. 4636 - 4645

[ 101990-70-9 ] Synthesis Path-Downstream 1~81

1
[ 506-59-2 ]
[ 101990-70-9 ]
[ 162475-78-7 ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 4636 - 4645

2
(6-methoxypyridin-3-yl)methyl methanesulfonate [ No CAS ]
[ 101990-70-9 ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 4636 - 4645

3
[ 5006-66-6 ]
[ 101990-70-9 ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 4636 - 4645

4
[ 66572-55-2 ]
[ 101990-70-9 ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 4636 - 4645
[2]Tetrahedron,2014,vol. 70,p. 7207 - 7220

5
[ 58584-63-7 ]
[ 101990-70-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With methanesulfonyl chloride; triethylamine; In dichloromethane; at 20℃; for 1h;Inert atmosphere;	j0259j To a stirred solution of <strong>[58584-63-7](6-methoxypyridin-3-yl)methanol</strong> (75 mg, 0.54 mmol) in dichloromethane (2 mL) under nitrogen was added triethylamine (0.083 mL, 0.59 mmol) followed by methanesulfonyl chloride (0.044 mL, 0.57 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between dichioromethane (10 mL) and water (10 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the title compound 88 mg (quantitative yield) as a yellow oil.Tr(METCR1278) = 1.63 mm, (ESj (M-J-H) 1581160.
96%	With thionyl chloride; In toluene; at 20℃; for 1h;Inert atmosphere;	Under nitrogen, thionyl chloride (2.05mL, 3.34g, 28.09mmol) was added to a solution of (6-methoxy-pyridin-3-yl)methanol 2c (3.56g, 25.60mmol) in dry toluene (10.6mL) and the solution was stirred at room temperature for 1h before NaOH (2M, 10mL) was added. The solution was stirred for 10min before extraction with toluene (2×20mL). The organic extracts were washed water and concentrated under reduced pressure to give the product 24 (3.85g, 24.52mmol, 96% yield) as a yellow oil; deltaH (400MHz, CDCl3) 8.15 (1H, d, J 2.7, H3), 7.62 (1H, dd, J 8.5, 2.7, H2), 6.75 (1H, d, J 8.5, H1), 4.55 (2H, s, H4), 3.94 (3H, s, CH3); deltaC (101MHz, CDCl3) 163.6, 146.7, 139.2, 126.1, 111.3, 53.6, 43.3.
91.4%	With thionyl chloride; In N,N-dimethyl-formamide; at 0℃; for 2.3h;	Preparation Example 2 Synthesis of 5-chloromethyl-2-methoxypyridine (3) To a solution of <strong>[58584-63-7](6-methoxypyridin-3-yl)methanol</strong> (2) (537.8 g, 3.86 mol) obtained in Preparation Example 1 in dimethylformamide (1.6 L) was added dropwise thionyl chloride (310 mL, 4.25 mol) over a period of 1.3 hours while cooling in an ice bath under a nitrogen atmosphere. After stirring for 1 hour while cooling in an ice bath, toluene (5.4 L) and a 2N aqueous solution of sodium hydroxide (5.4 L) were added successively to the reaction mixture at 23 C. or below. The reaction mixture was stirred for about 10 minutes and then the aqueous layer was separated, the organic layer was washed with water (2.7 L). The organic layer was concentrated under reduced pressure to dryness, and then toluene (1.0 L) was added to the residue and azeotropic distillation was carried out to give 618.8 g of the title compound as a pale yellow oil (content 556.3 g, yield 91.4%). 1H-NMR (CDCl3) delta (ppm): 8.15 (1H, d, J=2.4 Hz), 7.63 (1H, dd, J=2.4 Hz, 8.4 Hz), 6.75 (1H, d, J=8.4 Hz), 4.55 (2H, s), 3.94 (3H, s)

88%		Step 2: 5-Chloromethyl-2-methoxy-pyridine Thionyl chloride (9.2 mL, 126 mmol) was added dropwise to a solution of <strong>[58584-63-7](6-methoxy-pyridin-3-yl)-methanol</strong> (1.00 g, 7.2 mmol) in dichloromethane (38 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was washed with saturated aqueous sodium hydrogen carbonate (this resulted in bubbling). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2*100 mL). The combined organic layers were washed with brine (150 mL), dried (sodium sulfate), filtered, and evaporated to give 5-chloromethyl-2-methoxy-pyridine (995 mg, 88%) as a clear oil.
88%		Step B: Preparation of 5-(Chloromethyl)-2-methoxypyridine. Thionyl chloride (0.23 ml, 3.23 mmol) was added to a solution of <strong>[58584-63-7](6-methoxypyridin-3-yl)methanol</strong> (1.10 g, 8.41 mmol) in DCM at 0 C. and the reaction mixture was stirred for 2 h at room temperature. After completion of reaction, the volatiles were evaporated and the reaction mixture was basified with saturated sodium bicarbonate solution. The compound was extracted with DCM (2×30 ml) and washed with brine (15 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and dried to afford 1.1 g (88%) of 5-(chloromethyl)-2-methoxypyridine as a colorless liquid. This compound was directly taken to the next step.
	With thionyl chloride;N,N-dimethyl-formamide; for 2.3h;Inert atmosphere; Cooling with ice;	Preparation Example 2; Synthesis of 5-chloromethyl-2-methoxypyridine (3) To a solution of <strong>[58584-63-7](6-methoxypyridin-3-yl)methanol</strong> (2) (537.8 g, 3.86 mol) obtained in Preparation Example 1 in dimethylformamide (1.6 L), thionyl chloride (310 mL, 4.25 mol) was added dropwise under a nitrogen atmosphere over a period of 1.3 hours while cooling in an ice bath. After stirring for 1 hour while cooling in an ice bath, toluene (5.4 L) and a 2 N aqueous solution of sodium hydroxide (5.4 L) were added successively to the reaction mixture at 23 C. or below. The reaction mixture was stirred for about 10 minutes. Then, the aqueous layer was separated, and the organic layer was washed with water (2.7 L). The organic layer was concentrated under reduced pressure to dryness. Toluene (1.0 L) was added to the residue, followed by azeotropic distillation to give 618.8 g of the title compound as a pale yellow oil (content 556.3 g, yield 91.4%).1H-NMR (CDCl3) delta (ppm): 8.15 (1H, d, J=2.4 Hz), 7.63 (1H, dd, J=2.4 Hz, 8.4 Hz), 6.75 (1H, d, J=8.4 Hz), 4.55 (2H, s), 3.94 (3H, s)
	With thionyl chloride; In dichloromethane; at 0℃; for 15h;	To a solution of the above compound (1.00 g, 7.19 mrnol) in 25 mL of dichloromethane at 0 C was added thionyl chloride (1.57 mL, 21.6 mmol). After 15 h, the mixture was concentrated in vacuo to provide 5-(chloromethyl)-2-methoxypyridine.
	With thionyl chloride; In dichloromethane; at 0℃; for 15h;	To a solution of the above compound (1.00 g, 7,19 mmoi) in 25 mL of dichloromethane at 0 C was added thionyl chloride (1.57 mL, 21.6 mmoi). After 15 h, the mixture was concentrated in vacuo to provide 5-(chloromethyl)-2-methoxypyridine.
	With thionyl chloride; In dichloromethane; at 40℃; for 1.5h;	To a solution of the above compound (0.40 g, 2.9 mmol) in 11.5 mL CH2CI2 was added thionyl chloride (0.41 g, 3.5 mmol). The reaction mixture was heated to 40 C for 1.5 h and cool to room temperature. Saturated sodium bicarbonate was added until the reaction mixture was pH basic. The reaction mixture was diluted with CH2CI2, and the layers were separated. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated to afford 5- (chloromethyl)-2-methoxypyridine (K3) that gave a mass ion (ES+) of 158.1 for M+H+.
0.58 g	With thionyl chloride; In dichloromethane; at 0 - 30℃; for 2h;Inert atmosphere;	To a solution of <strong>[58584-63-7]2-methoxy-5-hydroxymethylpyridine</strong> (0.71 g, 0.005mole) in DCM (5 mL) at 0 C under N2, was added thionyl chloride (0.7 mL, 0.009 mole) drop wise. The reaction mixture was warmed to RT and stirred for 2 hours. The reaction mixture was diluted with DCM (50 mL) and treated with saturated aqueous sodium bicarbonate (10 mL). Organic layer was washed with water (20 mL), brine solution (20 mL), dried over Na2SC>4 and concentrated under vacuum to obtain the title compound. Yield: 0.58 g; lH - NMR (CDC13, 400 MHz) delta ppm: 3.94 (s, 3H), 4.55 (s, 2H), 6.75 - 6.77 (d, J = 8.5 Hz, 1H), 7.61 - 7.64 (dd, J = 2.2, 8.5 Hz, 1H), 8.14 (s, 1H); Mass (m/z): 158.0 - 160.0 (M+H) +.

Reference： [1]Patent: WO2016/33445,2016,A1 .Location in patent: Paragraph 0259
[2]Tetrahedron,2014,vol. 70,p. 7207 - 7220
[3]Patent: US2006/235225,2006,A1 .Location in patent: Page/Page column 4
[4]Patent: US2007/49632,2007,A1 .Location in patent: Page/Page column 38
[5]Patent: US2011/224225,2011,A1 .Location in patent: Page/Page column 23
[6]Journal of Medicinal Chemistry,2019,vol. 62,p. 7210 - 7232
[7]Journal of Organic Chemistry,1991,vol. 56,p. 4636 - 4645
[8]Patent: US2010/179321,2010,A1 .Location in patent: Page/Page column 4
[9]Organic Letters,2010,vol. 12,p. 5004 - 5007
[10]Journal of Medicinal Chemistry,2011,vol. 54,p. 4721 - 4734
[11]Journal of Organic Chemistry,2011,vol. 76,p. 8336 - 8346
[12]Patent: WO2011/159554,2011,A1 .Location in patent: Page/Page column 31
[13]Patent: WO2011/159553,2011,A1 .Location in patent: Page/Page column 28
[14]Patent: WO2011/84368,2011,A1 .Location in patent: Page/Page column 55
[15]Organic Letters,2017,vol. 19,p. 3895 - 3898
[16]Patent: WO2018/42362,2018,A1 .Location in patent: Page/Page column 41

6
[ 101990-70-9 ]
5-Dimethylaminomethyl-3H-pyridin-2-one [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 4636 - 4645

7
[ 321974-06-5 ]
[ 101990-70-9 ]
[ 910911-68-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; toluene; at -15 - -5℃; for 2.7h;	A solution of furan-2-yl-morpholin-4-yl-acetonitrile (5) (818.0 g, content 737.9 g, 3.84 mol) obtained in Preparation Example 3 and <strong>[101990-70-9]5-chloromethyl-2-methoxypyridine</strong> (3) (611.8 g, content 550.0 g, 3.49 mol) obtained in Preparation Example 2 in toluene (4.4 L) was cooled to -15 C., and then a solution of potassium-t-butoxide (508.9 g, 4.54 mol) in tetrahydrofuran (4.4 L) was added at -5 C. or below over a period of 72 minutes, and the reaction mixture was further stirred for 1.5 hours. Next, to the reaction mixture was added a 6N aqueous solution of hydrochloric acid (4.4 L), followed by heating to 70 C. and stirring for 2 hours. The reaction mixture was cooled to 5 C. and a 3N aqueous solution of sodium hydroxide (3.0 L) was added at 20 C. or below. The organic layer was separated, the aqueous layer was re-extracted with toluene (6.0 L), and the organic layers were combined and concentrated under reduced pressure to dryness to give 828.5 g of the title compound as a brown oil (content 647.8 g, yield 85.5%). 2-Furan-2-yl-3-(6-methoxy-pyridin-3-yl)-2-morpholin-4-yl-propionate (6) 1H-NMR (CDCl3) delta (ppm): 7.71 (1H, d, J=2.4 Hz), 7.48 (1H, d, J=1.6 Hz), 7.11 (1H, dd, J=2.4 Hz, 8.4 Hz), 6.56 (1H, d, J=8.4 Hz), 6.27 (2H, m), 3.87 (3H, s), 3.80 (4H, m), 3.38 (1H, d, J=13.2), 3.26 (1H, d, J=13.2), 2.78-2.81 (2H, m), 2.45-2.78 (2H, m) 1-Furan-2-yl-2-(6-methoxy-pyridin-3-yl)-ethanone (7) 1H-NMR (CDCl3) delta (ppm): 8.08 (1H, d, J=2.4 Hz), 7.61 (1H, d, J=1.7 Hz), 7.53 (1H, dd, J=2.4 Hz, 8.2 Hz), 7.24 (1H, d, J=3.6 Hz), 6.71 (1H, d, J=8.2 Hz), 6.55 (1H, dd, J=1.7 Hz, 3.6 Hz), 4.05 (2H, s), 3.91 (3H, s)
	With potassium tert-butylate; In tetrahydrofuran; toluene; at -15 - -5℃;	Preparation Example 4; Synthesis of 1-furan-2-yl-2-(6-methoxy-pyridin-3-yl)-ethanone (7) A solution of furan-2-yl-morpholin-4-yl-acetonitrile (5) (818.0 g, content 737.9 g, 3.84 mol) obtained in Preparation Example 3 and <strong>[101990-70-9]5-chloromethyl-2-methoxypyridine</strong> (3) (611.8 g, content 550.0 g, 3.49 mol) obtained in Preparation Example 2 in toluene (4.4 L) was cooled to -15 C. A solution of potassium-t-butoxide (508.9 g, 4.54 mol) in tetrahydrofuran (4.4 L) was added thereto at -5 C. or below over a period of 72 minutes, and the reaction mixture was further stirred for 1.5 hours.Next, to the reaction mixture, a 6 N aqueous solution of hydrochloric acid (4.4 L) was added, followed by heating to 70 C. and stirring for 2 hours. The reaction mixture was cooled to 5 C., and a 3 N aqueous solution of sodium hydroxide (3.0 L) was added at 20 C. or below. The organic layer was separated, and the aqueous layer was re-extracted with toluene (6.0 L). The organic layers were combined and concentrated under reduced pressure to dryness to give 828.5 g of the title compound as a brown oil (content 647.8 g, yield 85.5%).2-Furan-2-yl-3-(6-methoxy-pyridin-3-yl)-2-morpholin-4-yl-propionate (6)1H-NMR (CDCl3) delta (ppm): 7.71 (1H, d, J=2.4 Hz), 7.48 (1H, d, J=1.6 Hz), 7.11 (1H, dd, J=2.4 Hz, 8.4 Hz), 6.56 (1H, d, J=8.4 Hz), 6.27 (2H, m), 3.87 (3H, s), 3.80 (4H, m), 3.38 (1H, d, J=13.2), 3.26 (1H, d, J=13.2), 2.78-2.81 (2H, m), 2.45-2.78 (2H, m)1-Furan-2-yl-2-(6-methoxy-pyridin-3-yl)-ethanone (7)1H-NMR (CDCl3) delta (ppm): 8.08 (1H, d, J=2.4 Hz), 7.61 (1H, d, J=1.7 Hz), 7.53 (1H, dd, J=2.4 Hz, 8.2 Hz), 7.24 (1H, d, J=3.6 Hz), 6.71 (1H, d, J=8.2 Hz), 6.55 (1H, dd, 1=1.7 Hz, 3.6 Hz), 4.05 (2H, s), 3.91 (3H, s)

Reference： [1]Patent: US2006/235225,2006,A1 .Location in patent: Page/Page column 4-5
[2]Patent: US2010/179321,2010,A1 .Location in patent: Page/Page column 4-5

8
[ 405103-04-0 ]
[ 101990-70-9 ]
5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 138 By the reaction and treatment in the same manner as in Example 132 using <strong>[101990-70-9]5-chloromethyl-2-methoxypyridine</strong> (0.63 g) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.87 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(6-methoxypyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.23 g) was obtained. 1H-NMR(CDCl3)delta: 1.29(6H,d,J=7.0Hz), 1.40-1.60(1H,m), 1. 80-2.15(3H,m), 2.65-2.80(2H,m), 3.00-3.20(1H,m), 3.60-3.75(1H,m), 3.92(3H,s), 4.81(1H,d,J=14.3Hz), 4.90(1H,d,J=14.3Hz), 5.04(2H,s), 6.50-6.80(3H,m), 7.00-7.50(7H,m), 7.60-7.70(1H,m), 7.87(1H,d,J=2.2Hz), 8.02(1H,s), 8.32(1H,d,J=2.3Hz).

Reference： [1]Patent: EP1318140,2003,A1

9
[ 928053-53-6 ]
[ 101990-70-9 ]
[ 928052-71-5 ]

Yield	Reaction Conditions	Operation in experiment
9%	With tetra-(n-butyl)ammonium iodide; In N,N-dimethyl-formamide; at 100℃; for 48h;	Example 114 (4R,7S)-2-(2,4-Difluoro-phenyl)-1-(6-methoxy-pyridin-3-ylmethyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 480 mg, 1.6 mmol), <strong>[101990-70-9]5-chloromethyl-2-methoxy-pyridine</strong> (Intermediate 50; 995 mg, 6.3 mmol) and tetrabutylammonium iodide (583 mg, 1.6 mmol) in dimethylformamide (63 mL) was heated at 100 C. for 48 h. The solvent was evaporated and dichloromethane (150 mL) was added. The solution was washed with saturated aqueous sodium thiosulfate (200 mL), saturated aqueous sodium hydrogen carbonate (200 mL) and brine (200 mL), dried (sodium sulfate), filtered, evaporated and purified using a Biotage 40M system, eluding with 20-50% ethyl acetate/hexanes and then 2% methanol/dichloromethane, to give a crude product that contains some tetrabutylammonium iodide. This material was taken up in dichloromethane (50 mL) and washed with 5% dimethylformamide in water (2100 mL) and water (5100 mL). The organic phase was dried (sodium sulfate), filtered and evaporated to give (4R,7S)-2-(2,4-difluoro-phenyl)-1-(6-methoxy-pyridin-3-ylmethyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (59 mg, 9%). APCI(+)-MS (M+H) 426.

Reference： [1]Patent: US2007/49632,2007,A1 .Location in patent: Page/Page column 93

10
potassium cyanide [ No CAS ]
[ 101990-70-9 ]
[ 154403-85-7 ]

Reference： [1]Organic Letters,2010,vol. 12,p. 5004 - 5007
[2]Journal of Organic Chemistry,2011,vol. 76,p. 8336 - 8346

11
[ 1268515-68-9 ]
[ 101990-70-9 ]
[ 1268515-74-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 5-(chloromethyl)-2-methoxy pyridine (0.158 g, 0.999 mmol) in 0.5 mL of THF under an atmosphere of nitrogen, was added Rieke Zn (1.3 mL, 1.0 mmol, 0.76 M in THF). The mixture was heated to reflux for 18 h, then cooled to 0 0C. A solution of 6-bromo-3-[(3R,4S)-3- hydroxytetrahydro-2H-pyran-4-yl]benzo[h]ambda;]quinazolin-4(5H)-one (see Example 1, 0.125 g, 0.333 mmol) in 0.5 mL of THF was added, followed by bis(tri-rerr-butylphosphine)palladium(0) (5.1 mg, 0.010 mmol). The mixture was warmed to rt. After 2 h, the reaction was diluted with dichloromethane and water, and the aqueous layer was extracted with additionaldichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0- 3% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 418.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) delta 8.94-8.92 (m, IH), 8.27 (s, IH), 8.03 (s, IH), 7.91-7.87 (m, 2H), 7.65-7.61 (m, 2H), 7.29 (dd, J = 2.4 Hz, 8.5 Hz, 1 H), 6.58 (d, J= 8.5 Hz, IH), 4.86-4.79 (m, IH), 4.28 (s, 2H), 4.23-4.06 (m, 3H), 3.85 (s, 3H), 3.58-3.53 (m, IH), 3.31 (t, J= 10.3 Hz, IH), 2.96 (d, J= 6.7 Hz, IH), 2.30- 2.20 (m, IH), 2.01-1.97 (m, IH).

Reference： [1]Patent: WO2011/25851,2011,A1 .Location in patent: Page/Page column 49-50

12
[ 65873-72-5 ]
[ 101990-70-9 ]

Yield	Reaction Conditions	Operation in experiment
74%		Reference Example 28Step 15-chloromethyl-2-methoxypyridine (Compound A80)2-methoxy-5-pyridinecarbaldehyde (137 mg, 0.999 mmol) was dissolved in methanol (5.0mL). To this, sodium borohydride (37.8 mg, 0.999 mmol) was added at 0C, and the mixture was stirred for 1 hour. To the reaction mixture, a saturated ammonium chloride aqueous solution was added, and extraction with ethyl acetate was performed twice. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was dissolved in dichloromethane (5.0 mL). To this, triethylamine (278 muL, 2.00 mmol) and methanesulfonyl chloride (116 muL, 1.50 mmol) were added, and the mixture was stirred overnight. After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, extraction with chloroform was performed twice. The organic layer was dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography to give Compound A80 (116 mg, yield: 74%). ESI-MS: m/z 158 [M + H]+; 1H NMR (CDCl3)delta(ppm): 3.94 (s, 3H), 4.55 (s, 2H), 6.76 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 2.4, 8.4 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H).

Reference： [1]Patent: EP2308880,2011,A1 .Location in patent: Page/Page column 56
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 4721 - 4734

13
[ 101990-70-9 ]
C₁₁H₁₈NO₅P [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 4721 - 4734

14
[ 101990-70-9 ]
C₁₀H₁₆NO₅P [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 4721 - 4734

15
[ 101990-70-9 ]
(1-hydroxy-2-oxo-1,2-dihydropyridin-5-yl)methylphosphonic acid disodium salt [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 4721 - 4734

16
[ 101990-70-9 ]
[ 122-52-1 ]
C₁₁H₁₈NO₄P [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 4721 - 4734

17
[ 101990-70-9 ]
[ 1333468-60-2 ]

Reference： [1]Patent: US2011/224225,2011,A1

18
[ 26218-80-4 ]
[ 101990-70-9 ]

Reference： [1]Patent: US2011/224225,2011,A1
[2]Journal of Organic Chemistry,2011,vol. 76,p. 8336 - 8346
[3]Patent: WO2011/159554,2011,A1
[4]Patent: WO2011/159553,2011,A1
[5]Patent: WO2011/84368,2011,A1
[6]Organic Letters,2017,vol. 19,p. 3895 - 3898
[7]Tetrahedron,2014,vol. 70,p. 7207 - 7220
[8]Journal of Medicinal Chemistry,2019,vol. 62,p. 7210 - 7232

19
[ 773837-37-9 ]
[ 101990-70-9 ]
[ 154403-85-7 ]

Yield	Reaction Conditions	Operation in experiment
63.8%	In dimethyl sulfoxide; at 20℃; for 18h;	Step C: Preparation of 2-(6-Methoxypyridin-3-yl)acetonitrile. Sodium cyanide (1.25 g, 25.4 mmol) was added to a solution of <strong>[101990-70-9]5-(chloromethyl)-2-methoxypyridine</strong> (1.00 g, 6.34 mmol) in DMSO (10 ml) and stirred for 18 h at room temperature. After completion of reaction, the reaction mixture was diluted with brine and the compound was extracted with DCM (3×35 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. The crude compound was purified by column chromatography using 100-200 silica gel, 10% ethyl acetate in petroleum ether as eluent to afford 0.6 g (63.8%) of 2-(6-methoxypyridin-3-yl)acetonitrile as white color solid.

Reference： [1]Patent: US2011/224225,2011,A1 .Location in patent: Page/Page column 23

20
[ 101990-70-9 ]
[ 1046834-24-5 ]