[ CAS No. 135124-71-9 ] {[proInfo.proName]}

Name: 135124-71-9|5-(Hydroxymethyl)nicotinonitrile|97%
Brand: Ambeed
SKU: A116541
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Quality Control of [ 135124-71-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 135124-71-9 ]

SDS Specification

Alternatived Products of [ 135124-71-9 ]

Product Details of [ 135124-71-9 ]

CAS No. :	135124-71-9	MDL No. :	MFCD07367899
Formula :	C₇H₆N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MNMDVGJZONSKMO-UHFFFAOYSA-N
M.W :	134.14	Pubchem ID :	22416540
Synonyms :

Calculated chemistry of [ 135124-71-9 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	35.08
TPSA :	56.91 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.35 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.13
Log Po/w (XLOGP3) :	-0.32
Log Po/w (WLOGP) :	0.29
Log Po/w (MLOGP) :	-0.75
Log Po/w (SILICOS-IT) :	1.15
Consensus Log Po/w :	0.3

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.85
Solubility :	19.0 mg/ml ; 0.142 mol/l
Class :	Very soluble
Log S (Ali) :	-0.41
Solubility :	51.7 mg/ml ; 0.385 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.91
Solubility :	1.66 mg/ml ; 0.0124 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.46

Safety of [ 135124-71-9 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	1759
Hazard Statements:	H314	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 135124-71-9 ]

* 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 [ 135124-71-9 ]
Downstream synthetic route of [ 135124-71-9 ]

[ 135124-71-9 ] Synthesis Path-Upstream 1~8

1
[ 135124-71-9 ]
[ 70416-53-4 ]

Yield	Reaction Conditions	Operation in experiment
55%	With manganese(IV) oxide In dichloromethane at 60℃; for 98 h;	d) 5-Cyano-pyridine-3-carbaldehyde A black suspension of (5-cyano-pyridin-3-yl)-methanol (0.070 g, 0.52 mmol), anhydrous CH₂Cl₂ (1.04 mL) and manganese oxide (0.181 g, 2.09 mmol) was heated to reflux and monitored by TLC. After 8 h, the reaction mixture was cooled to room temperature and additional manganese oxide (0.095 g, 1.1 mmol) was added to the reaction flask. The reaction mixture was then heated to reflux. After 18 h, the reaction was still not complete by TLC and additional manganese oxide (0.097 g, 1.1 mmol) was added to the reaction flask. After heating at 60° C. for 72 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), passed through celite and washed with additional EtOAc (50 mL). The organic filtrate was dried over MgSO₄, filtered through sintered glass and concentrated to yield 0.064 g (93percent) of a white solid. It was purified by column chromatography (elution with EtOAC:hexanes, 1:3) and yielded 0.038 g (55percent) of the title compound as a white solid. ¹H NMR (CDCl₃): 10.17 (s, 1H), 9.28 (d, J=1.9 Hz, 1H), 9.11 (d, J=2.2 Hz, 1H), 8.45 (dd, J=2.2, 1.9 Hz, 1H).

Reference： [1] Patent: US2006/104998, 2006, A1, . Location in patent: Page/Page column 16

2
[ 37669-64-0 ]
[ 135124-71-9 ]

Yield	Reaction Conditions	Operation in experiment
51%	Stage #1: at 160℃; for 20 h; Stage #2: With ammonia; ammonium chloride In pyridine; water at 20℃; for 2 h;	19.2 5-(hydroxymethyl)pyridine-3-carbonitrile A mixture of 4.2 g (22.34 mmol) of (5-bromopyridin-3-yl)methanol and 5 g (55.84 mmol) of copper cyanide in 22 mL of pyridine is heated for 20 hours in a sealed tube at 160° C. After cooling to room temperature, the medium is taken up in 10 mL of concentrated aqueous ammonia and 30 mL of saturated NH₄Cl solution and then stirred for 2 hours. The medium is then extracted with 200 mL of a DCM/iPrOH mixture (85/15), dried over Na₂SO₄ and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 98/2 DCM/MeOH mixture. 2.13 g of 5-(hydroxymethyl)pyridine-3-carbonitrile are obtained in the form of a white solid. Yield=51percent ¹H NMR, CDCl₃, 400 MHz, δ (ppm): 8.9 (d, 2H); 8.0 (s, 1H); 4.9 (s, 2H); 2.3 (bs, 1H)

Reference： [1] Patent: US2011/294788, 2011, A1, . Location in patent: Page/Page column 24

3
[ 557-21-1 ]
[ 37669-64-0 ]
[ 135124-71-9 ]

Yield	Reaction Conditions	Operation in experiment
35%	With 1,1'-bis-(diphenylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium⁽⁰⁾ In N,N-dimethyl-formamide at 170℃; for 4 h; Microwave irradiation	To a stirred solution of (5-bromopyridin-3-yl)methanol (3.1 g, 16.57 mmol) in DMF (50 mL) at room temperature were added Zn(CN)₂(2 g, 16.57 mmol), dppf (460 mg, 0.828 mmol) and Pd₂(dba)₃(307 mg, 0.335 mmol). The reaction mass was heated to 170° C. under microwave for 4 h. The reaction mass was filtered through celite pad, the filtrate was concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel column chromatography (100-200) using CH₂Cl₂in MeOH (90:10) as eluent and obtained 5-(hydroxymethyl)nicotinonitrile (800 mg, yield: 35percent LC/MS: 88percent) as a brown solid. NMR (CDCl₃, 400 MHz): δ 8.81 (dd, J=9.6 Hz, 6.0 Hz, 2H), 8.03-8.02 (m, 1H), 4.83 (s, 2H), 2.11 (bs, 1H).

Reference： [1] Patent: US2018/65917, 2018, A1, . Location in patent: Paragraph 0377

4
[ 106726-82-3 ]
[ 135124-71-9 ]

Yield	Reaction Conditions	Operation in experiment
11%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at -78℃; for 1.05 h; Stage #2: With sodium hydroxide; water In tetrahydrofuran	Preparation 67; 5-Hydroxymethyl-nicotinonitrile; Add lithium aluminum hydride (l. OM in THF ; 1. 5mL, 1. 5mmol, 0. 5equiv) over a period of 3min to a solution of 5-cyano-nicotinic acid methyl ester (479mg, 2. 95mmol, lequiv) in anhydr THF (15mL) and cool to-78°C. After lh while still at-78°C, quench the reaction with H20 (60, uL), 5M aq NaOH (60pL), and more H20 (180μL). Filter the reaction mixture through paper. Rotary evaporate the filtrate (40°C) to give 369mg of material as a yellow solid. Transfer this material to a column of silica gel (130mm x 25mmdia. ) and elute (2percent MeOH/CH2Cl2) to yield 180mg of a mixture of ester, hemiacetal, and aldehyde as a yellow solid and 45mg (11percent) of 5-hydroxymethyl- nicotinonitrile as a yellow solid. MS (m/e) : 163.07 (M+1).

Reference： [1] Patent: WO2005/66126, 2005, A1, . Location in patent: Page/Page column 66-67

5
[ 37669-64-0 ]
[ 544-92-3 ]
[ 135124-71-9 ]

Yield	Reaction Conditions	Operation in experiment
24%	at 170℃; for 48 h;	c) (5-Cyano-pyridin-3-yl)-methanol A yellow solution of (5-bromo-pyridin-3-yl)-methanol (1.30 g, 6.91 mmol), anhydrous DMF (27.7 mL) and copper (1) cyanide (0.92 g, 10 mmol) was heated at 170° C. for 36 h. The reaction mixture was cooled to room temperature and additional copper (I) cyanide (0.058 g, 0.65 mmol) was added to the yellow solution. The reaction flask was then heated at 170° C. for an additional 12 h. The yellow solution was cooled to room temperature, quenched with NaHCO₃ (120 mL), and extracted with EtOAc (3*100 mL). The combined organic extracts were dried over MgSO₄, filtered through sintered glass and concentrated to yield 0.502 g (54percent) of a brown oil residue. The residue was purified by column chromatography (elution with EtOAC:hexanes, 1:1) and yielded 0.225 g (24percent) of the title compound as a white solid. ¹H NMR (CDCl₃): 8.80 (dd, J=2.20, 1.92 Hz, 2H), 8.03 (m, J=2.20, 1.92 Hz, 1H), 4.83 (d, J=4.7 Hz, 2H).

Reference： [1] Chemistry - A European Journal, 1997, vol. 3, # 3, p. 410 - 416
[2] Patent: US2006/104998, 2006, A1, . Location in patent: Page/Page column 16

6
[ 37669-64-0 ]
[ 135124-71-9 ]

Reference： [1] Patent: US5002949, 1991, A,

7
[ 20826-04-4 ]
[ 135124-71-9 ]

Reference： [1] Patent: US2011/294788, 2011, A1,

8
[ 29681-44-5 ]
[ 135124-71-9 ]

Reference： [1] Patent: US2018/65917, 2018, A1,

[ 135124-71-9 ] Synthesis Path-Downstream 1~78

1
[ 37669-64-0 ]
[ 544-92-3 ]
[ 135124-71-9 ]

Yield	Reaction Conditions	Operation in experiment
24%	In N,N-dimethyl-formamide; at 170℃; for 48h;	c) (5-Cyano-pyridin-3-yl)-methanol A yellow solution of (5-bromo-pyridin-3-yl)-methanol (1.30 g, 6.91 mmol), anhydrous DMF (27.7 mL) and copper (1) cyanide (0.92 g, 10 mmol) was heated at 170 C. for 36 h. The reaction mixture was cooled to room temperature and additional copper (I) cyanide (0.058 g, 0.65 mmol) was added to the yellow solution. The reaction flask was then heated at 170 C. for an additional 12 h. The yellow solution was cooled to room temperature, quenched with NaHCO3 (120 mL), and extracted with EtOAc (3*100 mL). The combined organic extracts were dried over MgSO4, filtered through sintered glass and concentrated to yield 0.502 g (54%) of a brown oil residue. The residue was purified by column chromatography (elution with EtOAC:hexanes, 1:1) and yielded 0.225 g (24%) of the title compound as a white solid. 1H NMR (CDCl3): 8.80 (dd, J=2.20, 1.92 Hz, 2H), 8.03 (m, J=2.20, 1.92 Hz, 1H), 4.83 (d, J=4.7 Hz, 2H).

Reference： [1]Chemistry - A European Journal,1997,vol. 3,p. 410 - 416
[2]Patent: US2006/104998,2006,A1 .Location in patent: Page/Page column 16

2
[ 135124-71-9 ]
5-(chloromethyl)pyridine-3-carbonitrile hydrogen chloride salt [ No CAS ]

Reference： [1]Chemistry - A European Journal,1997,vol. 3,p. 410 - 416

3
[ 135124-71-9 ]
5-Iodomethyl-nicotinonitrile; hydriodide [ No CAS ]

Reference： [1]Chemistry - A European Journal,1997,vol. 3,p. 410 - 416

4
[ 135124-71-9 ]
5-(chloromethyl)pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.4%	With thionyl chloride; In dichloromethane; at 20℃; for 3h;	Compound I-2-3 (2.0 g, 14.91 mmol) was added to a 50 mL single-mouth bottle.Add thionyl chloride (6.5mL),After dichloromethane (20 mL) was reacted at room temperature for 3 h,The reaction was completed by TLC, the reaction system was spun dry, and the oil pump was dried to obtain compound I-2-4.The yield was 1.8 g, and the yield was 79.4%.
73%	With hydrogenchloride; thionyl chloride; In 1,4-dioxane; dichloromethane; at 60℃; for 3h;	19.3 5-(chloromethyl)pyridine-3-carbonitrile To 0.2 g (1.49 mmol) of <strong>[135124-71-9]5-(hydroxymethyl)pyridine-3-carbonitrile</strong> in 2 mL of DCM is added 1 mL (4 mmol) of HCl 4N in dioxane. The mixture is concentrated under reduced pressure and then added to 0.65 mL (8.95 mmol) of thionyl chloride followed by heating for 3 hours at 60 C. After cooling to room temperature, the medium is taken up in 20 mL of toluene, and the precipitate formed is filtered off and then treated with 30 mL of DCM and 30 mL of saturated NaHCO3 solution. The organic phase is separated out and dried over Na2SO4 and then concentrated under reduced pressure. 161 mg of 5-(chloromethyl)pyridine-3-carbonitrile are obtained in the form of an oil. Yield=73% 1H NMR, 1H NMR, CDCl3, 400 MHz, delta (ppm): 8.9 (d, 2H); 8.0 (s, 1H); 3.5 (s, 2H)
35%	With hydrogenchloride; thionyl chloride; In 1,4-dioxane; dichloromethane; water; at 60℃; for 3h;	To a stirred solution of <strong>[135124-71-9]5-(hydroxymethyl)nicotinonitrile</strong> (3 g, 0.022 mol) in DCM (30 mL), 4M HC1 in l,4-dioxane (5 mL) was added and concentrated the mixture under vacuum. To the resulting residue, thionyl chloride (20 mL) was added and stirred the mixture at 60 C for 3h. After completion, the reaction was cooled to room temperature and diluted with toluene (150 mL) and filtered off the solid that precipitated out. The filtrate was diluted with DCM (200 mL) and washed with saturated sodium bicarbonate solution (200 mL). The organic layer was dried over sodium sulphate and concentrated to obtain 5-(chloromethyl)nicotinonitrile (Yield: 1.2 g, 35%) as yellow solid. 1H NMR (400 MHz, DMSO-d6, ppm): d 4.86 (s, 2H), 8.42 (s, 1H), 8.94 (d, / = 2.0 Hz, 1H), 8.99 (d, J = 2.0 Hz, 1H). Scheme -9: Synthesis of 3-(hydroxymethyl)-[l,l'-biphenyl]-2-carbonitrile

32%	With hydrogenchloride; thionyl chloride; In 1,4-dioxane; dichloromethane; at 60℃; for 3h;	IIb-5-2 (1.50 g, 11.3 mmol, 1.0 equivalent weight) was dissolved in DCM (50 mL), and 4N of dioxane hydrochloride(10mL) was added. After concentrating the mixture, SOCl2 (10mL) was added, heated to 60 C and stirred for3h. The end of the reaction was detected by TLC test. The temperature was cooled to room temperature. The reactionsolution was concentrated. The crude product was separated and purified by column chromatography, to obtain 0.55gsolid IIb-5 (the yield was 32%).1H-NMR (400 MHz, CDCl3) delta ppm 8.85 (s, 1H), 8.83 (s, 1H), 8.04 (s, 1H), 4.63 (s, 2H).
9.6%	With thionyl chloride; In dichloromethane; for 0.333333h;	Preparation 68; 5-Chloromethyl-nicotinonitrile; Add thionyl chloride (1mL) to a solution of 5-hydroxymethyl-nicotinonitrile (45mg, 0. 34mmol, lequiv) in anhydr CH2C12 (1mL). After 20min, basify the reaction with satd aq NaHC03 (12 mL). Extract this mixture with Et2O (2x 5mL). Dry the combined organic layers (anhydr MgS04) and rotary evaporate (40C) to yield 4.9mg (9.6%) of 5-chloromethyl-nicotinonitrile as a yellow film. MS (m/z): 152.
1.7 g	With hydrogenchloride; thionyl chloride; In 1,4-dioxane; dichloromethane; at 60℃; for 3h;	To a solution of <strong>[135124-71-9]5-(hydroxymethyl)pyridine-3-carbonitrile</strong> (2 g, 14.91 mmol) in DCM (10 mL) was added hydrogen chloride in dioxane (4M, 5 mL) and concentrated. To the residue was added SOCl2(6.50 mL, 89.61 mmol) and stirred for 3 hr at 60 C. After cooling, toluene (200mL) was added and the mixture was filtered. The filtrate was adjusted to pH = 7 with sat. NaHCCh and extracted with DCM (3 x 50 mL). The organic phase was combined and dried over Na2S04and then concentrated under reduced pressure to give 5-(chloromethyl)pyridine-3- carbonitrile (l .7g, 74.72% yield) as a black solid.

Reference： [1]Patent: CN110092779,2019,A .Location in patent: Paragraph 0122; 0128-0130
[2]Patent: US2011/294788,2011,A1 .Location in patent: Page/Page column 24
[3]Patent: WO2019/175897,2019,A1 .Location in patent: Paragraph 00098
[4]Patent: EP3564237,2019,A1 .Location in patent: Paragraph 0074; 0075
[5]Patent: WO2005/66126,2005,A1 .Location in patent: Page/Page column 67
[6]Patent: WO2019/191624,2019,A1 .Location in patent: Page/Page column 78

5
[ 106726-82-3 ]
[ 135124-71-9 ]

Yield	Reaction Conditions	Operation in experiment
11%		Preparation 67; 5-Hydroxymethyl-nicotinonitrile; Add lithium aluminum hydride (l. OM in THF ; 1. 5mL, 1. 5mmol, 0. 5equiv) over a period of 3min to a solution of 5-cyano-nicotinic acid methyl ester (479mg, 2. 95mmol, lequiv) in anhydr THF (15mL) and cool to-78C. After lh while still at-78C, quench the reaction with H20 (60, uL), 5M aq NaOH (60pL), and more H20 (180muL). Filter the reaction mixture through paper. Rotary evaporate the filtrate (40C) to give 369mg of material as a yellow solid. Transfer this material to a column of silica gel (130mm x 25mmdia. ) and elute (2% MeOH/CH2Cl2) to yield 180mg of a mixture of ester, hemiacetal, and aldehyde as a yellow solid and 45mg (11%) of 5-hydroxymethyl- nicotinonitrile as a yellow solid. MS (m/e) : 163.07 (M+1).

Reference： [1]Patent: WO2005/66126,2005,A1 .Location in patent: Page/Page column 66-67

6
[ 135124-71-9 ]
[ 70416-53-4 ]

Yield	Reaction Conditions	Operation in experiment
55%	With manganese(IV) oxide; In dichloromethane; at 60℃; for 98h;	d) 5-Cyano-pyridine-3-carbaldehyde A black suspension of <strong>[135124-71-9](5-cyano-pyridin-3-yl)-methanol</strong> (0.070 g, 0.52 mmol), anhydrous CH2Cl2 (1.04 mL) and manganese oxide (0.181 g, 2.09 mmol) was heated to reflux and monitored by TLC. After 8 h, the reaction mixture was cooled to room temperature and additional manganese oxide (0.095 g, 1.1 mmol) was added to the reaction flask. The reaction mixture was then heated to reflux. After 18 h, the reaction was still not complete by TLC and additional manganese oxide (0.097 g, 1.1 mmol) was added to the reaction flask. After heating at 60 C. for 72 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), passed through celite and washed with additional EtOAc (50 mL). The organic filtrate was dried over MgSO4, filtered through sintered glass and concentrated to yield 0.064 g (93%) of a white solid. It was purified by column chromatography (elution with EtOAC:hexanes, 1:3) and yielded 0.038 g (55%) of the title compound as a white solid. 1H NMR (CDCl3): 10.17 (s, 1H), 9.28 (d, J=1.9 Hz, 1H), 9.11 (d, J=2.2 Hz, 1H), 8.45 (dd, J=2.2, 1.9 Hz, 1H).

Reference： [1]Patent: US2006/104998,2006,A1 .Location in patent: Page/Page column 16

Yield	Reaction Conditions	Operation in experiment
		The crude product was next dissolved in methanol (10 ml), and 2-(2-chlorophenyl)ethylamine (0.5 g, 3.2 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue obtained was purified by silica gel thin layer chromatography (Merck, No. 5744; developed with chloroform: methanol=10:1) and further crystallized from methanol/diethyl ether to give the title compound (0.12 g, 0.38 mmol) as colorless powder (yield starting from 3-cyano-5-hydroxymethylpyridine, 6%). IR (KBr) cm-1: 3350, 2200, 1580. FD-MS m/z 314 (M, C16 H15 N4 OCl). 1 H-NMR (90 MHz, CDCl3):delta (ppm) 8.72(1H, brs, H-6), 8.68(1H, brs, H-2), 7.99(1H, m, H-4), 7.4-7.2(4H, C6 H4 Cl), 6.82(1H, brs, NH), 4.78(2H, CH2 OH), 3.82(2H, m, NHCH2 CH2 C6 H4 Cl), 3.12(2H, t, NHCH2 CH2 C6 H4 Cl).

8
disodium hydrogenphosphate [ No CAS ]
NaH₂ PO₄ *2H₂ O [ No CAS ]
[ 420-04-2 ]
[ 135124-71-9 ]
propyl N-cyano-5-hydroxymethyl-3-pyridinecarboximidate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In propan-1-ol; acetonitrile;	Synthesis of N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-hydroxymethyl-3-pyridinecarboximidamide After <strong>[135124-71-9]3-cyano-5-hydroxymethylpyridine</strong> (0.79 g, 5.9 mmol) was dissolved in 1-propanol (30 ml) and hydrogen chloride gas was passed into the solution under ice-cooling for 30 minutes, the reactor was tight sealed for stirring the mixture at room temperature for 20 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was neutralized with a saturated aqueous sodium carbonate solution and extracted with chloroform (30 ml3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in acetonitrile (20 ml), and an aqueous solution (30 ml) of cyanamide (0.50 g, 11.9 mmol), Na2 HPO4 (0.84. g, 5.9 mmol) and NaH2 PO4 2H2 O (3.79 g, 23.7 mmol) was added to the solution. The mixture was stirred at room temperature for 10 hours. After the completion of the reaction, the mixture was extracted with chloroform (100 ml*3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl N-cyano-5-hydroxymethyl-3-pyridinecarboximidate.

Reference： [1]Patent: US5508293,1996,A

9
[ 37669-64-0 ]
[ 135124-71-9 ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine; chloroform; ethyl acetate;	EXAMPLE 2 5-[[(5-Bromo-3,6-dihydro-2-methyl-6-oxo-4-pyrimidinyl)amino]methyl]-3-pyridinecarbonitrile A stirred mixture of 5-hydroxymethyl-3-bromopyridine (8.50 g, 45.2 mmol) and copper (I) cyanide (10.1 g, 11.3 mmol) in pyridine (50 mL) was heated in a sealed pressure reaction vessel at 165 C. for 20 hours. After cooling to 23 C., the mixture was diluted with concentrated ammonium hydroxide (15 mL) and saturated aqueous ammonium chloride (60 mL), after stirring for 2 hours, the mixture was treated with chloroform (50 mL) and allowed to set for 72 hours. The aqueous layer was then extracted with chloroform. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 2 inch column, 4:1 EtOAc:hexane as eluant) followed by crystallization from diethyl ether to afford 5-hydroxymethyl-3-pyridinecarbonitrile (5.42 g, 40.4 mmol, 89% yield): Rf 0.49 (EtOAc); 1 H NMR (CDCl3, 200 MHz)delta8.80 (m, 2H), 8.03 (s, 1H), 4.83 (s, 2H).

Reference： [1]Patent: US5002949,1991,A

10
[ 135124-71-9 ]
5-aminomethyl-3-pyridinecarbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; thionyl chloride; diethyl ether;	A solution of <strong>[135124-71-9]5-hydroxymethyl-3-pyridinecarbonitrile</strong> (4.39 g, 32.7 mmol) in diethyl ether (250 mL) at 23 C. was saturated with gaseous HCl. Solvent was then removed in vacuo and the residue was suspended in thionyl chloride (14.3 mL, 196 mmol). The mixture was then heated at reflux for 2 hours, cooled to 23 C., and diluted with benzene (150 mL). The tan precipitate was isolated by filtration, transferred to a pressure reactor, and dissolved in methanol (30 mL). The methanolic solution was saturated with gaseous ammonia, sealed in the reaction vessel, and heated with stirring at 80 C. for 2.5 hours. After cooling to 23 C., the solution was again saturated with gaseous ammonia, sealed in the vessel, and heated at 80 C. for 5 hours. The reaction mixture was then concentrated in vacuo, and the residue was diluted with aqueous 0.5M NaOH (60 mL). The aqueous layer was extracted with chloroform (3*60 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to provide 5-aminomethyl-3-pyridinecarbonitrile (2.79 g, 21.0 mmol, 64% yield): Rf 0.19 (20% MeOH in EtOAc); 1 H NMR (DMSO-D6, 200 MHz)delta8.88 (dd, J=7,2 Hz, 1H), 8.79 (m, 1H), 8.25 (d, J=7 Hz), 3.75 (s, 2H), 2.8 (br s, 2H).

Reference： [1]Patent: US5002949,1991,A

11
[ 37669-64-0 ]
copper(l) cyanide [ No CAS ]
[ 135124-71-9 ]

Yield	Reaction Conditions	Operation in experiment
51%		19.2 5-(hydroxymethyl)pyridine-3-carbonitrile A mixture of 4.2 g (22.34 mmol) of (5-bromopyridin-3-yl)methanol and 5 g (55.84 mmol) of copper cyanide in 22 mL of pyridine is heated for 20 hours in a sealed tube at 160 C. After cooling to room temperature, the medium is taken up in 10 mL of concentrated aqueous ammonia and 30 mL of saturated NH4Cl solution and then stirred for 2 hours. The medium is then extracted with 200 mL of a DCM/iPrOH mixture (85/15), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 98/2 DCM/MeOH mixture. 2.13 g of 5-(hydroxymethyl)pyridine-3-carbonitrile are obtained in the form of a white solid. Yield=51% 1H NMR, CDCl3, 400 MHz, delta (ppm): 8.9 (d, 2H); 8.0 (s, 1H); 4.9 (s, 2H); 2.3 (bs, 1H)
42%	With pyridine; at 165℃; for 48h;Sealed tube;	The IIb-5-1 (5.00 g, 26.5 mmol, 1.0 equivalent weight) and CuCN (6.00 g, 65.0 mmol, 2.5 equivalent weight)were respectively weighted and dissolved in Py, and the mixture was disposed in a sealed tube and heated to 165C.After reacting for 48h, the end of the reaction was detected by TLC test. The reaction mixture was cooled to roomtemperature, diluted with aq. NH3 and aq. NH4Cl, and extracted with CHCl3 (150mL33). The organic phase was combinedand washed with water (100mL32), washed with saturated NaCl solution (100mL32), and dried with anhydrous Na2SO4.The organic phase was concentrated. The crude product was separated and purified by column chromatography, toobtain 1.50g solid IIb-5-2 (the yield was 42%).1H-NMR (400 MHz, CDCl3) delta ppm 8.81 (s, 1H), 8.80 (s, 1H), 8.03 (s, 1H), 4.83 (s, 2H).

Reference： [1]Patent: US2011/294788,2011,A1 .Location in patent: Page/Page column 24
[2]Patent: EP3564237,2019,A1 .Location in patent: Paragraph 0072; 0073

12
[ 135124-71-9 ]
[ 1233560-93-4 ]

Reference： [1]Patent: US2011/294788,2011,A1

13
[ 20826-04-4 ]
[ 135124-71-9 ]

Reference： [1]Patent: US2011/294788,2011,A1

14
(2,4-dichloro-3-iodophenyl)methanol [ No CAS ]
[ 131088-02-3 ]
[ 135124-71-9 ]
5-((4-chloro-5-((2,4-dichloro-3-iodobenzyl)oxy)-2-formylphenoxy)methyl)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%		Intermediate: 5-((4-chloro-5-((2,4-dichloro-3-iodobenzyl)oxy)-2-formylphenoxy)methyl)nicotinonitrile To a dry vial under N2 was added (2,4-dichloro-3-iodophenyl)methanol (150 mg, 0.495 mmol), 5-chloro-2,4-dihydroxybenzaldehyde (85 mg, 0.495 mmol), triphenylphosphine (136 mg, 0.519 mmol) and THF (2.5 mL). The reaction was flushed with argon, treated with DIAD (100 muL, 0.514 mmol), capped and stirred at room temp for 1 h. The reaction was charged with additional PPh3 (27 mg, 0.103 mmol) and DIAD (20 mulit, 0.103 mmol), flushed with argon, capped, and stirred at room temp for 18 h. The reaction was then treated with triphenylphosphine (170 mg, 0.648 mmol), <strong>[135124-71-9]5-(hydroxymethyl)nicotinitrile</strong> (83 mg, 0.619 mmol), TMAD (107.3 mg, 0.617 mmol), THF (4.5 mL). The mixture was flushed with N2, capped and heated at 65 C. in an oil bath for 2 h, followed by room temp for 18 h. The reaction was filtered and the filtrate was evaporated to dryness in vacuo. The residue was applied to the head of a 40 g Teledyne Isco Silica Flash Column, and the column was eluted with a linear gradient from 100% Hexanes to 100% EtOAc over 15 column volumes. The fractions containing the desired product were pooled and evaporated to dryness to give the title compound (91.5 mg, 32%). 1H NMR (500 MHz, CHLOROFORM-d) delta 10.31 (s, 1H), 8.93 (br d, J=6.4 Hz, 2H), 8.10 (s, 1H), 7.97 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.55 (s, 1H), 5.31 (s, 2H), 5.25 (s, 2H).

Reference： [1]Patent: US2017/107202,2017,A1 .Location in patent: Paragraph 1265; 1266; 1267

15
[ 29681-44-5 ]
[ 135124-71-9 ]

Reference： [1]Patent: US2018/65917,2018,A1

16
[ 557-21-1 ]
[ 37669-64-0 ]
[ 135124-71-9 ]

Yield	Reaction Conditions	Operation in experiment
35%	With 1,1'-bis-(diphenylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium(0); In N,N-dimethyl-formamide; at 170℃; for 4h;Microwave irradiation;	To a stirred solution of (5-bromopyridin-3-yl)methanol (3.1 g, 16.57 mmol) in DMF (50 mL) at room temperature were added Zn(CN)2 (2 g, 16.57 mmol), dppf (460 mg, 0.828 mmol) and Pd2(dba)3 (307 mg, 0.335 mmol). The reaction mass was heated to 170 C. under microwave for 4 h. The reaction mass was filtered through celite pad, the filtrate was concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel column chromatography (100-200) using CH2Cl2 in MeOH (90:10) as eluent and obtained 5-(hydroxymethyl)nicotinonitrile (800 mg, yield: 35% LC/MS: 88%) as a brown solid. NMR (CDCl3, 400 MHz): delta 8.81 (dd, J=9.6 Hz, 6.0 Hz, 2H), 8.03-8.02 (m, 1H), 4.83 (s, 2H), 2.11 (bs, 1H).
13.86%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; zinc; In 1,2-dimethoxyethane; at 130℃; for 15h;Inert atmosphere; Sealed tube;	A solution of (5-bromo-3-pyridyl)methanol (3 g, 15.96 mmol), Zn(CN)2(2.06 g, 17.55 mmol), DPPF (0.88g, 1.60 mmol), Zn (O. lg, 1.60 mmol) and Pd(dppf)Cl2(1.17 g, 1.60 mmol) in DME (40 mL) was degassed and purged with N2for 3 times. The mixture was stirred at 130 C for 15 hr under N2atmosphere. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography (silica gel, Petroleum ether : Ethyl acetate=40: l to 0: 1) to give 5-(hydroxymethyl)pyridine-3-carbonitrile (1 g, 13.86% yield, 89% purity) as a black solid that can be used directly for next step. MS: m/z found 135.1 [M+H]+; 1H NMR (400 MHz, CDCl3): d 8.72 (s, 2H), 7.95 (s, 1H), 4.75 (s, 2H).

Reference： [1]Patent: US2018/65917,2018,A1 .Location in patent: Paragraph 0377
[2]Patent: WO2019/191624,2019,A1 .Location in patent: Page/Page column 77; 78

17
[ 135124-71-9 ]
5-(chloromethyl)nicotinonitrile hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In dichloromethane; at 50℃; for 3h;	A solution of <strong>[135124-71-9]5-(hydroxymethyl)nicotinonitrile</strong> (1 g, 7.462 mmol) in dry CH2Cl2 (15 mL) was treated with thionyl chloride (1.7 g, 14.92 mmol) and stirred at 50 C. for 3 h. The reaction mixture was concentrated under reduced pressure to afford the 5-(chloromethyl)nicotinonitrile HCl (900 mg) as a white solid. This compound was used immediately for next step.

Reference： [1]Patent: US2018/65917,2018,A1 .Location in patent: Paragraph 0378

18
[ 135124-71-9 ]
5-(((5,6-dichloro-3-(hydroxymethyl)pyridin-2-yl)oxy)methyl)nicotinonitrile [ No CAS ]

Reference： [1]Patent: WO2018/195321,2018,A1

19
[ 135124-71-9 ]
5-(((5,6-dichloro-3-formylpyridin-2-yl)oxy)methyl)nicotinonitrile [ No CAS ]

Reference： [1]Patent: WO2018/195321,2018,A1

20
[ 135124-71-9 ]
5-(((6-((3-bromo-2-methylbenzyl)oxy)-5-chloro-3-formylpyridin-2-yl)oxy)methyl)nicotinonitrile [ No CAS ]

Reference： [1]Patent: WO2018/195321,2018,A1

21
[ 135124-71-9 ]
C₅₀H₄₈Cl₂N₈O₁₀*2C₂HF₃O₂ [ No CAS ]

Reference： [1]Patent: WO2018/195321,2018,A1

22
[ 135124-71-9 ]
C₅₀H₄₈Cl₂N₈O₁₀*2C₂HF₃O₂ [ No CAS ]

Reference： [1]Patent: WO2018/195321,2018,A1

23
[ 135124-71-9 ]
C₄₆H₄₄Cl₂N₈O₆*2C₂HF₃O₂ [ No CAS ]

Reference： [1]Patent: WO2018/195321,2018,A1

24
[ 135124-71-9 ]
5,5’-((((((2,2’-dimethyl-[1,1‘-biphenyl]-3,3’-diyl)bis(methylene))bis(oxy))bis(5-chloro-3-formylpyridine-6,2-diyl))bis(oxy))bis(methylene))dinicotinonitrile [ No CAS ]

Reference： [1]Patent: WO2018/195321,2018,A1

25
[ 54718-39-7 ]
[ 135124-71-9 ]
5,6-dichloro-2-((5-cyanopyridin-3-yl)methoxy)nicotinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[135124-71-9]5-(hydroxymethyl)nicotinonitrile</strong> (1.51 g, 9.7 mmol, 1 equiv) in THF (10 mL) at0 C was added NaH (292 mg, 12.2 mmol, 1.25 equiv). After an additional 20 minutes of stirring theslurry was added to a stirred solution of 2,5,6-trichloronicotinic acid (2.2 g, 9.7 mmol, 1 equiv) in THF at0 C. The solution was slowly allowed to warm to room temperature and stirred for 1 hour. The reactionmixture was then acidified with 1 M HC1 and the precipitated 5,6-dichloro-2-((5-cyanopyridin-3-yl)methoxy)nicotinic acid was collected by vacuum filtration.

Reference： [1]Patent: WO2018/195321,2018,A1 .Location in patent: Page/Page column 220

26
[ 35590-37-5 ]
[ 135124-71-9 ]

Reference： [1]Patent: WO2019/87214,2019,A1
[2]Patent: WO2019/175897,2019,A1

27
[ 100949-02-8 ]
[ 135124-71-9 ]

Reference： [1]Patent: WO2019/87214,2019,A1
[2]Patent: WO2019/175897,2019,A1

28
[ 70416-53-4 ]
[ 135124-71-9 ]

Yield	Reaction Conditions	Operation in experiment
60.7%	With sodium tetrahydroborate; In methanol; at 0℃; for 2.5h;	To a stirred solution of 5formylnicotinonitrile (12 g, 91 mmol) in methanol (100 mL) at 0C, sodium borohydride (5.12 g, 136 mmol) was added portion wise for 30 minutes and stirred the mixture at 0C for 2 h. After TLC showed completion, the reaction mixture was concentrated and the residue was diluted with water (100 mL) and DCM (200 mL). The organic layer was dried over sodium sulfate and concentrated. The crude was purified by column chromatography (silicagel, 100- 200) using 1% MeOH in DCM to obtain 5-(hydroxymethyl)nicotinonitrile as yellow solid (Yield: 7.4 g, 60.7%). lH NMR (400 MHz, DMSO-d6): delta 4.50 (bs, 1H), 5.54 (s, 2H), 8.19 (s, 1H), 8.80 (s, 1H), 8.91 (s, 1H).
60.7%	With methanol; sodium tetrahydroborate; at 0℃; for 2.5h;	To a stirred solution of 5-formylnicotinonitrile (12 g, 0.091 mol) in methanol (100 mL) at 0C, sodium borohydride (5.12 g, 0.136 mol) was added portion wise for 30 minutes and stirred the mixture at 0C for 2 h. The reaction mixture was concentrated and the residue was diluted with water (100 mL) and DCM (200 mL). The organic layer was dried over sodium sulfate and concentrated. The crude was purified by column chromatography (silica gel, 100-200 mesh) using 1% MeOH in DCM to obtain 5- (hydroxymethyl)nicotinonitrile as yellow solid (Yield: 7.4 g, 60.7%). 1 H NMR (400 MHz, DMSO-de, ppm): d, 8.91 (s, 1H), 8.80 (s, 1H), 8.19 (s, 1H), 5.54 (s, 2H), 4.50 (bs, 1H).

Reference： [1]Patent: WO2019/87214,2019,A1 .Location in patent: Paragraph 000172
[2]Patent: WO2019/175897,2019,A1 .Location in patent: Paragraph 00098

29
[ 135124-71-9 ]
(S)-1-((4-((5-cyanopyridin-3-yl)methoxy)-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2019/87214,2019,A1

30
[ 135124-71-9 ]
5-(((5-bromo-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)methyl)nicotinonitrile [ No CAS ]

Reference： [1]Patent: WO2019/87214,2019,A1

31
[ 135124-71-9 ]
5-(((2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-5-vinylpyrimidin-4-yl)oxy)methyl)nicotinonitrile [ No CAS ]

Reference： [1]Patent: WO2019/87214,2019,A1

32
[ 135124-71-9 ]
5-(((5-formyl-2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)pyrimidin-4-yl)oxy)methyl)nicotinonitrile [ No CAS ]

Reference： [1]Patent: WO2019/87214,2019,A1

33
[ 36082-50-5 ]
[ 135124-71-9 ]
5-(((5-bromo-2-chloropyrimidin-4-yl)oxy)methyl)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		To a stirred solution of <strong>[135124-71-9]5-(hydroxymethyl)nicotinonitrile</strong> (0.59 g, 4.3 mmol) in THF (20 mL) at 0C, sodium hydride (0.26 g, 60% in mineral oil, 6.5 mmol) was added and stirred at 0C for 30 minutes. To this mixture, a solution of 5-bromo-2,4- dichloropyrimidine (1.0 g, 4.3 mmol) in THF (5 mL) was added and the reaction mixture was stirred at room temperature for 5 h. After completion, the reaction was quenched with ice cold water (100 mL) and extracted with 10% IPA in chloroform (4 x 100 mL). The combined organic layer was dried over sodium sulphate and concentrated. The crude was purified by column chromatography (silicagel, 100-200) using 5% MeOH in DCM to obtain 5-(((5-bromo-2-chloropyrimidin-4- yl)oxy)methyl)nicotinonitrileas yellow solid (Yield: 1.0 g, 70%). NMR (400 MHz, DMSO-de): delta 5.59 (s, 2H), 8.43 (s, 1H), 8.80 (s, 1H), 9.00 (s, 1H), 9.05 (s, 1H). HPLC purity 214 nm: 97.07%.

Reference： [1]Patent: WO2019/87214,2019,A1 .Location in patent: Paragraph 000173

34
C₂₀H₁₂BrFN₂O₄ [ No CAS ]
[ 135124-71-9 ]
C₂₇H₁₇BrN₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate; In acetonitrile; at 20℃; for 12h;	Take compound E-2 (900mg)Add acetonitrile (25 mL),Add anhydrous potassium carbonate (655mg)And <strong>[135124-71-9]5-(hydroxymethyl)nicotinonitrile</strong> (320mg),The reaction solution was stopped after reacting at room temperature for 12 hours.Evaporate the solvent under reduced pressure.Diluted with ethyl acetate (25 mL).Wash with water (10 mL x 3) and saturated brine (10 mL x 2).Dry over anhydrous sodium sulfate.Evaporate the solvent under reduced pressure.The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1:1).Yellow solid compound E-3 (756 mg) was obtained.

Reference： [1]Patent: CN109776445,2019,A .Location in patent: Paragraph 0311; 0315; 0320; 0321

35
[ 135124-71-9 ]
5-((5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4-fluoro-2-formylphenoxy)methyl)nicotinonitrile [ No CAS ]

Reference： [1]Patent: CN110092779,2019,A

36
[ 135124-71-9 ]
C₃₀H₂₃FN₂O₆ [ No CAS ]

Reference： [1]Patent: CN110092779,2019,A

37
[ 135124-71-9 ]
C₄₂H₄₆FN₃O₈ [ No CAS ]

Reference： [1]Patent: CN110092779,2019,A

38
[ 135124-71-9 ]
C₃₄H₃₀FN₃O₈ [ No CAS ]

Reference： [1]Patent: CN110092779,2019,A

39
[ 135124-71-9 ]
5-(((4-formyl-7-((2-methyl-[1,1‘-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile [ No CAS ]

Reference： [1]Patent: WO2019/175897,2019,A1

40
[ 135124-71-9 ]
(S)-1-((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1’-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2019/175897,2019,A1

41
[ 135124-71-9 ]
5-(((7-((2-cyano-[1,1’-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile [ No CAS ]

Reference： [1]Patent: WO2019/175897,2019,A1

42
[ 135124-71-9 ]
(S)-1-((7-((2-cyano-[1,1‘-biphenyl]-3-yl)methoxy)-5-((5-cyanopyridin-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2019/175897,2019,A1

43
[ 135124-71-9 ]
5-[[2-formyl-5-[(2-methyl-3-phenylphenyl)methoxy]phenoxy]methyl]pyridine-3-carbonitrile [ No CAS ]