135124-71-9|5-(Hydroxymethyl)nicotinonitrile| Ambeed

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Quality Control of [ 135124-71-9 ] Purity: 97% SDS Specification

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Product Details of [ 135124-71-9 ]

CAS No. :	135124-71-9
Formula :	C₇H₆N₂O
M.W :	134.14
SMILES Code :	N#CC1=CN=CC(CO)=C1
MDL No. :	MFCD07367899
InChI Key :	MNMDVGJZONSKMO-UHFFFAOYSA-N
Pubchem ID :	22416540

Safety of [ 135124-71-9 ]

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

Computational Chemistry of [ 135124-71-9 ] Show Less

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 ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	56.91 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.13
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	-0.32
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.29
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.	-0.75
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	1.15
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.3

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.85
Solubility	19.0 mg/ml ; 0.142 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-0.41
Solubility	51.7 mg/ml ; 0.385 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	-1.91
Solubility	1.66 mg/ml ; 0.0124 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	No
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.	-7.35 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	1.0
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	0.0 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)	1.46

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.

Downstream synthetic route of [ 135124-71-9 ]

[ 135124-71-9 ] Synthesis Path-Downstream 1~35

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).

References: [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 ]

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

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

References: [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.

References: [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).

References: [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).

References: [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.

References: [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).

References: [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).

References: [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).

References: [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 ]

References: [1]Patent: US2011/294788,2011,A1 .

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

References: [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).

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

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

References: [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).

References: [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.

References: [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 ]