[ CAS No. 97004-04-1 ] {[proInfo.proName]}

Name: 97004-04-1|(6-Chloropyridin-3-yl)methanamine|96%
Brand: Ambeed
SKU: A444779
Rating: 94 (40 reviews)

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Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 97004-04-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 97004-04-1 ]

Product Details of [ 97004-04-1 ]

CAS No. :	97004-04-1	MDL No. :	MFCD00673153
Formula :	C₆H₇ClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XPARFBOWIYMLMY-UHFFFAOYSA-N
M.W :	142.59	Pubchem ID :	7020927
Synonyms :

Calculated chemistry of [ 97004-04-1 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	36.92
TPSA :	38.91 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.69 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.39
Log Po/w (XLOGP3) :	0.67
Log Po/w (WLOGP) :	1.04
Log Po/w (MLOGP) :	0.49
Log Po/w (SILICOS-IT) :	1.61
Consensus Log Po/w :	1.04

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.57
Solubility :	3.81 mg/ml ; 0.0267 mol/l
Class :	Very soluble
Log S (Ali) :	-1.06
Solubility :	12.3 mg/ml ; 0.0864 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.66
Solubility :	0.311 mg/ml ; 0.00218 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.56

Safety of [ 97004-04-1 ]

Signal Word:	Danger	Class:	9
Precautionary Statements:	P264-P273-P280-P280-P337+P313-P391	UN#:	3077
Hazard Statements:	H315-H318-H410	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 97004-04-1 ]

* 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 [ 97004-04-1 ]
Downstream synthetic route of [ 97004-04-1 ]

[ 97004-04-1 ] Synthesis Path-Upstream 1~12

1
[ 33252-28-7 ]
[ 3731-52-0 ]
[ 97004-04-1 ]

Reference： [1] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888

2
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[ 3731-52-0 ]
[ 23100-12-1 ]
[ 97004-04-1 ]

Reference： [1] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[2] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[3] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[4] Bulletin of the Chemical Society of Japan, 2000, vol. 73, # 5, p. 1227 - 1231

3
[ 124-41-4 ]
[ 97004-04-1 ]
[ 262295-96-5 ]

Reference： [1] Journal of Agricultural and Food Chemistry, 2003, vol. 51, # 17, p. 5030 - 5035

4
[ 33252-28-7 ]
[ 3731-52-0 ]
[ 23100-12-1 ]
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5
[ 70258-18-3 ]
[ 97004-04-1 ]

Reference： [1] Patent: US5084459, 1992, A,
[2] Patent: CN103242225, 2016, B,
[3] Patent: , 2016, , . Location in patent: Paragraph 0004; 0007
[4] Patent: US5034404, 1991, A,

6
[ 3731-52-0 ]
[ 75-44-5 ]
[ 97004-04-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium hydroxide; dihydrogen peroxide; trimethylamine In hydrogenchloride; chloroform; water	EXAMPLE 7 Manufacturing of 3-(aminomethyl)-6-chloropyridine starting from 3-(aminomethyl)pyridine: STR18 To a suspension consisting of 3-pyridine methane amine in an amount of 21.6g (0.2 mol), 80 ml aqueous solution of sodium hydroxide in an amount of 8.8g and chloroform in a volume of 60 ml, was fed dropwise isopropoxycarbonyl chloride in an amount of 25.7 g (0.21 mol) at a temperature of from 5° to 10° C. while stirring and spending 30 minutes, and thereaction mixture was further stirred for 30 minutes. After separating the mixture, the organic layer was concentrated under reduced pressure and wasthen dissolved in 20 ml water together with sodium tungstate in an amount of 0.58 g and 35percent hydrochloric acid in an amount of 1.0 g. To this solution, 34.5percent hydrogen peroxide solution in an amount of 27.6 g was fed dropwise at 100° C. while spending 30 minutes. After adjusting the pH of the solution to 5 and allowing the solution to proceed a reaction for 3.5 hours at 100° C., the solution was then cooled down to a room temperature and added with hypo to an extent that an iodo-starch reaction in the solution changes to the negative one. The reaction mixturewas then repeatedly extracted with chloroform in a volume of 100 ml, and all of the chloroform solution collected together was subjected to an azeotropic dehydration. To 250 ml chloroform solution obtained as described above, was added trimethylamine in an amount of 30.0 g (0.51 mol), and the resultant solution was added phosgene in an amount of 24.0 g(0.24 mol) at -5° C. while stirring and spending 1 hour. The reaction mixture was then transferred into an autoclave, whereto hydrogen chloride gas in an amount of 67.0 g was subsequently introduced, and the solution was allowed to a reaction for 5 hours at 50° C. under a pressure of 5 kgf/cm² while stirring. After cooling the solution to aroom temperature, the solution was then extracted with 35percent hydrochloric acid in a volume of 160 ml. The aqueous solution of hydrochloric acid obtained was then heated for 3.5 hours at a temperature of from 90°to 65° C. After cooling the solution to a room temperature, the reaction mixture was then added with 28percent aqueous solution of sodium hydroxide to adjust the pH of the solution to 13.5. The solution was then extracted with 150 ml chloroform, and the aqueous layer was further repeatedly extracted with chloroform. All chloroform layers were collectedtogether to dry it with magnesium sulfate and the solvent therein was removed by distillation, thereby affording 3-(aminomethyl)-6-chloropyridine in an amount of 24.8 g in a crystalline form The yield was 87percent.

Reference： [1] Patent: US5744608, 1998, A,

7
[ 1080018-12-7 ]
[ 97004-04-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: With hydrogenchloride; water In methanol at 75 - 80℃; for 6 h; Stage #2: With sodium hydroxide In methanol; chloroform; water	(Example 5) Production of (2-chlorogyridin-5-yl)methylamine (4); To 0.77 g (1.66 mol) of 1,3,5-tris[(2-chloropyridin-5-yl)methyl]-1,3,5-perhydrotriazine (II-4) were sequentially added 0.40 g of methanol and 1.83 g of concentrated hydrochloric acid, and the resulting mixture was stirred at 75 to 80°C for 6 hours. The reaction mixture was then diluted with chloroform, and following conversion of the mixture to an alkaline state by adding a 28percent aqueous solution of sodium hydroxide, the chloroform layer was separated and concentrated, yielding 0.68 g (yield: 95percent) of (2-chloropyridin-5-yl)methylamine (III-1).
95%	Stage #1: With hydrogenchloride In methanol at 75 - 80℃; for 6 h; Stage #2: With sodium hydroxide In methanol; chloroform; water	Example 5 Production of (2-chloropyridin-5-yl)methylamine (4) To 0.77 g (1.66 mol) of 1,3,5-tris[(2-chloropyridin-5-yl)methyl]-1,3,5-perhydrotriazine (II-4) were sequentially added 0.40 g of methanol and 1.83 g of concentrated hydrochloric acid, and the resulting mixture was stirred at 75 to 80° C. for 6 hours. The reaction mixture was then diluted with chloroform, and following conversion of the mixture to an alkaline state by adding a 28percent aqueous solution of sodium hydroxide, the chloroform layer was separated and concentrated, yielding 0.68 g (yield: 95percent) of (2-chloropyridin-5-yl)methylamine (III-1).

Reference： [1] Patent: EP2141149, 2010, A1, . Location in patent: Page/Page column 17
[2] Patent: US2010/121054, 2010, A1, . Location in patent: Page/Page column 9

8
[ 33252-28-7 ]
[ 97004-04-1 ]

Reference： [1] Patent: WO2011/161615, 2011, A1, . Location in patent: Page/Page column 58
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 19, p. 7965 - 7983

9
[ 136918-14-4 ]
[ 70258-18-3 ]
[ 97004-04-1 ]

Reference： [1] Patent: CN104788378, 2017, B, . Location in patent: Paragraph 0057; 0058; 0060

10
[ 33252-28-7 ]
[ 3731-52-0 ]
[ 97004-04-1 ]

Reference： [1] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888

11
[ 120739-60-8 ]
[ 97004-04-1 ]

Yield	Reaction Conditions	Operation in experiment
9.5 g	With hydrazine hydrate In ethanolReflux	The above-mentioned the resulting solid is soluble in ethanol (150 ml) in, mechanical stirring 15-30min rear, dropping 8-10mL hydrazine hydrate, reflux 2-6hr, filtering, using 20percent aqueous sodium hydroxide solution of adjusting PH value to be alkaline, dichloromethane extraction, water washing, drying by anhydrous sodium sulfate, decompression removes dissolved strawcoloured liquid 2-chloro-5-ammonia methylpyridinio 9.50g, content 99.0percent, GC-MS (M ⁺) (EI, 70eV, m/z) (relativeintensity percent) calc: 142; found: 142.

Reference： [1] Journal of Agricultural and Food Chemistry, 2008, vol. 56, # 1, p. 204 - 212
[2] Patent: CN103242225, 2016, B, . Location in patent: Paragraph 0096; 0098

12
[ 33252-28-7 ]
[ 3731-52-0 ]
[ 23100-12-1 ]
[ 97004-04-1 ]

[ 97004-04-1 ] Synthesis Path-Downstream 1~88

1
[ 124-41-4 ]
[ 97004-04-1 ]
[ 262295-96-5 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2003,vol. 51,p. 5030 - 5035

2
[ 372-09-8 ]
[ 97004-04-1 ]
[ 565214-73-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;	Cyanoacetic acid (2.6 g, 0.030 mmol), 5-aminomethyl-2-chloropyridine (4.3 g, 0.030 mmol) and 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloric acid salt (5.8 g, 0.030 mol) were added to dichloromethane (50 ml), and stirred overnight. Chloroform and 1N hydrochloric acid were added thereto, and crystals were separated out. The crystals were filtered off, dissolved in ethyl acetate, and water was added thereto and subjected to extraction. The organic phase was washed with a saturated sodium bicarbonate and a saturated brine, and then dried anhydrous sodium sulfate. The residue obtained by filtrating and concentrating was washed with hexane and a little amount of ethyl acetate to obtain N-(6-chloro-3-pyridylmethyl)-2-cyanoacetic acid amide (6.1 g, 0.029 mmol, 97percent). mp 119°C; 1H NMR (400 MHz, DMSO-d6) delta 3.72 (2H, s), 4.32 (2H, d), 7.50 (1H, d), 7.75 (1 H, dd), 8.33 (1 H, d), 8.80 (1 H, brs).

Reference： [1]Patent: EP1470752,2004,A1 .Location in patent: Page 27

3
[ 791068-41-2 ]
[ 97004-04-1 ]
[ 791068-43-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 24h;	A mixture of 4-METHYL-3-OXO-3, 4-dihydro-quinoxaline-2-carbaldehyde (0.1 g), sodium triacetoxyborohydride (0.170 g, 1.5 eq), and 2-chloro-5-aminomethylpyridine (0.076 g, leq) in dry CH2CL2 (1.5 mL) was stirred at rt under nitrogen for 1 day. The orange reaction mixture was basified with a sat. NAHCO3 solution, extracted CH2Cl2. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give a crude oil. FC (CH2C12/MEOH : 9/1) gave the title compound as an orange oil. LC-MS: Rt = 2.93 min. m/z = 315 (M + 1).

Reference： [1]Patent: WO2004/96780,2004,A1 .Location in patent: Page 30

4
[ 565214-66-6 ]
[ 97004-04-1 ]
N-(6-chloro-3-pyridylmethyl)-2-(4-trifluoromethylphenylhydrazono)propionic acid amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); dichloromethane; for 30h;	2-(4-Trifluoromethylphenyl hydrazono) propionic acid (12.31 g, 50.0 mmol) was dissolved in dichloromethane (250 ml) and N,N-dimethylformamide (25 ml), and 5-aminomethyl-2-chloropyridine (7.13 g, 50.0 mmol) and 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloric acid salt (9.59 g, 50.0 mmol) were added thereto. 30 hours later, the mixture was washed with 1N hydrochloric acid, a saturated sodium bicarbonate water and a saturated brine, and dried on sodium sulfate and then filtrated. The residue obtained by concentrating the resulting filtrate was purified with a silica gel chromatography to obtain N-(6-chloro-3-pyridylmethyl)-2-(4-trifluoromethylphenyl hydrazono) propionic acid amide (Compound No. 63) (14.47 g, 39.02 mmol, 78percent). Compound No. 63: mp 184°C; 1H NMR (400 MHz, CDCl3) delta 2.16 (3H, s), 4.57 (2H, d), 7.15 (2H, d), 7.31 (2H, d), 7.35 (1H, brt), 7.54 (2H, d), 7.64 (1H, s), 7.66 (1 H, dd), 8.38 (1 H, d).

Reference： [1]Patent: EP1470752,2004,A1 .Location in patent: Page 24

5
[ 565214-71-3 ]
[ 97004-04-1 ]
N-(6-chloro-3-pyridylmethyl)-3-ethoxy-2-(4-trifluoromethylphenylhydrazono)propionic acid amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃;	A mixture of 3-ethoxy-2-(4-trifluoromethylphenyl hydrazono) propionic acid (0.3 g, 1 mmol), 5-aminomethyl-2-chloropyridine (0.21 g, 1.5 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloric acid salt (0.29 g, 1.5 mmol) and chloroform (10 ml) was left at room temperature overnight. The mixture was extracted with chloroform, washed 1 N hydrochloric acid, a saturated sodium bicarbonate water and a saturated brine, dried on anhydrous sodium sulfate and then filtered. The residue obtained by concentrating the resulting filtrate was purified with a silica gel chromatography to obtain N-(6-chloro-3-pyridylmethyl)-3-ethoxy-2-(4-trifluoromethylphenyl hydrazono) propionic acid amide (Compound No. 170) (0.3 g, 0.72 mmol, 72percent). Compound No. 170: mp 98-99°C; 1H NMR (400 MHz, CDCl3) delta 1.20 (3H, t), 3.57 (2H, q), 4.36 (2H, s), 4.51 (2H, d), 6.22 (2H, d), 7.33 (1 H, d), 7.37 (1 H, d), 7.52 (2H, d), 7.52 (2H, d), 7.64 (1H, dd), 7.85 (1 H, brt).

Reference： [1]Patent: EP1470752,2004,A1 .Location in patent: Page 26

6
[ 155432-14-7 ]
[ 97004-04-1 ]
N-(6-chloro-3-pyridylmethyl)-2-[(4-trifluoromethylphenyl)hydrazono]acetic acid amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 8h;	(4-Trifluoromethylphenyl hydrazono) acetic acid (2.3 g, 10 mmol), 5-aminomethyl-2-chloropyridine (1.4 g, 10 mmol) and 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloric acid salt were added to dichloromethane (30 ml), and stirred at room temperature for 8 hours. After leaving it overnight, 1 N hydrochloric acid and chloroform were added thereto, but they were not dissolved therein, and then crystals were filtered off. The resulting crystals were dried to obtain N-(6-chloro-3-pyridylmethyl)-4-trifluoromethylphenylhydrazono acetic acid amide (2.1 g, 5.9 mmol). Further, the filtrate was subjected to extraction, the organic phase was washed with a saturated brine and then dried on anhydrous sodium sulfate. The solvent was distilled off, and the resulting crystals were washed with hexane and a little amount of ethyl acetate to obtain N-(6-chloro-3-pyridylmethyl)-4-trifluoromethylphenyl hydrazono acetic acid amide (0.4 g, 1.1 mmol, 70percent).1H NMR (400 MHz, DMSO-d6) delta 4.41 (2H, d), 7.22 (1 H, s), 7.34 (2H, d), 7.49 (1 H, d), 7.58 (2H, d), 7.77 (1H, dd), 8.36 (1 H, d), 8.81 (1H, t).

Reference： [1]Patent: EP1470752,2004,A1 .Location in patent: Page 26-27

7
3-(5-carboxyindol-2-yl)indazole [ No CAS ]
[ 97004-04-1 ]
3-(5-(N-(2-chloropyrid-5-yl)methyl)carboxamideindol-2-yl)indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 29h;	The acid 3-(5-carboxyindol-2-yl)indazole and the <strong>[97004-04-1]5-(aminomethyl)-2-chloropyridine</strong> dissolved in 5 ml of CH2Cl2 are introduced into a 30 ml round-bottomed flask. The EDC and the HOBt dissolved in 5 ml of CH2Cl2 are then added at room temperature under nitrogen. The reaction mixture is stirred at room temperature under nitrogen for 24 hours. A sufficient amount of DMF to fully dissolve the reaction medium is added. A further 0.355 mmol of the reagents EDCI and HOBt are then added. The reaction medium is stirred at room temperature for 5 hours and then poured into water and extracted with EtOAc. After drying and concentrating, 268.5 mg of a yellow oil are thus obtained, which product is purified by chromatography on silica (Biotage), eluting with a 99.5/0.5, 98/2, 95/5, 91/10 CH2Cl2/MeOH mixture by volume. 23.9 mg of 3-(5-(N-(2-chloropyrid-5-yl)methyl)carboxamideindol-2-yl)indazole are thus obtained in the form of a beige-coloured powder. 118.6 mg of a mixture are also obtained, which mixture is repurified by chromatography on a column of 60H silica (12 g), eluting with 99/1, 98/2 CH2Cl2/MeOH by volume. Two fractions of comparable purity of 3-(5-(N-(2-chloropyrid-5-yl)methyl)carboxamideindol-2-yl)indazole are thus obtained (41.8 mg and 49.6 mg, respectively) in the form of whitish powders.

Reference： [1]Patent: US2004/242559,2004,A1 .Location in patent: Page 20

8
[ 57538-27-9 ]
[ 97004-04-1 ]
O-methyl-N-(6-chloro-pyridin-3-ylmethyl)-N'-nitroisourea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.3%	With hydrogenchloride; In water;	EXAMPLE 29 To a mixture of O-methyl-N-nitroisourea (1.25 g, 10.53 mmol), water (20 ml) and concentrated hydrochloric acid (0.85 ml, 10.03 mmol) was added <strong>[97004-04-1]5-(aminomethyl)-2-chloropyridine</strong> (1.43 g, 10.03 mmol) dropwise over 5 minutes at room temperature with stirring. The reaction mixture was neutralized with 40percent aqueous sodium hydroxide solution and adjusted to pH 7.2. After 17 hours of stirring at room temperature, the resulting crystals were collected. The crystals were washed with water and dried. As a result, 1.16 g (47.3percent yield) of O-methyl-N-(6-chloro-3-pyridylmethyl)-N'-nitroisourea was obtained as white crystals. M.p. 112-113° C. 1 H-NMR (CDCl3) delta: 3.98 (3H, s), 4.57 (2H, d, J=6.0 Hz), 7.38 (1H, d, J=8.2 Hz), 7.63 (1H, dd, J=8.2 Hz, 2.4 Hz), 8.36 (1H, d, J=2.4 Hz), 9.43 (1H, br). IR (nujol): 3250, 1590, 1520, 1390, 1240, 1210 (cm-1).

Reference： [1]Patent: US6008363,1999,A

9
O-methyl-N-nitro-N'-phthaloylisourea [ No CAS ]
[ 97004-04-1 ]
N-[(6-chloro-3-pyridinyl)methyl]-N'-methyl-N''-nitroguanidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64.0%	With sodium hydroxide; In dichloromethane; water;	EXAMPLE 11 In a mixture of dichloromethane (10 ml) and water (15 ml) was suspended O-methyl-N-nitro-N'-phthaloylisourea (5.0 g, 20.0 mmol) and then, dichloromethane (5 ml) solution of <strong>[97004-04-1]5-(aminomethyl)-2-chloropyridine</strong> (3.0 g, 21.0 mmol, 1.05 equivalents) was added dropwise over 5 minutes under stirring at 10° C. After 30 minutes of stirring at room temperature, the reaction mixture was diluted with water (60 ml) and then, methylamine (6.7 ml, 77.84 mmol, 4.0 equivalents) was added. After 1.5 hours of stirring at room temperature, 30 ml of 20percent aqueous sodium hydroxide solution was added to separate a water phase from an organic phase. The water phase was washed with dichloromethane, neutralized with concentrated hydrochloric acid, and adjusted to pH 3.0. The resulting crystals were collected by filtration, washed with water and subsequently methanol. The washed crystals were dried to provide 3.12 g (64.0percent yield) of 1-(6-chloro-3-pyridylmethyl)-3-methyl-2-nitroguanidine as white crystals. M.p. 159-160° C. 1 H-NMR (DMSO-d6) delta: 2.85 (3H, d, J=4.4 Hz), 4.44 (2H, d, J=6.0 Hz), 7.49 (1H, d, J=8.2 Hz), 7.80 (1H, dd, J=8.2 Hz, 2.6 Hz), 7.90 (1H, br), 8.37 (1H, d, J=2.6 Hz), 9.10 (1H, br). IR(nujol): 3300, 1620, 1570, 1380, 1341, 1240 (cm-1).

Reference： [1]Patent: US6008363,1999,A

10
[ 2469-99-0 ]
[ 97004-04-1 ]
2-(2-chloro-5-pyridylmethylamino)-1-cyano-1-propene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2 2-(2-chloro-5-pyridylmethylamino)-1-cyano-1-propene STR13 1.4 g of 2-chloro-5-pyridylmethylamine and 0.8 g of 1-cyano-2-propanone were mixed and the mixture was stirred at room temperature over night. The solvent was then distilled off and the residue was purified by column chromatography on silica gel to afford 1.7 g of compound No. 528. m.p. 95-98 C.

Reference： [1]Patent: US5304566,1994,A

11
[ 3731-52-0 ]
[ 75-44-5 ]
sodium tungstate [ No CAS ]
[ 97004-04-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium hydroxide; dihydrogen peroxide; trimethylamine; In hydrogenchloride; chloroform; water;	EXAMPLE 7 Manufacturing of 3-(aminomethyl)-6-chloropyridine starting from 3-(aminomethyl)pyridine: STR18 To a suspension consisting of 3-pyridine methane amine in an amount of 21.6g (0.2 mol), 80 ml aqueous solution of sodium hydroxide in an amount of 8.8g and chloroform in a volume of 60 ml, was fed dropwise isopropoxycarbonyl chloride in an amount of 25.7 g (0.21 mol) at a temperature of from 5° to 10° C. while stirring and spending 30 minutes, and thereaction mixture was further stirred for 30 minutes. After separating the mixture, the organic layer was concentrated under reduced pressure and wasthen dissolved in 20 ml water together with sodium tungstate in an amount of 0.58 g and 35percent hydrochloric acid in an amount of 1.0 g. To this solution, 34.5percent hydrogen peroxide solution in an amount of 27.6 g was fed dropwise at 100° C. while spending 30 minutes. After adjusting the pH of the solution to 5 and allowing the solution to proceed a reaction for 3.5 hours at 100° C., the solution was then cooled down to a room temperature and added with hypo to an extent that an iodo-starch reaction in the solution changes to the negative one. The reaction mixturewas then repeatedly extracted with chloroform in a volume of 100 ml, and all of the chloroform solution collected together was subjected to an azeotropic dehydration. To 250 ml chloroform solution obtained as described above, was added trimethylamine in an amount of 30.0 g (0.51 mol), and the resultant solution was added phosgene in an amount of 24.0 g(0.24 mol) at -5° C. while stirring and spending 1 hour. The reaction mixture was then transferred into an autoclave, whereto hydrogen chloride gas in an amount of 67.0 g was subsequently introduced, and the solution was allowed to a reaction for 5 hours at 50° C. under a pressure of 5 kgf/cm2 while stirring. After cooling the solution to aroom temperature, the solution was then extracted with 35percent hydrochloric acid in a volume of 160 ml. The aqueous solution of hydrochloric acid obtained was then heated for 3.5 hours at a temperature of from 90°to 65° C. After cooling the solution to a room temperature, the reaction mixture was then added with 28percent aqueous solution of sodium hydroxide to adjust the pH of the solution to 13.5. The solution was then extracted with 150 ml chloroform, and the aqueous layer was further repeatedly extracted with chloroform. All chloroform layers were collectedtogether to dry it with magnesium sulfate and the solvent therein was removed by distillation, thereby affording 3-(aminomethyl)-6-chloropyridine in an amount of 24.8 g in a crystalline form The yield was 87percent.

Reference： [1]Patent: US5744608,1998,A

12
[ 70258-18-3 ]
[ 97004-04-1 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; sodium hydroxide; In acetonitrile;	REFERENCE EXAMPLE 2 A stainless steel autoclave was charged with 14.99 g of 2-chloro-5-(chloromethyl)pyridine, 63.01 g of 25percent aqueous ammonia and 60 ml of acetonitrile and the mixture was stirred on an oil bath at 80° C. for 2 hours. The reaction mixture was diluted with 12.3 g of 30percent aqueous sodium hydroxide solution and concentrated. The residue was diluted with 200 ml of ethanol, dried over anhydrous magnesium sulfate and filtered to remove the insolubles. Finally, the filtrate was concentrated and purified by column chromatography (eluent: dichloromethane-methanol (4:1)) to give 7.66 g of 5-(aminomethyl)-2-chloropyridine as a yellow solid. 1 H NMR (CDCl3): 1.60 (2H, s), 3.90 (2H, s), 7.28 (1H, d, J=8.5 Hz), 7.67 (1H, dd, J=8.5, 2.5 Hz), 8.33 (1H, d, J=2.5 Hz)
		Into a 250 ml three-mouthed flask, add dry 11g hexamethylenetetramine, 100 ml acetonitrile and 13g 2-chloro-5-chloromethylpyridine. Then at 600r/min electromagnetic stirring for 10 min. After heating at reflux for 6h, stop heating and cooling to 20 °C, filter cake on the filter and collect; The above-mentioned collected filter cake was placed in a 250 ml three-mouthed flask. Then add 34 ml mass fraction of 10percent hydrochloric acid solution. At 600r/min, add 100 ml methanol. Then heat to 60 °C. After refluxing the reaction for 2h, continue to heat at 100 °C and react for 2h; After the reaction was finished, so that their natural cooling to 20 °C, by adding 40 ml of chloroform, in 300r/min dropping under 25percent of NaOH solution, adjusting the pH to 8, and then layering the aqueous phase is extracted with chloroform, the chloroform is removed by reduced pressure distillation, to prepare 2-chloro-5-aminomethylpyridine; Into a 250 ml three-mouthed flask, add 100 ml dimethylformamide, then, in order, sequentially add 21g m-trifluoromethylphenol, 18g anhydrous potassium carbonate, 15g 2-chloro-5-aminomethylpyridine and 0.6g of cuprous chloride. After the addition was complete, heat to 135 °C. At 600r/min, stir the reaction for 6h; completes the partner to be reaction, stop heating and cooling to 20 °C, then continues to stirring and adding 100 ml de-ionized water, to be stirring 10 min later, for mass fraction of 10percent hydrochloric acid adjust its pH to 3.0, and the collection filter cake afterward opens the eyes vacuum filtration, washing with de-ionized water 3 times, is the 60 °C drying in oven 6h, can prepare N-(2-(3-(trifluoromethyl)phenoxy)-4-pyridyl)methanimine.
	With sodium hydroxide; In ethanol; acetonitrile;	REFERENCE EXAMPLE 2 A mixture of 14.99g of 2-chloro-5-(chloromethyl) pyridine, 63.01g of 25percent ammonia water and 60ml of acetonitrile in a stainless steel autoclave was stirred for 2 hours in an oil bath of 80° C. After adding 12.3g of 30percent sodium hydroxide aqueous solution, the reaction mixture was concentrated. The residue to which 200ml of ethanol were added was dried over anhydrous magnesium sulfate and, filtered to remove insoluble materials. The filtrate was concentrated and purified by a column chromatography [developing solvent: dichloromethane-methanol (4:1)] to afford 7.66g of 5-(aminomethyl)-2- chloropyridine as a yellow solid. 1 H NMR(CDCl3): 1.60(2H,s), 3.90(2H,s), 7.28(1H,d,J=8.5Hz), 7.67(1H,dd,J=8.5, 2.5Hz),

Reference： [1]Patent: US5084459,1992,A
[2]Patent: CN103242225,2016,B
[3]Patent: ,2016, .Location in patent: Paragraph 0004; 0007
[4]Patent: US5034404,1991,A

13
[ 24424-99-5 ]
[ 97004-04-1 ]
[ 285119-72-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 20℃;	1. Synthesis of toerf-butyl(6-chloropyridin-3-yl)methylcarbamate[00167] A stirred solution of <strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong> (6.56 g, 46.01 mmol) in dichloromethane (50 mL) was treated with triethylamine (11.2 mL, 80.51 mmol, 1.75 eq) and di-tert-butyl-di-carbonate (12.55g, 57.51 mmol, 1.25 eq) at room temperature and this mixture was stirred overnight. Aqueous saturated ammonium chloride was added to the mixture and the two phases were separated. The aqueous phase was extracted with dichloromethane (3x) and the combined organic layers were <n="48"/>dried over anhydrous magnesium sulfated, filtered and concentrated to give the title material (UAIg, >100percent) as a solid. . 1H NMR (400 MHz, CDCl3) delta (ppm): 1.47 (9H, s), 4.33 (IH, d, J=6.1 Hz), 4.95 (IH, br s), 7.32 (IH, d, 8.0 Hz), 7.64 (IH, br dd, J=7.8 and 1.5 Hz), 8.33 (IH, d, J=2.0 Hz). Traces of Net3HCl salt were detected by NMR. LC/MS (M+H)+: 243. The compound was used as such for the next reaction.
99%	With sodium hydroxide; In dichloromethane; at 20℃; for 16h;	25.0 g (175.3 mmol) 5-aminomethyl-2-chloropyrimidine are initially introduced into 175 ml methylene chloride. 175 ml 10percent strength sodium hydroxide solution are added and a solution of 38.3 g (175.3 mmol) di-tert-butyl dicarbonate in 175 ml methylene chloride is added dropwise. The mixture is stirred at RT for 16 h. It is then diluted with 175 ml methylene chloride, the organic phase is separated off and the aqueous phase is extracted with 175 ml methylene chloride. The combined organic phases are dried over magnesium sulfate and concentrated in vacuo. The product is dried under a high vacuum.Yield: 42.0 g (99percent of th.)LC-MS (Method 7): Rt=1.58 min; MS (ESIpos): m/z=243 [M+H]+;1H-NMR (400 MHz, CDCl3): delta=8.31 (d, 1H), 7.61 (dd, 1H), 7.30 (d, 1H), 4.99 (br. s, 1H), 4.30 (d, 2H), 1.46 (s, 9H).
98%	With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;	To a solution of (6chioropyridin3yl)methanamine (3.30 g, 23.1 mmol) inDCM (30 inL) was added TEA (4.84 mL. 34.7 rnmoi) and BOC2O (6.72 mL, 28.9 mrnol), at 0 °C. The resulting mixture was stirred at ambient temperature for iii. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with DCM (3x l0() rnL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Intermediate 2A (5.50 g, 98.0percent) as a yellow oil. ?H NMR (300 MHz, DMSO-.ck) oe ppm1.38 (s, 9 H), 4,14 (d, J= 6.04 Hz, 2 H), 7.48 (d, J= 7.93 Hz, 2 H), 771 (dd, J= 8.12,2.46 Hz, I H), 8.28 (d, J = 189 Hz, I H). LCMS ,MethodD): retention time 2.31 mm,jM-H1-{i 243. 1.

86%	With triethylamine; In dichloromethane; at 20℃;	Preparation 37; (E)-3-Aminomethyl-6-(2-cyclohexylvinyl)-pyridine; 3-(fert-Butoxycarbonylamino-methyl)-6-chloropyridine; Dissolve 3-aminomethyl-6- chloropyridine (1.65 g, 11.57 mmol) in DCM (58 mL) and add triethylamine (2.42 mL, EPO <DP n="88"/>17.26 mmol) followed by di-tert-butyl-dicarbonate (3.03 g, 13.88 mmol). Stir the resulting solution at room temperature overnight. Add DCM and saturated aqueous NaHCO3. Separate the aqueous phase and extract twice with DCM. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (120 g, pre-packed cartridge) eluting stepwise with hexane/EtOAc (1:0 over 5 min, 19:1 over 5 min, 9:1 over 5 min and 85:15 over 5 min; 50 mL/min) to obtain the desired intermediate (2.41 g, 86percent). MS (APCI+) m/z: 187 [M-(^-BuHH]+.
	With triethylamine; In dichloromethane; at 20℃;	1. Synthesis of tert-butyl(6-chloropyridin-3-yl)methylcarbamate A stirred solution of <strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong> (6.56 g, 46.01 mmol) in dichloromethane (50 mL) was treated with triethylamine (11.2 mL, 80.51 mmol, 1.75 eq) and di-tent-butyl-di-carbonate (12.55 g, 57.51 mmol, 1.25 eq) at room temperature and this mixture was stirred overnight. Aqueous saturated ammonium chloride was added to the mixture and the two phases were separated. The aqueous phase was extracted with dichloromethane (3*) and the combined organic layers were dried over anhydrous magnesium sulfated, filtered and concentrated to give the title material (12.17 g, >100percent) as a solid. 1H NMR (400 MHz, CDCl3) delta (ppm): 1.47 (9H, s), 4.33 (1H, d, J=6.1 Hz), 4.95 (1H, br s), 7.32 (1H, d, 8.0 Hz), 7.64 (1H, br dd, J=7.8 and 1.5 Hz), 8.33 (1H, d, J=2.0 Hz). Traces of NEt3HCl salt were detected by NMR. LC/MS (M+H)+: 243. The compound was used as such for the next reaction.

Reference： [1]Patent: WO2008/124757,2008,A1 .Location in patent: Page/Page column 46-47
[2]Patent: US2010/305085,2010,A1 .Location in patent: Page/Page column 19-20
[3]Patent: WO2018/93569,2018,A1 .Location in patent: Page/Page column 45; 46
[4]Chemical Communications,2013,vol. 49,p. 3110 - 3112
[5]Patent: WO2007/28083,2007,A2 .Location in patent: Page/Page column 85-86
[6]Patent: US2010/48581,2010,A1 .Location in patent: Page/Page column 15

14
[ 108-94-1 ]
[ 97004-04-1 ]
[ 359445-31-1 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium cyanoborohydride; acetic acid; In methanol; at 0 - 20℃;	Preparation 54; 6-Aminomethyl-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-pyridine; 6-Chloro-S-fcyclohexylamino-methylVpyridine; Under a nitrogen atmosphere, add sodium cyanoborohydride (3.53 g, 56 mmol) to a solution of 3-aminomethyl-6-chloro- pyridine (2 g, 14 mmol), cyclohexanone (1.38 g, 14 mmol) and acetic acid (168 mg, 0.2 mmol) in methanol (20 mL) at 00C. Warm the mixture to room temperature and stir overnight. Add water (100 mL) and saturated aqueous K2CO3. Extract three times with DCM and wash the combined organic extracts with water and brine. Dry over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (150 g) eluting with 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the desired intermediate (2.86 g, 91percent). MS (APCI+) m/z: 225 (M+H)+.

Reference： [1]Patent: WO2007/28083,2007,A2 .Location in patent: Page/Page column 102

15
[ 915138-76-0 ]
[ 97004-04-1 ]
[ 915138-75-9 ]

Yield	Reaction Conditions	Operation in experiment
		In a 5-ml ground-glass tube under an argon atmosphere, dissolve 100 mg of the hydrochloride of 4-(1H-imidazo[4,5-c]pyridin-2-yl)-9H-fluorene-9(R,S)-carboxylic acid obtained in Example 29, in 1 ml of dichloromethane, then add successively 46 muL of triethylamine, 47 muL of N,N'-diisopropylcarbodiimide and 41 mg of 1-hydroxybenzotriazole and stir for 10 minutes. Then add a solution of 43 mg of 5-aminomethyl-2-chloropyridine in 1 ml and stir for 6 hours at room temperature. Pour the reaction mixture into 20 ml of a saturated aqueous solution of sodium hydrogen carbonate and extract twice with 10 ml of dichloromethane then with 10 ml of ethyl acetate. Combine the organic phases and wash with water, dry over sodium sulphate and concentrate under reduced pressure. After purification by flash chromatography on silica gel (40-63 mum), eluting with a mixture of dichloromethane and methanol (95-5 then 90-10 by volume), we obtain 21 mg of (6-chloropyridin-3-ylmethyl)-amide of 4-(1H-imidazo[4,5-c]pyridin-2-yl)-9H-fluorene-9(R,S)-carboxylic acid, in the form of a beige foam with the following characteristics:Mass spectrum (E/I): m/z=451 (M+)

Reference： [1]Patent: US2008/153837,2008,A1 .Location in patent: Page/Page column 24

16
[ 495415-34-4 ]
[ 97004-04-1 ]
[ 1035345-92-6 ]
[ 1035345-91-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 39.7% 2: 28.7%	With N-ethyl-N,N-diisopropylamine; HATU In ISOPROPYLAMIDE at 25 - 60℃; for 4h;	38.A EXAMPLE 384-(aminomethyl)-N-r(6-chloropyridin-3-yl)methyll-l-(7H-pyrrolor2,3-dlpyrimidin-4- vDpiperidine-4-carboxamide38 A. tert-Butyl 4-((6-chloropyridin-3-yl)methylcarbamoyl)-4-cvanopiperidine-l- carboxylate; HATU (1.255 g, 3.30 mmol) was added in one portion to l-(tert-butoxycarbonyl)-4- cyanopiperidine-4-carboxylic acid (0.763 g, 3 mmol), (6-chloropyridin-3-yl)methanamine (0.428 g, 3.00 mmol) and DIPEA (1.572 mL, 9.00 mmol) in DMA (20 mL) at 250C under nitrogen. The resulting solution was stirred at 6O0C for 4 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (150 mL), and washed sequentially with citric acid (50 mL), water (50 mL), and saturated NaHCCβ (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product thus obtained was concentrated, then purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to afford tert-butyl 4-((6-chloropyridin-3-yl)methylcarbamoyl)-4-cyanopiperidine-l -carboxylate (0.451 g, 39.7 %) as a colourless gum which solidified on drying under high vacuum. Additionally, the deprotected amine, N-((6-chloropyridin-3-yl)methyl)-4-cyanopiperidine-4- carboxamide (0.240 g, 28.7 %), was also recovered. IH NMR (400.13 MHz, DMSO-d6) δ 1.41 (9H, s), 1.81 - 1.89 (2H, m), 2.05 (2H, d), 2.90 - 3.00 (2H, m), 3.98 (2H, d), 4.34 (2H, d), 7.49 (IH, d), 7.72 - 7.74 (IH, m), 8.32 (IH, d), 8.94 (IH, t). MS m/e MH+ 277.

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD; UNIVERSITY OF LONDON; CANCER RESEARCH UK; ASTRAZENECA PLC - WO2008/75110, 2008, A1 Location in patent: Page/Page column 166-167

17
[ 495415-34-4 ]
[ 97004-04-1 ]
[ 1035345-96-0 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 18h;	EXAMPLE 44-Amino- 1 -(7H-pyrrolor2,3-dlpyrimidin-4-yl)-piperidine-4-carboxylic acid (6-chloro- pyridin-3 - ylmethvDamide 4A 4-tert-Butoxycarbonylamino-4-(6-chloropyridin-3-ylmethylcarbamoyl)-piperidine- 1 - carboxylic acid tert-butyl ester; <n="121"/>5-Aminomethyl-2-chloropyridine (4mmol) 4-toet-butoxycarbonylamino-piperidine- 1 ,4- dicarboxylic acid mono-toet-butyl ester compound (1.38g, 4 mmol), HOBT (0.648g 4.8 mmol) and EDC (0.92g, 4.8 mmol) in DMF (20 mis) are stirred at room temperature for 18h. . The reaction mixture is partitioned between dichloromethane and water. The organic layers are then dried, filtered and evaporated. The crude material is purified by flash silica column chromatography, eluting with petroleum ether/ethyl acetate gradient, to afford the title compound.

Reference： [1]Patent: WO2008/75110,2008,A1 .Location in patent: Page/Page column 118-119

18
[ 1038407-00-9 ]
[ 97004-04-1 ]
[ 1038407-17-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	With N-ethyl-N,N-diisopropylamine; HATU;dmap; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.16667h;	Example 3; Compound 82 was synthesized via the synthetic method described in Example 2 (Part B).Part A:To a solution of compound 81 (0.7 g, 3.36 mmol) in DMF (20 mL) was added 5-aminomethyl-2-chloropyridine (0.57 g, 4.04mmol) and diisopropylethylamine (1.75 mL, 10.1 mmol). The reaction mixture was stirred at room temperature for 10 minutes, <n="96"/>cooled to O0C (ice-bath) and then added HATU (1.54 g, 4.04 mmol) and DMAP (0.020 g, 0.16 mmol). The reaction mixture was allowed to warm to room temperature, stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with 0.1 N NaOH (x1 ), water (x2), 0.1 N HCI (x1 ) and brine, dried over sodium sulfate and concentrated. Purification by column chromatography (SiO2,ethyl acetate) afforded compound 172 as a white solid (0.62 g, 56percent). 1H NMR (400 MHz, DMSO-d6) delta 9.8 ( t, 1 H), 8.8 (d, 1 H), 8.4 (d, 1 H), 8.2 (m, 3H), 7.8 ( dd, 1 H),7.49 (d, 1 H), 4.65 (d, 2H), 4.2 (m, 1 H), 1.26 (d, 6H). HPLC-MS tR = 1.5 Min (UV254 nm); mass calculated for formula C16H17CIN4O2 332.1 , observed LC/MS m/z 333.0 (M + H).

Reference： [1]Patent: WO2008/82487,2008,A2 .Location in patent: Page/Page column 94-95

19
[ 407-25-0 ]
[ 97004-04-1 ]
[ 169506-55-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	In dichloromethane; at 0 - 20℃; for 1h;	Example 6BPart C XT NH713 Part A:To a solution of 2-chloro-5-aminomethylpyridine 310 (1g, 7.0 mmol) in dichloromethane (20 mL) at O0C (ice-bath) was added trifluoroacetic anhydride (1.2 mL, 8.5 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS analysis of the reaction indicated that the reaction was complete. The volatiles were removed in vacuo to afford compound 311 (100 percent yield) as a white solid. HPLC-MS tR = 1.37 min (U V254 nm); mass calculated fpr formula C8H6CIF3N2O 238.0, observed LCMS m/z 239.0 (M+H).

Reference： [1]Patent: WO2008/82490,2008,A2 .Location in patent: Page/Page column 155

20
[ 914612-23-0 ]
[ 97004-04-1 ]
[ 1073428-71-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 180℃; for 2h;Microwave irradiation;	Method J (Compound 13)5-Chloro-2-(4-((6-methoxypyridin-3-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile A) 6-Benzyl-N-((6-chloropyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amineA mixture of <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine</strong> (2.5 g, 9.6 mmol), 2-chloro-5-aminomethylpyridine (2.7 g, 19 mmol), acetonitrile (10 mL), and N,N-diisopropylethylamine (3.4 mL, 19 mmol) was subjected to microwave irradiation at 180 C. for 2 h. After standing at rt overnight, the precipitated solids were collected by filtration and washed with cold acetonitrile (5 mL×2), and dried to yield a yellow powder (2.8 g, 77%).LC-MS: 366.3 [M+H]+ 1H NMR (400 MHz, d6-DMSO): delta 8.34 (d, 1H, J=2.8 Hz), 8.23 (s, 1H), 7.74 (dd, 1H, J=8.4, 2.8 Hz), 7.45-7.25 (m, 7H), 4.56 (d, 2H, J=6.0 Hz), 3.72 (s, 2H), 3.36 (s, 2H), 2.72-2.62 (m, 4H).

Reference： [1]Patent: US2008/275037,2008,A1 .Location in patent: Page/Page column 39

21
[ 120739-60-8 ]
[ 97004-04-1 ]

Yield	Reaction Conditions	Operation in experiment
9.5 g	With hydrazine hydrate; In ethanol;Reflux;	The above-mentioned the resulting solid is soluble in ethanol (150 ml) in, mechanical stirring 15-30min rear, dropping 8-10mL hydrazine hydrate, reflux 2-6hr, filtering, using 20% aqueous sodium hydroxide solution of adjusting PH value to be alkaline, dichloromethane extraction, water washing, drying by anhydrous sodium sulfate, decompression removes dissolved strawcoloured liquid 2-chloro-5-ammonia methylpyridinio 9.50g, content 99.0%, GC-MS (M +) (EI, 70eV, m/z) (relativeintensity %) calc: 142; found: 142.

Reference： [1]Journal of Agricultural and Food Chemistry,2008,vol. 56,p. 204 - 212
[2]Patent: CN103242225,2016,B .Location in patent: Paragraph 0096; 0098

22
[ 1138153-58-8 ]
[ 97004-04-1 ]
[ 1138153-66-8 ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 50℃; for 16h;	Example 3N-[2-(6-Chloropyridin-3-ylmethyl)]-N-[4-(4-fluoro-3-trifluoromethylphenyl)]-6-{N'-[1-(4-trifluoromethoxyphenyl)-methylidene]-hydrazino}pvrimidine-2,4-diamine (3)Preparation of 3 is outlined in Scheme 11. To a stirred solution of (2,6-dichloropyrimidin-4-yl)(4-fluoro-3-trifluoromethylphenyl)amine (XXII) (3.26 g, 10 mmol) in dioxane (15 mL) were added diisopropylethylamine (1.55 g, 10 mmol) and ((6-chloropyridin-3-yl)methyl)amine (XXX) (1.43 g, 10 mmol) and the mixture was stirred at 50° C. for 16 h. The mixture was diluted with water and stirred vigorously for 10 min. The white slurry was filtered to give a precipitate which was washed with water and dried under vacuum to give XXXI as a white solid (2.95 g, 68percent yield). To a solution of this solid (432 mg, 1 mmol) in dioxane (1 mL) was added hydrazine monohydrate (0.5 mL) and the mixture stirred at 80° C. for 36 h. The reaction mixture was cooled to ambient temperature, diluted with water (15 mL), and stirred vigorously for 30 min resulting in a white precipitate. This precipitate was filtered and washed with water, and dried under vacuum to give 0.40 g (88percent yield) of XXXII (m.p. 127-129° C.). To a solution of crude compound XXXII (214 mg, 0.5 mmol) in ethanol (2 mL) was added 4-trifluoromethoxy benzaldehyde (140 mg, 0.75 mmol) and the mixture stirred for 30 min at ambient temperature. The mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel, hexanes/ethyl acetate) to give 3 as a white solid (122 mg, 40percent yield): 1H NMR (CDCl3) delta 8.38 (s, 1H), 7.81 M, 1H), 7.70 (s, 1H), 7.63 (m, 3H), 7.43 (m, 1H), 7.20 (m, 4H), 6.04 (s, 1H), 4.56 (d, J=5.7 Hz, 2H); ESIUMS 600.13 (M+H).

Reference： [1]Patent: US2009/93480,2009,A1 .Location in patent: Page/Page column 8

23
[ 1138566-86-5 ]
[ 97004-04-1 ]
[ 1138566-87-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 50℃; for 12h;	To a stirred solution of (4,6-Dichloro-[1,3,5]triazin-2-yl)-(4-fluoro-3-trifluoromethylphenyl)amine (XVII) (2.0 g, 6.11 mmol) in dioxane (5 mL) was added i-Pr2(Et)N (0.832 g, 6.44 mmol) and <strong>[97004-04-1](6-chloropyridin-3-yl)methylamine</strong> (0.912 g, 6.44 mmol), and the mixture heated at 50° C. for 12 h. The mixture was cooled to ambient temperature and diluted with water and ethyl acetate. The organic phase was separated, washed with brine and concentrated under vacuum to give 1 6-chloro-N-(6-chloropyridin-3-ylmethyl)-N'-(4-fluoro-3-trifluoromethylphenyl)-1,3,5-triazine-2,4-diamine (XVIII) (1.60 g (60percent yield): 1H NMR (DMSO) delta 8.32 (bs, 1H), 7.98 (bs, 1H), 7.58 (bd, 1H), 7.28 (m, 3H), 7.16 (t, J=9.0 Hz, 1H), 6.60 (bs, 1H), 4.64 (m, 2H); ESI/MS 433 (M+H), 431 (M-H).

Reference： [1]Patent: US2009/93481,2009,A1 .Location in patent: Page/Page column 6-7

24
[ 951676-03-2 ]
[ 97004-04-1 ]
[ 951675-89-1 ]

Yield	Reaction Conditions	Operation in experiment
73%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 21h;	Example V-1; 5-[2-([(6-Chloropyridin-3-yl)methyl]amino}methyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one (R1, R2H; B, Q=O; E-(D2)-Z-(D1)CHCH2C(CH2)CH2-; LG=N-pyrrolidino; A=6-chloropyrid-3-yl); At 60° C., 600 mg (2.48 mmol) of 5-[2-(chloromethyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one (V-1a), 354 mg (2.48 mmol) of <strong>[97004-04-1]1-<strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong></strong> and 0.43 ml (2.48 mmol) of N-ethyl-N-isopropylpropan-2-amine in 10 ml of acetonitrile are stirred for 21 hours. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture dichloromethane:methanol (98:2 to 90:10) gives 650 mg (73percent of theory) of 5-[2-([(6-chloropyridin-3-yl)methyl]amino}methyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one.1H-NMR (CD3CN): delta [ppm]=1.85 (m, 2H), 1.96 (m, 2H), 2.26 (dd, 1H), 2.80 (dd, 1H), 3.15 (m, 2H), 3.18 (d, 1H), 3.24 (d, 1H), 3.39 (m, 2H), 3.70 (s, 2H), 4.37 (s, 1H), 4.97 (s, 1H), 5.05 (dd, 1H), 5.09 (s, 1H), 7.34 (d, 1H), 7.72 (dd, 1H), 8.30 (d, 1H).

Reference： [1]Patent: US2009/181947,2009,A1 .Location in patent: Page/Page column 37

25
[ 372-48-5 ]
[ 97004-04-1 ]
[ 1176959-81-1 ]

Yield	Reaction Conditions	Operation in experiment
	In 1-methyl-pyrrolidin-2-one; at 230℃; for 0.5h;Microwave irradiation;	A mixture of 2-fluoropyridine (1.4 g, 15 mmol) and 6-chloro-3-pyridinemethanamine(alternatively named 5-aminomethyl-2-chloropyridine) (2.55 g, 18 mmol) in N- methylpyrrolidinone (5 mL) was heated at 230 0C in a microwave reactor for 30 min. This reaction was repeated four times using the same amounts of starting materials for each repetition. All five of the reaction mixtures were then poured into saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over Na2SC^, and concentrated under reduced pressure. The crude product was then purified by chromatography on silica gel using 10percent ethyl acetate in hexanes as the eluent to provide the title compound as an oil (5.1 g)- 1H NMR (CDCl3) delta 8.38 (s, IH), 8.1 (m, IH), 7.67 (d, IH), 7.42 (dd, IH), 7.28 (d, IH), 6.63(m, IH), 6.38 (d, IH), 4.88 (s, IH), 4.56 (d, 2H).
		SYNTHESIS EXAMPLE 2Preparation of l-[(6-chloro-3-pyridinyl)methyl]-3-[2-fluoro-5-(trifluoromethoxy)phenyl]- 2-hydroxy-4-oxo-4H-pyrido[l,2-alpha]pyrimidinium inner saltStep A: Preparation of 6-chloro-Lambda/-2-pyridinyl-3-pyridinemethanamineA mixture of 2-fluoropyridine (1.4 g, 15 mmol) and 6-chloro-3-pyridinemethanamine(2.55 g, 18 mmol) in JV-methylpyrrolidinone (5 mL) was heated at 230 0C in a microwave reactor for 30 min. This reaction was repeated four times using the same amounts of starting materials for each repetition. All five of the reaction mixtures were then poured into saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over Na2SC^, and concentrated under reduced pressure. The crude product was then purified by chromatography on silica gel using 10percent ethyl acetate in hexanes as the eluent to provide the title compound as an oil (5.1 g).1H NMR (CDCl3) delta 8.38 (s, IH), 8.1 (m, IH), 7.67 (d, IH), 7.42 (dd, IH), 7.28 (d, IH), 6.63 (m, IH), 6.38 (d, IH), 4.88 (s, IH), 4.56 (d, 2H).

Reference： [1]Patent: WO2009/99929,2009,A1 .Location in patent: Page/Page column 68
[2]Patent: WO2011/17351,2011,A2 .Location in patent: Page/Page column 28

26
[ 1192277-18-1 ]
[ 97004-04-1 ]
[ 1192277-16-9 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of tert-butyl 2-((2i?,65',E)-5,12-dioxo-2- phenyl-l-oxa-4-azacyclododec-8-en-6-yl)acetate (200 mg, 0.516 mmol) in CH2Cl2 (397 mL) cooled in an ice/water bath was added trifluoroacetic acid (179 muL, 2.32 mmol) and the reaction mixture was stirred 1 h at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was concentrated and a portion of the crude carboxylic acid was utilized immediately. To a solution of crude 2-((2i?,65'Ji)-5,12-dioxo-2-phenyl-l-oxa- 4-azacyclododec-8-en-6-yl)acetic acid (86 mg, 0.260 mmol) in CH2Cl2 (3.2 mL) cooled in an ice/water bath was added EDC (74.6 mg, 0.389 mmol) and HOBt (52.6 mg, 0.389 mmol) and the resulting solution was stirred 30 min. 2-chloro-5-aminomethylpyridine (40.7 mg, 0.285 mmol), /Pr2NEt (139 muL, 0.779 mmol) and DMAP (3.2 mg, 0.026 mmol) were subsequently added and the reaction mixture was slowly warmed to rt and stirred for 16h at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was diluted with saturated NH4CI and EtOAc and the layers separated. The aqueous was extracted 2x with EtOAc and the combined organic extracts were washed with 1 N HCl and brine, dried over Na2Spsi4, filtered, and concentrated. The crude product was purified using silica gel chromatography (MeOH/CH2Cl2 gradient) to yield the desired product as a colorless oil. LRMS (M + H)+: 456.1.

Reference： [1]Patent: WO2009/132032,2009,A2 .Location in patent: Page/Page column 111

27
[ 541-57-1 ]
[ 97004-04-1 ]
4-[[(6-chloropyridin-3-yl)methyl]-amino]furan-2(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	toluene-4-sulfonic acid; In toluene; for 24h;Reflux;	4-[[(6-Chloropyridin-3-yl)methyl]amino]furan-2(5H)-one (cf. EP 0539588 A1) On a water separator, 5.00 g (35.1 mmol) of 1-<strong>[97004-04-1](6-chloropyridin-3-yl)methylamine</strong>, 3.51 g (35.1 mmol) of tetronic acid and 20 mg (0.12 mmol) of 4-toluenesulphonic acid in 200 ml of toluene are heated under reflux for 24 hours. The reaction mixture is concentrated, and the residue that remains is then purified by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate. This gives 4.96 g (63percent of theory) of 4-[[(6-chloropyridin-3-yl)methyl]amino]furan-2(5H)-one, which can be used for subsequent reactions. 1H-NMR (CDCl3, delta ppm)=4.35 (d, 2H), 4.70 (s, 2H), 4.80 (s, 1H), 4.95 (br. s, 1H), 7.36 (d, 1H), 7.61 (dd, 1H), 8.37 (d, 1H).

Reference： [1]Patent: US2009/253749,2009,A1 .Location in patent: Page/Page column 23

28
[ 1080018-12-7 ]
[ 97004-04-1 ]

Yield	Reaction Conditions	Operation in experiment
95%		(Example 5) Production of (2-chlorogyridin-5-yl)methylamine (4); To 0.77 g (1.66 mol) of 1,3,5-tris[(2-chloropyridin-5-yl)methyl]-1,3,5-perhydrotriazine (II-4) were sequentially added 0.40 g of methanol and 1.83 g of concentrated hydrochloric acid, and the resulting mixture was stirred at 75 to 80°C for 6 hours. The reaction mixture was then diluted with chloroform, and following conversion of the mixture to an alkaline state by adding a 28percent aqueous solution of sodium hydroxide, the chloroform layer was separated and concentrated, yielding 0.68 g (yield: 95percent) of (2-chloropyridin-5-yl)methylamine (III-1).
95%		Example 5 Production of (2-chloropyridin-5-yl)methylamine (4) To 0.77 g (1.66 mol) of 1,3,5-tris[(2-chloropyridin-5-yl)methyl]-1,3,5-perhydrotriazine (II-4) were sequentially added 0.40 g of methanol and 1.83 g of concentrated hydrochloric acid, and the resulting mixture was stirred at 75 to 80° C. for 6 hours. The reaction mixture was then diluted with chloroform, and following conversion of the mixture to an alkaline state by adding a 28percent aqueous solution of sodium hydroxide, the chloroform layer was separated and concentrated, yielding 0.68 g (yield: 95percent) of (2-chloropyridin-5-yl)methylamine (III-1).

Reference： [1]Patent: EP2141149,2010,A1 .Location in patent: Page/Page column 17
[2]Patent: US2010/121054,2010,A1 .Location in patent: Page/Page column 9

29
[ 22842-59-7 ]
[ 97004-04-1 ]
[ 1202497-65-1 ]

Yield	Reaction Conditions	Operation in experiment
31%	With sodium tetrahydroborate; In methanol; at 0 - 20℃;	A solution of 3-allylsulfanyl-propionaldehyde (1.5 g, 11.8 mmol) in MeOH (15 ml.) was added to a solution of C-(6-chloro-pytauidin-3-yl)-methylamine (1.8 g, 12.6 mmol) in MeOH (15 ml.) at 0 0C. The resulting solution was stirred at this temperature for 1 h, then sodium borohydride (960 mg, 25.3 mmol) was added portionwise and stirring was continued for 16 h at room temperature. Volatiles were removed under reduced pressure and the residue was redissolved in CH2CI2 and washed with saturated aqueous NaHCU3 solution. The organic phase was dried over MgSO4 and evaporated. Flash column chromatography purification (NH2-modified Sipsi2, gradient of cyclohex- ane/EtOAc) of the residue yielded 950 mg (31 percent) of allyl sulfide (1.2).1H-NMR: delta 8.31 (d, J = 2.7 Hz, 1 H), 7.66 (dd, J = 8.2, 2.7 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1 H), 5.76 (m, 1 H), 5.08 (m, 2 H), 3.77 (s, 2 H), 3.11 (d, J = 7.1 Hz, 2 H), 2.70 (t, J = 7.1 Hz, 2 H), 2.51 (t, J = 7.1 Hz, 2 H), 1.75 (q, J = 7.1 Hz, 2 H) ppm.

Reference： [1]Patent: WO2009/156336,2009,A1 .Location in patent: Page/Page column 113

30
[ 676-85-7 ]
[ 97004-04-1 ]
[ 1202497-67-3 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran at 0 - 20℃;	S.2.1 Methanesulfinyl chloride was obtained as described in the literature. A solution of C-(6- chloro-pyridin-3-yl)-methylamine (2.1 ) (25 g, 178 mmol) in tetrahydrofuran ( 200 ml) was cooled to 00C and methanesulfinyl chloride (7 g, 71 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred for 16 hours. The precipitate was removed by filtration, the filtrate was diluted with EtOAc and washed with H2O. The organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (gradient of cyclohex- ane/EtOAc) to yield 7,2Og of the Methanesulfinic acid (6-chloro-pyridin-3-yl methyl- amide (2.2). LC-MS [M+H]+ 205,1. tR = 1.46 min

Reference： [1]Current Patent Assignee: BASF SE - WO2009/156336, 2009, A1 Location in patent: Page/Page column 115

31
[ 5652-84-6 ]
[ 97004-04-1 ]
[ 135410-03-6 ]

Yield	Reaction Conditions	Operation in experiment
52%	In methanol; at 20℃; for 3h;	At room temperature, 500 mg (3.51 mmol) of <strong>[97004-04-1]1-<strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong></strong> and 378 mg (3.86 mmol) of methyl N-cyanoethanimidoacetate in 10 ml of methanol are stirred for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by recrystallization from ethyl acetate/cyclohexane, giving 532 mg (52% of theory) of N-[(6-cyloropyridin-3-yl)methyl]-N-cyanoethanimidamideLC-MS: m/z=209.0 (M+H+, 100%).

Reference： [1]Patent: US2010/48646,2010,A1 .Location in patent: Page/Page column 27

32
[ 1227946-80-6 ]
[ 97004-04-1 ]
[ 1227946-42-0 ]

Yield	Reaction Conditions	Operation in experiment
28%	With 2-chloro-1,3-dimethylimidazolinium chloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	Example 4; 3- [5,6-Bis(methyloxy)-2-pyridinyll -N- [(6-chloro-3-pyridinyl)methyll -2,4-dioxo-l ,2,3,4- tetrahydrothieno[3,2-</\|pyrimidine-6-carboxamide To a mixture of 3-[5,6-bis(methyloxy)-2-pyridinyl]-2,4-dioxo- 1,2,3,4- tetrahydrothieno[3,2-d]pyrimidine-6-carboxylic acid (Id, 87 mg, 0.25 mmol), [(6-chloro-3- pyridinyl)methyl] amine (35.6 mg, 0.250 mmol), and 2-chloro-l,3-dimethylimidazolinium chloride (63.4 mg, 0.375 mmol) in N,N-dimethylformamide (DMF) (1.50 ml) was added DIEA (0.065 ml, 0.375 mmol). The mixture was stirred at room temperature overnight and purified by reversed- phase HPLC to provide 3-[5,6-bis(methyloxy)-2-pyridinyl]-N-[(6-chloro-3-pyridinyl)methyl]-2,4- dioxo-l,2,3,4-tetrahydrothieno[3,2-<i]pyrimidme-6-carboxamide. (33 mg, 28percent); MS(ES+) m/e 474 (MH+); IH NMR (400 MHz, OMSO-d6) delta ppm 3.80 (s, 3 H) 3.85 (s, 3 H) 4.50 (d, J=5.56 Hz, 2 H) 7.03 (d, J=8.08 Hz, 1 H) 7.45 (d, J=8.08 Hz, 1 H) 7.53 (d, J=8.34 Hz, 1 H) 7.65 (s, 1 H) 7.83 (dd, J=8.21, 2.40 Hz, 1 H) 8.41 (d, J=2.27 Hz, 1 H) 9.63 (t, J=5.68 Hz, 1 H) 12.28 (s, 1 H).

Reference： [1]Patent: WO2010/59555,2010,A1 .Location in patent: Page/Page column 18-19

33
[ 92741-40-7 ]
[ 97004-04-1 ]
[ 1246040-74-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dimethyl sulfoxide; at 150℃; for 0.333333h;	6-Chloro-3-nitro-2-pyrrolidin-1 -yl-pyridine (2.00 g, 8.79 mmol) was dissolved in DMSO (20 ml_) followed by addition of triethylamine (3.06 ml_, 22.0 mmol) and 5-aminomethyl-2-chloropyridine (1.23 ml_, 10.5 mmol). The mixture was heated at 1500C for 20 minutes. After cooling the mixture was poured into saturated NaHCO3 (200 ml_), the aqueous phase was extracted with ether (2 x 100 ml_), the combined organic phases were dried (MgSO4) and evaporated in vacuo. The crude product was purified by column chromatography (heptane/ethyl acetate) yielding the title compound (2.93 g, 100percent).

Reference： [1]Patent: WO2010/105960,2010,A1 .Location in patent: Page/Page column 23

34
[ 359-07-9 ]
[ 97004-04-1 ]
[ 1003859-14-0 ]

Yield	Reaction Conditions	Operation in experiment
83.1%	With 1-methyl-pyrrolidin-2-one; triethylamine; at 100℃; for 2h;	EXAMPLE 219.9 g (0.135 mol) of 2,2-difluoro-1-bromoethane, 10 g (0.067 mol) of <strong>[97004-04-1]1-<strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong></strong> and 8.2 g of triethylamine are initially charged with 31 g of N-methylpyrrolidone.The mixture is heated to 100° C. for 2 hours and then cooled again to 80° C.The N-methylpyrrolidone is distilled off at 80° C. under reduced pressure and the reaction mixture is poured onto 50 ml of water.2 ml of 45percent sodium hydroxide solution are used to adjust the pH to 12, and the mixture is then extracted twice with 30 ml of toluene.The product is subsequently finely distilled under reduced pressure.This gives 11.5 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine (corresponds to 83.1percent yield).NMR (d-DMSO): 1H (s, 8.35 ppm); 1H (dd, 7.82 ppm); 1H (d, 7.46 ppm); 1H (tt, 6.02 ppm); 2 H (s, 3.8 ppm); 2H (td, 2.9 ppm)

Reference： [1]Patent: US2011/306770,2011,A1 .Location in patent: Page/Page column 5

35
[ 338-65-8 ]
[ 97004-04-1 ]
[ 1003859-14-0 ]

Yield	Reaction Conditions	Operation in experiment
71%	With 1-methyl-pyrrolidin-2-one; triethylamine; potassium bromide; at 120℃; for 16h;Autoclave;	EXAMPLE 313.7 g (0.135 mol) of 2,2-difluoro-1-chloroethane, 10 g (0.067 mol) of <strong>[97004-04-1]1-<strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong></strong> and 8.2 g of triethylamine are initially charged with 31 g of N-methylpyrrolidone.In addition, 4 g (0.033 mol) of potassium bromide are added.The mixture is heated to 120° C. under autogenous pressure in an autoclave for 16 hours and then cooled again to 80° C.The N-methylpyrrolidone is distilled off at 80° C. under reduced pressure and the reaction mixture is poured onto 20 ml of 32percent hydrochloric acid.The mixture is concentrated to dryness under reduced pressure and then adjusted to pH 12 with 10 ml of 45percent NaOH.The mixture is extracted three times with 30 ml of toluene and the organic phases are distilled under reduced pressure.This gives 9.8 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine (corresponds to 71percent yield).NMR (d-DMSO): 1H (s, 8.35 ppm); 1H (dd, 7.82 ppm); 1H (d, 7.46 ppm); 1H (tt, 6.02 ppm); 2 H (s, 3.8 ppm); 2H (td, 2.9 ppm)

Reference： [1]Patent: US2011/306770,2011,A1 .Location in patent: Page/Page column 5

36
[ 598-39-0 ]
[ 97004-04-1 ]
[ 1003859-14-0 ]

Yield	Reaction Conditions	Operation in experiment
79.5%	With 1-methyl-pyrrolidin-2-one; triethylamine; at 100℃; for 0.833333h;	EXAMPLE 126.3 g (0.135 mol) of 2,2-difluoro-1-iodoethane, 10 g (0.067 mol) of <strong>[97004-04-1]1-<strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong></strong> and 8.2 g of triethylamine are initially charged with 31 g of N-methylpyrrolidone.The mixture is heated to 100° C. for 50 minutes and then cooled again to 80° C.The N-methylpyrrolidone is distilled off at 80° C. under reduced pressure and the reaction mixture is poured onto 50 ml of water.3 ml of 45percent sodium hydroxide solution are used to adjust the pH to 12, and the mixture is then extracted twice with 30 ml of toluene.The product is subsequently finely distilled under reduced pressure.This gives 11.1 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine (corresponds to 79.5percent yield).NMR (d-DMSO): 1H (s, 8.35 ppm); 1H (dd, 7.82 ppm); 1H (d, 7.46 ppm); 1H (tt, 6.02 ppm); 2 H (s, 3.8 ppm); 2H (td, 2.9 ppm)

Reference： [1]Patent: US2011/306770,2011,A1 .Location in patent: Page/Page column 4-5

37
[ 35351-34-9 ]
[ 97004-04-1 ]
[ 1225380-37-9 ]

Yield	Reaction Conditions	Operation in experiment
56%	In methanol; at 20℃; for 72h;	Step 2: Methyl 1-[(6-chloropyridin-3-yl)methyl]-5-methyl-1H-pyrrole-3-carboxylate A mixture of 4.20 g (22.73 mmol, purity of 85percent) of the compound from Example 50A/step 1 and 3.24 g (22.73 mmol) of <strong>[97004-04-1]5-(aminomethyl)-2-chloropyridine</strong> in 42 ml of methanol was stirred at RT for three days. The solvent was then removed on a rotary evaporator and the crude product was purified by means of MPLC (silica gel, cyclohexane/ethyl acetate 2:1). 3.37 g (56percent of th.) of the title compound were obtained. 1H-NMR (400 MHz, CDCl3, delta/ppm): 8.19 (d, 1H), 7.30-7.20 (m, 3H), 6.38 (d, 1H), 5.03 (s, 2H), 3.79 (s, 3H), 2.12 (s, 3H).
	In methanol; at 20℃; for 72h;	A mixture of 4.20 g (22.73 mmol, purity of 85percent) of the compound from Example 46A/step 1 and 3.24 g (22.73 mmol) of <strong>[97004-04-1]5-(aminomethyl)-2-chloropyridine</strong> in 42 ml of methanol was stirred at RT for three days. The solvent was then removed on a rotary evaporator and the crude product was purified by means of MPLC (silica gel, mobile phase: cyclohexane/ethyl acetate 2:1). 3.37 g (56percent of th.) of the title compound were obtained.1H-NMR (400 MHz, CDCl3, delta/ppm): 8.19 (d, 1H), 7.30-7.20 (m, 3H), 6.38 (d, 1H), 5.03 (s, 2H), 3.79 (s, 3H), 2.12 (s, 3H).HPLC (method A): Rt=4.10 min.MS (DCI, NH3): m/z=265 [M+H]+.
	In methanol; at 20℃; for 72h;	Step 2: Methyl 1-[(6-chloropyridin-3-yl)methyl]-5-methyl-1H-pyrrole-3-carboxylate ; A mixture of 4.20 g (22.73 mmol, purity 85percent) of the compound from Example 37A/step 1 and 3.24 g (22.73 mmol) of <strong>[97004-04-1]5-(aminomethyl)-2-chloropyridine</strong> in 42 ml of methanol was stirred at RT for three days. The solvent was then removed on a rotary evaporator and the crude product was purified by MPLC (silica gel, cyclohexane/ethyl acetate 2:1). 3.37 g (56percent of theory) of the title compound were obtained.1H-NMR (400 MHz, CDCl3, delta/ppm): 8.19 (d, 1H), 7.30-7.20 (m, 3H), 6.38 (d, 1H), 5.03 (s, 2H), 3.79 (s, 3H), 2.12 (s, 3H).HPLC (method A): Rt=4.10 min.MS (DCI, NH3): m/z=265 [M+H]+.

Reference： [1]Patent: US2013/196964,2013,A1 .Location in patent: Paragraph 1025; 1026; 1027; 1028
[2]Patent: US2011/301122,2011,A1 .Location in patent: Page/Page column 45
[3]Patent: US2011/312930,2011,A1 .Location in patent: Page/Page column 48

38
[ 33252-28-7 ]
[ 97004-04-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium borohydride; In ethanol; at 25 - 40℃; for 2.25h;	Synthesis of l-(6-Chloropyridin-3-Yl)MethanamineTo a solution of 6-chloropyridin-3-carbonitrile (1 g, 7.21 mmoles) in ethanol (15 ml) was added potassium borohydride (1.55 g, 28.87 mmoles) and Raney Nickel (0.5 g) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and then at 40°C for 2 hours. After completion, the reaction mixture was filtered through a prewashed celite pad in ethanol and concentrated. It was then diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated solution of ammonium chloride, water and brine, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford the title compound as brown oil. Yield: 0.7 g.Mass spectrum (m/z, +ve ion mode): 143 [M++l]

Reference： [1]Patent: WO2011/161615,2011,A1 .Location in patent: Page/Page column 58
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 7965 - 7983

39
[ 97004-04-1 ]
[ 401815-98-3 ]
[ 1354355-53-5 ]

Yield	Reaction Conditions	Operation in experiment
	dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In iso-butanol; at 100℃;Inert atmosphere;	Example 10N-((2'-fluoro-r2,4'-bipyridinl-5-yl)methyl)-4-(pyrazin-2-yl)benzamide (24) [0179] Step 1: A mixture of (2-fluoropyridin-4-yl)boronic acid 24-1 (200 mg, 1.42 mmol), <strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong> 18-1 (142 mg, 1.00 mmol), Pd(OAc)2 (12 mg, 0.05 mmol), dicyclohexyl(2',6'-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine (41 mg, 0.1 mmol) and K3PO4 (424 mg, 2.00 mmol) in 2-butanol (1 mL) was stirred at 100 °C under argon overnight. After cooling to room temperature, the mixture was filtered through celite (washed with ethyl acetate), concentrated by rotavap and the residue subjected to silica gel columnchromatography with 7percent ammonia- saturated methanol in dichloromethane as eluent to give (2'-fluoro-[2,4'-bipyridin]-5-yl)methanamine 24-2 as an oil.
	With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In iso-butanol; at 100℃; for 10h;Inert atmosphere;	Example 146'-(Dimethylamino)-N-((2'-fluoro-2^'-bipyridin-5-yl)methyl)-3 '-bipyridine-6-carboxamide(38)38-4 38-5 Compound 38[0192] Step 1 : To a flask containing <strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong> 33-2 (642 mg, 4.50 mmol), 2-fluoropyridin-4-ylboronic acid 38-1 (634 mg, 4.50 mmol), Pd(OAc)2 (51 mg, 0.23 mmol), S-Phos (186 mg, 0.45 mmol) and potassium phosphate (2.85 g, 13.50 mmol) under argon was added 2-butanol (5 mL). The mixture was stirred at 100 °C for 10 hours. After cooling to room temperature, the mixture was filtered through celite cake. The filtrate was diluted with ethyl acetate, washed with H20 and brine, dried over Na2S04, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flashchromatography, eluted with 5percent methanol containing ~ 7N ammonia in dichloromethane to give (2'-fluoro-2,4'-bipyridin-5-yl)methanamine 38-2 as yellow solid. MS m/z 204.1 (M + 1)

Reference： [1]Patent: WO2012/3189,2012,A1 .Location in patent: Page/Page column 82-83
[2]Patent: WO2012/3189,2012,A1 .Location in patent: Page/Page column 88

40
[ 97004-04-1 ]
[ 579476-63-4 ]
[ 1354355-39-7 ]

Yield	Reaction Conditions	Operation in experiment
45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	(6-chloropyridin-3-yl)methanamine (300mg, 2.1 mmol) and 2-methylpyridin-4-ylboronic acid (345mg, 2.52 mmol) were dissolved in a pressure tube with n-butanol (10 mL) and water (2 mL), K3P04 (893mg, 4.2mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), and S-phos (86.4 mg, 0.21mmol) were added under the nitrogen protection. The reaction was heated to 125C for 30 minutes and then cooled down to room temperature. The solution was pull in water and extracted by EA for three times. The combined organic layer was washed by brine and dried over Na2S04, and concentrated under the vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~2N NH3) in DCM to get the pure (6-(2-methylpyridin-4-yl)pyridin-3-yl)methanarnine (0.19g , yield -45%). MS m/z 200.1 (M + 1).
Ca. 45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	Step 3: (6-chloropyridin-3-yl)methanamine (300mg, 2.1 mmol) and 2-methylpyridin-4-ylboronic acid (345mg, 2.52 mmol) were dissolved in a pressure tube with n-butanol (10 mL) and water (2 mL). K3P04 (893mg, 4.2mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), and S-phos (86.4 mg, 0.21mmol) were added under the nitrogen protection. The reaction was heated to 125C for 30 minutes and then cooled down to room temperature. The solution was pull in water and extracted by EA for three times. The combined organic layer was washed by brine and dried over Na2S04, and concentrated under the vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~2N NH3) in DCM to get the pure (6-(2-rnethylpyridin-4-yl)pyridin-3-yl)methanainine (0.19g , yield -45%). MS m z 200.1 (M + 1).
Ca. 45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	[0191] (6-chloropyridin-3-yl)methanamine (300mg, 2.1 mmol) and 2-methylpyridin-4-ylboronic acid (345mg, 2.52 mmol) were dissolved in a pressure tube with n-butanol (10 mL) and water (2 mL). K3PO4 (893mg, 4.2mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), and S-phos (86.4 mg, 0.21mmol) were added under the nitrogen protection. The reaction was heated to 125C for 30 minutes and then cooled down to room temperature. The solution was pull in water and extracted by EA for three times. The combined organic layer was washed by brine and dried over Na2S04, and concentrated under the vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~2N NH3) in DCM to get the pure (6-(2-methylpyridin-4-yl)pyridin-3-yl)methanamine (0.19g , yield -45%). MS m/z 200.1 (M + 1).

Ca. 45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	(6-chloropyridin-3-yl)methanamine (300mg, 2.1 mmol) and 2-methylpyridin-4-ylboronic acid (345mg, 2.52 mmol) were dissolved in a pressure tube with n-butanol (10 mL) and water (2 mL). K3PO4 (893mg, 4.2mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), and S-phos (86.4 mg, 0.21mmol) were added under the nitrogen protection. The reaction was heated to 125C for 30 minutes and then cooled down to room temperature. The solution was pull in water and extracted by EA for three times. The combined organic layer was washed by brine and dried over Na2SO4, and concentrated under the vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~2N NH3) in DCM to get the pure (6-(2-methylpyridin-4-yl)pyridin-3-yl)methanamine (0.19g , yield -45%). MS m/z 200.1 (M + 1).
Ca. 45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	6-chloropyridin-3-yl)methanamine (300 mg, 2.1 mmol) and 2-methylpyridin-4-ylboronic acid (345 mg, 2.52 mmol) were dissolved in a pressure tube with n-butanol (10 mL) and water (2 mL). K3PO4 (893 mg, 4.2 mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), and S-phos (86.4 mg, 0.21 mmol) were added under the nitrogen protection. The reaction was heated to 125 C. for 30 minutes and then cooled down to room temperature. The solution was pull in water and extracted by EA for three times. The combined organic layer was washed by brine and dried over Na2SO4, and concentrated under the vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~2N NH3) in DCM to get the pure (6-(2-methylpyridin-4-yl)pyridin-3-yl)methanamine (0.19 g, yield ~45%). MS m/z 200.1 (M+1).
Ca. 45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Sealed tube; Inert atmosphere;	(6-chloropyridin-3-yl) methanamine (300 mg, 2.1 mmol) and 2-methylpyridine 4-ylboronic acid (345 mg, 2.52 mmol) was dissolved in n-butanol (10 mL) and water (2 mL) In a pressure tube. K 3 PO 4 (893 mg, 4.2 mmol), Pd 2 (dba) 3 (96.3 mg, 0.105 mmol) and S-phos (86.4 mg, 0.21 mmol) were added under nitrogen protection. The reaction was heated to 125 C. for 30 minutes and then cooled to room temperature. The solution was poured into water, And 3 times with EA. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude was further purified by flash chromatography with 10% MeOH in DCM (containing ~ 2 N NH3) to give pure (6- (2-methylpyridin-4-yl) pyridin-3-yl) methanamine (0.19 G, yield ~ 45%).
45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	6-chloropyridin-3-yl)methanamine (300mg, 2.1 mmol) and 2-methylpyridin-4- ylboronic acid (345mg, 2.52 mmol) were dissolved in a pressure tube with n-butanol (10 mL) and water (2 mL). K3P04 (893mg, 4.2mmol), Pd2(dba)3 (96.3 mg, 0.105 mmol), and S-phos (86.4 mg, 0.21 mmol) were added under the nitrogen protection. The reaction was heated to 125C for 30 minutes and then cooled down to room temperature. The solution was pull in water and extracted by EA for three times. The combined organic layer was washed by brine and dried over Na2S04, and concentrated under the vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~2N NH3) in DCM to get the pure (6- (2-methylpyridin-4-yl)pyridin-3-yl)methanamine (0.19g , yield -45%). MS m/z 200.1 (M + 1).
	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 96℃;Inert atmosphere;	Example 7N-((2'-methyl-r2,4'-bipyridinl-5-yl)methyl)-4-(pyrazin-2-yl)benzamide (18) Compound 18[0169] Step 1: A mixture of <strong>[579476-63-4](2-methylpyridin-4-yl)boronic acid</strong> 15-1 (476 mg, 3.48 mmol), (6-chloropyridin-3-yl)methanamine 18-1 (496 mg, 3.48 mmol), Pd(PPh3)4 (202 mg, 0.175 mmol) and K3P04 (1113 mg, 5.25 mmol) in dioxane (5 mL) was stirred at 96 C under argon overnight. After cooling to room temperature, the mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated by rotavap and the residue subjected to silica gel column chromatography with 7% ammonia-saturated methanol in dichloromethane as eluent to give (2'-methyl-[2,4'-bipyridin]-5-yl)methanamine 18-2 as an oil.

Reference： [1]Patent: WO2012/88712,2012,A1 .Location in patent: Page/Page column 16-17
[2]Patent: WO2013/185353,2013,A1 .Location in patent: Page/Page column 28
[3]Patent: WO2014/159733,2014,A1 .Location in patent: Paragraph 0190-0191
[4]Patent: WO2014/165232,2014,A1 .Location in patent: Paragraph 0204; 0205
[5]Patent: US2015/119387,2015,A1 .Location in patent: Paragraph 0205; 0206
[6]Patent: JP2017/95498,2017,A .Location in patent: Paragraph 0125; 0126
[7]Patent: WO2016/191525,2016,A1 .Location in patent: Paragraph 0259-0260
[8]Patent: WO2012/3189,2012,A1 .Location in patent: Page/Page column 78-79

41
[ 1093407-58-9 ]
[ 97004-04-1 ]
[ 1354355-66-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In iso-butanol; at 100℃; for 10h;Inert atmosphere;	Example 135-(3-Fluorophenyl)-N-((2'-(trifluoromethyl)-2,4'-bipyridin-5-yl)methyl)picolinamide (33)6-7 33-3 Compound 33[0188] Step 1: To a flask containing <strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong> 33-2 (375 mg, 2.63 mmol), 2-(trifluoromethyl)pyridin-4-ylboronic acid 33-1 (500 mg, 2.63 mmol), Pd(OAc)2 (34 mg, 0.15 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos) (124 mg, 0.30 mmol) and potassium phosphate (1.90 g, 9.00 mmol) under argon was added 2-butanol (4 mL). The mixture was stirred at 100 °C for 10 hours. After cooling to room temperature, the mixture was filtered through celite cake. The filtrate was diluted with ethyl acetate, washed with H20 and brine, dried over Na2S04, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5percent methanol containing ~ 7N ammonia in dichloromethane to give (2'-(trifluoromethyl)-2,4'-bipyridin-5- yl)methanamine 33-3 as a yellow solid. MS m/z 254.1 (M + 1)

Reference： [1]Patent: WO2012/3189,2012,A1 .Location in patent: Page/Page column 86-87

42
[ 430-69-3 ]
[ 97004-04-1 ]
[ 1245351-02-3 ]

Yield	Reaction Conditions	Operation in experiment
93.8%	In toluene; at 20℃; for 1.33333h;	Example 11-(6-Chloropyridin-3-yl)-N-[(1E)-2,2-difluoroethylidene]methanamineTo a solution of 63.73 g of 6-chloro-3-aminomethylpyridine in 41 g of toluene were added 35.4 g of 2,2-difluoroacetaldehyde at room temperature.After addition of the 2,2-difluoroacetaldehyde, the initial suspension became a clear solution over the course of 20 min.The reaction mixture was stirred at room temperature for 2 hours.Subsequently, 106 g of anhydrous magnesium sulphate were added and the mixture was stirred at 50° C. for a further 5 hours.The reaction mixture was cooled to room temperature and filtered, and the filter residue was washed with toluene.The solvent was removed under reduced pressure and the oily residue was distilled at 4 mbar.This gave 85.3 g of 1-(6-chloropyridin-3-yl)-N-[(1E)-2,2-difluoroethylidene]methanamine 99.5percent (this corresponds to 93.8percent yield).1H NMR (CDCl3, 298K) delta: 4.7 s (2H), 5.9-6.2 t (1H, CHF2), 7.43 d (1H), 7.6 d (1H), 7.7 d (1H), 8.3 s(1H)

Reference： [1]Patent: US2012/22264,2012,A1 .Location in patent: Page/Page column 6

43
[ 19975-56-5 ]
[ 97004-04-1 ]
[ 211555-73-6 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;Reflux;	A mixture of 4,5-dihydro-2-(methylthio)thiazole (1.46 g, 10 mmol) and 6-chloro-3- pyridinemethanamine (1.43 g, 10 mmol) in ethanol (30 mL) was heated to reflux overnight.The reaction mixture was cooled, concentrated under reduced pressure, and triturated with diethyl ether to yield the title compound.1H NMR (CDCl3) delta 8.33 (d, IH), 7.65 (dd, IH), 7.29 (d, IH), 4.47 (s, 2H), 3.96 (t, 2H), 3.36(t, 2H).

Reference： [1]Patent: WO2011/17347,2011,A2 .Location in patent: Page/Page column 53

44
[ 67-64-1 ]
[ 97004-04-1 ]
[ 120739-83-5 ]

Yield	Reaction Conditions	Operation in experiment
36%		Synthesis Example 4 2-chloro-5-(N-cyano-N-2-isopropyl)aminomethylpyridine (Compound 15) Acetone (2 mL) and 1 mL of methanol were added to 50 mg (0.26 mmol) of 2-chloro-5-aminoethylpyridine, 43 mg (0.52 mmol) of sodium acetate was added, and the mixture was stirred at room temperature for 4 hours. Next, 30 mg (0.78 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and then concentrated, after which ethyl acetate and water were added and liquid-liquid extraction was carried out. The organic phase was dried over anhydrous magnesium sulfate, then concentrated and subsequently purified on a preparative TLC plate, giving 17 mg of 2-chloro-5-[N-(2-isopropylaminomethyl)]pyridine (yield, 36percent). Using 57 mg of the resulting 2-chloro-5-[N-(2-isopropylaminomethyl)]pyridine, 54 mg of the target compound (yield, 47percent) was obtained by the method described in Synthesis Example 1.

Reference： [1]Patent: US2013/150414,2013,A1 .Location in patent: Paragraph 0334

45
[ 97004-04-1 ]
[ 491593-46-5 ]

Yield	Reaction Conditions	Operation in experiment
35%	With bromocyane; In chloroform; at 0℃; for 1h;	Comparative Example 1 N-[(6-chloropyridin-3-yl)methyl]cyanamide (JP 2003-26661 A, Compound 1) Cyanogen bromide (220 mg, 2.09 mmol) was dissolved in 10 mL of anhydrous chloroform, and the solution was cooled to 0° C. To this was dropwise added a solution of 500 mg (3.49 mmol) of 2-chloro-5-aminomethylpyridine dissolved in 10 mL of anhydrous chloroform, and the resulting mixture was stirred at 0° C. for 1 hour. The reaction mixture was filtered, then water was added and liquid-liquid extraction was carried out, following which the chloroform phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane/ethyl acetate=1:1), giving 122 mg (yield, 35percent) of the target compound. 1H-NMR (CDCl3, delta, ppm): 4.21 (2H, s), 5.74 (1H, brs), 7.36 (1H, d), 7.71 (1H, dd), 8.30 (1H, d) 13C-NMR (CDCl3, delta, ppm): 46.5, 116.1, 124.8, 131.5, 138.9, 148.9, 151.4 MS: m/z=166 (M-H)

Reference： [1]Patent: US2013/150414,2013,A1 .Location in patent: Paragraph 0444; 0445; 0446; 0447

46
[ 106-96-7 ]
[ 97004-04-1 ]
[ 1363400-95-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 70℃; for 3.5h;	Synthesis Example 5 2-chloro-5-[N-cyano-N-(2-propargyl)]aminomethylpyridine (Compound 42) 2-chloro-5-aminoethylpyridine (1.50 g, 10.6 mmol) was dissolved in 10 mL of anhydrous dimethylformamide, then 486 mg (net weight, 292 mg; 12.7 mmol) of 60percent sodium hydride and 1.25 g (10.6 mmol) of propargyl bromide were added in this order, and stirring was carried out at 70° C. for 3.5 hours. The reaction mixture was returned to room temperature and the reaction was stopped by slowly adding water, after which the reaction mixture was extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous magnesium sulfate and subsequently concentrated, then purified by silica gel column chromatography (hexane/ethyl acetate=1:1), giving 892 mg of 2-chloro-5-[N-(2-propargyl)]aminomethylpyridine (yield, 47percent). Using 60 mg of the resulting 2-chloro-5-[N-(2-propargyl)]aminomethylpyridine, 20 mg of the target compound (yield, 30percent) was obtained by the method described in Synthesis Example 1.

Reference： [1]Patent: US2013/150414,2013,A1 .Location in patent: Paragraph 0336

47
[ 112-80-1 ]
[ 97004-04-1 ]
[ 1450603-52-7 ]

Yield	Reaction Conditions	Operation in experiment
36%		General procedure: To a solution of palmitic acid (300mg, 1.17mmol) in dichloromethane (DCM, 10mL) was added 1,1?-carbonyldiimdazole (209mg, 1.29mmol). The reaction was stirred at room temperature for 2h. The reaction mixture was slowly added to a solution of benzylamine (153muL, 1.40mmol) and 4-dimethylaminopyridine (14mg, 0.12mmol) in dichloromethane (5mL). The solution was stirred at room temperature for 18h. DCM (100mL) and saturated aqueous NaHCO3 (30mL) were added to the reaction mixture. The organic layer was separated and washed with H2O (30mL), brine (30mL), dried over anhyd sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude was purified by flash chromatography on silica gel eluting with hexane/EtOAc (3:1, v/v) to give the title compound as a white solid (578mg, 86percent). Mp 85?87° [lit.45 mp 94.5?95°, and46 fp 95.1°]; 1H NMR (400MHz, CDCl3) delta 7.32?7.36 (m, 2H), 7.26?7.30 (m, 3H), 5.72 (br s, 1H), 4.45 (d, J=6.0Hz, 2H), 2.21 (t, J=7.2Hz, 2H), 1.61?1.67 (m, 2H), 1.25?1.34 (m, 24H), 0.88 (t, J=6.8Hz, 3H); 13C NMR (CDCl3, 100MHz) delta 173.21, 138.66, 128.92, 128.05, 127.71, 43.80, 37.06, 32.16, 29.92, 29.89, 29.84, 29.73, 29.59, 29.56, 26.01, 22.93, 14.36; LCMS, C23H39NO, [M+H]: 346.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5188 - 5197

48
JVM 67 [ No CAS ]
[ 97004-04-1 ]
JVM 96 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In dichloromethane; at 0 - 20℃; for 16h;	To a reaction mixture of MMB carboxylic acid (JVM 67), (50 mg, 0.14 mmol), EDC (40.26 mg, 0.21 mmol), N-hydroxybenzotriazole (HOBt, 28.35 mg, 0.21 mmol), and triethylamine (42.42 mg, 0.42 mmol) in dichloromethane (2 mL) was added 3-aminomethyl-6-chloropyridine (19.96 mg, 0.14 mmol) at 0° C. and the reaction mixture was stirred at ambient temperature for 16 hours. Upon completion as determined by TLC, water was added and the mixture extracted with dichloromethane. The organic layer was dried and concentrated to afford the crude compound. The crude product was further purified by column chromatography (silica gel using 3percent methanol in dichloromethane) to afford JVM 96 as pure product as white solid (yield 75percent). 1H NMR (CDCl3, 400 MHz): delta 8.28 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 6.22 (d, J=3.2 Hz, 1H), 6.07 (s, 1H), 5.68 (t, J=7.2 Hz, 1H), 5.55 (s, 1H), 4.65 (d, J=12.4 Hz, 1H), 4.49 (d, J=12.8 Hz, 1H), 4.42 (d, J=5.6 Hz, 2H), 3.85 (t, J=9.6 Hz, 1H), 2.95 (t, J=8.8 Hz, 1H), 2.85 (d, J=9.6 Hz, 1H), 2.68 (t, J=6 Hz, 2H), 2.52-2.11 (m, 7H), 1.67-1.62 (m, 2H), 1.53 (s, 3H), 1.12 (t, J=11.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz): delta 172.8, 171.5, 169.6, 150.7, 148.9, 138.9, 138.6, 134.8, 133.1, 130.8, 124.4, 120.4, 81.2, 67.2, 63.3, 60.1, 42.7, 40.5, 36.7, 30.7, 29.3, 25.8, 24.6, 23.9, 18.1 ppm.

Reference： [1]Patent: US2015/133444,2015,A1 .Location in patent: Paragraph 0211-0213

49
2,4,6-trivinylcyclotriboroxane*pyridine complex [ No CAS ]
[ 97004-04-1 ]
C₈H₁₀N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		The above aryl halide (0.5 g) was dissolved in 12 ml of DME and treated with tetrakis-(triphenylphosphine)palladium(0) (10 mol percent, 0.41 g). The solution was left to stir at room temperature for 20 minutes. K2CO3 (1.5 eq., 0.73 g) was added along with water (3 ml) and 2,4,6-trivinylcyclotriboroxane-pyridine complex (1.5 eq., 1.27 g). The reaction was refluxed for 24 hours. The reaction was allowed to cool to room temperature then filtered through celite. The reaction mixture was concentrated then resuspended in 200 ml of EtOAc. This was washed with water (2×100 ml). The water washes were pooled and concentrated down to 5 ml. The concentrate was loaded onto a C-18 reverse phase column and eluted with 1/10 MeOH/H2O. The relevant fractions were pooled and freeze-dried to yield the product as a white solid (188 mg, 40percent yield). ESI-MS: Expected for molecular ion C8H10N2=134.0844. Found M+H=135.0922.

Reference： [1]Patent: US9212148,2015,B2 .Location in patent: Page/Page column 19

50
[ 660867-80-1 ]
[ 97004-04-1 ]
[ 1354355-39-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃;	To a suspension of (6-chloropyridin-3-yl)methanamine (500 mg, 3.50 mmol), 17 (1.68 g, 50%, 3.85 mmol) and Pd(PPh3)4 (202 mg, 0.175 mmol) in dioxane/H2O (4 mL/1 mL) was added K2CO3 (1.93 g, 14.0 mmol). The mixture was stirred at 100 C under N2 overnight. After cooling to room temperature, H2O (30 mL) was added and the mixture was extracted with DCM (50 mLx6). The combined organic layers were dried and concentrated to give the desired product 37 (620 mg, 89%) as a brown solid. 1H NMR (400 MHz, CDCl3) d 8.68 (s, 1H), 8.60 (d, J = 5.2 Hz,1H), 7.84-7.75 (m, 3H), 7.66 (d, J = 4.8 Hz, 1H), 3.98 (s, 2H), 2.65(s, 3H).
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	Compound A30-1 (500mg, 3.50mmol) dissolved in dioxane / water (20mL / 4mL), was added crude intermediate A1-2 (1.51g, 27%,3.85mmol), potassium carbonate (1.93g, 14.0mmol), phosphorous tetrakistriphenylphosphine palladium (202mg, 0.175mmol), purged with nitrogen, stirred overnight at 100 deg.] C,Cooled to room temperature, water (30 mL), dichloromethane (50mL × 6). The organic phase was dried over anhydrous sodium sulfate, and sodium sulfate was filtered, spin-dry the solvent,To give a brown oil (620mg, 89%).

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5861 - 5872
[2]Patent: CN105254613,2016,A .Location in patent: Paragraph 0232; 0233; 0234

51
11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxylic acid 5,5-dioxide [ No CAS ]
[ 97004-04-1 ]
N-((6-chloropyridin-3-yl)methyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide 5,5-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;Inert atmosphere;	[000120] To a stirring solution of compound 30 (2 g, 6.60 mmol) in DMF (40 mL) under inert atmosphere were added EDCI.HC1 (1.91 g, 9.95 mmol), HOBt (1.34 g, 9.95 mmol), (6- chloropyridin-3-yl) methanamine 78 (938 mg, 6.60 mmol) and diisopropylethylamine (3.43 mL, 19.76 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice-cold water (100 mL). The solid obtained was filtered, washed with w-pentane (20 mL) and dried in vacuo to afford compound 79 (2.5 g, 89percent) as white solid. TLC: 5percent MeOH/ CH2C12 (Rf. 0.3); NMR (DMSO-i/6, 500 MHz): delta 11.51 (br s, 1H), 9.32 (t, J= 5.6 Hz, 1H), 8.37 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.01-7.95 (m, 2H), 7.90 (t, J= 7.4 Hz, 1H), 7.88-7.81 (m, 3H), 7.78 (dd, J = 8.1, 2.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.48 (d, J= 5.8 Hz, 2H); LC-MS: 96.13percent; 427.8 (M++l); (column; Ascentis Express CI 8, (50 chi 3.0 mm, 2.7 muiotaeta); RT 2.12 min. 0.025percent Aq. TFA + 5percent ACN: ACN + 5percent 0.025percent Aq. TFA, 1.2 mL/min).

Reference： [1]Patent: WO2017/48954,2017,A1 .Location in patent: Paragraph 000120

52
4-(((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2',3':9,10]cyclodeca[1,2-b]furan-5-yl)methoxy)-4-oxobutanoic acid [ No CAS ]
[ 97004-04-1 ]
((1aR,7aS,10aS,10bS,E)-1a-methyl-8-methylene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2',3':9,10]cyclodeca[1,2-b]furan-5-yl)methyl 4-(((6-chloropyridin-3-yl)methyl)amino)-4-oxobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h;	General procedure: To a stirred solution of MMB 14-O-succinate (2, 50 mg, 0.14 mmol) in dichloromethane was added EDC (40.26 mg, 0.21 mmol), HOBt (28.35 mg, 0.21 mmol), triethylamine (42.42 mg, 0.42 mmol) and the appropriate heterocyclic amine (0.14 mmol) at ambient temperature. The reaction mixture was stirred for 3-12 h at ambient temperature. When the reaction was complete (monitored by TLC), water was added and the resulting aqueous mixture was extracted with dichloromethane (2 * 10 mL). The organic layers were combined, washed with water followed by brine solution, and dried over anhydrous Na2SO4. The solvent was then evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (silica gel, 3-5% methanol in dichloromethane) to afford the desired succinamide analog as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3694 - 3705

53
[ 97004-04-1 ]
[ 579476-63-4 ]
(6-(2-methylpyridin-4-yl)pyridin-3-yl)methanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; In water; butan-1-ol; at 125℃; for 0.5h;Inert atmosphere;	(6-Chloropyridin-3-yl) methanamine (300 mg, 2.1 mmol) was treated with n-butanol (10 mL) and waterAnd 2-methylpyridin-4-ylboronic acid (345 mg, 2.52 mmol) were dissolved in a pressure tube.Under a nitrogen atmosphere, K3PO4 (893 mg,4.2 mmol), Pd2 (dba) 3 (96.3 mg, 0.105 mmol) and S-phos (86.4 mg, 0.21 mmol).The reaction was heated to 125 ° C for 30 minutes and then cooled to room temperature.The solution was poured into water and extracted three times with EA. The combined organic layers were washed with saturated brine and dried over Na2SO4 and then concentrated under vacuum. The crude product was further purified by flash chromatography with DCM containing 10percent methanol containing ~ 2N ammonia to obtain pure (6- (2-methylpyridin-4-yl) pyridin-3-yl) methanamine(0.19 g, yield ~45percent).

Reference： [1]Patent: CN104530042,2017,B .Location in patent: Paragraph 0216; 0225; 0226; 0227

54
[ 1255206-68-8 ]
[ 97004-04-1 ]
5-(2-(((6-chloropyridin-3-yl)methyl)amino)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57.2%	In ethanol; at 85℃; for 48h;	To a solution of (6-chioropyridin-3-yl)inethanarnine (0.270 g, 1.89 mrnol) in FtOH (10 mL) was added intermediate 1?i (03 g, 1 .577 rnmoi) and the resulting mixture was heated at 85 °C for 48 h. The reaction mixture was evaporated to dryness5 under reduced pressure. The residue was purified by preparative HPLC [Sunfire OBD (25() x 3() ID) 5 micron; Solvent A: 10 niM Ammonium Acetate in water, Solvent B:Acetonitrile; Gradient: 0-100 percent B over 15.5 mm. Flow : 25 mE/mm. retemion time 11.2 ni LIV 220 nm] to obtain Intermediate 13?1 (0.300 g, 572percent) as a light yellow solid. ?H NMR (400 MHz. DMSO-d6) ppm 2.20 (s, 3 H), 2.52-265 (rn, 2 H), 377 (s, 2 H),10 5.00 (dd,J= 7.53. 452 Hz, I H), 529- 5.43 (rn, 3 H), 744 (d,J= 7.53 Hz, I H), 7.66 (d, J= 1.00 Hz, 2H), 7.79 (dd,J= 8.03, 251 Hz, I H), 8.33 (d,J2.0i Hz, 1 H), (Exchangeable proton not observed). LCMS (Method-f-I): retention time 1.07 mi IM-FH1 3338.

Reference： [1]Patent: WO2018/93569,2018,A1 .Location in patent: Page/Page column 52; 53

55
[ 4595-60-2 ]
[ 97004-04-1 ]
N-[(6-chloropyridin-3-yl)methyl]pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23.9%	With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;	1. Synthesis of N-[(6-chloropyridin-3-yl)methyl]pyrimidin-2-amine To a solution of 2-bromopyrimidine (5.00 g, 31.5 mmol), palladium acetate (0.71 mg, 3.1 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.64 g, 6.3 mmol) and potassium carbonate (34.77 g, 251.6 mmol) in dioxane (80 ml) was added <strong>[97004-04-1]1-<strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong></strong> (6.73 g, 47.2 mmol), and then the mixture was heated to 100° C. The reaction mixture was filtered through Celite and taken up in dichloromethane. The organic phase was dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was adsorbed on silica gel and chromatographed. 1.750 g (23.9percent of theory) of N-[(6-chloropyridin-3-yl)methyl]pyrimidin-2-amine were obtained. HPLC-MS: log P=1.36; Mass (m/z): 221.1; 1HNMR (D6-DMSO): delta 8.32 (m, 4H), 7.76 (m, 2H), 7.46 (m, 1H), 6.60 (m, 1H), 4.49 (d, 2H).

Reference： [1]Patent: US2018/282323,2018,A1 .Location in patent: Paragraph 0625-0626

56
[ 97004-04-1 ]
[ 5527-95-7 ]
C₁₃H₁₁Cl₂FN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.3%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.20 g (1.26 mmol) of 4-chloro-3-fluorobenzaldehyde were added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto. Stir at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and the mixture was stirred at room temperature for 20 minutes, and the reaction was quenched to give a colorless, clear solvent. 45 mL of water was added to the residue, followed by extraction with dichloromethane (15 mL×3), and the organic solvent was collected and purified by column chromatography (P/E=2:1) to give 1-(6-chloropyridin-3-yl) )-N-(4-chloro-3-fluorobenzyl)methylamine 0.28 g, yield 93.3percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0019; 0021

57
[ 97004-04-1 ]
[ 165047-24-5 ]
C₁₃H₁₀ClF₃N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.6%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.2 g (1.26 mmol) of 2,4,5-trifluorobenzaldehyde were added to a 25 mL three-necked flask, and then methanol 25 mL was added thereto. Stir at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and the mixture was stirred at room temperature for 30 minutes, and the reaction was stopped to obtain a colorless, clear solvent. 45 mL of water was added to the residue, followed by extraction with dichloromethane (15 mL × 3), and organic solvent was collected.Concentration under reduced pressure gave 0.24 g of 1-(6-chloropyridin-3-yl)-N-(2,4,5-trifluorobenzyl)methylamine in a yield of 75.6percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0023

58
[ 455-19-6 ]
[ 97004-04-1 ]
C₁₄H₁₂ClF₃N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.8%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.22 g (1.26 mmol) of p-trifluoromethylbenzaldehyde were added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto, and stirred at room temperature. overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and the mixture was stirred at room temperature for 1 hour, and the reaction was stopped to obtain a colorless, clear solvent. 45 mL of water was added to the residue, followed by extraction with dichloromethane (15 mL × 3), and organic solvent was collected.Concentration under reduced pressure gave 0.30 g of 1-(6-chloropyridin-3-yl)-N-(4-trifluoromethylbenzyl)methylamine as a yield of 94.8percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0025

59
[ 437-81-0 ]
[ 97004-04-1 ]
C₁₃H₁₁ClF₂N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.4%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.18 g (1.26 mmol) of 2,6-difluorobenzaldehyde were added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto, at room temperature. Stir overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and the mixture was stirred at room temperature for 25 minutes, and the reaction was stopped to obtain a colorless, clear solvent. 45 mL of water was added to the residue, followed by extraction with dichloromethane (15 mL × 3), and organic solvent was collected.Concentration under reduced pressure gave 1-(6-chloropyridin-3-yl)-N-(2,6-difluorobenzyl)methylamine (0.30 g, yield: 96.4percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0027

60
[ 1122-91-4 ]
[ 97004-04-1 ]
C₁₃H₁₂BrClN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.5%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.25 g (1.37 mmol) of 4-bromobenzaldehyde were placed in a 25 mL three-necked flask, and then 25 mL of methanol was added thereto, and stirred at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and the mixture was stirred at normal temperature for 5 minutes, and the reaction was stopped to obtain a milky white solution. 45 mL of water was added to the residue, followed by extraction with dichloromethane (15 mL × 3), and organic solvent was collected.Concentration under reduced pressure gave 0.30 g of 1-(6-chloropyridin-3-yl)-N-(4-bromobenzyl)methylamine.Yield 91.5percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0029

61
[ 387-45-1 ]
[ 97004-04-1 ]
C₁₃H₁₁Cl₂FN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.3%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.20 g (1.26 mmol) of 2-chloro-6-fluorobenzaldehyde were added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto. Stir at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and the mixture was stirred at room temperature for 2 hours, and the reaction was quenched to give a colorless, clear solvent. 45 mL of water was added to the residue, followed by extraction with dichloromethane (15 mL×3).Collect organic solvents,Concentration under reduced pressure gave 0.28 g of 1-(6-chloropyridin-3-yl)-N-(2-chloro-6-fluorobenzyl)methylamine in a yield of 93.3percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0031

62
[ 446-52-6 ]
[ 97004-04-1 ]
C₁₃H₁₂ClFN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.9%		Will be 0.13g(0.91 mmol) of 5-aminomethyl-2-chloropyridine and 0.14 g (1.09 mmol)2-fluorobenzaldehyde added toIn a 25 mL three-necked flask, 25 mL of methanol was added thereto, and the mixture was stirred at room temperature overnight.Then slowly add 0.10 g (2.28 mmol) of sodium borohydride to the inside, and stir at room temperature for 1 h to stop the reaction.A colorless clear solution was obtained, which was concentrated under reduced pressure. 45 mL of water was added to the residue.Then extracted with dichloromethane (15 mL × 3), and the organic solvent was collected.Concentrated under reduced pressure1-(6-chloropyridin-3-yl)-N-(2-fluorobenzyl)methylamine 0.21 g, yield 91.9percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0033

63
[ 34036-07-2 ]
[ 97004-04-1 ]
C₁₃H₁₁ClF₂N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.1%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.18 g (1.26 mmol)The 3,4-difluorobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then, 0.10 g (2.28 mmol) of sodium borohydride was slowly added thereto, and stirred at room temperature for 25 minutes.The reaction was stopped, a colorless clear solution was obtained, and the solvent was evaporated. 45 mL of water was added to the residue.Then extracted with dichloromethane (15 mL × 3), and the organic solvent was collected.Concentration under reduced pressure gave 0.28 g of 1-(6-chloropyridin-3-yl)-N-(3,4-difluorobenzyl)methylamine as a yield of 99.1percent.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0035

64
[ 34328-61-5 ]
[ 97004-04-1 ]
C₁₃H₁₁Cl₂FN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.7%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.20 g (1.26 mmol)3-chloro-4-fluorobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and stirred at room temperature for 20 minutes.The reaction was stopped, a colorless clear solution was obtained, and the solvent was concentrated under reduced pressure.45 mL of water was added to the residue, followed by extraction with dichloromethane (15 mL × 3), and organic solvent was collected.Concentrated under reduced pressure1-(6-chloropyridin-3-yl)-N-(3-chloro-4-fluorobenzyl)methylamine 0.29 g, yield 96.7percent.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0037

65
3,4,5-trifluorobenzaldehyde [ No CAS ]
[ 97004-04-1 ]
C₁₃H₁₀ClF₃N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.2%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.20 g (1.26 mmol)3,4,5-trifluorobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then slowly add 0.10 g (2.63 mmol) of sodium borohydride to the inside and stir at room temperature for 1.2 h.The reaction was stopped, a colorless clear solution was obtained, and the solvent was concentrated under reduced pressure. 45 mL of water was added to the residue.Then, it was extracted with dichloromethane (15 mL × 3), and the organic solvent was collected and concentrated under reduced pressure.1-(6-chloropyridin-3-yl)-N-(3,4,5-trifluorobenzyl)methylamine 0.29 g, yield 96.2percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0039

66
[ 58551-83-0 ]
[ 97004-04-1 ]
C₁₃H₁₀ClF₃N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.8%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.20 g (1.26 mmol)<strong>[58551-83-0]2,4,6-trifluorobenzaldehyde</strong> was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then slowly add 0.10 g (2.63 mmol) of sodium borohydride to the inside and stir at room temperature for 25 min.The reaction was stopped, a colorless clear solution was obtained, and the solvent was concentrated under reduced pressure. 45 mL of water was added to the residue.Then, it was extracted with dichloromethane (15 mL × 3), and the organic solvent was collected and concentrated under reduced pressure.1-(6-chloropyridin-3-yl)-N-(2,4,6-trifluorobenzyl)methylamine 0.28 g,yield: 92.8%.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0041

67
[ 58551-83-0 ]
[ 97004-04-1 ]
4-[(6-chloropyridin-3-yl)methyl](2,4,6-trifluorobenzyl)amino}furan-2(5H)-one [ No CAS ]

Reference： [1]Patent: CN108558841,2018,A

68
[ 63082-45-1 ]
[ 97004-04-1 ]
C₁₄H₁₄ClFN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.4%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.17 g (1.26 mmol)<strong>[63082-45-1]4-fluoro-2-methylbenzaldehyde</strong> was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then slowly add 0.10 g (2.63 mmol) of sodium borohydride to the inside and stir at room temperature for 30 min.The reaction was stopped, a colorless clear solution was obtained, and the solvent was evaporated. 45 mL of water was added to the residue.Then extract with dichloromethane (15 mL × 3), collect organic solvent, minusConcentration under pressure gave 1-(6-chloropyridin-3-yl)-N-(4-fluoro-2-methylbenzyl)Methylamine 0.26 g, yield 93.4%.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0043

69
[ 63082-45-1 ]
[ 97004-04-1 ]
4-[(6-chloropyridin-3-yl)methyl](4-fluoro-2-methylbenzyl)amino}furan-2(5H)-one [ No CAS ]

Reference： [1]Patent: CN108558841,2018,A

70
[ 77771-02-9 ]
[ 97004-04-1 ]
C₁₃H₁₁BrClFN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.1%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.26 g (1.26 mmol)3-bromo-4-fluorobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and stirred at room temperature for 20 minutes.The reaction was stopped, a colorless clear solution was obtained, and the solvent was concentrated under reduced pressure. 45 mL of water was added to the residue.Then, it was extracted with dichloromethane (15 mL × 3), and the organic solvent was collected and concentrated under reduced pressure.1-(6-chloropyridin-3-yl)-N-(3-bromo-4-fluorobenzyl)methylamine 0.34 g, yield 98.1percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0045

71
[ 97004-04-1 ]
[ 218301-22-5 ]
5-([(6-chloropyridin-3-yl)methyl]amino}methyl)-2-fluorobenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.6%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.19 g (1.26 mmol)The 2-fluoro-5-formylbenzonitrile was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then slowly add 0.10 g (2.63 mmol) of sodium borohydride to the inside and stir at room temperature for 20 min.The reaction was stopped, a colorless clear solution was obtained, and the solvent was evaporated. 45 mL of water was added to the residue.Then extract with dichloromethane (15 mL × 3), collect the organic solvent, and concentrate under reduced pressure. To 5-([(6-chloropyridin-3-yl)methyl]amino}methyl)-2-fluorobenzonitrile 0.26 g, yield 98.6percent.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0045

72
[ 135427-08-6 ]
[ 97004-04-1 ]
C₁₄H₁₄ClFN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.2%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.17 g (1.26 mmol)4-Fluoro-3-methylbenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then slowly add 0.10 g (2.63 mmol) of sodium borohydride to the inside and stir at room temperature for 1 h.The reaction was stopped, a colorless clear solution was obtained, and the solvent was concentrated under reduced pressure.45 mL of water was added to the residue, followed by extraction with dichloromethane (15 mL × 3), and organic solvent was collected.Concentration under reduced pressure gave 1-(6-chloropyridin-3-yl)-N-(4-fluoro-3-methylbenzyl)methylamine0.27 g, yield 95.2percent.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0049

73
[ 135427-08-6 ]
[ 97004-04-1 ]
4-[(6-chloropyridin-3-yl)methyl](4-fluoro-3-methylbenzyl)amino}furan-2(5H)-one [ No CAS ]

Reference： [1]Patent: CN108558841,2018,A

74
[ 6287-38-3 ]
[ 97004-04-1 ]
C₁₃H₁₁Cl₃N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.8%		0.17 g (1.19 mmol) of 5-aminomethyl-2-chloropyridine and 0.25 g (1.43 mmol)Add 3,4-dichlorobenzaldehyde to a 25 mL three-necked flask, then add 25 mL of methanol to it.Stir at room temperature overnight. Then slowly add 0.10 g (2.63 mmol) of sodium borohydride to the inside.Stir at room temperature overnight,The reaction was stopped, a colorless clear solution was obtained, and the solvent was evaporated. 45 mL of water was added to the residue.Then extracted with dichloromethane (15 mL × 3), and the organic solvent was collected.Concentration under reduced pressure gave 1-(6-chloropyridin-3-yl)-N-(3,4-dichlorobenzyl)methylamine0.33g, yield 91.8percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0051

75
[ 89-98-5 ]
[ 97004-04-1 ]
C₁₃H₁₂Cl₂N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.6%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.18 g (1.26 mmol)2-chlorobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then slowly add 0.10 g (2.63 mmol) of sodium borohydride to the inside and stir at room temperature for 20 min.The reaction was stopped, a colorless clear solution was obtained, and the solvent was evaporated.45 mL of water was added to the residue, followed by extraction with dichloromethane (15 mL × 3), and organic solvent was collected.Concentration under reduced pressure gave 0.28 g of 1-(6-chloropyridin-3-yl)-N-(2-chlorobenzyl)methylamine yield 99.6percent.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0053

76
[ 98-03-3 ]
[ 97004-04-1 ]
C₁₁H₁₁ClN₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.6%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.15 g (1.37 mmol)Thiophene-2-carbaldehyde is added toIn a 25 mL three-necked flask, then add 25 mL of methanol to the inside.Stir at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and stirred at room temperature for 20 minutes.The reaction was stopped, a colorless clear solution was obtained, and the solvent was evaporated. 45 mL of water was added to the residue.Then extracted with dichloromethane (15 mL × 3), and the organic solvent was collected.Concentration under reduced pressure gave 0.24 g of 1-(6-chloropyridin-3-yl)-N-(thiophen-2-ylmethyl)methylamine as a yield of 95.6percent.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0055

77
[ 459-57-4 ]
[ 97004-04-1 ]
C₁₃H₁₂ClFN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.6%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.17 g (1.37 mmol)4-fluorobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then slowly add 0.10 g (2.63 mmol) of sodium borohydride to the inside.After stirring at room temperature for 5 min, the reaction was stopped to give a colorless, clear solvent, which was concentrated under reduced pressure.45 mL of water was added to the residue.Then extracted with dichloromethane (15 mL × 3), and the organic solvent was collected.Concentration under reduced pressure gave 0.26 g of 1-(6-chloropyridin-3-yl)-N-(4-fluorobenzyl)methylamine as a yield of 98.6percent.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0057

78
[ 3132-99-8 ]
[ 97004-04-1 ]
C₁₃H₁₂BrClN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.5%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.25 g (1.37 mmol)3-bromobenzaldehyde added toIn a 25 mL three-necked flask, 25 mL of methanol was added thereto, and the mixture was stirred at room temperature overnight.Then slowly add sodium borohydride to the inside0.10 g (2.63 mmol) was stirred at normal temperature for 5 min, and the reaction was stopped to give a milky white solution.45 mL of water was added to the residue, followed by extraction with dichloromethane (15 mL × 3), and organic solvent was collected.Concentration under reduced pressure gave 1-(6-chloropyridin-3-yl)-N-(3-bromobenzyl)methylamine0.30g,Yield 91.5percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0059

79
[ 653-37-2 ]
[ 97004-04-1 ]
C₁₃H₈ClF₅N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.3%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.25 g (1.26 mmol)2,3,4,5,6-pentafluorobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and stirred at normal temperature for 4 hours.The reaction was stopped, a colorless clear solution was obtained, and the solvent was concentrated under reduced pressure. 45 mL of water was added to the residue.Then, it was extracted with dichloromethane (15 mL × 3), and the organic solvent was collected and concentrated under reduced pressure.1-(6-chloropyridin-3-yl)-N-(2,3,4,5,6-pentafluorobenzyl)methylamine 0.32 g, yield 94.3percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0063

80
[ 42564-51-2 ]
[ 97004-04-1 ]
C₁₃H₁₁ClFN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.4%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.20 g (1.26 mmol)4-Fluoro-3-nitrobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and stirred at room temperature overnight.The reaction was stopped, and a reddish brown clear solution was obtained, which was concentrated under reduced pressure. 45 mL of water was added to the residue.Then extracted with dichloromethane (15 mL × 3), and the organic solvent was collected.Concentration under reduced pressure gave 1-(6-chloropyridin-3-yl)-N-(4-fluoro-3-nitrobenzyl)methylamine0.30 g, yield 96.4percent.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0065

81
[ 2646-91-5 ]
[ 97004-04-1 ]
C₁₃H₁₁ClF₂N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.5%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.18 g (1.26 mmol)2,3-difluorobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then slowly add 0.12 g (2.70 mmol) of sodium borohydride to the inside, and stir at room temperature for 30 min.The reaction was stopped, a colorless clear solution was obtained, and the solvent was evaporated. 45 mL of water was added to the residue.Then extracted with dichloromethane (15 mL × 3), and the organic solvent was collected.Concentrated under reduced pressure1-(6-chloropyridin-3-yl)-N-(2,3-difluorobenzyl)methylamine 0.27 g, yield 95.5percent.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0067

82
[ 96515-79-6 ]
[ 97004-04-1 ]
C₁₃H₁₁Cl₂FN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.7%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.20 g (1.26 mmol)5-chloro-2-fluorobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then slowly add 0.1 g (2.63 mmol) of sodium borohydride to the inside and stir at room temperature for 30 min.The reaction was stopped, a colorless clear solution was obtained, and the solvent was concentrated under reduced pressure. 45 mL of water was added to the residue.Then, it was extracted with dichloromethane (15 mL × 3), and the organic solvent was collected and concentrated under reduced pressure.1-(6-chloropyridin-3-yl)-N-(5-chloro-2-fluorobenzyl)methylamine 0.29 g, yield 96.7percent.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0069

83
[ 96515-79-6 ]
[ 97004-04-1 ]
4-[(6-chloropyridin-3-yl)methyl](5-chloro-2-fluorobenzyl)amino}furan-2(5H)-one [ No CAS ]

Reference： [1]Patent: CN108558841,2018,A

84
[ 99-61-6 ]
[ 97004-04-1 ]
C₁₃H₁₂ClN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.1%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.19 g (1.26 mmol)The 3-nitrobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and stirred at room temperature for 30 minutes.The reaction was stopped, a pale yellow clear solution was obtained, and the solvent was evaporated. 45 mL of water was added to the residue.Then extracted with dichloromethane (15 mL × 3), and the organic solvent was collected.Concentration under reduced pressure gave 1-(6-chloropyridin-3-yl)-N-(3-nitrobenzyl)methylamine 0.27 g, yield 93.1percent

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0073

85
[ 105-07-7 ]
[ 97004-04-1 ]
4-([(6-chloropyridin-3-yl)methyl]amino}methyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.19 g (1.43 mmol)4-formylbenzonitrile was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and stirred at room temperature for 2 hours.The reaction was stopped, a colorless clear solution was obtained, and the solvent was evaporated. 45 mL of water was added to the residue.Then extracted with dichloromethane (15 mL × 3), and the organic solvent was collected.Concentration under reduced pressure gave 0.32 g of 4-([(6-chloropyridin-3-yl)methyl]amino}methyl)benzonitrile as a yield of 90.0percent.

Reference： [1]Patent: CN108558841,2018,A .Location in patent: Paragraph 0077

86
[ 97004-04-1 ]
[ 886762-70-5 ]
C₁₂H₉BrClN₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 234 - 246

87
[ 97004-04-1 ]
[ 53554-29-3 ]
ethyl 2-(((6-chloropyridin-3-yl)methyl)amino)-4-hydroxypyrimidine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.8%	In ethanol; for 24h;Reflux; Sealed tube;	General procedure: To a Radley reaction carousel tube, add 1 equivalent 1, 1.1 equivalents of the amine, a stir bar, and 5 mL 95% ethanol. Reflux while stirring for 24 hours. After cooling to room temperature the resulting precipitate was collected by vacuum filtration, washing with 10 mL deionized water and 5 mL chloroform.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29

88
(3S,11aR)-6-(benzyloxy)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid [ No CAS ]
[ 97004-04-1 ]
C₂₅H₂₃ClN₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To asolution of 1 g (2.7 mmol) of 10 in 20 ml of DCM was added 1.2 ml(8.1 mmol) of TEA. This solution stirred at room temperature for15 min followed by the addition of TBTU (0.82 g, 3.3 mmol). Theresulting mixture stirred for 15 min, and 3.3 mmol of the corresponding(heterocyclylmethyl)amine 7 was added. The reactionmixture was washed with a 10% aqueous solution of potash andwater. The organic layer was dried over sodium sulfate and evaporatedon a rotary evaporator. Diethyl ether was added to the residue,and the resulting precipitatewas filtered and dried in vacuo. Atotal of 1.8 mmol of 8 was dissolved in a mixture of 18 ml of THF and2 ml of methanol, 0.09 g of 10% Pd/C was added, and the mixturestirred under a hydrogen atmosphere for 8 h. The reaction mixturewas passed through Celite and the filtrate was evaporated. Theresidue was stirred with ether, filtered and dried in vacuo.

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 189

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Precautionary Statements-General
Code	Phrase
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Prevention
Code	Phrase
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P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
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P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
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P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
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Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
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P320
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P321
P322
P330	Rinse mouth.
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P332	IF SKIN irritation occurs:
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P335	Brush off loose particles from skin.
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P337	If eye irritation persists:
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P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
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P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
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P372	Explosion risk in case of fire.
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P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
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P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
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P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
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H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 97004-04-1 ] {[proInfo.proName]}

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[ 97004-04-1 ] Synthesis Path-Upstream 1~12

[ 97004-04-1 ] Synthesis Path-Downstream 1~88

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Chlorides

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Pyridines

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