[ CAS No. 6419-36-9 ] {[proInfo.proName]}

Name: 6419-36-9|2-(Pyridin-3-yl)acetic acid hydrochloride|95%
Brand: Ambeed
SKU: A172627
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2D 3D

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Quality Control of [ 6419-36-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 6419-36-9 ]

Product Details of [ 6419-36-9 ]

CAS No. :	6419-36-9	MDL No. :	MFCD00012819
Formula :	C₇H₈ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XVCCOEWNFXXUEV-UHFFFAOYSA-N
M.W :	173.60	Pubchem ID :	2723724
Synonyms :	3-Pyridylacetic acid hydrochloride

Calculated chemistry of [ 6419-36-9 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	42.75
TPSA :	50.19 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) :	-6.83 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.74
Log Po/w (WLOGP) :	1.51
Log Po/w (MLOGP) :	0.39
Log Po/w (SILICOS-IT) :	1.04
Consensus Log Po/w :	0.74

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.65
Solubility :	3.85 mg/ml ; 0.0222 mol/l
Class :	Very soluble
Log S (Ali) :	-1.37
Solubility :	7.35 mg/ml ; 0.0424 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.77
Solubility :	2.93 mg/ml ; 0.0169 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.41

Safety of [ 6419-36-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 6419-36-9 ]

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

Upstream synthesis route of [ 6419-36-9 ]
Downstream synthetic route of [ 6419-36-9 ]

[ 6419-36-9 ] Synthesis Path-Upstream 1~12

1
[ 6419-36-9 ]
[ 6293-56-7 ]

Reference： [1] Patent: US2002/19531, 2002, A1,
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 14, p. 3041 - 3047
[3] Tetrahedron Letters, 1993, vol. 34, # 2, p. 331 - 334
[4] Patent: EP2390243, 2011, A1,
[5] Patent: WO2012/75917, 2012, A1,

2
[ 6419-36-9 ]
[ 6293-56-7 ]

Reference： [1] Patent: US4789745, 1988, A,

3
[ 6419-36-9 ]
[ 501-81-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium hydroxide In ethanol	(1) To a suspension of 2-(pyridin-3-yl)acetic acid-hydrochloride (13.2g, 75.6mmol) in ethanol (100mL) was added a solution (150mL) of 0.5mol potassium hydroxide/ethanol, and the mixture was stirred well, then filtered to remove potassium chloride, concentrated, and dried to give 2-(pyridin-3-yl)acetic acid (10.6g, quantitative).

Reference： [1] Patent: EP1559716, 2005, A1, . Location in patent: Page/Page column 20

4
[ 67-56-1 ]
[ 6419-36-9 ]
[ 39998-25-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: for 2.5 h; Inert atmosphere; Reflux Stage #2: With sodium hydrogencarbonate In water	In order to synthesize 3-pyridylethanethiol, 3-pyridylethanol as an intermediate therefor was synthesized by the following method. Into a 1-L flask to which a nitrogen gas introduction tube, thermometer, Dimroth condenser, and dropping funnel had been attached was introduced 25.12 g (0.145 mol) of 3-pyridylacetic acid monohydrochloride. Thereto was added 500 mL of anhydrous methanol. After the atmosphere in the flask was replaced with nitrogen, the contents were stirred at room temperature to dissolve the monohydrochloride. Thereto was added dropwise 31.12 g (0.248 mol) of thionyl chloride. Thereafter, the resultant mixture was heated and reacted for further 2.5 hours with refluxing. After the reaction, the reaction mixture was cooled to room temperature, and the methanol was distilled off under vacuum. The residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate. An extraction operation using 100 mL of ethyl acetate was conducted three times, and anhydrous sodium sulfate was added to the resultant organic phase to dry the phase. The anhydrous sodium sulfate was removed by decantation. Thereafter, the solvent was distilled off under vacuum. Thus, 21.29 g (0.141 mol) of methyl 3-pyridylacetate, which is the methanol ester of 3-pyridylacetic acid, was obtained (yield, 97percent).

Reference： [1] Patent: EP2390243, 2011, A1, . Location in patent: Page/Page column 26
[2] Tetrahedron Letters, 1993, vol. 34, # 2, p. 331 - 334

5
[ 64-17-5 ]
[ 6419-36-9 ]
[ 39931-77-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	for 6 h; Reflux	To a solution of 3-pyridylacetic acid hydrochloride (51) (12.00 g, 69.19 mmol) in EtOH (120 mL) was added concentrated H₂SO₄ (5 mL) and the solution was heated at reflux (6 h). The reaction mixture was concentrated in vacuo and diluted with EtOAc (200 mL). The EtOAc layer was washed with saturated aqueous NaHCO₃ (3 x 200 mL) and brine (2 x 200 mL), and dried (Na₂SO₄). The crude product was purified by flash column chromatography (SiO₂; 4:5 EtOAc/hexanes) to give the desired product (10.67 g, 93percent) as a pale yellow oil. R_f 0.37 (4:1 EtOAc/hexanes). ¹H NMR (CDCl₃) δ 1.26 (t, J = 7.2 Hz, CH₂CH₃), 3.63 (s, CH₂C₅H₄N), 4.17 (q, J = 7.2 Hz, CH₂CH₃), 7.25-7.30 (m, C₅H), 7.64-7.67 (m, C₄H), 8.45-8.59 (m, C₂H, C₆H).¹³C NMR (CDCl₃) δ 13.7 (CH₂CH₃), 38.0 (CH₂C₅H₄N), 60.7 (CH₂CH₃), 122.9 (C₅H), 129.5 (C₃H), 136.4 (C₄H), 148.0 (C₂H or C₆H), 149.9 (C₆H or C₂).

Reference： [1] Synthetic Communications, 2012, vol. 42, # 8, p. 1137 - 1145
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3551 - 3564
[3] Patent: WO2012/75917, 2012, A1, . Location in patent: Page/Page column 36

6
[ 6419-36-9 ]
[ 19690-13-2 ]

Reference： [1] Patent: US2005/227959, 2005, A1,

7
[ 61494-55-1 ]
[ 6419-36-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: With sodium hydroxide In water at 50 - 95℃; Stage #2: With hydrogen In water at 90 - 95℃; Stage #3: With hydrogenchloride In water	2-chloro-3-pyridineacetic acid 50 g,Prepared into a 25percent mass fraction of 2-chloro-3-pyridine sodium acetate solution,And 47 g of a 30percent sodium hydroxide solutionSouring (the system may produce some insoluble polymer),Stir evenly after filtration,In the filtrate, 20percent of Raney nickel catalyst was added,Heating up to 90-95 ,Through hydrogen reaction,In the atmospheric pressure or 1MPa pressure environment reaction,In the control,After the reaction is completed,After filtering the catalyst,The filtrate was adjusted to pH 4 with hydrochloric acid,Activated charcoal decolorization, desolate, offDry solvent (into a viscous fluid,And there is crystal presence (NaCl)Add 100 grams of anhydrous ethanol, fully dissolved,Filtration, the filtrate is 3-pyridine acetic acid in ethanol solution,The ethanol in the solution was removed (dried,Into a viscous fluid, can be added to the back of the amount of water,Dry the ethanol)Add water 50g, and add hydrochloric acid 35g,After sufficiently salt formation at 50 ° C,The solvent water is then dried (viscous solid)Cooling to room temperature,Plus 50g of absolute ethanol after washing,After filtration, the solid was rinsed with a portion of ethanol,Dry, that was finished3-pyridine acetic acid hydrochloride47.5 g, purity 99.1percent, yield 95.0percent.

Reference： [1] Patent: CN106366034, 2017, A, . Location in patent: Paragraph 0020; 0023; 0024; 0025; 0028; 0029

8
[ 501-81-5 ]
[ 6419-36-9 ]

Reference： [1] Patent: WO2009/50731, 2009, A2, . Location in patent: Page/Page column 15
[2] Patent: US2010/121066, 2010, A1, . Location in patent: Page/Page column 4

9
[ 110-91-8 ]
[ 350-03-8 ]
[ 5423-64-3 ]
[ 6419-36-9 ]

Yield	Reaction Conditions	Operation in experiment
72.6%	Stage #1: for 12 h; Reflux; Large scale; Green chemistry Stage #2: for 6 h; Reflux; Large scale; Green chemistry	Was added to the kettle 10L 3-acetyl pyridine (1.2kg, 9.91mol), morpholine (5.0kg, 57.39mol), sulfur was added with stirring (0.35kg, 10.92mol), heated at reflux for 12 hours, evaporated under reduced pressure to make morpholine , was added 36percent hydrochloric acid (3.5kg), refluxed for 6 hours, suction filtered, the filtrate was concentrated under reduced pressure to collect approximately 2.4kg solvent, cooled for 2 hours at 0-5 deg.] C, precipitate crystals. Suction filtration to give white needles I; the mother liquor was concentrated again and added 36percent hydrochloric acid (0.6kg), cooled, and dried to give white needles I, combined, 50 deg.]C under vacuum and dissolved, acicular white crystals were 1.25 kg, yield 72.6percent,

Reference： [1] Patent: CN103242222, 2016, B, . Location in patent: Paragraph 0022; 0023

10
[ 15504-40-2 ]
[ 6419-36-9 ]

Reference： [1] Tetrahedron, 1998, vol. 54, # 33, p. 9603 - 9612

11
[ 5423-64-3 ]
[ 6419-36-9 ]

Reference： [1] European Journal of Organic Chemistry, 2001, # 12, p. 2343 - 2361

12
[ 350-03-8 ]
[ 6419-36-9 ]

Reference： [1] European Journal of Organic Chemistry, 2001, # 12, p. 2343 - 2361

[ 6419-36-9 ] Synthesis Path-Downstream 1~83

1
[ 67-56-1 ]
[ 6419-36-9 ]
[ 39998-25-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sulfuric acid; for 1h;Reflux;	To a solution of 2-(pyri din-3 -yl)acetic acid hydrochloride (17.3 g, 100 mmol, 1 equiv) in MeOH (80 mL) was added concentrated H2SO4 (6.4 mL, 120 mmol, 1.2 equiv) dropwise at room temperature and the resulting mixture was refluxed for 1 hour. The reaction mixture was poured into saturated NaHC03 solution and extracted with DCM (3 *100 mL). The combined organic phase were washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo to afford the title compound methyl 2-(pyridin-3-yl)acetate as yellow solid (15 g, 98% yield). LC-MS: m/z 152.1 (M+H)+
97%		In order to synthesize 3-pyridylethanethiol, 3-pyridylethanol as an intermediate therefor was synthesized by the following method. Into a 1-L flask to which a nitrogen gas introduction tube, thermometer, Dimroth condenser, and dropping funnel had been attached was introduced 25.12 g (0.145 mol) of 3-pyridylacetic acid monohydrochloride. Thereto was added 500 mL of anhydrous methanol. After the atmosphere in the flask was replaced with nitrogen, the contents were stirred at room temperature to dissolve the monohydrochloride. Thereto was added dropwise 31.12 g (0.248 mol) of thionyl chloride. Thereafter, the resultant mixture was heated and reacted for further 2.5 hours with refluxing. After the reaction, the reaction mixture was cooled to room temperature, and the methanol was distilled off under vacuum. The residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate. An extraction operation using 100 mL of ethyl acetate was conducted three times, and anhydrous sodium sulfate was added to the resultant organic phase to dry the phase. The anhydrous sodium sulfate was removed by decantation. Thereafter, the solvent was distilled off under vacuum. Thus, 21.29 g (0.141 mol) of methyl 3-pyridylacetate, which is the methanol ester of 3-pyridylacetic acid, was obtained (yield, 97%).

Reference： [1]Patent: WO2019/169193,2019,A1 .Location in patent: Page/Page column 146
[2]Patent: EP2390243,2011,A1 .Location in patent: Page/Page column 26
[3]Tetrahedron Letters,1993,vol. 34,p. 331 - 334

2
[ 6419-36-9 ]
[ 162751-96-4 ]
[ 745063-48-3 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 4716 - 4732

3
[ 6419-36-9 ]
[ 6293-56-7 ]

Yield	Reaction Conditions	Operation in experiment
95.5%		(28-1) 2-(3-Pyridyl)ethanol 3-Pyridylacetic acid hydrochloride (25 g) was treated successively as in the above Production Examples 3-3 and 3-4 to give the title compound (16.938 g) as a yellow oil (yield: 95.5%). 1H-NMR (400 MHz, CDCl3): delta(ppm) 2.86(2H, t, J=6.8Hz), 3.88(2H, t, J=6.8Hz), 7.22(1H, dd, J=4.8, 7.6Hz), 7.527(1H, d, J=7.6Hz), 8.42(1H, dd, J=2.0, 4.8Hz), 8.44(1H, d, J=2.0Hz).

Reference： [1]Patent: US2002/19531,2002,A1
[2]Journal of Medicinal Chemistry,2002,vol. 45,p. 3041 - 3047
[3]Tetrahedron Letters,1993,vol. 34,p. 331 - 334
[4]Patent: EP2390243,2011,A1
[5]Patent: WO2012/75917,2012,A1

4
[ 43207-78-9 ]
[ 6419-36-9 ]
1-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2-pyridin-3-yl-ethanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 871 - 882

5
[ 42923-77-3 ]
[ 6419-36-9 ]
[ 869896-88-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 871 - 882

6
[ 103889-37-8 ]
[ 6419-36-9 ]
N-(4-chloro-2-fluoro-3-trifluoromethyl-phenyl)-2-pyridin-3-yl-acetamide [ No CAS ]
[ 899431-57-3 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3659 - 3666

7
[ 36556-52-2 ]
[ 6419-36-9 ]
[ 899431-55-1 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3659 - 3666

8
[ 6419-36-9 ]
[ 608-27-5 ]
N-(2,3-dichlorophenyl)-2-pyridin-3-ylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20 - 50℃;	2,3-Dichloroaniline (1.05 g, 6.49 mmol) in anhydrous tetrahydrofuran (30 mL) was treated with triethylamine (1.32 g, 1.81 mL, 13.0 mmol) followed by 3-pyridylacetic acid hydrochloride (1.02 g, 5.90 mmol), followed by hydroxybenzotriazole (877 mg, 6.49 mmol) followed by EDC (1.24 g, 6.49 mmol). The reaction mixture was stirred at room temperature overnight and then heated at 50 0C for 1 hour. After cooling to room temperature, the mixture was treated with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel/ ethyl acetate, product Rf = 0.4) to provide the title compound. 1H NMR (DMSO- d6) delta 9.98 (s, IH), 8.54 (d, IH), 8.47 (dd, IH), 7.76 (ddd, IH), 7.66 (dd, IH), 7.47 (dd, IH), 7.39-7.31(m, 2H), 3.91 (s, 2H); MS (ESI) calcd for C13H10Cl2N2O: 280.0170: Found: 280.9 (M+H)+.

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3659 - 3666
[2]Patent: WO2006/86229,2006,A1 .Location in patent: Page/Page column 61-62

9
[ 558464-92-9 ]
[ 6419-36-9 ]
[ 558465-04-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 14h;	Example 362: N- [[6-[(4-Chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methyl]-2-(pyridin-3-yl)acetamide The [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (30 mg, 0.073 mmol) obtained in Example 351, 3-pyridylacetic acid hydrochloride (16 mg, 0.092 mmol), 4-(dimethylamino)pyridine (5 mg, 0.04 mmol) and triethylamine (0.025 ml, 0.18 mmol) were dissolved in dichloromethane (5 ml).. To the resulting solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17 mg, 0.089 mmol).. After stirring at room temperature for 14 hours, a saturated aqueous solution (0.1 ml) of sodium bicarbonate was added to the reaction mixture.. The residue obtained by concentration of the reaction mixture under reduced pressure was subjected to flash silica gel chromatography.. A fraction obtained from the elution portion with dichloromethane:methanol = 30:1 was concentrated under reduced pressure, whereby a white solid was obtained.. The white solid was washed with ether, whereby the title compound (35 mg, 0.066 mmol, 90%) was obtained as a white powder.1H-NMR (400 MHz, CDCl3) delta: 3.59 (2H, s), 4.45 (2H, dd, J = 5.9, 1.5 Hz), 5.92 (1H, s), 5.96-6.10 (1H, m), 6.86-6.98 (1H, m), 6.99-7.05 (1H, m), 7.24-7.35 (1H, m), 7.39 (2H, d, J = 8.8 Hz), 7.55-7.60 (3H, m), 7.60-7.71 (2H, m), 7.96-8.06 (1H, m), 8.50 (2H, d, J = 1.6 Hz), 8.55 (1H, d, J = 4.8, 1.6 Hz). MS m/z: 528 (M++H).
90%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 14h;	The [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (30 mg, 0.073 mmol) obtained in Example 63, 3-pyridylacetic acid hydrochloride (16 mg, 0.092 mmol), 4-(dimethylamino)pyridine (5 mg, 0.04 mmol) and triethylamine (0.025 ml, 0.18 mmol) were dissolved in dichloromethane (5 ml). To the resulting solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17 mg, 0.089 mmol) at room temperature. The resulting mixture was stirred at room temperature for 14 hours. To the reaction mixture was added a saturated aqueous solution (0.1 ml) of sodium bicarbonate. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the dichloromethane:methanol=30:1 elute was concentrated under reduced pressure to afford a white solid. The resulting solid was washed with ether to give the title compound (35 mg, 0.066 mmol, 90%) as a white powder. 1H-NMR(400MHz,CDCl3) delta: 3.59(2H,s), 4.45(2H,dd,J=5.9,1.5Hz), 5.92(1H,s), 5.96-6.10(1H,m), 6.86-6.98(1H,m), 6.99-7.05(1H,m), 7.24-7.35(1H,m), 7.39(2H,d,J=8.8Hz), 7.55-7.60(3H,m), 7.60-7.71(2H,m), 7.96-8.06(1H,m), 8.50(2H,d,J=1.6Hz), 8.55(1H,d,J=4.8,1.6Hz). MSm/z: 528(M++H).

Reference： [1]Patent: EP1466898,2004,A1 .Location in patent: Page 232
[2]Patent: EP1640366,2006,A1 .Location in patent: Page/Page column 71-72

10
[ 6419-36-9 ]
[ 433919-41-6 ]
[ 631901-84-3 ]

Yield	Reaction Conditions	Operation in experiment
51%		[0175] To the solution of compound 2H-oxacyclotetradecino[4,3-d]oxazole-2,6,14(1H,7H)-trione, 10-[[2-O-acetyl-3,4,6-trideoxy-3-(dimethylamino)-beta-D-xylo-hexopyranosyl]oxy]-11-[(aminocarbonyl)oxy]-4-ethyldecahydro-8-hydroxy-3a,7,9,11,13,15-hexamethyl-, (3aS,4R,7R,8S,9S,10R,11R,13R,15R,15aR)-(500 mg, 0.73 mmol), [CHEMMOL-00062] [0176] catalytic amount of dimethylaminopyridine and 3-pyridylacetic acid hydrochloride (250 mg, 1.44 mmol) in CH2Cl2 (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (560 mg, 2.92 mmol). The reaction was stirred at room temperature for 16 h before being diluted with ethyl acetate (100 mL). The organic solution was washed with sat. aq. NH4Cl (10 mL), sat. aq. NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, and concentrated. Purification by chromatography (silica gel, 95:5:0.3 dichloromethane/methanol/conc. NH4OH) yielded 300 mg (51%) of the title compound.

Reference： [1]Patent: US2004/18994,2004,A1 .Location in patent: Page/Page column 28

11
[ 433920-55-9 ]
[ 6419-36-9 ]
3-pyridineacetic acid, (3aS,4R,7R,8S,9S,10R,11R,13R,15R,15aR)-4-ethyltetradecahydro-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxo-11-[[[[(2E)-3-[4-(2-pyrimidinyl)phenyl]-2-propenyl]amino]carbonyl]oxy]-10-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-oxacyclotetradecino[4,3-d]oxazol-8-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%		[0114] To the solution of compound of Example 1 (90 mg, 0.1 mmol), catalytic amount of dimethyaminopyridine and 3-pyridylacetic acid hydrochloride (35 mg, 0.2 mmol) in CH2Cl2 (2 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (80 mg, 0.42 mmol). The reaction was stirred at room temperature for 24 h before being diluted with ethyl acetate (50 mL). The organic solution was washed with sat. aq. NaHCO3 (5 mL), brine (5 mL), dried over MgSO4, and concentrated. The resulting crude product was stirred in methanol (5 mL) for 24 h. Concentration and purification by chromatography (silica gel, 94:6:0.3 dichloromethane/methanol/conc. NH4OH) yielded 35 mg (36%) of the title compound. MS 957 (M+H)+.

Reference： [1]Patent: US2004/18994,2004,A1 .Location in patent: Page/Page column 18-19

12
[ 631901-79-6 ]
[ 6419-36-9 ]
C₄₆H₆₅N₅O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		[0147] To the solution of compound of Example 19 (90 mg, 0.11 mmol), catalytic amount of dimethylaminopyridine and 3-pyridylacetic acid hydrochloride (80 mg, 0.46 mmol) in CH2Cl2 (2 mL) was added triethyl amine (0.12 mL, 0.86 mmol) and 1,3-dicyclohexylcarbodiimide (180 mg, 0.88 mmol). The reaction was stirred at room temperature for 36 h before being diluted with methanol (5 mL) and stirred for another 16 h. The mixture was diluted with ethyl acetate (50 mL). The resulting organic solution was washed with sat. aq. NH4Cl (5 mL), sat. aq. NaHCO3 (5 mL) and brine (5 mL), dried over MgSO4, and concentrated. Purification by chromatography (silica gel, 94:6:0.3 dichloromethane/methanol/conc. NH4OH) yielded 20 mg (20%) of the title compound. MS 881 (M+H)+.

Reference： [1]Patent: US2004/18994,2004,A1 .Location in patent: Page/Page column 24

13
[ 631901-80-9 ]
[ 6419-36-9 ]
C₄₇H₆₆N₄O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%		[0154] To the solution of compound of Example 24 (88 mg, 0.11 mmol), catalytic amount of dimethylaminopyridine and 3-pyridylacetic acid hydrochloride (80 mg, 0.46 mmol) in CH2Cl2 (2 mL) was added triethyl amine (0.12 mL, 0.86 mmol) and 1,3-dicyclohexylcarbodiimide (180 mg, 0.88 mmol). The reaction was stirred at room temperature for 36 h before being diluted with methanol (5 mL) and stirred for another 16 h. The mixture was diluted with ethyl acetate (50 mL). The resulting organic solution was washed with sat. aq. NH4Cl (5 mL), sat. aq. NaHCO3 (5 mL) and brine (5 mL), dried over MgSO4, and concentrated. Purification by chromatography (silica gel, 94:6:0.3 dichloromethane/methanol/conc. NH4OH) yielded 20 mg (21%) of the title compound. MS 879 (M+H)+.

Reference： [1]Patent: US2004/18994,2004,A1 .Location in patent: Page/Page column 25

14
carbamic acid, (3-quinolinylmethyl)-, (3aS,4R,7R,8S,9S,10R,11R,13R,15R,15aR)-10-[[2-O-acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-4-ethyltetradecahydro-8-hydroxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxo-2H-oxacyclotetradecino[4,3-d]oxazol-11-yl ester [ No CAS ]
[ 6419-36-9 ]
RWJ 424847-300-A [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%		[0159] To a solution of compound of Example 26 (100 mg, 0.12 mmol), catalytic amount of dimethylaminopyridine and 3-pyridylacetic acid hydrochloride (60 mg, 0.35 mmol) in CH2Cl2 (2 mL) was added 1,3-dicyclohexylcarbodiimide (120 mg, 0.58 mmol). The reaction was stirred at room temperature for 16 h before being diluted with ethyl acetate (50 mL). The organic solution was washed with sat. aq. NH4Cl (5 mL), sat. aq. NaHCO3 (5 mL) and brine (5 mL), dried over MgSO4, and concentrated. The resulting crude product was dissolved in methanol (5 mL) and stirred for 16 h. Concentration and purification by chromatography (silica gel, 94:6:0.3 dichloromethane/methanol/conc. NH4OH) yielded 28 mg (26%) of the title compound. MS 904 (M+H)+.

Reference： [1]Patent: US2004/18994,2004,A1 .Location in patent: Page/Page column 25-26

15
[ 631901-82-1 ]
[ 6419-36-9 ]
C₄₈H₆₇N₅O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%		[0164] To the solution of compound of Example 28 (54 mg, 0.065 mmol), catalytic amount of dimethylaminopyridine and 3-pyridylacetic acid hydrochloride (20 mg, 0.12 mmol) in CH2Cl2 (2 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol). The reaction was stirred at room temperature for 5 h before being diluted with ethyl acetate (50 mL). The resulting organic solution was washed with sat. aq. NH4Cl (5 mL), sat. aq. NaHCO3 (5 mL) and brine (5 mL), dried over MgSO4, and concentrated. The crude product was dissolved in methanol (5 mL) and stirred at room temperature for 24 h. Concentration and purification by chromatography (silica gel, 94:6:0.3 dichloromethane/methanol/conc. NH4OH) yielded 22 mg (37%) of the title compound. MS 906 (M+H)+.

Reference： [1]Patent: US2004/18994,2004,A1 .Location in patent: Page/Page column 26

16
[ 631901-85-4 ]
[ 6419-36-9 ]
C₄₆H₆₄BrN₅O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%		[0183] To the solution of compound of Example 36 (95 mg, 0.11 mmol), catalytic amount of dimethylaminopyridine and 3-pyridylacetic acid hydrochloride (37 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (85 mg, 0.44 mmol). The reaction was stirred at room temperature for 6 h before being diluted with ethyl acetate (50 mL). The organic solution was washed with sat. aq. NH4Cl (5 mL), sat. aq. NaHCO3 (5 mL) and brine (5 mL), dried over MgSO4, and concentrated. The crude product was dissolved in methanol (5 mL) and stirred at room temperature for 16 h. Concentration and purification by chromatography (silica gel, 95:5:0.3 dichloromethane/methanol/conc. NH4OH) yielded 65 mg (63%) of the title compound. MS 960 (M+H)+.

Reference： [1]Patent: US2004/18994,2004,A1 .Location in patent: Page/Page column 29

17
[ 631901-87-6 ]
[ 6419-36-9 ]
pyridin-3-yl-acetic acid 10-(4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-4-ethyl-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxo-11-(3-quinolin-3-yl-allylcarbamoyloxy)-tetradecahydro-3,5-dioxa-1-aza-cyclopentacyclotetradecen-8-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%		[0192] To the solution of compound of Example 40 (35 mg, 0.04 mmol), catalytic amount of dimethylaminopyridine and 3-pyridylacetic acid hydrochloride (15 mg, 0.09 mmol) in CH2Cl2 (2 mL) was added 1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol). The reaction was stirred at room temperature for 16 h before being diluted with ethyl acetate (50 mL). The organic solution was washed with sat. aq. NH4Cl (5 mL), sat. aq. NaHCO3 (5 mL) and brine (5 mL), dried over MgSO4, and concentrated. The crude product was dissolved in methanol (5 mL) and stirred at room temperature for 24 h. Concentration and purification by chromatography (silica gel, 95:5:0.3 dichloromethane/methanol/conc. NH4OH) yielded 14 mg (37%) of the title compound. MS 930 (M+H)+.

Reference： [1]Patent: US2004/18994,2004,A1 .Location in patent: Page/Page column 31

18
[ 631901-88-7 ]
[ 6419-36-9 ]
C₅₀H₆₇N₅O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		[0203] To the solution of compound of Example 44 (75 mg, 0.088 mmol), catalytic amount of dimethylaminopyridine and 3-pyridylacetic acid hydrochloride (31 mg, 0.18 mmol) in CH2Cl2 (2 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (85 mg, 0.44 mmol). The reaction was stirred at room temperature for 16 h before being diluted with ethyl acetate (50 mL). The organic solution was washed with sat. aq. NaHCO3 (5 mL), sat. aq. NH4Cl (5 mL), sat. aq. NaHCO3 (5 mL) and brine (5 mL), dried over MgSO4, and concentrated. The crude product was dissolved in methanol (5 mL) and stirred for 16 h. Concentration and purification by chromatography (silica gel, 93:7:0.3 dichloromethane/methanol/conc. NH4OH) yielded 40 mg (49%) of the title compound. MS 931 (M+H)+.

Reference： [1]Patent: US2004/18994,2004,A1 .Location in patent: Page/Page column 32-33

19
[ 6419-36-9 ]
[ 501-81-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium hydroxide; In ethanol;	(1) To a suspension of 2-(pyridin-3-yl)acetic acid-hydrochloride (13.2g, 75.6mmol) in ethanol (100mL) was added a solution (150mL) of 0.5mol potassium hydroxide/ethanol, and the mixture was stirred well, then filtered to remove potassium chloride, concentrated, and dried to give 2-(pyridin-3-yl)acetic acid (10.6g, quantitative).

Reference： [1]Patent: EP1559716,2005,A1 .Location in patent: Page/Page column 20

20
[ 6419-36-9 ]
[ 105462-24-6 ]

Yield	Reaction Conditions	Operation in experiment
79.75%		3-pyridylacetic acid hydrochloride (100 gm, 0.576 moles) and phosphorous acid (103.97 gm, 1.267 moles) were taken in a four necked round bottom flask fitted on a water bath and stirred for ten minutes at ambient temperature (250C to 3O0C). The reaction mixture was heated to 6O0C to 650C and at this temperature phosphorous trichloride (198.12 gm, 1.44 moles) was added slowly in one hour to the reaction mixture. Then the reaction mixture was heated to 7O0C to 750C and maintained for 8 hours at the same temperature. Reaction mixture was cooled to 550C and the unreacted phosphorous trichloride was distilled at 5O0C to 550C under vacuum. Water (725 ml) was added to the reaction mixture and heated at 9O0C to 950C for six hours. Reaction mass was cooled to ambient temperature (250C to 3O0C) and stirred for 2 hrs. Product is separated as crystalline solid, which was filtered, and dried at 430C to 450C under vacuum.Yield : 130 gms (79.75%) Purity (HPLC) : 99.83%
76.68%		Example D3 Synthesis of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic Acid In a 100 ml rounded bottom, three necked flask equipped with a magnetic stirrer, a thermometer, a reflux condenser and a compensated-pressure dropping funnel were charged: 1.00 g (5.76·10-3 mol) g of 3-pyridyl acetic acid hydrochloride, 1.46 g (1.78·10-2 mol) of phosphonic acid, 4.58 g (1.44·10-2 mol) of propylphosphonic anhydride and 7.2 ml of ethyl acetate. The mixture was heated up to reflux (76 C.) and stirred overnight at this temperature. 7.2 ml of water were added dropwise and the mixture maintained at reflux 86-89 C. for about 5.5 h. During the hydrolysis a white solid precipitated out. The mixture was let to cool down to room temperature, further cooled down to about 5 C. by means of a water/ice bath and filtered. The white solid obtained was dried into a vacuum oven at 50 C. until constant weight. 1.33 g of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid were obtained (Yield: 76.68%) Chromatographic purity: 99.32% (area percent) X-Ray Powder Diffractogram: see
74%		3.8 mmol (1 equiv) of the respective carboxylic acid (658 mg 3-pyridylacetic acid hydrochloride for 1, 478 mg imidazol-1-yl-acetic acid for 2, 339 mg beta-alanine for 3, 392 mg gamma-aminobutyric acid for 4, 499 mg 6-aminohexanoic acid for 5) were added to 11.4 mmol (3 equiv) H3PO3 in a dry flask. 1.6 mL of distilled sulfolane was added and the contents were heated briefly to dissolve the solids. The solution was cooled down to approximately 25-35 C, and 11.4 mmol (3 equiv) of PCl3 were immediately added. The flask was then placed in a Milestone Ethos Synth Microwave Synthesis Labstation and fitted with a condenser through which cold water was passed. The following microwave programs were applied:For synthesis of 1: 3 min ramp to 65 C, followed by 15 s at 65 C. For synthesis of 2: 3 min ramp to 65 C, followed by 45 s at 65 C.For synthesis of 3: 3 min ramp to 65 C, followed by 15 s at 65 C.For synthesis of 4: 3 min ramp to 65 C, followed by 4 min at 65 C.For synthesis of 5: 3 min ramp to 65 C, followed by 4 min at 65 C.The power was automatically adjusted to reach and maintain the temperature designated by the program, which is determined by a built-in IR sensor in the microwave reactor. For the synthesis of intermediates 1 and 2, the power fluctuated between 0 and a max of 300-400 W, while for 3, 4, and 5, the max power was typically 200-300 W.The solid mixture after microwave irradiation consists of intermediate phosphorus compound together with a yellow-orange unwanted side product which can be removed by centrifugation before or after hydrolysis. The reaction mixture was quenched with 6 mL of H2O, yielding a clear solution that was then transferred to a 50 mL sealed quartz reaction vessel and was hydrolyzed to the bisphosphonic acid in the microwave reactor with a 6 min ramp to 150 C, followed by 4 min at 150 C. The power applied fluctuated between 0 and a max of 450-500 W. The pH of the hydrolysis mixtures for acids 1, 3, 4, and 5 was adjusted15 with NaOH and the mixture then aged at 0-5 C until crystallization of the products was complete. Acids 4 and 5 were precipitated as monosodium salts by stirring with 2-5 mL ethanol for 1-2 h at room temperature. Acid 2 was precipitated by the addition of 9 mL acetone to the acidic hydrolysis mixture and stirring for 3-4 h at room temperature. The white crystalline products were then filtered and washed with cold H2O and acetone or ethanol and then dried under vacuum at 45 C to constant weight.15 with NaOH and the mixture then aged at 0-5 C until crystallization of the products was complete. Acids 4 and 5 were precipitated as monosodium salts by stirring with 2-5 mL ethanol for 1-2 h at room temperature. Acid 2 was precipitated by the addition of 9 mL acetone to the acidic hydrolysis mixture and stirring for 3-4 h at room temperature. The white crystalline products were then filtered and washed with cold H2O and acetone or ethanol and then dried under vacuum at 45 C to constant weight.

70.47%		Preparation of risedronic acid A suspension of 3-pyridylacetic acid hydrochloride (50g, 0. 288mol) and phosphorous acid (35.4g, 0. 432mol) in sulfolan (180ml) is heated to 75C for 30 min. The mixture is cooled to 35-40C and then gradually introduced phosphorous trichloride (85. 6ml, 0. 98mol) while maintaining the temperature between 35-45C. The mixture is heated to 63-67C for 3 hours whereby a thick white mass results. It is then cooled to 0-5 C and quenched by slow addition of water (500ml) at 0-5C over a period of 1 hour. The resulting clear solution is charcoalized and heated at 100C for 3hrs, cooled to ambient temperature and then cooled 0-5C. After stirring for 2hrs at 0-5C the crystallized product is filtered, washed sequentially with chilled water (100ml), rectified spirit (75ml) and dried in air oven at 55-60C until loss on drying is less than 0.5% w/w. Yield 60.4g, (70.47%), appearance :. white crystalline solid, purity >99.0%.
69.20%		C. Preparation of risedronic acid; 3-pyridyl acetic acid hydrochloride (lOOgm, 0.5759 mole) was suspended in methyl cyclohexane (500 ml) along with phosphorous acid (142gm, 1.73moles). Water was removed by azeotropically and then oithophosphoric acid (170gm, 1.91 mole) was added to Ae reaction mass. The reaction mass was further heated and water was removed azeotropically. After complete removal of water, the reaction mass was <n="17"/>cooled to 90-920C and phosphorous oxychloride (162ml, 1.73 mole) was added in 3thetamin.The? temperature was further raised to 95C and maintained for 20hrs. After completion of 20hrs, water (720ml) was added to the reaction mass and the temperature of the reaction mass was further raised to 95C and maintained for 30min. At same temperature, methyl cyclohexane layer was separated out and the lower aqueous layer was further heated at 95C for 5-6hrs. Now the reaction mass was cooled to 25-300C and isopropyl alcohol (1440ml) was added slowly in 30-45 min. Then the reaction mass was further cooled to 5C and maintained for lhr. The precipitated product was collected by filtration and washed with chilled isopropyl alcohol (100ml). The wet cake obtained was dried at 65-700C for 8-10 hrs to get120gm (Yield: 69.20%) as Risedronic acid monohydrate with HPLC purity more than 98%.
69.20%		C. Preparation of Risedronic Acid 3-pyridyl acetic acid hydrochloride (100 gm, 0.5759 mole) was suspended in methyl cyclohexane (500 ml) along with phosphorous acid (142 gm, 1.73 moles). Water was removed by azeotropically and then orthophosphoric acid (170 gm, 1.91 mole) was added to the reaction mass. The reaction mass was further heated and water was removed azeotropically. After complete removal of water, the reaction mass was cooled to 90-92 C. and phosphorous oxychloride (162 ml, 1.73 mole) was added in 30 min.Then temperature was further raised to 95 C. and maintained for 20 hrs. After completion of 20 hrs, water (720 ml) was added to the reaction mass and the temperature of the reaction mass was further raised to 95 C. and maintained for 30 min. At same temperature, methyl cyclohexane layer was separated out and the lower aqueous layer was further heated at 95 C. for 5-6hrs. Now the reaction mass was cooled to 25-30 C. and isopropyl alcohol (1440 ml) was added slowly in 30-45 min. Then the reaction mass was further cooled to 5 C. and maintained for 1 hr. The precipitated product was collected by filtration and washed with chilled isopropyl alcohol (100 ml). The wet cake obtained was dried at 65-70 C. for 8-10 hrs to get 120 gm (Yield: 69.20%) as Risedronic acid monohydrate with HPLC purity more than 98%.
60%		Example 1-Preparation of risedronic acid A mixture of (3-pyridyl) acetic acid hydrochloride (10 g 0.06 moles) and phosphorous acid (47 g, 0.58 moles) is slowly added with phosphorus oxychloride (28.8 g 0.19 moles). The fluid mixture is warmed up to 60-70C for 24 hours, then added with 60 ml water at the same temperature. The mixture is refluxed for 6 hours, added with 0.3 g charcoal and hot-filtered through celite. The clarified solution is added with 160 ml acetone. The resulting precipitate is filtered, suspended in 50 ml water, dissolved at pH 7.5 (+/-0.2) with 30% sodium hydroxide. The resulting solution is acidified to pH 0.8 (+/-0. 2) and the precipitate is filtered and dried under vacuum at 40-50C to constant weight. 9. 8 g pure risedronic acid is obtained (yield: 60%).
60%	With phosphonic Acid; phosphorus trichloride; In chlorobenzene; for 7.5h;Reflux;	The <strong>[6419-36-9]3-pyridine acetic acid hydrochloride</strong> obtained in step (4), phosphorous acid and chlorobenzene were added to a three - necked flask, and the amount ratio of the of the <strong>[6419-36-9]3-pyridine acetic acid hydrochloride</strong> to phosphorous acid was 1:25 . The amount of chlorobenzene used was calculated according to the addition of 0.1 moles of <strong>[6419-36-9]3-pyridine acetic acid hydrochloride</strong> per 100 mL of chlorobenzene. Reaction was stirr heated to reflux, dropping addition phosphorus trichloride, according to the ratio of the amount of <strong>[6419-36-9]3-pyridine acetic acid hydrochloride</strong> and phosphorus trichloride was 1: 3 drop of phosphorus trichloride. After completion of the dropwise addition, the mixture was further refluxed for 7.5 hours, cooled to room temperature, and dumped chlorobenzene. The concentrated hydrochloric acid having a mass fraction of 37.5% and water was added to the residue , and 100 mL of concentrated hydrochloric acid and 50 mL of water were added per 100 mL of chlorobenzene, and refluxed for 7 hours. The activated charcoal was decolorized and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was added to absolute ethanol and 100 mL of anhydrous ethanol was added per 100 mL of chlorobenzene, precipitated large solid precipitation, and crushed into a powder. filtered, filter cake recrystallization with water, then drying at 80 C, to obtain white solid that is risedronic acid, the based on amount calculation of 3- Pyridine carbonyl chloride hydrochloride , the yield of risedronic acid was 60%.
52%	With phosphonic Acid; phosphorus trichloride; In chlorobenzene; at 100℃; for 8h;	To a 500 mL flask, 3-pyridine acetimidoyl ethyl (26.0 g, 0.4 mol, 1 eq) in 200 mL chlorobenzene at 100 C was added solid phosphorous acid rapidly, followed by PCl3 (32 mL, 0.8 mol, 2 eq) drop-wise in about 2 h. The mixture was stirred at 100 C for 6 h, brought to room temperature. The solvent was removed, and the remainingchlorobenzene was evaporated in a vacuum desiccator overnight. The resulting solid was dissolved in 2 N HCl (500 mL), and the mixture was refluxed at 100 C for 12 h. The mixture was hot filtered to remove undissolvedimpurities. When the solution was cooled to 30-40 C, 500 mL of absolute ethyl alcohol was added slowly, and a large amount of white solid precipitate appeared. After freezing in refrigerator for 1 h, the precipitate was filtered, washed with H2O, and dried in a vacuum desiccator to afford 23.6 g of 11 as crystals with a yield of 52%. Anal. Calcd for C7H13NO8P2: C, 27.92; H, 4.35; N, 4.65. Found: C, 27.84; H, 3.95; N, 4.57.
		Example 1; EPO <DP n="18"/>42ml of water were charged to a 500ml four necked flask, to which was added dropwise 116ml of phosphorous trichloride over a period of 2.5 hours. During the dropwise addition of phosphorous trichloride, the reaction temperature was maintained in the range of 10-700C depending on reaction kinetics. At 2O0C, 26.6g of pyridylacetic acid hydrochloride were charged to the flask. The reaction was performed by slow heating to 7O0C over a period of one hour and maintained for half hour at this temperature. 34ml of water and 50ml of hydrochloric acid were then added dropwise. The solution was heated to reflux (-1120C) and maintained at the reflux temperature for four hours. The solution was cooled to 7O0C and 0.8g of active carbon was added. The suspension was mixed for 30 minutes, filtered and the resulting carbon cake was washed with 14ml of water. The filtrate was collected and vacuum evaporated. 50ml of water were then added and slowly cooled. Crystallization of risedronic acid started at about 560C. The suspension was then slowly cooled to 0-50C and retained for three hours at this temperature. Risedronic acid, 31.5g, was obtained after filtration, washing with 14 ml of cold water and drying. Example 2; 210ml of water were charged to a 2000ml four necked flask, to which was added dropwise 580ml of phosphorous trichloride over a period of 2.5 hours. During the dropwise addition of phosphorous trichloride, the reaction temperature was maintained in the range of 10-700C depending on reaction kinetics. At 2O0C, lOOg of pyridylacetic acid hydrochloride were charged to the flask. The reaction was performed by slow heating to 9O0C over a period of 1.5 hours. 170ml of water and 250ml of hydrochloric acid were then added dropwise. The solution was heated to reflux (~1120C) and maintained at the reflux temperature for four hours. The solution was cooled to 8O0C and 3g of active carbon were added. The suspension was mixed for 30 minutes, filtered and the resulting carbon cake was washed with 70ml of water. The filtrate was collected and vacuum evaporated. 250ml of water were added and slowly cooled. Crystallization of risedronic acid started at about 6O0C. The suspension was then slowly cooled to 0-50C and retained for two hours at this temperature. Risedronic acid, 115.8g, was obtained after filtration, washing with 100ml of cold water and drying. EPO <DP n="19"/>Example 3; 210ml of water were charged to a 2000ml four necked flask, to which was added dropwise 580ml of phosphorous trichloride over a period of 2.5 hours. During the dropwise addition of phosphorous trichloride the reaction temperature was maintained in the range of 10-700C depending on reaction kinetics. At 220C5 lOOg of pyridylacetic acid hydrochloride were charged. The reaction was performed by slow heating to 640C over a period of 1.5 hours. 200ml of water and 250ml of hydrochloric acid were then added dropwise. The solution was heated to reflux (~112C) and maintained at the reflux temperature for four hours. The solution was cooled to 8O0C and 3g of active carbon were added. The suspension was mixed for 30 minutes, filtered and the resulting carbon cake was washed with 70ml of water. The filtrate was collected and vacuum evaporated. 250ml of water were added and slowly cooled. Crystallization of risedronic acid started at about 580C. The suspension was than slowly cooled to 0-50C and retained for 1.5 hours at this temperature. Risedronic acid, 134.7g, was obtained after filtration, washing with 100ml of cold water and drying.
		Example 2 Preparation of Risedronic Acid 3-Pyridyl acetic acid hydrochloride (100 g), phosphorous acid (188.94 g) and n-octane (700 ml) were taken in a reaction flask and heated at 85-90 C. for 30 minutes. This was followed by the drop wise addition of phosphorous oxychloride (353.29 g) at 85-90 C. and the resulting mixture was stirred for 3-4 hours at the same temperature. The resulting mass was cooled to 70-75 C. followed by the drop wise addition of water (50 ml) and then stirred for 20-30 minutes. This was followed by the addition of water (650 ml) in 30-40 minutes and the resulting mixture was heated to 85-90 C. and maintained for 12 hours. The resulting hot reaction mixture was filtered through hyflow bed and washed with hot water (100 ml) followed by the addition of methanol (1400 ml) at 30-50 C. in 30-40 minutes. The resulting mixture was cooled to 0-5 C. and then stirred for 1 hour. The resulting solid was filtered, washed four times with water (300 ml*4) and then dried the product in air oven at 60-65 C. for 5-6 hours to produce 130 g of risedronic acid (HPLC Purity: 99.6%). Level of organic volatile impurities: n-octane-not detected, and methanol-600 ppm.

Reference： [1]Molecular Pharmaceutics,2016,vol. 13,p. 1217 - 1228
[2]Patent: WO2009/34580,2009,A1 .Location in patent: Page/Page column 7
[3]Patent: US2008/194525,2008,A1 .Location in patent: Page/Page column 8
[4]Tetrahedron Letters,2011,vol. 52,p. 2285 - 2287
[5]Patent: WO2005/44831,2005,A2 .Location in patent: Page/Page column 12
[6]Patent: WO2009/50731,2009,A2 .Location in patent: Page/Page column 15-16
[7]Patent: US2010/121066,2010,A1 .Location in patent: Page/Page column 4-5
[8]Patent: WO2005/63779,2005,A2 .Location in patent: Page/Page column 5-6
[9]Patent: CN104628770,2017,B .Location in patent: Paragraph 0023; 0034; 0035
[10]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 949 - 954
[11]Patent: WO2006/129056,2006,A2 .Location in patent: Page/Page column 16-18
[12]Patent: US2010/317859,2010,A1 .Location in patent: Page/Page column 4-5

21
[ 133010-65-8 ]
[ 6419-36-9 ]
N-[(pyridine-3-yl)acetyl]-D,L-alanine iso-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With isobutyl bromoacetate; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;	GENERAL PROCEDURE BF EDC Coupling of Acid and Amine The acid derivative was dissolved in methylene chloride. The amine (1 eq.), N-methylmorpholine (5 eq.), and hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence. The reaction was cooled to about 0C and then 1.2 eq. of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. The solution was allowed to stir overnight and come to room temperature under N2 pressure. The reaction mix was worked up by washing the solution with saturated, aqueous Na2CO3, 0.1M citric acid, and brine before drying with Na2SO4 and removal of solvents to yield crude product. Pure products were obtained by flash chromatography in an appropriate solvent.; Example B7 Synthesis of N-[(3-pyridyl)acetyl]-D,L-alanine iso-butyl ester Following General Procedure BF and using 3-pyridylacetic acid hydrochloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of-62-64C. The reaction was monitored by tic on silica gel (Rf = 0.48 10% methanol/dichloromethane) and Purification was by silica gel chromatography. NMR data was as follows: 1H-nmr (CDCl3): delta = 8.40 (d, J = 2.8, 2H); 7.6 (m, 1H): 7.16 (m, 2H); 4.5 (quint., J = 7.2, 7.2, 1H); 3.8 (m, 2H); 3.48 (s, 2H); 1.8 (m, 1H); 1.30 (d, J = 7.2, 3H); 0.81 (d, J = 6.7, 6H). 13C-nmr (CDCl3): delta = 173.4, 170.1, 150.6, 148.8, 137.4, 131.4, 124.1, 71.9, 48.9, 40.6, 28.1, 19.5, 19.4, 18.6.. C14H20N2O3 (MW = 264, Mass Spectroscopy (MH+ 265))
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;	Example 7 Synthesis of N-[(3-pyridyl)acetyl]-D,L-alanine iso-butyl ester Following General Procedure F and using 3-pyridylacetic acid hydrochloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example B above), the title compound was prepared as a solid having a melting point of 62-64C. The reaction was monitored by tlc on silica gel (Rf = 0.48 10% methanol/dichloromethane) and purification was by silica gel chromatography. NMR data was as follows: 1H-nmr (CDCl3): delta = 8.40 (d, J = 2.8, 2H); 7.6 (m, 1H): 7.16 (m, 2H); 4.5 (quint., J = 7.2, 7.2, 1H); 3.8 (m, 2H); 3.48 (s, 2H); 1.8 (m, 1H); 1.30 (d, J = 7.2, 3H); 0.81 (d, J = 6.7, 6H). 13C-nmr (CDCl3): delta = 173.4, 170.1, 150.6, 148.8, 137.4, 131.4, 124.1, 71.9, 48.9, 40.6, 28.1, 19.5, 19.4, 18.6. C14H20N2O3 (MW = 264, Mass Spectroscopy (MH+ 265)) GENERAL PROCEDURE FEDC Coupling of Acid and Amine The acid derivative was dissolved in methylene chloride. The amine (1 eq.), N-methylmorpholine (5 eq.), and hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence. The reaction was cooled to about 0C and then 1.2 eq. of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. The solution was allowed to stir overnight and come to room temperature under N2. pressure. The reaction mix was worked up by washing the solution with saturated, aqueous Na2CO3, 0.1M citric acid, and brine before drying with Na2SO4 and removal of solvents to yield crude product. Pure products were obtained by flash chromatography in an appropriate solvent.

Reference： [1]Patent: EP951466,2009,B1 .Location in patent: Page/Page column 285; 289
[2]Patent: EP951464,2005,B1 .Location in patent: Page/Page column 32-33; 28

22
[ 6419-36-9 ]
[ 7719-12-2 ]
[ 105462-24-6 ]

Yield	Reaction Conditions	Operation in experiment
82%		EXAMPLE 1 Process for the preparation of [l-hydroxy-2-(3-pyridinyl)ethylidene] bisphosphonic acid.Aqueous solution of 35.75 g (0.206 mole) of 3-pyridinyl acetic acid hydrochloride is added dropwise with vigorous mixing over 1 hour at a temperature of 0-5C into169.93 g (1.23 mole) of phosphorus trichloride cooled to a temperature of 0-50C. The reaction mixture is then slowly heated to a temperature of 75-800C and maintained at this EPO <DP n="6"/>temperature until the reaction mixture in its solid state is obtained. Excessive phosphorus trichloride used in the reaction is distilled off under reduced pressure. Then, 200 ml of water is added and the mixture is hydrolyzed by boiling for 6 hours. After cooling, the mixture is filtered, washed with water, and dried. As a result, 48 g (82% yield) of [l-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid was obtained.1H NMR (D2O) delta = 3.35 (t., J (H,P) = 11.9 Hz, 2H, CH2); 7.42 (dd., J = 8.1Hz, J = 4.9 Hz, IH, CH); 8.00 (d., J = 8.1Hz, IH, CH); 8.42 (dd., J = 4.9 Hz, J = 1.5 Hz, IH, CH); 8.59 (d., J = 1.5 IH, CH)13C NMR (D2O) delta = 40.8 (CH2); 78.2 (t., J = 128 Hz, C); 127.8 (CH); 138.8 (t., J = 8 Hz, C); 144.6 (CH); 150.5 (CH); 155.1 (CH)31P NMR (D2O) delta = 18.2

Reference： [1]Patent: WO2006/71128,2006,A1 .Location in patent: Page/Page column 4; 5

23
[ 6419-36-9 ]
[ 10294-56-1 ]
[ 105462-24-6 ]

Yield	Reaction Conditions	Operation in experiment
	In hydrogenchloride; anhydrous phosphorus trichloride; ethanol; water; chlorobenzene	3 Synthesis of 3-(2-Hydroxy-2,2-diphosphonoethyl)-1-methylpyridinium Iodide Disodium Salt STR10 I. Synthesis of [1-Hydroxy-2-(3-pyridinyl)ethylidene]bis[phosphonic acid] To a 250 ml 3-neck round bottom flask equipped with a condenser and a dropping funnel is added 3-pyridylacetic acid hydrochloride (1.74 g, 10 mmole), phosphorous acid (2.46 g, 30 mmole) and 50 ml chlorobenzene. The flask is placed in a boiling water bath and phosphorus trichloride (4.0 g, 30 mmole) is added dropwise from the dropping funnel to the reaction mixture. This is stirred for 3 hours at 100° C. and a yellow, gummy oil forms during the course of this reaction. After 3 hours, the reaction mixture is cooled in an ice bath and the excess chlorobenzene is decanted. The oil is hydrolyzed in 100 ml of 1N HCl overnight, cooled, and the first crop of crystals is filtered and washed with ethanol. The filtrate is evaporated to an oil and a small amount of water is added to dissolve the oil. Ethanol is added to induce crystallization. The second crop of crystals is filtered and washed with ethanol and combined with the first crop to yield 2.1 g after recrystallizing from hot water.

Reference： [1]Current Patent Assignee: PROCTER & GAMBLE CO; INK; TEVA PHARMACEUTICAL INDUSTRIES LTD. - US5391743, 1995, A

24
[ 118-45-6 ]
[ 6419-36-9 ]
5-Chloro-3-(pyrid-3-yl)methylenephthalide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium acetate; In ethanol;	Preparative Example 9 5-Chloro-3-(pyrid-3-yl)methylenephthalide STR24 A mixture comprising 5.0 g of <strong>[118-45-6]4-chlorophthalic anhydride</strong>, 5.5 g of 3-pyridylacetic acid hydrochloride and 0.5 g of anhydrous sodium acetate was stirred without any solvent at 200 C. for 10 minutes. Ethanol (100 ml) was added to the reaction mixture and the mixture thus obtained was cooled with ice to precipitate crystals, which were recovered by filtration to give 2.68 g of the title compound as a yellowish-orange crystal. 1H-NMR (400 MHz, DMSO-d6) delta: 7.24(1H, s), 7.79(1H, dd, J=8.0, 2.0 Hz), 7.89(1H, dd, J=8.0, 5.5 Hz), 8.03(1H, dd, J=8.0, 0.5 Hz), 8.35(1H, dd, J=2.0, 1.5 Hz), 8.56(1H, ddd, J=8.0, 2.0, 0.54 Hz), 8.74(1H, dd, J=5.5, 1.5), 9.00(1H, d, J=2.0)

Reference： [1]Patent: US5849741,1998,A

25
aqueous sodium sulfate [ No CAS ]
[ 6419-36-9 ]
[ 6293-56-7 ]

Yield	Reaction Conditions	Operation in experiment
34%	In tetrahydrofuran;	PREPARATION 7 2-(3-Pyridinyl)ethanol A round-bottomed flask equipped with a magnetic stirring bar is charged with 13.9 g (0.08 mol) of (3-pyridinyl)acetic acid, hydrochloride salt (Aldrich Chemical Co.) and 400 ml of tetrahydrofuran (THF) under a nitrogen atmoshphere. To this solution lithium aluminum hydride (6.0 g, 0.16 mol) is added at room temperature for 24 hr. Saturated aqueous sodium sulfate is then added dropwise until the mixture becomes white. The solution is dried over anhydrous sodium sulfate. After filtration and concentration the resulting yellow oil is purified by 324 g of HPLC grade silica gel, eluding with ethyl acetate-hexane-ethanol (10:1:1) and collecting 40 ml fractions. Fractions 21-43 homogeneous on TLC are combined and concentrated in vacuo to give a light yellow oil (3.4 g, 34%). The NMR (CDCl3, TMS, delta) spectrum shows peaks observed at 8.52-7.08, 3.86 and 2.84. The IR spectrum (film, numax) reveals peaks at 3300, 2920, 2860, 1640, 1620, 1590, 1580, 1480, 1420, 1050, 800, and 720 cm-1. The mass spectrum reveals an ion at m/e 123.0681.

Reference： [1]Patent: US4789745,1988,A

26
1-[4-(3-methyl-9-phenyl-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-8-yl)phenyl]methanamine hydrochloride [ No CAS ]
[ 6419-36-9 ]
3-(2-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzyl]amino}-2-oxoethyl)pyridinium chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 0.0833333h;Microwave reactor;	To l-[4-(3-methyl-9-phenyl[l,2,4]triazolo[3,4-/\|-l,6-naphthyridin-8- yl)phenyl]methanamine hydrochloride (5-3, 20 mg, 0.050 mmol) ), EDC (12 mg, 0.065 mmol), HOBT (10 mg, 0.0650 mmol), DIPEA (0.033 ml, 0.199 mmol), and pyridin-3-ylacetic acid hydrochloride (11 mg, 0.0650 mmol) was added 0.6 mL anhydrous dimethylformamide. The reaction mixture was then heated under microwave irradiation at 100C for 5 minutes. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSCl 8, 1% acetonitrile / 0.1% trifluoroacetic acid / water -» 95% acetonitrile / 0.1% trifluoroacetic acid / water) & conversion to HCl salt (addition of EPO <DP n="156"/>saturated solution of HCl in ethyl acetate (~ 4N) & concentration) gave the title compound as yellow solid. HRMS (M+H+): calculated = 243.1079, observed = 243.1083.

Reference： [1]Patent: WO2006/135627,2006,A2 .Location in patent: Page/Page column 154-155

27
[ 6419-36-9 ]
Risedronate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.20%		A mixture of 3-pyridyl-acetic acid or its hydrochloride (20.0 g, 0.145 mol) and phosphorous acid (14.4 g, 0.175 mol) in acetonitrile (300 ml) was heated at a temperature of 55-65 C. and phosphorous trichloride (40.06 g, 0.290 mol) was added slowly under stirring. After completion of the addition, the reaction temperature was raised to 70-75 C. and the reaction continued for 6-9 hours at the same temperature. The reaction mixture was cooled to 60-65 C. and water (300 ml) was added slowly at the same temperature. The reaction temperature was then increased to 90-100 C. and maintained for the next 4-6 hours. The reaction mixture was then cooled to 55-65 C. and the reaction mixture pH was adjusted to 4.3-4.8 with sodium hydroxide solution. The reaction mixture was cooled to 25-35 C. and the aqueous layer containing the product was separated from the upper acetonitrile layer. The aqueous layer was cooled to and maintained at 0-5 C. for 3 hours. The solid product was separated by filtration and washed with water and finally with methanol to obtain sodium risedronate. The product was dried in a vacuum oven at 45-50 C. until loss on drying was less than 0.5% w/w. Yield: 25 g (56.20%). Appearance: white crystalline solid. Purity >97% (HPLC).
28%		Example 1 Preparation of 3-pyridyl-1-hydroxyethylidene-1, 1-bisphosphonic acid monosodium salt in the presence of sunflower oil 1700 g of 3-Pyridyl acetic acid.HCl and 2000 g of phosphorus acid are charged through 25 L of sunflower oil and suspended in the same. Temperature is adjusted to 90 C at which all components of the reaction medium are provided in liquid form. A NaOH trap is mounted to the system to catch the possible HCl emition. At this temperature 4700 g of phosphorous trichloride is added dropwise. After completion of said addition, temperature is adjusted to 115C and reaction medium is stirred for 4 hours. Then reaction medium is allowed to cool down until 4 - 5 C and 31 L of water is slowly added to the reaction mixture. The mixture is stirred for 4 hours at reflux temperature (110 C) where the phosphorous intermediates are hydrolyzed and phases are separated thereafter. Water phase is filtered on celit and allowed to cool down until room temperature. The mixture at this temperature is treated with dropwise 50% NaOH solution (5.6 L) after which the pH is adjusted to 4.7. This mixture is stirred for 12 hours for obtaining the so formed white crystals in precipitated form. Cake of the crystalline precipitate is dissolved in 30 L of water and then by addition acetone (70L) product is re-precipitated. The yield of the overall process is 28 %. The analysis confirmed the identity of the product and the absence of impurities. 31 P-NMR, 1H-NMR and 13C-NMR spectra were obtained in D2O on a Varian Mercury 300 MHz instrument. 31P-NMR(D2O): 17.34 (s); 1H-NMR(D2O): 3.26 (t, 2H), 7.72 (t, 1H), 8.37 (m, 2H), 8.54 (t, 1H) 13C-NMR(D2O):149.04, 142.67, 138.62, 126.18, 36.2
27.0%		Example 3; Preparation of 3-pyridyl-1-hydroxyethylidene-1, 1-bisphosphonic acid monosodium salt in the presence of olive oil; The procedure of Example I is repeated except olive oil is used as the emulsifying agent instead of sunflower oil. The analysis confirmed the identity of the product and the absence of impurities. Overall yield of 27.0 % is obtained.

27.0%		Example 4; Preparation of 3-pyridyl-1-hydroxyethylidene-1, 1-bisphosphonic acid monosodium salt in the presence of recovered olive oil; The procedure of Example I is repeated except recovered olive oil is used as the emulsifying agent instead of sunflower oil. The analysis confirmed the identity of the product and the absence of impurities. Overall yield of 27.0 % is obtained.
27.5%		Example 2; Preparation of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monosodium salt in the presence of recovered sunflower oil; The procedure of Example I is repeated except recovered sunflower oil is used as the emulsifying agent instead of non-used sunflower oil. The analysis confirmed the identity of the product and the absence of impurities. Overall yield of 27.5 % is obtained.
25.0%		Example 5; Preparation of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monosodium salt in the presence of paraffin; The procedure of Example I is repeated except paraffin is used as the emulsifying agent instead of sunflower oil. The analysis confirmed the identity of the product and the absence of impurities. Overall yield of 25.0 % is obtained.
24.0%		Example 7; Preparation of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monosodium salt in the presence of nonyl phenol 4 mol ethoxylate; The procedure of Example I is repeated except nonyl phenol 4 mol ethoxylate is used as the emulsifying agent instead of sunflower oil. The analysis confirmed the identity of the product and the absence of impurities. Overall yield of 24.0 % is obtained.
23.5%		Example 9; Preparation of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monosodium salt in the presence of nonyl phenol 10 mol ethoxylate; The procedure of Example I is repeated except nonyl phenol 10 mol ethoxylate is used as the emulsifying agent instead of sunflower oil. The analysis confirmed the identity of the product and the absence of impurities. Overall yield of 23.5 % is obtained.
23.0%		Example 8; Preparation of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monosodium salt in the presence of nonyl phenol 6 mol ethoxylate; The procedure of Example I is repeated except nonyl phenol 6 mol ethoxylate is used as the emulsifying agent instead of sunflower oil. The analysis confirmed the identity of the product and the absence of impurities. Overall yield of 23.0 % is obtained.
22.0%		Example 6; Preparation of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monosodium salt without an emulsifying agent; The procedure of Example I is repeated except any emulsifying agent is used in the reaction medium. As a consequence, it is noticed that the yield of the process relatively lower than the processes wherein disclosed emulsifying agents are employed. Overall yield of 22.0 % is obtained.

Reference： [1]Patent: US2009/198062,2009,A1 .Location in patent: Page/Page column 6
[2]Patent: EP1798236,2007,A1 .Location in patent: Page/Page column 6
[3]Patent: EP1798236,2007,A1 .Location in patent: Page/Page column 7
[4]Patent: EP1798236,2007,A1 .Location in patent: Page/Page column 7
[5]Patent: EP1798236,2007,A1 .Location in patent: Page/Page column 7
[6]Patent: EP1798236,2007,A1 .Location in patent: Page/Page column 7
[7]Patent: EP1798236,2007,A1 .Location in patent: Page/Page column 8
[8]Patent: EP1798236,2007,A1 .Location in patent: Page/Page column 8
[9]Patent: EP1798236,2007,A1 .Location in patent: Page/Page column 8
[10]Patent: EP1798236,2007,A1 .Location in patent: Page/Page column 7-8

28
[ 5321-49-3 ]
[ 6419-36-9 ]
1-(4-phenethylpiperazin-1-yl)-2-(pyridine-3-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In N,N-dimethyl-formamide; at 20℃;pH 8;	To a solution of l-(2-Phenylethyl)piperazine (2.2 ml, 11.5 mmol) and 3-pyridylacetic acid hydrochloride (2.0 g, 11.5 mmol) in DMF (approximately 15 ml) is added HOBT (1.6 g, 11.5 mmol). The pH of the solution is adjusted to 8 by adding N-methylmorpholine. Coupling reagent EDC (2.3 g, 11.9 mmol) is added. After the reaction mixture is stirred at RT over night, the solvent is evaporated under reduced pressure and the residue is dissolved in EtOAc (20 ml). The organic layer is washed with aqueous saturated NaHCO3 (20 ml) and NaCl (20 ml) solution and dried (Na2SO4). The solvent is evaporated under reduced pressure to give a product which is chromatographed on silica (MeOH/EtOAc, 2:10) to give a brownish solid; yield: 3.56 g, 100 % (98 % pure by area % HPLC analysis); mp 91-93 C; chemical formula: C19H23N3O; molecular weight: 309,41.1H NMR (300 MHz, DMSO-J15) delta 2.37 - 2.43 (4H, m), 2.50 - 2.54 (4H, m), 2.71 - 2.76 (2H, m), 3.40 - 3.54 (2H, m), 3.76 (2H, s), 7.18 - 7.35 (6H, m), 7.61 (IH, td, J= 7.8 Hz, J= 1.7), 8.42 - 8.44 (2H, m); FT-IR (NaCl) 3409, 2776, 1652, 1579, 1424, 1311, 1237, 1134, 1237, 1134, 998, 767, 697 cm"1; EI MS m/z 310 [MH+], FAB MS m/z 310 [MH+]; HRMS m/z calcd for C19H24N3O [MH+] 310.1919, found 310.1928.

Reference： [1]Patent: WO2007/73935,2007,A1 .Location in patent: Page/Page column 14-15

29
[ 6419-36-9 ]
[ 120067-55-2 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorus trichloride; In chlorobenzene; at 50℃; for 1h;	87 g <strong>[6419-36-9]3-pyridineacetic acid hydrochloride</strong> (500 mmole) was suspended in 225 g chlorobenzene together with 103 g phosphorous trichloride (750 mmole) and heated to 50C for one hour to produce an <n="13"/>opaque, 2 phase liquid system containing the acid chloride of 3- pyridineacetic acid.
	With phosphorus pentachloride; In acetyl chloride; at 0 - 20℃; for 4.5h;	3-Pyridylacetic acid.HCl (1.0 g, 5.76 mmol) was added to a mixture of PCl5 (1.521 g, 7.3 mmol) in acetyl chloride (5 mL) at 0 C. The reaction was stirred at 0C for 30 minutes, then allowed to return to room temperature over 4 hours. The mixture was filtered, and the solid was washed with petroleum spirit (75-105 C) and a small amount of Et2O to give the acid chloride (1.26 g). The acid chloride was added in portions to a solution containing 9d (859 mg, 2.88 mmol) and DIPEA (1.0 mL, 5.7 mmol) in CH2Cl2 (2 mL). After stirring for 30 minutes, the reaction mixture was taken up in CHCl3:EtOAc (9:1), washed with 5% aqueous Na2CO3, dried (Na2SO4), and evaporated. The residue was chromatographed on silica gel (hexane:EtOAc 1:2) to yield a solid (527 mg, 44%). 1H NMR (300 MHz, CDCl3) delta 11.3 (br s, 1H, NH), 8.56 (m, 2H, Ar-H), 7.71 (m, 1H, Ar-H), 7.29 (m, 1H, Ar-H), 4.51 (s, 2H, 7-CH2), 4.26 (q, J = 7.2 Hz, 2H, CH2CH3), 4.16 (q, J = 6.9 Hz, 2H, CH2CH3), 3.79 (s, 2H, CH2Ar), 3.65 (m, 2H, 5-CH2), 2.84 (m, 2H, 4-CH2), 1.33 (t, J = 7.2 Hz, 3H, CH2CH3), 1.25 (t, J = 6.9 Hz, 3H, CH2CH3). ESI-MS m/z 418.5 [M + H]+.
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; for 8h;Heating / reflux;	N-Methoxy-N-methyl^-pyridine-S-yl-acetamide. (compound 12, Scheme 2) ; <n="33"/>To a solution of anhydrous dichloromethane (200 ml) containing compound 10 (15.35 g, 88.4 mmol) was added 14.93 ml (163.3 mmol) of oxalyl chloride and a few drops of DMF. The mixture was gently refluxed for 8 hours under N2. The mixture was cooled and concentrated, re-dissolved in dichloromethane and concentrated. The residue was dissolved in 200 ml of anhydrous dichloromethane and 1 1.09 g (1 13.7 mmol) of N,O-Dimethyl-hydroxylamine.HCI was added. To this mixture (O0C) was added 2.73 ml of pyridine (in 15 minutes). The reaction mixture was subsequently stirred for 4 hours at room temperature. The reaction was concentrated in vacuo. The resulting residue was taken up in dichloromethane and H2O (O0C), washed with a 2N NaOH solution followed by brine, dried (Na2SCU), filtered and concentrated in vacuo. Purification by flash chromatography (ethyl acetate) afforded compound 12 as an oil (5.2 g, 33%). 1H- NMR (400 MHz, CDCI3) : delta 8.53-8.49 (m, 2H), 7.66 (bd, J = 8 Hz, 1 H), 7.29-7.24 (m, 1 H), 3.78 (s, 2H), 3.68 (s, 3H), 3.20 (s, 3H).

Reference： [1]Patent: WO2008/58722,2008,A1 .Location in patent: Page/Page column 11-12
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7089 - 7093
[3]Patent: WO2008/129054,2008,A2 .Location in patent: Page/Page column 30-31

30
[ 6419-36-9 ]
[ 439134-66-4 ]

Yield	Reaction Conditions	Operation in experiment
80.71%		Example A1; Synthesis of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic Acid; This example is a reproduction of Example 1 in WO 03/097655 A1 and exemplifies the need of a suitable process to scale up.In a 100 ml rounded bottom, three necked flask equipped with a magnetic stirrer, a thermometer, a reflux condenser and a compensated-pressure dropping funnel were charged: 2 g (1.15·10-2 mol) of 3-pyridyl acetic acid hydrochloride, 2.92 g (3.56·10-2 mol) of phosphonic acid and 14.4 ml of toluene.The mixture was heated to 87 C. at which point 3.23 ml (3.53·10-2 mol) of POCl3 was added dropwise during about 20 minutes. The resulting mixture was heated up to 95 C. After a few minutes at regime a sticky solid appeared, disenabling a proper stirring. The mixture was kept at 95 C. 20.5 h in these deficient stirring conditions.After the regime, the resulting mixture was cooled down to about 65 C. and 14.4 ml of water were added dropwise. Exothermy was observed. The sticky solid was dissolved and the efficient stirring recovered. The mixture was then let to cool down to room temperature and the aqueous layer decanted. These additional steps required to dissolve the sticky solid makes this approach unsuitable for industrial scale up as the reactants are not maintained in substantially solution form prior to the precipitation step.The aqueous phase was heated up to 90-95 C. and stirred at this temperature overnight. Then, was let to cool down to room temperature and 28.8 ml of ethanol were added and the precipitation of a whitish solid observed. The mixture was cooled down to 5 C. and filtered washing the cake with ethanol. The white solid obtained was dried at 50 C. in a vacuum oven to obtain 2.80 g (9.30·10-3 mol) of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monohydrate (Yield: 80.71%) Chromatographic purity: 98.496% (area percent)
78.21%		Example D4; Synthesis of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic Acid (Semi-Batch Mode Description); In a 1 liter rounded bottom, three necked flask equipped with a mechanical anchor impeller, a thermometer, a reflux condenser and a compensated-pressure dropping funnel were charged: 40.00 g (2.30·10-1 mol) g of 3-pyridyl acetic acid hydrochloride, 58.68 g (6.91·10-1 mol) of phosphonic acid, and 80 ml of ethyl acetate. The mixture was heated up to reflux (76 C.) at which point addition of 366.4 g of a mixture of propylphosphonic anhydride and ethyl acetate (50% w/w) was added. The addition time was about 10 hours. The mixture was stirred at reflux for 10 additional hours, at which point 200 ml of water was added in about 2 hours. The mixture was hydrolyzed under reflux for about 3.5 hours, let cooled down to 5 C. and the whitish solid precipitated was filtered, the cake washed with water.After drying at 40 C. in a vacuum oven, 54.26 g of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monohydrate were obtained (Yield: 78.21%) Chromatographic purity: 99.397% (area percent)
74.95 - 89.94%		Example D1 Synthesis of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic Acid In a 100 ml rounded bottom, three necked flask equipped with a magnetic stirrer, a thermometer, a reflux condenser and a compensated-pressure dropping funnel were charged: 1.00 g (5.76·10-3 mol) of 3-pyridyl acetic acid hydrochloride, 1,46 g (1.78·10-2 mol) of phosphonic acid, 4.58 g (1.44·10-2 mol) of propylphosphonic anhydride and 7.2 ml of toluene. The heterogeneous mixture was heated up to 95 C. The mixture was stirred at 95 C. overnight and let to cool down to 80 C. at which point 7.2 ml of water were added dropwise. The resulting mixture was stirred at 80 C. for 15 minutes and let to cool down to room temperature. The aqueous phase was decanted and heated to 90-95 C. for 5.5 h. A white solid precipitated out from during this heating. The resulting mixture was let to cool down to room temperature, cooled down to 5 C. for 1 hour, filtered and the cake washed with water. The white solid obtained was dried into a vacuum oven at 50 C. until constant weight. 1.56 g of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monohydrate were obtained (Yield: 89.94%) Chromatographic purity: 99.63% (area percent) Example D2; Synthesis of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic Acid; In a 100 ml rounded bottom, three necked flask equipped with a magnetic stirrer, a thermometer, a reflux condenser and a compensated-pressure dropping funnel were charged: 1.00 g (5.76·10-3 mol) of 3-pyridyl acetic acid hydrochloride, 1.46 g (1.78·10-2 mol) of phosphonic acid, 4.58 g (1.44·10-2 mol) of propylphosphonic anhydride and 7.2 ml of toluene.The heterogeneous mixture was heated up to 75 C. The mixture was stirred at 95 C. overnight and let to cool down to 80 C. at which point 7.2 ml of water were added dropwise. The resulting mixture was stirred at 75 C. for 15 minutes and let to cool down to room temperature.The aqueous phase was decanted and heated to 90-95 C. for 5.5 h. A white solid precipitated out from the mixture.The resulting mixture was cooled down to room temperature again and 7.2 ml of ethanol are added. The mixture was further cooled down to 5 C. for 1 hour, filtered and the cake washed with ethanol. The white solid obtained was dried into a vacuum oven at 50 C. until constant weight. 1.30 g of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monohydrate are obtained (Yield: 74.95%) Chromatographic purity: 99.59% (area percent)

61.69%		Example C1 Synthesis of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic Acid In a 100 ml rounded bottom, three necked flask equipped with a magnetic stirrer, a thermometer, a reflux condenser and a compensated-pressure dropping funnel were charged: 1 g (5.76·10-3 mol) of 3-pyridyl acetic acid hydrochloride, 1.46 g (1.78·10-2 mol) of phosphonic acid, 2.01 g (1.15·10-2 mol) of methanesulfonic anhydride and 7.2 ml of toluene. The mixture was heated up to 90 C. and 0.54 ml of POCl3 were added dropwise for about 20 minutes. The mixture was heated up to 95 C. and stirred overnight at this temperature. No stirring problems were observed. The reaction mixture was let to cool down to 80 C. and 14.4 ml of water were added dropwise. The resulting mixture was stirred at 80 C. for 1 h, let to cool down and the aqueous layer decanted and heated to 95 C. for 5.5 h. After that regime, the aqueous layer was let to cool down to room temperature and 14.4 ml of ethanol were added. The resulting mixture was cooled down to 5 C. for 1 h and the solid filtered and washed with ethanol and dried at 40 C. in a vacuum oven until constant weight. 1.07 g of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monohydrate were obtained (Yield: 61.69%) Chromatographic purity: 99.20% (area percent)
58.23%		Example C2 Synthesis of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic Acid In a 100 ml rounded bottom, three necked flask equipped with a magnetic stirrer, a thermometer, a reflux condenser and a compensated-pressure dropping funnel were charged: 1.00 g (5.76·10-3 mol) of 3-pyridyl acetic acid hydrochloride, 1.46 g (1.78·10-2 mol) of phosphonic acid, 3.01 g (1.72·10-2 mol) of methanesulfonic anhydride and 7.2 ml of toluene. 1.22 g of PCl5 was steeply added at room temperature. Exothermy, gas evolution and foaming was observed. The mixture was then heated up to 95 C. At about 40 C., formation of two well defined liquid phases were observed. The mixture was kept overnight at 95 C. No stirring problems arose. The mixture was then let to cool down to 80 C. at which point 7.2 ml of water were added dropwise (exothermy was observed). The mixture was stirred at 80 C. for 15 minutes and then let to cool down to room temperature. The aqueous layer was decanted and heated to 95 C. for 5.5 h and let to cool down to room temperature, at which point 7.2 ml of ethanol were added. The resulting mixture was cooled down to 5 C., stirred for 1 h and filtered. The solid washed with ethanol and dried at 40 C. in a vacuum oven until constant weight. 1.01 g of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monohydrate are obtained (Yield: 58.23%) Chromatographic purity: 98.327% (area percent)
33.73%		Example B1 Synthesis of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic Acid In a 100 ml rounded bottom, three necked flask equipped with a magnetic stirrer, a thermometer, a reflux condenser and a compensated-pressure dropping funnel were charged: 2 g (1.15·10-2 mol) of 3-pyridyl acetic acid hydrochloride, 2.92 g (3.56·10-2 mol) of phosphonic acid and 14.4 ml of toluene. The mixture was heated to 87 C. at which point 6.02 g (3.46·10-2 mol) of methansulfonic anhydride was steeply added in about 20 minutes. The resulting mixture was heated up to 95 C. and stirred at this temperature for 20.5 h without observing stirring problems. Then, it was let to cool down to 65 C., at which point 14.4 ml of water were added dropwise in about 20 minutes. The mixture was then let to cool down to room temperature and the aqueous layer separated and heated up to 95 C., stirred overnight at this temperature and let to cool down to room temperature. 28.8 ml of ethanol were then added, the mixture cooled down to 5 C. for 1.2 h and the whitish solid filtered, washing the cake with ethanol. The solid was dried at 50 C. in a vacuum oven to obtain 1.17 g of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid monohydrate (Yield: 33.73%) Chromatographic purity: 95.93% (area percent)

Reference： [1]Patent: US2008/194525,2008,A1 .Location in patent: Page/Page column 6
[2]Patent: US2008/194525,2008,A1 .Location in patent: Page/Page column 8
[3]Patent: US2008/194525,2008,A1 .Location in patent: Page/Page column 7-8
[4]Patent: US2008/194525,2008,A1 .Location in patent: Page/Page column 7
[5]Patent: US2008/194525,2008,A1 .Location in patent: Page/Page column 7
[6]Patent: US2008/194525,2008,A1 .Location in patent: Page/Page column 7

31
[ 925920-62-3 ]
[ 6419-36-9 ]
[ 1061377-28-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 96h;	Example 25; N-(3-(3-morpholinopropoxy)phenyl)-2-(pyridin-3-yl)acetamide (13); A solution of 3-(3-morpholinopropoxy)aniline (F-4) (189 mg, 0.80 mmol, 1.0 equiv) and DMAP (5 mg, 0.04 mmol, 0.05 equiv) in CHCl3 (2.7 mL) was added to a mixture of solid HOBt-H2O (129 mg, 0.84 mmol, 1.05 equiv) and 3-pyridylacetic acid-HCl (146 mg, 0.84 mmol, 1.05 equiv). The solution was stirred, EDCetaC1 (184 mg, 0.96 mmol, 1.2 equiv) and Et3N (1 17 muL, 0.84 mmol, 1.05 equiv) were added and the reaction continued at rt for 4 days. The reaction was quenched with MeOH (ca. 1 mL) and the solvent was removed in vacuo. The crude material obtained was purified by reverse-phase HPLC.

Reference： [1]Patent: WO2008/116145,2008,A2 .Location in patent: Page/Page column 86

32
[ 1133710-89-0 ]
[ 6419-36-9 ]
[ 1133711-03-1 ]

Yield	Reaction Conditions	Operation in experiment
22%		A solution of pyridin-3-yl-acetic acid hydrochloride salt (57.3 mg, 0.33 mmol) in methylene chloride (1.84 mL) was treated with N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (119 mg, 0.39 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.99 mmol). The resulting solution was stirred at 25 C. for 2.5 h. At this time, 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (200 mg, 0.42 mmol) was added to the reaction. The reaction mixture was stirred at 25 C. for 18 h. At this time, the reaction mixture was diluted with methylene chloride (50 mL) and washed with water (3*150 mL). The organics were dried over sodium sulfate, filtered, rinsing with methylene chloride and concentrated in vacuo. Biotage flash chromatography (40S, 1-4% methanol/methylene chloride) followed by supercritical fluid chromatography (Daicel OD column, 60% methanol) afforded pyridin-3-yl-acetic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester (43.2 mg, 22%) as a yellow solid. ES+-HRMS m/e calcd for C25H19N7O6Cl2 (M+H+) 584.0847, found 584.0848.

Reference： [1]Patent: US2009/82310,2009,A1 .Location in patent: Page/Page column 6; 12

33
[ 6419-36-9 ]
[ 214902-67-7 ]
[ 1116512-69-6 ]

Yield	Reaction Conditions	Operation in experiment
99%		Compound 7 (0.120 g, 0.168 mmol) and N,N-dimethylaminopyridine (DMAP, 0.021 g, 0.168 mmol) were dissolved in CH2Cl2 (1 mL) and chilled to 0 C(degrees Celsius). Meanwhile, 3-pyridylacetic acid hydrochloride (0.092 g, 0.555 mmol) was dissolved in 2 mL CH2Cl2 and placed in 2-necked, round-bottomed flask. This solution was cooled to -15 0C (degrees Celsius) and flushed with argon. To this mixture, triethylamine (0.078 mL, 0.555 mmol) and pivaloyl chloride (0.069 mL, 0.555 mmol) were added. The mixture was stirred for 20 min, and then the chilled solution of 9 and DMAP was added via syringe. The mixture was stirred for about 5 h, at which point the completion of the reaction was confirmed by LC/MS. To the reaction mixture was added 20 mL Of CH2Cl2, and the organic phase was washed with small amounts of sodium bicarbonate and brine solutions (twice each). The solvent was removed in vacuo to a yellow oil. The compound was purified by flash chromatography (silica gel, 1.5 cm x 6" column) using 7% MeOH/ CH2Cl2 as eluent. The product was detected in fractions 6 - 9 (8 mL each). Following combination of the fractions and evaporation of solvent, 0.140 g (99%) of the 2'-acetyl derivative of the title compound was obtained as white crystals. LC/MS > 98% (ELSD); calcd. for C42H69N3O]4 839.5, found 840.53 (M+H)+. 13C NMR (CD3OD) delta ppm (signals assigned to the pyridylacetyl moiety are highlighted in bold): 182.37, 174.28, 172.58, 171.48, 150.34, 148.39, 139.14, 131.59, 124.70, <n="68"/>103.19, 101.70, 97.78, 83.86, 80.66, 78.06, 75.25, 74.92, 72.49, 71.34, 71.26, 69.51, 68.63, 65.54, 58.87, 43.61, 40.27, 38.59, 37.43, 34.30, 31.37, 28.26, 27.59, 26.18, 22.13, 20.85, 20.18, 18.76, 16.99, 15.30, 15.09, 10.68, 9.14.

Reference： [1]Patent: WO2009/23196,2009,A1 .Location in patent: Page/Page column 64; 66-67

34
[ 501-81-5 ]
[ 6419-36-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water; toluene; at 30 - 95℃; for 6 - 7h;	Example 1; A. Preparation of 3-pyridyI acetic acid hydrochloride salt; 100 gm, 3-pyridyl acetic acid was dissolved in 250 ml toluene and 133 gm, 30% aqueous solution of hydrochloric acid was added at 30-4O0C temperature in 60 minutes. After completion of addition of hydrochloric acid, the temperature of reaction mass was raised to 90-950C and the temperature was maintained for 4-6 hrs with continuous removal of water azeotropically. After complete removal of water, the reaction mass was cooled to room temperature (25-300C) and the solid was collected by filtration under nitrogen atmosphere followed by washing with 633 ml of petroleum ether. The obtained cake was dried under vacuum at 30-40 C. 120 gm of dried 3-pyridyl acetic acid hydrochloride was obtained .
	With hydrogenchloride; In water; toluene; at 30 - 95℃;	A. Preparation of 3-pyridyl Acetic Acid Hydrochloride Salt 100 gm, 3-pyridyl acetic acid was dissolved in 250 ml toluene and 133 gm, 30% aqueous solution of hydrochloric acid was added at 30-40 C. temperature in 60 minutes. After completion of addition of hydrochloric acid, the temperature of reaction mass was raised to 90-95 C. and the temperature was maintained for 4-6 hrs with continuous removal of water azeotropically. After complete removal of water, the reaction mass was cooled to room temperature (25-30 C.) and the solid was collected by filtration under nitrogen atmosphere followed by washing with 633 ml of petroleum ether. The obtained cake was dried under vacuum at 30-40 C. 120 gm of dried 3-pyridyl acetic acid hydrochloride was obtained.

Reference： [1]Patent: WO2009/50731,2009,A2 .Location in patent: Page/Page column 15
[2]Patent: US2010/121066,2010,A1 .Location in patent: Page/Page column 4

35
[ 6419-36-9 ]
[ 79-19-6 ]
[ 1170672-96-4 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 14: 5-(3-pyridinylmethyl)-1 ,2-dihvdro-3H-1 ,2,4-triazole-3-thione <n="39"/>HOBT (306 mg, 2.000 mmol) and DIC (0.312 ml, 2.000 mmol) was added to the hydrochloride salt of 3-pyridinylacetic acid (347 mg, 2 mmol) and DIPEA (0.699 ml, 4 mmol) in THF (5 ml). After about 5 minutes hydrazinecarbothioamide (182 mg, 2 mmol) was added and the reaction mixture heated in a microwave reactor at 1000C for 5 minutes. The reaction mixture was evaporated to dryness. Ethanol (8 ml) and sodium hydroxide (8 ml, 16 mmol) were added to the crude material. The reaction mixture was heated in a microwave reactor at 15O0C for 10 minutes. After solvent removal and addition of water (20 ml) the resulting suspension was washed with DCM (20ml). After acidification to approximately pH 1 (using aqueous 5M HCI) the aqueous phase was washed again with DCM (20ml). A precipitate was observed at this stage in the aqueous phase and was discarded by filtration. The aqueous filtrate was then basified (using aqueous 2M NaOH) to pH=5-6 then extracted with DCM/lsopropanol 3/1 (4 X 25ml). The organic phases were combined, dried over MgStheta4 and evaporated to dryness to give the title compound, contaminated with residual HOBt; MS: ES+ m/z: 193 [MH+] at RT 0.3 min. C8H8N4S requires 192 (analysed by LCMS A).

Reference： [1]Patent: WO2009/87218,2009,A1 .Location in patent: Page/Page column 37-38

36
[ 306934-99-6 ]
[ 6419-36-9 ]
[ 1194091-69-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-amino-4-(4-bromo-phenyl)-thiophene-3-carboxylic acid ethyl ester; 3-pyridineacetic acid hydrochloride With dicyclohexyl-carbodiimide In tetrahydrofuran Reflux; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; ethyl acetate	2.1 To a solution of ethyl 2-amino-4-(4-bromophenyl)thiophene-3- carboxylate (10g, 30.7 mmol), 3-pyridyl acetic acid hydrochloride (12.8g) in tetrahydrofurane (200 mL) was added dicyclohexylcarbodiimide (15g). The solution was heated to reflux overnight then filtered. The organic phase was taken up into ethyl acetate and washed with sodium bicarbonate solution. The organic solution was dried over sodium sulfate and the solvent removed under reduced pression. The crude solid obtained was washed with a mixture petroleum ether/minimum ethyl acetate. An off-white solid (9.8g) was recovered.1H NMR (DMSO-de, 300 MHz) δ [ppm] 11.10 (bs, 1 H), 8.59 (s, 1 H), 8.53 (d,1 H), , 7.82 (d, 1 H), 7.54 (d, 2H), 7.41 (dd, 1 H), 7.27 (d, 2H), 6.99 (s, 1 H), 4.06(q, 2H), 4.04 (s, 2H), 0.96 (t, 3H).

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2009/135580, 2009, A1 Location in patent: Page/Page column 44

37
[ 444287-40-5 ]
[ 6419-36-9 ]
[ 927672-16-0 ]

Yield	Reaction Conditions	Operation in experiment
57%		5.159 N-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1,3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLMETHYL]-2-PYRIDINYL-3-YL-ACETAMIDE To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3-pyridylacetic acid hydrochloride (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH:CH2Cl2 3:97) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-pyridinyl-3-yl-acetamide (0.5 g, 57%) as a white solid: mp 292-294 C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=0.87 min. (97%); 1H NMR (DMSO-d6) delta 2.04-2.07 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.59 (s, 2H), 4.74 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.2 and 12.7 Hz, 1H), 7.32-7.36 (m, 1H), 7.65-7.71 (m, 2H), 7.80-7.84 (m, 2H), 8.43-8.49 (m, 2H), 8.75 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) delta 21.95, 30.90, 37.89, 39.03, 48.83, 121.93, 123.33, 127.15, 131.52, 131.79, 133.26, 134.70, 136.64, 138.97, 147.65, 150.01, 166.89, 167.41, 169.78, 170.03, 172.73; Anal. Calcd. for C21H18N4O5: C, 62.07; H, 4.46; N, 13.79. Found: C, 61.73; H, 4.46; N, 13.55.

Reference： [1]Patent: US2007/49618,2007,A1 .Location in patent: Page/Page column 131

38
[ 1257236-27-3 ]
[ 6419-36-9 ]
[ 1257234-20-0 ]

Yield	Reaction Conditions	Operation in experiment
34%	With N-ethyl-N,N-diisopropylamine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In tetrahydrofuran; ISOPROPYLAMIDE; at 20℃; for 18h;	4-(4,6-dimethoxy-1 ,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride hydrate (76 mg, 0.26 mmol) was added to <strong>[6419-36-9]2-<strong>[6419-36-9](pyridin-3-yl)acetic acid hydrochloride</strong></strong> (40 mg, 0.26 mmol), 8-(8- aminodibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (A8, 100 mg, 0.23 mmol) and N.N-diisopropylethylamine (0.122 mL, 0.70 mmol) in THF (2 mL) and DMA (1 mL) at room temperature. The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was evaporated to dryness and re-dissolved in DCM (20 mL) and washed with water (10 mL). The organic layer was separated and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-(6-(2- morpholino^-oxo^H-chromen-delta-ylJdibenzoIb.dlthiophen^-yl^^pyridin-S-yOacetamide (45 mg, 34%) as a white solid; 1H NMR (400 MHz, CDCI3 + d4acetic acid) delta 3.11 (t, J = 4.7 Hz, 4H), 3.48 (t, 4H), 3.97 (s, 2H), 5.89 (s, 1 H), 7.44 - 7.56 (m, 4H), 7.62 (q, 1 H), 7.67 (d, 1 H), 7.76 (dd, 1 H), 8.17 (dd, 1 H), 8.27 (dd, 1 H), 8.30 (d, 1 H), 8.62 (d, 1 H), 8.67 (d, 1H), 9.09 (s, 1 H); m/z: 548.07 (MH+).

Reference： [1]Patent: WO2010/136778,2010,A1 .Location in patent: Page/Page column 115-116

39
[ 1257236-62-6 ]
[ 6419-36-9 ]
[ 1257235-26-9 ]

Yield	Reaction Conditions	Operation in experiment
42%	With N-ethyl-N,N-diisopropylamine; HATU; In ISOPROPYLAMIDE; at 20℃;	9-[8-(Methylamino)dibenzothiophen-4-yl]-2-morpholin-4-ylpyrido[1 ,2-a]pyrimidin-4-one (K2, 249 mg, 0.56 mmol) was added in one portion to 0-(7-Azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (535 mg, 1.41 mmol), <strong>[6419-36-9]2-<strong>[6419-36-9](pyridin-3-yl)acetic acid hydrochloride</strong></strong> (244 mg, 1.41 mmol) and N,N-diisopropylethylamine (0.588 ml_, 3.38 mmol) in anhydrous DMA (3 ml_). The resulting solution was stirred at ambient temperature for 2 hours and then left to stand at room temperature over the weekend. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Fractions were evaporated to dryness to afford product. LCMS looked fine but NMR indicated a slight impurity in the aromatic region so the compound was purified again as follows: The product was purified by flash silica chromatography, elution gradient 0 to 2% 7M NH3ZMeOH in DCM. Pure fractions were evaporated to dryness to N-methyl-N-[6-(2-morpholin-4-yl-4-oxopyrido[1 ,2-a]pyrimidin-9- yl)dibenzothiophen-2-yl]-2-pyridin-3-ylacetamide (133 mg, 42%) as a white solid; 1H NMR (400 MHz, CDCI3) delta 2.91 (3H, s), 3.30 (4H, t), 3.50 (4H, t), 5.55 (1 H, s), 6.75 (1 H, dd), 6.93 (1 H, t), 7.28 (1 H, d), 7.43 - 7.48 (3H, m), 7.81 (1 H, dd), 8.06 (1 H1 dd), 8.96 (1 H, dd); m/z: 443.43 (MH+).

Reference： [1]Patent: WO2010/136778,2010,A1 .Location in patent: Page/Page column 154-155

40
[ 1199555-32-2 ]
[ 6419-36-9 ]
[ 1199555-33-3 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 3h;	To a mixture of 7-[4-(l -aminocyclobutyl)phenyl]-8-pheny[ 1 ,2,43triazolo[4,3-a]-1,5-naphthylidin-1-ol (1-8) (16 mg, 0.036 mmol), HOBt (21 mg, 0.137 mmol), 3-rhoyridineacetic acid hydrochloride (20 mg, 0.115 mmol), and DIPEA (0.031 mL, 0.180 mmol) in NMP (2 mL) was added EDC (21 mg, 0.110 mmol), and the mixture was stirred at room temperature for 3 hours. To the mixture was added water, and resulting solid was collected by filtration to give N- {l-[4-(l-hydroxy-8-phenyl[1,2,4]triazolo[4>3-fl]-1,5-naphthylidin-7-yl)phenylJcyclobutyl}-2-(3- rhoyridinyl)acetamide (1-9) as a pale yellow solid. HRMS (M+H)+: observed = 527.2191, calculated = 527.2195.

Reference： [1]Patent: WO2009/148887,2009,A1 .Location in patent: Page/Page column 52

41
[ 197506-83-5 ]
[ 6419-36-9 ]
[ 1316694-84-4 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

42
[ 197506-83-5 ]
[ 6419-36-9 ]
[ 1316694-87-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

43
[ 52562-50-2 ]
[ 6419-36-9 ]
[ 1316694-78-6 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

44
[ 4771-50-0 ]
[ 6419-36-9 ]
[ 1316695-06-3 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

45
[ 876-72-2 ]
[ 6419-36-9 ]
[ 1316694-62-8 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

46
[ 933717-10-3 ]
[ 6419-36-9 ]
[ 1316694-41-3 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

47
[ 70555-46-3 ]
[ 6419-36-9 ]
[ 1316694-95-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

48
[ 53269-35-5 ]
[ 6419-36-9 ]
[ 1316694-66-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 3-pyridineacetic acid hydrochloride With triethylamine In 1,4-dioxane at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 3-formyl-1H-indole-4-carbonitrile With piperidine In 1,4-dioxane for 18h; Inert atmosphere; Reflux;

Reference： [1]Dolušić, Eduard; Larrieu, Pierre; Moineaux, Laurence; Stroobant, Vincent; Pilotte, Luc; Colau, Didier; Pochet, Lionel; Van Den Eynde, Benoît; Masereel, Bernard; Wouters, Johan; Frédérick, Raphaël [Journal of Medicinal Chemistry, 2011, vol. 54, # 15, p. 5320 - 5334]

49
[ 2795-41-7 ]
[ 6419-36-9 ]
(E)-6-fluoro-3-(2-pyridin-3-ylvinyl)-1H-indole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

50
[ 1008-07-7 ]
[ 6419-36-9 ]
[ 1316695-02-9 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334
[2]European Journal of Medicinal Chemistry,2012,vol. 54,p. 95 - 102

51
[ 6625-96-3 ]
[ 6419-36-9 ]
[ 1316694-82-2 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

52
[ 6419-36-9 ]
[ 4771-49-7 ]
[ 1316694-93-5 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

53
[ 6419-36-9 ]
[ 17380-18-6 ]
[ 1316694-81-1 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

54
[ 6419-36-9 ]
[ 53462-88-7 ]
[ 1316694-71-9 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

55
[ 6419-36-9 ]
[ 115666-21-2 ]
[ 1316695-05-2 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: 3-pyridineacetic acid hydrochloride With triethylamine In 1,4-dioxane at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 7-bromo-1 H-indole-3-carbaldehyde With piperidine In 1,4-dioxane for 36h; Inert atmosphere; Reflux;

56
[ 6419-36-9 ]
[ 133831-28-4 ]
[ 1316694-98-0 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

57
[ 6419-36-9 ]
[ 5235-10-9 ]
(E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 5320 - 5334

58
2-amino-4-(2-furyl)-5-(tetrahydropyran-4-ylcarbonyl)thiazole [ No CAS ]
[ 6419-36-9 ]
[ 1253959-81-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 80℃;	[Example 13] N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-(pyridin-3-yl)acetamide (Compound IF) 2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (105 mg, 0.377 mmol) described in was dissolved in DMF (2.0 mL), EDC hydrochloride (421 mg, 2.20 mmol), HOBt monohydrate (340 mg, 2.21 mmol) and 3-pyridylacetic acid hydrochloride (370 mg, 2.14mmol) were added thereto, and the mixture was stirred at 80C overnight. The mixture was allowed to cool to room temperature, and water and a saturated aqueous sodium hydrogen carbonate solution were added thereto. The precipitated solid was collected by filtration, and dried under reduced pressure. The obtained solid was purified by silica gel column chromatography (hexane:ethyl acetate=50:50), and recrystallized from ethanol-water to give Compound IF (112 mg, 75%) as white crystals. 1H NMR (CDCl3, deltappm): 1.80-2.01 (m, 4H), 3.05-3.16 (m, 1H), 3.45 (ddd, J = 2.8, 11.4, 11.4 Hz, 2H), 3.81 (s, 2H), 3.97-4.06 (m, 2H), 6.54 (dd, J = 1.8, 3.6 Hz, 1H), 7.32 (dd, J = 7.8, 4.8 Hz, 1H), 7.52-7.54 (m, 1H), 7.62-7.68 (m, 2H), 8.55-8.64 (m, 2H), 9.21 (s, 1H). APCIMS m/z: [M+H]+ 398.
75%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 80℃;	Reference Example 3 N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-(pyridin-3-yl)acetamide (compound (IF)) 2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (105 mg, 0.377 mmol) described in WO2005/06374 was dissolved in DMF (2.0 mL), EDC hydrochloride (421 mg, 2.20 mmol), HOBt monohydrate (340 mg, 2.21 mmol) and 3-pyridylacetic acid hydrochloride (370 mg, 2.14mmol)) were added thereto, and the mixture was stirred at 80C overnight. The mixture was allowed to cool to room temperature, and water and a saturated aqueous sodium hydrogen carbonate solution were added thereto. The precipitated solid was collected by filtration, and dried under reduced pressure. The obtained solid was purified by silica gel column chromatography (hexane:ethyl acetate=50:50), and recrystallized from ethanol-water to give compound (IF) (112 mg, 75%) as white crystals. 1H NMR (CDCl3, deltappm): 1.80-2.01 (m, 4H), 3.05-3.16 (m, 1H), 3.45 (ddd, J = 2.8, 11.4, 11.4 Hz, 2H), 3.81 (s, 2H), 3.97-4.06 (m, 2H), 6.54 (dd, J = 1.8, 3.6 Hz, 1H), 7.32 (dd, J = 7.8, 4.8 Hz, 1H), 7.52-7.54 (m, 1H), 7.62-7.68 (m, 2H), 8.55-8.64 (m, 2H), 9.21 (s, 1H). APCIMS m/z: [M+H]+ 398.
75%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 80℃;	Reference Example 3 N-[4-(2-Furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]-2-(pyridin-3-yl)acetamide (compound (IF)) 2-Amino-4-(2-furyl)thiazol-5-yl=tetrahydropyran-4-yl=ketone (105 mg, 0.377 mmol) described in was dissolved in DMF (2.0 mL), EDC hydrochloride (421 mg, 2.20 mmol), HOBt monohydrate (340 mg, 2.21 mmol) and 3-pyridylacetic acid hydrochloride (370 mg, 2.14mmol) were added thereto, and the mixture was stirred at 80C overnight. The mixture was allowed to cool to room temperature, and water and a saturated aqueous sodium hydrogen carbonate solution were added thereto. The precipitated solid was collected by filtration, and dried under reduced pressure. The obtained solid was purified by silica gel column chromatography (hexane:ethyl acetate=50:50), and recrystallized from ethanol-water to give compound (IF) (112 mg, 75%) as white crystals. 1H NMR (CDCl3, deltappm): 1.80-2.01 (m, 4H), 3.05-3.16 (m, 1H), 3.45 (ddd, J = 2.8, 11.4, 11.4 Hz, 2H), 3.81 (s, 2H), 3.97-4.06 (m, 2H), 6.54 (dd, J = 1.8, 3.6 Hz, 1H), 7.32 (dd, J = 7.8, 4.8 Hz, 1H), 7.52-7.54 (m, 1H), 7.62-7.68 (m, 2H), 8.55-8.64 (m, 2H), 9.21 (s, 1H). APCIMS m/z: [M+H]+ 398.

Reference： [1]Patent: EP2433938,2012,A1 .Location in patent: Page/Page column 39
[2]Patent: EP2474543,2012,A1 .Location in patent: Page/Page column 19
[3]Patent: EP2474544,2017,B1 .Location in patent: Paragraph 0116

59
[ 64-17-5 ]
[ 6419-36-9 ]
[ 39931-77-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sulfuric acid; for 6h;Reflux;	To a solution of 3-pyridylacetic acid hydrochloride (51) (12.00 g, 69.19 mmol) in EtOH (120 mL) was added concentrated H2SO4 (5 mL) and the solution was heated at reflux (6 h). The reaction mixture was concentrated in vacuo and diluted with EtOAc (200 mL). The EtOAc layer was washed with saturated aqueous NaHCO3 (3 x 200 mL) and brine (2 x 200 mL), and dried (Na2SO4). The crude product was purified by flash column chromatography (SiO2; 4:5 EtOAc/hexanes) to give the desired product (10.67 g, 93%) as a pale yellow oil. Rf 0.37 (4:1 EtOAc/hexanes). 1H NMR (CDCl3) delta 1.26 (t, J = 7.2 Hz, CH2CH3), 3.63 (s, CH2C5H4N), 4.17 (q, J = 7.2 Hz, CH2CH3), 7.25-7.30 (m, C5H), 7.64-7.67 (m, C4H), 8.45-8.59 (m, C2H, C6H). 13C NMR (CDCl3) delta 13.7 (CH2CH3), 38.0 (CH2C5H4N), 60.7 (CH2CH3), 122.9 (C5H), 129.5 (C3H), 136.4 (C4H), 148.0 (C2H or C6H), 149.9 (C6H or C2).
		D56Pyridin-3-yI-acetic acid ethyl esterTo a solution of 3-pyridylacetic acid hydrochloride (40g, 230.41mmol) in ethanol (90 mL) was added sulfuric acid(73 g, 744.3 mmole, 98%) under N2. The reaction mixture was refluxed for 4 h, then cooled to rt. Ammonium hydroxide (250 mL, 25%) was added and extracted with DCM (500 mL) twice, dried over sodium sulfate, concentrated to afford the title product (33 g).

Reference： [1]Synthetic Communications,2012,vol. 42,p. 1137 - 1145
[2]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 3551 - 3564
[3]Patent: WO2012/75917,2012,A1 .Location in patent: Page/Page column 36

60
[ 6419-36-9 ]
[ 188883-58-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: thionyl chloride / 16.25 h / 0 °C / Reflux 2: acetonitrile / 12 h / Reflux 3: 5%-palladium/activated carbon; hydrogen / ethanol / 8 h / 20 °C / 7500.75 Torr 4: (R)-Mandelic Acid / ethyl acetate / 4 h / Reflux; Resolution of racemate

Reference： [1]Zhu, Ying-Guang; Kan, Hong-Zhu; Jiang, Li-Qin; Hu, Wen-Hao [Synthetic Communications, 2012, vol. 42, # 8, p. 1137 - 1145]

61
[ 6419-36-9 ]
[ 1233200-48-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: thionyl chloride / 16.25 h / 0 °C / Reflux 2: acetonitrile / 12 h / Reflux 3: 5%-palladium/activated carbon; hydrogen / ethanol / 8 h / 20 °C / 7500.75 Torr 4: (S)-Mandelic acid / ethyl acetate / 4 h / Reflux; Resolution of racemate 5: hydrogenchloride / diethyl ether / 2 h / 0 °C

Reference： [1]Zhu, Ying-Guang; Kan, Hong-Zhu; Jiang, Li-Qin; Hu, Wen-Hao [Synthetic Communications, 2012, vol. 42, # 8, p. 1137 - 1145]

62
[ 1375085-85-0 ]
[ 6419-36-9 ]
[ 1375087-02-7 ]

Yield	Reaction Conditions	Operation in experiment
29%		Example 98 2-(pyridin-3-yl)-N-{3-[4-(trifluoromethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-2-yl}acetamide 3-Pyridylacetic acid hydrochloride (41.6 mg, 0.239 mmol) was suspended in dichloromethane (3.0 mL). Oxalyl chloride (24 muL, 0.28 mmol) and a drop of dimethylformamide were added and the mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was concentrated under vacuum. To this residue was added a solution of the product from Example 1C (59 mg, 0.2 mmol) in pyridine (2.0 mL). The mixture was stirred at ambient temperature for 1 hour and then at 40 C. for 1 hour. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC [Waters XBridge RP18 column, 5 mum, 30*100 mm, flow rate 40 mL/minute, 30-100% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford 24 mg (29%) of the title compound. 1H NMR (400 MHz, CD3OD) delta ppm 8.86 (d, J=5.8 Hz, 1H), 8.52-8.59 (m, 2H), 8.44-8.49 (m, 1H), 7.79-7.89 (m, 1H), 7.71-7.74 (m, 2H), 7.33-7.44 (m, 1H), 7.20-7.23 (m, 2H), 7.07 (dd, J=7.0, 4.1 Hz, 1H), 3.81 (s, 2H); MS (ESI) m/z 414 (M+H)+.

Reference： [1]Patent: US2012/122888,2012,A1 .Location in patent: Page/Page column 35

63
[ 6419-36-9 ]
[ 39892-24-5 ]

Reference： [1]Patent: WO2012/75917,2012,A1

64
[ 1003315-95-4 ]
[ 6419-36-9 ]
[ 1095165-59-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 12h;	C. Compounds synthesized according to scheme 31,1-dimethylethyl [2-[(4-[(pyridin-3-ylacetyl)amino]methyl}phenyl)carbonyl]amino}-4-(2- thienyl)phenyl] carbamate. A suspension of 1,1-dimethylethyl [3-([4- (aminomethyl)phenyl]carbonyl}amino)biphenyl-4-yl] carbamate (100 mg, 0.23 mmol), pyridin- 3-ylacetic acid hydrochloride (44 mg, 0.26 mmol), DIPEA (0.2 mL, 1 mmol) and HATU (110 mg, 0.28 mmol) in 10 mL of DCM was stirred at room temperature for 12 hours. Then 100 mL of DCM was added the reaction mixture and washed with 10% NaHCO3 and brine, the organic layer was dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative TLC to give 1,1-dimethylethyl [2-[(4-[(pyridin-3- ylacetyl)amino]methyl}phenyl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate.

Reference： [1]Patent: WO2009/2495,2008,A1 .Location in patent: Page/Page column 70

65
[ 1523494-14-5 ]
[ 6419-36-9 ]
[ 1523494-16-7 ]

Yield	Reaction Conditions	Operation in experiment
89%		Step 3: 3-(carboxymethyl)pyridinium chloride (538 mg, 3.10 mmol) and oxalyl dichloride (0.788 mL, 9.31 mmol) and a drop of dimethylformamide were dissolved in dichloromethane (3 mL). After 2 hours, solvent was removed and dimethylformamide (4 mL) was added, followed by potassium carbonate (1.28 g, 9.3 mmol) and step 2 compound (1.04 g, 3.10 mmol) in dimethylformamide (8 mL). The reaction mixture was stirred overnight and poured in iced water. An ethyl acetate extraction was performed and the organic layer was washed twice with brine and dried over sodium sulfate. A brown oil (1.25 g, 89%) was recovered after removal of the solvent. LC/MS: purity 96%, M+1= 455

Reference： [1]Patent: EP2679591,2014,A1 .Location in patent: Paragraph 0083

66
[ 774-55-0 ]
[ 6419-36-9 ]
[ 105-56-6 ]
2-chloro-4-hydroxy-5-(3-pyridyl)-3-tetralin-6-yl-7H-thieno[2,3-b]pyridin-6-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 6-Acetyl-1,2,3,4-tetrahydronaphthalene; ethyl 2-cyanoacetate With morpholine; sulfur In ethanol at 90℃; for 20h; Stage #2: With N-chloro-succinimide In chloroform at -5℃; for 3h; Stage #3: 3-pyridineacetic acid hydrochloride Further stages;	13 2-chloro-4-hydroxy-5-(3-pyridyl)-3-tetralin-6-yl-7H-thieno[2,3-b]pyridin-6-one Step 1 : 1 -(5,6,7,8-tetrahydronaphthalen-2-yl)ethanone (20 g, 1 15 mmol), ethyl 2- cyanoacetate (14.66 mL, 138 mmol), morpholine (20.08 mL, 230 mmol), and 14.72 g of sulfur were added to ethanol (1 15 mL) to give a yellow suspension. The reaction mixture was refluxed 20h at 90 °C. Upon cooling, the reaction mixture was filtered and the solvent removed under reduced pressure. The crude brown oil was dissolved in ethyl acetate, washed with HCI 1 N, brine twice and dried over sodium sulfate. After removal of the solvent, the crude was purified over silica (dichloromethane/cyclohexane 40/60) affording 9.6 g (28%) of a yellow oil. LC/MS: purity 84%, M+1 =302 Step 2: step 1 compound (9.2 g, 30.5 mmol) was dissolved in chloroform (400 mL). Upon cooling at - 5°C, N-chlorosuccinimide (4.08 g) was added and the reaction mixture wasstirred for 3 hours. The reaction mixture was purified over silica (heptane/ethyl acetate 80/20) affording 2.9 g (28%) of a brown oil. NMR H (DMSO-d6): 0,75 (t, 3H); 1 ,75 (m, 4H); 2,50 (m, 4H); 3,80 (q, 2H); 6,70 (s, 1 H); 6,80 (d, 1 H); 7,00 (d, 1 H)7,50 (bs, 1 H) Step 3: 3-(carboxymethyl)pyridinium chloride (538 mg, 3.10 mmol) and oxalyl dichloride (0.788 mL, 9.31 mmol) and a drop of dimethylformamide were dissolved in dichloromethane (3 mL). After 2 hours, solvent was removed and dimethylformamide (4 mL) was added, followed by potassium carbonate (1 .28 g, 9.3 mmol) and step 2 compound (1 .04 g, 3.10 mmol) in dimethylformamide (8 mL). The reaction mixture was stirred overnight and poured in iced water. An ethyl acetate extraction was performed and the organic layer was washed twice with brine and dried over sodium sulfate. A brown oil (1 .25 g, 89%) was recovered after removal of the solvent. LC/MS: purity 96%, M+1 = 455 Step 4: Potassium bis(trimethylsilyl)amide (2.2 g, 1 1 mmol) was dissolved in tetrahydrofuran (5 mL) and a solution of step 3 compound (1 .25 g, 2.75 mmol) in tetrahydrofuran (9 mL) was added. After 30 minutes, a mixture of water/acetic acid was added (until pH 4) and an ethylacetate extraction was performed. The organic layer was washed twice with brine and dried over sodium sulfate. After removal of the solvent, a brown solid (0.62 g; 55%) was obtained. LC: 4.15 min, purity 99%, MS: M+1 = 409 NMR H (DMSO-d6): 1 ,76 (m, 4H); 2,74 (m, 4H); 7,06 (m, 3H); 7,34 (dd, 1 H); 7,75 (d, 1 H) 8,38 (d, 1 H); 8,51 (s, 1 H)

Reference： [1]Current Patent Assignee: POXEL - WO2014/1554, 2014, A1 Location in patent: Page/Page column 33; 34; 35

67
[ 6419-36-9 ]
[ 52727-57-8 ]
[ 1600563-26-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	Into a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol, 1.00 equivalent), <strong>[6419-36-9]2-<strong>[6419-36-9](pyridin-3-yl)acetic acid hydrochloride</strong></strong> (4.5 g, 25.92 mmol, 1.20 equivalents), HATU (10 g, 26.30 mmol, 1.20 equivalents), and DIEA (8.5 g, 65.77 mmol, 3.00 equivalents) in N,N-dimethylformamide (100 mL). After stirring overnight at 20 C., the reaction was quenched with 100 mL of water and extracted with 3×100 mL of dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2-1:1) to give the title compound as a yellow solid.
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Into a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol, 100%), <strong>[6419-36-9]2-<strong>[6419-36-9](pyridin-3-yl)acetic acid hydrochloride</strong></strong> (4.5 g, 25.92 mmol), HATU (10 g, 26.30 mmol 100%) and DIEA (8.5 g, 65.77 mmol, 100%) in N,N-dimethylformamide (100 mL). The resulting solution was stirred overnight at 20 C. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3*100 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2-1:1) to provide the title compound as a yellow solid.
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	intermediate 10: step amethyl 5-bromo-2-(2-(pyridin-3-yl)acetamido)benzoateInto a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol, 100%), <strong>[6419-36-9]2-<strong>[6419-36-9](pyridin-3-yl)acetic acid hydrochloride</strong></strong> (4.5 g, 25.92 mmol), HATU (10 g, 26.30 mmol 100%) and DIEA (8.5 g, 65.77 mmol, 100%) in N,N-dimethylformamide (100 mL). The resulting solution was stirred overnight at 20 C. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3x100 mL of dichioro methane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :2-1 : 1) to provide the title compound as a yellow solid.

Reference： [1]Patent: US2014/107097,2014,A1 .Location in patent: Paragraph 0430; 0431
[2]Patent: US2015/105404,2015,A1 .Location in patent: Paragraph 0235
[3]Patent: WO2015/57203,2015,A1 .Location in patent: Page/Page column 60

68
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(4-methoxybenzyl)quinoline-3,4-diamine [ No CAS ]
[ 6419-36-9 ]
N-(7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-4-((4-methoxybenzyl)amino)quinolin-3-yl)-2-(pyridin-3-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 25 - 35℃; for 16h;	To a solution of 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(4-methoxybenzyl)quinoline-3,4-diamine (0.37 g, 0.92 mmol) in dichloromethane were added EDC.HCl (0.57 g, 2.74 mmol), 1 -hydroxybenzotriazole (0.37 g, 2.74 mmol), triethylamine (0.44 mL, 3.2 mmol) and pyridine-3-acetic acid hydrochloride (0.24 g, 1.37 mmol). The reaction mixture stirred at 25-35C for 16h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was diluted with DCM and the organic layer was washed with water, dried over sodium sulfate and evaporated under vacuum to get the desired crude product as a brown solid (0.4 g, 83%), which was used in the next step without further purification. LC-MS: m/z 524 (M+1)+.

Reference： [1]Patent: WO2014/128655,2014,A1 .Location in patent: Page/Page column 24

69
N-[4-(benzyloxy)phenyl]-N-methyl-3-{6-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2,3-dihydro-1H-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-1-carboxamide [ No CAS ]
[ 6419-36-9 ]
N-[4-(benzyloxy)phenyl]-N-methyl-3-{6-[(3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-2-[2-(pyridin-3-yl)acetyl]-2,3-dihydro-1H-isoindol-5-yl}-5,6,7,8-tetrahydroindolizine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;	Example 42: N-(4-Hydroxyphenyl)-N-methyl-3- (6- [(38)-3-(morpholin-4-ylmethyl)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonylj -2- j2-(pyridin-3-yl)acetylj -2,3- dihydro-1H-isoindol-5-yI}-5,6,7,8-tetrahydroindolizine-1 -carboxamideStep A: N-[4-(beuzyoxy)phenyJ-N-methyl-3-{6-[(3S)-3-(morpholin-4-ylmethy-1,2,3,4- tetral:ydroisoquinoline-2-carbonylJ-2-f2-(pyridin-3-yl)acetylJ-2,3-dihydro-1H-isoindol-5- ylj-S, 6, 7,8-tetrahydroindolizine-1-earboxamideTo a solution of the product from Preparation 7aa (40 mg, 0.05 mmol) in DMF (2 mL) was added triethylamine (28 paL, 0.2 mmol), and HBTU (19 rng, 0.05 mmol) followed by 2- (pyridin-3-yl)aeetie acid hydrochloride (9.4 mg, 0.05 mmol), and the mixture was stirred at ambient temperature for I h. The reaction was concentrated in vacuo and directly used in the next step.LC/MS (C53H54N605) no ionisation; RT 1.20 (Method B)

Reference： [1]Patent: WO2015/11164,2015,A1 .Location in patent: Page/Page column 103

70
N-(5-(4-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridin-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide [ No CAS ]
[ 6419-36-9 ]
2-(pyridin-3-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15 mg	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;	Intermediate 5 (70 mg, 0.15 mmol), 3-Pyridylacetic acid hydrochloride (31 mg, 0.18 mmol), HATU (67 mg, 0.18 mmol), N-Ethyldiisopropyl amine (0.1 ml, 0.45 mmol) were dissolved in DMF (2 ml). This mixture was stirred at rt for 16 h. Reaction mass was diluted with water and extracted with DCM. Organic layer was washed with water. Organic layer was dried on anhydrous Na2SO/t. DCM was removed on rotavapour to obtain crude. Crude was purified by column chromatography on 60-120 mesh silica gel using Methanol and DCM (5:95) as eluent to afford the titled compound (15 mg) as a pale-brown solid. M.P.: 208-210C. JH-NMR (delta ppm, DMSO-<, 400 MHz): 12.70 (s, 1H), 10.47 (s, 1H), 8.58 (s, 1H), 8.54 (d, J 4.8, 1H), 8.03 (d, J 2.7, 1H), 7.91-7.85 (m, 2H), 7.51-7.39 (m, 3H), 7.38-7.32 (m, 2H), 7.22 (d, J 7.6, 1H), 3.92 (s, 2H), 3.73 (s, 2H), 3.72-3.65 (m, 2H), 3.31-3.20 (m, 1H), 2.85 (t, J 10.8, 2H), 2.10 (d, J 11.9, 2H), 1.90-1.76 (m, 2H).

Reference： [1]Patent: WO2015/101957,2015,A2 .Location in patent: Page/Page column 63-64

71
N-(5-(3-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl)pyridin-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide [ No CAS ]
[ 6419-36-9 ]
2-(pyridin-3-yl)-N-(5-(1-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridin-3-yl)piperidin-3-yl)-1,3,4-thiadiazol-2-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6 mg	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 0.5h;	Intermediate 10 (500 mg, 1.04 mmol), 3-Pyridylacetic acid hydrochloride (220 mg, 1.26 mmol), HATU (480 mg, 1.25 mmol), N-Ethyldiisopropyl amine (0.5 ml, 3.1 mmol) were dissolved in DMF (3 ml). This mixture was stirred at rt for 30 mins. Reaction mass was diluted with water and extracted with DCM. Organic layer was washed with water. Organic layer was dried on anhydrous Na2SO/t. DCM was removed on rotavapour to obtain crude. Crude was purified by combi-flash using Methanol and DCM (5:95) as eluent to afford the titled compound (6 mg) as a Pale-Yellow solid. M.P.: 145-147C. JH-NMR (delta ppm, DMSO-<, 400 MHz): 12.69 (s, 1H), 10.47 (s, 1H), 8.55-8.51 (m, 2H), 8.03 (s, 1H), 7.90-7.80 (m, 2H), 7.49-7.40 (m, 3H), 7.30-7.27 (m, 2H), 7.22 (d, J 8, 1H), 3.89 (s, 2H), 3.75-3.70 (m, 3H), 3.20-3.10 (m, 2H), 3.05-2.92 (m, 2H), 2.13-2.04 (m, 1H), 1.80-1.60 (m, 3H).

Reference： [1]Patent: WO2015/101957,2015,A2 .Location in patent: Page/Page column 62

72
[ 1006-94-6 ]
[ 6419-36-9 ]
1-(5-methoxy-1H-indol-3-yl)-2-pyridin-3-yl-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%		1) Preparation of 1-(5-methoxy-1H-indol-3-yl)-2-pyridin-3-yl-ethanone A mixture of 3-pyridylacetic hydrochloride reduced in powder (2.36 g, 13.6 mmol, 1.0 eq.) in acetic anhydride was heated in a sealed tube at 85 C. for 60 minutes and then, 5-methoxyindole (2 g, 13.6 mmol, 1.0 eq.) was added. The whole was heated at 85 C. for 20 minutes and then, 105 C. for 30 minutes. The reaction was allowed to cool to room temperature and then ethyl acetate and water were added. The pH was adjusted to 7 with saturated aqueous sodium carbonate. The aqueous layer was extracted with ethyl acetate and then, the organic layer was dried over MgSO4. The solvent was removed under reduced pressure and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 96/4 to 94/6). The product impure was triturated with ethanol and diethyl ether to afford 1-(5-methoxy-1H-indol-3-yl)-2-pyridin-3-yl-ethanone as a beige powder (1.74 g, 48%).
48%		A mixture of 3-pyridylacetic (2.36 g, 13.6 mmol,1.0 equiv) in acetic anhydride (12 mL) was heated in a sealed tubeat 85 C for one hour, then 5-methoxyindole (2 g, 13.6 mmol,1.0 equiv) was added. The reaction mixture was heated at 85 Cfor 20 min then at 105 C for 30 min. After cooling to room temperaturethe mixture was quenched with water and EtOAc. The mixturewas basified to pH 7 with saturated aqueous Na2CO3solution. The mixture was extracted with EtOAc. The combinedorganic layers were washed with brine, dried (MgSO4) and evaporated.The residue was purified by silica gel flash-column chromatography(eluent: CH2Cl2/EtOH, 96/4 to 94/6). The residue wastriturated with ethanol and diethyl ether to afford 27 as a beigepowder (1.74 g, 48%). IR mmax (cm1): 3130 (mN-H), 1621 (mCO).Mp 210 C. 1H NMR (d6-DMSO, 500 MHz) d (ppm): 3.75 (3H, s),4.21 (2H, s), 6.85 (1H, dd, J = 8.7 Hz, J = 2.4 Hz), 7.34 (1H, dd,J = 7.9 Hz, J = 4.7 Hz), 7.38 (1H, d, J = 8.7 Hz), 7.67 (1H, d,J = 2.4 Hz), 7.73 (1H, d, J = 7.9 Hz), 8.44 (1H, dd, J = 4.7 Hz,J = 1.5 Hz), 8.51 (1H, s), 8.55 (1H, d, J = 1.5 Hz), 11.95 (1H, s).13CNMR (d6-DMSO, 75.5 MHz) d (ppm): 42.4, 55.2, 102.9, 112.8,115.7, 123.2, 126.3, 131.5, 132.1, 134.8, 137.0, 147.4, 150.4,155.5, 191.7; ESI-MS: m/z 267.0 ([M+H]+). HRESI-MS: m/z267.1132 (calcd for C16H15N2O2 + 267.1134). Anal. Calcd forC16H14N2O2, 0.2 H2O%: C, 71.20; H, 5.38; N, 10.38. Found: C,71.08; H, 5.45; N, 10.31.

Reference： [1]Patent: US9212138,2015,B2 .Location in patent: Page/Page column 89; 90
[2]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 721 - 734

73
(R)-N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride [ No CAS ]
[ 6419-36-9 ]
(1R)-N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-2-(pyridin-3-ylacetyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.8%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	HATU (41.6 mg, 0.11 mmol) was added to a solution of DIEA (0.048 mL, 0.27 mmol), <strong>[6419-36-9]2-<strong>[6419-36-9](pyridin-3-yl)acetic acid hydrochloride</strong></strong> (18.98 mg, 0.11 mmol) and (R)-N-(3,5-difluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride (45 mg, 0.09 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0?25% MeOH/ethyl acetate) to give the title compound (33.0 mg, 0.057 mmol, 62.8%) as a white solid.

Reference： [1]Patent: TW2016/2105,2016,A .Location in patent: Paragraph 0814

74
[ 1267986-38-8 ]
[ 6419-36-9 ]
4-chloro-N-(pyridin-3yl-acetyl)deacetyl colchicine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%		3-pyridyl acetate acid chloride (27 mg, 0.128 x 1.2 mmol) was dissolved in N.N-dimethylformamide (1 mL) under argon atmosphere, and cooled at 0 degree C. Triethylamine (21 mul, 0.128 x 1.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (29 mg, 0.128 x 1.2 mmol) and 1-hydroxybenzotriazol monohydrate (21 mg, 0.128 x1.2 mmol) were added, and stirred at 0 degree C for 30 minutes. 4-chloro deacetyl colchicine (50 mg, 0.128 mol) was added, and stirred at room temperature for 4 hours. Water was added and the reaction mixture was quenched, ethyl acetate was added, and washed with 10% aqueous-citric-acid solution, saturated sodium bicarbonate solution, and a saturated sodium chloride solution. The ethyl acetate layer was dried with anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by Silica gel chromatography (Biotage Isolera One, SNAP 10 g, methanol/chloroform) to obtain title compound (brown solid and 8 mg, 0.016 mmol, 11%).

Reference： [1]Patent: JP5829520,2015,B2 .Location in patent: Paragraph 0151

75
[ 61494-55-1 ]
[ 6419-36-9 ]

Yield	Reaction Conditions	Operation in experiment
95.0%		<strong>[61494-55-1]2-chloro-3-pyridineacetic acid</strong> 50 g,Prepared into a 25% mass fraction of 2-chloro-3-pyridine sodium acetate solution,And 47 g of a 30% sodium hydroxide solutionSouring (the system may produce some insoluble polymer),Stir evenly after filtration,In the filtrate, 20% of Raney nickel catalyst was added,Heating up to 90-95 ,Through hydrogen reaction,In the atmospheric pressure or 1MPa pressure environment reaction,In the control,After the reaction is completed,After filtering the catalyst,The filtrate was adjusted to pH 4 with hydrochloric acid,Activated charcoal decolorization, desolate, offDry solvent (into a viscous fluid,And there is crystal presence (NaCl)Add 100 grams of anhydrous ethanol, fully dissolved,Filtration, the filtrate is 3-pyridine acetic acid in ethanol solution,The ethanol in the solution was removed (dried,Into a viscous fluid, can be added to the back of the amount of water,Dry the ethanol)Add water 50g, and add hydrochloric acid 35g,After sufficiently salt formation at 50 C,The solvent water is then dried (viscous solid)Cooling to room temperature,Plus 50g of absolute ethanol after washing,After filtration, the solid was rinsed with a portion of ethanol,Dry, that was finished3-pyridine acetic acid hydrochloride47.5 g, purity 99.1%, yield 95.0%.

Reference： [1]Patent: CN106366034,2017,A .Location in patent: Paragraph 0020; 0023; 0024; 0025; 0028; 0029

76
fluorosilicic acid [ No CAS ]
[ 6419-36-9 ]
(3-carboxymethylpyridinium) hexafluorosilicate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	In methanol; at 20℃;Reflux;	4.2 Synthesis of bis(3-carboxymethylpyridinium) hexafluorosilicate, (II) 3-Pyridineacetic acid hydrochloride (L2 ? HCl; 5.21 g, 0.003 mol) was dissolved in boiling methanol (250 mL) and to the obtained solution the fluorosilicic acid (FSA, 45%, 2.7 mL, molar ratio L2 ? HCl: FSA = 1: 3) was added. A reaction mixture stored at ambient conditions prior to the beginning of crystallization of the reaction product (6.03 g, 76%). Colorless transparent crystals with the composition (L2H)2[SiF6] (II). Anal. found, %: Si 7.39, N 7.04, F 29.35. Calcd. for C14H16F6N2O4S?: Si 7.18, N 7.18, F 29.22. Mass spectrum: [ML2]+· (m/z = 137, I = 41%). IR-spectrum: 3124, 3078, 3059 [nu(N+H)], 1724, 1716, 1631 [nu(C = ?), delta(N+H)], 741 [nu(SiF)], 482, 461 [delta(SiF2)]. 19F NMR (376.4 MHz, D2O): delta = -133.0 ppm (s, SiF62-).

Reference： [1]Journal of Fluorine Chemistry,2018,vol. 205,p. 15 - 21

77
N-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-2-hydroxyacetamide [ No CAS ]
[ 6419-36-9 ]
2-((3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)amino)-2-oxoethyl 2-(pyridin-3-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%		To a solution of 2-(2-methyl-1 H-indol-1-yl)acetic acid (54.7 mg, 289 mumol) in anhydrous 33 CH2Cl2 (4 mL) was added 43 DCC (59.9 mg, 290 mumol), 44 DMAP (8 mg, 65 mumol) and 37 N-(3,5-dimethyl-1-phenyl-1 H-pyrazol-4-yl)-2-hydroxyacetamide (71.0 mg, 290 mumol) at 0 C under argon. The mixture was allowed to warm to room temperature and for 18 h. The reaction mixture was filtered over cotton, washed with NH4Cl (2 mL), dried (MgSO4), filtered, and concentrated in vacuo. Purification by column chromatography (75% 24 EtOAc in 25 petroleum ether) gave 98 mg (81%) of the title compound.TLC: Rf (5% MeOH in CH2Cl2): 0.15.1H NMR (400 MHz, DMSO-d6) delta: 9.37 (bs, 1H), 7.48 - 7.54 (m, 4H), 7.36-7.45 (m, 3H), 7.04 (ddd, 1 H, J = 8.3, 7.1, 1.3 Hz), 6.98 (ddd, 1 H, J = 7.8, 7.2, 1.2 Hz), 6.24 (dq, J = 2.0, 0.9 Hz, 1 H), 5.21 (s, 2H), 4.79 (s, 2H), 2.37 (d, J= 0.8 Hz, 3H), 2.13 (s, 3H), 2.05 (s, 3H) ppm.13C NMR (100 MHz, DMSO-d6) delta: 168.9, 165.9, 144.7, 139.6, 137.1, 137.1, 134.4, 129.2, 127.7, 127.0, 123.8, 120.3, 119.3, 119.1, 116.6, 109.2, 100.1, 63.0, 44.0, 12.1, 11.3, 10.6 ppm HRMS (ESI) m/z: (M+H)+ calcd for C24H25N4O3: 417.1921; found: 417.1926.<strong>[6419-36-9]2-<strong>[6419-36-9](pyridin-3-yl)acetic acid hydrochloride</strong></strong> (32.5 mg, 0.2 mmol) was suspended in DCM (4 mL) under Argon,cooled to 0 C and added trimethylamine (26 mL, 0.2 mmol). After 30 minutes a clear solution is observed and EDCI(35.9 mg, 0.2 mmol) and DMAP (4.8 mg, 0.04 mmol) followed by N-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-2-hydroxyacetamide(44.1 mg, 0.2 mmol), synthesized as reported in Example 1. The mixture was left stirring overnight and thendiluted with water and extracted 3 times with DCM. The organic phase was washed with brine, dried over MgSO4, filteredand concentrated. Purification by column chromatography (5% MeOH in DCM) yielded 60.6 mg of the title compound(92%).TLC: Rf (5% MeOH in DCM, 2x): 0.381H NMR (400 MHz, DMSO-d6) delta: 9.35 (bs, 1 H), 8.53 (dd, J = 2.3, 0.6 Hz, 1 H), 8.48 (dd, J = 4.8, 1.6 Hz, 1 H),7.74-7.78 (m, 1 H), 7.46-7.54 (m, 4H), 7.34-7.42 (m, 2H), 4.73 (s, 2H), 3.90 (s, 2H), 2.14 (s, 3H), 2.05 (s, 3H) ppm13C NMR (101 MHz, DMSO-d6) delta: 170.6, 166.1, 150.2, 147.9, 144.7, 139.6, 137.3, 134.4, 130.1, 129.1, 127.0,123.7, 123.4, 116.7, 62.9, 36.9, 11.3, 10.6 ppmHRMS (ESI) m/z: (M+H)+ calcd for C20H21N4O3: 365.1608; found: 365.1612

Reference： [1]Patent: EP3305781,2018,A1 .Location in patent: Paragraph 0187-0191; 0666-0671

78
[ 1477-68-5 ]
[ 6419-36-9 ]
N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(pyridin-3-yl)acetamide [ No CAS ]

Reference： [1]ACS Chemical Neuroscience,2018,vol. 9,p. 587 - 602

79
[ 887144-97-0 ]
[ 6419-36-9 ]
[ 1099598-09-0 ]

Yield	Reaction Conditions	Operation in experiment
55 %Spectr.	With 2,2'-dipyridyl ketone; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; water; copper dichloride; N,N,N',N'-tetramethylguanidine In ethyl acetate at 20℃; for 12h; Inert atmosphere; Irradiation; Sealed tube;

Reference： [1]Kautzky, Jacob A.; Wang, Tao; Evans, Ryan W.; Macmillan, David W. C. [Journal of the American Chemical Society, 2018, vol. 140, # 21, p. 6522 - 6526]

80
[ 6419-36-9 ]
[ 19690-13-2 ]

Reference： [1]Patent: US2005/227959,2005,A1

81
[ 1178531-12-8 ]
[ 6419-36-9 ]
(S)-((3R,3aR,6R,6aR)-6-(2-(pyridin-3-yl)acetoxy)hexahydrofuro[3,2-b]furan-3-yl) 5,6-bis(nitrooxy)hexanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43.8%	With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;	To a solution of (S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl) 5,6-bis(nitrooxy)hexanoate (Example 1, Step 8) (100 mg, 0.273 mmol) in dry DCM (3 ml), DMAP (73 mg, 0.601 mmol), DCC (112 mg, 0.546 mmol) and 3-pyridylacetic acid hydrochloride (57 mg, 0.328 mmol) were added. The mixture was stirred overnight at room temperature, then DMAP (73 mg, 0.601 mmol) and 3-pyridylacetic acid hydrochloride (57 mg, 0.328 mmol) were added. The mixture was allowed to stir for 4 hours. The solid was filtered off, water and DCM were added, the two phases were separated and the aqueous phase extracted twice with DCM. The combined organic phases were dried over MgS04 and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (H20/CH3CN from 95:5 to 30:70), to give 58 mg of the desired product (yield: 43.8%). NMR (600 MHz, DMSO-d6) delta 8.49 - 8.46 (m, 2Eta), 7.72 - 7.68 (m, IH), 7.38 - 7.34 (m, IH), 5.45 - 5.40 (m, IH), 5.05 (q, IH), 4.97 (q, IH), 4.93 (dd, IH), 4.71 (dd, IH), 4.64 - 4.58 (m, 2H), 3.92 (dd, IH), 3.87 (dd, IH), 3.79 (s, 2H), 3.68 (dd, IH), 3.56 (dd, IH), 2.41 (t, 2H), 1.80 - 1.72 (m, 2H), 1.68 - 1.60 (m, 2H).

Reference： [1]Patent: WO2018/224419,2018,A1 .Location in patent: Page/Page column 32-33

82
[ 487-89-8 ]
[ 6419-36-9 ]
C₁₅H₁₂N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%		Compound 1 was prepared according to the method of a literature reported [28]. The pyrid-3-ylacetic acid hydrochloride (0.9g, 5.2mM) and triethylamine (1.4g, 13.1mM) were dissolved in dioxane (15mL), and the mixture was stirred at room temperature for about 10min. Then 1H-indole-3-carbaldehyde (0.5g, 3.5mM) and piperidine (0.6g, 15.2mM) were added, and the resulting mixture was stirred at reflux temperature for one day. After the reaction was completed, the solution was diluted with ethyl acetate, evaporated with silica and purified by flash chromatography to give the product. Yield: 1.06g (83%). 1H NMR (400MHz, DMSO-d6) delta 11.42 (s, 1H), 8.77 (d, J=2.1Hz, 1H), 8.38 (dd, J=4.7, 1.5Hz, 1H), 8.06 (d, J=7.8Hz, 1H), 8.02 (dt, J=8.0, 1.9Hz, 1H), 7.69 (d, J=2.6Hz, 1H), 7.57 (d, J=16.6Hz, 1H), 7.45 (d, J=8.0Hz, 1H), 7.36 (dd, J=7.9, 4.7Hz, 1H), 7.21-7.17 (m, 1H), 7.16-7.10 (m, 2H). HRMS (ESI) m/z calculated for C15H12N2 [M+H]+: 221.10375, found: 221.10375.
		Compound 9 was synthesized according to literature methods (J. Med. Chem. 2011, 54, 5320-5334): 2.7 g (15.5 mmol) of pyridine-3-acetic acid hydrochloride and 3.9 g (38.5 mmol) of triethylamine Add to dry dioxane,Stir for 10min at room temperature,1.5 g (10.3 mmol) of indole-3-carboxaldehyde and 1.9 g (22.3 mmol) of pyridine were added to the reaction solution, and the reaction was refluxed for 24 h.The reaction solution was cooled to room temperature, and the reaction solution was concentrated.Orange product 9 was separated by column chromatography, and the eluent was a mixed solvent of petroleum ether: ethyl acetate 2: 1.

Reference： [1]Bioorganic Chemistry,2019,vol. 92
[2]European Journal of Medicinal Chemistry,2019,vol. 169,p. 29 - 41
[3]Patent: CN110229112,2019,A .Location in patent: Paragraph 0033; 0053-0055

83
2′-O-acetyl-3-O-decladinosyl-6-acryloylazithromycin-11,12-cyclic carbonate [ No CAS ]
[ 6419-36-9 ]
2′-O-acetyl-3-O-descladinosyl-3-O-[2-(3-pyridyl)acetyl]-6-O-acryloylazithromycin-11,12-cyclic carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54.8%	With pyridine; dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0℃; for 1h;Inert atmosphere;	General procedure: To a solution of compound 24 (9.61g, 14.0mmol) in CH2Cl2 (60mL) under argon, 2-pyridylacetic acid hydrochloride (4.86g, 28.0mmol), DCC (5.77g, 28.0mmol), pyridine (4.00mL, 49.0mmol) and DMAP (0.170g, 1.40mmol) were added at 0C and the mixture was stirred for 1h. The N,N?-dicyclohexylurea was filtered off, and the filtrate was successively washed with saturated NH4Cl, saturated NaHCO3, water and saturated brine, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (CH2Cl2/EtOH/NH3H2O=10:0.1:0.05) to afford pure compound 25 (3.98g, 4.94mmol, 35.3%) as a yellow solid.

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 193

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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.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
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 ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
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. 6419-36-9 ] {[proInfo.proName]}

Quality Control of [ 6419-36-9 ]

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Product Details of [ 6419-36-9 ]

Calculated chemistry of [ 6419-36-9 ]

Physicochemical Properties

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[ 6419-36-9 ] Synthesis Path-Upstream 1~12

[ 6419-36-9 ] Synthesis Path-Downstream 1~83

Similar Product of [ 6419-36-9 ]

Related Functional Groups of [ 6419-36-9 ]

Carboxylic Acids

Related Parent Nucleus of [ 6419-36-9 ]

Pyridines

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[ 6419-36-9 ]

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[ 6419-36-9 ]

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