5622-36-6|Methyl 2-(quinolin-6-yl)acetate| Ambeed

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Quality Control of [ 5622-36-6 ] Purity: 98% SDS Specification

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Product Details of [ 5622-36-6 ]

CAS No. :	5622-36-6
Formula :	C₁₂H₁₁NO₂
M.W :	201.22
SMILES Code :	O=C(OC)CC1=CC=C2N=CC=CC2=C1
MDL No. :	MFCD04038669
InChI Key :	PCUOFKCRVNHDEB-UHFFFAOYSA-N
Pubchem ID :	1514202

Safety of [ 5622-36-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315
Precautionary Statements:	P280

Computational Chemistry of [ 5622-36-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	10
Fraction Csp3	0.17
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	57.61
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	39.19 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.18
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.99
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.95
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.65
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.65
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.08

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.64
Solubility	0.465 mg/ml ; 0.00231 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.44
Solubility	0.732 mg/ml ; 0.00364 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.19
Solubility	0.0131 mg/ml ; 0.000065 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.11 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.46

Application In Synthesis of [ 5622-36-6 ]

* 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 [ 5622-36-6 ]
Downstream synthetic route of [ 5622-36-6 ]

[ 5622-36-6 ] Synthesis Path-Upstream 1~2

1
[ 67-56-1 ]
[ 5622-34-4 ]
[ 5622-36-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: Reflux Stage #2: With sodium hydroxide In ethyl acetateCooling with ice	Example 1. Preparation of 6-((5)-l-(6-(l-methyl-lH-pyrazol-4-yl)-[l,2,4]triazolo[3,4- δ][l,3,4]thiadiazol-3-yl)ethyl)quinoline (compound 1); [0064] As shown in step i of Scheme 1, concentrated sulfuric acid (206 mL, 3.868 mol) was added dropwise to a solution of 2-(quinolin-6-yl)acetic acid (compound 1001, 658.2 g, 3.516 mol, Okeanos Tech Co., Cat. No. OK-J-05024) in 6.5 liters of methanol. During the addition, a slight exotherm was observed. After the addition was complete, the reaction was stirred at reflux for 4 hours. After cooling, the volatiles were removed under reduced pressure, the resulting residue was diluted with 4 liters of ethyl acetate, cooled in an ice bath, treated with 2N NaOH (2.1 liters, 1.2 equiv.) until a pH of 4 was achieved, and then treated with saturated sodium bicarbonate until a pH of 8 was achieved. The layers were separated and the aqueous layer extracted twice with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate, washed with water, washed with brine, dried over anhydrous MgSO₄, filtered, and evaporated under reduced pressure to afford methyl 2-(quinolin-6-yl)acetate as a clear brown oil (compound 1002, 696.8 g, 98 percent yield): ESMS (M+l), 202.14; ¹H NMR (300.0 MHz, DMSO-d₆) δ 8.90 (IH, dd, J = 1.7, 4.2 Hz), 8.14 - 8.10 (IH, m), 8.08 (IH, d, J = 8.7 Hz), 7.72 (IH, d, J = 1.4 Hz), 7.65 (IH, dd, J = 2.0, 8.7 Hz), 7.40 (IH, dd, J = 4.2, 8.3 Hz), 3.83 (2H, s), 3.73 (3H, s).
85%	at 20℃; for 6 h;	To a solution of 2-(quinolin-6-yl)acetic acid (2.0 g, 11 mmol) in methanol (40 mL) wasadded concentrated sulphuric acid (0.2 mL). The mixture was stirred at roomtemperature for 6 hours. The reaction mass was poured into water and the resulting solution was neutralised with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2504 and evaporated in vacuo to give methyl 2-(quinolin-6-yl)acetate (1.8 g, 85percent). LCMS: m/z202.25 [M+H].
76%	With thionyl chloride In methanol at 0℃; for 2 h; Reflux	2-(quinolin-6-yl)acetic acid (12.0 g, 0.064 mol) was dissolved in dry MeOH (120 mL) and cooled to 0 °C. SOCl₂ (7.0 mL, 0.096 mol) was added, and the reaction mixture was refluxed for 2 h. The reaction mixture was concentrated under reduced pressure and the resultant residue was dissolved in EtOAc, washed with water and brine, dried over anhydrous Na₂SO/t, filtered, and concentrated under reduced pressure. The resultant residue was purified by columnchromatography (20 - 25percent EtOAc/petroleum ether) to afford the title compound (9.8 g, 76percent).TLC: 20percent MeOH/CH₂Cl₂, Rf= 0.6. ^lU NMR (300 MHz, DMSO-d₆) δ ppm 8.86 (dd, J= 4.3, 1.6 Hz, 1H), 8.32 - 8.29 (m, 1H), 7.97 (d, J= 8.6 Hz, 1H), 7.84 (m, 1H), 7.66 (dd, J= 8.8, 2.0 Hz, 1H), 7.50 (dd, J= 8.2, 4.3 Hz, 1H), 3.90 (s, 2H), 3.63 (s, 3H).

73.6%	for 3 h; Heating / reflux	To a stirred solution of quinolin-6-yl-acetic acid (10 g, 53.0 mmol) in 100 ml of methanol was added 2.5 ml of concentrated H₂SO₄ The mixture was then heated to reflux for 3 hours. The reaction mixture was concentrated to give a brown residue, which was diluted with 100 ml of dichloromethane, washed with sat. aq.NaHCO₃ and brine, then the organic layer was dried over anhydrous Na₂Sψ₄ and concentrated to return title compound as a brown oil (7.9 g, 73.6percent).
72.6%	Stage #1: at 0 - 5℃; for 2 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In water; ethyl acetate	To a suspension of compound 2 (60 g, 0.32 mol) in MeOH (600 mL) cooled to 0~5°C, SOCI₂ (30 mL, 0.35 mol) was added dropwise. After the mixture was heated to reflux for 2 h, the mixture was evaporated under reduced pressure, and the residue was taken up with EtOAc (600 mL). The mixture was washed with aq. NaHCO₃ and brine, dried over Na₂SO₄ and concentrated to give crude product, which was purified via a silica column chromatography (EtOAc: Petroleum ether = 1 :5) to give pure compound 3 (50 g, 72.6percent) as a yellow oil. ¹H NMR (400 MHz, CDCI₃): δ 8.898-8.878 (dd, 1 H), 8.130-8.055 (m, 2H), <n="31"/>7.718 (s, 1 H), 7.670-7.634 (dd, 1 H), 7.407-7.365 (q, 1 H), 4.207-4.135(q, 2 H), 3.799(s, 2H), 1.279-1.232 (t, 3H).

References: [1] Patent: WO2010/59668, 2010, A1, . Location in patent: Page/Page column 20-21.
[2] Patent: WO2016/8011, 2016, A1, . Location in patent: Page/Page column 67.
[3] Patent: WO2013/19682, 2013, A1, . Location in patent: Page/Page column 117.
[4] Patent: WO2008/144767, 2008, A1, . Location in patent: Page/Page column 110; 115.
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 6651 - 6665.
[6] Patent: WO2007/138472, 2007, A2, . Location in patent: Page/Page column 28-29.

2
[ 1197-55-3 ]
[ 5622-36-6 ]

References: [1] Patent: WO2013/19682, 2013, A1, .
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 6651 - 6665.

[ 5622-36-6 ] Synthesis Path-Downstream 1~35

1
[ 67-56-1 ]
[ 5622-34-4 ]
[ 5622-36-6 ]

Yield	Reaction Conditions	Operation in experiment
98%		Example 1. Preparation of 6-((5)-l-(6-(l-methyl-lH-pyrazol-4-yl)-[l,2,4]triazolo[3,4- delta][l,3,4]thiadiazol-3-yl)ethyl)quinoline (compound 1); [0064] As shown in step i of Scheme 1, concentrated sulfuric acid (206 mL, 3.868 mol) was added dropwise to a solution of 2-(quinolin-6-yl)acetic acid (compound 1001, 658.2 g, 3.516 mol, Okeanos Tech Co., Cat. No. OK-J-05024) in 6.5 liters of methanol. During the addition, a slight exotherm was observed. After the addition was complete, the reaction was stirred at reflux for 4 hours. After cooling, the volatiles were removed under reduced pressure, the resulting residue was diluted with 4 liters of ethyl acetate, cooled in an ice bath, treated with 2N NaOH (2.1 liters, 1.2 equiv.) until a pH of 4 was achieved, and then treated with saturated sodium bicarbonate until a pH of 8 was achieved. The layers were separated and the aqueous layer extracted twice with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate, washed with water, washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure to afford methyl 2-(quinolin-6-yl)acetate as a clear brown oil (compound 1002, 696.8 g, 98 percent yield): ESMS (M+l), 202.14; 1H NMR (300.0 MHz, DMSO-d6) delta 8.90 (IH, dd, J = 1.7, 4.2 Hz), 8.14 - 8.10 (IH, m), 8.08 (IH, d, J = 8.7 Hz), 7.72 (IH, d, J = 1.4 Hz), 7.65 (IH, dd, J = 2.0, 8.7 Hz), 7.40 (IH, dd, J = 4.2, 8.3 Hz), 3.83 (2H, s), 3.73 (3H, s).
85%	With sulfuric acid; at 20℃; for 6h;	To a solution of 2-(quinolin-6-yl)acetic acid (2.0 g, 11 mmol) in methanol (40 mL) wasadded concentrated sulphuric acid (0.2 mL). The mixture was stirred at roomtemperature for 6 hours. The reaction mass was poured into water and the resulting solution was neutralised with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2504 and evaporated in vacuo to give methyl 2-(quinolin-6-yl)acetate (1.8 g, 85percent). LCMS: m/z202.25 [M+H].
76%	With thionyl chloride; In methanol; at 0℃; for 2h;Reflux;	2-(quinolin-6-yl)acetic acid (12.0 g, 0.064 mol) was dissolved in dry MeOH (120 mL) and cooled to 0 °C. SOCl2 (7.0 mL, 0.096 mol) was added, and the reaction mixture was refluxed for 2 h. The reaction mixture was concentrated under reduced pressure and the resultant residue was dissolved in EtOAc, washed with water and brine, dried over anhydrous Na2SO/t, filtered, and concentrated under reduced pressure. The resultant residue was purified by columnchromatography (20 - 25percent EtOAc/petroleum ether) to afford the title compound (9.8 g, 76percent).TLC: 20percent MeOH/CH2Cl2, Rf= 0.6. lU NMR (300 MHz, DMSO-d6) delta ppm 8.86 (dd, J= 4.3, 1.6 Hz, 1H), 8.32 - 8.29 (m, 1H), 7.97 (d, J= 8.6 Hz, 1H), 7.84 (m, 1H), 7.66 (dd, J= 8.8, 2.0 Hz, 1H), 7.50 (dd, J= 8.2, 4.3 Hz, 1H), 3.90 (s, 2H), 3.63 (s, 3H).

73.6%	With sulfuric acid; for 3h;Heating / reflux;Product distribution / selectivity;	To a stirred solution of quinolin-6-yl-acetic acid (10 g, 53.0 mmol) in 100 ml of methanol was added 2.5 ml of concentrated H2SO4 The mixture was then heated to reflux for 3 hours. The reaction mixture was concentrated to give a brown residue, which was diluted with 100 ml of dichloromethane, washed with sat. aq.NaHCO3 and brine, then the organic layer was dried over anhydrous Na2Spsi4 and concentrated to return title compound as a brown oil (7.9 g, 73.6percent).
72.6%		To a suspension of compound 2 (60 g, 0.32 mol) in MeOH (600 mL) cooled to 0~5°C, SOCI2 (30 mL, 0.35 mol) was added dropwise. After the mixture was heated to reflux for 2 h, the mixture was evaporated under reduced pressure, and the residue was taken up with EtOAc (600 mL). The mixture was washed with aq. NaHCO3 and brine, dried over Na2SO4 and concentrated to give crude product, which was purified via a silica column chromatography (EtOAc: Petroleum ether = 1 :5) to give pure compound 3 (50 g, 72.6percent) as a yellow oil. 1H NMR (400 MHz, CDCI3): delta 8.898-8.878 (dd, 1 H), 8.130-8.055 (m, 2H), <n="31"/>7.718 (s, 1 H), 7.670-7.634 (dd, 1 H), 7.407-7.365 (q, 1 H), 4.207-4.135(q, 2 H), 3.799(s, 2H), 1.279-1.232 (t, 3H).

References: [1]Patent: WO2010/59668,2010,A1 .Location in patent: Page/Page column 20-21.
[2]Patent: WO2016/8011,2016,A1 .Location in patent: Page/Page column 67.
[3]Patent: WO2013/19682,2013,A1 .Location in patent: Page/Page column 117.
[4]Patent: WO2008/144767,2008,A1 .Location in patent: Page/Page column 110; 115.
[5]Journal of Medicinal Chemistry,2013,vol. 56,p. 6651 - 6665.
[6]Patent: WO2007/138472,2007,A2 .Location in patent: Page/Page column 28-29.

2
[ 5622-36-6 ]
2-(6-quinolinyl)ethanamidine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride;trimethylaluminum; In toluene;	EXAMPLE 8A 2-(6-Quinolinyl)ethanamidine hydrochloride 21.4 g (400 mmol) of ammonium chloride are suspended in 400 ml of dry toluene and the suspension is cooled to 0° C. 200 ml of a 2M solution of trimethylaluminium in toluene are added dropwise and the mixture is stirred at room temperature until the evolution of gas is complete. After addition of 17.9 g (88.9 mmol) of <strong>[5622-36-6]methyl 6-quinolinylacetate</strong>, the reaction mixture is stirred overnight at 100° C. (bath). The cooled reaction mixture is treated with 90 g of silica gel and then stirred at room temperature for a further 15 min. The solid is then filtered off with suction, and the filter cake is washed several times more with dichloromethane/methanol 10/1. The filtrate is concentrated. 1H-NMR (DMSO-d6): delta/ppm 3.97 (s, 2 H), 7.54-9.31 (m, 6 H).

References: [1]Patent: US2002/198377,2002,A1 .

3
[ 5622-36-6 ]
[ 943541-37-5 ]

Yield	Reaction Conditions	Operation in experiment
58%	With selenium(IV) oxide; In 1,4-dioxane; for 72h;Heating / reflux;	To the solution of <strong>[5622-36-6]methyl 6-quinolineacetate</strong> (1.2 g, 6 mmmol) in dioxane (30 mL) was added Selenium dioxide (1.65 g, 15 mmol). The mixture was heated to reflux for 3 days, cooled to room temperature, filtered through Celite and concentrated. The residue was purified by chromatography (methylene chloride to 5percent ethyl acetate in chloride) to a white solid (0.75 g, 58percent). 1H-NMR (CDCl3): delta 9.07-9.06 (IH, q, J = 1.7, 2.5 Hz), 8.62-8.61 (IH, d, / = 1.7 Hz), 8.32-8.31 (2H, m), 8.22-8.20 (IH, d, J = 8.8 Hz), 7.54-7.51 (IH, q, J = 8.8Hz), 4.05 (3H, s).

References: [1]Patent: WO2007/75567,2007,A1 .Location in patent: Page/Page column 114.

4
[ 5622-36-6 ]
[ 943541-42-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 3-chloro-benzenecarboperoxoic acid; In 1,2-dimethoxyethane; at 20℃; for 2h;	m-Perchlorobenzoic acid (6.85g, 39.8piiotamol) was added to a solution of commercially available <strong>[5622-36-6]quinolin-6-yl-acetic acid methyl ester</strong> (5.00g, 24.8mmol) in 1,2- dimethoxyethane at room temperature and stirred for 2 hours. Water was added and . the solution was basified to pH 9-10 with saturated potassium carbonate and the product was extracted with ethyl acetate to give quantitative yield of (1-hydroxy- quinolin-6-yl)-acetic acid methyl ester. 1H NMR (400 MHz, CDCl3) S 7.99 (d, IH, J=8.4Hz), 7.93 (d, IH, J=8.4Hz), 7.65 (m, IH), 7.60 (m, IH), 732 (d, IH, J=8.8Hz), 7.19 (s, IH), 3.74 (s, 2H), 3.65 (s, 3H).
800 mg		771-CPBA (0.77 g, 4.4 mmol) was added to a solution of <strong>[5622-36-6]methyl 2-(quinolin-6-yl)acetate</strong>(0.6 g, 2.98 mmol) in DME (5 mL) at rt and stirred for 2 h. The reaction mixture was diluted with water and basified to pH -10 using saturated aq. K2C03. The reaction mixture was extracted with EtOAc, dried over anhydrous Na2SO/t, filtered, and concentrated under reduced pressure to afford the title compound (800 mg). TLC: 10percent MeOH/CHCl3, Rf= 0.1. lU NMR (300 MHz, DMSO- d6) delta ppm 8.55 - 8.53 (m, 1H), 8.48 - 8.45 (m, 1H), 7.95 (m, 1H), 7.86 (m, 1H), 7.72 - 7.69 (m, 1H), 7.45 - 7.41 (m, 1H), 3.92 (s, 2H), 3.63 (s, 3H).

References: [1]Patent: WO2007/75567,2007,A1 .Location in patent: Page/Page column 122-123.
[2]Journal of the American Chemical Society,2017,vol. 139,p. 16822 - 16829.
[3]Patent: WO2013/19682,2013,A1 .Location in patent: Page/Page column 117.

5
[ 5622-36-6 ]
[ 227809-77-0 ]

Yield	Reaction Conditions	Operation in experiment
84%		Example 124; 6-Phenyl-2-(2-(quinolin-6-yl)ethyl)pyridaziii-3(2//)-oiie.(1) To a 25 mL round-bottomed flask was added lithium aluminum hydride (0.057 g, 1.5 mmol, Strem Chemicals) and THF (8.0 mL). The mixture was cooled to - 30 °C and <strong>[5622-36-6]methyl 2-(quinolin-6-yl)acetate</strong> (0.30 g, 1.5 mmol, Tyger) in 2 mL THF was added over 1 minute. The mixture was stirred at -30 °C for 30 min, then quenched with 0.056 mL H2O. The solution was allowed to warm to rt and 0.056 mL 15percent aq. NaOH and then 0.168 mL H2O were added. The mixture was stirred for 15 minutes and then filtered. The filtercake was washed with THF and the filtrate was concentrated. Purification by silica gel chromatography (0.5 to 5.0percent MeOH (2 M in NH3)/CH2C12) afforded the title compound as a yellow solid (0.22 g, 84percent yield). MS (ESI pos. ion) m/z (MH+): 174. Calc'd exact mass for CHHI 1NO: 173. 1H NMR (400 MHz, DMSO-^6) delta ppm 8.83 (dd, J= 4.2, 1.7 Hz, 1 H), 8.28 (dd, J = 8.3, 0.9 Hz, 1 H), 7.93 (d, J= 8.6 Hz, 1 H), 7.77 (d, J= 1.2 Hz, 1 H), 7.65 (dd, J= 8.6, 2.0 Hz, 1 H), 7.49 (dd, J= 8.3, 4.2 Hz, 1 H), 4.73 (X, J = 5.2 Hz, 1 H), 3.72 (dt, J= 6.8, 5.3 Hz, 2 H), 2.92 (t, J= 6.8 Hz, 2 H).
84%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4.16667h;	To a mixture of LiAIH4 (680 mg, 17.9 mmol) in THE (50 mL) at 0 °C was added <strong>[5622-36-6]methyl 2-(quinolin-6-yl)acetate</strong> (1.8 g, 8.9 mmol). The mixture was stirred for 10 minutes at this temperature, after which the reaction mass was slowly warmed to room temperatureand stirred for 4 hours. After complete consumption of the starting material as determined by TLC, the reaction mixture was quenched with ethyl acetate (3 mL) and saturated ammonium chloride solution (20 mL) at 0 °C, filtered and concentrated to give 2-(quinolin-6-yl)ethan-1 -ol (1.3 g, 84percent). LCMS: m/z 174.28 [M+H].

References: [1]Patent: WO2008/103277,2008,A2 .Location in patent: Page/Page column 167.
[2]Patent: WO2016/8011,2016,A1 .Location in patent: Page/Page column 67.

6
[ 5622-36-6 ]
[ 5622-41-3 ]

Yield	Reaction Conditions	Operation in experiment
93.9%	With hydrazine; In ethanol; for 1.5h;Heating / reflux;	Quinolin-6-yl-acetic acid methyl ester (15g, 74.5mmol) was dissolved in 90 ml of ethanol, and hydrazine hydrate (16.6mL, 342.9mmol) was added dropwise to the solution while stirring. The resulting solution was heated to reflux for 1.5 h. Excess ethanol and hydrazine hydrate were distilled off and the contents <n="112"/>allowed to cool. The precipitate was collected via filtration, washed with cold ethanol and dried in vacuo to return the title compound (15.4g, 93.9percent) as a white solid

References: [1]Patent: WO2008/144767,2008,A1 .Location in patent: Page/Page column 110-111.

7
[ 5622-36-6 ]
[ 1022091-89-9 ]

Yield	Reaction Conditions	Operation in experiment
45.3%		To a stirred solution of <strong>[5622-36-6]quinolin-6-yl-acetic acid methyl ester</strong> (21.6 g, 107 mmol) in 150 ml of carbon tetrachloride was treated with bromine (34.4 g, 215 mmol) and heated to reflux for 4 hours. The reaction mixture was treated with 17.0 g of pyridine, and further stirred for 2 hours under reflux. After cooling down to ambient temperature, the mixture was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate, the organic layer was washed with water and brine, dried over magnesium sulfate then evaporated under reduced pressure to give a brown residue. The residue was purified by column chromatography, eluting with petroleum (60~90°C) and then a 30:1 mixed solvent of petroleum and ethyl acetate to return title compound (13.6 g, 45.3percent) as a white crystalline solid. (300MHz, DMSO-d6): 8.89 (d, IH), 8.27 (d, IH), 8.06 (d, IH), 7.67~7.64(m, 2H), 3.82(s, 2H), 3.72(s, 3H). ES-MS m/z: 280 (M+H+).

References: [1]Patent: WO2008/144767,2008,A1 .Location in patent: Page/Page column 115.

8
[ 50-00-0 ]
[ 5622-36-6 ]
[ 1227467-55-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; Hexadecyltrimethylammonium hydrogen sulfate; In toluene;Reflux;	[0065] As shown in step ii of Scheme 1, <strong>[5622-36-6]methyl 2-(quinolin-6-yl)acetate</strong> (82 g, 407.5 mmol) , paraformaldehyde (25.89 g, 862.1 mmol) , K2CO3 (101.4 g, 733.5 mmol), and hexadecyl(trimethyl)ammonium hydrogen sulfate (15.55 g, 40.75 mmol) were taken up in toluene (1.6 liters) and refluxed for 2 hours until the starting material was completely consumed, as monitored by HPLC. The reaction mixture was cooled down using an ice-water bath and filtered through diatomaceous earth. The filtrate was washed with 1 liter of water and the organic layer dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford methyl 2-(quinolin-6-yl)acrylate as a clear colorless oil (75.0 g). This material was used immediately without further purification in the next reaction.

References: [1]Patent: WO2010/59668,2010,A1 .Location in patent: Page/Page column 20-21.

9
[ 5622-36-6 ]
[ 106-93-4 ]
[ 1266238-14-5 ]

Yield	Reaction Conditions	Operation in experiment
20%		Example 50 (.pound.)-1-Methyl-2-(1-(3-(1-(quinolin-6-yl)cyclopropyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-6- yl)ethylidene)hydrazinecarboxamide1-Quinolin-6-yl-cyclopropanecarboxylic acid methyl ester (50.1) A solution of LDA (1.8 M solution in toluene, 14.8 ml, 26.6 mmol) was added dropwise to a solution of <strong>[5622-36-6]quinolin-6-yl-acetic acid methyl ester</strong> (2.14 g, 10.64 mmol) in dry THF (40 ml.) under a nitrogen atmosphere at -78 0C. After 30 min, 1 ,2-dibromoethane (2.40 g, 12.76 mmol) was added dropwise over 3 min. The resulting mixture was stirred for 1 h at room temperature, then quenched with satd aq. NH4CI. The mixture was extracted with DCM, washed with brine, dried over Na2SO4, and stripped of solvent. The residue was purified by flash chromatography in silica gel eluting with a EtOAC/hexane gradient to afford 463 mg (20percent) of the title compound as yellow solid. 1H-NMR (400MHz, CDCI3) delta ppm 8.91 (dd, 1 H), 8.12 (d, 1 H), 8.07 (d, 1 H), 7.77-7.74 (m, 2H), 7.40 (dd, 1 H), 3.65 (s, 3H), 1.73-1.71 (m, 2H), 1.33-1.30 (m, 2H). LCMS (method A): [MH]+ = 228, tR = 4.37 min.
20%		LDA (1.8 M solution in toluene, 14.8 mL, 26.6 mmol) was added dropwise to a solution of <strong>[5622-36-6]quinolin-6-yl-acetic acid methyl ester</strong> (2.14 g, 10.64 mmol) in dry THF (40 mL) under nitrogen at -78 0C. After 30 min, 1 ,2-dibromoethane (2.40 g, 12.76 mmol) was added dropwise over 3 min. The resulting mixture was stirred for 1 h at rt, then quenched with saturated aqueous NH4CI, extracted with DCM, washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with EtOAc/hexane gradient to afford the title compound as a yellow solid (463 mg, 20percent). 1H- NMR (400 MHz, CDCI3) delta ppm 8.91 (dd, 1 H), 8.12 (d, 1 H), 8.07 (d, 1 H), 7.77-7.74 (m, 2H), 7.40 (dd, 1 H), 3.65 (s, 3H), 1.73-1 .71 (m, 2H), 1.33-1 .30 (m, 2H). LCMS (method A): [MH]+ = 228, tR = 4.37 min.

References: [1]Patent: WO2011/18454,2011,A1 .Location in patent: Page/Page column 100-101.
[2]Patent: WO2011/20861,2011,A1 .Location in patent: Page/Page column 122.

10
[ 5622-36-6 ]
[ 1266238-15-6 ]

References: [1]Patent: WO2011/18454,2011,A1 .
[2]Patent: WO2011/20861,2011,A1 .

11
[ 5622-36-6 ]
[ 1266238-16-7 ]

References: [1]Patent: WO2011/18454,2011,A1 .
[2]Patent: WO2011/20861,2011,A1 .

12
[ 5622-36-6 ]
C₂₁H₁₉N₅O [ No CAS ]

References: [1]Patent: WO2011/18454,2011,A1 .
[2]Patent: WO2011/20861,2011,A1 .

13
[ 5622-36-6 ]
[ 1266238-17-8 ]

References: [1]Patent: WO2011/18454,2011,A1 .
[2]Patent: WO2011/20861,2011,A1 .

14
[ 5622-36-6 ]
[ 1266237-33-5 ]

References: [1]Patent: WO2011/18454,2011,A1 .

15
[ 5622-36-6 ]
[ 1268260-46-3 ]

References: [1]Patent: WO2011/20861,2011,A1 .

16
[ 5622-36-6 ]
[ 1268260-47-4 ]

References: [1]Patent: WO2011/20861,2011,A1 .

17
[ 1197-55-3 ]
[ 5622-36-6 ]

References: [1]Patent: WO2013/19682,2013,A1 .
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 6651 - 6665.

18
[ 5622-36-6 ]
[ 943541-43-3 ]

References: [1]Patent: WO2013/19682,2013,A1 .
[2]Journal of the American Chemical Society,2017,vol. 139,p. 16822 - 16829.

19
[ 5622-36-6 ]
[ 1422169-98-9 ]

References: [1]Patent: WO2013/19682,2013,A1 .

20
[ 5622-36-6 ]
[ 959585-30-9 ]