[ CAS No. 13721-01-2 ] {[proInfo.proName]}

Name: 13721-01-2|4-Oxo-1,4-dihydroquinoline-3-carboxylic acid|97%
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SKU: A219765
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3d Animation Molecule Structure of 13721-01-2

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Quality Control of [ 13721-01-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 13721-01-2 ]

Product Details of [ 13721-01-2 ]

CAS No. :	13721-01-2	MDL No. :	MFCD00498984
Formula :	C₁₀H₇NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ILNJBIQQAIIMEY-UHFFFAOYSA-N
M.W :	189.17	Pubchem ID :	220875
Synonyms :

Calculated chemistry of [ 13721-01-2 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	51.53
TPSA :	70.16 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.15 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.75
Log Po/w (XLOGP3) :	1.84
Log Po/w (WLOGP) :	1.23
Log Po/w (MLOGP) :	0.41
Log Po/w (SILICOS-IT) :	1.94
Consensus Log Po/w :	1.23

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.63
Solubility :	0.439 mg/ml ; 0.00232 mol/l
Class :	Soluble
Log S (Ali) :	-2.93
Solubility :	0.22 mg/ml ; 0.00116 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.98
Solubility :	0.197 mg/ml ; 0.00104 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.39

Safety of [ 13721-01-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 13721-01-2 ]

* 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 [ 13721-01-2 ]
Downstream synthetic route of [ 13721-01-2 ]

[ 13721-01-2 ] Synthesis Path-Upstream 1~15

1
[ 26892-90-0 ]
[ 34785-11-0 ]
[ 13721-01-2 ]

Reference： [1] Patent: US2011/98311, 2011, A1,

2
[ 26892-90-0 ]
[ 13721-01-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: for 2 h; Heating / reflux Stage #2: With hydrogenchloride In water	4-Oxo-1,4-dihydroquinoline-3-carboxylic acid 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92percent). ¹H NMR (DMSO-d₆) δ 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H).
92%	Stage #1: for 2 h; Heating / reflux Stage #2: With hydrogenchloride In water	[0219] 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The <n="49"/>resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-l,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 percent). ¹H NMR (DMSO-flfe) δ 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, IH), 8.28 (d, J= 8.0 Hz, IH), 7.88 (m, IH), 7.81 (d, J = 8.4 Hz, IH), 7.60 (m, IH).
10.5 g	for 2 h; Reflux	4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-l,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 percent). ¹H NMR (DMSO-

10.5 g	for 2 h; Reflux	4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 percent).¹H NMR (DMSO-d₆) δ 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).
10.5 g	for 2 h; Reflux	Step C: 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in a sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92percent). ¹H NMR (DMSO-d₆) δ 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H) ppm.
10.5 g	for 2 h; Reflux	4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HC1. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-l,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 percent). ^lU NMR (DMSO-4) δ 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).

Reference： [1] Patent: US2008/90864, 2008, A1, . Location in patent: Page/Page column 7
[2] Patent: WO2007/79139, 2007, A2, . Location in patent: Page/Page column 46; 47
[3] Patent: US2012/309758, 2012, A1, . Location in patent: Page/Page column 61
[4] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 0352
[5] Patent: WO2018/64632, 2018, A1, . Location in patent: Paragraph 00215; 00216
[6] Patent: WO2018/107100, 2018, A1, . Location in patent: Paragraph 00234; 00235
[7] Patent: US2018/280349, 2018, A1, . Location in patent: Paragraph 0097
[8] Patent: WO2018/227049, 2018, A1, . Location in patent: Paragraph 00206; 00207

3
[ 52980-28-6 ]
[ 13721-01-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	at 0 - 80℃; for 16 h;	Ex mple 2: Synthesis of 4-Oxo-l,4-dihydroquinoline-3-carboxylic acid (3): (0084) (0085) To a suspension of ethyl 4-oxo- l,4-dihydroquinoline-3-carboxylate (2) (0.5 g, 2.30 mmol) in THF (10 mL), a solution of aqueous 1 M LiOH (aq) (4.60 mL, 4.60 mmol) was added drop wise at 0 °C, and then the reaction mixture was heated at 80 °C for 16h. Reaction mass was evaporated to dryness, dissolved in H₂0 (5 mL), washed with diethyl ether (2x5 mL).The aqueous layer was acidified with 1 M HC1 (aq),compound thus precipitated was filtered, dried under vacuum to give desired compound as off-white solid. Yield: (0.35g; 80percent) 1H NMR (400MHz ,DMSO-d6) δ = 15.36 (brs, 1H), 13.43 (brs, 1H), 8.91 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.98 - 7.75 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H).
75%	With sodium hydroxide In ethanol for 5 h; Reflux	General procedure: A suspension of ester 3e–k (2 mmol) in 4percent NaOHhydroalcoholic solution (5 ml) was refluxed until no startingmaterial could be detected by Thin Layer Chromatography(5 h). After cooling, the mixture was completely acidifiedby adding concentrated HCl and the solid obtained wascollected by filtration, washed with water, and crystallizedfrom ethanol to afford compound 4e–k. 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (4e) Starting from 3e (1 g); Yield (white powder): 600 mg(75 percent); m.p. 280 °C (decomposed); IR (KBr) νmax1400–1600 (aromatic), 1717 (carbonyl), 2790–3260 (acidicOH) cm−1; 1H-NMR (DMSO-d6, 500 MHz) δ = 7.59–7.63 (1H, t, J = 7.2 Hz, H6), 7.83 (1H, d, J = 8.2 Hz, H8), 7.90(1H, t, J = 7.0 Hz, H7), 8.30 (1H, d, J = 7.3 Hz, H5), 8.90(1H, s, H2), 13.42 (1H, br s, enolic OH), 15.34 (1H, br s,carboxylic OH); 13C-NMR (DMSO-d6, 60 MHz) δ = 105.3(C, C-3), 119.7 (CH, C-9), 123.6 (CH, C-7), 125.6 (CH,C-6), 125.9 (C, C-5), 133.9 (CH, C-8), 138.5 (C,C-10), 158.9 (CH, C-2), 167.2 (C,COOH), 178.5 (C, C=O);LC-MS (ESI) m/z 212.1 (M+Na+); Anal. Calcd. forC10H7NO3: C, 63.49; H, 3.73; N, 7.40. Found: 63.62; H,3.96; N, 7.69.
7.5 g	at 80 - 85℃; for 3 h;	In a clean round bottom flask, ethyl 4-oxo-l, 4-dihydroquinoline-3-carboxylate (10.0 gm) was charged to a solution of sodium hydroxide (3.7 gm) in 13.0 ml water. The reaction mass was heated for 3.0 hr at 80-85 C and then cooled to 25-30. To this was added 0.10 gm of activated charcoal and filtered. The pH was adjusted using con HCL and the product was filtered and washed with water. The wet cake slurried in methanol at 25 -30 C and filtered. The product was dried under vacuum at 50.0 C to get 7.50 gm of title productPurity by HPLC - 99.75 percent

Reference： [1] Chemical Communications, 2005, # 43, p. 5438 - 5440
[2] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 6, p. 3169 - 3173
[3] Patent: WO2017/208253, 2017, A2, . Location in patent: Page/Page column 13-14
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5405 - 5418
[5] Medicinal Chemistry Research, 2016, vol. 25, # 9, p. 1861 - 1876
[6] Journal of Medicinal Chemistry, 2006, vol. 49, # 22, p. 6443 - 6450
[7] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 17, p. 5261 - 5265
[8] Patent: WO2010/108155, 2010, A1, . Location in patent: Page/Page column 14; 33-34
[9] Patent: WO2010/108162, 2010, A1, . Location in patent: Page/Page column 62-64
[10] Patent: US2011/230519, 2011, A1, . Location in patent: Page/Page column 15-16
[11] Patent: WO2013/67410, 2013, A1, . Location in patent: Paragraph 0083
[12] Patent: WO2013/185112, 2013, A1, . Location in patent: Paragraph 00536
[13] Patent: WO2014/71122, 2014, A1, . Location in patent: Paragraph 00156; 00321; 00322; 00325; 00327
[14] Patent: WO2014/118805, 2014, A1, . Location in patent: Paragraph 0290
[15] Patent: US2014/221424, 2014, A1, . Location in patent: Paragraph 0077
[16] Patent: WO2015/73231, 2015, A1, . Location in patent: Paragraph 00340-00341
[17] Patent: WO2015/189560, 2015, A1,
[18] Patent: US2017/96397, 2017, A1, . Location in patent: Paragraph 0093

4
[ 26892-90-0 ]
[ 34785-11-0 ]
[ 13721-01-2 ]

Reference： [1] Patent: US2011/98311, 2011, A1,

5
[ 54535-22-7 ]
[ 13721-01-2 ]

Reference： [1] Chemical Communications, 2005, # 43, p. 5438 - 5440
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 22, p. 6443 - 6450
[3] Patent: US2011/230519, 2011, A1,
[4] Patent: US2012/309758, 2012, A1,
[5] Patent: WO2013/67410, 2013, A1,
[6] Patent: WO2014/71122, 2014, A1,
[7] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5405 - 5418
[8] Patent: WO2014/118805, 2014, A1,
[9] Patent: WO2015/73231, 2015, A1,
[10] Patent: US2015/231142, 2015, A1,
[11] Patent: WO2015/189560, 2015, A1,
[12] Medicinal Chemistry Research, 2016, vol. 25, # 9, p. 1861 - 1876
[13] Patent: WO2007/79139, 2007, A2,
[14] Patent: US2011/98311, 2011, A1,
[15] Patent: WO2018/64632, 2018, A1,
[16] Patent: WO2018/107100, 2018, A1,
[17] Patent: US2018/280349, 2018, A1,
[18] Patent: US2017/96397, 2017, A1,
[19] Patent: WO2018/227049, 2018, A1,

6
[ 62-53-3 ]
[ 13721-01-2 ]

Reference： [1] Patent: US2011/230519, 2011, A1,
[2] Patent: US2012/309758, 2012, A1,
[3] Patent: WO2013/67410, 2013, A1,
[4] Patent: WO2013/185112, 2013, A1,
[5] Patent: WO2014/71122, 2014, A1,
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5405 - 5418
[7] Patent: WO2014/118805, 2014, A1,
[8] Patent: WO2015/73231, 2015, A1,
[9] Patent: US2015/231142, 2015, A1,
[10] Patent: WO2015/189560, 2015, A1,
[11] Medicinal Chemistry Research, 2016, vol. 25, # 9, p. 1861 - 1876
[12] Patent: WO2007/79139, 2007, A2,
[13] Patent: WO2018/64632, 2018, A1,
[14] Patent: WO2018/107100, 2018, A1,
[15] Patent: US2018/280349, 2018, A1,
[16] Patent: US2017/96397, 2017, A1,
[17] Patent: WO2018/227049, 2018, A1,

7
[ 61707-79-7 ]
[ 13721-01-2 ]

Reference： [1] Heterocycles, 1999, vol. 51, # 10, p. 2377 - 2384

8
[ 4916-29-4 ]
[ 13721-01-2 ]

Reference： [1] Heterocycles, 1999, vol. 51, # 10, p. 2377 - 2384

9
[ 61707-75-3 ]
[ 13721-01-2 ]

Reference： [1] Heterocycles, 1999, vol. 51, # 10, p. 2377 - 2384

10
[ 61707-70-8 ]
[ 13721-01-2 ]

Reference： [1] Heterocycles, 1999, vol. 51, # 10, p. 2377 - 2384

11
[ 251986-52-4 ]
[ 13721-01-2 ]

Reference： [1] Heterocycles, 1999, vol. 51, # 10, p. 2377 - 2384

12
[ 108-88-3 ]
[ 13721-01-2 ]

Reference： [1] Patent: US2014/221424, 2014, A1,

13
[ 552-16-9 ]
[ 13721-01-2 ]

Reference： [1] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 6, p. 3169 - 3173

14
[ 52119-39-8 ]
[ 13721-01-2 ]

Reference： [1] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 6, p. 3169 - 3173

15
[ 778-82-5 ]
[ 13721-01-2 ]

Reference： [1] Patent: WO2017/208253, 2017, A2,

[ 13721-01-2 ] Synthesis Path-Downstream 1~88

1
[ 13721-01-2 ]
[ 101620-10-4 ]
[ 124502-66-5 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1989,vol. 37,p. 1256 - 1259

2
[ 13721-01-2 ]
4-oxo-1,4-dihydroquinoline-3-carbonyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.5 g	With thionyl chloride; triethylamine; In dichloromethane; at 0 - 50℃; for 2h;	To a 500-mL round-bottom flask was placed a solution of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid (6 g, 31.72 mmol) in DCM (250 mL), TEA (6.4 g, 63.25 mmol) then the solution was cooled to 0°C and thionyl chloride (7.49 g) was added dropwise with stirring. The reaction was stirred for 2 h at 50°C then concentrated under reduced pressure affording 5.5 g of the title compound as a white solid.

Reference： [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,1988,vol. 43,p. 769 - 777
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9776 - 9795
[3]Patent: WO2017/177124,2017,A1 .Location in patent: Paragraph 0109

3
anilinomethylenemalonate [ No CAS ]
[ 13721-01-2 ]

Reference： [1]Archiv der Pharmazie,1994,vol. 327,p. 129 - 132

4
[ 13721-01-2 ]
[ 765222-35-3 ]

Yield	Reaction Conditions	Operation in experiment
19 g	With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 20 - 45℃; for 3h;	Compound 3 (15 g, 79.37 mmol, 1.0 eq) was added to a 500 mL three-neck flaskAdd SOCl2 (47.2 g, 396.8 mmol, 5.0 eq) dropwise with dichloromethane (300.0 ml) while stirring at room temperature.Then DMF (1.7 g, 24 mmol, 0.3 eq) was added dropwise.The reaction solution was heated to 40-45°C and reacted at 40-45°C for 3 hours. The reaction solution was concentrated to give a yellow solid.Add 50.0 mL of acetonitrile to the flask, stir for 1 hour, and filter.The solid was dried as a pale yellow powdered solid 19g (purity 95percent, used directly in the next step).

Reference： [1]Chemical and Pharmaceutical Bulletin,1995,vol. 43,p. 693 - 698
[2]Patent: CN105130891,2018,B .Location in patent: Paragraph 0041; 0042; 0043

5
[ 52980-28-6 ]
[ 13721-01-2 ]

Yield	Reaction Conditions	Operation in experiment
87%	With lithium hydroxide monohydrate; In tetrahydrofuran; water; at 20℃;	General procedure: The ethyl 4(1H)-oxo-quinolone-3-carboxylate (1?2 mmol) was dissolved in 5 mL MeOH. LiOH·H2O (3.0equiv), dissolved in 1?2 mL H2O, was added to the reaction mixture. The reaction mixture was stirredat ambient temperature overnight or monitored by TLC analysis. After the starting material was fullyconsumed (judged by TLC-analysis), the reaction volume was reduced to one third of its initialvolume. The solution was acidified to pH 2?3 (pH-paper) with 1 M HCl. The resulting white solutionwas centrifuged and the liquid carefully removed. The remaining solid was washed with water andcentrifuged twice, leaving a pure off-white solid.
80%	With water; lithium hydroxide; at 0 - 80℃; for 16h;	Ex mple 2: Synthesis of 4-Oxo-l,4-dihydroquinoline-3-carboxylic acid (3): (0084) (0085) To a suspension of ethyl 4-oxo- l,4-dihydroquinoline-3-carboxylate (2) (0.5 g, 2.30 mmol) in THF (10 mL), a solution of aqueous 1 M LiOH (aq) (4.60 mL, 4.60 mmol) was added drop wise at 0 C, and then the reaction mixture was heated at 80 C for 16h. Reaction mass was evaporated to dryness, dissolved in H20 (5 mL), washed with diethyl ether (2x5 mL).The aqueous layer was acidified with 1 M HC1 (aq),compound thus precipitated was filtered, dried under vacuum to give desired compound as off-white solid. Yield: (0.35g; 80%) 1H NMR (400MHz ,DMSO-d6) delta = 15.36 (brs, 1H), 13.43 (brs, 1H), 8.91 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.98 - 7.75 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H).
75%	With sodium hydroxide; In ethanol; for 5h;Reflux;	General procedure: A suspension of ester 3e-k (2 mmol) in 4% NaOHhydroalcoholic solution (5 ml) was refluxed until no startingmaterial could be detected by Thin Layer Chromatography(5 h). After cooling, the mixture was completely acidifiedby adding concentrated HCl and the solid obtained wascollected by filtration, washed with water, and crystallizedfrom ethanol to afford compound 4e-k. 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (4e) Starting from 3e (1 g); Yield (white powder): 600 mg(75 %); m.p. 280 C (decomposed); IR (KBr) numax1400-1600 (aromatic), 1717 (carbonyl), 2790-3260 (acidicOH) cm-1; 1H-NMR (DMSO-d6, 500 MHz) delta = 7.59-7.63 (1H, t, J = 7.2 Hz, H6), 7.83 (1H, d, J = 8.2 Hz, H8), 7.90(1H, t, J = 7.0 Hz, H7), 8.30 (1H, d, J = 7.3 Hz, H5), 8.90(1H, s, H2), 13.42 (1H, br s, enolic OH), 15.34 (1H, br s,carboxylic OH); 13C-NMR (DMSO-d6, 60 MHz) delta = 105.3(C, C-3), 119.7 (CH, C-9), 123.6 (CH, C-7), 125.6 (CH,C-6), 125.9 (C, C-5), 133.9 (CH, C-8), 138.5 (C,C-10), 158.9 (CH, C-2), 167.2 (C,COOH), 178.5 (C, C=O);LC-MS (ESI) m/z 212.1 (M+Na+); Anal. Calcd. forC10H7NO3: C, 63.49; H, 3.73; N, 7.40. Found: 63.62; H,3.96; N, 7.69.

	With hydrogenchloride; water; at 85 - 90℃; for 6.5h;Product distribution / selectivity;	Compound 25 (1.0 eq) was suspended in a solution of HCl (10.0 eq) and H2O (11.6 vol). The slurry was heated to 85 - 90 0C, although alternative temperatures are also suitable for this hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperature of from about 75 to about 100 C. In some instances, the hydrolysis is performed at a temperature of from about 80 to about 95 0C. In others, the hydrolysis step is performed at a temperature of from about 82 to about 93 C (e.g., from about 82.5 to about 92.5 C or from about 86 to about 89 0C). After stirring at 85 - 90 0C for approximately 6.5 hours, the reaction was sampled for reaction completion. Stirring may be performed under any of the temperatures suited for the hydrolysis. The solution was then cooled to 20 - 25 0C and filtered. The reactor/cake was rinsed with H2O (2 vol x 2). The cake was then washed with 2 vol H2O until the pH >; 3.0. The cake was then dried under vacuum at 60 0C to give compound 26.
		Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL) and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 0C and then the pH was adjusted to 2-3 with 8% HCl. The mixture was then stirred for 0.5 hours and filtered. The cake was washed with water (50 mL) and then dried in vacuo to give compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 15.33 (s), delta 13.39 (s), delta 8.87 (s), delta 8.26 (m), delta 7.87 (m), delta 7.80 (m), delta 7.56 (m).
		Procedure for the preparation of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (26) Method 2Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL) and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 C. and then the pH was adjusted to 2-3 with 8% HCl. The mixture was then stirred for 0.5 hours and filtered. The cake was washed with water (50 mL) and then dried in vacuo to give compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 15.33 (s), delta 13.39 (s), delta 8.87 (s), delta 8.26 (m), delta 7.87 (m), delta 7.80 (m), delta 7.56 (m).
	With water; sodium hydroxide; In ethanol; for 16h;Reflux;	Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL) and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 C and then the pH was adjusted to 2-3 with 8% HC1. The mixture was then stirred for 0.5 hours and filtered. The cake was washed with water (50 mL) and then dried in vacuo to give Compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 15.33 (s), delta 13.39 (s), delta 8.87 (s), delta 8.26 (m), delta 7.87 (m), delta 7.80 (m), delta 7.56 (m).
	With hydrogenchloride; water; at 85 - 90℃;	Compound 25 (1.0 eq) was suspended in a solution of HQ (10,0 eq) and H20 (1 1.6 vol). The slum'' was heated to 85 - 90 C, although alternative temperatures are also suitable for this hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperature of from about 75 to about 100 C. in some instances, fee hydrolysis is performed at a temperature of from about 80 to about 95 C. In others, the hydrolysis step is performed at a temperature of from about 82 to about 93 C (e.g., from about 82.5 to about 92.5 C or from about 86 to about 89 C). After stirring at 85 - 90 C for approximately 6.5 hours, fee reaction was sampled for reaction completion. Stirring may be performed under any of the temperatures suited for the hydrolysis. The solution was then cooled to 20 - 25 C and filtered. The reactor/cake was rinsed wife H2?> (2 vol x 2), The cake was then washed with 2 vol 0 until fee pH > 3.0, The cake was then dried under vacuum at 60 C to give Compound 26.
	With water; sodium hydroxide; In ethanol; for 16h;Reflux;	Method 1[00326] Compound 25 (1.0 eq) was suspended in a solution ofHCl (10.0 eq) and H20 (11.6vol). The slurry was heated to 85 - 90 C, although alternative temperatures are also suitable forthis hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperatureof from about 75 to about 100 C. In some instances, the hydrolysis is performed at atemperature of from about 80 to about 95 C. In others, the hydrolysis step is performed at atemperature of from about 82 to about 93 oc (e.g., from about 82.5 to about 92.5 oc or fromabout 86 to about 89 C). After stirring at 85 - 90 oc for approximately 6.5 hours, the reactionwas sampled for reaction completion. Stirring may be performed under any of the temperaturessuited for the hydrolysis. The solution was then cooled to 20 - 25 oc and filtered. Thereactor/cake was rinsed with H20 (2 vol x 2). The cake was then washed with 2 vol H20 untilthe pH 2: 3.0. The cake was then dried under vacuum at 60 octo give compound 26.Method 2[00327] Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL)and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 oc andthen the pH was adjusted to 2-3 with 8% HCl. The mixture was then stirred for 0.5 hours andfiltered. The cake was washed with water (50 mL) and then dried in vacuo to give compound 26as a brown solid. 1H NMR (DMSO-d6; 400 MHz) 8 15.33 (s), 8 13.39 (s), 8 8.87 (s), 8 8.26 (m),8 7.87 (m), 8 7.80 (m), 8 7.56 (m).
7.5 g	With water; sodium hydroxide; at 80 - 85℃; for 3h;	In a clean round bottom flask, ethyl 4-oxo-l, 4-dihydroquinoline-3-carboxylate (10.0 gm) was charged to a solution of sodium hydroxide (3.7 gm) in 13.0 ml water. The reaction mass was heated for 3.0 hr at 80-85 C and then cooled to 25-30. To this was added 0.10 gm of activated charcoal and filtered. The pH was adjusted using con HCL and the product was filtered and washed with water. The wet cake slurried in methanol at 25 -30 C and filtered. The product was dried under vacuum at 50.0 C to get 7.50 gm of title productPurity by HPLC - 99.75 %
		Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL) and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 C. and then the pH was adjusted to 2-3 with 8% HCl. The mixture was then stirred for 0.5 hours and filtered. The cake was washed with water (50 mL) and then dried in vacuo to give Compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 15.33 (s), delta 13.39 (s), delta 8.87 (s), delta 8.26 (m), delta 7.87 (m), delta 7.80 (m), delta 7.56 (m).
	With hydrogenchloride; In water; at 85 - 90℃;	Method 1 [00341] Compound 25 (1.0 eq) was suspended in a solution of HC1 (10.0 eq) and H20 (1 1.6 vol). The slurry was heated to 85 - 90 C, although alternative temperatures are also suitable for this hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperature of from about 75 to about 100 C. In some instances, the hydrolysis is performed at a temperature of from about 80 to about 95 C. In others, the hydrolysis step is performed at a temperature of from about 82 to about 93 C (e.g., from about 82.5 to about 92.5 C or from about 86 to about 89 C). After stirring at 85 - 90 C for approximately 6.5 hours, the reaction was sampled for reaction completion. Stirring may be performed under any of the temperatures suited for the hydrolysis. The solution was then cooled to 20 - 25 C and filtered. The reactor/cake was rinsed with H20 (2 vol x 2). The cake was then washed with 2 vol H20 until the pH > 3.0. The cake was then dried under vacuum at 60 C to give compound 26.
	With sodium hydroxide; at 90 - 100℃;	Step c : 4-Oxo 1,4-dihydroquinoline- 3-carboxylic acid 4-hydroxyquinoline 3- carboxylic acid ethyl ester (100 g) was suspended in 2N sodium hydroxide solution at room temperature and was heated to 90-100 C. and maintained for 2-4 hours. After completion, the reaction mass was cooled to room temperature and filtered to remove undissolved material. The obtained filtrate was acidified to pH 3-4 with 2N Hydrochloric acid at 25-30 C. The resultant solid was filtered, washed with water and dried at 50 C. until constant weight was observed to obtain the title compound (55-65 g).

Reference： [1]Chemical Communications,2005,p. 5438 - 5440
[2]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 3169 - 3173
[3]Beilstein Journal of Organic Chemistry,2019,vol. 15,p. 2156 - 2160
[4]Patent: WO2017/208253,2017,A2 .Location in patent: Page/Page column 13-14
[5]Journal of Medicinal Chemistry,2014,vol. 57,p. 5405 - 5418
[6]Medicinal Chemistry Research,2016,vol. 25,p. 1861 - 1876
[7]Journal of Medicinal Chemistry,2006,vol. 49,p. 6443 - 6450
[8]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5261 - 5265
[9]Patent: WO2010/108155,2010,A1 .Location in patent: Page/Page column 14; 33-34
[10]Patent: WO2010/108162,2010,A1 .Location in patent: Page/Page column 62-64
[11]Patent: US2011/230519,2011,A1 .Location in patent: Page/Page column 15-16
[12]Patent: WO2013/67410,2013,A1 .Location in patent: Paragraph 0083
[13]Patent: WO2013/185112,2013,A1 .Location in patent: Paragraph 00536
[14]Patent: WO2014/71122,2014,A1 .Location in patent: Paragraph 00156; 00321; 00322; 00325; 00327
[15]Patent: WO2014/118805,2014,A1 .Location in patent: Paragraph 0290
[16]Patent: US2014/221424,2014,A1 .Location in patent: Paragraph 0077
[17]Patent: WO2015/73231,2015,A1 .Location in patent: Paragraph 00340-00341
[18]Patent: WO2015/189560,2015,A1
[19]Patent: US2017/96397,2017,A1 .Location in patent: Paragraph 0093

6
[ 4916-29-4 ]
[ 13721-01-2 ]

Reference： [1]Heterocycles,1999,vol. 51,p. 2377 - 2384

7
[ 61707-75-3 ]
[ 13721-01-2 ]

Reference： [1]Heterocycles,1999,vol. 51,p. 2377 - 2384

8
[ 61707-70-8 ]
[ 13721-01-2 ]

Reference： [1]Heterocycles,1999,vol. 51,p. 2377 - 2384

9
[ 62-53-3 ]
Wang resin-bound styrene 4 [ No CAS ]
[ 13721-01-2 ]

Reference： [1]Heterocycles,1999,vol. 51,p. 2377 - 2384

10
[ 251986-52-4 ]
[ 13721-01-2 ]

Reference： [1]Heterocycles,1999,vol. 51,p. 2377 - 2384

11
[ 13721-01-2 ]
4-Chloro-quinoline-3-carboxylic acid allylamide [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1995,vol. 43,p. 693 - 698

12
[ 13721-01-2 ]
4-o-Tolylamino-quinoline-3-carboxylic acid allylamide; hydrochloride [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1995,vol. 43,p. 693 - 698

13
[ 62-53-3 ]
p-toluenesulfonic acid-<p-amino-phenyl>-ester [ No CAS ]
[ 13721-01-2 ]

Reference： [1]Archiv der Pharmazie,1994,vol. 327,p. 129 - 132

14
[ 13721-01-2 ]
9,10,11,11a-Tetrahydro-13H-pyrrolo<1',2':1,2><1,4>diazepino<6,5-c>chinolin-7,12(7H)-dion [ No CAS ]

Reference： [1]Zeitschrift fur Naturforschung, B: Chemical Sciences,1988,vol. 43,p. 769 - 777

15
[ 4795-29-3 ]
[ 541-41-3 ]
[ 13721-01-2 ]
[ 306728-26-7 ]
N-Tetrahydrofurfuryl 4-oxo-1,4-dihydro-guinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; triethylamine; In tetrahydrofuran; ethanol; N,N-dimethyl-formamide;	EXAMPLE 2 N-Tetrahydrofurfuryl 4-oxo-1,4-dihydro-guinoline-3-carboxamide To a solution of <strong>[13721-01-2]4-oxo-1,4-dihydro-quinoline-3-carboxylic acid</strong> (95 mg, 0.5 mmol) in a 4:1 mixture of THF:DMF (2.5 mL) and triethylamine (146 muL, 1.05 mmol) at 0° C. is added ethyl chloroformate (98 muL, 1.03 mmol). The reaction mixture is allowed to stir for 1 h before tetrahydrofurfurylamine (155 muL, 1.5 mmol) is added. The reaction mixture is stirred for 3/4 h and then allowed to warm to ambient temperature for 20 h. The mixture is subsequently poured into aqueous ammonium chloride, the THF is removed in vacuo, and the mixture is extracted with ethyl acetate. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is treated with 1N NaOH (2 mL) and ethanol (0.5 mL) at reflux for 1 h. The reaction mixture is cooled, diluted with aqueous ammonium chloride and extracted 2* with dichloromethane. The combined organic layers are dried (Na2SO4), filtered, and concentrated to give 65 mg of N-tetrahydrofurfuryl 4-oxo-1,4-dihydro-quinoline-3-carboxamide (compound 1) as a cream solid; m.p. 205-209° C.

Reference： [1]Patent: US6413956,2002,B1

16
[ 26892-90-0 ]
[ 13721-01-2 ]

Yield	Reaction Conditions	Operation in experiment
92%		4-Oxo-1,4-dihydroquinoline-3-carboxylic acid 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92%). 1H NMR (DMSO-d6) delta 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H).
92%		[0219] 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The <n="49"/>resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-l,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 %). 1H NMR (DMSO-flfe) delta 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, IH), 8.28 (d, J= 8.0 Hz, IH), 7.88 (m, IH), 7.81 (d, J = 8.4 Hz, IH), 7.60 (m, IH).
92%	With sodium hydroxide; for 2h;Reflux;	4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92%). 1H NMR (DMSO-d6) delta 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H).

		4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h under reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (A-1) as a pale white solid (10.5 g, 92%). 1H NMR (d-DMSO) delta 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H).
	With sodium hydroxide; for 2h;Reflux;	4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxidesolution (2N, 150 mL) and stirred for 2 h under reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (A-1) as a pale white solid (10.5 g, 92%).1H NMR (d-DMSO) delta 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H).
10.5 g	With sodium hydroxide; for 2h;Reflux;	4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-l,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 %). 1H NMR (DMSO-
10.5 g	With sodium hydroxide; for 2h;Reflux;	4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 %).1H NMR (DMSO-d6) delta 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).
10.5 g	With sodium hydroxide; for 2h;Reflux;	Step C: 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in a sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92%). 1H NMR (DMSO-d6) delta 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H) ppm.
10.5 g	With sodium hydroxide; for 2h;Reflux;	j00332J 4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HC1. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 %). ?H NIVIR (DMSO-d6) 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H), 8.28 (d, J= 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).
10.5 g	With sodium hydroxide; for 2h;Reflux;	4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HC1. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-l,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 %). lU NMR (DMSO-4) delta 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, = 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).
10.5 g	With sodium hydroxide; for 2h;Reflux;	4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-l,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 %). lU NMR (DMSC fc) delta 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, 7 = 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).
10.5 g	With water; sodium hydroxide; for 2h;Reflux;	4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HC1. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-l,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 %). lU NMR (DMSO-4) delta 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).
10.5 g	With sodium hydroxide; for 2h;Reflux;	4-Hydroxyquinoline-3 -carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HC1. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-l,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 %). 1H NMR (DMSO-ifc) d 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H), 8.28 (d, 7 = 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).
10.5 g	With sodium hydroxide; for 2h;Reflux;	4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HC1. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92 %). 1H NMR (DMSO-rfc) d 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, 7 = 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (m, 1H).
10.5 g	With water; sodium hydroxide; at 2℃;Reflux;	4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92%). 1H NMR (DMSO-d6) delta 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H).

Reference： [1]Patent: US2008/90864,2008,A1 .Location in patent: Page/Page column 7
[2]Patent: WO2007/79139,2007,A2 .Location in patent: Page/Page column 46; 47
[3]Patent: US2019/119253,2019,A1 .Location in patent: Paragraph 0512; 0515
[4]Patent: US2012/309758,2012,A1 .Location in patent: Page/Page column 61
[5]Patent: US2015/231142,2015,A1 .Location in patent: Paragraph 0352
[6]Patent: WO2018/64632,2018,A1 .Location in patent: Paragraph 00215; 00216
[7]Patent: WO2018/107100,2018,A1 .Location in patent: Paragraph 00234; 00235
[8]Patent: US2018/280349,2018,A1 .Location in patent: Paragraph 0097
[9]Patent: WO2019/10092,2019,A1 .Location in patent: Paragraph 00324; 00325; 00326; 00331; 00332
[10]Patent: WO2019/18353,2019,A1 .Location in patent: Paragraph 00147
[11]Patent: WO2019/18395,2019,A1 .Location in patent: Paragraph 00178
[12]Patent: WO2018/227049,2018,A1 .Location in patent: Paragraph 00206; 00207
[13]Patent: WO2019/113089,2019,A1 .Location in patent: Paragraph 00245
[14]Patent: WO2019/191620,2019,A1 .Location in patent: Paragraph 00426
[15]Patent: US2019/240197,2019,A1 .Location in patent: Paragraph 0574

17
[ 79-37-8 ]
[ 13721-01-2 ]
(4-Chloroquinoline-3-carboxylate)(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epimutilin 14-ester [ No CAS ]
[ 765222-35-3 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; N,N-dimethyl-formamide;	(a) (4-Chloroquinoline-3-carboxylate)(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epimutilin 14-ester A suspension of <strong>[13721-01-2]4-quinolone-3-carboxylic acid</strong> (189 mg) in dichloromethane (5 ml) was treated with 1 drop DMF and oxalyl chloride (0.2 ml), stirred 1.5 hours and the solvent evaporated. The residue was briefly put under vacuum to provide 4-chloroquinoline-3-carbonyl chloride as a white solid.

Reference： [1]Patent: US2004/58937,2004,A1

18
[ 13721-01-2 ]
C₁₀H₇Cl₂NO [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5261 - 5265

19
[ 13721-01-2 ]
[ 95-55-6 ]
[ 1233376-20-9 ]

Yield	Reaction Conditions	Operation in experiment
54.55%		Example 88: Synthesis of 6-(3-(benzo[d]oxazol-2-yl)-4-oxoquinolin-l(4H)-yl)-N- hydroxyhexanamide; Step-I: Preparation of 3-(benzo[d]oxazol-2-yI)quinolin-4(lH)-one; A mixture of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid ( 0.2g, 1.05 mmol), oe-aminophenol (0.138g, 1.3mmol) and polyphosphoric acid (5mL) were heated at 16O0C for 4hrs. After cooling, water was added followed by the addition of 50percent10 aqueous KOH solution (20ml). The solid that precipitated out was filtered washed with water and dried under vaccum (0.150 g, 54.55 percent yield).

Reference： [1]Patent: WO2010/73078,2010,A2 .Location in patent: Page/Page column 52

20
[ 1246213-32-0 ]
[ 13721-01-2 ]
[ 1246213-33-1 ]

Yield	Reaction Conditions	Operation in experiment
78%	With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; ethyl acetate; at 55℃; for 16h;	A 50% solution of propylphosphonic anhydride in ethyl acetate (6.5 mL, 11.0 mmol, 2.5 equiv) and pyridine (0.70 mL, 8.8 mmol, 2 equiv) were added to a suspension of powdered VII (0.82 g, 4.4 mmol, 1 equiv) and XXXVII (1.55 g, 4.4 mmol, 1 equiv) in 2-methyltetrahydrofuran (35 mL). The reaction mixture was heated at 55 C for 16 hours. The reaction mixture was cooled to room temperature and ethyl acetate (300 mL) was added. The mixture was washed with 10% sodium carbonate solution (1 x 300 mL, 1 x 200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give XXXVIII (1.80 g, 78% yield) as a tan foam that was used without purification.
		To a stirred solution of compound 26 (5.0 g, 0.026 mol) in anhydrous DMF (120 mL) was added EDCI (5.6 g, 0.029 mol), HOBT (3.8 g, 0.028 mol) and DIEA (6.6 g, 0.051 mol) at 0 0C. After stirring for 1 hour, the mixture was added dropwise a solution of compound 13 (3.0 g, 0.008 mol) in DCM (30 ml) at 0 C. The mixture was stirred at 25 C for 72 hours, and then was concentrated in vacuo. The residue was dissolved in EtOAc (225 mL) and washed with water (120 mLxl), IN HCl (120 mL) and brine, dried with Na2SO4 and concentrated in vacuo. The residue was purified via column chromatography on silica gel (1:1 EtOAc:Petroleum ether) to give compound 14 as a white solid. 1H NMR (400 MHz, CDCl3) delta 12.34 (s, IH), 11.58 (s, IH), 9.07 (s, IH), 8.42 (d, IH), 7.66 (s, IH), 7.51 (s, IH), 7.47 (s, IH), 7.39 (s, IH), 6.72 (s, IH), 4.34 (s, 2H), 3.82 (s, 3H), 3.74 (s, 3H), 1.41 (s, 9H), 1.40 (s, 6H).
		To a stirred solution of compound 26 (5.0 g, 0.026 mol) in anhydrous DMF (120 mL) was added EDCI (5.6 g, 0.029 mol), HOBT (3.8 g, 0.028 mol) and DIEA (6.6 g, 0.051 mol) at 0 0C. After stirring for 1 hour, the mixture was added dropwise a solution of compound 13 (3.0 g, 0.008 mol) in DCM (30 ml) at 0 0C. The mixture was stirred at 25 C for 72 hours, and then was concentrated in vacuo. The residue was dissolved in EtOAc (225 mL) and washed with water (120 mLxl), IN HCl (120 mL) and brine, dried with Na2SO4 and concentrated in vacuo. The residue was purified via column chromatography on silica gel (1:1 EtOAc:Petroleum ether) to give compound 14 as a white solid. 1H NMR (400 MHz, CDCl3) delta 12.34 (s, IH), 11.58 (s, IH), 9.07 (s, IH), 8.42 (d, IH), 7.66 (s, IH), 7.51 (s, IH), 7.47 (s, IH), 7.39 (s, IH), 6.72 (s, IH), 4.34 (s, 2H), 3.82 (s, 3H), 3.74 (s, 3H), 1.41 (s, 9H), 1.40 (s, 6H).

Reference： [1]Journal of Pharmacology and Experimental Therapeutics,2017,vol. 362,p. 359 - 367
[2]Patent: WO2010/108155,2010,A1 .Location in patent: Page/Page column 14; 35; 40-41
[3]Patent: WO2010/108162,2010,A1 .Location in patent: Page/Page column 65; 70-71

21
[ 1246213-40-0 ]
[ 13721-01-2 ]
N-(5-tert-butyl-3,3-dimethyl-2-oxo-2,3-dihydrobenzofuran-6-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A suspension of HATU ( 17.6 g, 46.3 mol) and compound 26 (8.36 g, 44.2 mmol) in anhydrous acetonitrile (1 L) was stirred at room temperature for 1 hour. Compound 20 (3.40 g, 14.6 mmol) was added to the suspension, and then DIEA (11.5 g, 89.0 mmol) was added dropwise. The mixture was stirred at 45 0C for 4 days. The resulting precipitate was filtered and thoroughly washed with DCM. The filtrate was concentrated to dryness and the residue was dissolved in DCM (200 mL) and washed with IN HCl (200 mLx2) followed by 5percent aqueous NaHCO3 (200 mLx3) and then brine (200 mLxl). The mixture was then dried over Na2SO4 and concentrated in vacuo. The residue was purified via column chromatography on silica gel (CH2ClVMeOH 100: 1 - >;50: l) to give compound 21 as a light yellow solid. 1H-NMR (400MHZ, DMSCM6) delta 12.96 (d J 6.4 Hz, IH); 12.1 (s, IH); 8.9 (d,76.4Hz, IH); 8.33 (d, 78Hz, IH); 7.84-7.75 (m, 2H); 7.55-7.48 (m, 3H); 1.47 (s, 6H); 1.45(s, 9H).

Reference： [1]Patent: WO2010/108155,2010,A1 .Location in patent: Page/Page column 15; 45; 48-49

22
[ 1246213-40-0 ]
[ 13721-01-2 ]
[ 1246213-41-1 ]

Yield	Reaction Conditions	Operation in experiment
		A suspension of HATU (17.6 g, 46.3 mol) and compound 26 (8.36 g, 44.2 mmol) in anhydrous acetonitrile (1 L) was stirred at room temperature for 1 hour. Compound 20 (3.40 g, 14.6 mmol) was added to the suspension, and then DIEA (11.5 g, 89.0 mmol) was added dropwise. The mixture was stirred at 45 0C for 4 days. The resulting precipitate was filtered and thoroughly washed with DCM. The filtrate was concentrated to dryness and the residue was dissolved in DCM (200 mL) and washed with IN HCl (200 mLx2) followed by 5percent aqueous NaHCO3 (200 mLx3) and then brine (200 mLxl). The mixture was then dried over Na2SO4 and concentrated in vacuo. The residue was purified via column chromatography on silica gel (CH2Cl2/Me0H 100:l-->50:l) to give compound 21 as a light yellow solid. 1H-NMR (400MHZ, OMSO-d6) delta 12.96 (d J 6.4 Hz, IH); 12.1 (s, IH); 8.9 (d,76.4Hz, IH); 8.33 (d, / 8Hz, IH); 7.84-7.75 (m, 2H); 7.55-7.48 (m, 3H); 1.47 (s, 6H); 1.45(s, 9H).

Reference： [1]Patent: WO2010/108162,2010,A1 .Location in patent: Page/Page column 75; 78-79

23
[ 1182822-31-6 ]
[ 13721-01-2 ]
[ 1246213-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine;2-propane phosphonic acid anhydride; In 2-methyltetrahydrofuran; at 47.5℃; for 8h;Product distribution / selectivity;	4-Oxo-l,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di- tert-butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P.(R). 50percent solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5 +/- 5.0 0C and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0 0C +/- 2.5 0C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (-16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), and washed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 350C (jacket temperature) and no less than 8.00C (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 35 0C (jacket temperature) and no less than 8.00C (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H2O to make a final concentration of 40 vol of 10percent H2O/CH3CN relative to the starting acid. This slurry was heated to 78.00C +/- 5.00C (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.00C +/- 5 0C over 5 hours, and filtered. The cake was washed with 0.0 0C +/- 5.0 0C CH3CN (5 vol) 4 times. The resulting solid (compound 34) was dried in a vacuum oven at 50.0 0C +/- 5.0 0C. 1H NMR (400 MHz, DMSO-<;/6) delta 12.8 (s, IH), 11.8 (s, IH), 9.2 (s, IH), 8.9 (s, IH), 8.3 (s, IH), 7.2 (s, IH), 7.9 (t, IH), 7.8 (d, IH), 7.5 (t, IH), 7.1 (s, IH), 1.4 (s, 9H), 1.4 (s, 9H).
	With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; at 47.5℃; for 8h;Product distribution / selectivity;	Preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (1) 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tert-butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P.(R). 50percent solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5+/-5.0° C. and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0° C.+/-2.5° C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), and washed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H2O to make a final concentration of 40 vol of 10percent H2O/CH3CN relative to the starting acid. This slurry was heated to 78.0° C.+/-5.0° C. (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0° C.+/-5° C. over 5 hours, and filtered. The cake was washed with 0.0° C.+/-5.0° C. CH3CN (5 vol) 4 times. The resulting solid (compound 1) was dried in a vacuum oven at 50.0° C.+/-5.0° C. 1H NMR (400 MHz, DMSO-d6) delta 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2 (s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H).
	With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; ethyl acetate; at 45 - 50℃; for 15h;	Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2- MeTHF (4.0 vol., relative to Compound A) was added followed by T3P® 50percent solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0 °C and held at thistemperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0 °C +/- 5.0 °C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2- MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0 °C +/- 5 °C from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0percent w/w. The solution was cooled to 20.0 °C +/- 5.0 °C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HC1 / H20 (10.0 vol.), and washed with 0.1 N HC1 (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0 °C +/- 5.0 °C under reduced pressure to 20 vol. CCN was added to 40 vol. and the solution concentrated at 25.0 °C +/- 5.0 °C to 20 vol. The addition of CCN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H20 to make a final concentration of 40 vol. of 10percent H2O/CH3CN relative to Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0 °C +/- 5 °C and filtered. The cake was washed with CH3CN (5 vol.) 2 times. The resulting solid was dried in a vacuum oven at 50.0 °C +/- 5.0 °C until a constant weight is attained

	With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; at 47.5℃; for 8h;	4-Oxo-l ,4-dihydroquinoline-3-carboxylic acid (26) (1.0 eq) and 5-amino-2,4-di-tert- butylphenyl methyl carbonate (32) (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P® 50percent solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5 +/- 5.0 °C and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0 °C +/- 2.5 °C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (-16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methano lysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), and washed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 45 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 45 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H20 to make a final concentration of 40 vol of 10percent H20/CH3CN relative to the starting acid. This slurry was heated to 78.0 °C +/- 5.0 °C (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0 °C +/- 5 °C over 5 hours, and filtered. The cake was washed with 0.0 °C +/- 5.0 °C CH3CN (5 vol) 4 times. The resulting solid (Compound 1) was dried in a vacuum oven at no more than 50.0 °C. 1H NMR (400 MHz, DMSO-< ) delta 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2 (s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H).
	With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; ethyl acetate; at 45 - 50℃; for 15h;	Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P® 50percent solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0° C. and held at this temperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0° C.+/-5.0° C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0° C.+/-5° C. from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0percent w/w. The solution was cooled to 20.0° C.+/-5.0° C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl/H2O (10.0 vol.), and washed with 0.1; N HCl (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0° C.+/-5.0° C. under reduced pressure to 20 vol. CH3CN was added to 40 vol. and the solution concentrated at 25.0° C.+/-5.0° C. to 20 vol. The addition of CH3CN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H2O to make a final concentration of 40 vol. of 10percent H2O/CH3CN relative to Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0° C.+/-5° C. and filtered. The cake was washed with CH3CN (5 vol.)2 times. The resulting solid was dried in a vacuum oven at 50.0° C.+/-5.0° C. until a constant weight is attained.
	With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; at 47.5℃; for 8h;	[00339] 4-0xo-1,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tertbutylphenylmethyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P® 50percent solution in 2-MeTHF (1.7 eq). The T3P chargedvessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resultingsuspension was heated to 47.5 +/- 5.0 oc and held at this temperature for 8 hours. A sample wastaken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to25.0 oc +/- 2.5 °C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixturewas washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume ofreaction to 40.0 vol (~16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv)to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked forcompletion by HPLC. Once complete, the reaction was quenched with 1 N HCl (10.0 vol), andwashed with 0.1 N HCl (10.0 vol). The organic solution was polish filtered to remove anyparticulates and placed in a second reactor. The filtered solution was concentrated at no morethan 35 oc (jacket temperature) and no less than 8.0 oc (internal reaction temperature) underreduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at nomore than 35 oc (jacket temperature) and no less than 8.0 oc (internal reaction temperature) to 20vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0vol of CH3CN was added followed by 4.0 vol of H20 to make a final concentration of 40 vol of10percent H20/CH3CN relative to the starting acid. This slurry was heated to 78.0 oc +/- 5.0 oc(reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0 oc +/-5 oc over 5 hours, and filtered. The cake was washed with 0.0 oc +/- 5.0 oc CH3CN (5 vol) 4times. The resulting solid (Compound 2) was dried in a vacuum oven at 50.0 oc +/- 5.0 °C. 1HNMR ( 400 MHz, DMSO-d6) 8 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2(s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H).
	With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; ethyl acetate; at 45 - 50℃; for 15h;	Compound (VII), Form XX Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P® 50percent solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0°C and held at this temperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0°C +/- 5.0°C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0°C +/- 5°C from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0percent w/w. The solution was cooled to 20.0°C +/- 5.0°C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl / H2O (10.0 vol.), and washed with 0.1 N HCl (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0°C +/- 5.0°C under reduced pressure to 20 vol. CCN was added to 40 vol. and the solution concentrated at 25.0°C +/- 5.0°C to 20 vol. The addition of CCN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H20 to make a final concentration of 40 vol. of 10percent H2O/CH3CN relative to Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0°C +/- 5°C and filtered. The cake was washed with CH3CN (5 vol.) 2 times. The resulting solid was dried in a vacuum oven at 50.0°C +/- 5.0°C until a constant weight is attained.
	With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; at 42.5 - 52.5℃; for 8h;	[00354] 4-Oxo-l ,4-dihydroquinoline-3-carboxylic acid, 26, (1.0 eq) and 5-amino-2,4-di-tert- butylphenyl methyl carbonate, 32, (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative l iotaupsilon to the acid) was added followed by T3P® 50percent solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5 +/- 5.0 °C and held at this temperature for 8 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 25.0 °C +/- 2.5 °C. 2-MeTHF was added (12.5 vol) to dilute the mixture. The reaction mixture was washed with water (10.0 vol) 2 times. 2-MeTHF was added to bring the total volume of reaction to 40.0 vol (-16.5 vol charged). To this solution was added NaOMe/MeOH (1.7 equiv) to perform the methanolysis. The reaction was stirred for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HC1 (10.0 vol), and washed with 0.1 N HC1 (10.0 vol). The organic solution was polish filtered to remove any particulates and placed in a second reactor. The filtered solution was concentrated at no more than 35 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) under reduced pressure to 20 vol. CH3CN was added to 40 vol and the solution concentrated at no more than 35 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) to 20 vol. The addition of CH3CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH3CN was added followed by 4.0 vol of H20 to make a final concentration of 40 vol of 10percent H20/CH3CN relative to the starting acid. This slurry was heated to 78.0 °C +/- 5.0 °C (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0 °C +/- 5 °C over 5 hours, and filtered. The cake was washed with 0.0 °C +/- 5.0 °C CH3CN (5 vol) 4 times. The resulting solid (Compound 2) was dried in a vacuum oven at 50.0 °C +/- 5.0 °C. NMR (400 MHz, DMSO-d6) delta 12.8 (s, 1H), 11.8 (s, 1H), 9.2 (s, 1H), 8.9 (s, 1H), 8.3 (s, 1H), 7.2 (s, 1H), 7.9 (t, 1H), 7.8 (d, 1H), 7.5 (t, 1H), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H).
	With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; at 47.5℃; for 8h;	4-Oxo-1,4-dihydroquinoline-3-carboxylic acid 26 (1.0 eq) and 5-amino-2,4-di-tert-butylphenyl methyl carbonate 32 (1.1 eq) were charged to a reactor. 2-MeTHF (4.0 vol, relative to the acid) was added followed by T3P® 50percent solution in 2-MeTHF (1.7 eq). The T3P charged vessel was washed with 2-MeTHF (0.6 vol). Pyridine (2.0 eq) was then added, and the resulting suspension was heated to 47.5+/?5.0° C. and held at this temperature for 8 hours.
	With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; at 45 - 50℃; for 15h;	(0444) Compound 1 was prepared as described in WO 2010/18162, US 2010/0267768 and U.S. Pat. No. 8,476,442, which are incorporated by reference herein. The preparation is also described below. (0445) Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P® 50percent solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0° C. and held at this temperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0° C.+/?5.0° C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (?16.5 vol. charged). Residual water was removed by continuous distillation at 35.0° C.+/?5° C. from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0percent w/w. The solution was cooled to 20.0° C.+/?5.0° C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HCl/H2O (10.0 vol.), and washed with 0.1 N HCl (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0° C.+/?5.0° C. under reduced pressure to 20 vol. CH3CN was added to 40 vol. and the solution concentrated at 25.0° C.+1-5.0° C. to 20 vol. The addition of CH3CN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H2O to make a final concentration of 40 vol. of 10percent H2O/CH3CN relative to Compound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0° C.+/?5° C. and filtered. The cake was washed with CH3CN (5 vol.) 2 times. The resulting solid was dried in a vacuum oven at 50.0° C.+/?5.0° C. until a constant weight is attained.
	With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In 2-methyltetrahydrofuran; ethyl acetate; at 45 - 50℃; for 15h;	[003931 Compound A (1.0 eq.) and Compound B (1.1 eq.) were charged to a reactor. 2-MeTHF (4.0 vol., relative to Compound A) was added followed by T3P® 50percent solution in EtOAc (2.5 eq.). The T3P charge vessel was washed with 2-MeTHF (3.5 vol.). Pyridine (2.0 eq.) was then charged. The resulting suspension was heated to 45.0 to 50.0 °C and held at this temperature for 15 hours. A sample was taken and checked for completion by HPLC. Once complete, the resulting mixture was cooled to 20.0 °C +1- 5.0 °C. 2-MeTHF was charged (12.5 vol.) to dilute the mixture. The reaction mixture was washed with water (10.0 vol.) 3 times. 2-MeTHF was charged to bring the total volume of reaction to 40.0 vol. (-16.5 vol. charged). Residual water was removed by continuous distillation at 35.0 °C +1- 5 °C from 40 vol. to 30 vol. with 2-MeTHF until in-process control testing using the Karl Fisher method shows the water content to be no more than 1.0percent w/w. The solution was cooled to 20.0 °C +1- 5.0 °C. To this solution was charged NaOMe/MeOH (1.7 equiv) to perform the hydrolysis of the carbonate. The reaction was stirred for no less than 1.0 hours, and checked for completion by HPLC. Once complete, the reaction was quenched with 1 N HC1 / H20 (10.0 vol.), and washed with 0.1 N HC1 (10.0 vol.). The organic solution was polish filtered to remove any particulates and placed in a second flask. The filtered solution was concentrated at 25.0 °C +1- 5.0 °C under reduced pressure to 20 vol. CH3CN was added to 40 vol. and the solution concentrated at 25.0 °C +I5.0 °C to 20 vol. The addition of CH3CN and concentration was repeated 2 more times for a total of 3 additions of CH3CN and 4 concentrations to 20 vol. After the final concentration to 20 vol., 16.0 vol. of CH3CN was charged followed by 4.0 vol. of H2O to make a final concentration of 40 vol. of 10percent H20/CH3CN relative toCompound A. This slurry was refluxed for 5 hours. The slurry was cooled to 20.0 °C +1- 5 °C and filtered. The cake was washed with CH3CN (5 vol.) 2 times. The resulting solid was dried in a vacuum oven at 50.0 °C +I. 5.0 °C until a constant weight is attained.

Reference： [1]Patent: WO2010/108162,2010,A1 .Location in patent: Page/Page column 86; 89-90
[2]Patent: US2011/230519,2011,A1 .Location in patent: Page/Page column 19
[3]Patent: WO2013/158121,2013,A1 .Location in patent: Page/Page column 53; 54
[4]Patent: WO2013/67410,2013,A1 .Location in patent: Paragraph 0096
[5]Patent: US2013/281487,2013,A1 .Location in patent: Paragraph 00581; 00582
[6]Patent: WO2014/71122,2014,A1 .Location in patent: Paragraph 00156; 00328; 00338; 00339
[7]Patent: EP2815749,2014,A1 .Location in patent: Paragraph 0239; 0240
[8]Patent: WO2015/73231,2015,A1 .Location in patent: Paragraph 00353-00354
[9]Patent: US2015/231142,2015,A1 .Location in patent: Paragraph 0904
[10]Patent: US2016/96807,2016,A1 .Location in patent: Paragraph 0444-0445
[11]Patent: WO2016/57730,2016,A1 .Location in patent: Paragraph 00392; 00393

24
[ 62-53-3 ]
[ 13721-01-2 ]

Reference： [1]Patent: US2011/230519,2011,A1
[2]Patent: US2012/309758,2012,A1
[3]Patent: WO2013/67410,2013,A1
[4]Patent: WO2013/185112,2013,A1
[5]Patent: WO2014/71122,2014,A1
[6]Journal of Medicinal Chemistry,2014,vol. 57,p. 5405 - 5418
[7]Patent: WO2014/118805,2014,A1
[8]Patent: WO2015/73231,2015,A1
[9]Patent: US2015/231142,2015,A1
[10]Patent: WO2015/189560,2015,A1
[11]Medicinal Chemistry Research,2016,vol. 25,p. 1861 - 1876
[12]Patent: WO2007/79139,2007,A2
[13]Patent: WO2018/64632,2018,A1
[14]Patent: US2017/96397,2017,A1
[15]Patent: WO2018/227049,2018,A1
[16]Patent: US2019/240197,2019,A1

25
[ 1413431-28-3 ]
[ 13721-01-2 ]
[ 1413430-93-9 ]

Yield	Reaction Conditions	Operation in experiment
36%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;	Step 5. N-(2.4-Di-(tert-butyl-do )-3.6-dz-5-hvdroxyphenyl)-4-oxo- 1.4- dihydroquinoline-3-carboxamide (Compound 110). To a solution of 22 (250 mg, 1.04 mmol), 4-oxo- l,4-dihydroquinoline-3-carboxylic acid (23, purchased from Matrix Scientific, 98.0 mg, 0.518 mmol) and N,N-diisopropylethylamine (181 xL, 1.04 mmol) in DMF (5.00 mL) was added HATU (197 mg, 0.518 mmol). The reaction mixture was stirred at room temperature for 3 hours then was diluted with saturated aHC03 and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (3 x 20 mL), dried (Na2S04), filtered and concentrated in vacuo. The resulting residue was purified via column chromatography (S1O2, 0-70percent ethyl acetate/heptanes) to afford Compound 110 (77.0 mg, 36percent Yield) as a white solid. JH NMR (d6-DMSO, 400 MHz): delta 12.87 (br s, 1H), 1 1.80 (s, 1H), 9.18 (s, 1H), 8.86 (s, 1H), 8.32 (d, / = 8.2 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.76 (t, 7 = 8.2 Hz, 1H), 7.51 (t, / = 7.4 Hz, 1H), 7.10 (s, 0.2H); MS (ESI) 413.5 [(M+H)+]. The 3/4 NMR signal at 7.10 ppm indicates approximately 80percent deuterium incorporation at one of the two deuterated aryl positions. The absence of signals at 7.20 ppm and 1.37 ppm indicate high levels of incorporation (>95percent) at the remaining deuterated positions.
36%	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℃; for 3h;	22 (250 mg, 1.04 mmol), 4- oxo-1,4-dihydroquinoline-3-carboxylic acid (23, purchased from Matrix Scientific, 98.0 mg, 0.518 mmol) and N, N- diisopropylethylamine (181 [mu] L, 1.04 Mmol) in DMF (5.00 mL) was added HATU (197 mg, 0.518 mmol). The reaction mixture was stirred at room temperature for 3 h, then diluted with saturated NaHCO 3 and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with water (3 × 20 mL), dried (Na 2 SO 4), filtered and dried under vacuum. Purification by resulting residue was purified by column chromatography (SiO2,0-70percent ethyl acetate / heptane) to give compound 110 (77.0 mg, 36percent yield) as a white solid. * 1 H NMR signal at 7.10 ppm indicates that the incorporation of deuterium in one of the two deuterated positions of aryl is about 80percent. 95">The absence of signals at 7.20 ppm and 1.37 ppm indicates that the level of incorporation at the remaining deuterated positions is high (> 95percent).
36%	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℃; for 3h;	22 (250 mg, 1.04 mmol),4-Oxo-1,4-dihydroquinoline-3-carboxylic acid(23, purchased from Matrix Scientific, 98.0 mg, 0.518 mmol)And N, N-diisopropylethylamine(187 muL, 1.04 mmol) in DMF (5.00 mL) was added HATU (197 mg, 0.518 mmol).The reaction mixture was stirred at room temperature for 3 hours,Then diluted with saturated NaHCO 3, extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with water (3 x 20 mL)Washed with water, dried (Na 2 SO 4), filtered,And dried under vacuum.The resulting residue was purified by column chromatography(SiO2, 0-70percent ethyl acetate / heptane)To give Compound 110(77.0 mg, yield 36percent) as a white solid.

36%	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℃; for 3h;	To 22 (250 mg, 1.04 mmol), <strong>[13721-01-2]4-oxo-1,4-dihydroquinoline-3-carboxylic acid</strong> (23, available from Matrix Scientific, 98.0 mg, 0.518 mmol), a solution of N,N-diisopropylethylamine (181 muL, 1.04 mmol) in DMF (5.00 mL) and HATU (197 mg, 0.518 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. It was then diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (3×20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue obtained was subjected to column chromatography (SiO2, 0-70percent ethyl acetate / heptane) to obtain the pure compound 110 as a white solid (77.0mg, 36percent yield).
36%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;	22 (250 mg, 1.04 mmol),A solution of <strong>[13721-01-2]4-oxo-1,4-dihydroquinoline-3-carboxylic acid</strong> (23, purchased from Matrix Scientific, 98.0 mg, 0.518 mmol) and N, N- diisopropylethylamine (181 muL, 1.04 mmol) in DMF Was added HATU (197 mg, 0.518 mmol). The reaction mixture was stirred at room temperature for 3 hours,Then diluted with saturated NaHCO 3,And extracted with ethyl acetate (3 x 50 mL).The combined organic extracts were washed with water (3 × 20 mL)Dried (Na 2 SO 4), filtered and dried under vacuum.The obtained residue was purified by column chromatography (SiO 2, 0 to 70percent ethyl acetate / heptane)Compound 110 (77.0 mg, yield 36percent) was obtained as a white solid.

Reference： [1]Patent: WO2012/158885,2012,A1 .Location in patent: Page/Page column 21; 23-24
[2]Patent: JP6146990,2017,B2 .Location in patent: Paragraph 0096; 0101
[3]Patent: JP2017/105824,2017,A .Location in patent: Paragraph 0096; 0101
[4]Patent: CN103833630,2018,B .Location in patent: Paragraph 0127; 0131; 0136
[5]Patent: JP2018/188474,2018,A .Location in patent: Paragraph 0096; 0101

26
[ 13721-01-2 ]
[ 62-53-3 ]
[ 857208-58-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;	To a solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (19 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol) and DIEA (34.9 muL, 0.2 mmol) in DMF (1 mL) was added aniline (18.2 muL, 0.2 mmol) and the reaction mixture was stirred at room temperature for 3 h. The resulting solution was filtered and purified by HPLC (10-99percent CH3CN/H2O) to yield 4-oxo-N-phenyl-1H-quinoline-3-carboxamide (215) (12 mg, 45percent). 1H NMR (400 MHz, DMSO-d6) delta 12.97 (s, 1H), 12.50 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J=8.1, 1.1 Hz, 1H), 7.83 (t, J=8.3 Hz, 1H), 7.75 (m, 3H), 7.55 (t, J=8.1 Hz, 1H), 7.37 (t, J=7.9 Hz, 2H), 7.10 (t, J=6.8 Hz, 1H); HPLC ret. time 3.02 min, 10-99percent CH3CN, 5 min run; ESI-MS 265.1 m/z (MH+).
45%	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℃; for 3h;	To a solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (19 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol) and DIEA (34.9 muL, 0.2 mmol) in DMF (1 mL) was added aniline (18.2 muL, 0.2 mmol) and the reaction mixture was stirred at room temperature for 3 h. The resulting solution was filtered and purified by HPLC (10-99percent CH3CN/H2O) to yield 4-oxo-N-phenyl-1H-quinoline-3-carboxamide (215) (12 mg, 45percent). 1H NMR (400 MHz, DMSO-d6) delta 12.97 (s, 1H), 12.50 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J=8.1, 1.1 Hz, 1H), 7.83 (t, J=8.3 Hz, 1H), 7.75 (m, 3H), 7.55 (t, J=8.1 Hz, 1H), 7.37 (t, J=7.9 Hz, 2H), 7.10 (t, J=6.8 Hz, 1H); HPLC ret. time 3.02 min, 10-99percent CH3CN, 5 min run; ESI-MS 265.1 m/z (MH+).

Reference： [1]Patent: US2012/309758,2012,A1 .Location in patent: Page/Page column 119
[2]Patent: US2015/231142,2015,A1 .Location in patent: Paragraph 0738

27
[ 100-39-0 ]
[ 13721-01-2 ]
[ 35975-86-1 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5405 - 5418

28
[ 13721-01-2 ]
[ 824-94-2 ]
1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5405 - 5418

29
C₁₂H₉BrO₂ [ No CAS ]
[ 13721-01-2 ]
[ 1613052-76-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5405 - 5418

30
[ 13721-01-2 ]
4-(bromomethyl)benzene-1-sulfonyl fluoride [ No CAS ]
[ 1613052-75-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 5405 - 5418

31
[ 108-88-3 ]
[ 13721-01-2 ]

Reference： [1]Patent: US2014/221424,2014,A1

32
[ 134-84-9 ]
[ 13721-01-2 ]
1-(4-benzoylbenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [ No CAS ]