13721-01-2|4-Oxo-1,4-dihydroquinoline-3-carboxylic acid| Ambeed

Structure of 13721-01-2

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Quality Control of [ 13721-01-2 ] Purity: 97% SDS Specification

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Product Details of [ 13721-01-2 ]

CAS No. :	13721-01-2
Formula :	C₁₀H₇NO₃
M.W :	189.17
SMILES Code :	OC(=O)C1=CNC2=C(C=CC=C2)C1=O
MDL No. :	MFCD00498984
InChI Key :	ILNJBIQQAIIMEY-UHFFFAOYSA-N
Pubchem ID :	220875

Safety of [ 13721-01-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 13721-01-2 ] Show Less

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 ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	70.16 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.75
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	1.84
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.23
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.41
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.94
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.23

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.63
Solubility	0.439 mg/ml ; 0.00232 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.	-2.93
Solubility	0.22 mg/ml ; 0.00116 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	-2.98
Solubility	0.197 mg/ml ; 0.00104 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.15 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

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)	1.39

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.

Downstream synthetic route of [ 13721-01-2 ]

[ 13721-01-2 ] Synthesis Path-Downstream 1~35

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

References: [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.

References: [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 ]

References: [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).

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

5
[ 61707-79-7 ]
[ 13721-01-2 ]

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

Yield	Reaction Conditions	Operation in experiment
		(b) 800 mg of a 60percent sodium hydride-in-oil suspension is slowly added to a solution of 2.03 g methyl N-(2-fluorophenyl) iminochlorothioformate (4) (R=H) and 4.34 g ketoester (3) (R11=C2H5). The mixture is then heated at reflux for 24 hours. It is then cooled and evaporated under reduced pressure to dryness. The residue is dissolved in methylene chloride and washed with saturated sodium chloride solution. Organic layer is separated and dried over magnesium sulfate. The product is purified through silica gel column yielding the 1,4-dihydro-4-oxo-quinoline-3-carboxylate (5) (R11=C2H5, R=H).
		(b) 800 mg of a 60percent sodium hydride-in-oil suspension is slowly added to a solution of 2.03 g methyl N-(2-fluorophenyl) iminochlorothioformate (4') (R=H) and 4.34 g ketoester (3') (R11=C2H5). The mixture is then heated at reflux for 24 hours. It is then cooled and evaporated under reduced pressure to dryness. The residue is dissolved in methylene chloride and washed with saturated sodium chloride solution. Organic layer is separated and dried over magnesium sulfate. The product is purified through silica gel column yielding the 1,4-dihydro-4-oxo-quinoline -3-carboxylate (5') (R11=C2H5, R=H).
		Preparation 3 4-Quinolone-3-carboxylic Acid A suspension of ethyl 4-quinolone-3-carboxylate (900 mg) (Maybridge Chemical Co. Ltd) in dioxan (6 ml)/water (6 ml) was treated with 40percent NaOH solution (8 ml) and refluxed 6 hours. The solution was cooled, acidified to pH2 with conc. HCl and the solid filtered off and dried under vacuum in the presence of P2O5 to provide the title compound (785 mg). MS (-ve ion chemical ionisation) m/z188([M-H]-, 100percent).

		(b) (4-Quinolone-3-carboxylic acid) mutilin 14-ester The material from step (a) in dioxan (10 ml) was treated with conc. HCl (5 ml) and left overnight. The solution was diluted with EtOAc (20 ml) and water (20 ml) and treated with solid NaHCO3 until basic. The layers were shaken and separated, the organic dried and evaporated. The residue was triturated under ether and the white solid filtered off and washed with ether to give the title compound (35 mg). MS (-ve ion electrospray) 490 ([M-H]-, 100percent).
	With 10 wt% Pd(OH)2 on carbon; hydrogen; In ethanol; for 12h;	General procedure: Compound 1d (887 mg, 2.9 mmol) was dissolved in 50 ml of ethanol,80 mg of palladium hydroxide was added,And stirred for 12 h in a hydrogen atmosphere.The palladium-carbon was removed by filtration,Recrystallization from ethyl acetate gave the off-white powder 1e (550 mg, 89percent).

7
[ 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).

References: [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.

8
[ 54535-22-7 ]
[ 13721-01-2 ]

References: [1]Chemical Communications,2005,p. 5438 - 5440.
[2]Journal of Medicinal Chemistry,2006,vol. 49,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,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,p. 1861 - 1876.
[13]Patent: WO2007/79139,2007,A2 .
[14]Patent: US2011/98311,2011,A1 .
[15]Patent: WO2018/64632,2018,A1 .
[16]Patent: US2017/96397,2017,A1 .
[17]Patent: WO2018/227049,2018,A1 .
[18]Patent: US2019/240197,2019,A1 .

9
[ 4916-29-4 ]
[ 13721-01-2 ]

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

10
[ 61707-75-3 ]
[ 13721-01-2 ]

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

11
[ 61707-70-8 ]
[ 13721-01-2 ]

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

12
[ 62-53-3 ]
Wang resin-bound styrene 4 [ No CAS ]
[ 13721-01-2 ]

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

13
[ 251986-52-4 ]
[ 13721-01-2 ]

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

14
[ 13721-01-2 ]
4-Chloro-quinoline-3-carboxylic acid allylamide [ No CAS ]

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

15
[ 13721-01-2 ]
4-o-Tolylamino-quinoline-3-carboxylic acid allylamide; hydrochloride [ No CAS ]

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

16
[ 62-53-3 ]
p-toluenesulfonic acid-<p-amino-phenyl>-ester [ No CAS ]
[ 13721-01-2 ]

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

17
[ 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 ]

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

18
[ 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.

References: [1]Patent: US6413956,2002,B1 .

19
[ 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).

References: [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.

20
[ 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.

References: [1]Patent: US2004/58937,2004,A1 .

21
[ 13721-01-2 ]
C₁₀H₇Cl₂NO [ No CAS ]

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

22
[ 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).

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

23
[ 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).

References: [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.

24
[ 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).

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

25
[ 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).

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

26
[ 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.

References: [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.

27
[ 134271-94-6 ]
[ 1182822-31-6 ]
T₃P [ No CAS ]
[ 13721-01-2 ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; hydrogenchloride; sodium methylate; In methanol; water; acetonitrile;	An alternative synthesis of Compound 1 is depicted in Scheme 1-7.4-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 20° C.+/-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 and 2-MeTHF (16.5 vol) was charged to the reactor.This solution was charged with 30percent w/w NaOMe/MeOH (1.7 equiv) to perform the methanolysis.The reaction was stirred at 25.0° C.+/-5.0° C. for no less than 1.0 hour, and checked for completion by HPLC. Once complete, the reaction was quenched with 1.2 N HCl/H2O (10.0 vol), and washed with 0.1 N HCl/H2O (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 charged 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 20 to 25° C. over 5 hours, and filtered.The cake was washed with CH3CN (5 vol) heated to 20 to 25° C. 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; hydrogenchloride; sodium methylate; In methanol; water; acetonitrile;	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).

References: [1]Patent: US2011/98311,2011,A1 .
[2]Patent: US2011/98311,2011,A1 .

28
[ 26892-90-0 ]
[ 34785-11-0 ]
[ 13721-01-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	In sodium hydroxide;	A-1; 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid4-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, 92percent).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).

References: [1]Patent: US2011/98311,2011,A1 .

29
[ 62-53-3 ]
[ 13721-01-2 ]

References: [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 .

30
[ 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.

References: [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.

31
[ 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+).

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

32
[ 1182822-31-6 ]
[ 13721-01-2 ]
[ 873054-44-5 ]

Yield	Reaction Conditions	Operation in experiment
		4-Oxo-l,4-dihydroqiiinoline-3-carboxylic acid (26) (1.0 eq) and 5-amino-2,4-di-tert- butylphenyl methyl carbonate (32) (L I eq) were charged to a reactor, 2- eTHF (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 addedNaOMe/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 45 °C (jacket temperature) and no less than 8.0 °C (internal reaction temperature) under reduced pressure to 20 vol, CCN 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 CCN 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 0 to make a final concentration of 40 vol of 10percent H?Q/CCN 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. H NMR (400 MHz, DMSO-rf6) delta 12.8 (s, lH), 1 1 ,8 (s, lH), 9.2 (s, I H), 8.9 (s, 1H), 8.3 (s, IH), 7.2 (s, 1H), 7.9 (t, IH), 7.8 (d, IH), 7.5 (t, lH), 7.1 (s, 1H), 1.4 (s, 9H), 1.4 (s, 9H).
		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. 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 1N HCl (10.0 vol), and washed with 0.1N 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 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 (Ivacaftor) was dried in a vacuum oven at no more than 50.0° 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).
		To a solution of 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (1.0 eq) in 2-Me THE added 5-amino-2,4-di-tert-, butylphenyl methyl carbonate (1.1 eq), Propane phosphonic acid anhydride 50percent solution in 2-MeTHF (1.7 eq) was added, followed by Pyridine (2.0 eq) and the resultant suspension was heated to 45° to 50° C., and held at this same temperature for 8 to 10 hours, until completion of the reaction (checked for completion by HPLC). Once complete, the resulting mixture was cooled to 20-25° C., and 2-MeTHF (12.5 vol) was added to dilute the mixture. The reaction mixture was then washed with water (10.0 vol)., and 2-MeTHF was added to bring the total volume of the reaction to 40.0 vol. To this solution was added NaOMe/MeOH (1.7 equiv) followed by stirring for 1 to 2 hour, where the reaction was 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 filtered and the filtrate concentrated at 35° C. to obtain a residue. The residue was charged in 40:20 acetonitrile and water, the slurry was stirred for 5 to 6 hours and then cooled to 0° C. hours, followed by stirring for 2 hours. The resultant solid was filtered and dried under vacuum to obtain a title compound.

References: [1]Patent: WO2013/185112,2013,A1 .Location in patent: Paragraph 00545; 00546.
[2]Patent: WO2014/71122,2014,A1 .
[3]Patent: US2014/221424,2014,A1 .Location in patent: Paragraph 0086.
[4]Patent: EP2815749,2014,A1 .
[5]Patent: WO2015/73231,2015,A1 .
[6]Patent: US2015/231142,2015,A1 .
[7]Patent: US2017/96397,2017,A1 .Location in patent: Paragraph 0095.

33
[ 100-39-0 ]
[ 13721-01-2 ]
[ 35975-86-1 ]

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

34
[ 13721-01-2 ]
[ 824-94-2 ]
1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [ No CAS ]

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

35
C₁₂H₉BrO₂ [ No CAS ]
[ 13721-01-2 ]
[ 1613052-76-8 ]

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

Historical Records

Technical Information

• Arndt-Eistert Homologation • Baeyer-Villiger Oxidation • Barbier Coupling Reaction • Baylis-Hillman Reaction • Bucherer-Bergs Reaction • Clemmensen Reduction • Corey-Bakshi-Shibata (CBS) Reduction • Corey-Chaykovsky Reaction • Fischer Indole Synthesis • Grignard Reaction • Henry Nitroaldol Reaction • Horner-Wadsworth-Emmons Reaction • Hunsdiecker-Borodin Reaction • Hydride Reductions • Lawesson's Reagent • Leuckart-Wallach Reaction • McMurry Coupling • Meerwein-Ponndorf-Verley Reduction • Passerini Reaction • Paternò-Büchi Reaction • Petasis Reaction • Peterson Olefination • Pictet-Spengler Tetrahydroisoquinoline Synthesis • Preparation of Aldehydes and Ketones • Preparation of Amines • Preparation of Carboxylic Acids • Prins Reaction • Reactions of Aldehydes and Ketones • Reactions of Amines • Reactions of Carboxylic Acids • Reformatsky Reaction • Robinson Annulation • Schlosser Modification of the Wittig Reaction • Schmidt Reaction • Specialized Acylation Reagents-Ketenes • Stobbe Condensation • Tebbe Olefination • Ugi Reaction • Wittig Reaction • Wolff-Kishner Reduction

Related Functional Groups of
[ 13721-01-2 ]

Ketones

A402663 [52980-28-6]

Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate

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A231002 [948573-55-5]

4-Oxo-1,4-dihydroquinoline-7-carboxylic acid

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Ethyl 8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate

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A240110 [58781-08-1]

4-Oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid

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Carboxylic Acids

A231002 [948573-55-5]

4-Oxo-1,4-dihydroquinoline-7-carboxylic acid

Similarity: 0.87

A204691 [858515-65-8]

4-Methyl-1H-indole-3-carboxylic acid

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A188858 [771-50-6]

1H-Indole-3-carboxylic acid

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5-Methyl-1H-indole-3-carboxylic acid

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3-Methyl-1H-indole-4-carboxylic acid

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Related Parent Nucleus of
[ 13721-01-2 ]

Quinolines

A402663 [52980-28-6]

Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate

Similarity: 0.91

A231002 [948573-55-5]

4-Oxo-1,4-dihydroquinoline-7-carboxylic acid

Similarity: 0.87

A196439 [77156-75-3]

Ethyl 8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate

Similarity: 0.86

A124567 [863785-96-0]

Methyl 4-oxo-1,4-dihydroquinoline-7-carboxylate

Similarity: 0.84

A133847 [338747-41-4]

1-(4-Methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Similarity: 0.78

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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CAS No.: 13721-01-2

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CAS No.: 13721-01-2

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Product Details of [ 13721-01-2 ]

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Physicochemical Properties

Lipophilicity

Water Solubility

Pharmacokinetics

Druglikeness

Medicinal Chemistry

Application In Synthesis of [ 13721-01-2 ]

[ 13721-01-2 ] Synthesis Path-Downstream 1~35

Related Products

Historical Records

Technical Information

Categories

Related Functional Groups of
[ 13721-01-2 ]

Ketones

Carboxylic Acids

Related Parent Nucleus of
[ 13721-01-2 ]

Quinolines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Molarity Calculator

Total Compounds Calculator

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{[proInfo.proName]}

CAS No.: 13721-01-2

{[proInfo.proName]}

CAS No.: 13721-01-2

Alternative Products

Product Details of [ 13721-01-2 ]

Safety of [ 13721-01-2 ]

Computational Chemistry of [ 13721-01-2 ] Show Less

Physicochemical Properties

Lipophilicity

Water Solubility

Pharmacokinetics

Druglikeness

Medicinal Chemistry

Application In Synthesis of [ 13721-01-2 ]

[ 13721-01-2 ] Synthesis Path-Downstream 1~35

Related Products

Historical Records

Technical Information

Categories

Related Functional Groups of [ 13721-01-2 ]

Ketones

Carboxylic Acids

Related Parent Nucleus of [ 13721-01-2 ]

Quinolines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Molarity Calculator

Total Compounds Calculator

Dissolution Calculator

Related Functional Groups of
[ 13721-01-2 ]

Related Parent Nucleus of
[ 13721-01-2 ]