[ CAS No. 611-34-7 ] {[proInfo.proName]}

Name: 611-34-7|Quinolin-5-amine|97%
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Quality Control of [ 611-34-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 611-34-7 ]

Product Details of [ 611-34-7 ]

CAS No. :	611-34-7	MDL No. :	MFCD00006797
Formula :	C₉H₈N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XMIAFAKRAAMSGX-UHFFFAOYSA-N
M.W :	144.17	Pubchem ID :	11911
Synonyms :

Calculated chemistry of [ 611-34-7 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	46.15
TPSA :	38.91 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.36 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.38
Log Po/w (XLOGP3) :	1.16
Log Po/w (WLOGP) :	1.82
Log Po/w (MLOGP) :	1.19
Log Po/w (SILICOS-IT) :	1.77
Consensus Log Po/w :	1.47

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.14
Solubility :	1.05 mg/ml ; 0.00729 mol/l
Class :	Soluble
Log S (Ali) :	-1.57
Solubility :	3.86 mg/ml ; 0.0268 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.32
Solubility :	0.0693 mg/ml ; 0.000481 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.23

Safety of [ 611-34-7 ]

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

Application In Synthesis of [ 611-34-7 ]

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

Upstream synthesis route of [ 611-34-7 ]
Downstream synthetic route of [ 611-34-7 ]

[ 611-34-7 ] Synthesis Path-Upstream 1~11

1
[ 607-34-1 ]
[ 613-51-4 ]
[ 580-19-8 ]
[ 611-34-7 ]

Reference： [1] Patent: US6750348, 2004, B1, . Location in patent: Page column 41-42

2
[ 611-34-7 ]
[ 578-67-6 ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: With sodium hydrogen sulfate In water for 36 h; Reflux Stage #2: for 8 h; Reflux	5-(2,2,2-Trifluoroethoxy)quinoline (I-E) To a stirred solution of amine 5-aminoquinoline (5.0 g, 34.67 mmol) in H₂O (100 mL) was added sodium bisulfate (NaHSO₃; 25.2 g, 242.1 mmol) at RT, and the mixture was stirred at reflux temperature for 36 h. The resulting solution was cooled to RT, NaOH (9.7 g, 242.5 mmol) was added, and the mixture was stirred at reflux temperature for 8 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to RT and the pH was adjusted to 7.0 with 6 Normal (N) hydrochloride acid (HCl). The precipitate was filtered, washed with H₂O, and dried under high vacuum to obtain the desired alcohol M (3.2 g, 22.04 mmol, 64percent) as pale-yellow solid. ¹H NMR (500 MHz, CDCl₃): δ 8.92 (s, 1H), 8.58 (d, J=8.5 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.41 (dd, J=8.5, 4.5 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.10 (br s, 1H). MS (ESI): m/z 146 [M+H]⁺.
56%	With sulfuric acid; acetic acid; sodium nitrite In water at 0℃; for 5.5 h; Inert atmosphere; Reflux	5-aminoquinoline (15.0 g, 104.0 mmol) was dissolved in a solvent of acetic acid / water / sulfuric acid (8: 1: 1, v / v / v, 130 mL) under an argon atmosphere, and a solution of sodium nitrite (8.6 g, 124.8 mmol) dissolved therein. After the reaction mixture was stirred at 0 °C for 30 minutes, 10percent sulfuric acid solution (780 mL) was boiled, slowly added to the reaction solution, The mixture was refluxed for 5 hours, The completion of the reaction was confirmed by TLC (hexane: ethyl acetate = 2: 1). The reaction mixture was cooled to room temperature, and a saturated solution of sodium hydrogencarbonate (250 mL) was added thereto, followed by extraction with ethyl acetate (10 X 400 mL). The organic solvent layer was washed with a saturated solution of sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The concentrate was separated and purified by column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (8.5 g, 56percent yield).

Reference： [1] Patent: US2012/329802, 2012, A1, . Location in patent: Page/Page column 25-26
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 14, p. 3307 - 3312
[3] Patent: KR101778938, 2017, B1, . Location in patent: Paragraph 0147-0148; 0155; 0160-0162
[4] Journal fuer Praktische Chemie (Leipzig), 1893, vol. <2> 47, p. 431
[5] Journal of the American Chemical Society, 1946, vol. 68, p. 1562
[6] Monatshefte fuer Chemie, 1884, vol. 5, p. 532
[7] Journal fuer Praktische Chemie (Leipzig), 1893, vol. <2> 47, p. 431

3
[ 611-34-7 ]
[ 394-69-4 ]

Yield	Reaction Conditions	Operation in experiment
55%	at 0℃; for 1 h;	Preparation LIII 5-fluoro-1,2,3,4-tetrahydroquinoline [0363] 5-fluoroquinoline [0364] To a suspension of 5-aminoquinoline (50 g, 347 mmol) in 48percent HBF4 (200 mL) at 0° C. was added portionwise sodium nitrite. This was stirred for 1 hour and then poured into 1:1 ethyl acetate/diethyl ether (500 mL). The resulting suspension was filtered and the solid dried. This solid (82.5 g, 338 mmol) was added portionwise to refluxing xylene (1 L) and stirred for 2 hours then allowed to cool. The xylene was decanted off and the residue dissolved in 1N hydrochloric acid (600 mL). After neutralization with sodium carbonate, the mixture was extracted with ethyl acetate (10.x.500 mL). The extracts were dried over sodium sulfate, filtered and the volatiles removed under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10-20percent diethyl ether in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 28.1 g (55percent) of the desired compound. MS (EI, m/z) C9H6FN (M+1) 148.0 [0365] Reduction [0366] A mixture of 5-fluoroquinoline (28.1 g), 5percent palladium on carbon (5.6 g) in methanol was shaken over night at 40° C. under 60 psi hydrogen. The mixture was filtered through celite and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5-10percent ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 22.5 g (78percent) of the title compound. [0367] MS (EI, m/z) C9H10FN (M+1) 152.0
24.5%	With tetrafluoroboric acid; sodium nitrite In xylene at 0℃; Reflux	To a suspension of 5-aminoquinoline (lO.Og, 0.069 mol) in 48percent HBF₄ (40 mL) at 0°C was added portionwise sodium nitrite. This was stirred for 1 hour and then poured into 1 : 1 ethyl acetate/diethyl ether (50 mL). The resulting suspension was filtered and the solid dried. This solid was added portionwise to refluxing xylene (80 mL) and stirred for 2 hours then allowed to cool. The xylene was decanted off and the residue was dissolved in IN aqueous hydrochloric acid (100 mL). After neutralization with sodium carbonate, the mixture was extracted with ethyl acetate (3 x 80 mL). The extracts were dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel column chromatography, eluting with 2percent ethyl acetate in petroleum ether to afford 5-fluoroquinoline as a colorless oil (2.5 g, 24.5percent).'H-NMR (300 MHz, CDC1₃) δ 8.93 - 8.98 (m, 1H), 8.43 - 8.46 (m, H), 7.92 (d, / = 8.4 Hz, 1H), 7.62 - 7.78 (m, 1H), 7.41 - 7.49 (m, 1H), 7.22 - 7.26 (m, 1H)
800 mg	at 0℃; for 1 h;	To a solution of quinolin-5 -amine (2 g, 13.9 mmol) in 10 mL of 48percent HBF₄ at 0°C was added sodium nitrite (933 mg, 13.5 mmol) portionwise. This was stirred for 1 hour and then poured into 1 : 1 ethyl acetate diethyl ether mixture (50 mL). The resulting suspension was filtered and the solid was dried. This solid was added portionwise to refluxing xylene (30 mL) and stirred for 3 hours, then allowed to cool. The xylene was decanted off and the residue was dissolved in IN HC1 (50 mL). After neutralization with NaHC0₃, the mixture was extracted with ethyl acetate (3 x 50 mL). The extracts were dried over sodium sulfate, filtered and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (3percent EtOAc/PE) to afford 800 mg of title compound as colorless oil. LC-MS: m/z 148.2 (M+H)⁺

800 mg	at 0℃; for 1 h;	To a solution of quinolin-5-amine (2 g, 13.9 mmol) in 10 mL of 48percent HBF₄at 0° C. was added sodium nitrite (933 mg, 13.5 mmol) portionwise. This was stirred for 1 hour and then poured into 1:1 ethyl acetate diethyl ether mixture (50 mL). The resulting suspension was filtered and the solid was dried. This solid was added portionwise to refluxing xylene (30 mL) and stirred for 3 hours, then allowed to cool. The xylene was decanted off and the residue was dissolved in 1N HCl (50 mL). After neutralization with NaHCO₃, the mixture was extracted with ethyl acetate (3×50 mL). The extracts were dried over sodium sulfate, filtered and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (3percent EtOAc/PE) to afford 800 mg of title compound as colorless oil. LC-MS: m/z 148.2 (M+H)⁺
800 mg	at 0℃; for 1 h;	To a solution of quinolin-5 -amine (2 g, 13.9 mmol) in 10 mL of 48percent HBF₄ at 0°C was added sodium nitrite (933 mg, 13.5 mmol) portionwise. This was stirred for 1 hour and then poured into 1 : 1 ethyl acetate diethyl ether mixture (50 mL). The resulting suspension was filtered and the solid was dried. This solid was added portionwise to refluxing xylene (30 mL) and stirred for 3 hours, then allowed to cool. The xylene was decanted off and the residue was dissolved in IN HC1 (50 mL). After neutralization with NaHC0₃, the mixture was extracted with ethyl acetate (3 x 50 mL). The extracts were dried over sodium sulfate, filtered and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (3percent EtOAc/PE) to afford 800 mg of title compound as colorless oil. LC-MS: m/z 148.2 (M+H)⁺

Reference： [1] Patent: US2003/229026, 2003, A1, . Location in patent: Page 25
[2] Bioorganic and medicinal chemistry, 2002, vol. 10, # 8, p. 2611 - 2623
[3] Patent: WO2012/94462, 2012, A2, . Location in patent: Page/Page column 75
[4] Biological and Pharmaceutical Bulletin, 1997, vol. 20, # 6, p. 646 - 650
[5] Patent: WO2014/139144, 2014, A1, . Location in patent: Page/Page column 179
[6] Patent: US2014/288081, 2014, A1, . Location in patent: Paragraph 0738; 0739
[7] Patent: WO2014/139325, 2014, A1, . Location in patent: Page/Page column 192; 193
[8] Journal of Medicinal Chemistry, 2017, vol. 60, # 16, p. 6998 - 7011

4
[ 611-34-7 ]
[ 635-27-8 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: With hydrogenchloride; sodium nitrite In water at 0 - 20℃; for 0.5 h; Inert atmosphere Stage #2: With hydrogenchloride; copper(l) chloride In water at 20℃; for 24 h; Inert atmosphere	To a suspension of 5-aminoquinoline (756 mg, 5.24 mmol) in aqueous 2 N HCl (31 mL) cooled to 0 °C was added a solution of NaNO₂ (470 mg, 6.80 mmol) in H₂O (14 mL). The reaction mixture was stirred at 0 °C for 30 min and a solution of CuCl (644 mg, 6.51 mmol) in conc. HCl (16 mL) was added. The mixture was allowed to warm to room temperature and stirred for additional 24 h. Saturated NaHCO3 was slowly added to the mixture until no gas was generated. The organic phase was extracted with CH₂Cl₂(3 x 50 mL), washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (EtOAc/hexane = 1:1) to give 5-chloroquinoline 2d (579 mg, 68percent)

Reference： [1] Bioorganic and medicinal chemistry, 2002, vol. 10, # 8, p. 2611 - 2623
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1472 - 1476
[3] Patent: WO2016/86200, 2016, A1, . Location in patent: Page/Page column 235

5
[ 611-34-7 ]
[ 4964-71-0 ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: With hydrogen bromide; sodium nitrite In water at 0 - 20℃; for 0.0833333 h; Stage #2: With hydrogen bromide; copper(I) bromide In water at 20 - 75℃; for 2 h; Stage #3: With sodium hydroxide In water	PREPARATION 7 5-Bromoquinoline Quinolin-5-amine (3.37 g, 23.38 mmol) was dissolved in 9 ml of water and 11 ml of hydrogen bromide (48percent in water); the resulting solution was cooled at 0°C. Sodium nitrite (1.94 g, 28.12 mmol) dissolved in 9 ml of water was dropwise added. The resultant solution was stirred at room temperature for 5 minutes. This solution was dropwise added to a solution of copper(I) bromide (4.02 g, 28.02 mmol) in 23 mL of HBr (48percent in water) at 75°C. The resulting mixture was stirred at room temperature for 2 h. Then the reaction mixture was basified with sodium hydroxide and extracted twice with ethyl acetate. The organic phase is washed with brine, filtered and dried over sodium sulfate. After filtration and evaporation of the solvent, 2.98 g (61 percent) of the final product were obtained. ¹H NMR (CDCl3) δ ppm: 7.44 - 7.63 (m, 2 H) 7.84 (d, J=7.42 Hz, 1 H) 8.10 (d, J=8.24 Hz, 1 H) 8.56 (d, J=8.51 Hz, 1 H) 8.94 (br.s., 1H) HPLC/MS (9 min) retention time 5.68 min. LRMS: m/z 208 (M)/21 0 (M+2)
35%	Stage #1: With hydrogen bromide; sodium nitrite In water at 0 - 20℃; for 0.5 h; Inert atmosphere Stage #2: With copper(I) bromide In water at 20℃; for 3 h; Inert atmosphere	To a suspension of 5-aminoquinoline (2.11 g, 14.7 mmol) in aqueous HBr (8.6 mL, 48percent in H₂O) cooled to 0 °C was added a solution of NaNO₂ (2.58 g, 37.5 mmol) in H₂O (35 mL). The reaction mixture was stirred at 0 °C for 30 min and a solution of CuBr (2.58 g, 17.6 mmol) in H₂O (29 mL) was added. The mixture was allowed to warm to room temperature and stirred for additional 3 h. 4 N NaOH was slowly added to the mixture until pH reached to about 10. The organic phase was extracted with EtOAc (3 x 75 mL), washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (EtOAc/hexane = 1:1) to give 5-bromoquinoline 2e (1.08 g, 35percent)
80%	With sodium nitrite In water; hydrogen bromide	5-Bromo-quinoline Sodium nitrite (2.5 g, 41.8 mmol) was dissolved in 15 mL water. Copper (I) bromide (6.0 g, 41.8 mmol) was dissolved in 38 mL of 48percent HBr and heated to 75° C. The 5-aminoquinoline (5.0 g, 34.7 mmol) was suspended in 15 mL water and 18 mL 48percent HBr and cooled to 0° C. The sodium nitrite solution was added to the 5-aminoquinoline solution at 0° C. The resulting diazonium solution was added slowly to the warmed CuBr solution. The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was basified with sodium hydroxide, then filtered through celite. The solid was washed with methylene chloride, and the aqueous material was extracted with methylene chloride. The organic layers were combined, dried with Na₂SO₄, and concentrated in vacuo. The crude product was chromatographed with 2:1 hexane/ethyl acetate to yield 5.7 g (80percent) of 5-bromo-quinoline as a yellow oil. MS (APCI) m/z 208.0 (M+1).

Reference： [1] Bioorganic and medicinal chemistry, 2002, vol. 10, # 8, p. 2611 - 2623
[2] Patent: EP2394998, 2011, A1, . Location in patent: Page/Page column 16
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1472 - 1476
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 1994, vol. 34, # 10, p. 905 - 913
[5] Patent: US2003/96826, 2003, A1,
[6] Patent: US2002/6923, 2002, A1,

6
[ 611-34-7 ]
[ 10470-83-4 ]

Reference： [1] Tetrahedron Letters, 1990, vol. 31, # 34, p. 4871 - 4872
[2] Tetrahedron Letters, 1990, vol. 31, # 34, p. 4871 - 4872

7
[ 611-34-7 ]
[ 6931-19-7 ]

Reference： [1] Patent: KR101778938, 2017, B1,

8
[ 611-34-7 ]
[ 59412-12-3 ]

Reference： [1] Bioorganic and medicinal chemistry, 2002, vol. 10, # 8, p. 2611 - 2623
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1472 - 1476

9
[ 611-34-7 ]
[ 160893-07-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 14, p. 3307 - 3312
[2] Patent: KR101778938, 2017, B1,

10
[ 611-34-7 ]
[ 160893-04-9 ]

Reference： [1] Patent: KR101778938, 2017, B1,

11
[ 611-34-7 ]
[ 355386-94-6 ]

Reference： [1] Patent: US2002/19527, 2002, A1,

[ 611-34-7 ] Synthesis Path-Downstream 1~88

1
[ 611-34-7 ]
[ 79-04-9 ]
[ 121221-08-7 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate In dichloromethane at 0 - 20℃; for 3h;	2-chloro-N-(quinolin-5-yl)acetamide (51) To a stirring suspension of 5-aminoquinoline (28.8 mg, 0.2 mmcl, 1 equiv.) and potassium carbonate (82.9 mg, 0.6 minol, 3 equiv.) in anhydrous CH2CI2 (3 mL) at 0 °C was added chioroacetyl chloride (24 iL, 1.5 equiv.). The reaetion was allowed to slowly warm up to room temperature. After 3 hours, the mixture was filtered, washed with EtOAc (10 mL) and CH2C12 (10 mL). The solid cake was then eluted with MeOH (20 mL) and the f1trate concentrated in vacuo. The residue was taken up in 10% MeOH / CH2C12 and passed through a pad of silica to provide the title compound as an off-white solid (42.6 mg, 82%). ‘H NME. (500 MHz, CDC13) 8 8.96 (d, J= 2.5 Hz, 111), 8.71 (s, 1H), 8.20 (d, J= 8.6 Hz, 1H), 8.04 (d, J= 8.5 liz, 1H), 7.94 (d, J=7.5 Hz, 1FI), 7.74 (t, J= 8.0 Hz, 1H), 7.48 (dd, J= 8.5, 4.2 Hz, 111), 4.35 (s, 2H); HRMS-ESI (mlz) calculated for C, ,H9C1N2O [M+H]: 221.0476; found: 221.0477.
82%	With potassium carbonate In dichloromethane at 0 - 20℃; for 3h;	1 To a stirring suspension of 5-aminoquinoline (28.8 mg, 0.2 mmol, 1 equiv.) and potassium carbonate (82.9 mg, 0.6 mmol, 3 equiv.) in anhydrous CH2Cl2 (3 mL) at 0 °C was added chloroacetyl chloride (24 µL, 1.5 equiv.). The reaction was allowed to slowly warm up to room temperature. After 3 hours, the mixture was filtered, washed with EtOAc (10 mL) and CH2Cl2 (10 mL). The solid cake was then eluted with MeOH (20 mL) and the filtrate concentrated in vacuo. The residue was taken up in 10% MeOH / CH2Cl2 and passed through a pad of silica to provide the title compound as an off-white solid (42.6 mg, 82%).1H NMR (500 MHz, CDCl3) δ 8.96 (d, J = 2.5 Hz, 1H), 8.71 (s, 1H), 8.20 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.48 (dd, J = 8.5, 4.2 Hz, 1H), 4.35 (s, 2H); HRMS-ESI (m/z) calculated for C11H9ClN2O [M+H]: 221.0476; found: 221.0477. 1
20%	With triethylamine In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere;	General procedure D: Synthesis of acetamides 3n-w General procedure: To a solution of a substituted aniline 24n-w (1 equiv.) and triethylamine (1.2 equiv.) in CH2Cl2 at 0 C was added chloroacetyl chloride (1.2 equiv.) over 15 minutes and the reaction stirred for 1 h at 0 C, followed by 2 h at r.t.. The salt was filtered off and washed with CH2Cl2 and EtOAc. This was dissolved in 1:1 MeOH/H2O, basified with sat. NaHCO3 and extracted with CH2Cl2 followed by drying with Na2SO4. The solvent was removed in vacuo to give the acetamides 3n-w.

	With diethyl ether
	With triethylamine In tetrahydrofuran	R.7.1 Preparation of [2-(1-naphthylamino)ethylamino]-N-(5-quinolyl)acetamide dihydrochloride monohydrate (1) A solution of 17.6 g (0.156 mol) of chloroacetyl chloride in 35.2 ml of tetrahydrofuran was dropwise added to a mixture of 15 g (0.104 mol) of 5-aminoquinoline, 21.1 g (0.208 mol) of triethylamine and 150 ml of tetrahydrofuran, under cooling with ice water. The reaction mixture was then stirred at room temperature for 4 hours, and thereafter poured into water. The resulting mixture was acidified with hydrochloric acid, and extracted with ethyl acetate. The mixture was filtered through celite, and the filtrate was twice washed with water, dried over magnesium sulfate, and subjected to a distillation operation under a reduced pressure to remove the solvent therefrom. 11.2 g (48.8%) of N-(5-quinolyl)-2-chloroacetamide was obtained.
	With triethylamine In acetone at 20℃;
	With potassium iodide In acetonitrile at 80℃;
	Stage #1: 5-Aminoquinoline With sodium hydrogencarbonate In chloroform at 20℃; for 0.25h; Stage #2: chloroacetyl chloride In chloroform at 20℃; for 2h;

Reference： [1]Current Patent Assignee: SCRIPPS RESEARCH - WO2017/210600, 2017, A1 Location in patent: Paragraph 0354
[2]Current Patent Assignee: SCRIPPS RESEARCH - WO2021/76755, 2021, A1 Location in patent: Paragraph 0250; 0287
[3]Haverkate, Natalie A.; van Rensburg, Michelle; Kumara, Sisira; Reynisson, Jóhannes; Leung, Euphemia; Pilkington, Lisa I.; Barker, David [Bioorganic and Medicinal Chemistry, 2021, vol. 37]
[4]Gaind et al. [Journal of the Indian Chemical Society, 1940, vol. 17, p. 619,621]
[5]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Pharma (in: Sumitomo Chemical); Sumitomo Chemical (w/o Dongwoo Fine-Chem) - EP443862, 1991, A1
[6]Location in patent: scheme or table Zhang, Shu Lan; Liu, Ya Jing; Zhao, Yan Fang; Guo, Qiu Ting; Gong, Ping [Chinese Chemical Letters, 2010, vol. 21, # 9, p. 1071 - 1074]
[7]Shang, Fan-Fan; Wang, Jing Ying; Xu, Qian; Deng, Hao; Guo, Hong-Yan; Jin, Xuejun; Li, Xiaoting; Shen, Qing-Kun; Quan, Zhe-Shan [European Journal of Medicinal Chemistry, 2021, vol. 220]
[8]Li, Qi; Chen, Ying; Xing, Shuaishuai; Liao, Qinghong; Xiong, Baichen; Wang, Yuanyuan; Lu, Weixuan; He, Siyu; Feng, Feng; Liu, Wenyuan; Chen, Yao; Sun, Haopeng [Journal of Medicinal Chemistry, 2021, vol. 64, # 10, p. 6856 - 6876]

2
[ 611-34-7 ]
[ 625-36-5 ]
[ 16880-67-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine In dichloromethane at 0 - 20℃;	1.8.4 General procedures for synthesis of 6b1-6b20 General procedure: Two mmol 5b1-5b20 was added to a dichloromethane solution containing 0.3 mL triethylamine at 0 °C. Then 1.2 equiv. 3-chloropropionyl chloride was dissolved in dry dichloromethane, and the obtained mixture was slowly added to the aniline solution at 0 °C. The reaction mixture was allowed to slowly warm up to room temperature, extracted with dichloromethane and finally washed with 2 M HCl. The organic phase was combined and dried with anhydrous MgSO4. Filtration and removal of the solvent under reduced pressure gave the crude product. The desired product was further purified by flash column chromatography with petroleum ether-EtOAc (20:1 to 10:1) to produce 6b1-6b20.
	With diethyl ether

Reference： [1]Zhu, Kongkai; Song, Jia-Li; Tao, Hong-Rui; Cheng, Zhi-Qiang; Jiang, Cheng-Shi; Zhang, Hua [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 23-24, p. 3693 - 3699]
[2]Gaind et al. [Journal of the Indian Chemical Society, 1940, vol. 17, p. 619,621]

3
[ 611-34-7 ]
[ 578-67-6 ]

Yield	Reaction Conditions	Operation in experiment
64%		5-(2,2,2-Trifluoroethoxy)quinoline (I-E)To a stirred solution of amine 5-aminoquinoline (5.0 g, 34.67 mmol) in H2O (100 mL) was added sodium bisulfate (NaHSO3; 25.2 g, 242.1 mmol) at RT, and the mixture was stirred at reflux temperature for 36 h.The resulting solution was cooled to RT, NaOH (9.7 g, 242.5 mmol) was added, and the mixture was stirred at reflux temperature for 8 h.After completion of the reaction (monitored by TLC), the reaction mixture was cooled to RT and the pH was adjusted to 7.0 with 6 Normal (N) hydrochloride acid (HCl).The precipitate was filtered, washed with H2O, and dried under high vacuum to obtain the desired alcohol M (3.2 g, 22.04 mmol, 64percent) as pale-yellow solid. 1H NMR (500 MHz, CDCl3): delta 8.92 (s, 1H), 8.58 (d, J=8.5 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.41 (dd, J=8.5, 4.5 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.10 (br s, 1H). MS (ESI): m/z 146 [M+H]+.
56%	With sulfuric acid; acetic acid; sodium nitrite; In water; at 0℃; for 5.5h;Inert atmosphere; Reflux;	5-aminoquinoline (15.0 g, 104.0 mmol) was dissolved in a solvent of acetic acid / water / sulfuric acid (8: 1: 1, v / v / v, 130 mL) under an argon atmosphere, and a solution of sodium nitrite (8.6 g, 124.8 mmol) dissolved therein. After the reaction mixture was stirred at 0 °C for 30 minutes, 10percent sulfuric acid solution (780 mL) was boiled, slowly added to the reaction solution, The mixture was refluxed for 5 hours, The completion of the reaction was confirmed by TLC (hexane: ethyl acetate = 2: 1). The reaction mixture was cooled to room temperature, and a saturated solution of sodium hydrogencarbonate (250 mL) was added thereto, followed by extraction with ethyl acetate (10 X 400 mL). The organic solvent layer was washed with a saturated solution of sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The concentrate was separated and purified by column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (8.5 g, 56percent yield).

Reference： [1]Patent: US2012/329802,2012,A1 .Location in patent: Page/Page column 25-26
[2]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3307 - 3312
[3]Patent: KR101778938,2017,B1 .Location in patent: Paragraph 0147-0148; 0155; 0160-0162
[4]Journal fur praktische Chemie (Leipzig 1954),1893,vol. <2> 47,p. 431
[5]Journal of the American Chemical Society,1946,vol. 68,p. 1562
[6]Monatshefte fur Chemie,1884,vol. 5,p. 532

4
[ 611-34-7 ]
[ 15793-79-0 ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: 5-Aminoquinoline With hydrogenchloride In water at 0℃; for 0.166667h; Stage #2: With sodium nitrite In water at 0℃; for 1.17h; Stage #3: With ascorbic acid In water at 0 - 80℃; for 1.25h;	4.a A solution of 5-aminoquinoline (0.75 g, 5.2 mmol) in concentrated hydrochloric acid (3.8 mL) was stirred at 0° C. for 10 min. A solution of sodium nitrite (0.43 g, 6.2 mmol) in deionized water (0.5 mL) was added to the cold reaction mixture over 10 min and stirred at 0° C. for 1 h to form a heterogeneous mixture. L-ascorbic acid (0.95 g, 5.4 mmol) was then added to the reaction mixture over 10 min. The reaction mixture was warmed to room temperature and stirred for 45 min. The reaction slurry was then heated at 80° C. for 20 min and deionized water (4 mL) was added. The suspension was re-cooled to 0° C. and stirred for 2 h. The solid was collected by filtration and washed with methanol to give the desired product (0.45 g, 2.8 mmol, 54%).
54%	Stage #1: 5-Aminoquinoline With hydrogenchloride In water at 0℃; for 0.166667h; Stage #2: With sodium nitrite In water at 0℃; for 1.16667h; Stage #3: With D-ascorbic acid In water at 0 - 80℃; for 1.08333h;	4.a Synthesis of 4-t-butyl-N-(3 -methyl-i - (quinolin-5-yl)-1 H-pyrazol-5-yl)benzenesulfonamide A solution of 5-aminoquinoline (0.75 g, 5.2 mmol) in concentrated hydrochloric acid (3.8 mE) was stirred at 0° C. for 10 mm. A solution of sodium nitrite (0.43 g, 6.2 mmol) in deionized water (0.5 mE) was added to the cold reaction mixture over 10 mm and stirred at 0° C. for 1 h to form a heterogeneous mixture. E-ascorbic acid (0.95 g, 5.4 mmol) was then added to the reaction mixture over 10 mm. The reaction mixture was warmed to room temperature and stirred for 45 mm. The reaction slurry was then heated at 80° C. for 20 mm and deionized water (4 mE) was added. The suspension was re-cooled to 0° C. and stirred for 2 h. The solid was collected by filtration and washed with methanol to give the desired product (0.45 g, 2.8 mmol, 54%)
51.55%	Stage #1: 5-Aminoquinoline With hydrogenchloride; sodium nitrite at 0 - 25℃; for 1h; Stage #2: With tin(II) chloride dihdyrate at 0℃; for 0.5h;	44 [0684] a mixture consisting of compound 78a (1.0 g, 6.94 mmol) in cone. HCl (4.00 ml) at 0 °C was added NaNO2 (526.8 mg, 7.63 mmol) dropwise and the resultant mixture was stirred at 0 °C for 0.5 hour. The reaction mixture was warmed to 25 °C over 0.5 hour, and then cooled to 0 °C. The sncl22H2O (3.13 g, 13.88 mmol, in 1.2 ml cone. HCl) was added dropwise to the reaction mixture, and stirred at 0 °C for 0.5 hour. The resulting mixture was allowed to warm to room temperature with vigorous stirring over 4 hours and then concentrated under reduced pressure to remove solvent. The residue was filtered, and the cake was washed with ethanol (30 ml x 3), and then dried under reduced pressure to afford compound 78b (700.0 mg, 51.55% yield) as a yellow solid. 1H NMR (DMSO-d6, 400 mhz) δ 9.95 (br s, 1h), 9.25 - 9.13 (m, 2h), 8.04 - 7.95 (m, 2h), 7.88 (d, = 8.8 hz, 1h), 7.26 (d, = 7.6 hz, 1h), 7.28 - 7.23 (m, 1h).

38%	Stage #1: 5-Aminoquinoline With hydrogenchloride In water at 0℃; for 1.5h; Stage #2: With hydrogenchloride; sodium nitrite In water Cooling with ice; Stage #3: With hydrogenchloride; tin(ll) chloride In water at 8℃; Cooling with ice;
	With hydrogenchloride Diazotization_.man reduziert dann mit Zinnchloruer und Salzsaeure;
	With hydrogenchloride; hydrogen sulfide; tin(ll) chloride; sodium nitrite Yield given. Multistep reaction;
	With hydrogenchloride; tin(ll) chloride; sodium nitrite 1.) H₂O; 2.) H₂O; Yield given. Multistep reaction;
	Stage #1: 5-Aminoquinoline With hydrogenchloride; sodium nitrite at 0℃; for 1h; Stage #2: With hydrogenchloride; tin(ll) chloride at 0 - 23℃; for 3h;

Reference： [1]Current Patent Assignee: CHEMOCENTRYX INC - US2013/225580, 2013, A1 Location in patent: Paragraph 0136; 0137
[2]Current Patent Assignee: CHEMOCENTRYX INC - US2018/9797, 2018, A1 Location in patent: Paragraph 0133; 0134
[3]Current Patent Assignee: BLADE THERAPEUTICS INC - WO2018/64119, 2018, A1 Location in patent: Paragraph 0684
[4]Location in patent: experimental part Fathalipour, Soghra; Shahrokhnia, Nazila; Afghan, Arash; Baradarani, Mehdi M. [Asian Journal of Chemistry, 2010, vol. 22, # 8, p. 5808 - 5814]
[5]Dufton [Journal of the Chemical Society, 1892, vol. 61, p. 788]
[6]Dionne, Gervais; Humber, Leslie G.; Asselin, Andre; McQuillan, Juanita; Treasurywala, Adi M. [Journal of Medicinal Chemistry, 1986, vol. 29, # 8, p. 1452 - 1457]
[7]Ferlin; Chiarelotto; Basadonna; Gia; Mobilio; Baccichetti; Carlassare [Il Farmaco, 1989, vol. 44, # 12, p. 1141 - 1155]
[8]Guzman-Perez, Angel; Wester, Ronald T.; Allen, Mary C.; Brown, Janice A.; Buchholz, Allan R.; Cook, Ewell R.; Day, Wesley W.; Hamanaka, Ernest S.; Kennedy, Scott P.; Knight, Delvin R.; Kowalczyk, Paul J.; Marala, Ravi B.; Mularski, Christian J.; Novomisle, William A.; Ruggeri, Roger B.; Tracey; Hill, Roger J. [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 6, p. 803 - 807]

5
[ 607-34-1 ]
[ 611-34-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With hydrazine hydrate; In ethanol; at 70℃; for 4h;	General procedure: In a typical reaction, 5.0 mg of Pd-gCN (5.0 wt% of Pd) catalyst was added to the solution of 1.0 mM of nitroarene in ethanol (2 mL)and 2 mM (1.2 equiv. 0.07 mL) of 60% of hydrazine hydrate. The mixture was placed into a 10 mL round-bottom flask at the reflux temperature (70 C) for the 4 h and then allowed to cool at room temperature. The resultant material was filtered and the filtrate was subjected to column chromatography over silica gel to obtain the corresponding products. For di-nitroarenes substrates 4.0 mM(2.4 equiv. 0.14 mL) of 60% of hydrazine hydrate solution was used.
96%		<strong>[607-34-1]5-Nitroquinoline</strong> (20.0 g, 114.8 mmol) was dissolved in ethanol (400 mL) under an argon atmosphere, and then tin chlorodihydrate (SnCl 2 2H 2 O; 145.6 g, 678.0 mmol) was added thereto. After refluxing the mixture at 60 DEG C for 1 hour, sodium borohydride (0.3 g, 7.7 mmol) was added to the reaction solution, and the mixture was refluxed with stirring for 30 minutes. The completion of the reaction was confirmed by TLC (hexane: ethyl acetate = 1: 1). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The solvent was then dissolved in water (300 mL). The mixture was poured into 40% sodium hydroxide solution (79 mL) and extracted with ethyl acetate (5 X 400 mL). The extracted organic solvent layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent to obtain the target compound (16.0 g, 96% yield).
96%	With palladium 10% on activated carbon; ammonium formate; silica gel; In methanol; for 1.5h;Milling;	General procedure: In a typical experiment, a mixture of nitroarene compound (1.0 mmol),ammonium formate (3.3 mmol, 208 mg, 1.1 equivalent), palladium catalyst (10 % Pdon activated carbon, 2 mol%, 21 mg) and silica (175 mg) was ball milled in thepresence of dry methanol (eta = 0.25 muL mg-1) for 90 minutes. After milling, a smallsample (? 1 mg) of the crude reaction mixture was suspended in methanol andimmediately analyzed by TLC (typically using dichloromethane : methanol = 20 : 1mixture as an eluent). The crude mixture was left in a well ventilated hood overnight,suspended in methanol and filtered over a Buechner funnel. Evaporation of the filtrateafforded the desired amino-derivative. If necessary, the final product was purified bycolumn chromatography.

86%	With tetrahydroxydiboron; 5%-palladium/activated carbon; water; In acetonitrile; at 50℃; for 24h;	General procedure: Nitrobenzene (0.6mmol), 5wt% Pd/C (0.5mmol %, 0.003mmol), H2O (10 equiv, 6.0mmol), B2(OH)4 (3.3 equiv, 2.0mmol), and CH3CN (1.0mL) were added in a 10mL tube. The reaction mixture was stirred at 50C for 24h. When the reaction was complete monitored by TLC, the mixture was cooled to room temperature. Water (5mL) was added, and extracted with EtOAc (3×5mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give aniline 2a (55mg, 99%).
76%	With tetrahydroxydiboron; copper diacetate; In acetonitrile; at 80℃; for 24h;Schlenk technique;	General procedure: A 20 mL Schlenk tube was charged with 8-nitroquinoline (1k; 87 mg, 0.5 mmol), Cu(OAc)2 (4.5 mg, 0.025 mmol), B2(OH)4(135 mg, 1.5 mmol), and MeCN (2.0 mL). The mixture was stirred at 80 C for 24 h, then cooled to room temperature and concentrated under reduced pressure. Similar workup to 2a gave a brown solid (4a: 63 mg, 87% yield).
60%	With hydrazine hydrate; palladium 10% on activated carbon; In ethanol; for 17h;Reflux;	<strong>[607-34-1]5-Nitroquinoline</strong> (2.05 g, 11.8 mmol)and Pd/C (10%) (0.64 g, 0.6 mmol) were suspended in 90 mLethanol. The suspension was heated to reflux and hydrazinehydrate (2.9 mL, 57.5 mmol) in 50 mL ethanol was added during60 min. Subsequently, the mixture was stirred for 16 h at constanttemperature,filtered hot and thefiltrate was concentrated underreduced pressure. Column chromatography on silica gel (ethylacetate/petroleum ether (3:1)) afforded 5-amino quinoline as acolorless solid in 60% yield (1.02 g, 7.1 mmol).
97%Spectr.	With 0.5% Pd on alumina; hydrogen; In ethyl acetate; at 30℃; for 10h;Green chemistry;	General procedure: The hydrogenationwas carried out in a 100 mL vial equipped with an FB-generator without additional stirring. Nitroarene 1 (10mmol) was dissolved in ethyl acetate (80 mL), and then warmed to 30 C. Using the FB-generator (MA3-FS), H2-FB was introduced into the reactor in the presence of palladium on alumina spheres (0.5%Pd, 2-4 mm, 0.3 mmol,3 mol%) at an H2-flow rate of 5 mL/min. The samples of the reaction mixture were taken out periodically tomonitor the reaction progress using the GC analysis. After the completion of the hydrogenation reaction, ethylacetate was evaporated in vacuo to afford the desired aniline 2 with good to excellent purity.
	With hydrazine hydrate; In ethanol; at 30℃; for 1h;Autoclave;	General procedure: The catalytic reduction of nitro aromatics was conducted in a 25 mlTelfon-lined stainless steel autoclave with magnetic stirring. In a typicalprocess, 6 mmol nitroarene, and desired amounts of reducing agent andsolvents were introduced in the reactor. The autoclave was transferredinto a water bath at the set temperature with an accuracy of better than0.2 C for ?0.5 h. Then, 10 mg catalyst was added into the reactionmixture and started the reduction at a stirring rate of 450 rpm. After thereaction, the catalyst was rapidly separated by ltration. n-Decane(500 muL) as standard was added into the ltrate and was dried withanhydrous Na 2 SO 4 . The products were analyzed by gas chromato-graphy-mass spectrometry (GC-MS) (Shimadzu GCMS-QP2010 Plus)and GC (Varian CP-3800) with a capillary column (column VF-1 ms,15 m, 0.25 mm, 0.25 mum) and a ame ionization detector (FID).

Reference： [1]Green Chemistry,2017,vol. 19,p. 809 - 815
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[3]Applied Catalysis A: General,2016,vol. 523,p. 31 - 38
[4]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3307 - 3312
[5]Patent: KR101778938,2017,B1 .Location in patent: Paragraph 0147-0148; 0155-0158
[6]Molecules,2018,vol. 23
[7]Synlett,2000,p. 683 - 685
[8]Synlett,2007,p. 2557 - 2558
[9]Angewandte Chemie - International Edition,2016,vol. 55,p. 8979 - 8983
Angew. Chem.,2016,vol. 128,p. 9125 - 9129,5
[10]Tetrahedron,2017,vol. 73,p. 3898 - 3904
[11]Journal of Heterocyclic Chemistry,2009,vol. 46,p. 428 - 431
[12]ARKIVOC,2010,vol. 2010,p. 265 - 290
[13]Chemical and pharmaceutical bulletin,1980,vol. 28,p. 2515 - 2518
[14]Tetrahedron,2018,vol. 74,p. 2121 - 2129
[15]Organic Letters,2019,vol. 21,p. 3764 - 3768
[16]Heterocycles,1990,vol. 31,p. 2201 - 2204
[17]Journal of Fluorine Chemistry,2017,vol. 193,p. 98 - 105
[18]Journal of Organic Chemistry,1984,vol. 49,p. 2626 - 2627
[19]Journal of the Chemical Society,1892,vol. 61,p. 788
[20]Journal fur praktische Chemie (Leipzig 1954),1896,vol. <2> 53,p. 392
[21]Chemische Berichte,1917,vol. 50,p. 1630
[22]Journal of the American Chemical Society,1940,vol. 62,p. 1640,1644
[23]Justus Liebigs Annalen der Chemie,1940,vol. 544,p. 280,284
[24],1947,vol. 67,p. 67
[25]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1954,vol. 74,p. 1274
Chem.Abstr.,1955,p. 3192
[26]Justus Liebigs Annalen der Chemie,1940,vol. 544,p. 280,284
[27]Chemical and Pharmaceutical Bulletin,1981,vol. 29,p. 651 - 656
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[40]Applied Catalysis A: General,2018,vol. 559,p. 127 - 137

6
[ 611-34-7 ]
[ 20377-01-9 ]

Yield	Reaction Conditions	Operation in experiment
96.9%	Stage #1: 5-Aminoquinoline With sulfuric acid; sodium nitrite In water at 0℃; for 0.0833333h; Stage #2: With sodium azide In water at 20℃; for 0.166667h;	1 Synthesis of INT 12-b A mixture of quinolin-5-amine (700 mg, 4.85 mmol) in sulfuric acid (1.25 mL) and H2O (0.7 mL ) was cooled to 0 °C, and then sodium nitrite (400 mg, 5.81 mmol) in H2O (0.5 mL) was added. The mixture was stirred at 0 °C for 5 min. Then, NaN3 (315 mg, 4.85 mmol) in H2O (0.5 mL) was added and the reaction mixture was stirred at 20 °C for 10 min. The reaction mixture was neutralized with NH3.H2O. The solid was collected by filtration to give 5- azidoquinoline (800 mg, 96.9% yield) as a solid which was used for next step directly m/z: [M + H]+ Calcd for CoHeNr 171.1; Found 170.9.
89%	Stage #1: 5-Aminoquinoline With hydrogenchloride In water at 0 - 20℃; for 0.5h; Stage #2: With sodium nitrite In water at 0 - 20℃; for 0.5h; Stage #3: With sodium azide In water at 20℃; for 1h;	9.2 (2) Synthesis of compound 3k (5-azidoquinoline) Take compound 5-aminoquinoline (2k) (720mg, 5mmol) in a 50ml round-bottomed flask, add 5ml of 6M HCl aqueous solution dropwise at 0, and restore to React at room temperature for 30 minutes. Then, at 0, 7.14ml of 0.6M NaNO2 aqueous solution was added dropwise to the above system, and it was returned to room temperature for 30min. Finally, 14.29ml of 0.8M NaN3 aqueous solution was added dropwise to the above system at room temperature, and stirred at room temperature for 1 hour. After the reaction was monitored by TLC, it was extracted with dichloromethane, dried over sodium sulfate, concentrated, and separated by column chromatography to obtain a light yellow liquid 3k (791mg , 4.65mmol), yield 89%
57%	Stage #1: 5-Aminoquinoline With sulfuric acid; sodium nitrite In water at 0 - 5℃; for 0.0833333h; Stage #2: With sodium azide In water at 20℃; for 0.166667h;

With hydrogenchloride; sodium azide; sodium nitrite Multistep reaction;

Reference： [1]Current Patent Assignee: RHEOS MEDICINES INC - WO2021/138298, 2021, A1 Location in patent: Paragraph 00120; 00176
[2]Current Patent Assignee: ZHENGZHOU UNIVERSITY - CN111454252, 2020, A Location in patent: Paragraph 0087; 0090
[3]Location in patent: experimental part Pokhodylo; Matiichuk; Obushak [Russian Journal of Organic Chemistry, 2010, vol. 46, # 6, p. 894 - 897]
[4]Khan, Zafar U.; Nay, Barry; Scriven, Eric F.V.; Suschitsky, Hans [Journal of the Chemical Society. Perkin transactions I, 1982, p. 671 - 672]

7
[ 611-34-7 ]
[ 4964-71-0 ]

Yield	Reaction Conditions	Operation in experiment
61%		PREPARATION 75-BromoquinolineQuinolin-5-amine (3.37 g, 23.38 mmol) was dissolved in 9 ml of water and 11 ml of hydrogen bromide (48percent in water); the resulting solution was cooled at 0°C. Sodium nitrite (1.94 g, 28.12 mmol) dissolved in 9 ml of water was dropwise added.The resultant solution was stirred at room temperature for 5 minutes.This solution was dropwise added to a solution of copper(I) bromide (4.02 g, 28.02 mmol) in 23 mL of HBr (48percent in water) at 75°C.The resulting mixture was stirred at room temperature for 2 h.Then the reaction mixture was basified with sodium hydroxide and extracted twice with ethyl acetate.The organic phase is washed with brine, filtered and dried over sodium sulfate.After filtration and evaporation of the solvent, 2.98 g (61 percent) of the final product were obtained.1H NMR (CDCl3) delta ppm: 7.44 - 7.63 (m, 2 H) 7.84 (d, J=7.42 Hz, 1 H) 8.10 (d, J=8.24 Hz, 1 H) 8.56 (d, J=8.51 Hz, 1 H) 8.94 (br.s., 1H) HPLC/MS (9 min) retention time 5.68 min.LRMS: m/z 208 (M)/21 0 (M+2)
35%		To a suspension of 5-aminoquinoline (2.11 g, 14.7 mmol) in aqueous HBr (8.6 mL, 48percent in H2O) cooled to 0 °C was added a solution of NaNO2 (2.58 g, 37.5 mmol) in H2O (35 mL). The reaction mixture was stirred at 0 °C for 30 min and a solution of CuBr (2.58 g, 17.6 mmol) in H2O (29 mL) was added. The mixture was allowed to warm to room temperature and stirred for additional 3 h. 4 N NaOH was slowly added to the mixture until pH reached to about 10. The organic phase was extracted with EtOAc (3 x 75 mL), washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (EtOAc/hexane = 1:1) to give 5-bromoquinoline 2e (1.08 g, 35percent)
5.7 g (80%)	With sodium nitrite;copper(I) bromide; In water; hydrogen bromide;	5-Bromo-quinoline Sodium nitrite (2.5 g, 41.8 mmol) was dissolved in 15 mL water. Copper (I) bromide (6.0 g, 41.8 mmol) was dissolved in 38 mL of 48percent HBr and heated to 75° C. The 5-aminoquinoline (5.0 g, 34.7 mmol) was suspended in 15 mL water and 18 mL 48percent HBr and cooled to 0° C. The sodium nitrite solution was added to the 5-aminoquinoline solution at 0° C. The resulting diazonium solution was added slowly to the warmed CuBr solution. The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was basified with sodium hydroxide, then filtered through celite. The solid was washed with methylene chloride, and the aqueous material was extracted with methylene chloride. The organic layers were combined, dried with Na2SO4, and concentrated in vacuo. The crude product was chromatographed with 2:1 hexane/ethyl acetate to yield 5.7 g (80percent) of 5-bromo-quinoline as a yellow oil. MS (APCI) m/z 208.0 (M+1).

With sodium hydroxide; copper(I) bromide; sodium nitrite; In water; hydrogen bromide;

Step 1: 5-bromoquinoline (10). To a 0° C. mixture of 1.0022 g (6.94 mmol) 5-aminoquinoline (9) and 6 mL 24percent aqueous hydrobromic acid was added a solution of 0.5 g (7 mmol) sodium nitrite in 3 mL H2O. After 5 min at 0° C., the mixture was added over 5 min to 1.2026 g (8.38 mmol) cuprous bromide in 10 mL 47percent aqueous hydrobromic acid. After stirring at room temperature for 7.5 h, the reaction mixture was basified with ice and 50percent aqueous NaOH and filtered. The filtrate was extracted three times with 50 mL ethyl ether, and the combined ether layers were concentrated in vacuo. The resulting residue was combined with precipitate from the above filtration, dissolved in 50percent MeOH:CH2Cl2 and filtered. The filtrate was concentrated in vacuo, dissolved in 10percent (10percent NH4OH:MeOH):CH2Cl2 and filtered over silica. The filtrate was concentrated in vacuo to yield 10. 1H NMR (DMSO, 400 MHz) delta 8.997 (d, 1H, J=2.83 Hz, ArH); 8.525 (d, 1H, J=8.59 Hz, ArH); 8.089 (d, 1H, J=8.50 Hz, ArH); 8.000 (d, 1H, J=7.49 Hz, ArH); 7.741-7.701 Hz (m, 2H, ArH); MS (Electrospray): m/z 207.9, 209.9 (M+H, 79Br, 81Br).

Reference： [1]Bioorganic and medicinal chemistry,2002,vol. 10,p. 2611 - 2623
[2]Patent: EP2394998,2011,A1 .Location in patent: Page/Page column 16
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1472 - 1476
[4]Journal of labelled compounds and radiopharmaceuticals,1994,vol. 34,p. 905 - 913
[5]Patent: US2003/96826,2003,A1
[6]Patent: US2002/6923,2002,A1

8
[ 611-34-7 ]
[ 75318-43-3 ]
[4-Chloro-[1,2,3]dithiazol-(5Z)-ylidene]-quinolin-5-yl-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With pyridine In dichloromethane at -20℃;

Reference： [1]Thiery, Valerie; Rees, Charles W.; Besson, Thierry; Cottenceau, Gilles; Pons, Anne-Marie [European Journal of Medicinal Chemistry, 1998, vol. 33, # 2, p. 149 - 153]

9
[ 578-67-6 ]
[ 7462-74-0 ]
[ 611-34-7 ]
2-Hydroxy-2-methyl-N-quinolin-5-yl-propionamide [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,1997,vol. 34,p. 1857 - 1860

10
[ 7647-01-0 ]
[ 607-34-1 ]
iron [ No CAS ]
[ 611-34-7 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1896,vol. <2> 53,p. 392

11
[ 7647-01-0 ]
[ 607-34-1 ]
tin dichloride [ No CAS ]
[ 611-34-7 ]

Reference： [1]Journal of the Chemical Society,1892,vol. 61,p. 788

12
[ 611-34-7 ]
[ 394-69-4 ]

Yield	Reaction Conditions	Operation in experiment
55%	With tetrafluoroboric acid; sodium nitrite; at 0℃; for 1h;	Preparation LIII 5-fluoro-1,2,3,4-tetrahydroquinoline [0363] 5-fluoroquinoline [0364] To a suspension of 5-aminoquinoline (50 g, 347 mmol) in 48percent HBF4 (200 mL) at 0° C. was added portionwise sodium nitrite. This was stirred for 1 hour and then poured into 1:1 ethyl acetate/diethyl ether (500 mL). The resulting suspension was filtered and the solid dried. This solid (82.5 g, 338 mmol) was added portionwise to refluxing xylene (1 L) and stirred for 2 hours then allowed to cool. The xylene was decanted off and the residue dissolved in 1N hydrochloric acid (600 mL). After neutralization with sodium carbonate, the mixture was extracted with ethyl acetate (10.x.500 mL). The extracts were dried over sodium sulfate, filtered and the volatiles removed under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10-20percent diethyl ether in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 28.1 g (55percent) of the desired compound. MS (EI, m/z) C9H6FN (M+1) 148.0 [0365] Reduction [0366] A mixture of 5-fluoroquinoline (28.1 g), 5percent palladium on carbon (5.6 g) in methanol was shaken over night at 40° C. under 60 psi hydrogen. The mixture was filtered through celite and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5-10percent ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 22.5 g (78percent) of the title compound. [0367] MS (EI, m/z) C9H10FN (M+1) 152.0
24.5%	With tetrafluoroboric acid; sodium nitrite; In xylene; at 0℃;Reflux;	To a suspension of 5-aminoquinoline (lO.Og, 0.069 mol) in 48percent HBF4 (40 mL) at 0°C was added portionwise sodium nitrite. This was stirred for 1 hour and then poured into 1 : 1 ethyl acetate/diethyl ether (50 mL). The resulting suspension was filtered and the solid dried. This solid was added portionwise to refluxing xylene (80 mL) and stirred for 2 hours then allowed to cool. The xylene was decanted off and the residue was dissolved in IN aqueous hydrochloric acid (100 mL). After neutralization with sodium carbonate, the mixture was extracted with ethyl acetate (3 x 80 mL). The extracts were dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel column chromatography, eluting with 2percent ethyl acetate in petroleum ether to afford 5-fluoroquinoline as a colorless oil (2.5 g, 24.5percent).'H-NMR (300 MHz, CDC13) delta 8.93 - 8.98 (m, 1H), 8.43 - 8.46 (m, H), 7.92 (d, / = 8.4 Hz, 1H), 7.62 - 7.78 (m, 1H), 7.41 - 7.49 (m, 1H), 7.22 - 7.26 (m, 1H)
800 mg	With tetrafluoroboric acid; sodium nitrite; at 0℃; for 1h;	To a solution of quinolin-5 -amine (2 g, 13.9 mmol) in 10 mL of 48percent HBF4 at 0°C was added sodium nitrite (933 mg, 13.5 mmol) portionwise. This was stirred for 1 hour and then poured into 1 : 1 ethyl acetate diethyl ether mixture (50 mL). The resulting suspension was filtered and the solid was dried. This solid was added portionwise to refluxing xylene (30 mL) and stirred for 3 hours, then allowed to cool. The xylene was decanted off and the residue was dissolved in IN HC1 (50 mL). After neutralization with NaHC03, the mixture was extracted with ethyl acetate (3 x 50 mL). The extracts were dried over sodium sulfate, filtered and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (3percent EtOAc/PE) to afford 800 mg of title compound as colorless oil. LC-MS: m/z 148.2 (M+H)+

800 mg	With tetrafluoroboric acid; sodium nitrite; at 0℃; for 1h;	To a solution of quinolin-5-amine (2 g, 13.9 mmol) in 10 mL of 48percent HBF4 at 0° C. was added sodium nitrite (933 mg, 13.5 mmol) portionwise. This was stirred for 1 hour and then poured into 1:1 ethyl acetate diethyl ether mixture (50 mL). The resulting suspension was filtered and the solid was dried. This solid was added portionwise to refluxing xylene (30 mL) and stirred for 3 hours, then allowed to cool. The xylene was decanted off and the residue was dissolved in 1N HCl (50 mL). After neutralization with NaHCO3, the mixture was extracted with ethyl acetate (3×50 mL). The extracts were dried over sodium sulfate, filtered and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (3percent EtOAc/PE) to afford 800 mg of title compound as colorless oil. LC-MS: m/z 148.2 (M+H)+
800 mg	With tetrafluoroboric acid; sodium nitrite; at 0℃; for 1h;	To a solution of quinolin-5 -amine (2 g, 13.9 mmol) in 10 mL of 48percent HBF4 at 0°C was added sodium nitrite (933 mg, 13.5 mmol) portionwise. This was stirred for 1 hour and then poured into 1 : 1 ethyl acetate diethyl ether mixture (50 mL). The resulting suspension was filtered and the solid was dried. This solid was added portionwise to refluxing xylene (30 mL) and stirred for 3 hours, then allowed to cool. The xylene was decanted off and the residue was dissolved in IN HC1 (50 mL). After neutralization with NaHC03, the mixture was extracted with ethyl acetate (3 x 50 mL). The extracts were dried over sodium sulfate, filtered and the volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography (3percent EtOAc/PE) to afford 800 mg of title compound as colorless oil. LC-MS: m/z 148.2 (M+H)+

Reference： [1]Patent: US2003/229026,2003,A1 .Location in patent: Page 25
[2]Bioorganic and medicinal chemistry,2002,vol. 10,p. 2611 - 2623
[3]Patent: WO2012/94462,2012,A2 .Location in patent: Page/Page column 75
[4]Biological and Pharmaceutical Bulletin,1997,vol. 20,p. 646 - 650
[5]Patent: WO2014/139144,2014,A1 .Location in patent: Page/Page column 179
[6]Patent: US2014/288081,2014,A1 .Location in patent: Paragraph 0738; 0739
[7]Patent: WO2014/139325,2014,A1 .Location in patent: Page/Page column 192; 193
[8]Journal of Medicinal Chemistry,2017,vol. 60,p. 6998 - 7011

13
[ 611-34-7 ]
[ 635-27-8 ]

Yield	Reaction Conditions	Operation in experiment
68%		To a suspension of 5-aminoquinoline (756 mg, 5.24 mmol) in aqueous 2 N HCl (31 mL) cooled to 0 C was added a solution of NaNO2 (470 mg, 6.80 mmol) in H2O (14 mL). The reaction mixture was stirred at 0 C for 30 min and a solution of CuCl (644 mg, 6.51 mmol) in conc. HCl (16 mL) was added. The mixture was allowed to warm to room temperature and stirred for additional 24 h. Saturated NaHCO3 was slowly added to the mixture until no gas was generated. The organic phase was extracted with CH2Cl2 (3 x 50 mL), washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (EtOAc/hexane = 1:1) to give 5-chloroquinoline 2d (579 mg, 68%)
		To a solution of 5-quinolinamine (9 g, 62.4mmo]) in water (80 mL) at 0 C was added concentrated NC] (5.2 mL, 62.4 mmol) and NaNO2 (6.5 g, 93.6 mmol) portionwise. Themixture was stirred at 0 C for 1 h, then a solution of CuCI (9.2 g, 93.7 mmol) in concentrated HC1 (5.2 mL, 62.4 mmol) was added dropwise at 0 C. After stirring at 0 C for 2 h, the mixture was made basic with sat. aq. NaHCO3 to pH 7 and then extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The cmde residue was purified by siLica gel chromatography(petroleum ether / EtOAc = 9: 1 to 5 : 1) to give the title compound (9.2 g, 90%) as clear oil.?H NMR (400 MHz, DMSO-d6) 8 8.99 - 8.98 (m, 111), 8.51 (d, J 8.0 Hz, IN), 8.01 (d, .J 8.0 Hz, 111), 7.77 - 7.73 (m, 211), 7.68 - 7.65 (m, IN).

Reference： [1]Bioorganic and medicinal chemistry,2002,vol. 10,p. 2611 - 2623
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1472 - 1476
[3]Patent: WO2016/86200,2016,A1 .Location in patent: Page/Page column 235

14
[ 611-34-7 ]
[ 1006-50-4 ]

Yield	Reaction Conditions	Operation in experiment
72%		Example 1.1: Preparation of 5-iodoquinoline (0081) After adding 5 5-aminoquinoline (333 mg, 2.31 mmol) to a flask and cooling to 0 C., 1.6 N 6 HCl (7.70 mL) was slowly added. To the solution which turned red, an aqueous solution (4.00 mL) of 7 sodium nitrite (530 mg, 7.68 mmol) was slowly added at 0 C. 10 minutes later, to the solution which turned brown, an aqueous solution (6.70 mL) of 8 copper(I) iodide (530 mg, 2.78 mmol) was slowly added at 0 C. 9 N2 gas was produced and the copper(I) iodide was added after completely dispersing in H2O as a solvent. Then, 57% 11 HI (3.35 mL) was slowly added at 0 C. 10 minutes later, the reaction mixture was stirred at 60 C. for 3 hours. After cooling the reaction mixture to room temperature and adding ice, 4 N 12 NaOH was slowly added until the pH reached 14. The reaction mixture was separated into an ethyl acetate layer and an H2O layer using a separatory funnel. After drying the organic layer with anhydrous MgSO4, the solvent was removed by vacuum distillation. The mixture was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the target 13 compound (yellow solid, 422 mg, 72%). (0082) 1H NMR (CDCl3, 400 MHz) delta 8.89 (dd, J1=4.2 Hz, J2=1.5 Hz, 1H), 8.39 (d, J=8.5 Hz, 1H), 8.13 (d, J=6.5 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.49 (dd, J1=9.6 Hz, J2=3.2 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H).
	With potassium iodide; sodium thiosulfate; sodium nitrite; In hydrogenchloride; water; acetone;	EXAMPLE 43A 5-iodoquinoline A solution of 5-aminoquinoline (5.5 g, 38.1 mmol) in 3M HCl (100 mL) at 0 C. was treated dropwise with a solution of sodium nitrite (3.65 g, 52.9 mmol) in water (25 mL), then with a solution of potassium iodide (13.0 g, 78.3 mmol) in water (25 mL) with periodic treatment with acetone to prevent foaming. The reaction was warmed to room temperature, stirred for 16 hours, treated with saturated sodium thiosulfate, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 8:1 to 4:1/hexanes:ethyl acetate to provide the desired product. 1H NMR (400 MHz, CDCl3) delta 8.89 (d, 1H), 8.39 (d, 1H), 8.14-8.10 (m, 2H), 7.51-7.41 (m, 2H).

Reference： [1]Patent: US2017/354650,2017,A1 .Location in patent: Paragraph 0081; 0082
[2]Bioorganic and medicinal chemistry,2002,vol. 10,p. 2611 - 2623
[3]Patent: US2002/19527,2002,A1
[4]Chemistry - A European Journal,2019,vol. 25,p. 6355 - 6361

15
[ 611-34-7 ]
[ 1885-14-9 ]
quinolin-5-ylcarbamic acid phenyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.9%	With pyridine In tetrahydrofuran at 0℃; for 0.5h;	2.1 To a stirred solution of 5-Aminoquinoline (1 g, 6.94 mmol) dissolved in tetrahydrofuran (10 ml), was added pyridine (2.88 ml, 35 mmol) at room temperature and the reaction mass was cooled to 0 °C. Phenyl chloroformate (1.5 ml, 11.79 mmol) was added at 0 0C and the reaction mass was stirred at the same temperature.After 30 minutes (the starting material absence was conformed by TLC using 50 %EtOAc in n-hexane as an eluent) the reaction mass was quenched with water (10 ml) and extracted with dichloromethane (2 X 10 ml). The combined organic layer was washed with water (3 X 20 ml) and dried over anhydrous sodium sulphate.Concentrated under vacuum to afford the desired product (1.7 g, yield 92.9%).1H-NMR (300 MHz, CDCl3): δ 6.81 - 7.04 (m, 3H)3 7.21 - 7.41 (m, 9H).MS: 265.2 (M++.)
	at 0 - 20℃;
	With pyridine In tetrahydrofuran; acetonitrile at 0 - 20℃;	4.1.2.9 Carbamation General procedure: To a solution of the appropriate amine (1.0mmol) in THF was added pyridine (1.1mmol) and phenyl chloroformate (1.0mmol) at 0°C and stirred at room temperature for 1h. The reaction mixture was quenched with water and extracted with EtOAc several times. The combined organic layer was washed with brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel colunm chromatography to afford the desired product.

With pyridine at 50℃; for 4h;

4.1.1. General method for semicarbazones preparation General procedure: Typically, 10 mmol of substituted amines were dissolved in 10 mLof pyridine and allowed to stir. 11 mmol of phenyl chloroformate wereadded dropwise into the pyridine solution. The reaction was proceededat 50 °C for 4 h. After the total conversion of amines monitored by TLC,20 mL of dichloromethane were added, and the mixture was then washedwith water (20 mL × 3). The organic phase was concentrated in arotary evaporator at 50 °C to afford crude carbamates. These carbamatescould be directed used in the next step without further purification.

Reference： [1]Current Patent Assignee: VIATRIS INC - WO2010/23512, 2010, A1 Location in patent: Page/Page column 34
[2]Swanson, Devin M.; Dubin, Adrienne E.; Shah, Chandra; Nasser, Nadia; Chang, Leon; Dax, Scott L.; Jetter, Michele; Breitenbucher, J. Guy; Liu, Changlu; Mazur, Curt; Lord, Brian; Gonzales, Lisa; Hoey, Kenway; Rizzolio, Michele; Bogenstaetter, Michael; Codd, Ellen E.; Lee, Doo H.; Zhang, Sui-Po; Chaplan, Sandra R.; Carruthers, Nicholas I. [Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1857 - 1872]
[3]Lee, Hobin; Ahn, Songyeon; Ann, Jihyae; Ha, Heejin; Yoo, Young Dong; Kim, Young Ho; Hwang, Ji-Young; Hur, Kwang-Hyun; Jang, Choon-Gon; Pearce, Larry V.; Esch, Timothy E.; Lewin, Nancy E.; Blumberg, Peter M.; Lee, Jeewoo [European Journal of Medicinal Chemistry, 2019, vol. 182]
[4]Du, Guohua; Jia, Xinxin; Li, Yan; Liu, Qi; Wang, Shiyi; Zeng, Binglin; Zhang, Chen [Bioorganic and medicinal chemistry, 2020, vol. 28, # 13]

16
[ 67-56-1 ]
[ 611-34-7 ]
[ 1006-50-4 ]

Reference： [1]Journal of Organic Chemistry,2002,vol. 67,p. 3972 - 3974

17
[ 611-34-7 ]
[ 3262-03-1 ]
1-(quinolin-5-ylamino)-3,4-dihydronaphthalene-2-carbaldehyde [ No CAS ]

Reference： [1]Synthesis,2007,p. 1571 - 1575

18
[ 611-34-7 ]
[ 59412-12-3 ]

Reference： [1]Bioorganic and medicinal chemistry,2002,vol. 10,p. 2611 - 2623
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1472 - 1476

19
[ 611-34-7 ]
[ 99455-13-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: hydrobromic acid; sodium nitrite / H₂O / -10 - 0 °C 1.2: 63 percent / copper(I) bromide; hydrobromic acid / H₂O / 0.5 h / 60 °C 2.1: peroxyacetic acid / CHCl₃ / 4 h / Heating 3.1: 820 mg / phosphorus(V) oxychloride / 1 h / 100 °C
	Multi-step reaction with 3 steps 1: 1.) aq.HBr, NaNO₂, 2.) Cu / 1.) -78 deg C, 15 min, 2.) H₂O, 100 deg C, 1 h 2: aq. CH₃CO₃H / CHCl₃ / 3 h / Heating 3: POCl₃ / 1 h / 100 °C
	Multi-step reaction with 3 steps 1.1: sodium nitrite; hydrogen bromide / water / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 3 h / 20 °C / Inert atmosphere 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3.5 h / 0 - 20 °C / Inert atmosphere 3.1: trichlorophosphate / dichloromethane / 3 h / 60 °C / Inert atmosphere

Reference： [1]Karramkam, Mylene; Dolle, Frederic; Valette, Heric; Besret, Laurent; Bramoulle, Yann; Hinnen, Francoise; Vaufrey, Francoise; Franklin, Carine; Bourg, Sebastien; Coulon, Christine; Ottaviani, Michele; Delaforge, Marcel; Loc'h, Christian; Bottlaender, Michel; Crouzel, Christian [Bioorganic and medicinal chemistry, 2002, vol. 10, # 8, p. 2611 - 2623]
[2]Mathis; Enas; Hanrahan; Akgun [Journal of labelled compounds and radiopharmaceuticals, 1994, vol. 34, # 10, p. 905 - 913]
[3]Son, Myung-Hee; Kim, Ji Young; Lim, Eun Jeong; Baek, Du-Jong; Choi, Kihang; Lee, Jae Kyun; Pae, Ae Nim; Min, Sun-Joon; Cho, Yong Seo [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 5, p. 1472 - 1476]

20
[ 611-34-7 ]
[ 91004-60-3 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 5-Aminoquinoline With hydrogenchloride; sodium nitrite In water at 0 - 20℃; for 1h; Stage #2: With tin(ll) chloride In water at 0 - 20℃; for 4.5h;	85.A Example 85 EPO JV-qumolin-5-yladamantane-l-carbohydrazideExample 85 A 5 -hydrazino quino line; To an oven-dried, round-bottomed flask containing a magnetic stir bar was added solid 5-aminoquinoline (5.05 g, 35.0 mmol). The flask was cooled to O0C in an ice bath and concentrated hydrochloric acid (30 mL) was added dropwise. A solution of sodium nitrite (2.42 g, 38.5 mmol) in water (10 mL) was added dropwise to the cold reaction slurry. The reaction mixture was stirred at O0C for 30 minutes and allowed to warm to room temperature over 30 minutes during which an orange/red solution formed. The flask was again cooled to O0C and a solution of tin(II) chloride dihydrate (15.8 g, 70.0 mmol) dissolved in the minimum amount of concentrated hydrochloric acid was added dropwise. A yellow precipitate formed immediately upon addition of the tin salt. The mixture was stirred at O0C for 30 minutes and then allowed to warm to room temperature with vigorous stirring over 4 hours. The solid yellow product was collected by vacuum filtration on a glass frit. The product was washed with cold ethanol and dried under vacuum to give 6.18 g of the title compound as a bis hydrogen chloride salt (76%). MS (DCVNH3) m/z 375 (M+H)+.
76%	Stage #1: 5-Aminoquinoline With hydrogenchloride; sodium nitrite In water at 0 - 20℃; for 1h; Stage #2: With hydrogenchloride; tin(II) chloride dihdyrate In water at 0 - 20℃;
	Multi-step reaction with 2 steps 1: 1.) sodium nitrite, HCl; 2.) stannous chloride dihydrate, HCl / 1.) H₂O; 2.) H₂O 2: 89 percent / hydrogen chloride gas / ethanol

Stage #1: 5-Aminoquinoline With sodium azide Stage #2: With tin(ll) chloride

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC - WO2006/110516, 2006, A1 Location in patent: Page/Page column 42-43
[2]Location in patent: experimental part Nelson, Derek W.; Sarris, Kathy; Kalvin, Douglas M.; Namovic, Marian T.; Grayson, George; Donnelly-Roberts, Diana L.; Harris, Richard; Honore, Prisca; Jarvis, Michael F.; Faltynek, Connie R.; Carroll, William A. [Journal of Medicinal Chemistry, 2008, vol. 51, # 10, p. 3030 - 3034]
[3]Ferlin; Chiarelotto; Basadonna; Gia; Mobilio; Baccichetti; Carlassare [Il Farmaco, 1989, vol. 44, # 12, p. 1141 - 1155]
[4]Location in patent: body text Rashidi; Afghan; Baradarani, Mehdi M.; Jouleb, John A. [Journal of Heterocyclic Chemistry, 2009, vol. 46, # 3, p. 428 - 431]

21
[ 580-19-8 ]
[ 611-34-7 ]
[ 108-24-7 ]
[ 42464-80-2 ]
[ 36164-42-8 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; dmap; In dichloromethane; for 1h;	Following the procedure described by Filippi, J. (Bull. Soc. Chim. Fr. 1968, 1, 259-67). [00200] The Skraup reaction of m-nitroaniline and glycerol in the presence of As2O3 and H2SO4 afforded a 65:35 mixture of 5-nitroquinoline and 7-nitroquinoline, respectively, in a combined yield of 21percent. This mixture (6.6 g, 38 mmol) was taken up in EtOAc (50 mL), placed in a 250 mL round-bottom flask, and flushed with nitrogen. Next, 10percent Pd/C (0.6 g) was added and the mixture was placed under a hydrogen atmosphere (H2 balloon) and stirred vigorously for 18 h. The residue was filtered through a pad of celite, eluting with CHCl3 (100 mL), and the solvent was removed in vacuo to afford 5.0 g of a 65:35 mixture of 5-aminoquinoline and <strong>[580-19-8]7-aminoquinoline</strong>, respectively (91percent yield). This material was taken up in CH2Cl2 (100 mL) and pyridine (3 mL, 37 mmol) and DMAP (100 mg, 0.82 mmol) followed by Ac2O (5 mL, 53 mmol) were added. Stirring was continued for 1 h, at which point 4 N NaOH (50 mL) was added and the mixture was extracted with CH2Cl2 (3.x.50 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give 6.5 g of a mixture of N-acetylated products (quant. yield).

Reference： [1]Patent: US6750348,2004,B1 .Location in patent: Page column 41-42

22
[ 607-34-1 ]
[ 613-51-4 ]
[ 580-19-8 ]
[ 611-34-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium 10% on activated carbon; In ethyl acetate; for 18h;	Following the procedure described by Filippi, J. (Bull. Soc. Chim. Fr. 1968, 1, 259-67). [00200] The Skraup reaction of m-nitroaniline and glycerol in the presence of As2O3 and H2SO4 afforded a 65:35 mixture of <strong>[607-34-1]5-nitroquinoline</strong> and 7-nitroquinoline, respectively, in a combined yield of 21percent. This mixture (6.6 g, 38 mmol) was taken up in EtOAc (50 mL), placed in a 250 mL round-bottom flask, and flushed with nitrogen. Next, 10percent Pd/C (0.6 g) was added and the mixture was placed under a hydrogen atmosphere (H2 balloon) and stirred vigorously for 18 h. The residue was filtered through a pad of celite, eluting with CHCl3 (100 mL), and the solvent was removed in vacuo to afford 5.0 g of a 65:35 mixture of 5-aminoquinoline and 7-aminoquinoline, respectively (91percent yield). This material was taken up in CH2Cl2 (100 mL) and pyridine (3 mL, 37 mmol) and DMAP (100 mg, 0.82 mmol) followed by Ac2O (5 mL, 53 mmol) were added. Stirring was continued for 1 h, at which point 4 N NaOH (50 mL) was added and the mixture was extracted with CH2Cl2 (3.x.50 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give 6.5 g of a mixture of N-acetylated products (quant. yield).

Reference： [1]Patent: US6750348,2004,B1 .Location in patent: Page column 41-42

23
[ 611-34-7 ]
[ 214470-55-0 ]
6,7-dimethoxy-4-(quinolin-5-ylamino)-quinoline-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine hydrochloride; In 1-ethoxyethanol; at 200℃; for 2h;Alkaline aqueous solution;	A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.288 g of 5-aminoquinoline, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was heated under nitrogen in a sealed tube at 200C for 2 hours. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.132 g of 6,7-dimethoxy-4-(quinolin-5-ylamino)-quinoline-3-carbonitrile as a solid, mp 115C (decomposed); mass spectrum (EI, m/e): M 356.1276.

Reference： [1]Patent: EP1117659,2003,B1 .Location in patent: Page 74

24
[ 611-34-7 ]
[ 501-53-1 ]
[ 70875-63-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydrogencarbonate In water; acetone at 20℃; for 2h;	32 To A stirred 0°C solution of 5-aminoquinoline (1. 0 g, 6. 9 mmol) in 2 : 1 acetone/water (15 ML) was added NaHC03 (1. 0 g, 13. 7 mmol) followed by benzyl chloroformate (1. 1 ML, 7. 7 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2h then cooled to 0°C and filtered. The filtrate was washed with water and ether and dried in A vacuum oven at 40°C overnight. The yellow solid (carbamate 324) thus obtained (1. 9 g, 100% yield) was used as-is without further purification.

Reference： [1]Current Patent Assignee: BIOVERSYS AG - WO2004/29066, 2004, A2 Location in patent: Page/Page column 274

25
[ 611-34-7 ]
[ 102878-84-2 ]

Yield	Reaction Conditions	Operation in experiment
48%	With hydrogenchloride; thionyl chloride; copper(l) chloride; sodium nitrite In water at -5 - 7℃;	c a) Thionyl chloride (4.2 ml_) was added dropwise over 30 min to water (25 ml_), cooled to 0 5C, maintaning the temperature of the mixture 0-7 5C. The solution was allowed to warm to 18 5C over 17 h. CuCI (15 mg, 0.14 mmol) was added, and the resulting yellow-green solution was cooled to -3 5C. b) Concentrated hydrochloric acid (14 ml_) was cooled to 0 5C for the portionwise addition of quinolin-5-amine (2 g, 13.9 mmol). This was allowed to warm sligthly between additions. After complete addition and at -5 5C a solution of sodium nitrite (1 .053 g, 15.3 mmol) in water (4 ml_) was added dropwise over 45 min, maintaining the temperature of the reaction mixture between -5 to 0 5C. c) The slurry from step b, was cooled to -5 5C and added dropwise to the solution obtained from step a over 30 min, maintaining the temperature of the reaction mixture between -3 to 0 5C (the slurry from step b was maintained at -5 5C throughout the addition). When the addition was complete, the reaction mixture was agitated at 0 5C for 90 min. The solid precipitated was filtered, washed with water and dried under vacuum at 40 5C to give quinoline-5-sulfonyl chloride (1 .5 g, 48% yield) as a red-orange solid.1 H NMR (400 MHz, Chloroform-d) ? 9.18 (dt, J = 8.7, 0.8 Hz, 1 H), 9.12 (dd, J = 4.3, 1 .6 Hz, 1 H), 8.57 (d, J = 8.5 Hz, 1 H), 8.45 (dd, J = 7.6, 1 .2 Hz, 1 H), 7.89 (dd,J = 8.5, 7.6 Hz, 1 H), 7.75 (dd, J = 8.8, 4.3 Hz, 1 H).
	Stage #1: 5-Aminoquinoline With hydrogenchloride In water at 0℃; Stage #2: With sodium nitrite In water at -5℃; Stage #3: With thionyl chloride In water at 0 - 5℃; for 1.5h;	71 (a) Thionyl chloride (2.1ml) was added dropwise to water (12.5ml) at 5 C. This mixture was allowed to warm to room temperature and stirred for 16h. Copper I chloride (10mg) was then added and the resulting yellow solution coofed to0 C. (b) Concentrated hydrochloric acid (6.75mut) was cooled to0 C for the portionwise addition of 5-amino quinoline(1g). This was allowed to warm slightly between additions, when the reaction mixture turned red/orange. After complete addition, the reaction mixture was cooled to-5 C for the dropwise addition of a solution ofNaN02 (0.5g) in water(2ml). After complete addition andat-5 C, the resulting mixture was added slowly to the cooled thionyl chloride/CuCI mixture from part (a).. A solid precipitated and the mixture was stirred at0 C for 1.5h. The brick red solid was filtered and washed with water (300mg), 8H(CDCI3) 7.71 (1H, m), 7.88 (1H, m), 8.44 (1H, m), 8.52 (1H, m), 9.1-9. 2 (2H, m).

Reference： [1]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - WO2013/37960, 2013, A1 Location in patent: Page/Page column 81; 82
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/49023, 2005, A1 Location in patent: Page/Page column 60

26
[ 611-34-7 ]
5-(diazonium)chinolinyl tetrafluoroborate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With tetrafluoroboric acid; isopentyl nitrite In ethanol at 5℃; for 3h;	4.2.5.2. 5-(Trifluoromethylthio) quinoline HBF4 (3.1 mL,24.7 mmol) and isoamyl nitrite (4.1 mL, 30.4 mmol) were addedto a solution of 5-aminoquinoline in 90 mL ethanol while keepingthe temperature below 5 C. After 3 h stirring the mixture wascooled in an ice-water bath, and diethyl ether (20 mL) was added.Subsequently, the mixture was stored overnight at20 C. Theresulting suspension wasfiltered, and the red solid was washedwith a mixture ethanol/diethyl ether (1/10, 40 mL). 5-(Diazonium)chinolinyl tetrafluoroborate was dried under air (2.26 g, 9.3 mmol,93% yield) and was used without further purification for thesubsequent reaction.Under argon atmosphere, CuSCN (0.25 g, 2.1 mmol), NaSCN(0.5 g, 6.1 mmol), and Cs2CO3 (2.7 g, 8.3 mmol) were added to 16 mLacetonitrile and the resulting suspension was stirred for 10 min. Asolution of 5-(diazonium)chinolinyl tetrafluoroborate (1.00 g,4.1 mmol) in 16 mL acetonitrile was added dropwise to thesuspension. Subsequently, Me3SiCF3 was added dropwise andthe solution was stirred for 16 h at room temperature. The resultingmixture wasfiltered over approx. 10 g Celite. The Celite pad waswashed with 310 mL diethyl ether. Thefiltrate was washed withwater and brine, and dried over anhydrous Na2SO4. Column chromatography on silica gel (diethyl ether) afforded5-(trifluoromethylthio) quinoline as a colorless solid in 61% yield(0.57 g, 2.5 mmol).
69%	With tetrafluoroboric acid diethyl ether; isopentyl nitrite In ethanol at -15 - 0℃; for 0.25h;
	With tetrafluoroboric acid; sodium nitrite In water at 0℃;	1 Preparation 1 5-fluoro-1, 2,3, 4-tetrahydroquinoline; 5-fluoroquinoline; Add sodium nitrite in portions to a suspension of 5-aminoquinoline (50 g, 347 mmol) in 4S% HBF4 (200 mL) at 0°C. Stir for 1 hour and then pour into 1: 1 diethyl ether/ethyl acetate (500 mL). Filter the resulting suspension and dry the solid. Add this solid (82.5 g, 338 mmol) in portions to refluxing xylene (1 L), stir for 2 hours, and then cool. Decant the xylene and dissolve the residue in 1N hydrochloric acid (600 mL). Neutralize with sodium carbonate, extract with ethyl acetate (10 x 500 mL), dry the extracts over sodium sulfate, filter and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 10-20% diethyl ether in hexanes. Combine fractions containing product and concentrate them under reduced pressure to provide the desired compound (28.1 g, 55%). MS (EI, m/z) C9H6FN (M+1) 148.0

Reference： [1]Lüdtke, Carsten; Haupt, Axel; Wozniak, Martin; Kulak, Nora [Journal of Fluorine Chemistry, 2017, vol. 193, p. 98 - 105]
[2]Nikolaienko, Pavlo; Rueping, Magnus [Chemistry - A European Journal, 2016, vol. 22, # 8, p. 2620 - 2623]
[3]Current Patent Assignee: ELI LILLY & CO - WO2003/76442, 2003, A1 Location in patent: Page/Page column 22

27
[ 611-34-7 ]
[ 76-02-8 ]
[ 712284-58-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine In dichloromethane at 0 - 20℃; for 1.5h;	25 2,2,2-Trichloro-N-(5-quinolinyl)acetamide 2,2,2-Trichloro-N-(5-quinolinyl)acetamide To a solution of 5-aminoquinoline (1.0 g, 6.9 mmol) and triethylamine (1.0 mL, 7.2 mmol) in dichloromethane (40 mL) was added trichloroacetyl chloride (1.4 g, 7.7 mmol) at 0°C, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was concentrated, and to the residue was added ethyl acetate, and the resulting mixture was extracted three times with 1 N hydrochloric acid. The aqueous layers were combined and neutralized with an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was washed with diisopropyl ether and collected by filtration to obtain the title compound (1.9 g, yield 94%) as colorless crystals. Melting point 145-147°C. 1H NMR (CDCl3) δ 7.49 (1H, dd, J=4.2 Hz, 8.6 Hz), 7.75 (1H, t, J=7.8 Hz), 7.85 (1H, d, J=7.3 Hz), 8.09 (1H, d, J=8.4 Hz), 8.18 (1H, d, J=8.5 Hz), 8.76 (1H, br s), 8.97 (1H, dd, J=1.5 Hz, 4.2 Hz).
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1661898, 2006, A1 Location in patent: Page/Page column 51
[2]Zhang, Yuanyuan; Yang, Weiqing; Xu, Keping; Ma, Menglin; Wang, Yuliang [Letters in drug design and discovery, 2013, vol. 10, # 3, p. 219 - 225]

28
[ 611-34-7 ]
[ 50-81-7 ]
[ 91004-60-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogenchloride; sodium nitrite In water	4 Preparation of 5-hydrazinoquinoline Dihydrochloride EXAMPLE 4 Preparation of 5-hydrazinoquinoline Dihydrochloride To a 250 ml flask under a nitrogen atmosphere, water (20 ml) and concentrated HCl (60 ml, 0.61 moles) were charged and cooled down to -2 to 0° C. 5-Aminoquinoline (10 g, 0.069 moles) was added in one portion as a solid. An increase in temperature of 10° C. was observed. The orange-yellow suspension was re-cooled to -2 to 0° C. and sodium nitrite (5.8 g, 0.084 moles) dissolved in water (10 ml) was added dropwise to the acidic solution through an addition funnel over a period of 20 minutes at -2 to 0° C. The resulting mixture (dark-brown solution) was stirred for 1 hour at -2 to 0° C. L-Ascorbic acid (14.3 g, 0.081 moles) was then added in portions as a solid over a period of 20 minutes at -2 to 0° C. The reaction was allowed to come to room temperature (18-20° C.) over a period of 30 minutes, then heated at 50° C. and stirred for 30 hours at this temperature. The resultant slurry was cooled to room temperature (18-20° C.), stirred for 1 hour at this temperature, filtered and washed with propan-2-ol (40 ml). The product was dried to constant weight in an air tray drier at 40° C. to afford 11.75 g of 5-hydrazinoquinoline dihydrochloride as a green solid (HPLC purity calculated as area percent: 98%, with 1.6% of oxalic acid intermediate; 71.5% molar yield).
	With hydrogenchloride; sodium nitrite In water	1 5-Hydrazinoquinoline dihydrochloride EXAMPLE 1 5-Hydrazinoquinoline dihydrochloride Concentrated hydrochloric acid (300 ml) was added to a one liter round-bottomed flask under a nitrogen atmosphere and equipped with mechanical stirrer, thermometer and reflux condenser. The reaction vessel was cooled to 0+-2° C. and 5-aminoquinoline (50 g) was charged in one portion. An increase in temperature was observed from 0+-2° C. up to 25-26° C. resulting in a pink suspension. The reaction mixture was again cooled to 0+-2° C. and a solution of sodium nitrite (29 g) in water (50 ml) was added to the reaction vessel over a period of 30 minutes, while maintaining the temperature at 0+-2° C. The reaction was stirred for 1 hour at 0+-2° C. Then, L-ascorbic acid (50 g) was added portionwise over a period of 30 minutes. The addition of the first portion of L-ascorbic (1-2 grams) led to effervescence, while the next portions (about 5 grams each) could be added faster as effervescene was not significant. The reaction mixture (brown-red suspension) was stirred at 0+-2° C. for 5-10 minutes, then it was allowed to come to room temperature (18-22° C.) spontaneously in about 40 minutes. Finally, it was heated to 38-42° C. and stirred for about 3 hours at this temperature. Product precipitation was observed after about 30 minutes at 38-42° C., leading to formation of an orange suspension. After 3 hours at 38-40° C. the reaction was deemed complete by HPLC analysis calculated by area percent: 90% (sum of oxalic acid intermediate and 5-hydrazinoquinoline). The reaction mixture was cooled to room temperature (18-22° C.) and water (100 ml) was added. The slurry was stirred for 16 hours at 20+-2° C., then cooled to 0-2° C. and stirred 1.5 hours at 0-2° C. The product was filtered and washed with methanol (230 ml), thus obtaining 107 g of the oxalic acid intermediate as a wet product. A portion of the wet product (97 g) was added to a one liter round-bottomed flask equipped with mechanical stirrer, thermometer, reflux condenser and under a nitrogen atmosphere. Water (100 ml) and concentrated hydrochloric acid (300 ml) were added. The resulting yellow suspension was heated to 90+-2° C. and stirred 1.5 hours, maintaining the temperature at 90+-2°. The mixture was then cooled to room temperature (20+-2° C.) and stirred for two hours at this temperature. The resulting solid was filtered, washed with methanol (330 ml) and dried for 16 hours in an air tray drier at 40° C. affording 61.3 g of 5-hydrazinoquinoline dihydrochloride as a yellow crystalline solid.

Reference： [1]Current Patent Assignee: PFIZER INC - US2002/82274, 2002, A1
[2]Current Patent Assignee: PFIZER INC - US2003/119873, 2003, A1

29
[ 578-67-6 ]
Cs₂ CO₃ [ No CAS ]
[ 7462-74-0 ]
[ 611-34-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; NaH; In 1,4-dioxane;	Preparation of 5-aminoquinoline To a solution of 5-hydroxyquinoline (537 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2 CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150 C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2*50 mL), dried (Na2 SO4), and concentrated to about 3 g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluding with 7:3 EtOAc/hexane to obtain 5-aminoquinoline as a brown solid (90 mg, 0.62 mmol, 16.8% yield).: mp 98-100 C. (lit. 108-109 C., Akita, Y., et. al., Synthesis, 1977, 792); 1 H NMR (300 MHz, CDCl3) delta8.89 (dd, 1 H, J=4.13, 2.06 Hz), 8.18 (dd, 1 H, J=8.49, 0.93), 7.60-7.48 (om's, 2 H), 7.35 (dd, 1 H, J=8.56, 4.26), 6.83 (dd, 1 H, J=7.13, 1.31), 4.21 (br s, 2 H, N--H2); 13 C NMR (75 MHz, CDCl3) delta150.2, 149.1, 142.2, 130.0, 129.5, 120.1, 119.6, 118.7, 110.0; MS (CI/CH4) 145.

Reference： [1]Patent: US6034241,2000,A

30
[ 611-34-7 ]
[ 102308-97-4 ]
1'-carbonyl diimidazole [ No CAS ]
N-(1-Methyl-5-indolyl)-N'-(6-quinolyl)-urea hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		Example 12 N-(1-Methyl-5-indolyl)-N'-(5-quinolyl) urea (E12) The title compound was prepared from 5-aminoquinoline, 1, 1'-carbonyl diimidazole and 5-amino-1-methyl-indole (D2) using a procedure similar to that described for Example 10, in 20% yield, m.p 243-245 C. NMR (D6 -DMSO) delta: 3.76 (3H, s), 6.35 (1H, d, J 2), 7.20 (1H, d, J 6), 7.29 (1H, d, J 2), 7.38 (1H, d, J 6), 7.60-7.65 (1H, m), 7.72 (2H, d, J 3), 7.77 (1H, s), 8.10 (1H, t, J 2), 8.57 (1H, d, J 6) 8.84 (2H, d, J 3), 8.93 (1H, d, J 2) Found: M+ 316 C19 H16 N4 O requires 316

Reference： [1]Patent: US5508288,1996,A

31
[ 872-50-4 ]
[ 578-67-6 ]
[ 7462-74-0 ]
[ 611-34-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; NaH; caesium carbonate; In 1,4-dioxane;	Preparation of 5-aminoquinoline. To a solution of 5-hydroxyquinoline (537 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150 C for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2 x 50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluding with 7:3 EtOAc/hexane to obtain 5-aminoquinoline as a brown solid (90 mg, 0.62 mmol, 16.8 % yield).: mp 98-100 C (lit. 108-109 C, Akita, Y., et. al., Synthesis, 1977, 792); 1H NMR (300 MHz, CDCl3) delta 8.89 (dd, 1 H, J = 4.13, 2.06 Hz), 8.18 (dd, 1 H, J = 8.49, 0.93), 7.60-7.48 (om's, 2 H), 7.35 (dd, 1 H, J = 8.56, 4.26), 6.83 (dd, 1 H, J = 7.13, 1.31), 4.21 (br s, 2 H, N-H2); 13C NMR (75 MHz, CDCl3) delta 150.2, 149.1, 142.2, 130.0, 129.5, 120.1, 119.6, 118.7, 110.0; MS (CI/CH4) 145. The rearrangement product was also isolated from the column as a brown solid (480 mg, 2.08 mmol, 56.2% yield): mp 177-179 C; 1H NMR (300 MHz, CDCl3) delta 9.37 (br s, 1H, N-H), 8.90 (dd, 1 H, J = 4.26, 1.58 Hz), 8.21 (d, 1 H, J = 8.22), 8.09 (d, 1 H, J = 7.80 Hz), 7.96 (d, 1 H, J = 8.66 Hz) 7.70 (apparent t, 1 H, J = 8.06), 4.01 (br s, O-H), 1.63 (s, 6 H, C(CH3)2) 13C NMR (75 MHz, CDCl3) delta 175.3, 150.1, 148.4, 132.3, 129.55, 129.46, 122.1, 120.9, 120.0, 47.8, 27.9; MS (CI/CH4) 231: IR (KBr pellet) 1649 (CO), 3371 (OH).

Reference： [1]Patent: EP944600,2002,B1

32
[ 611-34-7 ]
[ 75-11-6 ]
[ 110-46-3 ]
[ 1006-50-4 ]
5-indoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 1a 5-indoquinoline A suspension of 10 g (0.07 mol) of 5-aminoquinoline, 94 ml (0.7 mol) of isoamylnitrite and 100 ml of diiodomethane was heated at 80C for 2 hours. The reaction mixture was evaporated under reduced pressure at 60-70C. The residue was slurried with diethyl ether, decanted and the filtrate was evaporated under reduced pressure. The resulting residue was chromatographed on a silica gel column eluding with 3:1 hexane-ethyl acetate to yield 2.81 g of 5-iodoquinoline. 1H-NMR (CDCl3, 300MHz) delta 7.42(d, 1H, J= 7.7 Hz); 7.48 (dd, 1H, J= 4.3 Hz); 8.1 (m, 2H,); 8.38 (d, 1H, J= 8.5 Hz); 8.88 (m, 1H,). Mass spec. m/e = 255 = p.

Reference： [1]Patent: EP844244,1998,A1

33
[ 611-34-7 ]
[ 7518-70-9 ]
[ 214470-55-0 ]
6,7-dimethoxy-4-(quinolin-5-ylamino)-quinoline-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine hydrochloride; sodium carbonate; In water;	EXAMPLE 132 6,7-Dimethoxy-4-(quinolin-5-ylamino)-quinoline-3-carbonitrile A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.288 g of 5-aminoquinoline, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was heated under nitrogen in a sealed tube at 200 C. for 2 hours. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.132 g of 6,7-dimethoxy-4-(quinolin-5-ylamino)-quinoline-3-carbonitrile as a solid, mp 115 C. (decomposed); mass spectrum (EI, m/e): M 356.1276.

Reference： [1]Patent: US6288082,2001,B1

34
[ 611-34-7 ]
[ 814-68-6 ]
[ 591251-19-3 ]

Yield	Reaction Conditions	Operation in experiment
36%	With triethylamine In dichloromethane at 0℃; for 2h;	56.1 500 mg of 5-aminoquinoline was dissolved in dichloromethane, and the solution was cooled to 0° C. Then, 0.98 mL of triethylamine was added followed by gradual addition of 0.42 mL of acryloyl chloride. The reaction mixture was stirred for 2 hours, followed by addition of water and extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford 250 mg (36%) of the title compound.1H NMR (CDCl3): δ 8.83 (bs, 1H), 8.29 (bs, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.682 (bs, 1H), 7.60-7.56 (m, 1H), 7.28-7.25 (m, 1H), 6.48-6.30 (m, 2H), and 5.72 (d, J=9.2 Hz, 1H)
36%	With triethylamine In dichloromethane at 0℃; for 2h;	56.1 Example 56: Preparation of cis-4-ammo-5-chloro-N-fl-(3-oxo-3-(quinolin-5-yl- amino)propyD-3-methoxypiperidin-4-vϖ-2-methoxybenzamideStep 1: Preparation of N-(qumolin-5-yl)acrylamide500 mg of 5-aminoquinoline was dissolved in dichloromethane, and the solution was cooled to 0°C . Then, 0.98 niL of triethylamine was added followed by gradual addition of 0.42 mL of acryloyl chloride. The reaction mixture was stirred for 2 hours, followed by addition of water and extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford 250 mg (36%) of the title compound.1H NMR(CDCl3): δ 8.83(bs, IH), 8.29(bs, IH), 8.12(d, J=8.0Hz, IH), 7.90(d, J=7.2Hz, IH), 7.682(bs, IH), 7.60-7.56(m, IH), 7.28-7.25(m, IH), 6.48-6.30(m, 2H), and 5.72(d, J=9.2Hz, IH)

Reference： [1]Current Patent Assignee: DONG-A SOCIO HOLDINGS CO.,LTD. - US2010/105727, 2010, A1 Location in patent: Page/Page column 18-19
[2]Current Patent Assignee: DONG-A SOCIO HOLDINGS CO.,LTD. - WO2008/114971, 2008, A1 Location in patent: Page/Page column 47

35
[ 611-34-7 ]
[ 22809-37-6 ]
[ 1061458-86-3 ]

Yield	Reaction Conditions	Operation in experiment
65%	With triethylamine In dichloromethane at 0℃;	58.1 836 mg of 5-aminoquinoline was dissolved in dichloromethane, and the solution was cooled to 0° C. Then, 1.22 mL of triethylamine was added followed by gradual addition of 1.05 mL of 6-bromohexanoyl chloride. The reaction mixture was stirred for 4 hours, followed by addition of water and extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then purified by column chromatography to afford 1.20 g (65%) of the title compound.1H NMR (CDCl3): δ 8.85 (bs, 1H), 8.11 (d, J=8.4 Hz), 7.95-7.88 (m, 2H), 7.68-7.57 (m, 2H), 7.34-7.28 (m, 1H), J=6.8 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H), 1.88-1.84 (m, 2H), 1.77-1.73 (m, 2H), and 1.53-1.49 (m, 2H)
65%	With triethylamine In dichloromethane at 0℃; for 4h;	58.1 Example 58: Preparation of cis-4-amino-5-chloro-N-fl-(6-oxo-6-(quinolin-5- v0amino)hexyl)-3-methoxypiperidm-4-vII-2-methoxybenzamideStep 1: Preparation of 6-bromo-N-(quinolin-5-yl)hexanamide 836 mg of 5-aminoquinoline was dissolved in dichloromethane, and the solution was cooled to 0°C . Then, 1.22 mL of triethylamine was added followed by gradual addition of 1.05 mL of 6-bromohexanoyl chloride. The reaction mixture was stirred for 4 hours, followed by addition of water and extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then purified by column chromatography to afford 1.20 g (65%) of the title compound.1H NMR(CDCl3): δ 8.85(bs, IH), 8.1 l(d, J=8.4Hz), 7.95-7.88(m, 2H), 7.68-7.57(m, 2H), 7.34-7.28(m, IH), 3.40(t, J=6.8Hz, 2H), 2.44(t, J=7.2Hz, 2H), 1.88-1.84(m, 2H), 1.77-1.73(m, 2H), and l.53-1.49(m, 2H)

Reference： [1]Current Patent Assignee: DONG-A SOCIO HOLDINGS CO.,LTD. - US2010/105727, 2010, A1 Location in patent: Page/Page column 19
[2]Current Patent Assignee: DONG-A SOCIO HOLDINGS CO.,LTD. - WO2008/114971, 2008, A1 Location in patent: Page/Page column 48

36
[ 611-34-7 ]
[ 95233-37-7 ]
4-(4-chlorophenyl)-N-5-quinolinylcyclohexanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%		Example 2 4- (4-CHLOROPHENYL)-N-5-QUINOLINYLCYCLOHEXANECARBOXAMIDE (E2) To a solution OF 4- (4-CHLOROPHENYL) CYCLOHEXANECARBOXYLIC acid (11.9 mg, 0.05 MMOL) in N, N-dimethylacetamide (1 ML) was added thionyl chloride (2.0 M solution in DCM (25 JJI., 0.05 MMOL) and the resultant solution stirred for 30 min. 5-Aminoquinoline (7.2 mg, 0.05 MMOL) and diisopropylethylamine (19 ILL, 0.15 MMOL) in N, N-dimethylacetamide (0.5 mL) were added. The mixture stirred for 16 h and then EVAPORATED IN VACUO. Purification of the residue by reverse phase HPLC gave the title compound as a white solid (6.0 mg, 33%).

Reference： [1]Patent: WO2005/16915,2005,A1 .Location in patent: Page/Page column 14

37
[ 611-34-7 ]
[ 23138-50-3 ]
[ 1250865-91-8 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide at 20℃;

Reference： [1]Location in patent: scheme or table Zhang, Yiqun; Anderson, Marc; Weisman, Jennifer L.; Lu, Min; Choy, Cindy J.; Boyd, Vincent A.; Price, Jeanine; Sigal, Martina; Clark, Julie; Connelly, Michele; Zhu, Fangyi; Guiguemde, W. Armand; Jeffries, Cynthia; Yang, Lei; Lemoff, Andrew; Liou, Ally P.; Webb, Thomas R.; Derisi, Joseph L.; Guy, R. Kiplin [ACS Medicinal Chemistry Letters, 2010, vol. 1, # 9, p. 460 - 465]

38
[ 611-34-7 ]
[ 24424-99-5 ]
[ 161604-57-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine In tetrahydrofuran at 70℃; for 14h;	3.3-1 Step 3-1. Synthesis of tert-butyl quinolin-5-ylcarbamate 5-Aminoquinoline (5.4 g) was dissolved in THF (150 ml). To the solution were added triethylamine (10 ml) and di-tert-butyldicarbonate (10 ml). The reaction mixture was stirred for 14 hours at 70° C. After cooling, the reaction mixture was concentrated in vacuo to give crude material that was purified by silica gel column chromatography to give tert-butyl quinolin-5-ylcarbamate (6.4 g, 70% yield). 1H-NMR (CDCl3) δ: 1.31 (9H, s), 7.40-7.46 (2H, m), 7.70-7.72 (1H, m), 8.09-8.19 (2H, m), 8.94-8.96 (1H, m)
	In ethanol at 20℃;

Reference： [1]Current Patent Assignee: BAYER AG - US2012/129854, 2012, A1 Location in patent: Page/Page column 25
[2]Wang, Peng; Farmer, Marcus E.; Huo, Xing; Jain, Pankaj; Shen, Peng-Xiang; Ishoey, Mette; Bradner, James E.; Wisniewski, Steven R.; Eastgate, Martin D.; Yu, Jin-Quan [Journal of the American Chemical Society, 2016, vol. 138, # 29, p. 9269 - 9276]

39
[ 611-34-7 ]
[ 355386-94-6 ]

Reference： [1]Patent: US2002/19527,2002,A1

40
[ 611-34-7 ]
[ 415913-05-2 ]

Reference： [1]Patent: WO2013/37960,2013,A1

41
[ 611-34-7 ]
[ 1293-79-4 ]
[ 7732-18-5 ]
C₂₀H₁₆FeN₂O*0.8H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: 5-Aminoquinoline; ferrocenoyl chloride With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; Schlenk technique; Stage #2: water With sodium hydrogencarbonate In dichloromethane Inert atmosphere; Schlenk technique;	2 2.5.1. Preparation of FcC(O)(L) compounds 4-12: general procedure The ligands (1 mmol) and NEt3 (2 ml) were added to a red solution of FcC(O)Cl (1 mmol) in CH2Cl2 (20 ml) at 0 °C, under nitrogen and stirring. After the addition, the mixture was allowed to reach room temperature and stirred for 14-16 h.A saturated aqueous solution of NaHCO3 was added. The phases were separated and the organic phase was dried with anhydrous Na2SO4. After filtration, the solvent was evaporated under vacuum. The solid was recrystallized by diffusion of n-hexane into a CH2Cl2 solution. Suitable crystals of 7 and 8 were selected for single crystal X-ray diffraction structure determination.

Reference： [1]Quintal, Susana; Morais, Tânia S.; Matos, Cristina P.; Paula Robalo; Piedade, M. Fátima M.; Villa De Brito, Maria J.; Helena Garcia; Marques, Mónica; Maia, Carla; Campino, Lenea; Madureira, João [Journal of Organometallic Chemistry, 2013, vol. 745-746, p. 299 - 311]

42
[ 611-34-7 ]
[ 874-42-0 ]
N-(2,4-dichlorobenzylidene)quinolin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With acetic acid In ethanol at 60℃; for 3h;	General Procedure for the Synthesis of Compounds 1-19 General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19
	In butan-1-ol Reflux;

Reference： [1]Bano, Bilquees; Abbasi, Sanaullah; Khan, Jalaluddin A. J.; Hussain, Shafqat; Rasheed, Saima; Perveen, Shahnaz; Khan, Khalid Mohammed; Choudhary, M. Iqbal [Medicinal Chemistry, 2015, vol. 11, # 1, p. 60 - 68]
[2]Kozlov; Tereshko [Russian Journal of Organic Chemistry, 2013, vol. 49, # 9, p. 1335 - 1343][Zh. Org. Khim., 2013, vol. 49, # 9, p. 1350 - 1358,9]

43
[ 611-34-7 ]
[ 2160-38-5 ]
[ 1542913-32-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With 5,11,17,23,29,35,41,47-octakis(tert-butyl)-49,50,51,52,53,54,55,56-octakis(hydroxy)calix[8]arene In water at 25℃; for 2 - 2.5h;	General procedure for the synthesis of N-substituted 3,5-dinitrothiophene-2-amine compounds6aa-6av & 6ba-6bf (Scheme 2) General procedure: p-tert-Butylcalix[8]arene (129.6 mg, 0.1 mmol) was stirred in water(5 ml) in a 10 ml round bottomed flask for 30 minutes. Aryl or alkylamine (1 mmol) and 2-bromo-3,5-dinitrothiophene (1 mmol) were added to it and stirred for 2-2.5 h at 25 C. Greenish yellow colourcrude product-catalyst mixture was separated by simple filtration. Then the residue was dispersed in 10ml cold ethylacetate and stired for 5 minutes. The product was then dissolved in ethyl acetate and thecatalyst 1 seperated out as residue by filtration. The residue was further washed with cold ethyl acetate(2 ml) for three times and reuse for letter. All the EtOAc solution was taken in a 100 ml round bottomflaskand evaporated. Finally crystallization from ethyl acetate gave pure product in good to excellentyield (80-88%).
85%	With 5,11,17,23,29,35,41,47-octakis(tert-butyl)-49,50,51,52,53,54,55,56-octakis(hydroxy)calix[8]arene In water at 25℃;	General procedure for the synthesis of N-substituted 3,5-dinitrothiophene-2-amine compounds6aa-6av & 6ba-6bf General procedure: p-tert-Butylcalix[8]arene (129.6 mg, 0.1 mmol) was stirred in water(5 ml) in a 10 ml round bottomed flask for 30 minutes. Aryl or alkylamine (1 mmol) and 2-bromo-3,5-dinitrothiophene (1 mmol) were added to it and stirred for 2-2.5 h at 25 C. Greenish yellow colourcrude product-catalyst mixture was separated by simple filtration. Then the residue was dispersed in 10ml cold ethylacetate and stired for 5 minutes. The product was then dissolved in ethyl acetate and thecatalyst 1 seperated out as residue by filtration. The residue was further washed with cold ethyl acetate(2 ml) for three times and reuse for letter. All the EtOAc solution was taken in a 100 ml round bottomflaskand evaporated. Finally crystallization from ethyl acetate gave pure product in good to excellentyield (80-88%).

Reference： [1]Sarkar, Piyali; Maiti, Samares; Ghosh, Krishnendu; Sengupta, Sumita; Butcher, Ray J.; Mukhopadhyay, Chhanda [Tetrahedron Letters, 2014, vol. 55, # 5, p. 996 - 1001]
[2]Sarkar, Piyali; Maiti, Samares; Ghosh, Krishnendu; Bandyopadhyay, Sumita Sengupta; Butcher, Ray J.; Mukhopadhyay, Chhanda [Tetrahedron Letters, 2014, vol. 55, # 5, p. 996 - 1001]

44
[ 611-34-7 ]
2-chloro-3,4-bis[(4-methoxybenzyl)oxy]benzoic acid [ No CAS ]
[ 1407156-38-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 2-chloro-3,4-bis[(4-methoxybenzyl)oxy]benzoic acid With 1-chloro-1-(dimethylamino)-2-methyl-1-propene In dichloromethane at 0 - 20℃; for 0.583333h; Stage #2: 5-Aminoquinoline In dichloromethane at 0 - 20℃;	1 Synthesis of Compound (iii) To a solution of Compound (ii) (0.86 g, 5 mmol) in dichloromethane (25 ml), 1-chloro-N,N, 2-trimethylpropyl-1-en-1-amine (0.728 ml, 5.5 mmol) was added at 0 °C, and the solution was stirred at room temperature for 35 min. Compound (i) (0.86 g, 6 mmol) was added to the reaction solution at 0 °C, and the solution was let stand overnight at room temperature. Aqueous saturated sodium bicarbonate was added to the reaction solution, and the solution was extracted three times with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. Concentration, washing the solid with diisopropyl ether and filtration yielded Compound (iii) (2.24 g, 80 %). 1H-NMR (CDCl3) δ: 8.96 (1H, d, J = 4.4 Hz), 8.50 (1H, br s), 8.35 (1H, d, J = 8.2 Hz), 8.09-8.01 (2H, m), 7.79-7.69 (2H, m), 7.49-7.34 (6H, m), 7.07-7.02 (1H, m), 6.97-6.92 (2H, br m), 6.86-6.83 (2H, br m), 5.14 (2H, s), 5.02 (2H, s), 3.84 (3H, s), 3.81 (3H, s).

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - EP2703406, 2014, A1 Location in patent: Paragraph 0436

45
[ 611-34-7 ]
[ 50-00-0 ]
[ 939-19-5 ]
[ 1612849-53-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With titanium(IV) dioxide In ethanol; water at 25 - 28℃; for 5h;	General experimental procedure for the synthesis of chromeno-oxazine derivatives General procedure: A mixture of 3-hydroxycoumarin (1mmol), amine (1 mmol), formaldehyde (2.2mmol, 37-41 % aqueous solution) and a catalytic amount of TiO2 nanopowder (10 mol %) inethyl alcohol (5 mL) were taken in a 25 mL round-bottomed with stirring at rt (25-28°C) open to air for 4-6 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was filtered to remove TiO2 nanopowder.The solvent ethyl alcohol was then pumped out by rotary evaporation. The crude product thus obtained was purified directly by recrystallization from ethyl alcohol-water mixture (5:1 v/v).The spectral and analytical data of all compounds (4a-4q) reported in Table 2, are given below.

Reference： [1]Mondal, Animesh; Rana, Sunil; Mukhopadhyay, Chhanda [Tetrahedron Letters, 2014, vol. 55, # 24, p. 3498 - 3502]

46
[ 611-34-7 ]
[ 14588-61-5 ]
C₂₅H₂₂N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With triethylamine In tetrahydrofuran at 0 - 20℃; for 18h; Inert atmosphere;	P.1 Preparation of Compound Represented by Formula 2 (VVZ-001) As shown in reaction scheme 2 above, after cooling a solution of 5-aminoquinoline represented by Formula 84 (439.93 mg, 3.05 mmol, purchased from TCI Co.) and triethylamine (0.95 mL, 6.78 mmol) in THF (10 mL) at 0° C. under a nitrogen atmosphere, a solution of 4-n-benzyloxy-3,5-dimethoxybenzoic acid chloride represented by Formula 85 (1.04 g, 3.39 mmol) in THF (15 mL) was slowly added to the above cold solution. After agitating the prepared solution at the same temperature for 30 minutes, this solution was left at room temperature for 18 hours. After filtering and removing a precipitate generated during the reaction, the remaining solution was diluted with chloroform and washed with a potassium carbonate solution, followed by separation and drying with (anhydrous) sodium sulfate. A concentrate remaining after removing the solvent under reduced pressure was recrystallized using ethyl acetate and hexane, resulting in a benzamide compound represented by Formula 2 as a desired product (VVZ-001; 1.08 g, 77% yield). Analysis data of the produced benzamide compound is provided as follows. Rf (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) 0.3; HRMS (EI+) calcd for C25H22N2O4 ([M+]) 414.1580, 1H NMR (500 MHz, DMSO-d6) d 3.89 (s, 6H), 5.02 (s, 2H), 7.32 (t, 1H, J=7.5 Hz), 7.38 (t, 2H, J=7.5 Hz), 7.43 (s, 2H), 7.48 (d, 2H, J=7.5 Hz), 7.56 (dd, 1H, J=8.5 Hz, 8.5 Hz), 7.66 (d, 1H, J=7.5 Hz), 7.81 (t, 1H, J=7.5 Hz), 7.97 (d, 1H, J=8.5 Hz), 8.35 (d, 1H, J=8.0 Hz), 8.94 (dd, 1H, J=4.0 Hz, 4.0 Hz), 10.48 (s, 1H)
1.08 g	With triethylamine In tetrahydrofuran at 0 - 20℃; for 18.5h; Inert atmosphere; Cooling;	1 Preparative Example 1: Preparation of compound represented by Formula 2 (VVZ-001) 0060] As shown in reaction scheme 2 above, after cooling a solution of 5-aminoquinoline represented by Formula 84 (439.93 mg, 3.05 mmol, purchased from TCI Co.) and triethylamine (0.95 mL, 6.78 mmol) in THF (10 mL) at 0°C under a nitrogen atmosphere, a solution of 4-n-benzyl-3,5-dimethoxybenzoic acid chloride represented by Formula 85 (1.04 g, 3.39 mmol) in THF (15 mL) was slowly added to the above cold solution. After agitating the prepared solution at the same temperature for 30 minutes, this solution was left at room temperature for 18 hours. After filtering and removing a precipitate generated during the reaction, the remaining solution was diluted with chloroform and washed with a potassium carbonate solution, followed by separation and drying with (anhydrous) sodium sulfate. A concentrate remaining after removing the solvent under reduced pressure was recrystallized using ethyl acetate and hexane, resulting in a benzamide compound represented by Formula 2 as a desired product (VVZ-001; 1.08 g, 77% yield). [0061] Analysis data of the produced benzamide compound is provided as follows. Rf (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) 0.3; HRMS (EI+) calcd for C25H22N2O4 ([M+]) 414.1580, 1H NMR (500 MHz, DMSO-d6) d 3.89 (s, 6 H), 5.02 (s, 2 H), 7.32 (t, 1 H, J = 7.5 Hz), 7.38 (t, 2 H, J = 7.5 Hz), 7.43 (s, 2 H), 7,48 (d, 2 H, J = 7.5 Hz), 7.56 (dd, 1 H, J = 8.5 Hz, 8.5 Hz), 7.66 (d, 1 H, J = 7.5 Hz), 7.81 (t, 1 H, J = 7.5 Hz), 7.97 (d, 1 H, J = 8.5 Hz), 8.35 (d, 1 H, J = 8.0 Hz), 8.94 (dd, 1 H, J = 4.0 Hz, 4.0 Hz), 10.48 (s, 1 H).

Reference： [1]Current Patent Assignee: VIVOZON - US2014/336378, 2014, A1 Location in patent: Paragraph 0088; 0089; 0090; 0091; 0092; 0093
[2]Current Patent Assignee: VIVOZON - EP2786986, 2014, A2 Location in patent: Paragraph 0060-0061

47
[ 611-34-7 ]
5-aminoquinolinium nitrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With nitric acid In N,N-dimethyl-formamide	2.1 Synthesis and characterization General procedure: 5-(hydroxyimino)quinolin-8-one was prepared byreported procedure.29,30 Salts 1-4 were preparedby adding hydrochloric, hydrobromic, nitric or perchloricacid (1 mL in each case) to solution of5-(hydroxyimino)quinolin-8-one (0.173 g, 1mmol) indimethylformamide (15 mL). A homogeneous solutionin each case was formed. Each salt crystallized at roomtemperature after about a week. Salt Hamq.NO3(5)and Hquin.NO3(6) were prepared in a similar procedureto that of salt 1-4. In case of Hamq.NO3, 5-aminoquinoline (0.144g, 1 mmol) and for Hquin.NO3, 4-hydroxyquinazoline (0.146g, 1 mmol) was used withconc. nitric acid (1 mL) respectively.

Reference： [1]Khakhlary, Prithiviraj; Baruah, Jubaraj B. [Journal of Chemical Sciences, 2015, vol. 127, # 1, p. 95 - 102]

48
[ 611-34-7 ]
[ 613-45-6 ]
N-(2,4-dimethoxybenzylidene)quinolin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With acetic acid In ethanol at 60℃; for 3h;	General Procedure for the Synthesis of Compounds 1-19 General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

49
[ 611-34-7 ]
[ 86-51-1 ]
N-(2,3-dimethoxybenzylidene)quinolin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With acetic acid In ethanol at 60℃; for 3h;	General Procedure for the Synthesis of Compounds 1-19 General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

50
[ 673-22-3 ]
[ 611-34-7 ]
5-methoxy-2-((quinolin-5-ylimino)methyl)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With acetic acid In ethanol at 60℃; for 3h;	General Procedure for the Synthesis of Compounds 1-19 General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

51
[ 611-34-7 ]
[ 57848-46-1 ]
N-(4-bromo-2-fluorobenzylidene)quinolin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With acetic acid In ethanol at 60℃; for 3h;	General Procedure for the Synthesis of Compounds 1-19 General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

52
[ 611-34-7 ]
[ 59142-68-6 ]
N-(2-bromo-4-fluorobenzylidene)quinolin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With acetic acid In ethanol at 60℃; for 3h;	General Procedure for the Synthesis of Compounds 1-19 General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

53
[ 611-34-7 ]
[ 54881-49-1 ]
N-(2-chloro-3-methoxybenzylidine)quinolin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With acetic acid; In ethanol; at 60℃; for 3h;	General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

Reference： [1]Medicinal Chemistry,2015,vol. 11,p. 60 - 68

54
[ 611-34-7 ]
[ 347-54-6 ]
4-fluoro-2-((quinolin-5-ylimino)methyl)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With acetic acid In ethanol at 60℃; for 3h;	General Procedure for the Synthesis of Compounds 1-19 General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

55
[ 611-34-7 ]
[ 5417-17-4 ]
N-(2-chloro-3,4-dimethoxybenzylidene)quinolin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With acetic acid; In ethanol; at 60℃; for 3h;	General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

Reference： [1]Medicinal Chemistry,2015,vol. 11,p. 60 - 68

56
[ 611-34-7 ]
[ 90-60-8 ]
2,4-dichloro-6-((quinolin-3-ylimino)methyl)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With acetic acid In ethanol at 60℃; for 3h;	General Procedure for the Synthesis of Compounds 1-19 General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

57
[ 611-34-7 ]
[ 134-96-3 ]
2,6-dimethoxy-4-((quinolin-5-ylimino)methyl)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With acetic acid In ethanol at 60℃; for 3h;	General Procedure for the Synthesis of Compounds 1-19 General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

58
[ 611-34-7 ]
[ 635-93-8 ]
4-chloro-2-((quinolin-5-ylimino)methyl)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With acetic acid In ethanol at 60℃; for 3h;	General Procedure for the Synthesis of Compounds 1-19 General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

59
[ 611-34-7 ]
[ 19652-32-5 ]
2-bromo-4-chloro-6-((quinolin-5-ylimino)methyl)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With acetic acid; In ethanol; at 60℃; for 3h;	General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

Reference： [1]Medicinal Chemistry,2015,vol. 11,p. 60 - 68

60
[ 611-34-7 ]
[ 83-38-5 ]
N-(2,6-dichlorobenzylidene)quinolin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With acetic acid In ethanol at 60℃; for 3h;	General Procedure for the Synthesis of Compounds 1-19 General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

61
[ 611-34-7 ]
[ 2144-08-3 ]
4-((quinolin-5-ylimino)methyl)benzene-1,2,3-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With acetic acid In ethanol at 60℃; for 3h;	General Procedure for the Synthesis of Compounds 1-19 General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19

62
[ 611-34-7 ]
[ 542-92-7 ]
[ 587-04-2 ]
(6S*,6aR*,9aS*)-6-(m-chlorophenyl)-6,6a,7,9a-tetrahydro-5H-cyclopenta[c][1,7]phenanthroline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With trifluoroacetic acid In trifluoroacetic acid at 25℃; Inert atmosphere; diastereoselective reaction;	Synthesis of 6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]1,7 (7-10) and 6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]1,8phenanthrolines (11-14) (general procedure). The compound CF3COOH (0.08 mL, 1 mmol), a freshly distilled cyclopentadiene (0.33 mL, 4 mmol), and the corresponding aldehyde 3-6 (1 mmol) were sequentially added to a solution of aminoquinoline 1 or 2 (144 mg, 1 mmol) in anhydrous CF3CH2OH (15 mL) (Ar, ~25 °C). The reaction mixture was stirred at room temperature until the amine disappeared (2-3 h, TLC monitoring, eluent ethyl acetate). The solvent was evaporated, a saturated solution of NaHSO3-NaHCO3 was added to the residue untilneutrality (~5 mL), followed by extraction with ethyl acetate (3×10 mL). The organic layer was concentrated, the residue was subjected to chromatography (SiO2, n-hexane/ethyl acetate,4 : 1) to isolate the corresponding 1,7- (7-10) or 1,8- phenanthrolines (11-14).

Reference： [1]Tolstikov; Savchenko; Lukina; Limantseva; Odinokov [Russian Chemical Bulletin, 2014, vol. 63, # 9, p. 2077 - 2080][Izv. Akad. Nauk, Ser. Khim., 2014, # 9, p. 2077 - 2080,5]

63
[ 611-34-7 ]
[ 542-92-7 ]
[ 446-52-6 ]
(6S*,6aR*,9aS*)-6-(o-fluorophenyl)-6,6a,7,9a-tetrahydro-5H-cyclopenta[c][1,7]phenanthroline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With trifluoroacetic acid In trifluoroacetic acid at 25℃; Inert atmosphere; diastereoselective reaction;	Synthesis of 6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]1,7 (7-10) and 6-aryl-6,6a,7,9a-tetrahydro-5H-cyclopenta[c]1,8phenanthrolines (11-14) (general procedure). The compound CF3COOH (0.08 mL, 1 mmol), a freshly distilled cyclopentadiene (0.33 mL, 4 mmol), and the corresponding aldehyde 3-6 (1 mmol) were sequentially added to a solution of aminoquinoline 1 or 2 (144 mg, 1 mmol) in anhydrous CF3CH2OH (15 mL) (Ar, ~25 °C). The reaction mixture was stirred at room temperature until the amine disappeared (2-3 h, TLC monitoring, eluent ethyl acetate). The solvent was evaporated, a saturated solution of NaHSO3-NaHCO3 was added to the residue untilneutrality (~5 mL), followed by extraction with ethyl acetate (3×10 mL). The organic layer was concentrated, the residue was subjected to chromatography (SiO2, n-hexane/ethyl acetate,4 : 1) to isolate the corresponding 1,7- (7-10) or 1,8- phenanthrolines (11-14).

Reference： [1]Tolstikov; Savchenko; Lukina; Limantseva; Odinokov [Russian Chemical Bulletin, 2014, vol. 63, # 9, p. 2077 - 2080][Izv. Akad. Nauk, Ser. Khim., 2014, # 9, p. 2077 - 2080,5]

64
[ 611-34-7 ]
[ 15486-96-1 ]
3-bromo-N-(5-quinolyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With dmap In tetrahydrofuran at 0 - 20℃;	5 General procedure for the synthesis of 3-bromo-N-substituted propanamide derivatives (2-8) General procedure: A solution of the appropriate amine (1 equiv) and 4-(dimethylamino)pyridine (DMAP) (0.47 equiv) in dry THF was added dropwise to a solution of 3-bromopropionyl chloride (1.5equiv) in THF (10mL) cooled at 0°C. The reaction mixture was kept under vigorous stirring at rt for 4h and then was quenched with H2O and extracted with CHCl3. The organic phase was washed with a saturated aqueous solution of NaHCO3 and brine, and dried over anhydrous Na2SO4. After the solvent was removed in vacuo, the residue was purified by flash chromatography using a silica gel column with a cyclohexane/AcOEt (7/3) solvent system to give the compounds (1-7) as solids.

Reference： [1]Pasquinucci, Lorella; Turnaturi, Rita; Aricò, Giuseppina; Parenti, Carmela; Pallaki, Paschalina; Georgoussi, Zafiroula; Ronsisvalle, Simone [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 12, p. 2832 - 2842]

65
[ 611-34-7 ]
[ 160893-07-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3307 - 3312
[2]Patent: KR101778938,2017,B1

66
[ 611-34-7 ]
[ 871268-57-4 ]
C₈₈H₈₈N₈O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 5-Aminoquinoline; 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetracarboxymethoxycalix[4]arene In dichloromethane for 0.25h; Stage #2: With dmap; dicyclohexyl-carbodiimide at 25℃; for 48h;	Synthesis of compound D General procedure: A mixture of compound C (1 g, 1.13 mmol) and differentquinoline and pyrimidine moiety (X) (0.6 g) were dissolvedin anhydrous dichloromethane (20-25 ml) and stirred thissolution for 15 min. Then N,N0-dicyclohexylcarbodiimide(DCC) (0.93 g, 0.004 mol) and catalytic amount of 4-dimethylaminopyridine (DMAP) were added into thereaction mixture. This reaction mixture was stirred at roomtemperature for 48 h. The reaction progress was monitoredby TLC using mixture of chloroform:methanol (7:3). Afterthe completion of reaction, solvent was evaporated. Thecrude product was then wash with 1 N HCl followed byNaHCO3for the removal of unreacted quinoline and pyrimidinecompounds and unreacted compound C. The productwas then crystalized with dichloromethane, solubility: solublein CHCl3, CH2Cl2, CH3CN and insoluble in H2O.

Reference： [1]Shah, Rahul B.; Valand, Nikunj N.; Sutariya, Pinkesh G.; Menon, Shobhana K. [Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2016, vol. 84, # 1-2, p. 173 - 178]

67
[ 611-34-7 ]
4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)benzoic acid [ No CAS ]
4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(quinolin-5-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24.29%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	29 Example 29 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N- (quinolin-5-yl)benzamide (31) [00165]A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA (0.23 ml, 1.32 mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 5-aminoquinoline (0.13 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. The residue was purified by flash column over silica gel (ethyl acetate: n-hexane = 1:2, Rf = 0.20) to afford 31 (0.10 g, 24.29 %) as a red solid. 1H-NMR (300 MHz, DMSO-d6): ^5.06 (s, 2H), 7.47-7.53 (m, 3H), 7.68 (d, J= 6.9 Hz, 1H), 7.73-7.83 (m, 3H), 7.92-8.05 (m, 5H), 8.14 (s, 1H), 8.37 (d, J= 8.7 Hz, 1H), 8.91 (s, 1H), 10.48 (s, 1H).
24.29%	Stage #1: 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)benzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide Stage #2: 5-Aminoquinoline In N,N-dimethyl-formamide at 20℃;	27 Example 27 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N- (quinolin-5-yl)benzamide (31) A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA (0.23 ml, 1.32 mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 5- aminoquinoline (0.13 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. The residue was purified by flash column over silica gel (ethyl acetate: n-hexane = 1:2, Rf = 0.20) to afford 31 (0.10 g, 24.29 %) as a red solid. 1H-NMR (300 MHz, DMSO- d6): δ 5.06 (s, 2H), 7.47-7.53 (m, 3H), 7.68 (d, J= 6.9 Hz, 1H), 7.73-7.83 (m, 3H), 7.92-8.05 (m, 5H), 8.14 (s, 1H), 8.37 (d, J= 8.7 Hz, 1H), 8.91 (s, 1H), 10.48 (s, 1H).
24.29%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	10 4.1.1.1 4-(((3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-phenylbenzamide (10a) General procedure: A mixture of 12 (0.25 g, 0.73 mmol), HBTU (0.42 g, 1.10 mmol), DIPEA (0.29 ml, 1.65 mmol) and DMF (2.0 ml) was stirred for a while then the aniline (0.08 g, 0.88 mmol) was added at room temperature and the mixture was stirred overnight. The residue was filtered and purified by washing with different solvents to afford 10a (0.23 g, 76.33%) as a red solid.

24.29%

Stage #1: 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)benzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide Stage #2: 5-Aminoquinoline In N,N-dimethyl-formamide at 20℃;

29 Example 29
4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylamino)methyl)-N-(quinolin-5-yl)benzamide (31) A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA (0.23 ml, 1.32 mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 5-aminoquinoline (0.13 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. The residue was purified by flash column over silica gel (ethyl acetate: n-hexane=1:2, Rf=0.20) to afford 31 (0.10 g, 24.29%) as a red solid. 1H-NMR (300 MHz, DMSO-d6): δ 5.06 (s, 2H), 7.47-7.53 (m, 3H), 7.68 (d, J=6.9 Hz, 1H), 7.73-7.83 (m, 3H), 7.92-8.05 (m, 5H), 8.14 (s, 1H), 8.37 (d, J=8.7 Hz, 1H), 8.91 (s, 1H), 10.48 (s, 1H).

Reference： [1]Current Patent Assignee: CALGENT BIOTECHNOLOGY - WO2017/14788, 2017, A1 Location in patent: Paragraph 00165
[2]Current Patent Assignee: CALGENT BIOTECHNOLOGY - WO2017/87695, 2017, A1 Location in patent: Paragraph 0090
[3]Liu, Yi-Min; HuangFu, Wei-Chun; Huang, Han-Li; Wu, Wei-Cheng; Chen, Yi-Lin; Yen, Yun; Huang, Hsiang-Ling; Nien, Chih-Ying; Lai, Mei-Jung; Pan, Shiow-Lin; Liou, Jing-Ping [European Journal of Medicinal Chemistry, 2017, vol. 140, p. 84 - 91]
[4]Current Patent Assignee: CALGENT BIOTECHNOLOGY - US2020/148643, 2020, A1 Location in patent: Paragraph 0194; 0195

68
[ 611-34-7 ]
[ 23095-05-8 ]
5-bromo-2-methoxy-N-(quinolin-5-yl)benzene sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With pyridine Reflux;	4.3. General procedure for synthesis of compounds 1-40 General procedure: Quinoline analogs were synthesized by refluxing 1 mmol ofsulfonyl chloride with 1 mmol of different quinoline in 10 mL ofpyridine for 6 h. Succession of reaction was studied by thin layerchromatography (TLC) analysis. On completion of reactions, themixturewas poured into coolwater which resulted in precipitation.The precipitates were filtered, washed with hexane and dried toafford target compounds.
	With pyridine at 120℃;	General Procedure for the Synthesis of Compounds(1-50) General procedure: Compounds (1-50) were synthesized by refluxing1 mmol of sulfonyl chloride with 1 mmol of 3-amino,5-amino, 8-amino, and 5-hydroxy quinolines in 10 mL ofpyridine for 40-45 min at 120°C. The completion of the reactionwas studied by thin-layer chromatography (TLC) analysis.Upon completion, the mixture was poured into ice-coldwater which resulted in precipitation. The precipitates werefiltered, washed with hexane, and dried to afford target compounds

Reference： [1]Bano, Bilquees; Arshia; Khan, Khalid Mohammed; Kanwal; Fatima, Bibi; Taha, Muhammad; Ismail, Nor Hadiani; Wadood, Abdul; Ghufran, Mehreen; Perveen, Shahnaz [European Journal of Medicinal Chemistry, 2017, vol. 139, p. 849 - 864]
[2]Bano, Bilquees; Kanwal; Khan, Khalid Mohammed; Jabeen, Almas; Faheem, Aisha; Taha, Muhammad; Haider, Syed Moazzam; Perveen, Shahnaz [Letters in drug design and discovery, 2021, vol. 18, # 2, p. 112 - 120]

69
[ 611-34-7 ]
[ 36887-98-6 ]

Yield	Reaction Conditions	Operation in experiment
84%		General procedure: In a 1.5 mL reaction vial, B(C6F5)3 (0.025 mmol, 5.0 mol %) was dissolved in chloroform (0.60 mL), towhich diethylsilane (1.75 mmol, 3.5 equiv) was added. After shaking briefly, quinolines (1a-p, 0.50 mmol, 1.0equiv) was subsequently added to the above catalyst solution under argon atmosphere. The reaction mixturewas stirred at 25-65 oC for 6-24 h for the reaction of 1a-h, and at 25-100 oC for 2-24 h for the reaction of 1i-p,then allowed to cool down to room temperature and concentrated under reduced pressure to give the crudeproduct. This reaction mixture was then treated with 0.25 N HCl ethereal solution (7 mL) and stirred at roomtemperature for 1 h to give the solid residue, which was subsequently washed with ether. The solid residue wasthen dissolved or suspended in MeOH (1.0 mL) and neutralized with Na2CO3·H2O (0.5 g) at 0 oC. After stirringfor 2 h, MeOH was removed under reduced pressure, and the neutralized reaction residue was dissolved inCH2Cl2 and washed with brine (5 mL) and water (5 mL). The crude product was then obtained from the organicphase of CH2Cl2 solution and finally purified by column chromatography on silica gel to give 2a-h(EtOAc/Hexane = 1/9) and 2i-p (EtOAc/Hexane = 3/7).

Reference： [1]Synlett,2017,vol. 28,p. 2396 - 2400
[2]Organic and biomolecular chemistry,2020,vol. 18,p. 1214 - 1220
[3]Chinese Journal of Chemistry,2021,vol. 39,p. 2504 - 2508

70
[ 611-34-7 ]
[ 6931-19-7 ]

Reference： [1]Patent: KR101778938,2017,B1

71
[ 611-34-7 ]
[ 160893-04-9 ]

Reference： [1]Patent: KR101778938,2017,B1

72
[ 611-34-7 ]
[ 7560-50-1 ]
(E)-N-hydroxy-3-(4-((quinolin-5-ylamino)methyl)phenyl)acrylamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 905 - 917

73
[ 611-34-7 ]
[ 7560-50-1 ]
(E)-methyl 3-(4-((quinolin-5-ylamino)methyl)phenyl)acrylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 905 - 917

74
[ 611-34-7 ]
C₃₀H₂₀IN [ No CAS ]
C₃₉H₂₇N₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 110℃;	10 Synthesis of intermediate XI Add 29.7g of reaction type to a dry 1L three-necked flask45 of the iodoform obtained and 9.0 g of 5-aminoquinoline,Dry and degassed 600 mL of toluene was added as a solvent.Added 16.4 g of sodium tert-butoxide, 0.26 g of palladium acetate catalyst (2% mol)And 1.42 g of ligand 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP, 4% mol).The temperature was raised to 110°C and the reaction ended overnight.Cool to room temperature, add activated carbon adsorption, suction filtration, spin off the solvent,Recrystallization from toluene and ethanol,26 g of intermediate XI are obtained (yield 85%).

Reference： [1]Current Patent Assignee: NANJING TOPTO SEMICONDUCTOR MATERIAL CO LTD - CN107686484, 2018, A Location in patent: Paragraph 0277-0280

75
[ 611-34-7 ]
[ 909871-48-3 ]
2,4-bis(benzyloxy)-5-isopropyl-N-(quinolin-5-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
54%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;	4.1.1. 2,4-Bis(benzyloxy)-5-isopropyl-N-(quinolin-3-yl)benzamide (28) General procedure: 2,4-Bis(benzyloxy)-5-isopropylbenzoic acid (1.28 g, 3.4 mmol), N-methylmorpholine (0.9 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide)(0.97 g, 5.1 mmol) and hydroxybenzotriazole (0.55 g,4.1 mmol) were added to a solution of 3-aminoquinoline (23) (0.5 g,3.4 mmol) in DMF (5 mL). The reaction mixture was stirred at rt for 12 h and then diluted with water. Extraction was with EtOAc (3×50 mL), and the organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography(EtOAc:n-hexane=1:3) to afford compound 6 (1.03 g,61% yield).

Reference： [1]Current Patent Assignee: TAIPEI MEDICAL UNIVERSITY - WO2018/171575, 2018, A1 Location in patent: Page/Page column 25; 33; 35; 79; 80
[2]Nepali, Kunal; Lin, Mei-Hsiang; Chao, Min-Wu; Peng, Sheng-Jhih; Hsu, Kai-Cheng; Eight Lin, Tony; Chen, Mei-Chuan; Lai, Mei-Jung; Pan, Shiow-Lin; Liou, Jing-Ping [Bioorganic Chemistry, 2019, vol. 91]

76
[ 91-22-5 ]
[ 580-19-8 ]
[ 580-15-4 ]
[ 578-66-5 ]
[ 611-34-7 ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 532 - 536
Angew. Chem.,2019,vol. 131,p. 542 - 546,5

77
[ 611-34-7 ]
[ 1677-50-5 ]
2,6-dichloro-N-(quinolin-5-yl)quinolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	In neat (no solvent); at 180℃; for 0.5h;	General procedure: 2-Chloro-NH substituted quinoline amines were prepared asdescribed, by one of the co-authors, in literature (Vennilaet al. 2010; Prabha and Prasad 2014). In a typical experiment, an equimolar mixture of 8-methyl or 6-chloroquinoline (0.01 mol) and varieties of aminoquinoline/aminocarboxylicacids (0.01 mol) was heated under neat condition.The reaction was monitored by TLC. The productobtained was washed with water, dried and purified bysilica gel column chromatography ethylacetate:methanol(99:1) as an eluent to get the respective 4-amino substitutedproducts which was recrystallized using ethanol (Scheme2). The reaction temperature and time are collected in Table2. The prepared compounds were characterized by elementalanalysis, IR, 1H NMR and mass studies (Fig. S2).The results obtained are accordance with those reportedearlier.

Reference： [1]Medicinal Chemistry Research,2019,vol. 28,p. 1298 - 1307

78
[ 611-34-7 ]
[ 32315-10-9 ]
(5-(2,5-dichlorophenyl)furan-2-yl)methanamine [ No CAS ]
1-((5-(2,5-dichlorophenyl)furan-2-yl)methyl)-3-(quinolin-5-yl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: 5-Aminoquinoline; bis(trichloromethyl) carbonate With triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: (5-(2,5-dichlorophenyl)furan-2-yl)methanamine In dichloromethane at 20℃; for 6h;	1-((5-(2,5-Dichlorophenyl)furan-2-yl)methyl)-3-(quinolin-5-yl)urea (12). A solution of quinolin-5-amine(7, 250 mg, 1.73 mmol) and TEA (200 L, 2.03 mmol) dissolved in CH2Cl2 (DCM, 15 mL) wasslowly dripped into a stirred solution of triphosgene (BTC, 256 mg, 0.85 mmol) in DCM (10 mL)by using a constant-pressure dropping funnel. Then, the mixture was stirred for another 0.5 h at room temperature (RT). After evaporation of the solvent, the residue was taken up in DCM (30 mL),and (5-(2,5-dichlorophenyl)furan-2-yl)methanamine (5b, 230 mg, 0.95 mmol) was added directly to the residue. The reaction mixture was stirred at RT for 6 h, and the solvent was subsequently removed in vacuo. The residue obtained was purified by column chromatography (V(PE):V(EA) = 1:1) to give the desired target compound 12 (343 mg, 0.84 mmol) in 88% yield. 96.8% HPLC purity. Mp: 245-246 °C.1H-NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.89 (dd, J = 4.0 Hz, J = 4.0 Hz, 1H), 8.54 (d, J = 8.4 Hz,1H), 8.06-8.04 (m, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.69 (s, 1H), 7.68 (d, J = 2.8 Hz, 1H), 7.60-7.53 (m, 2H),7.39 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 7.20 (d, J = 3.2 Hz, 2H), 6.53 (d, J = 3.2 Hz, 1H), 4.47 (d, J = 5.6 Hz,2H) ppm. 13C-NMR (101 MHz, DMSO-d6) δ 155.9, 154.7, 150.7, 148.7, 147.3, 135.8, 133.0, 132.7, 130.8,130.3, 129.9, 128.6, 127.7, 126.9, 123.8, 121.3, 121.0, 117.4, 113.6, 109.5, 36.90 ppm. HRMS: m/z calcd for C21H16N3O2 [M + H]+ 412.0577, found 412.0573.

Reference： [1]Wang, Lijiao; Li, Chao; Chen, Wei; Song, Chen; Zhang, Xing; Yang, Fan; Wang, Chen; Zhang, Yuanyuan; Qian, Shan; Wang, Zhouyu; Yang, Lingling [Molecules, 2019, vol. 24, # 15]

79
[ 611-34-7 ]
[ 86-57-7 ]
C₁₉H₁₄N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium phosphate tribasic trihydrate; 2-(2,4,6-trimethylphenyl)-5-(2,4,6-triisopropylphenyl)-2H-imidazo[1,5-a]pyridin-4-ium chloride; palladium(II) acetylacetonate In 1,4-dioxane at 130℃; for 24h; Sealed tube; Inert atmosphere;	19 Example 19 In a nitrogen atmosphere, 103.9 mg of the above nitroaromatic hydrocarbon, 171.8 mg of 5-aminoquinoline, and 9.2 mg of Pd(acac) 2 were added to the dried sealed tube.15.0 mg of imidazolium salt L1, 480 mg of tripotassium phosphate trihydrate,3 mL of dioxane, then tighten the sealing cap and react at 130 ° C for 24 h.After the reaction, it was filtered through celite, concentrated, and passed through a silica gel column.The product was obtained in 141.8 mg.The yield was 87%.
87%	With bis(acetylacetonato)palladium(II); potassium phosphate tribasic trihydrate; 2-(2,6-diethyl-4-methylphenyl)-5-(2,4,6-triisopropylphenyl)imidazo[1,5-a]pyridin-2-ium chloride In 1,4-dioxane at 130℃; for 24h; Inert atmosphere;

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY - CN110105230, 2019, A Location in patent: Paragraph 0131-0135
[2]Chen, Kai; Chen, Wanzhi; Chen, Wei; Liu, Miaochang; Wu, Huayue [ACS Catalysis, 2019, p. 8110 - 8115]

80
[ 611-34-7 ]
butanedioic acid [3R-(3α,5aβ,6β,8aβ,9α,12β,12aR*)]-mono(decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-yl) ester [ No CAS ]
(3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl 4-oxo-4-(quinolin-5-ylamino)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	2.1.4. Procedure for the preparation of compound E1-E10 General procedure: A 25 mL round bottomed flask was charged with D (100 mg,0.26 mmol), heterocyclic rings (0.51 mmol), EDCI (0.51 mmol) andDMAP (0.26 mmol) and DCM (5 mL). This reaction mixture was stirredat room temperature for 5-8 h. The mixture was extracted with DCMand the organic phase was washed with saturated sodium bicarbonatesolution and brine, and dried over Na2SO4. The solid was removed byfiltration and the solvent was evaporated under reduced pressure toafford the crude product further purified by chromatography(DCM:MeOH = 100:1-30:1) and characterized by the physical andspectroscopic data shown below.

Reference： [1]Deng, Hao; Huang, Xing; Jin, Chun-Mei; Jin, Chunmei; Quan, Zhe-Shan [Bioorganic Chemistry, 2020, vol. 94]

81
[ 4964-71-0 ]
[ 611-34-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With ammonium hydroxide; L-2-O-methyl-chiro-inositol; copper(II) acetate monohydrate In 1-methyl-pyrrolidin-2-one at 110℃; for 12h;	Synthesis of 5a-z, 5aa; General Procedure C General procedure: To a sealed reaction vessel were added ammonia (aq, 25%) (1.8 mL, 12.8 mmol),Cu(OAc)2·H2O (0.13 mmol), QCT (0.26 mmol) in NMP (1.8 mL) and aryl halides(1.28 mmol). The resulting mixture was heated in an oil bath with appropriatetemperature under rapid stirring for the indicated time. After complete consumption ofthe aryl halide as monitored by TLC, the reaction vessel was cooled to r.t. It was openedto air, and the reaction mixture was extracted with ethyl acetate (3×10 mL), and theorganic layer was washed with water (2×10 mL) and once with brine (10 mL), driedwith magnesium sulfate and concentrated in vacuo. The product was purified bycolumn chromatography on silica gel.

Reference： [1]Chen, Guoliang; Chen, Yuanguang; Du, Fangyu; Fu, Yang; Wu, Ying; Zhou, Qifan [Synlett, 2019, vol. 30, # 19, p. 2161 - 2168]

82
[ 611-34-7 ]
2β,3β-diacetyloxy-20-oxo-30-norlupan-28-oic acid [ No CAS ]
quinolin-5-yl 2β,3β-diacetyloxy-20-oxo-30-norlupan-28-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: 2β,3β-diacetyloxy-20-oxo-30-norlupan-28-oic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 23℃; for 1h; Stage #2: 5-Aminoquinoline With dmap; triethylamine In pyridine; dichloromethane at 120℃; for 2h; Microwave irradiation;	4.3. General procedure for the synthesis of quinolinyl amides (GP C) General procedure: The corresponding acetylated compound (5, 13, 17 and 21) wasdissolved in dry DCM (10 mL), and activated with oxalyl chloride (4eq.) and catalytic quantities of DMF as described above. The volatileswere removed under reduced pressure, the residue was dissolvedin dry DCM (4 mL), and dry pyridine (8 mL), and therespective amine (3 eq.) and catalytic quantities of DMAP andtriethylamine were added. The reaction mixture was stirred withthe help of microwave irradiation (Anton Parr, Graz/Austria, Monowave)at 120 °C for 2 h. Usual aqueous workup followed by columnchromatographic purification gave compounds 7, 8, 15, 16, 19,20, 23 and 24, respectively.

Reference： [1]Deigner, Hans-Peter; Heise, Niels V.; Hoenke, Sophie; Kahnt, Michael; Csuk, René [European Journal of Medicinal Chemistry, 2020, vol. 207]

83
[ 611-34-7 ]
3-O-acetylbetulinic acid [ No CAS ]
quinolin-5-yl 3β-acetoxy-lup-20(29)-en-28-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: 3-O-acetylbetulinic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 23℃; for 1h; Stage #2: 5-Aminoquinoline With dmap; triethylamine In pyridine; dichloromethane at 120℃; for 2h; Microwave irradiation;	4.3. General procedure for the synthesis of quinolinyl amides (GP C) General procedure: The corresponding acetylated compound (5, 13, 17 and 21) wasdissolved in dry DCM (10 mL), and activated with oxalyl chloride (4eq.) and catalytic quantities of DMF as described above. The volatileswere removed under reduced pressure, the residue was dissolvedin dry DCM (4 mL), and dry pyridine (8 mL), and therespective amine (3 eq.) and catalytic quantities of DMAP andtriethylamine were added. The reaction mixture was stirred withthe help of microwave irradiation (Anton Parr, Graz/Austria, Monowave)at 120 °C for 2 h. Usual aqueous workup followed by columnchromatographic purification gave compounds 7, 8, 15, 16, 19,20, 23 and 24, respectively.

Reference： [1]Deigner, Hans-Peter; Heise, Niels V.; Hoenke, Sophie; Kahnt, Michael; Csuk, René [European Journal of Medicinal Chemistry, 2020, vol. 207]

84
[ 611-34-7 ]
[ 26581-14-6 ]
quinolin-5-yl 3β-acetyloxy-20-oxo-30-norlupan-28-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	Stage #1: (3β)-3-acetyloxy-20-oxo-30-norlupan-28-oic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 23℃; for 1h; Stage #2: 5-Aminoquinoline With dmap; triethylamine In pyridine; dichloromethane at 120℃; for 2h; Microwave irradiation;	4.3. General procedure for the synthesis of quinolinyl amides (GP C) General procedure: The corresponding acetylated compound (5, 13, 17 and 21) wasdissolved in dry DCM (10 mL), and activated with oxalyl chloride (4eq.) and catalytic quantities of DMF as described above. The volatileswere removed under reduced pressure, the residue was dissolvedin dry DCM (4 mL), and dry pyridine (8 mL), and therespective amine (3 eq.) and catalytic quantities of DMAP andtriethylamine were added. The reaction mixture was stirred withthe help of microwave irradiation (Anton Parr, Graz/Austria, Monowave)at 120 °C for 2 h. Usual aqueous workup followed by columnchromatographic purification gave compounds 7, 8, 15, 16, 19,20, 23 and 24, respectively.

Reference： [1]Deigner, Hans-Peter; Heise, Niels V.; Hoenke, Sophie; Kahnt, Michael; Csuk, René [European Journal of Medicinal Chemistry, 2020, vol. 207]

85
[ 611-34-7 ]
[ 1190957-92-6 ]
quinolin-5-yl 2β,3β-diacetyloxy-lup-20(29)-en-28-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	Stage #1: 2β,3β-diacetyloxy-lup-20(29)-en-28-oic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 23℃; for 1h; Stage #2: 5-Aminoquinoline With dmap; triethylamine In pyridine; dichloromethane at 120℃; for 2h; Microwave irradiation;	4.3. General procedure for the synthesis of quinolinyl amides (GP C) General procedure: The corresponding acetylated compound (5, 13, 17 and 21) wasdissolved in dry DCM (10 mL), and activated with oxalyl chloride (4eq.) and catalytic quantities of DMF as described above. The volatileswere removed under reduced pressure, the residue was dissolvedin dry DCM (4 mL), and dry pyridine (8 mL), and therespective amine (3 eq.) and catalytic quantities of DMAP andtriethylamine were added. The reaction mixture was stirred withthe help of microwave irradiation (Anton Parr, Graz/Austria, Monowave)at 120 °C for 2 h. Usual aqueous workup followed by columnchromatographic purification gave compounds 7, 8, 15, 16, 19,20, 23 and 24, respectively.

Reference： [1]Deigner, Hans-Peter; Heise, Niels V.; Hoenke, Sophie; Kahnt, Michael; Csuk, René [European Journal of Medicinal Chemistry, 2020, vol. 207]

86
[ 611-34-7 ]
[ 70395-35-6 ]
2-chloro-2-fluoro-N-(quinolin-5-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; at 0 - 20℃; for 1.0h;	General procedure: To a stirred solution of 5-amino-1-naphthol (126 mg, 0.792 mmol) and <strong>[70395-35-6]sodium chlorofluoroacetate</strong> (159 mg,1.18 mmol) in dichloromethane (8 mL) was added T3P (50 wt%solution in AcOEt, 701 μL, 1.18 mmol) and N,N-diisopropylethylamine(DIPEA) (273 μL, 1.57 mmol) at 0C. Afterstirred at ambient temperature for 1 h, the reaction mixturewas diluted with water and extracted thrice with CHCl3. Thecombined organic layers were washed with brine, dried overNa2SO4, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (hexane/AcOEt = 3 : 1) to afford the title compound (37.2 mg, 18% yield) as a pale purple solid.

Reference： [1]Chemical and Pharmaceutical Bulletin,2020,vol. 68,p. 1074 - 1081

87
[ 611-34-7 ]
6-chloro-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one [ No CAS ]
1-cyclopentyl-3-methyl-6-(quinolin-5-ylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; Cs₂CO₃; dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane In 1,4-dioxane at 120℃; for 16h; Sealed tube;	59 Example 59: SN39322 1-Cyclopentyl-3-methyl-6-(quinolin-5-ylamino)-1,3-dihydro- 2H-imidazo[4,5-c]pyridin-2-one (65) A degassed mixture of chloride 6 (120 mg, 0.48 mmol), quinolin-5-amine (83 mg, 0.57 mmol), Pd2dba3(22 mg, 24 µmol), XPhos (46 mg, 96 µmol) and Cs2CO3(344 mg, 1.06 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 h. The mixture was cooled, diluted with EtOAc (30 mL) filtered through diatomaceous earth and the filtrate was evaporated The residue was partitioned between EtOAc (50 ml) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give imidazopyridinone 65 (94 mg, 55%) as tan crystals: mp (EtOAc/pet ether) 150-152 °C;1H NMR (CDCl3) δ 8.95 (dd, J = 4.2, 1.6 Hz, 1 H, H-2), 8.40 (ddd, J = 8.5, 1.4, 0.8 Hz, 1 H, H-4), 7.94 (d, J = 8.5 Hz, 1 H, H-6), 7.82 (s, 1 H, H-4), 7.71 (dd, J = 8.4, 7.6 Hz, 1 H, H-7), 7.57 (d, J = 7.4 Hz, 1 H, H-8), 7.40 (dd, J = 8.5, 4.2 Hz, 1 H, H-3), 6.85 (br s, 1 H, 6-NH), 6.36 (s, 1 H, H-7), 4.68 (pent, J = 8.8 Hz, 1 H, 1-CH), 3.40 (s, 3 H, 3-CH3), 1.79-1.96 (m, 4 H, 2 × CH2), 1.52-1.63 (m, 4 H, 2 × CH2); MS m/z 360.2 (MH+, 100%); HRMS calcd for C21H22N5O (MH+) m/z 360.1819, found 360.1824 (-1.3 ppm). HPLC purity 99.8%.
55%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; Cs₂CO₃; dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane In 1,4-dioxane at 120℃; for 16h; Sealed tube;	59 Example 59: SN39322 1-Cyclopentyl-3-methyl-6-(quinolin-5-ylamino)-1,3-dihydro- 2H-imidazo[4,5-c]pyridin-2-one (65) A degassed mixture of chloride 6 (120 mg, 0.48 mmol), quinolin-5-amine (83 mg, 0.57 mmol), Pd2dba3(22 mg, 24 µmol), XPhos (46 mg, 96 µmol) and Cs2CO3(344 mg, 1.06 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 h. The mixture was cooled, diluted with EtOAc (30 mL) filtered through diatomaceous earth and the filtrate was evaporated The residue was partitioned between EtOAc (50 ml) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give imidazopyridinone 65 (94 mg, 55%) as tan crystals: mp (EtOAc/pet ether) 150-152 °C;1H NMR (CDCl3) δ 8.95 (dd, J = 4.2, 1.6 Hz, 1 H, H-2), 8.40 (ddd, J = 8.5, 1.4, 0.8 Hz, 1 H, H-4), 7.94 (d, J = 8.5 Hz, 1 H, H-6), 7.82 (s, 1 H, H-4), 7.71 (dd, J = 8.4, 7.6 Hz, 1 H, H-7), 7.57 (d, J = 7.4 Hz, 1 H, H-8), 7.40 (dd, J = 8.5, 4.2 Hz, 1 H, H-3), 6.85 (br s, 1 H, 6-NH), 6.36 (s, 1 H, H-7), 4.68 (pent, J = 8.8 Hz, 1 H, 1-CH), 3.40 (s, 3 H, 3-CH3), 1.79-1.96 (m, 4 H, 2 × CH2), 1.52-1.63 (m, 4 H, 2 × CH2); MS m/z 360.2 (MH+, 100%); HRMS calcd for C21H22N5O (MH+) m/z 360.1819, found 360.1824 (-1.3 ppm). HPLC purity 99.8%.

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF AUCKLAND - WO2022/64430, 2022, A1 Location in patent: Page/Page column 101; 102
[2]Current Patent Assignee: THE UNIVERSITY OF AUCKLAND - WO2022/64430, 2022, A1 Location in patent: Page/Page column 101; 102

88
[ 611-34-7 ]
[ 53713-44-3 ]
[ 542-92-7 ]
4-[(6-benzyloxy)-2,5,7,8-tetramethylchroman-2-yl]methyl}-3a,4,5,11b-tetrahydro-3H-cyclopenta[c]-1,7-phenanthroline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With trifluoroacetic acid In 2,2,2-trifluoroethanol at 20℃; for 0.5h;	Synthesis of tetrahydro-3H-cyclopenta[c]-1,7-phenanthrolines 7 and 13 (general procedure) General procedure: Trifl uoroacetic acid,0.02 mL (0.3 mmol), 0.05 mL (0.6 mmol) of freshlydistilled CPD, and 0.3 mmol of aldehyde 4 or 5 wereadded in succession to a solution of 5-aminoquinoline 1 1(0.03 mL, 0.3 mmol) in 10 mL of anhydrous CF3CH2OH(Ar, ~25°C). The reaction mixture was stirred at roomtemperature until amine was completely consumed(0.5 h, TLC, eluent hexane-ethyl acetate, 3 : 1). Thesolvent was removed by distillation, the residue wasneutralized with a saturated NaHSO3-NaHCO3 solution(~ 5 mL), and the product was extracted with ethyl acetate(3 × 10 mL). The organic layer was evaporated, and theresidue was subjected to column chromatography (SiO2,hexane-ethyl acetate, 3 : 1

Reference： [1]Limantseva, R. M.; Meshcheryakova, E. S.; Odinokov, V. N.; Safarova, I. V.; Savchenko, R. G.; Sharipova, G. M.; Tolstikov, A. G. [Russian Journal of Organic Chemistry, 2022, vol. 58, # 2, p. 226 - 235][Zh. Org. Khim., 2022, vol. 58, # 2, p. 188 - 189]

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Precautionary Statements-General
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P378
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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.
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Physical hazards
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H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
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H252	Self-heating in large quantities; may catch fire
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H261	In contact with water releases flammable gas
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Health hazards
Code	Phrase
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H319	Causes serious eye irritation
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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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