Name: 703-61-7|2,4-Dichloroquinoline|98%
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SKU: A277996
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1
[ 7499-66-3 ]
[ 703-61-7 ]
(6-bromo-[2]naphthyl)-(4-chloro-[2]quinolyl)-amine [ No CAS ]

Reference： [1]Journal of the Chemical Society,1947,p. 899,909

2
[ 703-61-7 ]
[ 106-47-8 ]
[ 873399-49-6 ]

Yield	Reaction Conditions	Operation in experiment
73%	With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran for 2h; Inert atmosphere; Reflux;	1.4 1.4. Synthesis of 2-(4-chlorophenylamino)-4-chloroquinoline (1-4) To a solution, under nitrogen gas, of 2,4-dichloroquinoline 1-3 (2.00 g, 10.1 mmol) in dry THF (20 ml) were added 4-chloroaniline (1.45 g, 11.1 mmol) and K2CO3 (3.91 g, 28.3 mmol). The resulting mixture was degassed 5 min with nitrogen, then Xantphos (590 mg, 1.01 mmol) and Pd(OAc)2 (120 mg, 0.5 mmol) were added and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtred and concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash chromatography (gradient cyclohexane/EtOAc from 7/3 to 0/10) to give 2.13 g (yield 73%) of a yellow solid corresponding to 2-(4-chlorophenylamino)-4-chloroquinoline (1-4). Mass, Method A: (ES+) C15H10Cl2N2 required 288; found 289 [M+H] 1H NMR (300 MHz, CDCl3)
	With acetic acid

Reference： [1]Current Patent Assignee: GENOSCIENCE PHARMA - EP3620164, 2020, A1 Location in patent: Paragraph 1420; 1421
[2]Curd et al. [Journal of the Chemical Society, 1947, p. 899,909]

3
[ 70254-44-3 ]
[ 703-61-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With trichlorophosphate; at 85℃; for 2.5h;	0242] A suspension of the 4-hydroxyquinolin-2(lH)-one (8.1, 5g, 31 mmol) in POCl3 (28.9 mL, 310 mmol)was heated at 85 C for 2.5 hours. Following a procedure described inEP 1464335 A2, the reaction was cooled and ice was carefully added until a precipitate formed.The mixture was stirred for 1 hour, the precipitate (starting material) was filtered off and DCM was added. The layers were separated and the organic phase was concentrated and purified by a silica gel plug, rinsing with 10-20% ethyl acetate/hexanes, yielding 3.95 g of 8.2 as a light orange solid (64%).MS analysis m/z = 198+1.
53%	With trichlorophosphate; at 20 - 100℃; for 6h;	4-Hydroxy-2-quinolinone (8.05g, 5mol) was added to the reaction flask, 200ml of phosphorus oxychloride was slowly added dropwise with stirring at room temperature, and a lot of heat and gas were released during the dropwise addition. After the dropwise addition is completed, the brown viscous reaction liquid is formed, and the temperature is slowly raised to 100 C. to react for about 6 hours. After the reaction is completed by dot plate detection, after the reaction solution is cooled to room temperature, the reaction solution is slowly poured into a large amount of ice water to be fully cooled, and ethyl acetate is added for extraction, and the organic phases are combined three times and spin-dried. Add an appropriate amount of 60-80 mesh silica gel to mix the sample, and use a fast column machine to pass the column for purification to obtain a light yellow product with a yield of 53%.
		4-hydroxyquinolin-2(1H)-one (10g, 0.062mol) was first put in a round-bottom flask and POCl3 (40ml) was slowly pour into the flask in 1h under stirring. After stirring for another 30min, the black mixture was heated to 100C and stirred for another 6h. When it was cooled to room temperature, the solution was removed under reduced pressure to afford an oil-like black product. Ice NaHCO3 saturated solution was added to the mixture slowly until no bubbles formed. Ethyl acetate (100ml) was added subsequently. The organic phase was separated, dried over anhydrous Na2SO4, and then evaporated. Petroleum ether (200ml) was added to the crude product and stirred about 30min. The mixture was filtered, then the filter liquor was collected and dried in vacuum to obtain compound 8 as a yellow solid (7.9g, 65% yield) without further purification. MS (ESI+): [M+ H]+ calculated for C9H5NCl2, 196.9799; found, 197.9877.

Reference： [1]Journal of Medicinal Chemistry,2020,vol. 63,p. 638 - 655
[2]Molecules,2011,vol. 16,p. 7649 - 7661
[3]Patent: WO2008/63625,2008,A2 .Location in patent: Page/Page column 68; 95
[4]Patent: CN112574159,2021,A .Location in patent: Paragraph 0143-0146
[5]Heterocycles,2006,vol. 68,p. 1973 - 1979
[6]Journal fur Praktische Chemie - Chemiker-Zeitung,1994,vol. 336,p. 311 - 318
[7]Heterocycles,2012,vol. 86,p. 1583 - 1590
[8]Bioorganic Chemistry,2019,vol. 90
[9]Bioorganic Chemistry,2020,vol. 96
[10]Molecular Diversity,2021,vol. 25,p. 13 - 27
[11]European Journal of Medicinal Chemistry,2020,vol. 197
[12]Zeitschrift fur Naturforschung, B: Chemical Sciences,2021,vol. 76,p. 395 - 403

4
[ 124-41-4 ]
[ 703-61-7 ]
[ 4295-05-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	In toluene; for 16.0h;Reflux;	Step A: 4-Chloro-2-methoxy-quinoline; To a solution of (2.5 g, 12,6 mmol) 2,4-dichloro-quinoline in anhydrous toluene (20 ml) was added a suspension of solid sodium methoxide (2.5 g, 46.3 mmol) in anhydrous toluene (20 ml). The mixture was stirred under reflux for 16 hours and then allowed to cool to room temperature. The solid that had formed was filtered off and washed with 50 ml toluene. The filtrate was evaporated to dryness under reduced pressure to yield a red solid (2.1 g, 10.8 mmol, 86%). MS (ES) m/z = 193.1 [M+H]+.
81.6%	In toluene; at 120.0℃;	2,4-Dichloroquinoline (100 mg, 0.5 mmol) was dissolved in 10 mL of toluene.Add sodium methoxide (100 mg, 1.9 mmol),Stir at 120 degrees overnight,Extracted with ethyl acetate (25 mL × 3),The organic phases were combined, washed with water, washed with saturated brine and dried over anhydrous sodium sulfate.Concentrated to a white solid, 2-methoxy-4-chloroquinoline 80 mg.The yield is 81.6%;

Reference： [1]Patent: WO2012/41873,2012,A1 .Location in patent: Page/Page column 89
[2]Patent: CN109608435,2019,A .Location in patent: Paragraph 0097; 0098; 0099; 0100
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 5419 - 5434
[4]Journal of the Chemical Society. Perkin transactions I,1993,p. 181 - 184
[5]Journal of the Chemical Society. Perkin transactions I,1993,p. 181 - 184

5
[ 703-61-7 ]
2-Azido-4-chloro-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium azide In N,N-dimethyl-formamide at 40℃; for 3h;

Reference： [1]Malle; Stadlbauer; Ostermann; Hofmann; Leis; Kostner [European Journal of Medicinal Chemistry, 1990, vol. 25, # 2, p. 137 - 142]

6
[ 703-61-7 ]
[ 157027-30-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium azide In N,N-dimethyl-formamide at 55℃; for 4h;
72%	With sodium azide In N,N-dimethyl-formamide at 55℃;	2.2.1 General procedure for synthesis of 2-chloro-4-azido quinolines 2(a-f) General procedure: To a vigorously stirred solution of 2,4-dichloroquinoline 1(a-f) its derivatives (9mmol) in DMF (20mL) at 55°C, sodium azide (9mmol) was added slowly for 15min, the whole reaction was stirred for 3-4h. After the completion of reaction as it indicated by TLC spot change, the reaction mixture was poured into crushed ice, filtered, dried and chromatographed over silica gel using petroleum ether: ethyl acetate (92:8) (v/v) as eluent which yielded yellow/white colored compound 2(a-f), it was recrystallised from ethyl acetate. 2.2.1.1 2-Chloro-4-azidoquinoline (2a) Yield: 72%; white solid; mp 104-106°C. IR (KBr, cm-1): 1302, 1565, 2126, 2911. 1H NMR (400MHz, CDCl3): δ 7.13 (s, 1H, Ar-H), 7.56 (t, J=7.6Hz, 1H, Ar-H), 7.78 (t, J=7.6Hz, 1H, Ar-H), 8.02 (t, J=8.4Hz, 1H, Ar-H), 7.96 (s, 1H, Ar-H). 13C NMR (100MHz, CDCl3): δ 109.38, 120.46, 122.41, 124.22, 126.89, 128.44, 131.66, 148.44, 148.52, 150.48; ESI-MS (m/z): calcd for [M+H]+ 204.62, found 204.83; Anal. Calcd for C9H5ClN4: C, 52.83; H, 2.46; N, 27.38 Found: C, 52.79; H, 2.44; N,

Reference： [1]Steinschifter, Waltraud; Stadlbauer, Wolfgang [Journal fur Praktische Chemie - Chemiker-Zeitung, 1994, vol. 336, # 4, p. 311 - 318]
[2]Magesh Selva Kumar; Vijaya Pandiyan; Mohana Roopan; Rajendran [Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 332, p. 72 - 86]

7
[ 141-82-2 ]
[ 62-53-3 ]
[ 703-61-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With trichlorophosphate for 15h; Heating;
70%	With trichlorophosphate at 110 - 140℃; for 5h;	2 To a suspension of malonic acid (100 mmol) in POCI3 (100 mL) was added aniline or substituted aniline in portions. The mixture was heated at 110 0C for 1 hr and 140 0C for another 4 hr. After cooling, the mixture was poured slowly into crushed ice while shaking. The mixture was allowed to stand in a refrigerator overnight before filtration. The precipitate was collected, washed several times with water and dried under vacuum. CH2CI2 was used to extract the solid. The extract was dried and purified on column to give 2,4-dichloroquinoline or substituted 2,4-dichloroquinoline in yields of approximately 70%
65%	With trichlorophosphate Reflux;

63%	With trichlorophosphate for 3h; Heating;
62%	With trichlorophosphate at 150℃; for 5h;
55%	With trichlorophosphate Heating;
48%	With trichlorophosphate for 5h; Heating;
48%	With trichlorophosphate for 5h;
39%	With trichlorophosphate for 5h; Reflux;
35%	With trichlorophosphate for 2.5h; Cooling with ice; Reflux;
35%	Stage #1: malonic acid; aniline With trichlorophosphate Cooling with ice; Reflux; Stage #2: With sodium hydroxide In water Cooling with ice;	Compound 8 was prepared as described elsewhere [Osbome, A. G. et al. 2,4- Dihalogenoquinolines. Synthesis, Orientation Effects and 1H and 13C NMR Spectral Studies. J. Chem. Soc. Perkin Trans.1. 1993, 1, 2747-2755]. In brief, malonic acid (8.32 g, 0.08 mol) was dissolved in POCl3 (60 mL) and cooled in an ice-bath. Aniline (1.25 eq) was added dropwise. The reaction was refluxed for 2.5 hours, then it was cooled to room temperature and poured on ice. pH was adjusted to 9 with 2M NaOH. The precipitate was filtered off and the aqueous layer was extracted with DCM. The product was purified by column chromatography, eluent DCM. Yield: 5.51 g (35%). 1H NMR (CDCl3) δ 1.25 (s5 IH, Ar)5 7.64 (t, IH5 J= 7.84, 6.16 Hz5 Ar)5 7.79 (t, IH5 J= 6.89, 6.71 Hz5 Ar), 8.03 (d, IH, J = 8.16 Hz, Ar), 8.21 (d, IH, J = 8.21 Hz5 Ar). 1H NMR spectrum was identical with 1H NMR spectrum in literature.
30%	Stage #1: malonic acid With trichlorophosphate at 0℃; for 0.5h; Inert atmosphere; Stage #2: aniline at 0 - 110℃; for 1.5h;
20%	With trichlorophosphate at 120℃;	E1 Example El: Preparation of 2,4-dichloroquinoline Aniline (10 g, 108 mmol) and malonic acid (11 g, 108 mmol) was suspended in POC13 (100 mL). The resulting mixture was stirred at 120 °C overnight. After cooling to room temperature, the mixture was poured into crushed ice while shaking. The mixture was partitionedbetween water (150 mL) and EA (150 mL). The aqueous phase was extracted with EA (200 mL x2). The combined organic phase was washed with water (250 mL x2) and brine (250 mL), and dried over NaSO4. After filtration, the solvent was removed, and the residue was purified by silica gel column chromatography (PE/EA = 50/1) to give 2,4-dichloroquinoline (4.3 g, yield:20%) as a white solid. MS (El): mlz 197.8 [(M+1)+].
	With trichlorophosphate at 110 - 140℃; for 5h;	2 Example 2 General Procedure for 2,4-Dichloroquinolines To a suspension of malonic acid (100 mmol) in POCl3 (100 mL) was added aniline or substituted aniline in portions. The mixture was heated at 110° C. for 1 hr and 140° C. for another 4 hr. After cooling, the mixture was poured slowly into crushed ice while shaking. The mixture was allowed to stand in a refrigerator overnight before filtration. The precipitate was collected, washed several times with water and dried under vacuum. CH2Cl2 was used to extract the solid. The extract was dried and purified on column to give 2,4-dichloroquinoline or substituted 2,4-dichloroquinoline in yields of approximately 70%.
	With trichlorophosphate for 5h;
	With trichlorophosphate at 110℃; for 6.5h; Cooling with ice; Inert atmosphere;

Reference： [1]Arul Prakash; Rajendran [Heterocyclic Communications, 2001, vol. 7, # 4, p. 353 - 358]
[2]Current Patent Assignee: XTL BIOPHARMACEUTICALS LTD - WO2008/24423, 2008, A2 Location in patent: Page/Page column 35
[3]Ouyang, Liang; Huang, Yuhui; Zhao, Yuwei; He, Gu; Xie, Yongmei; Liu, Jie; He, Jun; Liu, Bo; Wei, Yuquan [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049]
[4]Osborne, Alan G.; Buley, Jill M.; Clarke, Helen; Dakin, Rachel C. H.; Price, Paul I. [Journal of the Chemical Society. Perkin transactions I, 1993, # 22, p. 2747 - 2756]
[5]Location in patent: experimental part Ramasamy; Balasubramaniam; Mohan [E-Journal of Chemistry, 2010, vol. 7, # 3, p. 1066 - 1070] Location in patent: experimental part Ramasamy; Balasubramaniam; Mohan [Asian Journal of Chemistry, 2012, vol. 24, # 10, p. 4726 - 4728]
[6]Farhanullah; Kim, Su Yeon; Yoon, Eun-Jeong; Choi, Eung-Chil; Kim, Sunghoon; Kang, Taehee; Samrin, Farhana; Puri, Sadhna; Lee, Jeewoo [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 21, p. 7154 - 7159]
[7]Jones, Keith; Roset, Xavier; Rossiter, Sharon; Whitfield, Philip [Organic and biomolecular chemistry, 2003, vol. 1, # 24, p. 4380 - 4383]
[8]Rajesh; Iniyavan; Sarveswari; Vijayakumar [Research on Chemical Intermediates, 2014, vol. 40, # 5, p. 1851 - 1866] Rajesh, Kancherla; Lavanya, Pandian; Iniyavan, Pethaperumal; Sarveswari, Sundaramoorthy; Ramaiah, Sudha; Anbarasu, Anand; Vijayakumar, Vijayaparthasarathi [Medicinal Chemistry, 2015, vol. 11, # 8, p. 789 - 797]
[9]Neve, Juliette E.; Wijesekera, Hasanthi P.; Duffy, Sandra; Jenkins, Ian D.; Ripper, Justin A.; Teague, Simon J.; Campitelli, Marc; Garavelas, Agatha; Nikolakopoulos, George; Le, Phuc V.; De A. Leone, Priscila; Pham, Ngoc B.; Shelton, Philip; Fraser, Neil; Carroll, Anthony R.; Avery, Vicky M.; McCrae, Christopher; Williams, Nicola; Quinn, Ronald J. [Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1252 - 1275]
[10]Heitman, Laura H.; Göblyös, Anikó; Zweemer, Annelien M.; Bakker, Renée; Mulder-Krieger, Thea; Van Veldhoven, Jacobus P. D.; De Vries, Henk; Brussee, Johannes; Ijzerman, Adriaan P. [Journal of Medicinal Chemistry, 2009, vol. 52, # 4, p. 926 - 931]
[11]Current Patent Assignee: LEIDEN UNIVERSITY - WO2010/20981, 2010, A1 Location in patent: Page/Page column 29; 2/2
[12]Du, Yufeng; Huang, Linyu; Wang, Neng; Li, Xiaohuan; Zhou, Xian-Li; Zhang, Lan; Huang, Shuai; Walsh, Patrick J.; Gao, Feng [Advanced Synthesis and Catalysis, 2022, vol. 364, # 5, p. 1002 - 1008]
[13]Current Patent Assignee: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE; LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY - WO2016/61280, 2016, A1 Location in patent: Paragraph 0338; 0339
[14]Current Patent Assignee: XTL BIOPHARMACEUTICALS LTD - US2009/54477, 2009, A1 Location in patent: Page/Page column 14
[15]Balaji; Rajesh; Priya; Iniyavan; Siva; Vijayakumar [Medicinal Chemistry Research, 2013, vol. 22, # 7, p. 3185 - 3192]
[16]Davis, Tyler A.; Dobish, Mark C.; Schwieter, Kenneth E.; Chun, Aspen C.; Johnston, Jeffrey N. [Organic Syntheses, 2012, vol. 89, p. 380 - 393]

8
[ 703-61-7 ]
[(4-methoxycarbonylphenyl)methyl]zinc bromide [ No CAS ]
4-(4-chloro-quinolin-2-ylmethyl)-benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In tetrahydrofuran at 60℃; for 2h;

Reference： [1]Shiota, Takeshi; Yamamori, Teruo [Journal of Organic Chemistry, 1999, vol. 64, # 2, p. 453 - 457]

9
[ 20151-40-0 ]
[ 703-61-7 ]

Reference： [1]Russian Journal of Organic Chemistry,2002,vol. 38,p. 137 - 138

10
[ 124-41-4 ]
[ 703-61-7 ]
[ 40335-00-0 ]
[ 4295-05-0 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 1252 - 1275
[2]Journal of Chemical Research, Miniprint,2002,p. 124 - 148

11
[ 91-21-4 ]
[ 703-61-7 ]
[ 332181-58-5 ]

Yield	Reaction Conditions	Operation in experiment
84%	In toluene at 110℃;
79%	With sodium hydrogencarbonate In toluene	115 4-Chloro-2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline EXAMPLE 115 4-Chloro-2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline A solution of 2,4-dichloroquinoline (0.2 g, 1 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.282 ml, 2.2 mmol) in toluene (2 ml) was refluxed during 18 hours then cooled to room temperature. The reaction mixture was diluted with CH2Cl2 and quenched with a saturated solution of NaHCO3. Aqueous phase was extracted with CH2Cl2 (2*). Combined organic phases were washed with H2O, dried over NaSO4, and concentrated. The residue was chromatographed over silica gel (hexane-ethyl acetate, 97:3) to provide 4-chloro-2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline (0.235 g, 79%) as a yellow oil, MS: m/e=295.3 (M+H+).

Reference： [1]Pinard, Emmanuel; Alanine, Alexander; Bourson, Anne; Buettelmann, Bernd; Heitz, Marie-Paule; Mutel Ramanjit Gill, Vincent; Trube, Gerhard; Wyler, Rene [Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 18, p. 2615 - 2619]
[2]Current Patent Assignee: ROCHE HOLDING AG; F (unclear) - US6440995, 2002, B1

12
[ 67-56-1 ]
[ 703-61-7 ]
[ 40335-00-0 ]
[ 4295-05-0 ]

Reference： [1]Organic and biomolecular chemistry,2003,vol. 1,p. 4380 - 4383

13
[ 70254-44-3 ]
[ 703-61-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With trichlorophosphate for 6h; Heating / reflux;	1.A Step A: Synthesis of 2,4-dichloro-quinoline. A suspension of quinoline-2,4-diol (150 g, 931 mmol) in POCl3 (975 mL, 10.4 mol) was stirred at reflux for 6 hr and the reaction mixture was concentrated. The residue was diluted with CHCl3 (500 mL) and the solution was poured into ice water. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtrated, concentrated, and purified by flash chromatography (silica gel, 20% EtOAc in hexane) to give 2,4-dichloro-quinoline (177 g, 96%) as a pale brown solid. EI MS m/e 197, M+; 1H NMR (300 MHz, CDCl3) δ 7.50 (s, 1 H), 7.65 (ddd, J = 8.3, 7.0, 1.3 Hz, 1 H), 7.79 (ddd, J = 8.5, 7.0, 1.3 Hz, 1 H), 8.00-8.06 (m, 1 H), 8.16-8.21 (m, 1 H).
94%	With trichlorophosphate for 24h; Heating / reflux;	26-A Synthesis 26-A; 2-(4-Chloroquinolin-2-yl)phenol; A solution of 2,4-quinolinediol (2.00 g, 12.41 mmol) in phosphorus oxychloride (30 mL) was heated at reflux for 24 hours. The resulting solution was cooled, concentrated, quenched with iced water (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic layers were combined, washed with brine (100 mL), dried (MgSO4), and concentrated to give 2,4-dichloroquinoline (2.31 g, 94%).
93%	With trichlorophosphate for 18h; Reflux;	50 2,4-dichloroquinoline A solution of 50.0 g (0.310 mol) of quinoline-2,4-diol in 250 mL of phosphoryl chloride was warmed to reflux and stirred for 18 h. The reaction mixture was cooled down to room temperature and concentrated to dryness. The residue was coevaporated twice with 500 mL of toluene. The residue was dissolved in 500 mL of dichloromethane and hydrolyzed carefully at 0 °C with 500 mL of water. The aqueous layer was extracted with 500 mL of dichloromethane. The combined organic layers were washed with 500 mL and water, dried over anhydrous Na2S04, filtered and evaporated under vacuum to give 57.0 g (93%) of a brown solid corresponding to 2,4-dichloroquinoline. This product was carried to the next step without further purification. HPLC-MS: conditions H: tr = 2.71 min, (ES+) C9H5C12N requires 197; found 198 [M + H], purity 94.6 %. 1H NMR (400 MHz, CDC13).

93%	With trichlorophosphate at 0℃; Reflux;	1.3 1.3. Synthesis of 2,4-dichloroquinoline (1-3) To quinoline-2,4-diol (50.0 g, 310 mmol) was added dropwise at 0°C Phosphoryl chloride (250 ml, 2682 mmol). The resulting mixture was stirred and heated under reflux overnight. Then, the reaction mixture was cooled, concentrated under reduced pressure and co-evapored twice with 500 ml of toluene. The residue was then taken up with CH2Cl2 (500 ml) and washed with cold water. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown solid (57.0 g, yield 93%) corresponding to 2,4-dichloroquinoline (1-3). Mass, Method A: (ES+) C9H5Cl2N required 197; found 198 [M+H] 1H NMR (300 MHz, CDCl3)
92.5%	With trichlorophosphate In toluene for 21h; Reflux; Inert atmosphere;
90%	Stage #1: 2,4-dihydroxyquinoline With trichlorophosphate at 100℃; for 2h; Stage #2: With sodium hydroxide In water Cooling with ice;
88%	With pyridine; trichlorophosphate at 140℃; for 2h; Autoclave; neat (no solvent);
83%	With trichlorophosphate for 3h; Heating / reflux;	1 A mixture of 2,4-quinolinediol (13.6 g, 84.47 mmol) in POCl3 (150 mL) was heated under reflux for 3h. After cooling down, the mixture was dropped slowly into crashed ice while shaking. The precipitate was collected by filtration and washed several times with water. The product was dried under vacuum overnight to give 13.86 g (yield 83%) of product as pale gray powder which is pure enough for further use. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 8.0 Hz, IH), 8.02 (d, J = 8.0 Hz, IH), 7.79 (t, J = 8.0 Hz, IH), 7.64 (t, J = 8.0 Hz, IH), 7.49 (s, IH); 13CNMR (125MHz, CDCl3) 150.06, 148.33, 144.62, 131.79, 129.20, 128.13, 125.39, 124.42, 122.19; LCMS (EI) m/z 198.0 (M+), 200.0, 202.0.
83%	With trichlorophosphate for 3h; Heating / reflux;	1 Example 1 2,4-Dichloroquinoline 2 A mixture of 2,4-quinolinediol (13.6 g, 84.47 mmol) in POCl3 (150 mL) was heated under reflux for 3 h. After cooling down, the mixture was dropped slowly into crashed ice while shaking. The precipitate was collected by filtration and washed several times with water. The product was dried under vacuum overnight to give 13.86 g (yield 83%) of product as pale gray powder which is pure enough for further use. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J=8.0 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.49 (s, 1H); 13C NMR (125 MHz, CDCl3) 150.06, 148.33, 144.62, 131.79, 129.20, 128.13, 125.39, 124.42, 122.19; LCMS (EI) m/z 198.0 (M+), 200.0, 202.0.
63%	With trichlorophosphate at 110℃; for 5h;	36; 9 2,4-Dichloroquinoline 2,4-Quinolinediol (3.22 g, 20 mmol) was suspended in phosphorus oxychloride (50 mL) and heated at 110° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and the phosphorus oxychloride was removed under reduced pressure. The residual oil was added to ice and then extracted with dichloromethane (3×100 mL). The organics were combined, washed with water (100 mL), then brine (200 mL), dried with magnesium sulfate, filtered, and evaporated to give a pale red solid. Analytical LCMS method 2, retention time 6.15 min, M+H=198. Yield 2.50 g, 63%. The product was used without further purification in the next step.
42%	With N-succinimide chlorotriphenylphosphonium salt for 0.0833333h; microwave irradiation;
	In trichlorophosphate	6 2,4-Dichloroquinoline Example 6 2,4-Dichloroquinoline A suspension of quinoline-2,4-diol (15 g, 92.6 mmol) in POCl3 was heated at reflux for 2 h. After cooling, the solvent was removed under reduced pressure to yield 2,4-dichloroquinoline, which was used without further purification.
	With trichlorophosphate In toluene for 24h; Reflux;
	With trichlorophosphate for 2h; Reflux;	6 A suspension of quinoline-2,4-diol (15 g, 92.6 mmol) in POCl3 was heated at reflux for 2 h. After cooling, the solvent was removed under reduced pressure to yield 2,4-dichloroquinoline, which was used without further purification
	With trichlorophosphate for 2h; Reflux;	6 2,4-Dichloroquinoline A suspension of quinoline-2,4-diol (15 g, 92.6 mmol) in POCl3 was heated at reflux for 2 h. After cooling, the solvent was removed under reduced pressure to yield 2,4-dichloroquinoline, which was used without further purification.

Reference： [1]Current Patent Assignee: PFIZER INC - EP1464335, 2004, A2 Location in patent: Page/Page column 162
[2]Current Patent Assignee: CANCER RESEARCH UK - WO2009/53694, 2009, A1 Location in patent: Page/Page column 125
[3]Current Patent Assignee: GENOSCIENCE PHARMA - WO2014/147611, 2014, A1 Location in patent: Page/Page column 172; 173
[4]Current Patent Assignee: GENOSCIENCE PHARMA - EP3620164, 2020, A1 Location in patent: Paragraph 1418; 1419
[5]Todorov, Aleksandar R.; Wirtanen, Tom; Helaja, Juho [Journal of Organic Chemistry, 2017, vol. 82, # 24, p. 13756 - 13767]
[6]Location in patent: experimental part Engen, William; O'Brien, Terrence E.; Kelly, Brendan; Do, Jacinda; Rillera, Liezel; Stapleton, Lance K.; Youngren, Jack F.; Anderson, Marc O. [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 16, p. 5995 - 6005]
[7]Location in patent: experimental part Wang, Han; Wen, Kun; Wang, Le; Xiang, Ye; Xu, Xiaocheng; Shen, Yongjia; Sun, Zhihua [Molecules, 2012, vol. 17, # 4, p. 4533 - 4544]
[8]Current Patent Assignee: XTL BIOPHARMACEUTICALS LTD - WO2008/24423, 2008, A2 Location in patent: Page/Page column 34
[9]Current Patent Assignee: XTL BIOPHARMACEUTICALS LTD - US2009/54477, 2009, A1 Location in patent: Page/Page column 14
[10]Current Patent Assignee: CANCER RESEARCH UK - US2009/247519, 2009, A1 Location in patent: Page/Page column 139
[11]Tanji, Ken-Ichi; Koshio, Jiro; Sugimoto, Osamu [Synthetic Communications, 2005, vol. 35, # 15, p. 1983 - 1987]
[12]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2011/98311, 2011, A1
[13]Gothard, Chris M.; Soh, Siowling; Gothard, Nosheen A.; Kowalczyk, Bartlomiej; Wei, Yanhu; Baytekin, Bilge; Grzybowski, Bartosz A. [Angewandte Chemie - International Edition, 2012, vol. 51, # 32, p. 7922 - 7927]
[14]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2012/309758, 2012, A1 Location in patent: Page/Page column 64
[15]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2015/231142, 2015, A1 Location in patent: Paragraph 0377

14
[ 703-61-7 ]
[ 105-13-5 ]
[ 20146-59-2 ]
[ 733053-60-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7154 - 7159

15
[ 87120-72-7 ]
[ 703-61-7 ]
[ 1007838-49-4 ]

Yield	Reaction Conditions	Operation in experiment
12%	With potassium <i>tert</i>-butylate In 1,2-dimethoxyethane at 90℃; for 2h;	1 To a degassed solution of 2,4-dichloro-quinoline (1.00 g, 5.05 mmol, 1.0 equiv; commercially available from Specs Research Laboratory, The Netherlands) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.21 g, 6.06 mmol, 1.2 equiv; commercially available) in dimethoxyethane (15 mL) was added KOtert-Bu (0.79 g, 7.07 mmol, 1.4 equiv), (R)-(-)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine (2.80 mg, 0.0051 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6]; commercially available from Strem Chemicals, USA) and palladium(II) acetate (1.13 mg, 0.0051 mmol, 0.1 mol %). The reaction mixture was stirred at 90° C. for 2 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 0.22 g (12%) of the title compound. 1H NMR (300 MHz, DMSO): δ1.27-1.41 (m, 2H), 1.42 (s, 9H), 1.93-1.97 (m, 2H), 2.95-3.03 (m, 2H), 3.86-3.90 (m, 2H), 4.09-4.16 (m, 1H), 6.96 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.24-7.30 (m, 1H), 7.55-7.57 (m, 2H), 7.86 (d, J=7.7 Hz, 1H). MS (ISP): 362.4 [M+H]-.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2008/45544, 2008, A1 Location in patent: Page/Page column 35

16
[ 371-42-6 ]
[ 703-61-7 ]
2-chloro-4-(4-fluoro-phenylsulfanyl)-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃;	3 To a solution of 2,4-dichloroquinoline (1.98 g, 10.0 mmol) in DMF (10 mL) was added Et3N (2.78 mL, 20 mmol) and a solution of thiol (10 mmol) in DMF (10 mL) dropwise at 0 0C. The reaction was warmed up after 10 min and stirred overnight at rt. 200 mL of EtOAc was added to the mixture and washed with water and brine successively. The organic layer was separated and dried over Na2SO4. The product was purified on column after removal of solvent under vacuum. In most of cases, less than 5% of dithio-substituted quinoline was formed.
62%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃;	3 Example 3; General Procedure for 2-chloro-4-thioarylquinolines; To a solution of 2,4-dichloroquinoline (1.98 g, 10.0 mmol) in DMF (10 mL) was added Et3N (2.78 mL, 20 mmol) and a solution of thiol (10 mmol) in DMF (10 mL) dropwise at 0° C. The reaction was warmed up after 10 min and stirred overnight at rt. 200 mL of EtOAc was added to the mixture and washed with water and brine successively. The organic layer was separated and dried over Na2SO4. The product was purified on column after removal of solvent under vacuum. In most of cases, less than 5% of dithio-substituted quinoline was formed. 2-Chloro-4-(4-fluoro-phenylsulfanyl)-quinoline; Yield: 62%. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.62-7.57 (m, 3H), 7.23 (t, J=8.0 Hz, 2H), 6.57 (s, 1H);13C NMR (125 MHz, CDCl3) 165.32, 163.31, 152.47, 150.65, 147.26, 138.29, 138.22, 131.24, 129.36, 127.09, 124.52, 123.41, 118.09, 117.91, 117.32; LCMS (EI) m/z 289.9 (M+), 291.9, 293.0.

Reference： [1]Current Patent Assignee: XTL BIOPHARMACEUTICALS LTD - WO2008/24423, 2008, A2 Location in patent: Page/Page column 36-37
[2]Current Patent Assignee: XTL BIOPHARMACEUTICALS LTD - US2009/54477, 2009, A1 Location in patent: Page/Page column 14-15

17
[ 703-61-7 ]
[ 20146-59-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrogenchloride; In 1,4-dioxane; water; for 18h;Reflux;	To a stirred solution of 2,4-dichloroquinoline (24.9 g, 126 mmol) in 1 ,4-dioxane (126 ml_) was added cone. HCI (83.8 ml_, 1.01 mol) dropwise. The reaction mixture was refluxed for 18h. The mixture was cooled to room temperature, poured into excess ice water and allowed to stir for 1 h. The precipitate was filtered and dried under vacuum to afford 4- chloroquinolin-2(1/-/)-one (19.2 g, 85%) as an off-white solid. LCMS (Method T2) RT 1.25 min; m/z 180.03 [M+H]+.
	With hydrogenchloride; In 1,4-dioxane;Heating / reflux;	To a solution of optionally substituted 2,4-dichloroquinoline (10.0 mmol) in 1,4- dioxane (20 mL) was added HCl (6 N, 30 mL). The mixture was refluxed overnight. After cooling, 200 mL of water was added and precipitate was formed. The precipitate was collected and dried under vacuum. To the dry solid was added anhydrous acetone (50 mL), K2CO3 (2 equiv.) and MeI (5 equiv.). The mixture was heated to reflux overnight. The insoluble solid was filtered off and the solution was dried and purified on a column. The yields were around 50% for the two steps.
19.2 g	With hydrogenchloride; water; In 1,4-dioxane; for 19h;Reflux;	To a stirred solution of 2,4-dichloroquinoline (24.9 g, 126 mmol) in 1,4-dioxane (126 mL) was added conc. HCl (83.8 mL, 1.01 mol) drop-wise. The reaction mixture was refluxed for 18 h. The mixture was cooled to room temperature, poured into excess ice water and allowed to stir for 1 h. The precipitate was filtered and dried under vacuum to afford 4-chloro- 1 H-quinolin-2-one (19.2 g) as an off-white solid. LCMS (Method T2) Rt = 1.25 mins, mlz 180.03 [M+H]+.

Reference： [1]Patent: WO2019/197842,2019,A1 .Location in patent: Paragraph 00348
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5419 - 5434
[3]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 5995 - 6005
[4]Patent: WO2008/24423,2008,A2 .Location in patent: Page/Page column 40-41
[5]Patent: WO2018/215798,2018,A1 .Location in patent: Paragraph 00341
[6]Bioorganic Chemistry,2019,vol. 90
[7],2020

18
[ 703-61-7 ]
[ 27667-34-1 ]

Reference： [1]Organic and biomolecular chemistry,2003,vol. 1,p. 4380 - 4383
[2]E-Journal of Chemistry,2010,vol. 7,p. 1066 - 1070
[3]Asian Journal of Chemistry,2012,vol. 24,p. 4726 - 4728

19
[ 703-61-7 ]
[ 1011-47-8 ]

Reference： [1]Tetrahedron,2001,vol. 57,p. 2507 - 2514

20
[ 703-61-7 ]
[ 110216-87-0 ]

Reference： [1]Journal fur Praktische Chemie - Chemiker-Zeitung,1994,vol. 336,p. 311 - 318

21
[ 703-61-7 ]
[ 74-89-5 ]
[ 870849-89-1 ]

Yield	Reaction Conditions	Operation in experiment
45%	In tetrahydrofuran; chloroform; water at 20℃; for 12h;	1.B Step B: Synthesis of (2-chloro-quinolin-4-yl)-methyl-amine. To a solution of 2,4-dichloro-quinoline (29.8 g, 150 mmol) in THF (300 mL) was added 40% MeNH2 in water (58.4 g, 752 mmol). The mixture was stirred at ambient temperature for 12 days and concentrated. The residue was suspended in CHCl3 and H2O. The precipitate was collected by filtration, washed with acetone, and dried at 50 °C under reduced pressure to give (2-chloro-quinolin-4-yl)-methyl-amine (13.2 g, 45%) as a colorless solid. ESI MS m/e 215, M + Na+; 1H NMR (300 MHz, DMSO-d6) δ 2.91 (d, J = 4.7 Hz, 3 H), 6.35 (s, 1 H), 7.47 (ddd, J = 8.3, 6.6, 1.7 Hz, 1 H), 7.62-7.75 (m, 3 H), 8.16 (d, J = 8.6 Hz, 1 H).

Reference： [1]Current Patent Assignee: PFIZER INC - EP1464335, 2004, A2 Location in patent: Page/Page column 162-163

22
[ 703-61-7 ]
[ 6041-50-5 ]
[ 5652-13-1 ]

Yield	Reaction Conditions	Operation in experiment
1: 41% 2: 15%	With dimethyl amine In tetrahydrofuran; water at 20℃; for 71h;	5.A Step A: Synthesis of (2-chloro-quinolin-4-yl)-dimethyl-amine. To a solution of 2,4-dichloro-quinoline (177 g, 894 mmol) in THF (2.1 L) was added 50% aqueous Me2NH (234 mL, 2-23 mol). The mixture was stirred at ambient temperature for 68 hr. To the mixture was added 50% aqueous Me2NH (47 mL, 448 mmol) and stirred at ambient temperature for 3 hr. The solution was poured into saturated aqueous NaHCO3 and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtrated, concentrated, and purified by flash chromatography (NH-silica, 1 % to 3% EtOAc in hexane) to give (2-chloro-quinolin-4-yl)-dimethyl-amine (75.9 g, 41 %) as a pale yellow oil and (4-chloro-quinolin-2-yl)-dimethyl-amine (28.0 g, 15%) as a pale yellow oil.

Reference： [1]Current Patent Assignee: PFIZER INC - EP1464335, 2004, A2 Location in patent: Page/Page column 167

23
[ 703-61-7 ]
[ 139301-27-2 ]
4-chloro-2-(4-trifluoromethoxy-phenyl)-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In water; N,N-dimethyl-formamide at 100℃; for 3h;	18.i Example 18Synthesis of 2-(4-Triβuoromethoxy-phenyl)-4-(3-trifluoromethyl-pyrazol-l-yl)- quinoline (E 18)Step (i): Synthesis of4-Chloro-2-(4-trifluoromethoxy-phenyl)-qninoline (24); Tetrakis(triphenylphosphine)palladium (88 mg, 0.07 mmol) and 4- triflouromethoxy phenyl boronic acid (303 mg, 1.83 mmol) were added to a stirred solution of 2,4-dichloroquinoline (300 mg, 1.52 mmol) in DMF (5 mL), under nitrogen, followed by Na2CO3 (1.29 g, 12.16 mmol) dissolved in water (6 mL). The resulting mixture was then heated at 100 0C for 3 hr, cooled to room temperature, poured into ice-cold water, and stirred for about 1 hr. The solid that separated was filtered off, washed with water and dried to give the desired product.

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2006/58201, 2006, A2 Location in patent: Page/Page column 138

24
[ 98546-51-1 ]
[ 703-61-7 ]
4-chloro-2-(4-methylsulfanyl-phenyl)-quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium carbonate In water; N,N-dimethyl-formamide at 100℃; for 1h;	16.i Example 16Synthesis of 2-(4-Methylsulfanyl-phenyl)-4-(3-trifluoromethyl-pyrazol-l-yl)-quinoline (E 16)Step (i): Synthesis of4~Chloro-2-(4-methylsulfanyl-phenyl)-quinoline (23); To a stirred solution of 2,4-dichloroquinoline (300 mg, 1.52 mmol) in DMF (5.0 mL) was added tetrakis(triphenylphosphine)palladium (88 mg, 0.07 mmol), 4- methylsulfanylphenyl boronic acid (312 mg, 1.83 mmol) and a solution Of Na2CO3 (1.29 g, 12.16 mmol dissolved in 6.0 mL of water) under nitrogen. This reaction mixture was heated to 100 0C for about 1 h, cooled to room temperature, poured into ice-cold water and then stirred for about 1.0 h, and then extracted with ethyl acetate. The organic layers were collected, combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography to give the desired compound; yield 89%.

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2006/58201, 2006, A2 Location in patent: Page/Page column 136

25
[ 703-61-7 ]
[ 94839-07-3 ]
2-(benzo[d][1,3]dioxol-5-yl)-4-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In water; N,N-dimethyl-formamide at 100℃; for 1h;	15.i Example 15Synthesis of 2-Benzo[l,3]dioxol-5-yl-4-(3-triflιwromethyl-pyrazol-l-yl)-quinoline (E 15)Step (i): Synthesis of 2-Benzo [1 ,3] dioxol-5-yl-4-chloro-quinoline (22); To a stirred solution of 2,4-dichloroquinoline (300 mg, 1.52 mmol) in DMF (5 mL) was added tetrakis(triphenylphosphine)palladium (88 mg, 0.07 mmol), benzodioxale boronic acid (303 mg, 1.83 mmol), and a solution Of Na2CO3 (1.29 g, 12.16 mmol dissolved in 6 mL of water under nitrogen. This mixture was heated to about 100 0C for about 1 hr, allowed to cool to room temperature, poured into ice-cold water, and then stirred for about 1 hr. The resulting solid that separated was filtered off, washed with water, and dried to give the desired compound. Step (ii): Synthesis of 2-Benzo [1, 3] dioxol-5-yl-4-(3-trifluoromethyl-pyrazol-l-yl)- quinoline (E 15)

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2006/58201, 2006, A2 Location in patent: Page/Page column 135

26
[ 75-09-2 ]
[ 703-61-7 ]
[ 64-04-0 ]
bis[2-phenylethyl]-2,4-quinolinediamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44.4%	With ammonium hydroxide In water; pentane	181 Bis[2-phenylethyl]-2,4-quinolinediamine EXAMPLE 181 Bis[2-phenylethyl]-2,4-quinolinediamine To 2.0 g of 2,4-dichloroquinoline was added 4.8 g of 2-phenylethylamine, and the mixture was heated to 150°-160° C. under nitrogen for 18 hours. The mixture was then cooled and a solution of ammonium hydroxide and water was added. The product was extracted into CH2 Cl2, which was then concentrated to dryness, giving an oil. To the oil, 100 mL of pentane and CH2 Cl2 was added and the oil went into solution. This solution was cooled, and the title product crystallized. Yield 44.4%. M.P. 70°-71° C.

Reference： [1]Current Patent Assignee: CORTEVA INC - US5114939, 1992, A

27
[ 110-91-8 ]
[ 703-61-7 ]
[ 341016-12-4 ]

Yield	Reaction Conditions	Operation in experiment
29%	With triethylamine In N,N-dimethyl-formamide at 60℃; for 72h;	8A; 8 0243] To a solution of the 8.2 (2.Og, 10.1 mmol) and TEA (4.22mL, 30.3 mmol) in DMF (2OmL) under nitrogen was added morpholine (bl, 1.76mL, 20.2 mmol). The reaction was stirred at 60 °C for 3 days. The mixture was concentrated, dissolved in DCM and washed with water. The organic layer was concentrated and purified by a flash silica gel column using an ethyl acetate/hexanes (5-30%) gradient to give 723 mg (29%) 8.3 as an off-white solid. MS analysis m/z = 248+1.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2008/63625, 2008, A2 Location in patent: Page/Page column 68; 95

28
[ 629-05-0 ]
[ 703-61-7 ]
[ 1046451-50-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With copper(l) iodide; palladium 10% on activated carbon; triethylamine; triphenylphosphine In water at 80℃; for 12h; regioselective reaction;
82%	Stage #1: 2,4-dichloroquinoline With copper(l) iodide; triethylamine; triphenylphosphine In water at 25 - 30℃; for 0.5h; Stage #2: n-octyne In water at 20 - 80℃; Further stages.;

Reference： [1]Location in patent: scheme or table Reddy, Ellanki A.; Islam, Aminul; Mukkanti, K.; Bandameedi, Venkanna; Bhowmik, Dipal R.; Pal, Manojit [Beilstein Journal of Organic Chemistry, 2009, vol. 5]
[2]Reddy, Ellanki Amarender; Barange, Deepak Kumar; Islam, Aminul; Mukkanti; Pal, Manojit [Tetrahedron, 2008, vol. 64, # 30-31, p. 7143 - 7150]

29
[ 703-61-7 ]
[ 931-50-0 ]
[ 952443-60-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: cyclohexylmagnesium bromide With zinc(II) chloride In tetrahydrofuran; diethyl ether; water at 20℃; for 0.333333h; Stage #2: 2,4-dichloroquinoline With 1-Methylpyrrolidine In tetrahydrofuran; diethyl ether at 20℃; for 4.08333h;	9.1 (1) To a solution of 2 M cyclohexylmagnesium bromide in diethyl ether (3.3 mL) was added a solution of 0.5 M zinc chloride in THF (14 mL) under nitrogen atmosphere, and the mixture was stirred at room temperature for 20 min. N-methylpyrrolidine (10 mL) was added, the mixture was stirred for 5 min, followed by addition of Pd(PtBu3)2 (0.13 g) and 2,4-dichloroquinoline (1.0 g), and the mixture was stirred at room temperature for 4 h. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate = 6:1) to obtain 2-chloro-4-cyclohexylquinazoline (1.1 g). MS: ESI+ (m/z) 247 (M++1)

Reference： [1]Current Patent Assignee: TAISHO PHARMACEUTICAL HOLDINGS CO., LTD.; NISSAN CHEMICAL CORPORATION - EP2003131, 2008, A1 Location in patent: Page/Page column 36-37

30
[ 703-61-7 ]
[ 100-46-9 ]
[ 1095661-27-0 ]

Yield	Reaction Conditions	Operation in experiment
35%	In ethanol at 110℃; for 1h; Microwave oven;	94.1 2,4-Dichloroquinoline (0.70 g, 3,53 mmole) and benzylamine (3,79 g, 35,3 mmole) in ethanol (2 ml.) were stirred at 110 0C in a microwave oven for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phases were washed with saturated NaCI solution, dried and concentrated. The residue thus obtained was purified using silica gel chromatography, eluting with dichloromethane:methanol 95:5 to give a white solid (330 mg, 35%). ESI-MS [M+H]+ =269.1/271.0 calculated for Ci6H13CIN2 = 269 g/ mole
	With triethylamine In 1-methyl-pyrrolidin-2-one at 150℃; for 17h;	1.8 2,4-Dichloroquinoline (300 mg, 1.51 mmol) was dissolved in NMP (5 mL). Triethylamine (1.00 mL, 7.56 mmol) was added, followed by benzylamine (1984, 1.80 mmol). The mixture was heated to 150° C. for 17 h. The mixture was cooled to room temperature, diluted with water (to form a precipitate) and EtOAc. The mixture was washed with brine (3×20 mL), the organic layer dried (MgSO4), filtered and concentrated. The crude mixture was purified by column chromatography (5% EtOAc-petrol to 20% EtOAc-petrol) to afford the title compound as a yellow solid (84 mg, 22%). This material was carried forward to further reaction.1H NMR (DMSO): 7.88 (1H, app. d), 7.69 (1H, t, J 5.7), 7.60-7.53 (2H, m), 7.41-7.21 (6H, m), 7.06 (1H, s) and 4.63 (2H, d, J 5.9).

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2009/24611, 2009, A2 Location in patent: Page/Page column 93-94
[2]Current Patent Assignee: INFECTIOUS DISEASE RESEARCH INSTITUTE - US2010/317607, 2010, A1 Location in patent: Page/Page column 31

31
[ 89466-08-0 ]
[ 703-61-7 ]
[ 178990-43-7 ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium carbonate In water; toluene for 0.25h; Heating / reflux;	26-A 2,4-Dichloroquinoline (0.500 g, 2.525 mmol), 2-hydroxyphenylboronic acid (0.332 g, 2.405 mmol), sodium carbonate (0.510 g, 4.810 mmol) and Pd(PPh3)4 (0.139 g, 120 mmol) were added to a degassed mixture of toluene (5 mL) and water (2 mL), and the mixture was heated for 15 hours. After cooling, water (100 mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, washed with brine (50 mL), dried (MgSO4), and concentrated. The crude product was purified by silica gel chromatography (dichloromethane) to give the title compound (0.322 g, 50%).LC-MS (LCT2) m/z 256 [M+H+], R, 5.84 minutes.

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK - WO2009/53694, 2009, A1 Location in patent: Page/Page column 125

32
[ 89488-25-5 ]
[ 703-61-7 ]
[ 956125-03-4 ]

Yield	Reaction Conditions	Operation in experiment
22%	With sodium carbonate In water; toluene for 15h; Reflux; Inert atmosphere;	37 4-Chloro-2-(4-chloro-quinolin-2-yl)-phenol 2,4-Dichloroquinoline (0.29 g, 1.5 mmol), 2-hydroxy-5-chloro boronic acid (0.24 g, 1.44 mmol), sodium carbonate (0.31 g, 3 mmol) and palladium tetrakistriphenylphosphine (0.086 g, 0.075 mmol) were suspended in a previously degassed mixture of toluene (3 mL) and water (1 mL). The reaction mixture was refluxed under nitrogen for 15 hours and allowed to cool to room temperature. The contents of the flask were dissolved in ethyl acetate (100 mL) and water (100 mL) and the layers were separated. The aqueous layer was extracted with another portion of ethyl acetate (100 mL), the organics were combined, washed with water (100 mL) and brine (100 mL), dried with magnesium sulfate, filtered, and evaporated to give a pale red solid. The solid was triturated with ethyl acetate to give a yellow solid. Yield: 100 mg, 22%. Analytical LCMS method 2 retention time 7.91 min, M+H=290.

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK - US2009/247519, 2009, A1 Location in patent: Page/Page column 139

33
[ 703-61-7 ]
[ 80947-25-7 ]

Yield	Reaction Conditions	Operation in experiment
44%	With ammonia; In water; at 160.0℃; for 2.5h;microwave irradiation;	Preparation of compound 9 is described elsewhere [von Btichi, J. et al. Die Tuberkulostatische Wirkung von 2-Oxy-4-amino-chinolin Derivaten. HeIv. Chim. Acta. 1949, 32, 1806-1814; Wojahn, H. Untersuchungen ber den Zusammenhang von chemischer Konstitution und anasthesierender Wirkung bei 2-Alkoxy-chinolin Deivaten. Arch. Pharm. 1936, 274, 83-106]. However, we prepared compound 9 as described here. In brief, compound 8 (0.35 g, 1.8 mmol) was suspended in ammonia (28-30% in water, 3 mL). The reaction was carried out in the microwave at 160 0C for 2.5 hours. After the reaction was completed, ammonia was evaporated off. The product was purified by column chromatography, eluent 3% MeOH in DCM. Yield: 0.14 g (44%). 1H NMR (CDCl3) delta 4.83 (bs, 2H, NH2), 6.62 (s, IH, Ar), 7.43-7.51 (m, IH, Ar), 7.63-7.73 (m, 2H, Ar), 7.89-7.95 (m, IH, Ar). 13C NMR (600MHz, CDCl3) delta 103.07, 117.60, 120.08, 125.27, 129.13, 130.46, 148.26, 151.40, 151.41.

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 926 - 931
[2]Patent: WO2010/20981,2010,A1 .Location in patent: Page/Page column 30; 2/2
[3]Journal of Photochemistry and Photobiology A: Chemistry,2017,vol. 332,p. 72 - 86

34
[ 20439-47-8 ]
[ 703-61-7 ]
[ 1229434-91-6 ]

Yield	Reaction Conditions	Operation in experiment
54%	With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium⁽⁰⁾; sodium t-butanolate In toluene at 85℃; for 3h; Inert atmosphere;
	With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium⁽⁰⁾; sodium t-butanolate In toluene at 80℃; for 1.5h; Inert atmosphere;

Reference： [1]Davis, Tyler A.; Wilt, Jeremy C.; Johnston, Jeffrey N. [Journal of the American Chemical Society, 2010, vol. 132, p. 2880 - 2882]
[2]Davis, Tyler A.; Dobish, Mark C.; Schwieter, Kenneth E.; Chun, Aspen C.; Johnston, Jeffrey N. [Organic Syntheses, 2012, vol. 89, p. 380 - 393]

35
[ 703-61-7 ]
4,6-dichloropyridine-2,3-dicarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.2%	With sodium periodate; ruthenium(III) chloride trihydrate; water In tetrachloromethane; acetonitrile at 25℃; for 25h; Large scale;	1 Example 1. Sodium periodate (10.4 kg, 12.0 eq.), acetonitrile (8 L, 10 V), carbon tetrachloride (8 L, 10 V), and water (12 L, 15 V) were charged into a 50 L reactor. Ruthenium chloride trihydrate (4.9 g, 0.6 % eq.) was added and the mixture stirred for 30 minutes at 25 °C. 2,4-dichloroquinoline (800 g , 1.0 eq.) was added in portions over 60 minutes at 25 °C, then the mixture was stirred vigorously for 24 hours at that temperature. Upon complete consumption of starting quinoline, the mixture was filtered and the filter cake washed with 34 L hot ethyl acetate. The aqueous layer was separated and extracted with 13 L hot ethyl acetate , the organic layers were combined and dried over anhydrous sodium sulfate, then filtered, evaporated under vacuum at 50 °C. The residue was triturated with 4.8 L dichloromethane, and the solids formed were filtered and dried under vacuum yielding the product A-2 (1153 g, 97.2 % yield) as an off-white solid.
49%	With sodium periodate; ruthenium(III) trichloride hydrate In dichloromethane; water; acetonitrile at 20℃; for 45.5h;
	With sodium periodate; ruthenium(III) chloride monohydrate In tetrachloromethane; water; acetonitrile at 20℃; for 48h;

Reference： [1]Current Patent Assignee: NIMBUS THERAPEUTICS INC - WO2018/165240, 2018, A1 Location in patent: Paragraph 00217-00218
[2]Henley, Zoë A.; Amour, Augustin; Barton, Nick; Bantscheff, Marcus; Bergamini, Giovanna; Bertrand, Sophie M.; Convery, Máire; Down, Kenneth; Dümpelfeld, Birgit; Edwards, Chris D.; Grandi, Paola; Gore, Paul M.; Keeling, Steve; Livia, Stefano; Mallett, David; Maxwell, Aoife; Price, Mark; Rau, Christina; Reinhard, Friedrich B. M.; Rowedder, James; Rowland, Paul; Taylor, Jonathan A.; Thomas, Daniel A.; Hessel, Edith M.; Hamblin, J. Nicole [Journal of Medicinal Chemistry, 2020, vol. 63, # 2, p. 638 - 655]
[3]Location in patent: experimental part Panda, Biswajit; Basak, Sankar; Hazra, Anindya; Sarkar, Tarun K. [Journal of Chemical Research, 2010, # 2, p. 109 - 113]

36
[ 703-61-7 ]
[ 147716-03-8 ]
[ 1265917-43-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 417 - 422

37
[ 205-25-4 ]
[ 703-61-7 ]
[ 1262867-01-5 ]

Yield	Reaction Conditions	Operation in experiment
70.38%	With caesium carbonate;copper(l) iodide; trans-1,2-cyclohexanediamine; In dichlorobenzene, 1,2-; at 180℃; for 12h;	After 2,4-Dichloroquinoline (15 g, 75.7 mmol), CuI (28.8 g, 151.4 mmol), Cs2CO3 (73 g, 227.2 mmol), trans-l,2-diaminocyclohexane (2.713 mL,22.72 mmol), and 1,2-Dichlorobenzene (500 mL) was added into Compound H-2 (24.6 g, 113.6 mmol), the mixture was stirred under reflux at 180C for 12 hours. Upon completion of the reaction, the mixture was cooled at room temperature. After washing with distilled water and extracting an organic layer with ethyl acetate, remaining moisture was removed by using magnesium sulfate. After drying and distillation under reduced pressure were performed, Compound H-3 (20 g, 52.79 mmol,70.38 %) was obtained by column separation.

Reference： [1]Patent: WO2011/14039,2011,A1 .Location in patent: Page/Page column 28

38
[ 703-61-7 ]
[ 40335-00-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; water;	2,4-Dimethoxyquinoline To a suspension of 2,4-dichloroquinoline in MeOH (100 mL) was added sodium methoxide (50 g). The mixture was heated at reflux for 2 days. After cooling, the mixture was filtered. The filtrate was concentrated under reduced pressure to yield a residue that was dissolved in water and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated to give 2,4-dimethoxyquinoline as a white solid (13 g, 74% over 2 steps).

Reference： [1]Asian Journal of Chemistry,2012,vol. 24,p. 4726 - 4728
[2]Patent: US2011/98311,2011,A1

39
[ 124-41-4 ]
[ 703-61-7 ]
[ 40335-00-0 ]

Yield	Reaction Conditions	Operation in experiment
13 g	In methanol; for 48h;Reflux;	To a suspension of 2,4-dichloroquinoline in MeOH (100 mL) was added sodium methoxide (50 g). The mixture was heated at reflux for 2 days. After cooling, the mixture was filtered. The filtrate was concentrated under reduced pressure to yield a residue that was dissolved in water and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated to give 2,4-dimethoxyquinoline as a white solid (13 g, 74% over 2 steps).

Reference： [1]E-Journal of Chemistry,2010,vol. 7,p. 1066 - 1070
[2]Patent: US2015/231142,2015,A1 .Location in patent: Paragraph 0378

40
[ 124-41-4 ]
[ 703-61-7 ]
[ 4295-04-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	In toluene; for 16h;Reflux;	Step A: 4-Chloro-6-methoxyquinoline2,4-Dichloroquinoline (2.5 g, 12.6 mmol) was dissolved in anhydrous toluene (20 ml), a suspension of sodium methoxide (2.5 g, 46.3 mmol) in anhydrous toluene (20 ml) was added and the mixture was heated under reflux for 16 hours. After cooling to room temperature the suspension was filtered, the filter cake washed once with toluene (50 ml), the combined filtrates were evaporated under reduced pressure to dryness to yield 2.1 g (10.8 mmol, 86percent) of a red solid. MS (ES) m/z = 193.1 [M+H]+.

Reference： [1]Patent: WO2012/41872,2012,A1 .Location in patent: Page/Page column 80

41
[ 67-56-1 ]
[ 124-41-4 ]
[ 703-61-7 ]
[ 40335-00-0 ]

Yield	Reaction Conditions	Operation in experiment
	for 48h;Reflux;	To a suspension of 2,4-dichloroquinoline in MeOH (100 mL) was added sodium methoxide (50 g). The mixture was heated at reflux for 2 days. After cooling, the mixture was filtered. The filtrate was concentrated under reduced pressure to yield a residue that was dissolved in water and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated to give 2,4-dimethoxyquinoline as a white solid (13 g, 74% over 2 steps).

Reference： [1]Patent: US2012/309758,2012,A1 .Location in patent: Page/Page column 64

42
[ 1679-18-1 ]
[ 703-61-7 ]
[ 50717-32-3 ]
[ 79039-71-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-Chlorophenylboronic acid; 2,4-dichloroquinoline With potassium carbonate In 1,4-dioxane; water at 20℃; for 0.333333h; Inert atmosphere; Stage #2: With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1,4-dioxane; water for 20h; Inert atmosphere; Reflux;	50 4-chloro-2-(4-chlorophenyl)-quinoline To a solution of 28.8 g (145 mmol) of 2,4-dichloroquinoline and 25.0 g (160 mmol) of 4- chlorophenylboronic acid in 350 mL of 1,4-dioxane, at room temperature, was added 120 mL of 5.4 M K2C03 aqueous solution. The reaction mixture was degazed for 20 minutes with nitrogen. Then, 8.4 g (7.3 mmol) of tetrakis (triphenylphosphine)palladium were added and the mixture was warmed to reflux and stirred for 20 hours. The reaction mixture was cooled down to room temperature and poured into 350 mL of a 5% NaCl aqueous solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous Na2S04, filtered and evaporated under vacuum to give 49.6 g of crude product. The residue was purified by silica gel column chromatography (Cyclohexane EtOAc 98:2) to give 40.5 g of an off-white solid corresponding to a mixture of 4-chloro-2-(4- chlorophenyl)quinoline and 2,4-bis(4-chlorophenyl)quinoline (72.7% of 4-chloro-2-(4- chlorophenyl)quinoline according to UPLC analysis at 260 nm). The mixture was used in the next step without further purification. HPLC-MS: conditions H: tT = 4.05 min, (ES+) C15H9C12N requires 273; found 274 [M + H], purity 72.7 %. 1H NMR (300 MHz, CDC13).

Reference： [1]Current Patent Assignee: GENOSCIENCE PHARMA - WO2014/147611, 2014, A1 Location in patent: Page/Page column 172; 173; 174

43
[ 688020-19-1 ]
[ 1679-18-1 ]
[ 703-61-7 ]
2-(4-chlorophenyl)-4-(4-tert-butylaminopiperidin-1-yl)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	Stage #1: 4-Chlorophenylboronic acid; 2,4-dichloroquinoline With potassium carbonate In 1,4-dioxane; water at 20℃; for 0.333333h; Inert atmosphere; Stage #2: With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1,4-dioxane; water for 20h; Inert atmosphere; Reflux; Stage #3: tert-butylaminopiperidin-4-yl-amine With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 140℃; for 20h;	50 To a solution of 28.8 g (145 mmol) of 2,4-dichloroquinoline and 25.0 g (160 mmol) of 4- chlorophenylboronic acid in 350 mL of 1,4-dioxane, at room temperature, was added 120 mL of 5.4 M K2C03 aqueous solution. The reaction mixture was degazed for 20 minutes with nitrogen. Then, 8.4 g (7.3 mmol) of tetrakis (triphenylphosphine)palladium were added and the mixture was warmed to reflux and stirred for 20 hours. The reaction mixture was cooled down to room temperature and poured into 350 mL of a 5% NaCl aqueous solution. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous Na2S04, filtered and evaporated under vacuum to give 49.6 g of crude product. The residue was purified by silica gel column chromatography (Cyclohexane EtOAc 98:2) to give 40.5 g of an off-white solid corresponding to a mixture of 4-chloro-2-(4- chlorophenyl)quinoline and 2,4-bis(4-chlorophenyl)quinoline (72.7% of 4-chloro-2-(4- chlorophenyl)quinoline according to UPLC analysis at 260 nm). The mixture was used in the next step without further purification. HPLC-MS: conditions H: tT = 4.05 min, (ES+) C15H9C12N requires 273; found 274 [M + H], purity 72.7 %. 1H NMR (300 MHz, CDC13). To a solution of 20.7 g of the above mixture of 4-chloro-2-(4-chlorophenyl)quinoline and 4-bis(4-chlorophenyl)quinoline and 14.2 g (90.6 mmol) of 4-(iert-butylamino)piperidine in 100 mL of NMP, at room temperature, was added dropwise 9.6 mL (113 mmol) of DIPEA. The reaction mixture was warmed to 140 °C and stirred for 20 hours. After cooling down to room temperature, 400 mL of 1 M NaOH aqueous solution and 200 mL of ethyl acetate were added. The aqueous layer was extrated with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04, filtered and evaporated under vacuum to give 34.3 g of crude product. The residue was purified by silica gel column chromatography (dichloromethane/methanol 95:5 to 90:10) to give a first fraction of 16.6 g as a brown oil containing the expected product contaminated with 30% w/w of residual NMP, and a second fraction of 5.6 g of a white solid corresponding to 2-(4- chloro-phenyl)-4-(4-N-teri-butylamino-piperidin-l-yl)quinoline (19% from 2,4- dichloroquinoline). The first fraction was triturated in a mixture of DCM-iPr20, filtrered off and dried under vacuum to give 5.2 g (yield 18% from 2,4-dichloroquinoline) of a white solid corresponding to 2-(4-chloro-phenyl)-4-(4-N-ieri-butylamino-piperidin-l- yl)quinoline. HPLC-MS: conditions G: τ = 1.38 min, (ES+) ^Η28αΝ3 requires 393; found 394 [M + H], purity 94.8 %. 1H NMR (300 MHz, CDC13).

Reference： [1]Current Patent Assignee: GENOSCIENCE PHARMA - WO2014/147611, 2014, A1 Location in patent: Page/Page column 172; 173; 174

44
4-(3-hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester [ No CAS ]
[ 703-61-7 ]
ethyl 4-(3-(2-chloroquinolin-4-yloxy)phenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; regioselective reaction;	General Procedure for the Synthesis of Ethyl 4-(3-(2-chloroquinolin-4-yloxy)phenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates (3a-j) General procedure: A mixture of substituted 2,4-dichloroquinolines 2a-j (1mol), powdered K2CO3 (1.2 mol) and 4-(3-hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate(1; 1 mol) in DMF was stirred at 70 °C for 48 h.The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was poured into a beaker containing ice cold water and stirred well, the separated solid filtered to dryness and purified through column chromatography of silica gel (60-120 mesh)using pet. ether and ethyl acetate (7:3) mixture as eluent,which afforded the products 3a-j in pure form. Ethyl 4-(3-(2-chloroquinolin-4-yloxy)phenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate(3a): IR (KBr, cm-1): 3419 (-NH stretching), 2966(aromatic -CH stretching), 1693 & 1614 (-C=O); 1H NMR(200 MHz, CDCl3) H: 0.94 (s, 3 protons at C-16), 1.12 (s, 3protons at C-15), 1.19 (t, J = 7.5 Hz, 3 protons at C-10),2.20-2.23 (m, 2 protons at C-14), 2.33-2.37 (m, 2 protons atC-12), 2.39 (s, 3 protons at C-7), 4.09 (q, J = 7.5 Hz, 2 protonsat C-9), 5.12 (s, 1 proton at C-4), 5.58 (bs, 1 proton at -NH), 6.36 (s, 1 proton at C-24), 6.93-7.01 (m, 1 proton at C-19), 7.12 (s, 1 aryl protons at C-21), 7.35 (d, 1 aryl proton atC-18), 7.49-7.62 (m, 2 aryl proton at C-28, 20), 7.77 (t, J =7.0 Hz, 1 aryl proton at C-29), 7.99 (d, J = 8.0 Hz, 1 arylproton at C-30), 8.32 (d, J = 8.0 Hz, 1 aryl proton at C-27);MS: m/z Calcd. For C30H29ClN2O4: 516.1; found. 517.1[M+1].

Reference： [1]Rajesh, Kancherla; Lavanya, Pandian; Iniyavan, Pethaperumal; Sarveswari, Sundaramoorthy; Ramaiah, Sudha; Anbarasu, Anand; Vijayakumar, Vijayaparthasarathi [Medicinal Chemistry, 2015, vol. 11, # 8, p. 789 - 797]

45
2-((1S,2S)-2-aminocyclohexyl)isoindoline-1,3-dione [ No CAS ]
[ 703-61-7 ]
2-((1S,2S)-2-((4-chloroquinolin-2-yl)amino)cyclohexyl)isoindolyl-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium⁽⁰⁾ In toluene for 27h; Reflux; Inert atmosphere;	2.c.ii.1 1) PREPARATION OF 2-((1R,2R)-2-((4-CHLOROQUINOLIN-2-YL)AMINO)CYCLOHEXYL)ISOINDOLINE-1,3-DIONE [00413] A flame dried flask equipped with a stir bar was charged with Pd(dba)2 (208 mg, 362 μιηο), rac-BINAP (225 mg, μιηο), cesium carbonate (8.84 g, 27.1 mmol), the amine (2.21 g, 9.05 mmol), and 2,4-dichloroquinoline (1.79 g, 9.05 mmol). An oven dried condenser was attached and the apparatus was purged twice with argon. Toluene (45 mL) was added and the resulting solution was stirred under reflux for 27 h. The reaction mixture was then cooled to r.t, filtered through a Celite pad with CH2CI2 and EtOAc, and concentrated. Flash column chromatography of the residue afforded the desired product as a r I20 light yellow foam (1.53 g, 42%). La-b +96 (c 0.68, CHC13); R/= 0.31 (20% EtOAc/Hexanes); IR (film) 3381, 3060, 2935, 2858, 1767, 1705, 1606, 1567, 1531 cm"1; NMR (400 MHz, CDC13) δ 7.65 (d, J= 7.6 Hz, 1H), 7.49 (m, 3H), 7.38 (ddd, J= 8.0, 6.8, 1.2 Hz, 1H), 7.31 (dd, J= 5.6, 3.2 Hz, 2H), 7.06 (ddd, J= 8.0, 8.0, 1.2 Hz, 1H), 6.59 (s, 1H), 4.84 (dddd, J= 10.8, 10.8, 10.8, 4.0 Hz, 1H), 4.74 (d, J= 10.0 Hz, 1H), 4.08 (ddd, J= 10.8, 10.8, 4.0 Hz, 1H), 2.66 (dddd, J= 12.8, 12.8, 12.8, 3.6 Hz, 1H), 2.23 (br m, 1H), 1.85 (m, 3H), 1.66 (ddddd, J= 13.2, 13.2, 13.2, 3.2, 3.2 Hz, 1H), 1.42-1.30 (m, 2H); 13C NMR (125.8 MHz, CDCl3) ppm 168.8, 156.0, 148.1, 142.3, 133.1, 131.3, 129.9, 126.3, 123.3, 122.4, 122.3, 120.9, 11 1.0, 56.1, 51.3, 33.4, 28.7, 25.5, 24.8; HRMS (ESI) Exact mass calcd for C23H21C1N302 [M+H]+ 406.1322, found 406.1308.

Reference： [1]Current Patent Assignee: ST. JUDE CHILDRENS RESEARCH HOSPITAL - WO2015/184383, 2015, A1 Location in patent: Paragraph 00413

46
[ 703-61-7 ]
[ 57260-71-6 ]
tert-butyl 4-(4-chloroquinolin-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With N,N-diethyl-N-isopropylamine at 100℃; for 48h; Sealed tube;	A A. Preparation of tert-butyl 4-(4-chloroquinolin-2-yl)piperazine-1-carboxylate A suspension of 2,4-dichloroquinoline (6.4 g, 32.2 mmol), tert-butyl piperazine-1-carboxylate (5.0 g, 26.8 mmol) and diethylisopropylamine (6.5 mL, 38.0 mmol) was stirred in a sealed at 100° C. for 2 days. Upon cooling, the reaction mixture was concentrated in vacuuo to afford material which was purified by column chromatography on SiO2 eluting with EtOAc in hexanes (0-15%) to afford tert-butyl 4-(4-chloroquinolin-2-yl)piperazine-1-carboxylate (3.2 g, 34%). ES/MS m/z=348.1 (M+H)+.
29%	With N-ethyl-N,N-diisopropylamine In toluene at 110℃; for 16h;
	With N,N-diethyl-N-isopropylamine at 100℃; for 48h; Sealed tube;	tert-Butyl 4-(4-chloroquinolin-2-yl)piperazine-1-carboxylate tert-Butyl 4-(4-chloroquinolin-2-yl)piperazine-1-carboxylate A suspension of 2,4-dichloroquinoline (6.4 g, 32.2 mmol), tert-butyl piperazine-1-carboxylate (5.0 g, 26.8 mmol) and diethylisopropylamine (6.5 mL, 38.0 mmol) was stirred in a sealed tube at 100° C. for 2 days. Upon cooling, the reaction mixture was concentrated in vacuuo to afford material which was purified by column chromatography on SiO2 eluting with EtOAc in hexanes (0-15%) to afford the title compound. ES/MS m/z=348.1 (M+H)+.

With N,N-diethyl-N-isopropylamine at 100℃; for 48h; Sealed tube; Inert atmosphere;

tert-Butyl 4-(4-chloroquinolin-2-yl)piperazine-1-carboxylate A suspension of 2,4-dichloroquinoline (6.4 g, 32.2 mmol), tert-butyl piperazine-1- carboxylate (5.0 g, 26.8 mmol) and diethylisopropylamine (6.5 mL, 38.0 mmol) was stirred in a sealed tube at 100 °C for 2 days. Upon cooling, the reaction mixture was concentrated in vacuuo to afford material which was purified by column chromatography on SiO2 eluting with EtOAc in hexanes (0-15%) to afford the title compound. ES/MS m/z = 348.1 (M+H)+.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2018/86768, 2018, A1 Location in patent: Paragraph 0430-0431
[2]Zheng, Xiufang; Wang, Lisha; Wang, Baoxia; Miao, Kun; Xiang, Kunlun; Feng, Song; Gao, Lu; Shen, Hong C.; Yun, Hongying [ACS Medicinal Chemistry Letters, 2016, vol. 7, # 6, p. 558 - 562]
[3]Current Patent Assignee: GILEAD SCIENCES INC - US2018/86747, 2018, A1 Location in patent: Paragraph 0846-847
[4]Current Patent Assignee: GILEAD SCIENCES INC - WO2018/57808, 2018, A1 Location in patent: Page/Page column 223-224

47
[ 3529-08-6 ]
[ 703-61-7 ]
[ 857239-43-1 ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium carbonate In N,N-dimethyl acetamide for 20h;	H1 Example Hi: Preparation of 2-chloro-N-(3-(piperidin-1-yl)propyl)quinolin-4-amine To a mixture of 2,4-dichloroquinolne (5 g), 3-(piperidin-1-yl)propan-1-amine (3.5 g),potassium carbonate (6.96 g) was added DMA (100 ml). The reaction was heated for 20 hours, cooled and the solvent removed under vacuum. The residue was extracted with DCM/ water and dried over sodium sulfate. The resulting solid was purified with silica gel eluted with 70% DCM/0% MeOH. The resulting solid was recrystallized from MeOH, to afford of 2-chloro-N-(3- (piperidin-1-yl)propyl)quinolin-4-amine (4 g, yield: 63%) as a white/tan solid, MS (El): mlz 304 [(M+ 1 )+].

Reference： [1]Current Patent Assignee: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE; LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY - WO2016/61280, 2016, A1 Location in patent: Paragraph 0430; 0431

48
[ 1423-27-4 ]
[ 703-61-7 ]
4-chloro-2-(2-trifluoromethylphenyl)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In water; acetonitrile	F1 Example Fl:Preparation of 4-chloro-2-(2-trifluoromethyl-phenyl)-quinoline j0343j To a mixture of 2,4-dichloro-quinoline (300 mg, 1.51 mmol) in CH3CN (12 mL) and H20 (4 mL), was added 2-(trifluoromethyl)phenyboronic acid (232 mg, 1.66 mmol), K2C03 (417 mg, 3.02 mmol) and Pd(PPh3)4 (36 mg, 0.03 mmol). The suspension was degassed under reduced pressure and purged with N2 atmophere for several times. The mixture was stirred at 80 °C overnight. The mixture was partitioned between water (30 mL) and EA (30 mL). The aqueousphase was extracted with EA (30 mL x2). The combined organic phase was washed with brinemL x2) and dried over Na504. After filtration, the solvent was removed, and the residue was purified by silica gel column chromatography (PE/EA = 50/1) to give 4-chloro-2-(2-trifluoromethyl-phenyl)-quinoline (400 mg, yield: 86%) as a white solid. MS (El): mlz 308.3[(M+ 1 )+]

Reference： [1]Current Patent Assignee: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE; LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY - WO2016/61280, 2016, A1 Location in patent: Paragraph 0342; 0343

49
[ 557-21-1 ]
[ 703-61-7 ]
[ 4552-43-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In N,N-dimethyl-formamide at 120℃; for 1h;	4.1.1. Synthesis of 4-chloroquinoline-2-carbonitrile 4 (93%) To a solution of 2,4-dichloroquinoline (444 mg, 2.24 mmol) in DMF (5 mL) was added zinc cyanide (117 mg, 1.14 mmol) andPd(PPh3)4 (259 mg, 0.22 mmol). The reaction mixturewas stirred at 120 °C for 1 h. A saturated NH4Cl solution (20 mL) was added andthe mixture was extracted with ethyl acetate (3 5 mL). Theorganic layer was washed with a NaCl solution (5 mL) and driedover sodium sulfate, filtered and evaporated. The product wasfurther purified by chromatography on silica gel eluting withcyclohexane/ethyl acetate (95:5) to give 4 (392 mg, 2.085 mmol,93%) as a white solid. White solid. F 108.9-109.3 °C. 1H NMR (300 MHz, CDCl3)δ 8.12 (d, J 8.4 Hz, 1H), 8.06 (d, J 8.4 Hz, 1H), 7.81 (t, J 7.6 Hz,1H), 7.70 (t, J 7.6 Hz, 1H), 7.61 (s, 1H). 13C NMR (75 MHz, CDCl3)δ 148.9, 144.3, 133.4, 132.2, 130.7 (2C), 127.3, 124.4, 123.4, 116.8. IRneat nmax/cm-1: 3093, 2344, 2240, 1570, 1491, 1403, 1292, 1024.HRMS calcd for C10H6N2Cl [M+H]+ 189.0220, obsd. 189.0217.
86%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In N,N-dimethyl-formamide at 120℃;
80%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In N,N-dimethyl-formamide at 120℃; for 1h;	4 Example 4: Generation and synthesis of the toxin unit ICQO-4 The toxic unit ICQO-4 was synthesized according the following process. Ina microwave vial, dried and flushed with argon, was charged 2,4-chloroquinoline(407 mg, 2.055 mmol, 1 eq.) in DMF (4.6 mL). Then, Zn(CN)2 (123 mg, 1.048 mmol,0.51 eq.) was added followed by Pd(PPh3)4 (237.5 mg, 0.206 mmol, 0.1 eq.). Thereaction mixture was warmed at 120°C and stirred at this temperature for 1 h. Aftercomplete consumption of the starting material (TLC: cyclohexane/EtOAc: 9/1), thereaction was hydrolyzed by addition of saturated solution of NH4CI (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x30 mL). The combined organic layers were dried over MgSO4, filtered andconcentrated under reduce pressure. The crude mixture was purified by flash columnchromatography on silica gel (cyclohexane/EtOAc: 9/1) to afford the desired product(310 mg, 80%).1H NMR (300 MHz, CDCI3): 6 [ppm] = 8.28 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 8.4 Hz,1 H), 7.92 (t, J = 7.5 Hz, 1 H), 7.82 (t, J = 7.8 Hz, 1 H), 7.80 (5, 1 H).

58.8%

With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In N,N-dimethyl-formamide at 120℃; for 2h; Inert atmosphere;

17 2,4-Dichloroquinoline (444 mg, 2.24 mmol) was dissolved in anhydrous 15 mL of DMF, and then added zinc cyanide (117 mg, 1.14 mmol), tetrakis(triphenylphosphine)palladium (259 mg, 0.22 mmol) in nitrogen The reaction was carried out under the conditions of 120 °C for 2 h, and extracted with ethyl acetate (25 mL×3). The organic phase was combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. EA 80: 1) 2-cyano-4-chloroquinoline 250 mg, yield 58.8%;

Reference： [1]Khelifi, Ilhem; Naret, Timothée; Renko, Dolor; Hamze, Abdallah; Bernadat, Guillaume; Bignon, Jérome; Lenoir, Christine; Dubois, Joëlle; Brion, Jean-Daniel; Provot, Olivier; Alami, Mouad [European Journal of Medicinal Chemistry, 2017, vol. 127, p. 1025 - 1034]
[2]Pecnard, Shannon; Provot, Olivier; Levaique, Hélène; Bignon, Jérome; Askenatzis, Laurie; Saller, Francois; Borgel, Delphine; Michallet, Sophie; Laisne, Marie-Catherine; Lafanechère, Laurence; Alami, Mouad; Hamze, Abdallah [European Journal of Medicinal Chemistry, 2021, vol. 209]
[3]Current Patent Assignee: UNIVERSITY OF PARIS SUD; AVICENNA ONCOLOGY; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - WO2018/178277, 2018, A1 Location in patent: Paragraph 00126
[4]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN109608435, 2019, A Location in patent: Paragraph 0097; 0098; 0099; 0100

50
2-chloroquinolin-4-ol [ No CAS ]
[ 703-61-7 ]

Yield	Reaction Conditions	Operation in experiment
87.5%	With trichlorophosphate at 80℃;	General preparation of 6a-c General procedure: Compounds 5a-c was added in POCl3, and the resulting mixture was refluxed for 12 h. The POCl3 was evaporated under reduced pressure, and the residue codisted once with CHCl3, and twice with toluene. The resulting solid was dissolved in CH2Cl2 and treated with triethylamine until aqueous washings of aliquots had pH >10. The solution was then filtered to yield the title compounds 6a-c. 2, 4-Dichloroquinoline (6a) Compound 6a was prepared from 2-chloroquinolin-4-ol (5a, 1.1 g, 6.0 mmol) as a light white solid, yield 87.5%. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 8.8, 1H), 8.04 (d, J = 8.0, 1H), 7.84-7.76 (m, 1H), 7.68-7.63 (m, 1H), 7.52 (s, 1H). MS (ESI, m/z): 197.87 [M + H]+.

Reference： [1]Zhou, Yuanyuan; Yan, Wei; Cao, Dong; Shao, Mingfeng; Li, Dan; Wang, Fang; Yang, Zhuang; Chen, Yong; He, Linhong; Wang, Taijin; Shen, Mingsheng; Chen, Lijuan [European Journal of Medicinal Chemistry, 2017, vol. 138, p. 1114 - 1125]

51
[ 577-72-0 ]
[ 703-61-7 ]
2-chloro-N-(4-methoxy-3-nitrophenyl)quinolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With hydrogenchloride; In isopropyl alcohol; at 80℃; for 2h;	General procedure: To a solution of 8a-c (1.0 equiv) in isopropanol was added 7a (1.2 equiv) with catalytic amount of HCl (conc) refluxed at 80 C for 2 h, then cooled to room temperature, and filtered to obtain solid. The resulting solid was dissolved in CH2Cl2 and treated with triethylamine until aqueous washings of aliquots had pH >10. The mixture washed with saturated NaHCO3 aq, brine, dried over Na2SO4, filtered and concentrated by vacuum to give compounds 8a-c. Compound 8d was prepared from 6b and 7b followig the same route. Compounds 11a-d were obtained by conducting the same method with 10a as the starting material.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 138,p. 1114 - 1125

52
[ 703-61-7 ]
[ 104-94-9 ]
[ 824935-60-6 ]

Yield	Reaction Conditions	Operation in experiment
73%	With hydrogenchloride In isopropyl alcohol at 80℃; for 2h;	General preparation of 8a-d and 11a-d General procedure: To a solution of 8a-c (1.0 equiv) in isopropanol was added 7a (1.2 equiv) with catalytic amount of HCl (conc) refluxed at 80 °C for 2 h, then cooled to room temperature, and filtered to obtain solid. The resulting solid was dissolved in CH2Cl2 and treated with triethylamine until aqueous washings of aliquots had pH >10. The mixture washed with saturated NaHCO3 aq, brine, dried over Na2SO4, filtered and concentrated by vacuum to give compounds 8a-c. Compound 8d was prepared from 6b and 7b followig the same route. Compounds 11a-d were obtained by conducting the same method with 10a as the starting material. 2-Chloro-N-(4-methoxyphenyl)quinolin-4-amine (8a) Compound 8a was prepared from 6a (330 mg, 1.7 mmol) and 7a (248 mg, 2.0 mmol) as a light yellow solid, yield 73%. 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 8.4, 0.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.65-7.58 (m, 1H), 7.39-7.32 (m, 3H), 7.00-6.92 (m, 3H), 3.83 (s, 3H). MS (ESI, m/z): 285.14 [M + H]+.

Reference： [1]Zhou, Yuanyuan; Yan, Wei; Cao, Dong; Shao, Mingfeng; Li, Dan; Wang, Fang; Yang, Zhuang; Chen, Yong; He, Linhong; Wang, Taijin; Shen, Mingsheng; Chen, Lijuan [European Journal of Medicinal Chemistry, 2017, vol. 138, p. 1114 - 1125]

53
[ 703-61-7 ]
[ 330793-01-6 ]
tert-butyl 4-(4-chloroquinolin-2-yl)phenylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 0.5h; Sealed tube;	13.A Step A: tert-Butyl 4-(4-chloroquinolin-2-yl)phenylcarbamate (31) Step A: tert-Butyl 4-(4-chloroquinolin-2-yl)phenylcarbamate (31) [00398] A mixture of 2,4-dichloroquinoline (2.0 g, 10 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenylcarbamate (3.8 g, 12 mmol), Cs2C03(6.5 g, 20 mmol) and Pd(PP3)4(600mg, 1.0 mmol) in DMF(25 mL) was stirred in a sealed tube at 100°C for 30 min. The reaction was cooled to room temperature; Water (200 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL x 3). The combined organic layers were concentrated and purified by silica gel column chromatography with petroleum ether/ ethyl acetate (3 : 1) to give the product (1 g, 28%) as a yellow solid. LC-MS: (M + H)+ 355.1

Reference： [1]Current Patent Assignee: STATE UNIVERSITY OF NEW YORK; NEW YORK UNIVERSITY - WO2017/184547, 2017, A1 Location in patent: Paragraph 00398

54
[ 703-61-7 ]
[ 104-86-9 ]
4-chloro-N-(4-chlorobenzyl)quinolin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In tetrahydrofuran for 2h; Inert atmosphere; Reflux;	2.1; 19.1 2.1 Synthesis of 2-(4-chlorobenzylamino)-4-chloroquinoline (2-1) To a solution under nitrogen gas of 2,4-dichloroquinoline 1-3 (1.00 g, 5.05 mmol) in dry THF (10 ml) was added 4-chlorobenzylamine (1.46 g, 10.1 mmol) and t-BuONa (1.36 g, 14.1 mmol). The resulting mixture was degassed 5 min with nitrogen, then Xantphos (295 mg, 0.51 mmol) and Pd(OAc)2 (58 mg, 0.25 mmol) were added and the reaction mixture was heated under reflux for 2 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between brine and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash chromatography (gradient cyclohexane/DCM from 5/5 to 0/10) to give 897 mg (yield 59%) of a brown solid corresponding to 2-(4-chlorobenzylamino)-4-chloroquinoline (2-1). Mass, Method A: (ES+) C16H12Cl2N2 required 302; found 303 [M+H] 1H NMR (300 MHz, CDCl3)
44%	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In tetrahydrofuran for 3h; Inert atmosphere; Reflux;	Synthesis of scaffod 2-(4-chlorobenzylam no)-4-choroqunoNne To a solution under nitrogen gas of 2,4-dichloroquinoline (20.0 g, 101 mmol) in dry THF (200 ml) was added 4-chlorobenzylamine (24.7 ml, 202 mmol, 2 eq.) and t-BuONa (27.2 g, 283 mmol, 2.8 eq.). The resulting mixture was degassed 10 min with nitrogen, then Xantphos (5.8 g, 10.1 mmol, 0.1 eq.) and Pd(OAc)2 (1.1 g, 5.0 mmol, 0.05 eq.) were added and the reaction mixture was heated under reflux for 3 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between brine and AcOEt and the aqueous layer was extracted with AcOEt. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash chromatography (gradient Petroleum ether/DCM from 5/5 to 0/10) to give 13.5 g (yield 44%) of a brown solid corresponding to 2-(4-chlorobenzylamino)-4-chloroquinoline. Mass: (ES+) C18H12Cl2N2, required 303; found 303-305 [M+H], HPLC/MS method 1.

Reference： [1]Current Patent Assignee: GENOSCIENCE PHARMA - EP3620164, 2020, A1 Location in patent: Paragraph 1427; 1428; 1557; 1558
[2]Current Patent Assignee: GENOSCIENCE PHARMA - WO2017/191599, 2017, A1 Location in patent: Page/Page column 133; 134

55
[ 703-61-7 ]
[ 104-11-0 ]
2-(4-chloro-N-methylbenzylamino)-4-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In tetrahydrofuran; for 3h;Inert atmosphere; Reflux;	To a solution under nitrogen gas of 2,4-dichloroquinoline (1.00 g, 5.0 mmol) in dry THF (10 ml) was added <strong>[104-11-0]4-chloro-N-methylbenzylamine</strong> (1.57 g, 10.1 mmol, 2 eq.) and t-BuONa (1.36 g, 14.1 mmol, 2.8 eq.). The resulting mixture was degassed 5 min with nitrogen, then Xantphos (292 mg, 0.51 mmol, 0.1 eq.) and Pd(OAc)2 (57 mg, 0.25 mmol) were added and the reaction mixture was heated under reflux for 3 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between brine and AcOEt and the aqueous layer was extracted with AcOEt. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash chromatography (gradient Petroleum ether/DCM from 5/5 to 0/10) to give 800 mg (yield 50%) of a brown solid corresponding to 2-(4-chloro-N-methylbenzylamino)-4- chloroquinoline. Mass: (ES+) C17H14Cl2N2, required 317; found 317-319 [M+H], HPLC/MS method 1.

Reference： [1]Patent: WO2017/191599,2017,A1 .Location in patent: Page/Page column 141; 142

56
[ 703-61-7 ]
[ 110-83-8 ]
[ 123005-17-4 ]

Yield	Reaction Conditions	Operation in experiment
72%	With Iron(III) nitrate nonahydrate; sodium tetrahydroborate In ethanol; acetonitrile at 0℃; for 0.5h;

Reference： [1]Liang, Bingyu; Wang, Qinglong; Liu, Zhong-Quan [Organic Letters, 2017, vol. 19, # 24, p. 6463 - 6465]

57
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole [ No CAS ]
[ 703-61-7 ]
4-chloro-2-(1-trityl-1H-pyrazol-3-yl)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1,4-dioxane; water at 90℃; for 3h;	4-Chloro-2-(1-trityl-1H-pyrazol-3-yl)quinoline 4-Chloro-2-(1-trityl-1H-pyrazol-3-yl)quinoline A sealed tube was charged with 2,4-dichloroquinoline (1.0 g, 5.05 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole (2.2 g, 5.05 mmol), K3PO4 (3.2 g, 15.1 mmol) and Pd(PPh3)4(0.58 g, 0.50 mmol) followed by dioxane (50 mL) and water (12 mL). The reaction mixture was stirred at 90° C. for 3 h. Upon cooling, the reaction mixture was absorbed on SiO2 followed by purification on column chromatography on SiO2 eluting with EtOAc in hexanes (0-100%) to afford the title compound. ES/MS m/z=472.2 (M+H)+.
	With potassium phosphate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1,4-dioxane; water at 90℃; for 3h; Sealed tube; Inert atmosphere;	4-Chloro-2-(1-trityl-1H-pyrazol-3-yl)quinoline A sealed tube was charged with 2,4-dichloroquinoline (1.0 g, 5.05 mmol), 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole (2.2 g, 5.05 mmol), K3PO4 (3.2 g, 15.1 mmol) and Pd(PPh3)4 (0.58 g, 0.50 mmol) followed by dioxane (50 mL) and water (12 mL). The reaction mixture was stirred at 90 °C for 3 h. Upon cooling, the reaction mixture was absorbed on SiO2 followed by purification on column (0251) chromatography on SiO2 eluting with EtOAc in hexanes (0-100%) to afford the title compound. ES/MS m/z = 472.2 (M+H)+.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2018/86747, 2018, A1 Location in patent: Paragraph 0848-0849
[2]Current Patent Assignee: GILEAD SCIENCES INC - WO2018/57808, 2018, A1 Location in patent: Page/Page column 224

58
[ 863238-73-7 ]
[ 703-61-7 ]
4-chloro-2-(1-trityl-1H-pyrazol-4-yl)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 3h;Sealed tube;	A sealed tube was charged with 2,4-dichloroquinoline (1.0 g, 5.05 mmol), <strong>[863238-73-7]4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole</strong> (2.2 g, 5.05 mmol), K3PO4 (3.2 g, 15.1 mmol) and Pd(PPh3)4 (0.58 g, 0.50 mmol) followed by dioxane (50 mL) and water (12 mL). The reaction mixture was stirred at 90 C. for 3 h. Upon cooling, the reaction mixture was absorbed on SiO2 followed by purification on column chromatography on SiO2 eluting with EtOAc in hexanes (0-100%) to afford 4-chloro-2-(1-trityl-1H-pyrazol-4-yl)quinoline (1.15 g, 48%). ES/MS m/z=472.2 (M+H)+.

Reference： [1]Patent: US2018/86768,2018,A1 .Location in patent: Paragraph 0432-0433

59
[ 616-45-5 ]
[ 703-61-7 ]
1-(4-chloroquinolin-2-yl)pyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With 1,1'-bis-(diphenylphosphino)ferrocene; potassium phosphate; palladium diacetate In 1,4-dioxane at 90℃; for 21h; Inert atmosphere; Sealed tube;

Reference： [1]Young, Ian S.; Glass, Anna-Lena; Cravillion, Theresa; Han, Chong; Zhang, Haiming; Gosselin, Francis [Organic Letters, 2018, vol. 20, # 13, p. 3902 - 3906]

60
[ 703-61-7 ]
[ 20151-42-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: 2,4-dichloroquinoline With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: With Benzophenone imine In toluene at 100℃; for 3h; Stage #3: With hydrogenchloride In tetrahydrofuran	28.1 Step 1: A solution of 2,4-dichloroquinoline (990 mg, 5 mmol, 1 equiv.), Pd2dba3 (115mg, 0.13 mmol, 2.5 mol %), rae-B INAP (311 mg, 0.5 mmol, 10 mol %), and sodium tertbutoxide (576 mg, 6 mmol, 1.2 equiv.) in toluene (20 mL) was stirred at room temperature under N2 for approximately 5 minutes. Benzophenone imine (0.84 mL, 5 mmol, 1 equiv.) was added,and the reaction vial was placed in a heating block preheated to 100 °C for three hours. The reaction mixture was cooled to room temperature, MTBE was added, and the mixture was filtered through a short plug of Celite and concentrated. The crude residue was dissolved in 25 mL THF, and 6 mL of 1M HC1 was added. The reaction mixture stirred overnight and was quenched by addition of saturated aqueous NaHCO3, extracted with EtOAc, dried, andconcentrated. The crude residue was purified by flash chromatography on Si02 (10-75% EtOAc/Hexanes) to afford 2-amino-4-chloroquinoline (637 mg, 71%) as a tan solid.
	Multi-step reaction with 2 steps 1.1: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 0.08 h / 20 °C 1.2: 4 h / 100 °C 2.1: hydrogenchloride / water; tetrahydrofuran / 1 h / 20 °C

Reference： [1]Current Patent Assignee: ARCUS BIOSCIENCES INC - WO2018/204661, 2018, A1 Location in patent: Paragraph 0311
[2]Current Patent Assignee: BCI PHARMA - WO2021/23888, 2021, A1

61
[ 703-61-7 ]
[ 98-59-9 ]
4-chloro-2-tosylquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With zinc In water at 80℃; for 12h; Sealed tube;	General procedure for the synthesis of sulfonylated quinolines. General procedure: In a tube (10 mL), halogenated quinolines 1 (0.3 mmol), 2 sulfonyl chloride (0.6 mmol), znic powder (0.3 mmol), and H2O (1 mL) were added. Then, the tube was sealed and the reaction vessel was allowed to stir at 80 oC for 12 h. Upon completion, the reaction was cooled to room temperature, water (3 mL) was added to the reaction mixtue. The mixture was extracted with CH2Cl2 (5 mL x 3) and the organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to give sulfonylated quinolines 3.

Reference： [1]Bao, Pengli; Wang, Leilei; Liu, Qishun; Yang, Daoshan; Wang, Hua; Zhao, Xiaohui; Yue, Huilan; Wei, Wei [Tetrahedron Letters, 2019, vol. 60, # 3, p. 214 - 218]

62
[ 703-61-7 ]
[ 23356-96-9 ]
(S)-(1-(2-chloroquinolin-4-yl)pyrrolidin-2-yl)methanol [ No CAS ]
(S)-(1-(4-chloroquinolin-2-yl)pyrrolidin-2-yl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 23% 2: 10%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 150℃; for 2h;	367.1 Step- 1 : Preparation of (S)-(l-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-2- yl)methanol (96a) General procedure: To a solution of 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (0.5 g, 2.7 mmol) in 2-Propanol (6 mL) was added (S)-pyrrolidin-2-ylmethanol (0.39 mL, 4.0 mmol), DIPEA (1.39 mL, 8.0 mmol) and heated at 90 °C for 1 hr. The reaction was cooled to room temperature and solid obtained was collected by filtration to afford (S)-(l-(2-chloropyrrolo[2,l-f][l,2,4]triazin-4- yl)pyrrolidin-2-yl)methanol (96a) (0.49 g, 73 % yield) as a white solid; NMR (300 MHz, DMSO-i/e): δ 7.70 (dd, J= 2.6, 1.4 Hz, 1H), 6.97 (dd, J= 4.7, 1.6 Hz, 1H), 6.80 - 6.57 (m, 1H), 5.15 (t, J = 5.7 Hz, 1H, D2O exchangeable), 4.87 (t, J= 5.7 Hz, 1H), 4.44 (d, J= 17.8 Hz, 1H), 4.05 - 3.82 (m, 1H), 3.72 - 3.39 (m, 2H), 2.22 - 1.84 (m, 4H). MS (ES+): 253.3, 255.3 (M+2); MS (ES-): 287.2, 289.2 (M+Cl).

Reference： [1]Current Patent Assignee: BIOCRYST PHARMACEUTICALS INC - WO2018/232094, 2018, A1 Location in patent: Page/Page column 179; 454; 455

63
[ 4198-90-7 ]
[ 703-61-7 ]
4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 16h;
59%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; Inert atmosphere;	1 Example 1: Synthesis of 4-((2-chloroquinolin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-Hydroxy-3,5-dimethylbenzonitrile (247 mg) and cesium carbonate (100 mg) wereadded to a solution of 2,4-dichioroquinoline (300 mg) in redistilled DMF (15 mL). The mixture was stirred at 80 °C under Argon protection. After the reaction, thin layer chromatography was performed until its completion. H20 with ice (50 mL) was added, and the aqueous solution was extracted with EtOAc (3 x 15 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, and then filtered and concentrated under reducedpressure. The residue was purified via column chromatography in which 10% EtOAc/hexane was used to obtain the target compound (280 mg; 59% yield).

Reference： [1]Makarasen, Arthit; Kuno, Mayuso; Patnin, Suwicha; Reukngam, Nanthawan; Khlaychan, Panita; Deeyohe, Sirinya; Intachote, Pakamas; Saimanee, Busakorn; Sengsai, Suchada; Boonsri, Pornthip; Chaivisuthangkura, Apinya; Sirithana, Wandee; Techasakul, Supanna [Drug Research, 2019, vol. 69, # 12, p. 671 - 682]
[2]Current Patent Assignee: CHULABHORN FOUNDATION; SRINAKHARINWIROT UNIVERSITY; KASETSART UNIVERSITY - WO2019/45655, 2019, A1 Location in patent: Page/Page column 35

64
[ 703-61-7 ]
[ 124-40-3 ]
[ 6041-50-5 ]

Yield	Reaction Conditions	Operation in experiment
72.1%	In tetrahydrofuran at 20℃;	19 ,4-Dichloroquinoline (100 mg, 0.5 mmol) was dissolved in 10 mL of THF.2M dimethylamine in THF (1.2 mL, 1.0 mmol) was added.Room temperature reaction,After concentration column chromatography (PE / EA 20:1) to give 2-dimethylamino-4-chloroquinoline 75 mg, yield 72.1%;
	In acetonitrile for 24h;	26 2,4-Dichloroquinoline (200mg, 1.01mmol) and dimethylamine (168mmL, 2.54mmol) were dissolved in 5mL acetonitrile, and stirred at room temperature for 24h to complete the reaction. After adding 3 mL of water to the reaction system, it was extracted three times with EA, the organic phases were combined and washed once with water, once with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated to obtain the intermediate 2-methoxy-4-chloroquinoline. The intermediate was synthesized according to the method in Example 10.

Reference： [1]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN109608435, 2019, A Location in patent: Paragraph 0117; 0018; 0019; 0120
[2]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN112390781, 2021, A Location in patent: Paragraph 0124-0127

65
[ 703-61-7 ]
[ 74-89-5 ]
2-methylamino-4-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45.1%	In ethanol at 20℃;	20 2,4-Dichloroquinoline (200 mg, 0.5 mmol) was dissolved in 2 mL of ethanol.Add methylamine in ethanol (1.2 mL, 1.0 mmol),The reaction was carried out at room temperature, concentrated, and washed with ethyl acetate. The filtrate was concentrated and then purified by column chromatography (PE/EA 5:1) to give 2-methylamino-4-chloroquinoline 105 mg, yield 45.1%;

Reference： [1]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN109608435, 2019, A Location in patent: Paragraph 0121; 0122; 0123; 0124

66
[ 703-61-7 ]
[ 172975-69-8 ]
4-chloro-2-(3,5-dimethylphenyl)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In tetrahydrofuran; water at 90℃;	2 Synthesis of Intermediate 1-C 3.70 g (18.67 mmol) of a starting material 1-A, 2.94 g (19.61 mmol) of a starting material 1-B, 1.08 g (0.93 mmol) of Pd(PPh3)4, and 6.45 g (46.68 mmol) of K2CO3 were mixed with 60 mL of THF and 30 mL of H2O and refluxed overnight at a temperature of 90° C. A result obtained therefrom was cooled to room temperature and washed with water and methylene chloride. Then, column chromatography was performed thereon to obtain 4.00 g (yield of 80%) of Intermediate 1-C. The obtained compound was identified by LC-MS analysis. LC-MS m/z=268.12 (M+H)+.
51%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,4-dioxane; water Inert atmosphere; Reflux;	1.1 Step 1: Synthesis of Intermediate 1 To a 1 L round bottom flask were added 2,4-dichloroquinoline (15 g, 75.7 mmol), 3,5-dimethylphenyl boronic acid (11.4 g, 75.7 mmol), Pd(PPh3)4 (4.37 g, 3.8 mmol), sodium carbonate (12 g, 113.6 mmol), 1,4-dioxane (300 mL) and water (75 mL). Then the mixture was bubbled with N2 for 5 min. Then the reaction was heated to reflux overnight under the protection of N2. After the finish of the reaction shown by TLC, the mixture was cooled to room temperature, and then water and ethyl acetate were added, extracted, and the organic phase was combined, dried over MgSO4 and evaporated to dryness, purified via silica gel column chromatography, eluting with ethyl acetate:PE=1:100 (v:v), afforded a crude product (18 g) as a white solid. Then recrystallization from n-hexane afforded the intermediate 1 (10.3 g, 51% yield) as a white crystal.
26%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,4-dioxane; water Inert atmosphere; Reflux;	6 Synthesis of 4-chloro-2-(3,5-dimethylphenyl)quinoline.2,4-Dichloroquinoline (24 g, 121 mmol) in a 1 L 3-neck round bottom flask at room temperature.(3,5-Dimethylphenyl)boronic acid (18.2 g, 121 mmol),Tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4) (6.99g, 6.05mmol)And sodium carbonate (19.2g, 181.5mmol)Add to 480mL 1,4-dioxane and120 mL water.The resulting mixture was purged with nitrogen for 5 min and refluxed under nitrogen overnight.After cooling to room temperature, the reaction mixture was filtered with EtOAc EtOAc.The layers were separated and the aqueous layer was extracted with ethyl acetate.The organic layer was then collected, dried over anhydrous Na 2SO 4 and evaporated.The residue was purified by flash chromatography (EtOAc:EtOAcEtOAcEtOAcEtOAcPure white crystals of 4-chloro-2-(3,5-dimethylphenyl)quinoline (8.3 g, 26%) were obtained.The structure of the product was confirmed by nuclear magnetic and GCMS.

Reference： [1]Current Patent Assignee: SAMSUNG ELECTRONICS CO.,LTD. - US2019/326526, 2019, A1 Location in patent: Paragraph 0267-0269
[2]Current Patent Assignee: BEIJING SUMMER SPROUT TECHNOLOGY CO LTD - US2019/194234, 2019, A1 Location in patent: Paragraph 0121; 0122
[3]Current Patent Assignee: BEIJING SUMMER SPROUT TECHNOLOGY CO LTD - CN109575083, 2019, A Location in patent: Paragraph 0160-0162

67
[ 703-61-7 ]
[ 35303-76-5 ]
4-(2-((2-chloroquinolin-4-yl)amino)ethyl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%	With triethylamine In N,N-dimethyl-formamide at 100℃; for 0.5h; Microwave irradiation;	3 Example 3: Synthesis of 4-(2-((2-chloroquinolin-4-yl)amino)ethyl)benzenesulfonamide 2,4-Dichloroquinoline (100.0 mg, 0.50 mmol), 4-(2-aminoethyl)benzenesulfonamide (100.0 mg, 0.50 mmol) and Et3N (210.0 μL, 1.50 mmol) were added to DMF (2.5 mL). The reaction mixture was reacted in a microwaver (50W, 100) for 30 minutes and cooled to room temperature. After addition of ice water, the reaction mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried with Na2SO4and filtered. The residue obtained under reduced pressure was purified by column chromatography (CH2Cl2:MeOH=20:1) on amine silica. The fractions containing the product were collected and evaporated to obtain the white solid compound, 4-(2-((2-chloroquinolin-4-yl)amino)ethyl)benzenesulfonamide (25.0 mg, 14%).[210][211]1H NMR (300 MHz, CD3OD) δ = 8.04 - 7.95 (m, 1H), 7.86 - 7.79 (m, 2H), 7.76 - 7.61 (m, 2H), 7.49 - 7.40 (m, 3H), 6.52 (s, 1H), 3.66 (t,J= 7.2 Hz, 2H), 3.12 (t,J= 7.1 Hz, 2H)[212]LC/MS ESI (+): 362 (M+1)

Reference： [1]Current Patent Assignee: JW PHARMACEUTICAL CO LTD - WO2019/231271, 2019, A1 Location in patent: Paragraph 207-212

68
4-(2-(phenethylamino)ethyl)benzenesulfonamide [ No CAS ]
[ 703-61-7 ]
4-(2-((2-chloroquinolin-4-yl)(phenethyl)amino)ethyl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2%	With triethylamine In N,N-dimethyl-formamide at 100℃; for 1h; Microwave irradiation;	4.b (b) Synthesis of 4-(2-((2-chloroquinolin-4-yl)(phenethyl)amino)ethyl)benzenesulfonamide 2,4-dichloroquinoline (54.0 mg, 0.27 mmol), 4-(2-(phenethylamino)ethyl)benzenesulfonamide (83.0 mg, 0.27 mmol) and Et3N (110.0 μL, 0.81 mmol) were added to DMF (1.5 mL). The reaction mixture was reacted in a microwaver (50W, 100) for 1 hour and cooled to room temperature. After addition of ice water, the reaction mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried with Na2SO4and filtered. The residue obtained under reduced pressure was purified by column chromatography (CH2Cl2) on amine silica. The fractions containing the product were collected and evaporated to obtain the ivory solid compound, 4-(2-((2-chloroquinolin-4-yl)(phenethyl)amino)ethyl)benzenesulfonamide (2.5 mg, 2%).[223][224]1H NMR (300 MHz, CDCl3) δ = 7.98 (dd,J= 1.0, 8.2 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.74 - 7.68 (m, 1H), 7.63 - 7.55 (m, 1H), 7.42 - 7.19 (m, 8H), 6.88 - 6.83 (m, 1H), 4.62 (s, 2H), 3.79 - 3.64 (m, 4H), 3.05 - 2.89 (m, 4H)[225]LC/MS ESI (+): 466 (M+1)

Reference： [1]Current Patent Assignee: JW PHARMACEUTICAL CO LTD - WO2019/231271, 2019, A1 Location in patent: Paragraph 221-225

69
[ 29968-78-3 ]
[ 703-61-7 ]
2-chloro-N-(4-nitrophenethyl)quinolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With N-ethyl-N,N-diisopropylamine; at 160℃; for 48h;	2,4-Dichloroquinoline (300.0 mg, 1.52 mmol), <strong>[29968-78-3]2-(4-nitrophenyl)ethan-1-amine hydrochloride</strong> (307.0 mg, 1.52 mmol) and DIPEA (1.3 mL, 7.57 mmol) were dissolved in sulforane (7.5 mL) and stirred at 160 for 2 days. After addition of H2O, the reaction mixture was stirred and extracted with EtOAc. The organic layer was washed with brine, dried with Na2SO4, filtered and distilled under reduced pressure. The residue was purified by C18 reversed-phase silica gel column chromatography (CH3CN:H2O condition) and freeze-dried to obtain the light brown solid compound, 2-chloro-N-(4-nitrophenethyl)quinolin-4-amine (130.0 mg, 25%).[856][857]1H NMR (400 MHz, METHANOL-d4) delta = 8.17 (d,J= 8.0 Hz, 2H), 8.00 (dd,J= 0.7, 8.4 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.69 - 7.63 (m, 1H), 7.52 (d,J= 8.7 Hz, 2H), 7.45 (ddd,J= 1.4, 6.8, 8.4 Hz, 1H), 6.51 (s, 1H), 3.70 (t,J= 7.0 Hz, 2H), 3.17 (t,J= 7.0 Hz, 2H)[858]LC/MS ESI (+): 328 (M+1)

Reference： [1]Patent: WO2019/231271,2019,A1 .Location in patent: Paragraph 854-858

70
[ 703-61-7 ]
[ 140-75-0 ]
2-(4-fluorobenzylamino)-4-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In tetrahydrofuran for 3h; Inert atmosphere; Reflux;	5.1 5.1 Synthesis of 2-(4-fluorobenzylamino)-4-chloroquinoline (5-1) To a solution of 2,4-dichloroquinoline 1-3 (25.0 g, 126 mmol) in dry THF (200 mL) under nitrogen gas were added 4-fluorobenzylamine (32.1 g, 257 mmol) and t-BuONa (25.0 g, 260 mmol). The reaction mixture was degassed 20 min with nitrogen, then Xantphos (2.651 g, 4.582 mmol) and Pd(OAc)2 (510 mg, 2.27 mmol) were added and the reaction mixture was heated under reflux for 3 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between brine and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash chromatography (gradient cyclohexane/EtOAc from 100:0 to 70:30) to give 13.6 g (yield 37%) of a brown solid corresponding to 2-(4-fluorobenzylamino)-4-chloroquinoline (5-1). HPLC-MS, Method B: tr = 1.79 min, (ES+) C16H12ClFN2 required 286; found 287 [M+H]

Reference： [1]Current Patent Assignee: GENOSCIENCE PHARMA - EP3620164, 2020, A1 Location in patent: Paragraph 1452; 1453

71
2-methyl-N₁-(pyrimidin-2-yl)-benzene-1,4-diamine [ No CAS ]
[ 703-61-7 ]
2-[4-(2-pyrimidinylamino)-3-methylphenylamino]-4-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran for 4h; Inert atmosphere; Reflux;	3.3 3.3 Synthesis of 2-[4-(2-pyrimidinylamino)-3-methyl-phenylamino]-4-chloroquinoline (3-3) A solution of 2-methyl-N1-(pyrimidin-2-yl)benzene-1,4-diamine 3-2 (771 mg, 3.85 mmol), 2,4-dichloroquinoline 1-3 (693 mg, 3.5 mmol) and K2CO3 (1.35 g, 9.80 mmol) in dry THF (7 ml) was degassed with nitrogen during 20 minutes. Then, Pd(OAc)2 (47 mg, 0.21 mmol) and XantPhos ligand (61 mg, 0.10 mmol) were added and the reaction mixture was degassed a second time during 20 minutes. The reaction mixture was finally heated under reflux during 4 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient cyclohexane/EtOAc from 10/0 to 5/5) to give 520 mg (yield 41%) of a yellow solid corresponding to 2-[4-(2-pyrimidinylamino)-3-methyl-phenylamino]-4-chloroquinoline (3-3). Mass, Method A: (ES+) C20H16ClN5 required 361; found 362 [M+H]

Reference： [1]Current Patent Assignee: GENOSCIENCE PHARMA - EP3620164, 2020, A1 Location in patent: Paragraph 1438; 1439

72
(4-chloro-2-methoxyphenyl)methanamine [ No CAS ]
[ 703-61-7 ]
2-(2-methoxy-4-chlorobenzylamino)-4-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In tetrahydrofuran at 100℃; for 0.5h; Inert atmosphere; Microwave irradiation;	14.4 14.4 Synthesis of 2-(2-methoxy-4-chlorobenzylamino)-4-chloroquinoline (14-4) To a solution under nitrogen gas of 2, 4-dichloroquinoline (1-3, 3.0 g, 15.15 mmol) in dry THF (50 ml) was added (4-chloro-2-methoxyphenyl) methanamine (14-3, 3.9 g, 22.72 mmol) and t-BuONa (2.9 g, 30.30 mmol). The resulting mixture was degassed 5 min with nitrogen, then Xantphos (0.87 g, 1.5 mmol) and Pd(OAc)2 (170 mg, 0.75 mmol) were added and the resulting reaction mixture was heated to 100°C under micro wave conditions for 30 minutes. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between brine and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash chromatography (gradient petroleum ether/DCM from 5/5 to 0/10) to give 2.1 g (yield 50%) corresponding to 2-(2-methoxy-4-chlorobenzylamino)-4-chloroquinoline (14-4) as a brown solid. HPLC-MS, Method E: tr = 1.31 min, (ES+) C17H14Cl2N2O required 332; found 333 [M+H]. 1H NMR (500 MHz, DMSO-d6)

Reference： [1]Current Patent Assignee: GENOSCIENCE PHARMA - EP3620164, 2020, A1 Location in patent: Paragraph 1520; 1521

73
2-methyl-N₁-[4-(pyridine-3-yl)-pyrimidin-2-yl]benzene-1,4-diamine [ No CAS ]
[ 703-61-7 ]
2-{4-[4-(pyridin-3-yl)-2-pyrimidinamino]-3-methylphenylamino}-4-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran Reflux;	4.1 4.1 Synthesis of 2-{4-[4-(pyridin-3-yl)-2-pyrimidinamino]-3-methyl-phenylamino}-4-chloroquinoline (4-1) To a solution of 2-methyl-N1-[4-(pyridine-3-yl)-pyrimidin-2-yl]benzene-1,4-diamine (1.18 g, 4.26 mmol), 2,4-dichloroquinoline 1-3 (767 mg, 3.87 mmol) in dry THF (11.9 ml) was added K2CO3 (2.7 g, 19.0 mmol) and the reaction mixture was degassed with nitrogen during 15 minutes. Then, XantPhos ligand (226 mg, 0.387 mmol) and Pd(OAc)2 (44 mg, 0.19 mmol) were added and the reaction mixture was degassed a second time during 15 minutes. Then, the resulting reaction mixture was finally heated under reflux overnight. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient cyclohexane/EtOAc from 10/0 to 0/10) to give 1.08 g (yield 64%) of a brown solid corresponding to 2-{4-[4-(pyridin-3-yl)-2-pyrimidinamino]-3-methyl-phenylamino}-4-chloroquinoline (4-1). Mass, Method A: (ES+) C25H19ClN6 required 438; found 439 [M+H] 1H NMR (300 MHz, CD3OD)

Reference： [1]Current Patent Assignee: GENOSCIENCE PHARMA - EP3620164, 2020, A1 Location in patent: Paragraph 1445; 1446

74
[ 703-61-7 ]
[ 91-00-9 ]
N-(4-chloro-2-quinolyl)-1,1-diphenylmethanimine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,4-dichloroquinoline With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 20℃; for 0.0833333h; Stage #2: Benzhydrylamine In toluene at 100℃; for 4h;	6 Preparation of N-(4-chloro-2-quinolyl)-1 ,1-diphenyl-methanimine (125): To a solution of 2,4-dichloroquinoline (1.51 mmol) in dry toluene (15ml_) were added NaOtBu (2.27 mmol), BINAP (0.15 mmol) and Pd2(dba)3 (0.076 mmol) and the reaction mixture was stirred at room temperature during 5 minutes. Finally, diphenylmethanamine (1.51 mmol) was added and the reaction mixture was stirred at 100°C during 4 hours. The reaction mixture was concentrated and the crude was partitioned in ethyl acetate and water. The organic layer was washed with water, brine, dried over Na2SC>4 and concentrated to give the expected intermediate 125 as a brown solid and used without purification for the next step.

Reference： [1]Current Patent Assignee: BCI PHARMA - WO2021/23888, 2021, A1 Location in patent: Page/Page column 181-182

75
(4-(5-(tert-butoxycarbonyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)phenyl)boronic acid pinacol ester [ No CAS ]
[ 703-61-7 ]
tert-butyl 2-(4-(4-chloroquinolin-2-yl)phenyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; water; toluene at 90℃;	84.3 Step 3: tert-butyl 2-(4-(4-chloroquinolin-2-yl)phenyl)-4,6-dihydropyrrolo[3,4- c]pyrazole-5(2H)-carboxylate. 2, 4-Dichloroquinoline (78 mg, 0.4 mmol), (4-(5-(tert- butoxycarbonyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)phenyl)boronic acid pinacol ester (170 mg, 0.41 mmol), tetrakis triphenylphosphine-palladium (14 mg, 0.012 mmol), aqueous 2M sodium carbonate (0.4 mL, 0.8 mmol) were dissolved in toluene (0.8 mL) and ethanol (0.8 mL). The reaction mixture was placed under vacuum and backfilled with nitrogen three times before being heated to 90° C and stirred overnight. After cooling to ambient temperature, the reaction was quenched by the addition of water and the organic layer was extracted three times with dichloromethane (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified via column chromatography using 0-100% EtO Ac/hexanes to provide 80 mg (45%) of tert-butyl 2-(4-(4-chloroquinolin-2- yl)phenyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate. MS m/z (M+H) = 447.25.

Reference： [1]Current Patent Assignee: BIOHAVEN PHARMACEUTICAL HOLDING COMPANY LTD - WO2021/35101, 2021, A1 Location in patent: Paragraph 0469; 0472

76
[ 1560796-24-8 ]
[ 703-61-7 ]
4-(4-(4-chloroquinolin-2-yl)phenyl)-1-methylpiperazin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; water; toluene at 90℃; Inert atmosphere;	115.3 Step 3: 2, 4-Dichloroquinoline (102 mg, 0.51 mmol), (4-(4-methyl-3-oxopiperazin-l- yl)phenyl)boronic acid pinacol ester (173 mg, 0.54 mmol), tetrakis triphenylphosphine- palladium (14 mg, 0.012 mmol), aqueous 2M sodium carbonate (0.4 mL, 0.8 mmol) were dissolved in toluene (0.8 mL) and ethanol (0.8 mL). The reaction mixture was placed under vacuum and backfilled with nitrogen three times before being heated to 90° C and stirred overnight. After cooling to ambient temperature, the reaction was quenched by the addition of water and the organic layer was extracted three times with dichloromethane (~10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified via column chromatography using 0-100% EtOAc/hexanes to provide 137 mg (76%) of 4-(4-(4- chloroquinolin-2-yl)phenyl)-l-methylpiperazin-2-one.1H NMR (300 MHz, Chloroform -T) d ppm 8.20 (d, 7=1.76 Hz, 1H), 8.08 - 8.15 (m, 3H), 7.92 (s, 1H), 7.74 (ddd, 7=8.50, 7.03, 1.47 Hz, 1H), 7.53 - 7.63 (m, 1H), 6.98 (d, J=8.79 Hz, 2H), 4.00 (s, 2H), 3.57 - 3.66 (m, 2H),3.47 - 3.56 (m, 2H), 3.06 (s, 3H). MS m/z (M+H) = 352.25

Reference： [1]Current Patent Assignee: BIOHAVEN PHARMACEUTICAL HOLDING COMPANY LTD - WO2021/35101, 2021, A1 Location in patent: Paragraph 0489; 0492

77
[ 5720-07-0 ]
[ 703-61-7 ]
[ 21202-79-9 ]

Yield	Reaction Conditions	Operation in experiment
59%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; toluene at 90℃; for 6h;	1 Step 1: To a stirring solution of 2,4-dichloroquinoline (6.16 g, 31.10 mmol) in toluene/ethanol (1:1 10 mL) was added 4-methoxyphenylboronic acid (5.2 g, 34.21 mmol), followed by sodium carbonate (1 M, 62 mL, 62.20 mmol). The reaction mixture was degassed over a slow flow of nitrogen for 15 minutes, then tetrakis(triphenylphosphine)- palladium(O) was added, the reaction flask flushed with nitrogen and placed in a heating bath to 90 °C for 6 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL), washed with water (25 mL), the aqueous washed with brine (20 mL), dried over sodium sulfate and filtered. The product was purified on silica gel (220 gm, 60-120 mesh) and concentrated under reduced pressure to give 4-chloro-2-(4-methoxyphenyl)quinoline as a white solid (5.0 g, 59%).1H NMR (CDCl3) d: 9.06 (d, J=8.2 Hz, 1H), 8.96-9.02 (m, 3H), 8.78-8.79 (m, 1H), 8.59-8.64 (m, 1H), 8.42-8.47 (m, 1H), 8.11-8.12 (m, 1H), 7.90 (d, J=7.6 Hz, 2H), 4.75 (s, 3H). MS m/z (M+) 270.03.

Reference： [1]Current Patent Assignee: BIOHAVEN PHARMACEUTICAL HOLDING COMPANY LTD - WO2021/35101, 2021, A1 Location in patent: Paragraph 0361

78
[ 703-61-7 ]
[ 208399-66-0 ]
4-chloro-2-(4-methoxy-2-methylphenyl)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; water; toluene at 90℃; for 6h;	10 Step 1: General procedure: To a stirring solution of 2,4-dichloroquinoline (6.16 g, 31.10 mmol) in toluene/ethanol (1:1 10 mL) was added 4-methoxyphenylboronic acid (5.2 g, 34.21 mmol), followed by sodium carbonate (1 M, 62 mL, 62.20 mmol). The reaction mixture was degassed over a slow flow of nitrogen for 15 minutes, then tetrakis(triphenylphosphine)- palladium(O) was added, the reaction flask flushed with nitrogen and placed in a heating bath to 90 °C for 6 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL), washed with water (25 mL), the aqueous washed with brine (20 mL), dried over sodium sulfate and filtered. The product was purified on silica gel (220 gm, 60-120 mesh) and concentrated under reduced pressure to give 4-chloro-2-(4-methoxyphenyl)quinoline as a white solid (5.0 g, 59%).1H NMR (CDCl3) d: 9.06 (d, J=8.2 Hz, 1H), 8.96-9.02 (m, 3H), 8.78-8.79 (m, 1H), 8.59-8.64 (m, 1H), 8.42-8.47 (m, 1H), 8.11-8.12 (m, 1H), 7.90 (d, J=7.6 Hz, 2H), 4.75 (s, 3H). MS m/z (M+) 270.03.

Reference： [1]Current Patent Assignee: BIOHAVEN PHARMACEUTICAL HOLDING COMPANY LTD - WO2021/35101, 2021, A1 Location in patent: Paragraph 0380

79
[ 470478-90-1 ]
[ 703-61-7 ]
tert-butyl 4-(4-(4-chloroquinolin-2-yl)phenyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; water; toluene at 90℃;	29.1; 99.1 Step 1: 2, 4-Dichloroquinoline (500 mg, 2.5 mmol), (4-(4-(tert- butoxycarbonyl)piperazin- 1 -yl)phenyl)boronic acid pinacol ester (1.03 g, 2.65 mmol), tetrakis triphenylphosphine-palladium (87 mg, 0.07 mmol), aqueous 2M sodium carbonate (2.5 mL, 5 mmol) were dissolved in toluene (5 mL) and ethanol (5 mL). The reaction mixture was placed under vacuum and backfilled with nitrogen three times before being heated to 90° C and stirred overnight. After cooling to ambient temperature, the reaction was quenched by the addition of water and the organic layer was extracted three times with dichloromethane (~10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified via column chromatography using 0-100% EtO Ac/hexanes to provide 1.92 g (91%) of tert-butyl 4-(4-(4-chloroquinolin-2-yl)phenyl)piperazine- 1 -carboxylate Intermediate ID.

Reference： [1]Current Patent Assignee: BIOHAVEN PHARMACEUTICAL HOLDING COMPANY LTD - WO2021/35101, 2021, A1 Location in patent: Paragraph 0405-0406; 0482-0483

80
[ 703-61-7 ]
[ 406463-06-7 ]
4-chloro-2,6'-biquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; water; toluene at 90℃; Inert atmosphere;	119.1 Step 1: 2, 4-Dichloroquinoline (100 mg, 0.5 mmol), quinolin-6-ylboronic acid pinacol ester (135 mg, 0.53 mmol), tetrakis triphenylphosphine-palladium (17 mg, 0.015 mmol), aqueous 2M sodium carbonate (0.5 mL, 1 mmol) were dissolved in toluene (1 mL) and ethanol (1 mL). The reaction mixture was placed under vacuum and backfilled with nitrogen three times before being heated to 90° C and stirred overnight. After cooling to ambient temperature, the reaction partitioned with water and the organic layer was extracted three times with dichloromethane (~10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified via column chromatography using 0-100% EtO Ac/hexanes to provide 139 mg (95%) of 4-chloro-2,6'-biquinoline.1H NMR (300 MHz, Chloroform-d) d ppm 8.98 (dd, J=4.10, 1.17 Hz, 1H), 8.60 - 8.64 (m, 1H), 8.58 (dd, J= 9.0, 3.0 Hz, 1H), 8.30 - 8.36 (m, 1H), 8.20 - 8.30 (m, 3H), 8.15 (s, 1H), 7.83 (t, J=7.62 Hz, 1H), 7.67 (t, J=7.72 Hz, 1H), 7.49 (dd, J=8.21, 4.10 Hz, 1H). MS m/z (M+H) = 291.32.

Reference： [1]Current Patent Assignee: BIOHAVEN PHARMACEUTICAL HOLDING COMPANY LTD - WO2021/35101, 2021, A1 Location in patent: Paragraph 0494-0495

81
[ 703-61-7 ]
[ 123-08-0 ]
4-(4′-formylphenoxy)-2-chloroquinoline [ No CAS ]
2-(4′-formylphenoxy)-4-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 67% 2: 11%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; Sealed tube;	General procedure for the preparation of 2-chloro-4-phenoxyquinoline (2a-2d). General procedure: Amixture of 2,4-dichloroquinoline (1, 10 mmol) and hydroxyl benzene (11 mmol) indimethylformamide (DMF, 30 mL) with anhydrous cesium carbonate ( Cs2CO3, 20mmol) was heated in a sealed tube, stirred at 80 °C for 16 h, and cooled. Then, themixture was poured into ice- water and extracted thrice with ethyl acetate. Thecombined organic layers were washed with saturated NaCl and dried over Na2SO4.The crude product was purified on a silica gel column (eluent: hexane/ethyl acetate) toobtain 2a-2d with 62%-69% yield. However, 4-chloro-2-phenoxyquinoline (3a-3d) wasalso found during the reaction progress as a side product with 5%-14% yield.4-(4′-formylphenoxy)-2-chloroquinoline (2) With 67% yield, the synthesis started with0.30 g (1.51 mmol) of 1 to obtain 0.29 g of 2a, which consisted of white solid and mp.113.9 °C -114.2 °C. The 1H-NMR (300 MHz, CDCl3): 6.64 (s, 1H, ArH-3), 7.35 (d, 2H, J = 8.7Hz, ArH-2′, 6′), 7.61 (td, 1H, J = 7.8, 1.2 Hz, ArH-6), 7.81 (td, 1H, J = 7.8, 1.2 Hz, ArH-7),8.04 (m, 3H, ArH-8, 3′, 5′), and 8.26 (dd, 1H, J = 8.4, 0.9 Hz, ArH-5), and 10.1 (s, 1H, CHO).The 13C-NMR (75 MHz, CDCl3): 106.5, 120.4, 121.0, 121.8, 126.9, 128.5, 131.6, 132.3, 134.0,149.0, 151.0, 159.1, 161.9, and 190.5. Finally, the HRMS (+ESI) was C16H11ClNO2 [M+H]+; itrequires 284. 0478, but has 284. 0465. 2- ( 4′ -formylphenoxy) - 4- chloroquinoline ( 3a)obtained as the side product with 11 % yield (47.2 mg), which consisted of white solidand mp. 121.7 °C -122.5 °C. The 1H-NMR (300 MHz, CDCl3): 7.26 (s, 1H, ArH-3), 7.41 (dd,2H, J = 8.6, 1.8 Hz, ArH-2′, 6′), 7.53 (td, 1H, J = 7.6, 1.2 Hz, ArH-6), 7.68 (td, 1H, J = 7.7, 1.4Hz, ArH-7), 7.79 (dd, 1H, J = 8.4, 0.5 Hz, ArH-8), 7.95 (dt, 2H, J = 8.6, 2.4 Hz, ArH-3′, 5′),8.16 (dd, 1H, J = 8.3, 1.0 Hz, ArH-5), and 10.0 (s, 1H, CHO). The 13C-NMR (75 MHz, CDCl3):112.9, 121.6, 124.0, 124.2, 126.1, 128.2, 131.0, 131.4, 133.1, 145.2, 146.4, 158.5, 159.9 and190.9. Finally, the HRMS (+ESI) was C16H11ClNO2 [M+H]+; it requires 284.0478, but has284.0468.

Reference： [1]Intachote, Pakamas; Khlaychan, Panita; Kuno, Mayuso; Makarasen, Arthit; Patnin, Suwicha; Reukngam, Nanthawan; Saimanee, Busakorn; Sengsai, Suchada; Techasakul, Supanna; Vijitphan, Pongsit [Molecules, 2022, vol. 27, # 2]

82
[ 703-61-7 ]
[ 123-08-0 ]
2,4-di-(4′-formylphenoxy)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With caesium carbonate In N,N-dimethyl-formamide at 120℃; Sealed tube;	General procedure for the preparation of 2,4-diphenoxyquinoline (4a-4d). General procedure: A mixtureof 1 (10 mmol) and hydroxyl benzene (21 mmol) in DMF (30 mL) with anhydrous Cs2CO3( 20 mmol) was heated in a sealed tube, stirred at 120 °C for 8- 16 h, and cooled.Afterward, the mixture was poured into ice-water and extracted thrice with ethylacetate. The combined organic layers were washed with saturated NaCl and driedover Na2SO4. The crude product was purified on a silica gel column ( eluent:hexane/ethyl acetate) to obtain 4a-4d with 55%-65% yield.2,4-di-(4′-formylphenoxy)-quinoline (4a) With 60 % yield, the synthesis started with 50.0mg (0.25 mmol) of 1 to obtain 55.9 mg of 4a, which consisted of white solid and mp.164.9 °C - 165.5 °C. The 1H-NMR (300 MHz, CDCl3): 6.43 (s, 1H, ArH-3), 7.36-7.43 (m, 4H,ArH-2′, 6′, 2′′, 6′′), 7.51 (td, 1H, J = 7.6, 1.3 Hz, ArH-6), 7.71 (td, 1H, J = 8.1, 1.5 Hz, ArH-7),7.80 (dd, 1H, J = 8.4, 0.5 Hz, ArH-8), 7.94 (ddd, 2H, J = 8.7, 2.0 Hz, ArH-3′, 5′), 8.03 (ddd,2H, J = 8.7, 2.0 Hz, ArH-3′′, 5′′), 8.22 (dd, 1H, J = 8.3, 0.9 Hz, ArH-5), 10.00 (s, 1H, CHO)and 10.04 (s, 1H, CHO). The 13C-NMR (75 MHz, CDCl3): 97.2, 119.7, 120.9, 121.5, 121.7,125.3, 127.9, 131.1, 131.4, 132.2, 132.9, 133.7, 147.3, 158.7, 159.5, 161.3, 163.2, 190.5 and191.0. Finally, the HRMS (+ESI) was C23H16NO4 [M+H]+; it requires 370.1079, but has370.1088.

Reference： [1]Intachote, Pakamas; Khlaychan, Panita; Kuno, Mayuso; Makarasen, Arthit; Patnin, Suwicha; Reukngam, Nanthawan; Saimanee, Busakorn; Sengsai, Suchada; Techasakul, Supanna; Vijitphan, Pongsit [Molecules, 2022, vol. 27, # 2]

83
[ 2233-18-3 ]
[ 703-61-7 ]
2,4-di-(2′,6′-dimethyl-4′-formylphenoxy)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate In N,N-dimethyl-formamide at 120℃; Sealed tube;	General procedure for the preparation of 2,4-diphenoxyquinoline (4a-4d). General procedure: A mixtureof 1 (10 mmol) and hydroxyl benzene (21 mmol) in DMF (30 mL) with anhydrous Cs2CO3( 20 mmol) was heated in a sealed tube, stirred at 120 °C for 8- 16 h, and cooled.Afterward, the mixture was poured into ice-water and extracted thrice with ethylacetate. The combined organic layers were washed with saturated NaCl and driedover Na2SO4. The crude product was purified on a silica gel column ( eluent:hexane/ethyl acetate) to obtain 4a-4d with 55%-65% yield.

Reference： [1]Intachote, Pakamas; Khlaychan, Panita; Kuno, Mayuso; Makarasen, Arthit; Patnin, Suwicha; Reukngam, Nanthawan; Saimanee, Busakorn; Sengsai, Suchada; Techasakul, Supanna; Vijitphan, Pongsit [Molecules, 2022, vol. 27, # 2]

84
[ 2233-18-3 ]
[ 703-61-7 ]
4-(2′,6′-dimethyl-4′-flormylphenoxy)-2-chloroquinoline [ No CAS ]
2-(2′,6′-dimethyl-4′-formylphenoxy)-4-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 69% 2: 14%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; Sealed tube;	General procedure for the preparation of 2-chloro-4-phenoxyquinoline (2a-2d). General procedure: Amixture of 2,4-dichloroquinoline (1, 10 mmol) and hydroxyl benzene (11 mmol) indimethylformamide (DMF, 30 mL) with anhydrous cesium carbonate ( Cs2CO3, 20mmol) was heated in a sealed tube, stirred at 80 °C for 16 h, and cooled. Then, themixture was poured into ice- water and extracted thrice with ethyl acetate. Thecombined organic layers were washed with saturated NaCl and dried over Na2SO4.The crude product was purified on a silica gel column (eluent: hexane/ethyl acetate) toobtain 2a-2d with 62%-69% yield. However, 4-chloro-2-phenoxyquinoline (3a-3d) wasalso found during the reaction progress as a side product with 5%-14% yield.

Reference： [1]Intachote, Pakamas; Khlaychan, Panita; Kuno, Mayuso; Makarasen, Arthit; Patnin, Suwicha; Reukngam, Nanthawan; Saimanee, Busakorn; Sengsai, Suchada; Techasakul, Supanna; Vijitphan, Pongsit [Molecules, 2022, vol. 27, # 2]

85
[ 767-00-0 ]
[ 703-61-7 ]
2,4-di-(4′-cyanophenoxy)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With caesium carbonate In N,N-dimethyl-formamide at 120℃; Sealed tube;	General procedure for the preparation of 2,4-diphenoxyquinoline (4a-4d). General procedure: A mixtureof 1 (10 mmol) and hydroxyl benzene (21 mmol) in DMF (30 mL) with anhydrous Cs2CO3( 20 mmol) was heated in a sealed tube, stirred at 120 °C for 8- 16 h, and cooled.Afterward, the mixture was poured into ice-water and extracted thrice with ethylacetate. The combined organic layers were washed with saturated NaCl and driedover Na2SO4. The crude product was purified on a silica gel column ( eluent:hexane/ethyl acetate) to obtain 4a-4d with 55%-65% yield.

Reference： [1]Intachote, Pakamas; Khlaychan, Panita; Kuno, Mayuso; Makarasen, Arthit; Patnin, Suwicha; Reukngam, Nanthawan; Saimanee, Busakorn; Sengsai, Suchada; Techasakul, Supanna; Vijitphan, Pongsit [Molecules, 2022, vol. 27, # 2]

86
[ 767-00-0 ]
[ 703-61-7 ]
4-(4′-cyanophenoxy)-2-chloroquinoline [ No CAS ]
2-(4′-cyanophenoxy)-4-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 60% 2: 9%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; Sealed tube;	General procedure for the preparation of 2-chloro-4-phenoxyquinoline (2a-2d). General procedure: Amixture of 2,4-dichloroquinoline (1, 10 mmol) and hydroxyl benzene (11 mmol) indimethylformamide (DMF, 30 mL) with anhydrous cesium carbonate ( Cs2CO3, 20mmol) was heated in a sealed tube, stirred at 80 °C for 16 h, and cooled. Then, themixture was poured into ice- water and extracted thrice with ethyl acetate. Thecombined organic layers were washed with saturated NaCl and dried over Na2SO4.The crude product was purified on a silica gel column (eluent: hexane/ethyl acetate) toobtain 2a-2d with 62%-69% yield. However, 4-chloro-2-phenoxyquinoline (3a-3d) wasalso found during the reaction progress as a side product with 5%-14% yield.

Reference： [1]Intachote, Pakamas; Khlaychan, Panita; Kuno, Mayuso; Makarasen, Arthit; Patnin, Suwicha; Reukngam, Nanthawan; Saimanee, Busakorn; Sengsai, Suchada; Techasakul, Supanna; Vijitphan, Pongsit [Molecules, 2022, vol. 27, # 2]

87
[ 4198-90-7 ]
[ 703-61-7 ]
2,4-di-(2′,6′-dimethyl-4′-cyanophenoxy)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With caesium carbonate In N,N-dimethyl-formamide at 120℃; Sealed tube;	General procedure for the preparation of 2,4-diphenoxyquinoline (4a-4d). General procedure: A mixtureof 1 (10 mmol) and hydroxyl benzene (21 mmol) in DMF (30 mL) with anhydrous Cs2CO3( 20 mmol) was heated in a sealed tube, stirred at 120 °C for 8- 16 h, and cooled.Afterward, the mixture was poured into ice-water and extracted thrice with ethylacetate. The combined organic layers were washed with saturated NaCl and driedover Na2SO4. The crude product was purified on a silica gel column ( eluent:hexane/ethyl acetate) to obtain 4a-4d with 55%-65% yield.

Reference： [1]Intachote, Pakamas; Khlaychan, Panita; Kuno, Mayuso; Makarasen, Arthit; Patnin, Suwicha; Reukngam, Nanthawan; Saimanee, Busakorn; Sengsai, Suchada; Techasakul, Supanna; Vijitphan, Pongsit [Molecules, 2022, vol. 27, # 2]

88
[ 4198-90-7 ]
[ 703-61-7 ]
4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-chloroquinoline [ No CAS ]
2-(2′,6′-dimethyl-4′-cyanophenoxy)-4-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 62% 2: 5%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 16h; Sealed tube;	General procedure for the preparation of 2-chloro-4-phenoxyquinoline (2a-2d). General procedure: Amixture of 2,4-dichloroquinoline (1, 10 mmol) and hydroxyl benzene (11 mmol) indimethylformamide (DMF, 30 mL) with anhydrous cesium carbonate ( Cs2CO3, 20mmol) was heated in a sealed tube, stirred at 80 °C for 16 h, and cooled. Then, themixture was poured into ice- water and extracted thrice with ethyl acetate. Thecombined organic layers were washed with saturated NaCl and dried over Na2SO4.The crude product was purified on a silica gel column (eluent: hexane/ethyl acetate) toobtain 2a-2d with 62%-69% yield. However, 4-chloro-2-phenoxyquinoline (3a-3d) wasalso found during the reaction progress as a side product with 5%-14% yield.

Reference： [1]Intachote, Pakamas; Khlaychan, Panita; Kuno, Mayuso; Makarasen, Arthit; Patnin, Suwicha; Reukngam, Nanthawan; Saimanee, Busakorn; Sengsai, Suchada; Techasakul, Supanna; Vijitphan, Pongsit [Molecules, 2022, vol. 27, # 2]

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	703-61-7	MDL No. :	MFCD00023939
Formula :	C₉H₅Cl₂N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QNBJYUUUYZVIJP-UHFFFAOYSA-N
M.W :	198.05	Pubchem ID :	607503
Synonyms :

Num. heavy atoms :	12
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	51.76
TPSA :	12.89 Å²

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) :	-4.82 cm/s

Log Po/w (iLOGP) :	2.32
Log Po/w (XLOGP3) :	3.78
Log Po/w (WLOGP) :	3.54
Log Po/w (MLOGP) :	2.98
Log Po/w (SILICOS-IT) :	3.72
Consensus Log Po/w :	3.27

[ CAS No. 703-61-7 ] {[proInfo.proName]}

Quality Control of [ 703-61-7 ]

Related Doc. of [ 703-61-7 ]

Product Details of [ 703-61-7 ]

Calculated chemistry of [ 703-61-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 703-61-7 ]

Application In Synthesis of [ 703-61-7 ]

[ 703-61-7 ] Synthesis Path-Upstream 1~9

[ 703-61-7 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 703-61-7 ]

Chlorides

Related Parent Nucleus of
[ 703-61-7 ]

Quinolines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Log S (ESOL) :	-4.07
Solubility :	0.017 mg/ml ; 0.0000859 mol/l
Class :	Moderately soluble
Log S (Ali) :	-3.74
Solubility :	0.0357 mg/ml ; 0.00018 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.94
Solubility :	0.00229 mg/ml ; 0.0000116 mol/l
Class :	Moderately soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.57

Signal Word:	Warning	Class:
Precautionary Statements:	P280-P305+P351+P338	UN#:
Hazard Statements:	H317-H319	Packing Group:
GHS Pictogram:

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

[ CAS No. 703-61-7 ] {[proInfo.proName]}

Quality Control of [ 703-61-7 ]

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[ 703-61-7 ] Synthesis Path-Upstream 1~9

[ 703-61-7 ] Synthesis Path-Downstream 1~88

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Chlorides

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Quinolines

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[ 703-61-7 ]

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[ 703-61-7 ]