[ CAS No. 86-99-7 ] {[proInfo.proName]}

Name: 86-99-7|7-Chloroquinolin-4-ol|95%
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Quality Control of [ 86-99-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 86-99-7 ]

CAS No. :	86-99-7	MDL No. :	MFCD00006778
Formula :	C₉H₆ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XMFXTXKSWIDMER-UHFFFAOYSA-N
M.W :	179.60	Pubchem ID :	66593
Synonyms :

Calculated chemistry of [ 86-99-7 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.78
TPSA :	33.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.56 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.65
Log Po/w (XLOGP3) :	2.59
Log Po/w (WLOGP) :	2.59
Log Po/w (MLOGP) :	1.76
Log Po/w (SILICOS-IT) :	2.6
Consensus Log Po/w :	2.24

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.2
Solubility :	0.113 mg/ml ; 0.000628 mol/l
Class :	Soluble
Log S (Ali) :	-2.93
Solubility :	0.209 mg/ml ; 0.00116 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.74
Solubility :	0.0327 mg/ml ; 0.000182 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.35

Safety of [ 86-99-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 86-99-7 ]

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

Upstream synthesis route of [ 86-99-7 ]
Downstream synthetic route of [ 86-99-7 ]

[ 86-99-7 ] Synthesis Path-Upstream 1~6

1
[ 86-98-6 ]
[ 91-22-5 ]
[ 612-61-3 ]
[ 86-99-7 ]

Reference： [1] Tetrahedron Letters, 2009, vol. 50, # 35, p. 4989 - 4993
[2] Tetrahedron Letters, 2010, vol. 51, # 12, p. 1562 - 1565

2
[ 86-99-7 ]
[ 98519-65-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With phosphorus tribromide In N,N-dimethyl-formamide at 20℃; for 1.5 h; Inert atmosphere	At 0 C under an atmosphere of argon, phosphorus tribromide (5.8 mL, 0.079 moles, 1.10 equiv.) was added slowly to a solution of 7-chloro-4-hydroxyquinoline (13.02 g, 0.073 moles, 1.00 equiv.) in anhydrous DMF (150 mL, 0.5 M soln.). The reaction was allowed to warm to rt and followed by TLC. Complete consumption of starting material was observed after 90 minutes stirring. The reaction mixture was poured onto ice and the pH was rendered alkaline using solid sodium bicarbonate. This resulted in a white precipitate. The mixture was then filtered and the resulting solid was dried under vacuum affording an off-white solid (17.30 g, 99 percent). The material was recrystallised from ethyl acetate to give white needles (12.20 g, 70percent). Rj-= 0.70 (hex:EtoAc; 1:1); Mp = 99— 101 °C, EtoAc (lit., Eur.J. Org. Chem. 20024181.103 — 104°C,hex).

Reference： [1] Patent: WO2016/22956, 2016, A1, . Location in patent: Page/Page column 30
[2] Journal of Organic Chemistry, 2007, vol. 72, # 6, p. 2232 - 2235
[3] Patent: WO2010/30722, 2010, A1, . Location in patent: Page/Page column 44-45
[4] Organic Letters, 2018, vol. 20, # 4, p. 1195 - 1199

3
[ 86-99-7 ]
[ 21295-51-2 ]
[ 98519-65-4 ]

Reference： [1] Patent: US5596002, 1997, A,

4
[ 86-99-7 ]
[ 54-05-7 ]

Reference： [1] Journal of Organic Chemistry, 2007, vol. 72, # 6, p. 2232 - 2235
[2] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 315 - 320

5
[ 86-99-7 ]
[ 837-52-5 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 1, p. 97 - 102

6
[ 21617-15-2 ]
[ 86-99-7 ]
[ 611-36-9 ]

Reference： [1] Patent: US4412076, 1983, A,

[ 86-99-7 ] Synthesis Path-Downstream 1~88

1
[ 21617-15-2 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
		a degree of conversion of the <strong>[21617-15-2]7-chloro-1,2,3,4-tetrahydroquinolin-4-one</strong> of 98.7%, and a yield of 7-chloro-4-hydroxyquinoline of 96.2% relative to the <strong>[21617-15-2]7-chloro-1,2,3,4-tetrahydroquinolin-4-one</strong> converted. The starting <strong>[21617-15-2]7-chloro-1,2,3,4-tetrahydroquinolin-4-one</strong> can be prepared in the following manner:

Reference： [1]Patent: US4412076,1983,A
[2]Patent: US2558211,1949,

2
[ 86-99-7 ]
[ 611-19-8 ]
[ 132467-00-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide

Reference： [1]Surrey et al. [Journal of the American Chemical Society, 1959, vol. 81, p. 2894,2895]

3
[ 86-99-7 ]
[ 79-11-8 ]
[ 860204-26-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide

Reference： [1]Surrey [Journal of the American Chemical Society, 1948, vol. 70, p. 2190,2191]

4
[ 86-99-7 ]
[ 86-98-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With trichlorophosphate for 1h; Heating;
89.5%	With trichlorophosphate Reflux;	1-3 Synthesis of 4,7-dichloroquinoline (9) (chloro) Add 120ml of phosphorus oxychloride to a 250mL three-necked flask, add 40g 4-hydroxy-7-chloroquinoline under stirring, and reflux for 1-2h until the reaction is complete. Cool to spin off the excess phosphorus oxychloride and slowly add the black oil Stir while adding in ice water, then neutralize the sodium bicarbonate aqueous solution to weak alkaline (pH 7-9), filter, wash with water, and crystallize with ethanol to obtain the product with a yield of 89.5%.
88.5%	With trichlorophosphate for 2h; Heating / reflux;	25 Phosphorus oxychloride (4mL, 429 mmol) was added to 7-chloro-4-hydroxyquinolme 2.86g, 15.9mmol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 2h, then allowed to cool to room temperature. The solution was concentrated in vacuo to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NaHCO3 (aq). The slurry was filtered and washed with water. The solids were dried under vacuum, afforded 4,7-dichloroquinoline as a white solid (2.79g, 88.5% yield).

88.5%	With trichlorophosphate for 2h; Heating / reflux;	49 Phosphorus oxychloride (4mL, 429 mmol) was added to 7-chloro-4-hydroxyquinoline 2.86g, 15. 9mmol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 2h, then allowed to cool to room temperature. The solution was concentrated III vacuo to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NAHC03 (aq). The slurry was filtered and washed with water. The solids were dried under vacuum, afforded 4,7-dichloroquinoline as a white solid (2.79g, 88. 5% yield).
81.6%	With trichlorophosphate for 6h; Reflux;	4.2.3. Preparation of 4,7-Dichloro-quinoline²⁹ (4) A Phosphorus oxychloride (10 mL, 1 vol) was added to 7-chloro-4-hydroxyquinoline (3) (10 g, 0.055 mol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 6 h, then allowed to cool to room temperature. The solution was concentrated under high vacuum to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NaHCO3 (aq), solid precipitated was filtered and washed with water. The solids were dried under vacuum and the crude compound was purified by column chromatography over silica gel using eluent 30 % ethyl acetate in hexane to afford 4,7-dichloroquinoline as a white solid. Yield; 8 g (81.6 %)
81.6%	With trichlorophosphate for 6h; Reflux;	Preparation of 4,7-Dichloro-quinoline (Int-4): A Phosphorus oxychloride (10 mL, 1 vol) was added to 7-chloro-4-hydroxyquinoline (3) (10 g, 0.055 mol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 6 h, then allowed to cool to room temperature. The solution was concentrated under high vacuum to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NaHCCh (aq), solid precipitated was filtered and washed with water. The solids were dried under vacuum. The crude compound was purifiedby column chromatography over silica gel using eluent 30 % ethyl acetate in hexane to afford 4,7-dichloroquinoline as a white solid Yield: 8 g (81.6 %) (analytical data reference of step-2, 3 and 4: Synthesis and Antitumor Activity of Halogen-Substituted 4-(3,3-Dimethyl-l-triazeno)quinolones, Journal q Medicinal Chemistry, 1978, Vol. 2i, No. 3)
79%	With trichlorophosphate at 120℃; for 6h; Inert atmosphere;	4,7-Dichloroquinoline (25) In a 100 mL, double neck RBF, 7-chloroquinolin-4-ol (89.0 mmol) was poured under dry atmosphere. Phosphorus oxychloride (536.0 mmol) was added into reaction flask at room temperature. The reaction mixture was allowed to reflux at 120 °C for 6 h. Reaction was monitored on TLC plate. After completion of reaction, excess of phosphorus oxychloride was removed under reduced pressure. The crude reaction mass was treated with 2N NaOH to get the precipitates. The precipitates were collected, washed with water and recrystallized with chloroform: Hexane (1:1) to get the pure 4,7-dichloroquinoline (25) as yellow solid (13.8 g, 79% yield). m.p. 95-96.4 1H NMR (400 MHz, CDCl3): δ 8.79 (d, J = 4.8 Hz, 1H); 8.12 (d, J = 8.8 Hz, 1H); 8.13 (d, J = 2 Hz, 1H); 7.61 (dd, J = 8.8, 2 Hz, 1H); 7.49 (d, J = 4.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 151.1, 149.6, 142.8, 136.6, 128.9, 128.8, 125.7, 125.1, 121.6. HRMS (ESI-ToF): m/z [M+H]+ calcd for C9H6Cl2 : 197.9872; found : 197.9871.
77%	With trichlorophosphate In toluene at 100 - 110℃; for 5h;	4-5 Synthesis of Z5 Add 100ml of toluene, 3.2mol of phosphorus oxychloride, and 2.67mol of 4-hydroxy-7-chloroquinoline into the reaction vessel. After reacting at 100-110°C for 5 hours, after the reaction, the toluene and unreacted trichloride are evaporated under reduced pressure. Phosphorus oxide, add 200ml of water, neutralize the liquid caustic soda (30% sodium hydroxide) to a pH value of 5-6, after filtering, add EDTA and activated carbon to the filtrate for decolorization, adjust the pH value to stabilize at 5-6 with acetic acid, filter and use alkali (Sodium carbonate or sodium bicarbonate) adjust the pH value to 7-8, precipitate the product, filter, and dry to obtain an off-white 4,7-dichloroquinoline 2.06 mol with a yield of 77%.
72.7%	With trichlorophosphate for 6h; Reflux;
	With trichlorophosphate
	With trichlorophosphate at 100℃;
	With trichlorophosphate for 3h; Heating;
	With trichlorophosphate at 150℃; for 3h;
	With bis(trichloromethyl) carbonate; N,N-dimethyl-formamide; triphenylphosphine In toluene at 50 - 100℃;	1-2 Example 1 Preparation of 4,7-dichloroquinoline 300 g of toluene, 5 g of N, N-dimethylformamide, 5 g of triphenylphosphine, and 100 g of 7-chloro-4-hydroxyquinoline were sequentially added to the reaction flask. The stirring was started, and the temperature was raised to 50 ° C to 100 ° C.287 g of a 23% triphosgene solution in toluene was prepared and completely dissolved and placed in a constant-pressure dropping funnel. While maintaining the temperature in the reaction flask at 50 ° C to 100 ° C, the 23% triphosgene toluene solution was slowly added dropwise to control the dropwise addition time to 1 to 8 hours. After the dropwise addition was completed, the reaction was continued until the reaction was monitored by TLC (the reaction was completed in about 1 to 3 hours). After the reaction is completed, the distillation is performed under reduced pressure at 50 ° C to 100 ° C, and the distillation is stopped after the reduced pressure is distilled until there are no obvious droplets in the condenser. 300 g of absolute ethanol and 1 to 5 g of activated carbon were added under stirring, and the temperature was raised to reflux for 1 hour to decolorize. The filtrate was filtered while hot, and then cooled to 10 ° C to 30 ° C to obtain a filter cake. The filter cake was washed with 10-50 g of absolute ethanol and dried, and the wet product was dried under reduced pressure at 60 ° C to obtain 4,7-dichloroquinoline.

Reference： [1]Theeraladanon, Chumpol; Arisawa, Mitsuhiro; Nishida, Atsushi; Nakagawa, Masako [Tetrahedron, 2004, vol. 60, # 13, p. 3017 - 3035]
[2]Current Patent Assignee: CHONGQING MEDICAL PHARMACEUTICAL COLLEGE - CN111362872, 2020, A Location in patent: Paragraph 0020; 0027-0028; 0029; 0036-0036; 0038; 0045-0046
[3]Current Patent Assignee: EXELIXIS INC - WO2006/108059, 2006, A1 Location in patent: Page/Page column 94
[4]Current Patent Assignee: EXELIXIS INC - WO2005/30140, 2005, A2 Location in patent: Page/Page column 213
[5]Shruthi; Eswaran, Sumesh; Shivarudraiah, Prasad; Narayanan, Shridhar; Subramanian, Sangeetha [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 1, p. 97 - 102]
[6]Current Patent Assignee: FOUNDATION FOR NEGLECTED DISEASE RES - WO2019/243971, 2019, A1 Location in patent: Page/Page column 17
[7]Chouhan; Ananthabhat, Sudarshana K.; Vaidya, Sandeep; Srihari [Synthetic Communications, 2022, vol. 52, # 7, p. 1004 - 1011]
[8]Current Patent Assignee: CHONGQING MEDICAL PHARMACEUTICAL COLLEGE - CN111747890, 2020, A Location in patent: Paragraph 0035-0040
[9]Eswaran, Sumesh; Shruthi, T. G.; Subramanian, Sangeetha [Heterocyclic Communications, 2020, vol. 26, # 1, p. 137 - 147]
[10]Andersag [Chemische Berichte, 1948, vol. 81, p. 499,505] Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115] Price; Roberts [Journal of the American Chemical Society, 1946, vol. 68, p. 1204,1206][Organic Syntheses, 1955, vol. Coll. Vol. III, p. 272]
[11]De; Byers; Krogstad [Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 315 - 320]
[12]Madrid, Peter B.; Sherrill, John; Liou, Ally P.; Weisman, Jennifer L.; DeRisi, Joseph L.; Guy, R. Kiplin [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 1015 - 1018]
[13]Bhagat, Shweta; Arfeen, Minhajul; Das, Gourav; Ramkumar, Mridula; Khan, Shabana I.; Tekwani, Babu L.; Bharatam, Prasad V. [Bioorganic Chemistry, 2019, vol. 91]
[14]Current Patent Assignee: TSINGHUA TONGFANG CO., LTD - CN110627716, 2019, A Location in patent: Paragraph 0023-0026

5
[ 86-99-7 ]
[ 860236-13-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-iodo-succinimide; acetic acid at 60℃; for 5h;	3 3) A Compound of Formula (I) Where X═I N-iodosuccinimide (626 mg, 2.78 mmol) was added to a suspension of 7-chloroquinolin-4-ol (500 mg, 2.78 mmol) in 16 mL of acetic acid. The reaction is heated at 60° C. for 5 hours and then diluted in water and filtered. The white solid is washed with water and dried under vacuum. (0257) Yield 87%. White solid; RMN 1H (DMSO, 400 MHz) δ 7.39 (1H, dd, J=8.8, 2.2 Hz); 7.62 (1H, d, J=2.2 Hz); 8.10 (1H, d, J=8.8 Hz), 8.55 (s, 1H); 12.21 (sl, 1H); RMN 13C (DMSO, 100 MHz) δ 81.3; 117.6; 120.9; 124.4; 127.3; 140.3; 145.3; 172.5. SM (ESI+): m/z=523 [M+1]
59%	With iodine; N-butylamine; potassium iodide In water; N,N-dimethyl-formamide at 20℃; for 36h;	[0059] In certain embodiments, 7-chloro-3-iodoquinolin-4-ol (B) may be synthesized as follows. To a stirred suspension of 7-chloro-quinolone (A) (20.0 gm, 1 1 1 mmol) in DMF (100 ml_) is added successively n-butylamine (81 .2 gm, 1 .1 1 mol), iodine (19.8 gm, 155.6 mmol) and 20 ml_ of saturated aqueous potassium iodide (Kl). Upon the addition of n-butyl amine all of (A) dissolves. The yellow solution is stirred at room temperature for 36 hours. Then 0.1 M sodium thiosulfate (Na2S03, 800 ml_, 80 mmol) is added and the solution changes to colorless with formation of white precipitate. This is filtered and the white precipitate is washed with 4 x 200 ml of water. The white precipitate is allowed to dry on the fritted funnel under vacuum under ambient conditions for 3-4 days to give approximately 20.0 g (approximately 59 % yield) of (B) as a white powder. This material may be used without further purification.
	With Iodine monochloride; acetic acid

Reference： [1]Current Patent Assignee: CENTRE INTERNATIONAL DE RECHERCHE AUX FRONTIERES DE LA CHIMIE; INOVIEM SCIENTIFIC; UNIVERSITY OF STRASBOURG; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - US2019/62278, 2019, A1 Location in patent: Paragraph 0255-0257
[2]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES; OREGON HEALTH & SCIENCE UNIVERSITY - WO2013/106847, 2013, A1 Location in patent: Paragraph 0059
[3]Surrey; Cutler [Journal of the American Chemical Society, 1946, vol. 68, p. 2570,2573]

6
[ 86-99-7 ]
[ 5350-50-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	With nitric acid; propionic acid; at 90℃; for 3.0h;Reflux;	Conc. nitric acid (66%, 3.6 mL) was added dropwise to a solution of 7-chloro-quinolin-4-ol (2.55 g, 14.3 mmol) in propionic acid (26 mL) at 90 C. The mixture was stirred and heated under reflux for 3 hours. The reaction mixture was cooled, filtered, and the precipitate was washed with water (3 x 10 mL) and dried to give the title compound (2.40 g, 74% yield) as a yellow solid. ?H NMR (400 MHz, DMSO-d6): 13.03 (bs, 1H), 9.27 (s, 1H), 8.25 (d, 1H), 7.77 (d, 1H), 7.56 (dd, 1H).
	With nitric acid; In water; at 85 - 90℃; for 5.58333h;	20 g (0.111 mol) 7-chloro-quinolin-4-ol (Aldrich) are added during 5 min to 200 ml nitric acid (66%) heated at 85-90C. After 4.5 h the title compound starts to precipitate as a crystalline solid. The reaction mixture is stirred for a total of 5.5 h. The hot mixture is filtered off, and the residue washed first with conc. nitric acid, then with boiling water followed by acetone. Addi- tional material can be isolated from the mother liquors. The solid materials are combined and heated in boiling methanol for 3 h to dissolve some un-reacted starting material. The inso- luble title compound is filtered off and dried for 16 h at 70C (high vacuum). mp: >300 C, MS: 225 (M++1) ; HPLC: tret=7. 30 min (Grad 1).
	With nitric acid; acetic acid; at 125℃;	To a stirred solution of 7-chloroquinolin-4-ol (186A) (5 g, 27.9 mmol) in HOAc (100 mL) was added HNO3 (63%, 5.41 g, 55.8 mmol) and stirred at 125 C overnight. After cooled down to room temperature, the mixture was concentrated under reduced pressure, the residue was diluted with EtOH (20 mL), the resulting solid was collected and dried under vacuum to afford Compound 186B. LC-MS: (ESI) m/z: 225 [M+H] ?H-NMR (DMSO-d6, 400 IVIHz): (5(ppm) 7.53 (dd, J 8.8, 2.0 Hz, 1H), 7.74 (d, J 2.0 Hz, 1H), 8.22 (d, J 8.8 Hz, 1H), 9.23 (s, 1H), 12.99 (s, 1H).

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 264 - 281
[2]Patent: WO2018/165385,2018,A1 .Location in patent: Paragraph 00351
[3]Justus Liebigs Annalen der Chemie,1955,vol. 593,p. 91,109
[4]Patent: WO2003/97641,2003,A2 .Location in patent: Page/Page column 54
[5]Patent: WO2019/133770,2019,A2 .Location in patent: Paragraph 001184; 001185; 001186

7
[ 86-98-6 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
15%	With hydrogenchloride In lithium hydroxide monohydrate; acetonitrile at 70℃; for 18h;
4%	With tetraethylammonium iodide; oxygen In N,N-dimethyl-formamide electrolysis, C-anode, Hg-cathode;
	With glacial acetic acid

	Multi-step reaction with 2 steps 1: glacial acetic acid / 1 h / 125 °C 2: sodium hydroxide
	With glacial acetic acid at 125℃; for 1h; Inert atmosphere;	4.1.1.1. Synthesis of 7-chloro-4-(prop-2-yn-1-yloxy)quinoline (1). 7-chloroquinolin-4-ol (0.2 g, 1.114 mmol) [55] was suspended in dry DMF(4 mL). Under argon atmosphere cesium carbonate (0.508 g, 1.56 mmol)was added, followed by dropwise addition of 80% solution of propargylbromide in toluene (0.143 mL, 1.337 mmol). The reaction was stirred atrt and under argon atmosphere for 1.5 h. Upon completion, the reactionmixture was poured into 40 mL of water. Product was extracted withEtOAc (3 × 40 mL). Organic layers were collected and washed withwater (2 × 100 mL), dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. After purification by column chromatography(DCM/methanol = 9:1) and trituration with diethyl ether0.143 g (59%) of 1 was obtained.
	With glacial acetic acid at 125℃; for 1h; Inert atmosphere;	4.1.1.1. Synthesis of 7-chloro-4-(prop-2-yn-1-yloxy)quinoline (1). 7-chloroquinolin-4-ol (0.2 g, 1.114 mmol) [55] was suspended in dry DMF(4 mL). Under argon atmosphere cesium carbonate (0.508 g, 1.56 mmol)was added, followed by dropwise addition of 80% solution of propargylbromide in toluene (0.143 mL, 1.337 mmol). The reaction was stirred atrt and under argon atmosphere for 1.5 h. Upon completion, the reactionmixture was poured into 40 mL of water. Product was extracted withEtOAc (3 × 40 mL). Organic layers were collected and washed withwater (2 × 100 mL), dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. After purification by column chromatography(DCM/methanol = 9:1) and trituration with diethyl ether0.143 g (59%) of 1 was obtained.

Reference： [1]Location in patent: experimental part Hirner, Joshua J.; Zacuto, Michael J. [Tetrahedron Letters, 2009, vol. 50, # 35, p. 4989 - 4993]
[2]Hess, Ulrich; Zabel, Lutz; Baizer, Manuel M. [Zeitschrift fur Chemie, 1984, vol. 24, # 4, p. 151 - 152]
[3]Cutler; Surrey [Journal of the American Chemical Society, 1950, vol. 72, p. 3394]
[4]Terzić, Natasa; Konstantinović, Jelena; Tot, Mikloš; Burojević, Jovana; Djurković-Djaković, Olgica; Srbljanović, Jelena; Štajner, Tijana; Verbić, Tatjana; Zlatović, Mario; Machado, Marta; Albuquerque, Inês S.; Prudêncio, Miguel; Sciotti, Richard J.; Pecic, Stevan; D'Alessandro, Sarah; Taramelli, Donatella; Šolaja, Bogdan A. [Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 264 - 281]
[5]Held, Jana; Moita, Diana; Pessanha de Carvalho, Lais; Poje, Goran; Vianello, Robert; Perković, Ivana; Prudêncio, Miguel; Rajić, Zrinka; Tandarić, Tana [European Journal of Medicinal Chemistry, 2022, vol. 238]
[6]Held, Jana; Moita, Diana; Pessanha de Carvalho, Lais; Poje, Goran; Vianello, Robert; Perković, Ivana; Prudêncio, Miguel; Rajić, Zrinka; Tandarić, Tana [European Journal of Medicinal Chemistry, 2022, vol. 238]

8
[ 86-47-5 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	In paraffin oil at 230℃; for 0.833333h;	1-3 Synthesis of hydroxy-7-chloroquinoline (8) (decarboxylation) Add 120mL of paraffin oil to the reaction vessel and add it in batches when the temperature reaches 23040g of 7-chloro-4-hydroxyquinoline-2-carboxylic acid, continue to react for 50 minutes at this temperature after the addition is complete,It was filtered when the temperature dropped to 30°C, and the filter cake was washed and dried with petroleum ether to obtain 31.6 g of product, with a yield of 98.5%. Melting point 276-279°C.
	at 250 - 270℃; oder in einem Gemisch von Diphenylaether und Biphenyl;
	In diphenylether for 1h; Heating;

480 kg

In water at 150 - 170℃; for 5h; Autoclave;

1-3 Preparation of Intermediate Z4: The water layer is added to the autoclave, and the decarboxylation reaction is carried out at 6.0-6.5kg pressure and 150-170 for 5h. After the reaction is completed, sulfuric acid is added to adjust the pH to 4-5. A solid is precipitated, centrifuged and washed to obtain a solid 4-hydroxy-7-chloroquinoline 480 kg (2.67 mol).

Reference： [1]Current Patent Assignee: CHONGQING MEDICAL PHARMACEUTICAL COLLEGE - CN111362872, 2020, A Location in patent: Paragraph 0020; 0025-0026; 0029; 0034-0035; 0038; 0043-0044
[2]Price; Roberts [Journal of the American Chemical Society, 1946, vol. 68, p. 1204,1206][Organic Syntheses, 1955, vol. Coll. Vol. III, p. 272]
[3]De; Byers; Krogstad [Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 315 - 320]
[4]Current Patent Assignee: CHONGQING MEDICAL PHARMACEUTICAL COLLEGE - CN111747890, 2020, A Location in patent: Paragraph 0023; 0026-0027; 0030-0031; 0034

9
[ 18000-24-3 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-Chloronaphthalene
	With mineral oil at 270℃;

Reference： [1]Andersag [Chemische Berichte, 1948, vol. 81, p. 499,505]
[2]Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115]

10
[ 6938-28-9 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; ethanol; water
	With hydrogenchloride; water

Reference： [1]Landquist [Journal of the Chemical Society, 1951, p. 1038,1046]
[2]Illuminati; Gilman [Journal of the American Chemical Society, 1950, vol. 72, p. 4288]

11
3t-(3-chloro-anilino)-acrylic acid methyl ester [ No CAS ]
[ 86-99-7 ]
[ 23443-05-2 ]

Yield	Reaction Conditions	Operation in experiment
	With diphenylether

Reference： [1]Current Patent Assignee: PFIZER INC - US2478125, 1944, A Price; Leonard; Reitsema [Journal of the American Chemical Society, 1946, vol. 68, p. 1256,1258]

12
[ 1027189-62-3 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; acetic acid; sodium nitrite Erwaermen der Diazoniumsalz-Loesung mit Kupfer(I)-chlorid und wss. Salzsaeure_.;

Reference： [1]Price et al. [Journal of the American Chemical Society, 1947, vol. 69, p. 374]

13
[ 86-99-7 ]
[ 2524-04-1 ]
[ 3689-24-5 ]
[ 93516-22-4 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium hydroxide In tetrachloromethane at 60℃; for 55h;

Reference： [1]Giorgi-Renault, Sylviane; Renault, Jean; Bukovec, Zjelka [Synthesis, 1984, # 6, p. 491 - 493]

14
[ 86-99-7 ]
[ 15463-66-8 ]

Yield	Reaction Conditions	Operation in experiment
15.64%	With hydrazine hydrate In ethylene glycol at 180 - 200℃; for 18h;

Reference： [1]McQuaid; Smith; South; Mitch; Schoepp; True; Calligaro; O'Malley; Lodge; Ornstein [Journal of Medicinal Chemistry, 1992, vol. 35, # 18, p. 3319 - 3324]

15
[ 86-99-7 ]
[ 37595-74-7 ]
Trifluoro-methanesulfonic acid 7-chloro-quinolin-4-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium hydride In N,N-dimethyl-formamide Ambient temperature;

Reference： [1]Cacchi, Sandro; Carangio, Antonella; Fabrizi, Giancarlo; Moro, Leonardo; Pace, Paola [Synlett, 1997, # 12, p. 1400 - 1402]

16
[ 675578-65-1 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydroxide In methanol Heating;

Reference： [1]Theeraladanon, Chumpol; Arisawa, Mitsuhiro; Nishida, Atsushi; Nakagawa, Masako [Tetrahedron, 2004, vol. 60, # 13, p. 3017 - 3035]

17
[ 2033-24-1 ]
[ 108-42-9 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: cycl-isopropylidene malonate With orthoformic acid triethyl ester at 145℃; Stage #2: 3-chloro-aniline at 50 - 145℃; Stage #3: In diphenylether at 250℃;

Reference： [1]Margolis, Brandon J.; Long, Kimberly A.; Laird, Dana L. T.; Ruble, J. Craig; Pulley, Shon R. [Journal of Organic Chemistry, 2007, vol. 72, # 6, p. 2232 - 2235]

18
[ 86-99-7 ]
[ 98519-65-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With phosphorus tribromide; In N,N-dimethyl-formamide; at 20℃; for 1.5h;Inert atmosphere;	At 0 C under an atmosphere of argon, phosphorus tribromide (5.8 mL, 0.079 moles, 1.10 equiv.) was added slowly to a solution of 7-chloro-4-hydroxyquinoline (13.02 g, 0.073 moles, 1.00 equiv.) in anhydrous DMF (150 mL, 0.5 M soln.). The reaction was allowed to warm to rt and followed by TLC. Complete consumption of starting material was observed after 90 minutes stirring. The reaction mixture was poured onto ice and the pH was rendered alkaline using solid sodium bicarbonate. This resulted in a white precipitate. The mixture was then filtered and the resulting solid was dried under vacuum affording an off-white solid (17.30 g, 99 %). The material was recrystallised from ethyl acetate to give white needles (12.20 g, 70%). Rj-= 0.70 (hex:EtoAc; 1:1); Mp = 99- 101 C, EtoAc (lit., Eur.J. Org. Chem. 20024181.103 - 104C,hex).
56%	With phosphorus tribromide; In N,N-dimethyl-formamide; at 60℃;	(0582) 7-chloro-4-hydroxylquinoline (180 mg, 1.00 mmol) was dissolved in DMF, to which was added slowly phosphorous tribromide (3.54 mL, 3.73 mmol). It was stirred at 60C overnight, and then cooled to room temperature and poured into ice water, neutralized with Na2C03. The precipitation was filtered out and washed with water, dried by pulling air through. Product was obtained as white solid (136 mg, 56% yield). :H NMR (400 MHz, chloroform-d) delta 8.68 (d, J = 4.6 Hz, 1H), 8.19 - 8.10 (m, 2H), 7.71 (d, J= 4.7 Hz, 1H), 7.61 (dd, J = 9.0, 2.1 Hz, 1H).
		INTERMEDIATE 6 4-BROMO-7-CHLORO-2-METHOXYQUINOLNEStep A, 4-Bromo-7-chioroquinolineA suspension of 7-chloroquinolin-4-ol (10.0 g, 55.7 mmol) and triphenylphospMne dibromide (35.3 g, 83.6 mmol) in CH3CN (370 niL) was refluxed for 16 hours then cooled to room temperature. The resulting precipitate was collected by vacuum filtration and washed with CH3CN (2 x 70 mL). The precipitate was then partitioned between MRLDOB-00006CH2Ci2 (300 mL) and 1 M NaOH (aq) (300 mL). The aqueous phase was extracted with CH2Cl2 (100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): delta 8.67 (d, J - 4.7 Hz, 1 H); 8.14 (d, J = 9.0 Hz, 1 H); 8.11 (d, J = 2.1 Hz, 1 H); 7.70 (d, J = 4.7 Hz, 1 H); 7.60 (dd, J = 9.0, 5 2.1 Hz, 1 H); LC4 1.86 min. (M+H) - 244.

Reference： [1]Patent: WO2016/22956,2016,A1 .Location in patent: Page/Page column 30
[2]Journal of Organic Chemistry,2007,vol. 72,p. 2232 - 2235
[3]Patent: WO2019/89648,2019,A1 .Location in patent: Page/Page column 73
[4]Patent: WO2010/30722,2010,A1 .Location in patent: Page/Page column 44-45
[5]Organic Letters,2018,vol. 20,p. 1195 - 1199

19
[ 86-99-7 ]
[ 696-62-8 ]
7-chloro-1-(4-methoxyphenyl)quinolin-4(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium phosphate In dimethyl sulfoxide at 120℃; for 24h;

Reference： [1]Altman, Ryan A.; Buchwald, Stephen L. [Organic Letters, 2007, vol. 9, # 4, p. 643 - 646]

20
[ 86-99-7 ]
[ 572-09-8 ]
4-(β-O-tetraacetyl-D-glucosyloxy)-7-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With silver carbonate In toluene for 1h; Heating;

Reference： [1]Suzuki, Hiroshi; Aly, Nagwa S. M.; Wataya, Yusuke; Kim, Hye-Sook; Tamai, Ikumi; Kita, Masaki; Uemura, Daisuke [Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 5, p. 821 - 824]

21
[ 86-99-7 ]
[ 54-05-7 ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 2232 - 2235
[2]Journal of Heterocyclic Chemistry,1997,vol. 34,p. 315 - 320

22
[ 86-99-7 ]
[ 32571-49-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: POCl₃ / 3 h / Heating 2: 2 h / 135 - 155 °C
	Multi-step reaction with 2 steps 1: POCl₃ / 100 °C 2: 90 percent / 1.) 100 deg C, 1 h, 2.) 135-150 deg C, 3 h
	Multi-step reaction with 2 steps 1: phosphoryl chloride

Reference： [1]Madrid, Peter B.; Sherrill, John; Liou, Ally P.; Weisman, Jennifer L.; DeRisi, Joseph L.; Guy, R. Kiplin [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 1015 - 1018]
[2]De; Byers; Krogstad [Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 315 - 320]
[3]Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115]

23
[ 39061-72-8 ]
[ 86-99-7 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 3017 - 3035
[2]Journal of the Chemical Society,1951,p. 1038,1046

24
[ 86-99-7 ]
[ 108841-81-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: POCl₃ / 100 °C 2: 90 percent / 1.) 80 deg C, 1 h, 2.) 135-145 deg C, 3 h 3: 70 percent / NaBH₄ / 1.) RT, 1 h, 2.) 55 deg C, 18 h
	Multi-step reaction with 2 steps 1: POCl₃ / 100 °C 2: 85 percent / 1.) 100 deg C, 1 h, 2.) 135-140 deg C, 3 h
	Multi-step reaction with 2 steps 1: phosphoryl chloride 2: phenol / 135 °C / Erhitzen des Reaktionsgemisches mit <i>N</i>,<i>N</i>-Diaethyl-aethylendiamin

Reference： [1]De; Byers; Krogstad [Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 315 - 320]
[2]De; Byers; Krogstad [Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 315 - 320]
[3]Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115]

25
[ 86-99-7 ]
[ 53462-15-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: POCl₃ / 100 °C 2: 80 percent / 1.) 100 deg C, 1 h, 2.) 135-150 deg C, 3 h
	Multi-step reaction with 2 steps 1: phosphoryl chloride 2: 160 - 180 °C
	Multi-step reaction with 2 steps 1: phosphoryl chloride 2: phenol; NaI

Reference： [1]De; Byers; Krogstad [Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 315 - 320]
[2]Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115]
[3]Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115]

26
[ 16600-22-9 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 2 N aq. NaOH / 1 h / Heating 2: diphenyl ether / 1 h / Heating
	Multi-step reaction with 2 steps 1: aqueous NaOH 2: 250 - 270 °C / oder in einem Gemisch von Diphenylaether und Biphenyl
	Multi-step reaction with 2 steps 1: sodium hydroxide; water / diphenylether / 0.5 h 2: paraffin oil / 0.83 h / 230 °C

Reference： [1]De; Byers; Krogstad [Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 315 - 320]
[2]Price; Roberts [Journal of the American Chemical Society, 1946, vol. 68, p. 1204,1206][Organic Syntheses, 1955, vol. Coll. Vol. III, p. 272]
[3]Current Patent Assignee: CHONGQING MEDICAL PHARMACEUTICAL COLLEGE - CN111362872, 2020, A

27
[ 3412-99-5 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
49.7%	With dowtherm for 4h;	4.2.2. Preparation of 7-chloro-4-hydroxyquinoline²⁹ (3) A solution of 2-[(3-Chloro-phenylamino)-methylene]-malonic acid diethyl ester (2) 50 g (0.168 mol) in dowtherm (100 mL, 2 vol) medium was heated at 250 °C for 4 h. The reaction mixture was cooled to room temperature. To the above mixture was added hexane and stirred for 15 min, the solid precipitated was filtered and dried to get compound 3 as an off-white solid. Yield; 15 g (49.7 %)
49.7%	In diphenylether; biphenyl at 240℃; for 4h;
	Multi-step reaction with 3 steps 1: diphenyl ether / 1 h / Heating 2: 2 N aq. NaOH / 1 h / Heating 3: diphenyl ether / 1 h / Heating

	Multi-step reaction with 3 steps 2: aqueous NaOH 3: 250 - 270 °C / oder in einem Gemisch von Diphenylaether und Biphenyl
15 g	at 250℃; for 4h;	Preparation of 7-chloro-4-hydroxyquinoline (Int-3): A solution of 2-[(3-Chloro-phenylamino)-methylene]-malonic acid diethyl ester (2) 50 g (0.168 mol) in dowtherm (100 mL, 2 vol) medium was heated at 250 °C for 4 h. The reaction mixture was cooled to room temperature. To the above mixturewas added hexane and stirred for 15 min, the solid thus precipitated was filtered and dried to get compound 3 as an off white solid. Yield: 15 g (49.7 %)
	Multi-step reaction with 3 steps 1: paraffin oil / 0.5 h / 220 °C 2: sodium hydroxide; water / diphenylether / 0.5 h 3: paraffin oil / 0.83 h / 230 °C

Reference： [1]Shruthi; Eswaran, Sumesh; Shivarudraiah, Prasad; Narayanan, Shridhar; Subramanian, Sangeetha [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 1, p. 97 - 102]
[2]Eswaran, Sumesh; Shruthi, T. G.; Subramanian, Sangeetha [Heterocyclic Communications, 2020, vol. 26, # 1, p. 137 - 147]
[3]De; Byers; Krogstad [Journal of Heterocyclic Chemistry, 1997, vol. 34, # 1, p. 315 - 320]
[4]Price; Roberts [Journal of the American Chemical Society, 1946, vol. 68, p. 1204,1206][Organic Syntheses, 1955, vol. Coll. Vol. III, p. 272]
[5]Current Patent Assignee: FOUNDATION FOR NEGLECTED DISEASE RES - WO2019/243971, 2019, A1 Location in patent: Page/Page column 17
[6]Current Patent Assignee: CHONGQING MEDICAL PHARMACEUTICAL COLLEGE - CN111362872, 2020, A

28
[ 108-42-9 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aqueous hydrochloric acid 2: diphenyl ether
	Multi-step reaction with 3 steps 1: acetic acid / Erhitzen des Reaktionsprodukts in Paraffinoel auf 250grad 2: aqueous NaOH 3: mineral oil / 270 °C
	Multi-step reaction with 4 steps 3: aqueous NaOH 4: 250 - 270 °C / oder in einem Gemisch von Diphenylaether und Biphenyl

	Multi-step reaction with 3 steps 1: acetic acid / Erhitzen des Reaktionsprodukts in Paraffinoel auf 250grad 2: aqueous NaOH 3: mineral oil / 270 °C
	Multi-step reaction with 3 steps 1: acetic acid / Erhitzen des Reaktionsprodukts in Paraffinoel auf 250grad 2: aqueous NaOH 3: mineral oil / 270 °C
	Multi-step reaction with 3 steps 1: acetic acid / Erhitzen des Reaktionsprodukts in Paraffinoel auf 250grad 2: aqueous NaOH 3: 1-chloro-naphthalene
	Multi-step reaction with 3 steps 1: acetic acid / Erhitzen des Reaktionsprodukts in Paraffinoel auf 250grad 2: aqueous NaOH 3: 1-chloro-naphthalene
	Multi-step reaction with 2 steps 1: 4 h / 110 °C 2: dowtherm / 4 h
	Multi-step reaction with 2 steps 1: 4 h / 110 °C 2: 4 h / 250 °C
	Multi-step reaction with 4 steps 1: iron(III) chloride / 10 h / 120 - 140 °C 2: paraffin oil / 0.5 h / 220 °C 3: sodium hydroxide; water / diphenylether / 0.5 h 4: paraffin oil / 0.83 h / 230 °C
	Multi-step reaction with 4 steps 1: iron(III) chloride / 9 h / 110 - 140 °C 2: paraffin oil / 0.5 h / 220 °C 3: sodium hydroxide; water / diphenylether / 0.5 h 4: paraffin oil / 0.83 h / 230 °C
	Multi-step reaction with 2 steps 1: paraffin oil / 5 h / 230 °C 2: water / 5 h / 150 - 170 °C / Autoclave
	Multi-step reaction with 2 steps 1: 4 h / 110 °C 2: biphenyl; diphenylether / 4 h / 240 °C

Reference： [1]Price; Leonard; Reitsema [Journal of the American Chemical Society, 1946, vol. 68, p. 1256,1258]
[2]Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115]
[3]Price; Roberts [Journal of the American Chemical Society, 1946, vol. 68, p. 1204,1206][Organic Syntheses, 1955, vol. Coll. Vol. III, p. 272]
[4]Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115]
[5]Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115]
[6]Andersag [Chemische Berichte, 1948, vol. 81, p. 499,505]
[7]Andersag [Chemische Berichte, 1948, vol. 81, p. 499,505]
[8]Shruthi; Eswaran, Sumesh; Shivarudraiah, Prasad; Narayanan, Shridhar; Subramanian, Sangeetha [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 1, p. 97 - 102]
[9]Current Patent Assignee: FOUNDATION FOR NEGLECTED DISEASE RES - WO2019/243971, 2019, A1
[10]Current Patent Assignee: CHONGQING MEDICAL PHARMACEUTICAL COLLEGE - CN111362872, 2020, A
[11]Current Patent Assignee: CHONGQING MEDICAL PHARMACEUTICAL COLLEGE - CN111362872, 2020, A
[12]Current Patent Assignee: CHONGQING MEDICAL PHARMACEUTICAL COLLEGE - CN111747890, 2020, A
[13]Eswaran, Sumesh; Shruthi, T. G.; Subramanian, Sangeetha [Heterocyclic Communications, 2020, vol. 26, # 1, p. 137 - 147]

29
[ 86-99-7 ]
[ 70237-22-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetic acid; iodine monochloride 2: phosphoryl chloride
	Multi-step reaction with 4 steps 1: water; nitric acid 2: phosphoryl chloride 3: Raney nickel; ethanol / Hydrogenation 4: aqueous sulfuric acid; sodium nitrite / anschl. mit wss. Kaliumjodid und Kupfer-Pulver
	Multi-step reaction with 2 steps 1: N-butylamine; iodine; potassium iodide / N,N-dimethyl-formamide; water / 36 h / 20 °C 2: trichlorophosphate / 4 h / Reflux

Multi-step reaction with 2 steps 1: acetic acid; N-iodo-succinimide / 5 h / 60 °C 2: phosphorus trichloride / 2 h / 100 °C

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1946, vol. 68, p. 2570,2573]
[2]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]
[3]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES; OREGON HEALTH & SCIENCE UNIVERSITY - WO2013/106847, 2013, A1
[4]Current Patent Assignee: CENTRE INTERNATIONAL DE RECHERCHE AUX FRONTIERES DE LA CHIMIE; INOVIEM SCIENTIFIC; UNIVERSITY OF STRASBOURG; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - US2019/62278, 2019, A1

30
[ 86-99-7 ]
[ 46980-74-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: phosphoryl chloride 2: phenol; NaI

Reference： [1]Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115]

31
[ 86-99-7 ]
[ 133325-72-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 200 °C 2: phosphoryl chloride

Reference： [1]Illuminati; Santucci [Journal of the American Chemical Society, 1955, vol. 77, p. 6651]

32
[ 86-99-7 ]
(7-chloro-4-oxo-4H-[1]quinolyl)-acetic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aq. NaOH solution 2: sulfuric acid

Reference： [1]Surrey [Journal of the American Chemical Society, 1948, vol. 70, p. 2190,2191]

33
[ 86-99-7 ]
7-chloro-3-iodo-N-phenylquinolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: acetic acid; iodine monochloride 2: phosphoryl chloride 3: 150 - 160 °C

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1946, vol. 68, p. 2570,2573]

34
[ 86-99-7 ]
[ 525-31-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: phosphoryl chloride

Reference： [1]Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115]

35
[ 86-99-7 ]
(7-chloro-[4]quinolyl)-[3-(2-methyl-piperidino)-propyl]-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: phosphoryl chloride 2: phenol; NaI

Reference： [1]Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115]

36
[ 86-99-7 ]
[ 102074-97-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: acetic acid; iodine monochloride 2: phosphoryl chloride

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1946, vol. 68, p. 2570,2573]

37
[ 85344-88-3 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: diphenyl ether / 225 - 245 °C 2: acetic acid; sodium nitrite; sulfuric acid / Erwaermen der Diazoniumsalz-Loesung mit Kupfer(I)-chlorid und wss. Salzsaeure_.

Reference： [1]Price et al. [Journal of the American Chemical Society, 1947, vol. 69, p. 374]

38
[ 21640-97-1 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aqueous NaOH 2: mineral oil / 270 °C
	Multi-step reaction with 2 steps 1: aqueous NaOH 2: 1-chloro-naphthalene

Reference： [1]Surrey; Hammer [Journal of the American Chemical Society, 1946, vol. 68, p. 113,115]
[2]Andersag [Chemische Berichte, 1948, vol. 81, p. 499,505]

39
[ 40107-10-6 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 2: iron-powder; aqueous acetic acid / Erwaermen des Reaktionsprodukts mit wss. NaOH 3: diphenyl ether / 225 - 245 °C 4: acetic acid; sodium nitrite; sulfuric acid / Erwaermen der Diazoniumsalz-Loesung mit Kupfer(I)-chlorid und wss. Salzsaeure_.

Reference： [1]Price et al. [Journal of the American Chemical Society, 1947, vol. 69, p. 374]

40
[ 7248-88-6 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: iron-powder; aqueous acetic acid / Erwaermen des Reaktionsprodukts mit wss. NaOH 2: diphenyl ether / 225 - 245 °C 3: acetic acid; sodium nitrite; sulfuric acid / Erwaermen der Diazoniumsalz-Loesung mit Kupfer(I)-chlorid und wss. Salzsaeure_.

Reference： [1]Price et al. [Journal of the American Chemical Society, 1947, vol. 69, p. 374]

41
[ 99-09-2 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 110 °C 3: iron-powder; aqueous acetic acid / Erwaermen des Reaktionsprodukts mit wss. NaOH 4: diphenyl ether / 225 - 245 °C 5: acetic acid; sodium nitrite; sulfuric acid / Erwaermen der Diazoniumsalz-Loesung mit Kupfer(I)-chlorid und wss. Salzsaeure_.

Reference： [1]Price et al. [Journal of the American Chemical Society, 1947, vol. 69, p. 374]

42
[ 86-99-7 ]
3-amino-7-chloroquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: water; nitric acid 2: phosphoryl chloride 3: Raney nickel; methanol; KOH / Hydrogenation
	Multi-step reaction with 5 steps 1: nitric acid; propionic acid / 125 °C 2: trichlorophosphate / 18 h / 115 °C 3: chloroform / 24 h / 20 °C 4: sodium hydroxide / 1 h / 80 °C 5: water; tin(ll) chloride / methanol / 1 h / 80 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: acetic acid; nitric acid / 125 °C 2.1: trichlorophosphate / 115 °C 3.1: toluene-4-sulfonic acid hydrazide / chloroform / 24 h / 20 °C 3.2: 1 h / 80 °C 4.1: stannous chloride dihydrate / methanol / 100 °C

Multi-step reaction with 4 steps 1.1: acetic acid; nitric acid / 125 °C 2.1: trichlorophosphate / 115 °C 3.1: toluene-4-sulfonic acid hydrazide / chloroform / 24 h / 20 °C 3.2: 1 h / 80 °C 4.1: tin(II) chloride dihdyrate / methanol / 100 °C

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]
[2]Terzić, Natasa; Konstantinović, Jelena; Tot, Mikloš; Burojević, Jovana; Djurković-Djaković, Olgica; Srbljanović, Jelena; Štajner, Tijana; Verbić, Tatjana; Zlatović, Mario; Machado, Marta; Albuquerque, Inês S.; Prudêncio, Miguel; Sciotti, Richard J.; Pecic, Stevan; D'Alessandro, Sarah; Taramelli, Donatella; Šolaja, Bogdan A. [Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 264 - 281]
[3]Current Patent Assignee: BIOMARIN PHARMACEUTICAL INC - WO2019/133770, 2019, A2
[4]Current Patent Assignee: BIOMARIN PHARMACEUTICAL INC; BIOMARIN PHARM INC - WO2020/257487, 2020, A1

43
[ 86-99-7 ]
[ 858468-08-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: water; nitric acid 2: phosphoryl chloride 3: Raney nickel; ethanol / Hydrogenation

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]

44
[ 86-99-7 ]
[ 110643-79-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: water; nitric acid 2: phosphoryl chloride 3: butan-1-ol; NH₃ 4: iron; acetic acid; aqueous ethanol

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]

45
[ 86-99-7 ]
[ 858468-18-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: water; nitric acid 2: phosphoryl chloride 3: butan-1-ol; NH₃

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]

46
[ 86-99-7 ]
[ 22931-74-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: water; nitric acid 2: phosphoryl chloride
	Multi-step reaction with 2 steps 1: nitric acid; propionic acid / 125 °C 2: trichlorophosphate / 18 h / 115 °C
	Multi-step reaction with 2 steps 1: acetic acid; nitric acid / 125 °C 2: trichlorophosphate / 115 °C

Multi-step reaction with 2 steps 1: nitric acid / 120 °C 2: trichlorophosphate / 100 °C

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]
[2]Terzić, Natasa; Konstantinović, Jelena; Tot, Mikloš; Burojević, Jovana; Djurković-Djaković, Olgica; Srbljanović, Jelena; Štajner, Tijana; Verbić, Tatjana; Zlatović, Mario; Machado, Marta; Albuquerque, Inês S.; Prudêncio, Miguel; Sciotti, Richard J.; Pecic, Stevan; D'Alessandro, Sarah; Taramelli, Donatella; Šolaja, Bogdan A. [Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 264 - 281]
[3]Current Patent Assignee: BIOMARIN PHARMACEUTICAL INC - WO2019/133770, 2019, A2 Current Patent Assignee: BIOMARIN PHARMACEUTICAL INC; BIOMARIN PHARM INC - WO2020/257487, 2020, A1
[4]Current Patent Assignee: BELL BROOK LABS - WO2020/142735, 2020, A1

47
[ 86-99-7 ]
7-chloro-N⁴-phenyl-quinoline-3,4-diyldiamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: water; nitric acid 2: phosphoryl chloride 3: acetic acid 4: Raney nickel; ethanol / Hydrogenation

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]

48
[ 86-99-7 ]
[ 860195-22-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: water; nitric acid 2: phosphoryl chloride 3: acetic acid

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]

49
[ 86-99-7 ]
N,N-diethyl-N'-(7-chloro-3-nitro-[4]quinolyl)-butanediyldiamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: water; nitric acid 2: phosphoryl chloride 3: 1,2-dichloro-ethane

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]

50
[ 86-99-7 ]
1-(7-chloro-3-nitro-[4]quinolylamino)-3-diethylamino-propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: water; nitric acid 2: phosphoryl chloride 3: CHCl₃

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]

51
[ 86-99-7 ]
2-{ethyl-[4-(7-chloro-3-nitro-[4]quinolylamino)-pentyl]-amino}-ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: water; nitric acid 2: phosphoryl chloride

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]

52
[ 86-99-7 ]
N⁴,N⁴-diethyl-N¹-(7-chloro-3-nitro-[4]quinolyl)-2-phenyl-butanediyldiamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: water; nitric acid 2: phosphoryl chloride 3: CHCl₃

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]

53
[ 86-99-7 ]
N⁴,N⁴-diethyl-N¹-(7-chloro-3-nitro-[4]quinolyl)-2-(4-chloro-phenyl)-butanediyldiamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: water; nitric acid 2: phosphoryl chloride 3: CHCl₃

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]

54
[ 86-99-7 ]
N⁴,N⁴-diethyl-N¹-(7-chloro-3-nitro-[4]quinolyl)-2-(3,4-dichloro-phenyl)-butanediyldiamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: water; nitric acid 2: phosphoryl chloride 3: 1,2-dichloro-ethane

Reference： [1]Surrey; Cutler [Journal of the American Chemical Society, 1951, vol. 73, p. 2413,2414]

55
[ 86-99-7 ]
(2S,4S)-N-tert-butoxycarbonyl-4-hydroxyproline methyl ester [ No CAS ]
[ 220424-77-1 ]

Yield	Reaction Conditions	Operation in experiment
68%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 30h;	H.III.371.1 Example 371: Preparation of Compound 371; Step 1: To a suspension of N-Boc-cis-L-4-Hydroxyproline methyl ester (10 g, 40. 7mmol) and 7-chloroquinolin-4-ol (8.73 g, 49.0 mmol) in THF (200 mL) cooled to0 C was added PPh3 (12.82 g, 48.9 mmol) and DIAD. (8.80 g, 42.13 mmol). The mixture was slowly allowed to warm to rtovernite, stirred at total of 30 h. The mixture was dissolved in EtOAc (800 mL), washed with 1N aqueous HCI, 5% aqueousK2CO3(3X100 mL), brine (2 X 100 mL) and dried(MgS04), and concentrated. The residue was purified several times over a Biotage 65M(MeOH-CH2CI2 : 0-10%) to afford cumulatively 10.57 g (68%) of the desired product as a glass:'H NMR (CDC13)8 1.40 (s, 9H), 2.33-2. 42 (m, 1H), 2.61-2. 72 (m, 1H), 3.75 (s, 3H), 3.91 (m, 2H), 4.45- 4.59 (m, 1H), 5.13 (m, 1H), 6.61-6. 64 (m, 1H), 7.41 (dd, J=9, 2 Hz, 1H), 7.98 (d, J=2 Hz, 1H), 8.03 (d, J=9 Hz, 1H), 8.67-8. 71 (m, 1H). LC-MS (retention time: 1.39, method D), MS m/e 407(M++1).
68%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 30h;	B.63.a Step 63a: Preparation of N-Boc-4-(7-Chloro-quinolin-4-yloxy)-proline Methyl Ester To a suspension of N-Boc-cis-L-4-Hydroxyproline methyl ester (10 g, 40.7 mmol) and 7-chloroquinolin-4-ol (8.73 g, 49.0 mmol) in TUF (200 mL) cooled to 0° C. was added PPh3 (12.82 g, 48.9 mmol) and DIAD. (8.80 g, 42.13 mmol). The mixture was slowly allowed to warm to rt overnite, stirred at total of 30 h. The mixture was dissolved in EtOAc (800 mL), washed with 1N aqueous HCl, 5% aqueous K2CO3 (3100 mL), brine (2100 mL) and dried (MgSO4), and concentrated. The residue was purified several times over a Biotage 65M (MeOH/CH2Cl2: 0 to 10%) to afford cumulatively 10.57 g (68%) of the desired product as a glass: 1H NMR (CDCl3) δ 1.40 (s, 9H), 2.33-2.42 (m, 1 H), 2.61-2.72 (m, 1 H), 3.75 (s, 3H), 3.91 (m, 2H), 4.45-4.59 (m, 1 H), 5.13 (m, 1 H), 6.61-6.64 (m, 1 H), 7.41 (dd, J=9, 2 Hz, 1 H), 7.98 (d, J=2 Hz, 1 H), 8.03 (d, J=9 Hz, 1 H), 8.67-8.71 (m, 1 H). LC-MS (retention time: 1.39, method D), MS m/e 407 (M++1).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2003/99274, 2003, A1 Location in patent: Page 501-502
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2004/77551, 2004, A1 Location in patent: Page/Page column 86

56
[ 86-99-7 ]
C₉H₅ClNO^(1-)*Na⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In DMF (N,N-dimethyl-formamide) at 20℃; for 0.333333h;	Synthesis of 5-(7-Chloro-quinolin-4-yloxy)-[1,3,4]thiadiazole-2-carboxylic Acid Ethyl Ester [CHEMMOL-00141] [0176] NaH (0.022 mg, 0.5 mmol) was added in portions to a solution of 7-chloro-4-hydroxyquinoline (0.093 mg, 0.5 mmol) in DMF (6 ml) at room temperature and the mixture stirred at room temperature for 20 min. 2-Chloro-[1,3,4]thiadiazole derivative (0.097 mg, 0.5 mmol) was then added in one portion and the mixture heated at 70-80° C. (oil bath temperature) for 18 h. The reaction mixture was allowed to cool to room temperature and water (15-30 ml) was added. The precipitate was separated by filtration, washed several times with cold water, then with Et2O and dried to afford the product (0.081 mg, 47% yield).

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2004/38992, 2004, A1 Location in patent: Page/Page column 27

57
[ 86-99-7 ]
[ 1423-27-4 ]
[ 573675-16-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate In toluene at 90℃; for 16h;	2.A.1 Combine 7-chloroquinolin-4-ol (1000 mg, 5.55 mmol, ) 2- (trifluoromethyl) PHENYLBORONIC acid (1583 mg, 8. 33 mmol) and toluene (50 mL), and bubble nitrogen into the solution for 10 minutes. Add palladium acetate (25 mg, 0.11 mmol), 2- (dicyclohexylphosphino) biphenyl (78 mg, 0.22 mmol), and K3PO4 (2353 mg, 11.1 mmol) and heat at 90°C for 16 hours. Let cool, add water (25 mL) and EtOAc (50 mL), and remove any insoluble material by filtration. Separate the EtOAc layer, and extract the aqueous layer twice with EtOAc (25 mL each). Combine the EtOAc extracts, dry (NA2S04), and evaporate. Purify by silica gel chromatography (94% CH2Cl2/5% MeOH/1% NH4OH) to provide 7- (2- trifluoromethyl-phenyl)-quinolin-4-ol AS-A white solid.

Reference： [1]Current Patent Assignee: LIGAND PHARMACEUTICALS INC - WO2005/7652, 2005, A2 Location in patent: Page/Page column 71-72

58
[ 86-99-7 ]
3-methyl-1-[methyl(phenyl)amino]carbonyl}-1H-imidazol-3-ium iodide [ No CAS ]
[ 431935-03-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine In acetonitrile	240 Methyl-phenyl-carbamic Acid 7-chloro-quinolin-4-yl Ester Example 240 Methyl-phenyl-carbamic Acid 7-chloro-quinolin-4-yl Ester A solution of 7-chloro-4-hydroxyquinoline (0.54 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (0.87 g, 93% yield) as a colourless oil which solidified upon standing. 1H NMR (300 MHz, CDCl3): δ 3.47 (br.s, 3H), 7.28-7.58 (m, 8H), 8.05 (br.s, 1H), 8.85 (d, 1H); HPLC-MS (Method A): m/z=313 (M+H); Rt=3.79 min.

Reference： [1]Current Patent Assignee: NOVO NORDISK A/S - US2003/166644, 2003, A1

59
[ 86-99-7 ]
7-chloro-2-propylthiazolo[4,5-c]quinolin-4-amine [ No CAS ]
[ 5350-50-5 ]

Yield	Reaction Conditions	Operation in experiment
	With nitric acid;	Example 63 7-Chloro-2-propylthiazolo[4,5-c]quinolin-4-amine STR66 Part A 7-Chloro-4-hydroxyquinoline (35 g, 0.195 mol; available from Aldrich, Milwaukee, Wis.) and nitric acid (350 mL of 70%) were combined and heated at reflux for 75 minutes. The reaction mixture was poured over ice while still hot. The resulting bright yellow precipitate was isolated by filtration and then washed 3 times with boiling ethyl acetate to provide 17.3 g of 7-chloro-3-nitro-4-hydroxyquinoline as a pale yellow solid.

Reference： [1]Patent: US6110929,2000,A

60
[ 4472-44-0 ]
[ 86-99-7 ]
[ 143946-42-3 ]

Yield	Reaction Conditions	Operation in experiment
20%	With sodium hydroxide; silver nitrate In water; benzene	5 Compound No. 262 EXAMPLE 5 Synthesis (Process B) of 7-chloro-4-(4,6-dimethyl-2-pyrimidinyloxy)quinoline Compound No. 262 To an aqueous solution containing 0.28 g of sodium hydroxide in 8.5 ml of water, 0.90 g of 7-chloro-4-hydroxyquinoline was added and dissolved by warming to 60°-70° C. After cooling the resulting solution, an aqueous solution containing 0.85 g of silver nitrate in 2 ml of water was added. Light gray precipitate was formed. After 10 minutes, 20 ml of dimethylimidazolidinone and 20 ml of benzene were added and azeotropic dehydration was carried out from 75° to 140° C. to obtain dehydrated silver salt. Successively, 0.86 g of 2-chloro-4,6-dimethylpyrimidine was added at 90°-110° C. and heated at 100°-150° C. for 9 hours. The reaction mixture was cooled and insoluble matter was filtered. Solvent was distilled off from the filtrate and the residue was separated by silica gel column chromatography(elude; ethyl acetate) to obtain 0.29 g (20% yield) of desired product 7-chloro-4-(4,6 -dimethyl-2-pyrimidinyloxy)quinoline. Melting point was 104°-105° C. NMR(CDCl3)δ: 2.46(6H,s), 6.91(1H,s), 7.27(1H,d,J=4.4 Hz), 7.50(1H,dd,J=2.2, 8.8 Hz), 8.13(1H,d,J=8.8 Hz), 8.14(1H,d,J=2.2 Hz), 8.89(1H,d,J=4,4 Hz)

Reference： [1]Current Patent Assignee: MITSUI CHEMICALS,INC. - US5202329, 1993, A

61
[ 86-99-7 ]
[ 21295-51-2 ]
[ 98519-65-4 ]

Yield	Reaction Conditions	Operation in experiment
	In ice-water;	Example 35 4-Bromo-7-chloro-quinoline 83.9 g of 7-chloro-4-hydroxyquinoline were added portionwise at 60 to 150 g of phosphorus oxybromide and the mixture was thereafter heated to 140 C. for 6 hours. After cooling, the mixture was treated with 3 l of ice-water and extracted with 2*1.5 l of dichloromethane. After evaporation of the solvent and crystallization from 1.3 l of hexane, 34 g of product were obtained as colourless crystals, m.p.: 102-103 C.

Reference： [1]Patent: US5596002,1997,A

62
[ 21617-15-2 ]
[ 86-99-7 ]
[ 611-36-9 ]

Yield	Reaction Conditions	Operation in experiment
88.3%		a degree of conversion of the <strong>[21617-15-2]7-chloro-1,2,3,4-tetrahydroquinolin-4-one</strong> of 88.3%, a yield of 4-hydroxy-7-chloroquinoline of 69.8% relative to the <strong>[21617-15-2]7-chloro-1,2,3,4-tetrahydroquinolin-4-one</strong> converted, and a yield of 4-hydroxyquinoline of 15% relative to the <strong>[21617-15-2]7-chloro-1,2,3,4-tetrahydroquinolin-4-one</strong> converted.

Reference： [1]Patent: US4412076,1983,A

63
[ 86-98-6 ]
[ 91-22-5 ]
[ 612-61-3 ]
[ 86-99-7 ]

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 4989 - 4993
[2]Tetrahedron Letters,2010,vol. 51,p. 1562 - 1565

64
[ 86-99-7 ]
[ 84654-29-5 ]
[ 1141428-17-2 ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: 7-chloro-4-hydroxylquinoline With potassium carbonate In acetone for 0.5h; Reflux; Stage #2: 5-(bromomethyl)-3-isoxazolecarboxylic acid ethyl ester In acetone Reflux;

Reference： [1]Location in patent: experimental part Lilienkampf, Annamaria; Jialin, Mao; Baojie, Wan; Yuehong, Wang; Franzblau, Scott G.; Kozikowski, Alan P. [Journal of Medicinal Chemistry, 2009, vol. 52, # 7, p. 2109 - 2118]

65
[ 86-99-7 ]
[ 90225-19-7 ]

Yield	Reaction Conditions	Operation in experiment
	With Lawessons reagent In tetrahydrofuran at 80℃;

Reference： [1]Location in patent: scheme or table Gage, Jennifer L.; Onrust, Rene; Johnston, Derek; Osnowski, Andrew; MacDonald, Wendy; Mitchell, Lee; Ürögdi, László; Rohde, Alex; Harbol, Kevin; Gragerov, Sasha; Dormán, György; Wheeler, Tom; Florio, Vince; Cutshall, Neil S. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 14, p. 4155 - 4159]

66
[ 86-99-7 ]
[ 98-88-4 ]
[ 1318249-24-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With 4-methyl-morpholine In dichloromethane at 10 - 25℃;

Reference： [1]Li, Wenjie; Gao, Joe J.; Zhang, Yongda; Tang, Wenjun; Lee, Heewon; Fandrick, Keith R.; Lu, Bruce; Senanayake, Chris H. [Advanced Synthesis and Catalysis, 2011, vol. 353, # 10, p. 1671 - 1675]

67
[ 86-99-7 ]
[ 4038-99-7 ]
[ 1233345-93-1 ]

Yield	Reaction Conditions	Operation in experiment
59.14%	With sodium hydroxide In water for 14h; Reflux;

Reference： [1]Location in patent: experimental part Bhovi, Manjunath G.; Tanwar, Pooja; Yadav, Gyan Chand [Indian Journal of Heterocyclic Chemistry, 2010, vol. 19, # 3, p. 215 - 220]

68
[ 26707-52-8 ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With water; hydrogen bromide; Aliquat 336 at 105℃; for 4h;	General experimental procedure for deprotection of aryl methyl ether General procedure: To a stirred solution of aryl methyl ether (20 mmol) and 47% aqueous HBr (4.5 mmol equiv. of substrate) added Aliquat-336 (10 wt. % of substrate) in a single lot. The resulting reaction mixture was heated at 105±5 °C, and the progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to room temperature and quenched by adding water (25 ml). The resulting reaction mass was extracted with 3x30 ml ethyl acetate. Ethyl acetate layer washed twice with 20 ml of water, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane system.

Reference： [1]Waghmode, Suresh B.; Mahale, Ganesh; Patil, Viraj P.; Renalson, Kartik; Singh, Dharmendra [Synthetic Communications, 2013, vol. 43, # 24, p. 3272 - 3280]

69
[ 86-99-7 ]
[ 358-23-6 ]
Trifluoro-methanesulfonic acid 7-chloro-quinolin-4-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine In dichloromethane at -78 - 20℃; for 1h;

Reference： [1]Sather, Aaron C.; Lee, Hong Geun; De La Rosa, Valentina Y.; Yang, Yang; Müller, Peter; Buchwald, Stephen L. [Journal of the American Chemical Society, 2015, vol. 137, # 41, p. 13433 - 13438]

70
[ 86-99-7 ]
[ 349120-86-1 ]
2-(7-chloro-4-oxoquinolin-1(4H)-yl)-N-(3,5-dimethylphenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere;	5 4.1.2. General method A General procedure: The appropriate 4-hydroxyquinoline/quinazoline/naphthyridine(1 eq.), 2-bromo-N-(3,5-dimethylphenyl)acetamide (1-1.1 eq.) and potassium carbonate (3 eq.) were dissolved in anhydrousDMF (0.09-0.11 M) and stirred for 3-18 h under nitrogen atmosphereat room temperature. Then, the reaction mixture waspoured into water and the resulting precipitate was filtered,washed with water and dried. If necessary, it was purified by silicagel column chromatography using n-heptane/ethyl acetate aseluent or by recrystallization using ethyl acetate as solvent.

Reference： [1]Pitta, Eleni; Balabon, Olga; Rogacki, Maciej K.; Gómez, Jesús; Cunningham, Fraser; Joosens, Jurgen; Augustyns, Koen; van der Veken, Pieter; Bates, Robert [European Journal of Medicinal Chemistry, 2017, vol. 125, p. 890 - 901]

71
[ 86-99-7 ]
[ 25294-59-1 ]
2-chloro-8,8-dimethylfuro[3',4':5,6]pyrano[2,3,4-de]quinolin-10(8H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; copper diacetate; lithium trifluoromethanesulfonate In 1,2-dimethoxyethane at 100℃; for 12h; Schlenk technique; Inert atmosphere;

Reference： [1]Liao, Gang; Song, Hong; Yin, Xue-Song; Shi, Bing-Feng [Chemical Communications, 2017, vol. 53, # 55, p. 7824 - 7827]

72
[ 86-99-7 ]
[ 123084-61-7 ]
3-chloro-11-methyl-7H-chromeno[3,2-c]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 7-chloro-4-hydroxylquinoline; (2,6-dimethylphenyl)-λ³-iodanediyl diacetate In 5,5-dimethyl-1,3-cyclohexadiene at 100℃; for 6h; Inert atmosphere; Schlenk technique; Stage #2: With palladium diacetate; caesium carbonate; triphenylphosphine In 5,5-dimethyl-1,3-cyclohexadiene at 130℃; for 30h; Schlenk technique; Inert atmosphere; Molecular sieve;

Reference： [1]Hong, Fenglin; Lu, Nannan; Lu, Beili; Cheng, Jiajia [Advanced Synthesis and Catalysis, 2017, vol. 359, # 19, p. 3299 - 3303]

73
[ 86-99-7 ]
4-(4-(3-bromopropyl)piperazin-1-yl)-7-chloroquinoline [ No CAS ]
[ 1233345-93-1 ]

Yield	Reaction Conditions	Operation in experiment
59.4%	With sodium hydroxide In water for 14h; Reflux;	2 2, impurities F(7-chloro-4- (4- (3 - ((Chloroquinolin-4-yl) oxy) propyl) piperazin-1-yl) quinoline)4- (4-(3-bromopropyl) piperazin-1-yl) -7-chloroquinoline and4-hydroxy-7-chloroquinoline as raw material condensation in the system. The synthetic route is: Specifically, 4-hydroxy-7-chloroquinoline (2.77 g, 0.015 mol), sodium hydroxide (1.23 g,0.030 mol) and 50 ml of water were placed in a reaction flask and 4- (4- (3-bromopropyl) piperazin-1-yl) -7-chloroquine(5g, 0.015mol) was added and the mixture was stirred for 14h at the reflux temperature. After the reaction was completed, 100ml of chloroform was extracted and the organic layer was washed with anhydrous sulfurDrying sodium sulfate, chloroform-spinning to give 4.27g of a white solid, yield 59.4%.

Reference： [1]Current Patent Assignee: SHANGHAI FOSUN PHARMACEUTICAL (GROUP) CO., LTD. - CN104402815, 2017, B Location in patent: Paragraph 0067; 0068; 0069

74
[ 86-99-7 ]
[ 35714-48-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: phosphorus tribromide / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere 2.2: 3 h / -78 °C / Inert atmosphere

Reference： [1]Tong, Mengchao; Wang, Sinan; Zhuang, Jinchen; Qin, Cong; Li, Hao; Wang, Wei [Organic Letters, 2018, vol. 20, # 4, p. 1195 - 1199]

75
[ 86-99-7 ]
[ 203261-30-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: phosphorus tribromide / N,N-dimethyl-formamide / 2 h / 20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere 2.2: 3 h / -78 °C / Inert atmosphere 3.1: sodium tetrahydroborate / 4 h / 0 - 20 °C

Reference： [1]Tong, Mengchao; Wang, Sinan; Zhuang, Jinchen; Qin, Cong; Li, Hao; Wang, Wei [Organic Letters, 2018, vol. 20, # 4, p. 1195 - 1199]

76
[ 86-99-7 ]
(4-tert-butyl-phenyl)-[7-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium phosphate / palladium diacetate; CyJohnPhos / toluene / 16 h / 90 °C 2: trichlorophosphate / 16 h / 90 °C 3: isopropyl alcohol / 3 h / Heating / reflux

Reference： [1]Current Patent Assignee: LIGAND PHARMACEUTICALS INC - WO2005/7652, 2005, A2

77
[ 86-99-7 ]
[ 573675-19-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium phosphate / palladium diacetate; CyJohnPhos / toluene / 16 h / 90 °C 2: trichlorophosphate / 16 h / 90 °C

Reference： [1]Current Patent Assignee: LIGAND PHARMACEUTICALS INC - WO2005/7652, 2005, A2

78
[ 86-99-7 ]
2-tert-butoxycarbonylamino-3-fluorobenzyl bromide [ No CAS ]
1-(2-tert-butoxycarbonylamino-3-fluorobenzyl)-7-chloro-1,4-dihydro-4-oxoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.18 g	With potassium carbonate In N,N-dimethyl-formamide at 80 - 90℃; for 3h;	4 Reference Example 4 A suspension of 8.4 mL of DMF with 0.28 g of 2-tert-butoxycarbonylamino-3-fluorobenzyl bromide, 0.15 g of 7-chloroquinolin-4-ol and 0.23 g of potassium carbonate was stirred at 80-90 ° C. for 3 hours.After cooling the reaction mixture, ethyl acetate and water were added.Separate the organic layer and wash with saturated aqueous sodium chlorideDry over anhydrous magnesium sulfate,The solvent was distilled off under reduced pressure.Silica gel column chromatography of the obtained residuePurified with [eluent; chloroform: acetone = 4: 1]Ethyl acetate and diisopropyl ether were added to the resulting solid. Filter off solids,White solid0.18 g of 1- (2-tert-butoxycarbonylamino-3-fluorobenzyl) -7-chloro-1,4-dihydro-4-oxoquinoline was obtained.

Reference： [1]Current Patent Assignee: FUJIFILM HOLDINGS CORP. - JP5745869, 2015, B2 Location in patent: Paragraph 0045

79
[ 86-99-7 ]
[ 76437-44-0 ]
7-chloro-1-(4-fluoro-2-nitrobenzyl)-1,4-dihydro-4-oxoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
300 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 70 - 80℃; for 2h;	1.54 g of potassium carbonate is added to a solution of 1.96 g of <strong>[76437-44-0]4-fluoro-2-nitrobenzyl bromide</strong> and 1.00 g of 7-chloroquinolin-4-ol in 20 mL of DMF,Stir at 70-80 C. for 2 hours.After cooling the reaction mixture, ethyl acetate is added,After washing sequentially with water and saturated aqueous sodium chloride solutionIt was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure.Silica gel column chromatography of the obtained residue[Eluent; hexane: ethyl acetate = 5: 1 ? 1: 1],Ethyl acetate and diisopropyl ether were added to the resulting solid. Filter off solids,300 mg of 7-chloro-1- (4-fluoro-2-nitrobenzyl) -1,4-dihydro-4-oxoquinoline as a brown solid was obtained.

Reference： [1]Patent: JP5745869,2015,B2 .Location in patent: Paragraph 0042

80
[ 86-99-7 ]
cinnamyl methyl carbonate [ No CAS ]
C₁₈H₁₄ClNO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With bis(1,5-cyclooctadiene)diiridium(I) dichloride; 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine; 1,8-diazabicyclo[5.4.0]undec-7-ene; (3,5-Dioxa-4-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-yl)-bis-((R)-1-phenyl-ethyl)-amine In tetrahydrofuran at 50℃; for 24h; Inert atmosphere; stereoselective reaction;

Reference： [1]Bai, Xue-dan; Wang, Jie; He, Ying [Advanced Synthesis and Catalysis, 2019, vol. 361, # 3, p. 496 - 501]

81
[ 86-99-7 ]
[ 93516-30-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-chloro-succinimide; acetic acid at 60℃; for 5h;	2 2) A Compound of Formula (I) Where X═Cl N-chlorosuccinimide (408 mg, 3.06 mmol) is added to a suspension of 7-chloroquinolin-4-ol (500 mg, 2.78 mmol) in 20 mL of acetic acid. The reaction is heated at 60° C. for 5 hours and then diluted in water and filtered. The white solid is washed with water and dried under vacuum. (0249) Yield 88%. White solid; RMN 1H (DMSO, 400 MHz) δ 7.40 (1H, dd, J=8.8. 2.0 Hz), 7.64 (1H, d, J=2.0 Hz), 8.14 (1H, d, J=8.8 Hz), 8.45 (1H, s), 12.24 (1H, sl); RMN 13C (DMSO, 100 MHz) δ 170.6; 139.9; 138.5; 136.5; 127.5; 124.2; 123.2; 117.7; 114.7.

82
[ 86-99-7 ]
[ 860715-45-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-Bromosuccinimide; acetic acid at 60℃; for 5h;	13 13) A Compound of Formula (I) Where X═Br N-iodosuccinimide (626 mg, 2.78 mmol) is added to a suspension of 7-chloroquinolin-4-ol (500 mg, 2.78 mmol) in 16 mL of acetic acid. The reaction is heated at 60° C. for 5 hours and then diluted in water and filtered. The white solid is washed with water and dried under vacuum. (0302) Yield 88%. White solid; RMN 1H (CDCl3, 400 MHz) δ 7.41 (1H, d, J=8.7 Hz); 7.64 (1H, s); 8.13 (1H, d, J=8.8 Hz); 8.53 (1H, s); 12.32 (1H, sl); RMN 13C (CDCl3, 100 MHz) δ 104.75; 117.68; 122.78; 124.33; 127.62; 136.45; 140.04; 140.77; 170.84; SM (ESI+): m/z=257 [M+1].

83
[ 86-99-7 ]
[ 98-59-9 ]
C₁₆H₁₂ClNO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine In dichloromethane at 0 - 50℃; for 4h;	8.6 6) At 010, to 7-chloro 4-hydroxyquinoline (17.9g, 0.1mol)And triethylamine (50g) in dichloromethane (120mL) solution,A solution of p-toluenesulfonyl chloride (22.8g, 0.12mol) and dichloromethane (100mL) was added dropwise.After the addition was completed, the mixture was heated to 50°C for 4 hours to react, and TLC detected the completion of the reaction.After cooling to room temperature, the reaction solution was transferred to ice water (100g) and stirred for 1 hour.Separate the liquids, wash the dichloromethane layer with sodium bicarbonate solution, concentrate,Crystallize, filter, and dry to obtain 31g of intermediate with a yield of 94%.

Reference： [1]Current Patent Assignee: BEIJING CHENGYU SPECIALTY CHEMICAL - CN111635358, 2020, A Location in patent: Paragraph 0114; 0125; 0131-0133

84
[ 86-99-7 ]
[ 421-83-0 ]
Trifluoro-methanesulfonic acid 7-chloro-quinolin-4-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 10h;	9 Example 9 To a solution of 7-chloro-4-hydroxyquinoline (17.9g, 0.1mol) and triethylamine (50g) in dichloromethane (120mL) at 05,A solution of trifluoromethanesulfonyl chloride (16.8g, 0.1mol) and N,N-dimethylformamide (25mL) was added dropwise.After the addition is complete, the reaction is carried out at room temperature for 10 hours, and TLC detects the completion of the reaction.The reaction solution was transferred to ice water (200g) and stirred for 1 hour,Separate the liquids, wash the dichloromethane layer with sodium bicarbonate solution, and concentrate to obtain 30 g of intermediate.The yield was 92%.

Reference： [1]Current Patent Assignee: BEIJING CHENGYU SPECIALTY CHEMICAL - CN111635358, 2020, A Location in patent: Paragraph 0134-0140

85
C₁₁H₁₁ClN₂O₃ [ No CAS ]
[ 86-99-7 ]

Yield	Reaction Conditions	Operation in experiment
14 g	With iron; acetic acid at 90℃; for 4h;	8.5 5) Add iron powder (11.2g, 0.2mol) to the condensate (23 g, 0.09mol) obtained in the above step (4) in batches) In acetic acid (60 mL), the mixture was heated to 90°C for 4 hours while stirring, and the reaction was completed by TLC detection.After cooling to room temperature, the reaction solution was poured into ice water (200g), and the precipitated solid was filtered after 1 hour.Wash with water and dry to obtain the cyclized product (14g), which is directly used in the next reaction;

Reference： [1]Current Patent Assignee: BEIJING CHENGYU SPECIALTY CHEMICAL - CN111635358, 2020, A Location in patent: Paragraph 0114; 0125; 0127-0130

86
[ 86-99-7 ]
[ 140-80-7 ]
[ 1915-92-0 ]
[ 54-05-7 ]

Yield	Reaction Conditions	Operation in experiment
1: 56% 2: 12%	With potassium pyrosulfite; palladium 10% on activated carbon; water; ammonium formate at 120℃; for 16h; Inert atmosphere; Schlenk technique;

Reference： [1]Liang, Wanyi; Xie, Feng; Yang, Zhihai; Zeng, Zheng; Xia, Chuanjiang; Li, Yibiao; Zhu, Zhongzhi; Chen, Xiuwen [Organic Letters, 2020, vol. 22, # 21, p. 8291 - 8295]

87
[ 86-99-7 ]
[ 149253-32-7 ]
7-chloroquinolin-4-yl 2-((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 23℃; for 3.25h;	3.7. Synthesis of quinolin-4-yl-2-((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl) Acetate (7) General procedure: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI, Sigma-Aldrich,99% purity, 171.7 mg, 0.90 mmol, 1.3 eq.), DMAP (4-Dimethylaminopyridine, 99%, ACROSOrganics, 98.5% purity, 25.7 mg, 0.21 mmol, 0.5 eq.), and DIEA (2.04 mmol, 0.36 mL, and3eq.) were added to a solution of 4-hydroxyquinoline (100 mg, 0.68 mmol, 1.0 eq., ArkPharm, Inc., 97% purity) and nopoic acid (0.42 mmol, 1.2 eq.) in tetrahydrofuran (THF, FisherScientific, 99.9%, 2.0 mL) at 0 °C and stirred for 15 min. [25]. The temperature was raisedto 23 °C, and the reaction mixture was stirred for 3 h while monitoring by analytical TLC.The reaction appeared cloudy at first but after stirring for 1 h at room temperature, it becameclear, with the formation of colorless solid precipitate. The reaction mixture was quenchedwith brine, extracted with EtOAc, concentrated, and separated by preparative TLC (20:1CHCl3/ethyl acetate, Rf = 0.55) with 25% yield.

Reference： [1]Collins, Jasmine T.; Crown, Olamide; Nyamwihura, Rogers J.; Ogungbe, Ifedayo Victor; Zhang, Huaisheng [Molecules, 2021, vol. 26, # 4]

88
[ 86-99-7 ]
[ 106-96-7 ]
[ 1206552-77-3 ]

Yield	Reaction Conditions	Operation in experiment
	With Cs₂CO₃ In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;	4.1.1.1. Synthesis of 7-chloro-4-(prop-2-yn-1-yloxy)quinoline (1). 7-chloroquinolin-4-ol (0.2 g, 1.114 mmol) [55] was suspended in dry DMF(4 mL). Under argon atmosphere cesium carbonate (0.508 g, 1.56 mmol)was added, followed by dropwise addition of 80% solution of propargylbromide in toluene (0.143 mL, 1.337 mmol). The reaction was stirred atrt and under argon atmosphere for 1.5 h. Upon completion, the reactionmixture was poured into 40 mL of water. Product was extracted withEtOAc (3 × 40 mL). Organic layers were collected and washed withwater (2 × 100 mL), dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. After purification by column chromatography(DCM/methanol = 9:1) and trituration with diethyl ether0.143 g (59%) of 1 was obtained.
	With Cs₂CO₃ In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;	4.1.1.1. Synthesis of 7-chloro-4-(prop-2-yn-1-yloxy)quinoline (1). 7-chloroquinolin-4-ol (0.2 g, 1.114 mmol) [55] was suspended in dry DMF(4 mL). Under argon atmosphere cesium carbonate (0.508 g, 1.56 mmol)was added, followed by dropwise addition of 80% solution of propargylbromide in toluene (0.143 mL, 1.337 mmol). The reaction was stirred atrt and under argon atmosphere for 1.5 h. Upon completion, the reactionmixture was poured into 40 mL of water. Product was extracted withEtOAc (3 × 40 mL). Organic layers were collected and washed withwater (2 × 100 mL), dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. After purification by column chromatography(DCM/methanol = 9:1) and trituration with diethyl ether0.143 g (59%) of 1 was obtained.

Reference： [1]Held, Jana; Moita, Diana; Pessanha de Carvalho, Lais; Poje, Goran; Vianello, Robert; Perković, Ivana; Prudêncio, Miguel; Rajić, Zrinka; Tandarić, Tana [European Journal of Medicinal Chemistry, 2022, vol. 238]
[2]Held, Jana; Moita, Diana; Pessanha de Carvalho, Lais; Poje, Goran; Vianello, Robert; Perković, Ivana; Prudêncio, Miguel; Rajić, Zrinka; Tandarić, Tana [European Journal of Medicinal Chemistry, 2022, vol. 238]

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Code	Phrase
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H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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[ 86-99-7 ] Synthesis Path-Upstream 1~6

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Chlorides

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