Name: 6627-53-8|5-Chloro-2-nitroanisole|98%
Brand: Ambeed
SKU: A127190
Price: 8.0 USD
Availability: InStock
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1
[ 6627-53-8 ]
[ 124-41-4 ]
[ 704-14-3 ]
[ 4920-84-7 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1902,vol. 21,p. 325

2
[ 6627-53-8 ]
[ 704-14-3 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1902,vol. 21,p. 325

3
[ 6627-53-8 ]
[ 93-50-5 ]

Yield	Reaction Conditions	Operation in experiment
91 - 93%		A suspension of ferrum (5.0 equiv.), ammonium chloride (0.65 equiv.), and distilled water were refluxed for fifteen minutes. The nitro compound (1.0 equiv.) was added and the resulting reaction mixture was allowed to stir at reflux. When TLC showed that the reaction had stopped the mixture was neutralized by drop wise addition of a 5% aqueous solution of sodium bicarbonate and it was filtered through Celite. The filtrate was washed thrice with ethyl acetate. The combined organic layers were washed once with brine and once with a 5% aqueous solution of hydrochloric acid. The combined water layers were neutralized with 20% aqueous sodium hydroxide and extracted thrice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and the solvent removed in vacuo. The pure product was obtained using column chromatography in ethyl acetate and hexanes but sometimes the product was kept crude. The purity of the product was determined using 1H- NMR.; 4-Chloro-2-methoxy-phenylamine was obtained from Ferrum (2.23 g, 40 mmol) ammonium chloride (278 mg, 5.2 mmol), water (48 mL) and 5-chloro-2-nitroanisole (1.5 g, 8.0 mmol) as a crude mixture, which was a dark purple oil (1.15g, 91 %). The reaction was complete in 1.5 hours. 1H NMR (300 MHz, CDCl3): delta(ppm) 6.78(m, 2H), 6.65(d, IH), 3.86(s, 3H). EPO <DP n="81"/>4-Chloro-2-methoxy-phenylamine was obtained from Ferrum (4.47 g, 80.0 mmol) ammonium chloride (556 mg, 10.4 mmol), water (80 mL) and 5-chloro-2-nitroanisole (3.0 g, 16.0 mmol) as a crude mixture, which was a dark purple oil (2.35g, 93%). The reaction was complete in 2 hours. No 1H-NMR was performed.
86%	With iron; ammonium chloride; In water; for 1.5h;Reflux;	3 g of iron powder and 375 mg of ammonium chloride solids were heated to reflux in 50 ml of water for 15 minutes, then 2 g of 4-chloro-2-methoxynitrobenzene was added, refluxed for 1.5 hours, and cooled to room temperature. pH was adjusted to neutral with a saturated aqueous solution of sodium bicarbonate. The mixture was filtered through diatomite, and the filtrate was extracted with ethyl acetate and dried over anhydrous sodium sulfate to obtain 1.45 g of product, yield 86%.
76%	With 5%-palladium/activated carbon; hydrogen; In methanol; for 72h;	A. A suspension of 5-chloro-2-nitroanisole (7s) (2.67 g, 14.2 mmol) and 5% Pt/C (200 nig) in methanol (60 niL) was placed under a hydrogen gas atmosphere and stirred 3 days. The suspension was filtered through diatoniaceous earth and concentrated. Purification by column chromatography (40 g), eluting with 15 to 30% EA/hexanes, gave compound 7b (1.69 g, 76%). 1H NMR (CHLOROFORM-d) delta: 6.70 - 6.83 (m, 2H), 6.58 - 6.64 (m, 1H), 3.84 (s, 3H), 3.76 (br. s., 2H). ESI-MS (m/z): Calcd. for C7H8ClNO: 158.0 (M+1); found: 158.0.

69.5%	With hydrogen;nickel; In tetrahydrofuran; at 20℃;	5-Chlor-2-nitroanisol in THF are hydrogenated in the presence of H2 and Raney nickel at room temperature overnight. The catalyst is separated by filtration and the filtrate evaporated to dryness. The residue is purified by chromatography (35 g silica gel, eluent : DICHLOROMETHANE : methanol = 99 : 1). Yield : 69.5 %, brown oil
65%		A mixture of 4-chloro-2-methoxy-l -nitrobenzene (938 mg, 5.0 mmol), tin(II) chloride dihydrate (3.38 g, 15 mmol) and EtOH (25 mL) was heated at reflux for 18 h. After cooling to rt, NaOH (aq, 4M, 50 mL) was added. The mixture was extracted with Et2O (3x20 mL) and the combined extracts dried (Na2SO4) and concentrated. Purification by chromatography gave the title compound (511 mg, 65%) as a red oil which solidified on standing.1H NMR (DMSO-J6, 400 MHz) delta 6.78 (IH, d), 6.67 (IH, dd), 6.57 (IH, d), 4.82 (2H, S)3 3.75 (3H, s).
64%		Preparation 91; 4-Chloro-2-methoxy-phenvlamine; To a suspension of 5-chloro-2-nitroanisole (10g, 53mmol) and potassium bicarbonate (28g, 280mol) in methanol (150mL) and water (150mL) was added sodium dithionite (28g, 159 mmol). The mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was acidified to pH1 with concentrated hydrochloric acid and the resulting brown suspension was heated for 2 hours at 60C before the solvent was evaporated under reduced pressure. The residual aqueous solution was washed with ethyl acetate, basified with sodium hydroxide pellets and re-extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title compound in 64% yield (5.35g). 'H NMR (DMSO-D6, 400MHz) zu : 3.66 (s, 3H), 4.76 (bs, 2H), 6.52 (m, 1H), 6.65 (m, 1 H), 6.79 (m, 1 H)
64%	With sodium dithionite; potassium hydrogencarbonate; In methanol; water; at 20℃; for 2h;	Preparation 37; (4-Chloro-2-methoxyphenyl)amine; Sodium dithionite (28g, 159mmol) was added portionwise to a mixture of 5-chloro-2-nitroanisole (1Og, 53mmol) and potassium hydrogen carbonate (28g, 275.6mmol) in methanol (15OmL) and water (15OmL) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then acidified with concentrated hydrochloric acid and the mixture was heated at 6O0C for 2 hours. The reaction mixture was then concentrated in vacuo and the aqueous residue was washed with ethyl acetate. The aqueous solution was then basified with sodium hydroxide and extracted with ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound in 64% yield, 5.35g. 1HNMR(400MHz, DMSO-Cl6) delta: 3.74(s, 3H), 4.78(s, 2H), 6.58(m, 1 H), 6.65(m, 1 H), 6.77(s, 1 H)
		REFERENTIAL EXAMPLE 363 4-Chloro-2-methoxyaniline The title compound was obtained from 5-chloro-2-nitroanisole in a similar manner to the process described in Referential Example 361. 1H-NMR (CDCl3) delta: 3.65-3.95(2H,br), 3.87(3H,s), 6.61(1H,d,J=8.8 Hz), 6.74-6.78(2H,m).
	With 2 wt% Pd/C; hydrogen; at 120℃; under 7500.75 Torr;	Examples 27 to 34 investigated the effect of carbon-supported large-particle palladium catalysts on the synthesis of halogenated aromatic amines by solvent-free hydrogenation of different halogenated aromatic nitro compounds. In a 500 ml reactor, 200 g of different halogenated aromatic nitro compounds were added, 2 g of a 2 wt% palladium catalyst containing a large particle size in Example 5, shutting down the reactor; first with nitrogen replacement reactor inside the air three times, and then replaced with hydrogen three times, And then heated to 120 C, and the hydrogen pressure rose to 1MPa, open stirring to 1000r/min; to maintain the reaction temperature and pressure until the end of the reaction; cooling cooling, remove the reactor liquid, filter separation The catalyst was used and the water in the filtrate was separated by phase separation to give the desired product Halogenated aromatic amine. The reaction product was analyzed by gas chromatography. The results are shown in Table 4.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3864 - 3867
[2]ChemMedChem,2014,vol. 9,p. 962 - 972
[3]Patent: WO2006/71730,2006,A1 .Location in patent: Page/Page column 79; 80
[4]Patent: EP3486244,2019,A1 .Location in patent: Paragraph 0374; 0375
[5]Patent: WO2014/28805,2014,A1 .Location in patent: Page/Page column 65
[6]Patent: WO2004/37789,2004,A2 .Location in patent: Page 312
[7]Patent: WO2007/51982,2007,A1 .Location in patent: Page/Page column 39
[8]Patent: WO2005/82866,2005,A2 .Location in patent: Page/Page column 92
[9]Patent: WO2006/100588,2006,A1 .Location in patent: Page/Page column 54
[10]Journal of the Chemical Society,1926,p. 543
Journal of the Chemical Society,1928,p. 628
[11]Collection of Czechoslovak Chemical Communications,1978,vol. 43,p. 1747 - 1759
[12]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 619 - 622
[13]Patent: US2005/20645,2005,A1
[14]Patent: CN104163764,2016,B .Location in patent: Paragraph 0050-0053

4
[ 611-07-4 ]
[ 77-78-1 ]
[ 6627-53-8 ]

Reference： [1]Journal of the Chemical Society,1926,p. 543
Journal of the Chemical Society,1928,p. 628

5
[ 6627-53-8 ]
[ 789-24-2 ]
[ 124233-19-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium hydroxide; tetrabutylammomium bromide In dimethyl sulfoxide at 45 - 50℃; for 4h;

Reference： [1]Wojciechowski, Krzysztof [Bulletin of the Polish Academy of Sciences: Chemistry, 1988, vol. 36, # 5-6, p. 235 - 241]

6
[ 6627-53-8 ]
[ 3598-13-8 ]
[ 111795-91-6 ]

Reference： [1]Liebigs Annalen der Chemie,1988,p. 203 - 208
[2]Synlett,2010,p. 2435 - 2438

7
[ 124-41-4 ]
[ 610-40-2 ]
[ 89-21-4 ]
[ 6627-53-8 ]

Yield	Reaction Conditions	Operation in experiment
55%	In methanol for 0.5h;
1: 82 % Chromat. 2: 18 % Chromat.	In methanol for 0.5h;

Reference： [1]Varenikova, S. F.; Nekhoroshev, A. A.; Sevbo, D. P. [Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, p. 1651 - 1652][Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 8, p. 1807 - 1808]
[2]Varenikova, S. F.; Nekhoroshev, A. A.; Sevbo, D. P. [Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, p. 1651 - 1652][Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 8, p. 1807 - 1808]

8
[ 6627-53-8 ]
[ 120-83-2 ]
[ 32861-85-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate In dimethyl sulfoxide at 150℃; for 5h;
	With potassium fluoride In sulfolane	1 Preparation of 2,4-dichloro-3'-methoxy-4'-nitrodiphenyl ether EXAMPLE 1 Preparation of 2,4-dichloro-3'-methoxy-4'-nitrodiphenyl ether A mixture of 48 g. of 5-chloro-2-nitroanisole, 43.2 g. of 2,4-dichlorophenol, and 29.8 g. of potassium fluoride dissolved in 121 g. of sulfolane is heated at 160°-180° C. overnight. The cooled reaction mixture is washed free of sulfolane with water and the residue is distilled to give a fraction with a boiling point of 130°-140° C. (0.3 mm). This fraction is dissolved in hot hexane and on cooling 25 g. (33%) of 2,4-dichloro-3'-methoxy-4'-nitrodiphenyl ether (m.p. 109°-110° C.) is isolated by filtration.

Reference： [1]Schoenowsky; Bieringer [Zeitschrift fur Naturforschung, Teil B: Anorganische Chemie, Organische Chemie, 1980, vol. 35, # 7, p. 902 - 908]
[2]Current Patent Assignee: DOW INC - US4039588, 1977, A

9
[ 611-07-4 ]
[ 74-88-4 ]
[ 6627-53-8 ]

Yield	Reaction Conditions	Operation in experiment
30 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	4-Chloro-2-methoxy-1-nitrobenzene To a solution of <strong>[611-07-4]5-chloro-2-nitrophenol</strong> (40 g, 0.23 mol) in DMF (200 mL), K2CO3 (47.6 g, 0.345 mol) and iodomethane (49 g, 0.345 mol) were added and the resulting mixture was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether) to afford the desired product (30 g, 70% yield).
30 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of <strong>[611-07-4]5-chloro-2-nitrophenol</strong> (40 g, 0.23 mol) in DMF (200mL), K2C03 (47.6 g, 0.345 mol) and iodomethane (49 g, 0.345 mol) were added and the resulting mixture was stirred at room temperature for 1 6h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried overMgSO, filtered and concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (petroleum ether) to afford the desired product (30 g, 70% yield).

Reference： [1]Liebigs Annalen der Chemie,1988,p. 203 - 208
[2]Patent: US2014/288045,2014,A1 .Location in patent: Paragraph 0461
[3]Patent: WO2016/44772,2016,A1 .Location in patent: Paragraph 323

10
[ 6627-53-8 ]
[ 7664-41-7 ]
[ 16292-88-9 ]

Reference： [1]Patent: US2048790,1933,

11
[ 6627-53-8 ]
[ 73183-34-3 ]
[ 755026-96-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; potassium acetate; tricyclohexylphosphine In 1,4-dioxane at 90℃; for 16h; Inert atmosphere;	1 Synthesis of 315 Synthesis of 315 A mixture of 313 (18.76 g, 0.1 mol), 314 (27.93 g, 0.11 mol), potassium acetate (14.72 g, 0.15ml), Pd2(dba)3 (2.75g, 3 mmol), tricyclohexylphosphine (2.02 g, 7.2 mmol) and 1,4-dioxane (200 ml) was stirred under an argon atmosphere at 90°C for 16 hours. The reaction solution was allowed to return to room temperature and poured into ethyl acetate-water, and then the solution was extracted with ethyl acetate. The extraction liquid was washed with saturated saline and dried, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting solvent: n-hexane → n-hexane/ethyl acetate = 19/1, 9/1, 6/1, 4/1) to obtain 315 (26.74 g, 96%) as a pale yellow solid. APCI-MS m/z 280[M+H]+
61%	With potassium acetate; tricyclohexylphosphine In 1,4-dioxane at 85℃; for 20h;
53.77%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; potassium acetate; tricyclohexylphosphine In 1,4-dioxane at 85℃; for 3h; Inert atmosphere;	142 Synthesis of compound 142.1 To a solution of 4-chloro-2-methoxy-1-nitrobenzene(15g, 79.97mmol, 1.Oeq), in 1,4-dioxane (l5OmL) was added Bis Pinacolatodiboron (30.56g,12.O3mmol, 1.5eq). The reaction mixture was degassed by argon for 30 mi Pd2(dba)3 (7.3g,8.O2mmol, 0.leq), potassium acetate (2.6g, 26.47mmol, 3.3eq), Tricyclohexylphosphine(4.5g,16.O4mmol, 0.2eq) were added into reaction mixture and again degassed by argon for 30 mm.Further reaction mixture was stirred at 85°C for 3h. After completion of reaction, water was addedto reaction mixture and extracted with ethyl acetate. Organic layers were combined, dried overNa2SO4 and concentrated in vacuo to obtain crude product. This was purified by column chromatography and compound was eluted in 20% ethyl acetate in hexane to obtain pure 142.1 (12g, 53.77 %). MS(ES): m/z 280.10 [M+H]t

Reference： [1]Current Patent Assignee: GENERAL ELECTRIC CO - EP2634177, 2013, A1 Location in patent: Paragraph 0462; 0463
[2]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]
[3]Current Patent Assignee: NIMBUS THERAPEUTICS INC - WO2018/75937, 2018, A1 Location in patent: Paragraph 00754; 00755

12
[ 6627-53-8 ]
[ 128796-39-4 ]
[ 858105-68-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 3h;	16.a a) 3-Methoxy-4-nitro-4'-(trifluoromethyl)biphenylA mixture of 4-chloro-2-methoxy-1 -nitrobenzene (6.76 g, 36.04 mmol), 4- (trifluoromethyl)benzeneboronic acid (10.27 g, 54.06 mmol), tetrakis(triphenylphosphine) palladium (0) (2.08 g, 1.802 mmol), and 2M aqueous potassium carbonate (100 ml_, 200.0 mmol) in dimethylformamide (100 mL) was heated for 3.0 hours at 1000C. The reaction was cooled and filtered through Celite. The filtrate was diluted with ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), and purified by flash chromatography on silica gel(9:1 hexanes: EtOAc) give the title compound (9.37 g, 88%) as a pale yellow solid. MS(ES+) m/e 298 [M+H]+.
42%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 17h;

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/113432, 2006, A2 Location in patent: Page/Page column 47
[2]Parrish, Cynthia A.; Adams, Nicholas D.; Auger, Kurt R.; Burgess, Joelle L.; Carson, Jeffrey D.; Chaudhari, Amita M.; Copeland, Robert A.; Diamond, Melody A.; Donatelli, Carla A.; Duffy, Kevin J.; Faucette, Leo F.; Finer, Jeffrey T.; Huffman, William F.; Hugger, Erin D.; Jackson, Jeffrey R.; Knight, Steven D.; Luo, Lusong; Moore, Michael L.; Newlander, Ken A.; Ridgers, Lance H.; Sakowicz, Roman; Shaw, Antony N.; Sung, Chiu-Mei M.; Sutton, David; Wood, Kenneth W.; Zhang, Shu-Yun; Zimmerman, Michael N.; Dhanak, Dashyant [Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4939 - 4952]

13
[ 6627-53-8 ]
[ 755027-09-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: 78 percent / Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

14
[ 6627-53-8 ]
[ 755027-44-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: 78 percent / Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: LiOH*H₂O / methanol / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

15
[ 6627-53-8 ]
2-[3-(3-methoxy-4-nitrophenyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-8-yl]-N,N-dimethylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: 78 percent / Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: LiOH*H₂O / methanol / Heating 4: 62 mg / HATU; Et₃N / dimethylformamide

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

16
[ 6627-53-8 ]
2-[3-(3-methoxy-4-nitro-phenyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-8-yl]N[4-(4-morpholinyl)phenyl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: 78 percent / Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: LiOH*H₂O / methanol / Heating 4: HATU; Et₃N / dimethylformamide

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

17
[ 6627-53-8 ]
[ 755030-88-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

18
[ 6627-53-8 ]
[ 755030-90-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: LiOH*H₂O / methanol / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

19
[ 6627-53-8 ]
2-[3-(3-methoxy-4-nitrophenyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-8-yl]-2-methylN(4-morpholin-4-ylphenyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: LiOH*H₂O / methanol / Heating 4: HATU; Et₃N / dimethylformamide

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

20
[ 6627-53-8 ]
[ 755029-56-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

21
[ 6627-53-8 ]
[ 755029-58-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: LiOH*H₂O / methanol / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

22
[ 6627-53-8 ]
3-[3-(3-methoxy-4-nitrophenyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-8-yl]-N,N-dimethylpropanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: LiOH*H₂O / methanol / Heating 4: HATU; Et₃N / dimethylformamide

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

23
[ 6627-53-8 ]
3-[3-(3-methoxy-4-nitrophenyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-8-yl]N(4-morpholin-4-ylphenyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: LiOH*H₂O / methanol / Heating 4: HATU; Et₃N / dimethylformamide

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

24
[ 6627-53-8 ]
methyl [3-(3-methoxy-4-nitrophenyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-7-yl]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

25
[ 6627-53-8 ]
[3-(3-methoxy-4-nitrophenyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-7-yl]acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: LiOH*H₂O / methanol / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

26
[ 6627-53-8 ]
2-[3-(3-methoxy-4-nitrophenyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-7-yl]-N,N-dimethylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: LiOH*H₂O / methanol / Heating 4: HATU; Et₃N / dimethylformamide

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

27
[ 6627-53-8 ]
C₂₅H₂₃N₃O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

28
[ 6627-53-8 ]
[ 755031-30-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: LiOH*H₂O / methanol / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

29
[ 6627-53-8 ]
2-[3-(3-methoxy-4-nitrophenyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-7-yl]-2-methylN(4-morpholin-4-ylphenyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: LiOH*H₂O / methanol / Heating 4: HATU; Et₃N / dimethylformamide

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

30
[ 6627-53-8 ]
C₂₁H₁₇N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

31
[ 6627-53-8 ]
C₂₃H₁₈N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

32
[ 6627-53-8 ]
[ 755027-14-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: 76 percent / CsF / Pd(PPh₃)4 / 1,2-dimethoxy-ethane; methanol / 16 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

33
[ 6627-53-8 ]
C₂₀H₁₇N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: 76 percent / CsF / Pd(PPh₃)4 / 1,2-dimethoxy-ethane; methanol / 16 h / Heating 3: H₂ / Pd/C / methanol / 20 °C

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

34
[ 6627-53-8 ]
3-(3-methoxy-4-nitrophenyl)-7-morpholin-4-yl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: 52 percent / Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

35
[ 6627-53-8 ]
3-(3-methoxy-4-nitrophenyl)-9-(methoxymethoxy)-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

36
[ 6627-53-8 ]
C₂₀H₁₅N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: 3 mg / aq. HCl / tetrahydrofuran; methanol / 0.5 h / 70 °C

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

37
[ 6627-53-8 ]
8-hydroxy-3-(3-methoxy-4-nitrophenyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

38
[ 6627-53-8 ]
8-methoxy-3-(3-methoxy-4-nitrophenyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

39
[ 6627-53-8 ]
7-amino-3-(3-methoxy-4-nitrophenyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

40
[ 6627-53-8 ]
C₂₁H₁₇N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

41
[ 6627-53-8 ]
[ 949570-64-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

42
[ 6627-53-8 ]
[ 949570-80-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: 65 mg / aq. HCl / tetrahydrofuran; methanol / 20 °C

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

43
[ 6627-53-8 ]
C₂₆H₂₀N₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: 65 mg / aq. HCl / tetrahydrofuran; methanol / 20 °C 4: K₂CO₃ / dimethylformamide / 50 °C

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

44
[ 6627-53-8 ]
[ 755027-95-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

45
[ 6627-53-8 ]
[ 755028-57-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: 68 percent / pyridine / 20 °C

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

46
[ 6627-53-8 ]
8-(1,1-dioxidoisothiazolidin-2-yl)-3-(3-methoxy-4-nitrophenyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 61 percent / PCy₃; KOAc / Pd₂(dba)3 / dioxane / 20 h / 85 °C 2: Cy-MAP; CsF / Pd(OAc)2 / 1,2-dimethoxy-ethane; methanol / 12 h / Heating 3: 68 percent / pyridine / 20 °C 4: 72 percent / sodium ethoxide / ethanol / 2 h / Heating

Reference： [1]Wang, Le; Sullivan, Gerard M.; Hexamer, Laura A.; Hasvold, Lisa A.; Thalji, Reema; Przytulinska, Magdalena; Tao, Zhi-Fu; Li, Gaoquan; Chen, Zehan; Xiao, Zhan; Gu, Wen-Zhen; Xue, John; Bui, Mai-Ha; Merta, Philip; Kovar, Peter; Bouska, Jennifer J.; Zhang, Haiying; Park, Chang; Stewart, Kent D.; Sham, Hing L.; Sowin, Thomas J.; Rosenberg, Saul H.; Lin, Nan-Horng [Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4162 - 4176]

47
[ 6627-53-8 ]
[ 791594-24-6 ]

Yield	Reaction Conditions	Operation in experiment
48%	Stage #1: methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate With potassium acetate; bis(pinacol)diborane In DMF (N,N-dimethyl-formamide) at 80℃; for 3.5h; Stage #2: 1-chloro-3-methoxy-4-nitrobenzene With caesium carbonate In DMF (N,N-dimethyl-formamide) at 20 - 80℃; for 16h; Stage #3: With water In DMF (N,N-dimethyl-formamide) at 20℃;	1 Step 1. A suspension of methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate (200 mg, 0.67 mmol), bis(pinacolato)diboron (170 mg, 0.67 mmol), potassium acetate (197 mg, 2.01 mmol), and palladium acetate (5 mg, 0.02 mmol) in N,N-dimethylformamide (4.0 mL) was degassed by bubbling a flow of argon for 30 minutes. The reaction mixture was then heated at 80° C. for 3 h. After the mixture was cooled to rt, 5-chloro-2-nitroanisole (125 mg, 0.67 mmol), tetrakis(triphenyl-phosphine)palladium(0) (23 mg, 0.02 mmol), and cesium carbonate (327 mg, 1.0 mmol) were added and the reaction mixture was heated at 80° C. for 16 h. The mixture was then cooled to rt, and water was added. The aqueous layer was extracted with ethyl acetate and the combined organic phases were dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the residue was purified by flash chromatography (Biotage Flash 40M, 1:3 ethyl acetate/hexane) to afford methyl 4-(3'-methoxy4'-nitro-1,1'-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (120 mg, 48%). LC-MS ret. time 3.38 min, m/z 371.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.19 (s, 6H), 3.36 (s, 2H), 3.51 (s, 3H), 4.02 (s, 3H), 7.21-7.24 (m, 2H), 7.64-7.69 (m, 2H), 7.93 (d, 1H), 8.00-8.04 (m, 2H).

Reference： [1]Current Patent Assignee: BAYER AG - US2004/224997, 2004, A1 Location in patent: Page 27

48
[ 6627-53-8 ]
[ 109-89-7 ]
[ 59820-49-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 200℃; for 0.25h; Microwave heating;	16.A 5-Diethylamino-2-nitro-phenol EXAMPLE 16A 5-Diethylamino-2-nitro-phenol A mixture of 5-chloro-2-nitroanisole (375 mg, 2.0 mmol), N,N-diethylamine (302 μL, 3.0 mmol), diisopropylethylamine (523 uL, 3.0 mmol) and DMF (2 mL) in a sealed tube was heated in a microwave oven at 200° C. for 15 minutes. It was partitioned between ethyl acetate and water (40 mL, 1:1). The organic phase was washed with brine (*3), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel with hexane/ethyl acetate (4/1) to provide the titled compound (50 mg). 1H NMR (300 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.86 (d, J=9.8 Hz, 1H), 6.45 (dd, J, =2.7 Hz, J2=9.8 Hz, 1H), 6.17 (d, J=2.7 Hz, 1H), 3.46 (q, J=7.1 Hz, 4H), 1.13 (t, J=71 Hz, 6H); MS (ESI(+)) m/e 211 (M+H)+.

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC - US2006/89398, 2006, A1 Location in patent: Page/Page column 14; 15

49
tin(II)chloride dihydrate [ No CAS ]
aqueous Na₂ CO₃ [ No CAS ]
[ 6627-53-8 ]
[ 3282-30-2 ]
[ 113137-29-4 ]

Yield	Reaction Conditions	Operation in experiment
4.68 g (97%)	With hydrogenchloride; triethylamine In ethanol-tetrahydrofuran; ethanol; dichloromethane	1.A Part A Part A Preparation of 4'-Chloro-2'-methoxy-2,2-dimethylpropionanilide A stirred solution of 22.6 g (100 mmol) of stannous chloride dihydrate in 40 mL of absolute ethanol was heated to reflux and treated with 3.75 g (20 mmol) of 5-chloro-2-nitroanisole in 20 mL of 1:1 ethanol-tetrahydrofuran over 3 min. Stirring at reflux for an additional 10 minutes gave a clear solution which was then cooled to 0° C. The mixture was treated with aqueous Na2 CO3 until a pH of 8-9 was reached. The colloidal suspension was extracted twice with ethyl acetate, and the combined organic extracts were washed with saturated NaHCO3 then brine. The solution was dried (MgSO4) and concentrated under reduced pressure. The crude oil was dissolved in 40 mL of CH2 Cl2 and cooled to 0° C. The solution was treated with 4.2 mL (30 mmol) of triethylamine followed by 2.8 mL (23 mmol) of pivaloyl chloride. After stirring 2 h at 0° C. the mixture was quenched with 0.5N HCl, and the phases were separated. The aqueous phase was extracted with 100 mL of 1:1 ether-hexanes, and the combined organic extracts were washed sequentially with 0.1N HCl, dilute K2 CO3, water, and brine. The solution was dried (MgSO4) and concentrated under reduced pressure to give 4.68 g (97%) of 4'-chloro-2'-methoxy-2,2-dimethylpropionanilide as an tan solid, mp 66°-69° C. 1 H NMR (300 MHz, CDCl3) δ8.36(d, 1H, J=8.8 Hz); 8.03(br. s, 1H); 6.94(dd, 1H, J=8.8, 2.2 Hz); 6.86(d, 1H, J=2.2 Hz); 3.90(s, 3H); 1.32(s, 9H). High resolution mass spec: calculated for C12 H17 NO2 Cl(M+H)+: 242.0948, found: 242.0943. Analysis calculated for C12 H16 NO2 Cl: C, 59.63; H, 6.67; N, 5.79; Cl, 14.67. Found: C, 59.73; H, 6.67; N, 5.57; Cl, 14.42.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US5874430, 1999, A

50
[ 6627-53-8 ]
[ 611-07-4 ]

Yield	Reaction Conditions	Operation in experiment
	With boron tribromide; In dichloromethane;	Step A Synthesis of 5-chloro-2-nitrophenol A 1M solution of boron tribromide in methylene chloride (400 mL, 0.40 mole) was cooled to -20 C. A solution of 37.5 g (0.20 mole) of 5-chloro-2-nitroanisole in 200 mL of methylene chloride was added slowly to the first solution. Upon completion of addition, the mixture was allowed to warm to ambient temperature at which it stirred for about 16 hours. At the conclusion of this period the reaction mixture was poured into ice water. The organic layer was separated from the aqueous layer and was evaporated under reduced pressure, leaving 31.40 g of 5-chloro-2-nitrophenol as a solid residue, m.p. 38-39 C.

Reference： [1]Patent: US5521147,1996,A

51
[ 6627-53-8 ]
[ 106-48-9 ]
[ 70870-44-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide In dimethyl sulfoxide	1.a EXAMPLE 1 (a) 169.8 g of 2-nitro-5-chloroanisole and 128.6 g of p-chlorophenol are dissolved in 700 ml of dimethyl sulfoxide. With stirring, 117 g of 50% potassium hydroxide solution are added dropwise at room temperature to the dimethyl sulfoxide solution in the course of 1/2 hour, whereupon the temperature of the mixture rises to 32° C. Stirring is continued for 1 to 2 hours, then the temperature is slowly raised to 90° C. and kept thereat for 2 hours. The reaction mixture is then stirred for 15 hours at 105° C., cooled and poured into ice-water. The precipitated crystal slurry is collected by suction and washed neutral, affording 242.4 g of brown crystals with a melting point of 69°-85° C. Recrystallisation from alcohol yields 220 g of 2-nitro-5-(4-chlorophenoxy)-anisole in the form of yellow crystals with a melting point of 88°-89° C.

Reference： [1]Current Patent Assignee: BASF SE - US4268693, 1981, A

52
tin(II)chloride dihydrate [ No CAS ]
[ 6627-53-8 ]
[ 3282-30-2 ]
[ 497-19-8 ]
[ 113137-29-4 ]

Yield	Reaction Conditions	Operation in experiment
4.68 g (97%)	With hydrogenchloride; triethylamine In ethanol-tetrahydrofuran; ethanol; dichloromethane	1.A Part A: Part A: Preparation of 4'-Chloro-2'-methoxy-2,2-dimethylpropionanilide A stirred solution of 22.6 g (100 mmol) of stannous chloride dihydrate in 40 mL of absolute ethanol was heated to reflux and treated with 3.75 g (20 mmol) of 5-chloro-2-nitroanisole in 20 mL of 1:1 ethanol-tetrahydrofuran over 3 min. Stirring at reflux for an additional 10 minutes gave a clear solution which was then cooled to 0°C. The mixture was treated with aqueous Na2CO3 until a pH of 8-9 was reached. The colloidal suspension was extracted twice with ethyl acetate, and the combined organic extracts were washed with saturated NaHCO3 then brine. The solution was dried (MgSO4) and concentrated under reduced pressure. The crude oil was dissolved in 40 mL of CH2Cl2 and cooled to 0°C. The solution was treated with 4.2 mL (30 mmol) of triethylamine followed by 2.8 mL (23 mmol) of pivaloyl chloride. After stirring 2h at 0°C the mixture was quenched with 0.5 N HCl, and the phases were separated. The aqueous phase was extracted with 100 mL of 1:1 ether-hexanes, and the combined organic extracts were washed sequentially with 0.1 N HCl, dilute K2CO3, water, and brine. The solution was dried (MgSO4) and concentrated under reduced pressure to give 4.68 g (97%) of 4'-chloro-2'-methoxy-2,2-dimethylpropionanilide as an tan solid, mp 66-69°C.1H NMR (300 MHz, CDCl3) δ 8.36(d, 1H, J = 8.8 Hz); 8.03(br. s, 1H); 6.94(dd, 1H, J = 8.8, 2.2 Hz); 6.86(d, 1H, J = 2.2 Hz); 3.90(s, 3H); 1.32(s, 9H). High resolution mass spec: calculated for C12H17NO2Cl (M + H)+: 242.0948, found: 242.0943. Analysis calculated for C12H16NO2Cl: C, 59.63; H, 6.67; N, 5.79; Cl, 14.67. Found: C, 59.73; H, 6.67; N, 5.57; Cl, 14.42.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - EP929533, 2003, B1

53
[ 6627-53-8 ]
[ 107-15-3 ]
N-(4-nitro-3-methoxyphenyl)-ethylenediamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one; ethanol at 110℃; for 24h;	13 Example 13 Synthesis of N-(2-aminoethyl)-N-(4-amino-3-methoxyphenyl)amine dihydrochloride (49) 5-Chloro-2-nitroanisole (0.2 mmol in 500 μL of NMP-EtOH), ethylenediamine (0.24 mmol in 500 μL of NMP), and diisopropylethylamine (0.48 mmol) were heated at 110° C. for 24 hours. The reaction medium was then cooled and concentrated under vacuum. The residue was taken up in 2 mL of ethanol, and cyclohexene (1 mL) was added, along with a suspension of 50 mg of 5% palladium-on-charcoal in 500 μL of ethanol. This mixture was heated at 80° C. for 3 hours. The reaction medium was then filtered and treated with hydrochloric ethanol solution. The solution was then concentrated to give the desired compound in dihydrochloride form.

Reference： [1]Current Patent Assignee: L'OREAL SA - US2006/26773, 2006, A1 Location in patent: Page/Page column 20

54
[ 6627-53-8 ]
[ 108-59-8 ]
[ 1028542-98-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: malonic acid dimethyl ester With sodium hydride In dimethyl sulfoxide at 20 - 100℃; Stage #2: 1-chloro-3-methoxy-4-nitrobenzene In dimethyl sulfoxide at 100℃; for 20h;	13 Description 13Dimethyl [3-(methyloxy)-4-nitrophenyl]propanedioateSodium hydride (60% in oil, 8.73g, 2.2eq) was washed with 40-60 petroleum ether (x2) then DMSO (225ml) was added followed by dimethylmalonate (25ml, 2.2eq) in portions. After addition the mixture was heated to 1000C for 30 minutes then cooled to room temperature overnight. The next day, 5-chloro-2-nitroanisole (18.61g, 1eq) was added and the solution heated to 1000C (internal). After 3 hours further sodium malonate (0.6eq) {dimethylmalonate (6.8ml) and sodium hydride (2.38g) in DMSO (60ml)} was added, plus further 5-chloro-2-nitroanisole (2.71g) and further dimethylmalonate (4ml). After 17 hours heating, the solution was cooled; acetic acid (18ml) added and then poured onto water (700ml) in portions. Extracted with diethyl ether/petroleum ether 40-60 (1 :1 , 4x140ml), then with DCM/cyclohexane (2:1). Organics combined and excess dimethyl malonate distilled off in vacuo to give a dark red oil (~30g). Purified by silica gel chromatography (DCM) to give oil (~20.4g) which was further purified twice by silica gel chromatography (CHCI3, then DCM) to give the title compound as a yellow solid (11.56g).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/61955, 2008, A1 Location in patent: Page/Page column 32

55
[ 680596-79-6 ]
[ 6627-53-8 ]
[ 1089280-36-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 80℃; for 16.0h;	To a stirred solution of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene (1.09 g, 4.13 mmol) in dioxane (17 mL) was added 5-chloro-2-nitroanisole (0.64 g, 3.44 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol) and 1.0 M Na2CO3 in H2O (10.32 mL, 10.32 mmol). The mixture was degassed by purging the reaction flask with vacuum/then N2 back-fill (5×). Under N2 the reaction was then heated to 80 C. and stirred overnight (approximately 16 h). The reaction was cooled to rt and diluted with EtOAc, then filtered through Celite, washing with EtOAc. The filtrate was concentrated under vacuum. The residue was taken up in EtOAc and H2O. The H2O layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step C (911 mg, 3.13 mmol, 91%) as an amber oil. MS (ESI): 292 [M+H]+.

Reference： [1]Patent: US2008/300242,2008,A1 .Location in patent: Page/Page column 102-103

56
[ 4318-42-7 ]
[ 6627-53-8 ]
[ 761440-36-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 5.25h;	Intermediate B46: 4-[4-(1 -methylethyl)-1 -piperazinyl]-2-(methyloxy)aniline; Step A/Intermediate B47: 1-(1-methylethyl)-4-[3-(methyloxy)-4- nitrophenyl]piperazine; To 4-chloro-2-(methyloxy)-1 -nitrobenzene (3.0 g, 16.0 mmol) in dioxane (75 mL) was added <strong>[4318-42-7]1-(1-methylethyl)piperazine</strong> (4.1 g, 32.0 mmol), XANTPHOS (1.4 g, 2.4 mmol), and Cs2CO3 (10.4 g, 32.0 mmol). The mixture was bubbled with N2 for 15 min prior to the addition of Pd2(dba)3 (1.5 g, 1.6 mmol). The reaction was stirred at 100 0C for 5 h. Following cooling to room temperature, the reaction mixture was diluted with ethyl acetate (150 mL) and water (100 mL). The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by silica gel chromatography to afford 1-(1-methylethyl)-4-[3-(methyloxy)-4-nitrophenyl]piperazine (4.0 g, 90percent yield). ESIMS (M+H)+ = 280.

Reference： [1]Patent: WO2009/20990,2009,A1 .Location in patent: Page/Page column 101-102

57
[ 6627-53-8 ]
[ 1692-15-5 ]
[ 103347-93-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 1-chloro-3-methoxy-4-nitrobenzene; 4-pyridylboronic acid In 1,4-dioxane for 0.25h; Stage #2: With sodium carbonate In 1,4-dioxane; water at 102℃; for 4h;	137.A A solution of 4-chloro-2-(methyloxy)-1-nitrobenzene (34.7 g, 184.8 mmol), PdCl2(PPh3)2 (6.5 g, 9.24 mmol) and 4-pyridylboronic acid (25.0 g, 203.2 mmol) in dioxane was deoxygenated by bubbling with N2(g) for ca 15 min. To this solution was added degassed 3.0 N Na2CO3(aq) (203 mL, 3.0 equiv.) and the resulting slurry was warmed to 102° C. for 4 h. The dioxane was removed under reduced pressure and the solids were dissolved in EtOAc and washed twice with brine. The organic layer was dried over Na2SO4, taken to a residue under reduced pressure, and the residue purified by trituration with diethyl ether to afford 4-[3-(methyloxy)-4-nitrophenyl]pyridine as a brown solid (34.0 g, 147.68 mmol, 80%) of sufficient purity for use in subsequent transformations. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64-8.73 (m, 2H), 8.00 (d, J=8.43 Hz, 1H), 7.78-7.85 (m, 2H), 7.67 (d, J=1.83 Hz, 1H), 7.51 (dd, J=8.43, 1.83 Hz, 1H), 4.03 (s, 3H).
66%	With sodium carbonate In 1,4-dioxane; water at 90℃; for 4h;	B25.A Intermediate B25: 4-[1 -(1 -methylethyl)-1 ,2,3,6-tetrahydro-4-pyridinyl]-2- (methyloxy)aniline; Step A/Intermediate B26: 4-[3-(methyloxy)-4-nitrophenyl]pyridine; Nitrogen was bubbled through dioxane (800 mL) for 1 h followed by the addition of 4- chloro-2-(methyloxy)-1-nitrobenzene (61 g, 0.33 mol), 3-pyridinylboronic acid (Boron Molecular, 40 g, 0.33 mmol), dichloro(triphenylphosphine)palladium (10 g, 14 mmol), and degassed aqueous 3 N Na2CO3 (325 mL, 975 mmol). The reaction mixture was stirred with a mechanical stirrer and heated at 90 0C for 3 h. The reaction was cooled and most of the dioxane was removed in vacuo. It was diluted with water and then extracted with Ethyl acetate. Combined organic phases were dried (Mg2SO4), filtered and concentrated. The resultant solid was washed with diethyl ether to afford 4-(3-methoxy-4-nitrophenyl)pyridine (50 g, 66% yield). 1 H NMR (400 MHz, DMSO- t/6) δ ppm 4.05 (s, 3 H), 7.53 (dd, J=QA, 1.8 Hz, 1 H), 7.69 (d, J=1.8 Hz, 1 H), 7.84 (d, J=6.2 Hz, 2 H), 8.02 (d, J=8.4 Hz, 1 H), 8.72 (d, J=6.2 Hz, 2 H). ESIMS (M+H)+ = 231.
66%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 125℃; for 0.666667h; Sealed tube; Microwave irradiation;	84.A 4-(3-methoxy-4-nitrophenyl)pyridine To a microwave vial was added 4-chloro-2-methoxy-l -nitrobenzene (580 mg, 3.09 mmol), bis(triphenylphosphine)palladium(II) chloride (43.4 mg, 0.062 mmol), pyridin-4-ylboronic acid (475 mg, 3.86 mmol) and Na2C03 (983 mg, 9.27 mmol) in DME (15 mL), ethanol (2 mL), and water (3 mL). The reaction vial was sealed and heated in a microwave for 40 min at 125 °C. The mixture was cooled to room temperature and concentrated under reduced pressure. Water (50 mL) was added and the mixture was extracted with EtOAc (120 mL). The organic layer was washed with water (3x70mL) followed by brine (70 mL). The solution was dried with Na2S04, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (DMC/EtOAc) to give 4-(3-methoxy-4-nitrophenyl)pyridine (471 mg, 2.025 mmol, 66 % yield) as a pale yellow solid. 1H NMR (500MHz, CHLOROFORM-d) δ 8.81 - 8.73 (m, 2H), 8.00 (d, J=8.8 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.31 - 7.29 (m, 2H), 4.08 (s, 3H); LC/MS (ESI) m/e 231.1 [(M+H)+, calcd for C12H11N203 231.1].

65%

With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,4-dioxane; water at 110℃; for 0.75h; Inert atmosphere; Microwave irradiation;

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2008/300242, 2008, A1 Location in patent: Page/Page column 141-142
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/20990, 2009, A1 Location in patent: Page/Page column 89-90
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2016/22312, 2016, A1 Location in patent: Page/Page column 163
[4]Watts, Ellen; Heidenreich, David; Tucker, Elizabeth; Raab, Monika; Strebhardt, Klaus; Chesler, Louis; Knapp, Stefan; Bellenie, Benjamin; Hoelder, Swen [Journal of Medicinal Chemistry, 2019, vol. 62, # 5, p. 2618 - 2637]

58
[ 6627-53-8 ]
tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate [ No CAS ]
[ 1089280-53-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 1-chloro-3-methoxy-4-nitrobenzene; tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate With sodium carbonate In 1,4-dioxane; water at 120℃; for 0.833333h; microwave irradiation; Stage #2: With hydrogen In 1,4-dioxane; ethanol; water	99.A 5-chloro-2-nitroanisole (0.094 g, 0.50 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (0.19 g, 0.60 mmol), Na2CO3 (0.16 g, 1.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.019 g, 0.030 mmol) in dioxane (3 mL) and H2O (1.5 mL) was degassed for 30 min. The mixture was heated at 120° C. for 20 min in the microwave. Upon completion by TLC, the reaction was placed under H2 (1 atm.). The mixture was transferred to a separate flask and diluted with EtOH and subsequently stirred under H2 (1 atm.) overnight. Upon completion by TLC, the reaction was filtered through Celite, washed with EtOAc, dried (MgSO4), concentrated and purified by flash chromatography to provide the title compound of step A (0.12 g, 0.40 mmol, 81%). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H), 1.52-1.64 (m, 2H), 1.79 (d, J=12.8 Hz, 2H), 2.54 (tt, J=12.1, 3.5 Hz, 1H), 2.77 (t, J=11.9 Hz, 2H), 3.65 (d, J=2.6 Hz, 1H), 3.70 (d, J=6.2 Hz, 1H), 3.83 (s, 3H), 4.22 (br. s., 2H), 6.60-6.66 (m, 3H).
	Multi-step reaction with 2 steps 1: sodium carbonate / bis-triphenylphosphine-palladium(II) chloride / 1,2-dimethoxyethane; water / 0.33 h / 130 °C / Irradiation with microwave 2: hydrogen / 5%-palladium/activated carbon / methanol / 20 - 50 °C / 3102.97 Torr

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2008/300242, 2008, A1 Location in patent: Page/Page column 109
[2]Current Patent Assignee: ABBVIE INC - WO2010/138576, 2010, A1

59
[ 350595-57-2 ]
[ 6627-53-8 ]
[ 1116229-31-2 ]

Yield	Reaction Conditions	Operation in experiment
43%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 12h;	Intermediate B67: 4-[(3S)-3-methyl-4-morpholinyl]-2-(methyloxy)aniline; Step A/Intermediate B68: (3S)-3-methyl-4-[3-(methyloxy)-4-nitrophenyl]morpholine; 4-chloro-2-(methyloxy)-1-nitrobenzene (6.71g, 29.7 mmol), <strong>[350595-57-2](3S)-3-methylmorpholine</strong> (Synthetech Inc., 2.0 g, 19.8 mmol), cesium carbonate (13.0 g, 40 mmol), Pd2dba3 <n="116"/>(1.83 g, 2.0 mmol), and XANTPHOS (1.73 g, 3.0 mmol) were added to degassed dioxane (200 mL) and heated to 1000C under a water cooled reflux condenser for 12 hours. The dioxane was removed under reduced pressure and the solids were partitioned between methylene chloride (500 mL) and water (500 mL). The organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and purified by chromatography on Sitheta2to give 4-[(3S)-3-methyl-4-morpholinyl]-2- (methyloxy)aniline as a yellow solid (2.46 g, 8.45 mmol, 43% yield). 1 H NMR (400 MHz, CDCI3) delta ppm 1.22 (dd, J=6.41 , 4.58 Hz, 3 H), 3.22 - 3.29 (m, J=12.11 , 8.03, 4.03, 4.03 Hz, 1 H), 3.31 - 3.37 (m, 1 H), 3.59 - 3.69 (m, 1 H), 3.78 (d, J=2.93 Hz, 2 H), 3.92 (d, J=4.21 Hz, 4 H), 4.02 (s, 1 H), 6.25 (s, 1 H), 6.32 - 6.39 (m, 1 H), 7.98 (dd, J=9.34, 4.21 Hz, 1 H).

Reference： [1]Patent: WO2009/20990,2009,A1 .Location in patent: Page/Page column 113-114

60
[ 6627-53-8 ]
[ 57260-71-6 ]
[ 1017782-79-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	With caesium carbonate In 1,4-dioxane at 100℃; for 12h;	B48.A Intermediate B48: 2-(methyloxy)-4-(4-propyl-1 -piperazinyl)aniline; Step A/Intermediate B49: 1 ,1-dimethylethyl 4-[3-(methyloxy)-4-nitrophenyl]-1- piperazinecarboxylate; 4-chloro-2-(methyloxy)-1 -nitrobenzene (1Og, 53.2 mmol, Aldrich), 1 ,1-dimethylethyl 1- piperazinecarboxylate (2Og, 107.5 mmol), cesium carbonate (35.Og, 107.5 mmol), Pd2dba3 (5g, 5.5 mmol), and XANTPHOS (4.62g, 8.0 mmol) were added to degassed dioxane (100 ml.) and heated to 100°C under a water cooled reflux condenser for 12 hours. The dioxane was removed under reduced pressure and the solids were partitioned between methylene chloride (500 ml.) and water (500 ml_). The organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and triturated with a methylene choride/hexanes mixture (15:85) to precipitate out analytically pure 1-dimethylethyl 4-[3-(methyloxy)-4-nitrophenyl]-1- piperazinecarboxylate as a yellow solid (13.2g, 39.2 mmol, 73% yield). 1 H NMR (400 MHz, CDCI3) δ ppm 1.49 (s, 9 H), 3.33 - 3.42 (m, 4 H), 3.62-3.64 (m, 4 H), 3.96 (s, 3 H), 6.39 (s, 1 H), 6.44 (dd, J=9.16, 2.56 Hz, 1 H), 8.01 (d, J=9.16 Hz, 1 H).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/20990, 2009, A1 Location in patent: Page/Page column 102-103

61
[ 6627-53-8 ]
[ 156-43-4 ]
[ 1264688-43-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: 1-chloro-3-methoxy-4-nitrobenzene; 4-Ethoxyaniline With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at -60℃; Stage #2: In N,N-dimethyl-formamide
	With potassium <i>tert</i>-butylate In tetrahydrofuran; N,N-dimethyl-formamide at -65℃; for 0.5h;

Reference： [1]Location in patent: experimental part Wrobel, Zbigniew; Kwast, Andrzej [Synthesis, 2010, # 22, p. 3865 - 3872]
[2]Wrobel, Zbigniew; Stachowska, Karolina; Kwast, Andrzej; Goscik, Agata; Krolikiewicz, Magdalena; Pawlowski, Robert; Turska, Izabela [Helvetica Chimica Acta, 2013, vol. 96, # 5, p. 956 - 968]

62
[ 6627-53-8 ]
tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate [ No CAS ]
[ 1233145-65-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium hydrogencarbonate In 1,4-dioxane; water at 80℃;
97%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water at 80℃; for 16h; Inert atmosphere;	1 Preparation of compound 1-g. 4-Nitrochlorobenzene (4.9 g, 25.9 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (8.0g, 25.9 mmol), potassium carbonate (8.28 g, 60 mmol) and tetrakis (triphenylphosphine) palladium (1.5 g, 1.3 mmol)were dissolved in dioxane (40 mL) and water (10 mL). The reaction mixturewas replaced with nitrogen three times toremove the oxygen inside the system and then heated at 80°C for 16 hours. The reaction mixture was cooled to roomtemperature, filtered through diatomite, and the filter cake was washed with ethyl acetate (50 mL 3 3). The combinedorganic phases were washed successively with water (20 mL 3 3) and brine (20 mL), dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel columnchromatography (petroleum ether: ethyl acetate = 10: 1) to deliver a yellow solid 1-g (8.5 g, yield: 97%).1H-NMR (400MHz, CDCl3) δ: 7.87 (d, J = 8.6Hz, 1H), 7.01 (m, 2H), 6.17 (s, 1H), 4.12 (m, 2H), 3.98 (s, 3H), 3.66 (m,2H), 2.53 (m, 2H), 1.50 (s, 9H) ppm
90%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium hydrogencarbonate In 1,4-dioxane; water at 80℃; Sealed tube;	1.1a Example 1. (±)-3,4-cis-l-(2-Methoxy-ethyl)-4-{3-methoxy-4-[7-(2-methoxy-phenyl)- pyrrolo [2, 1-f] [ 1 ,2,4] triazin-2-ylamino] -phenyl}-piperidin-3-ol la) 4-Chloro-2-methoxy-l-nitro-benzene (1.12 g, 5.96 mmol), 4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (1.84 g, 5.95 mmol), tetrakis(triphenylphosphine)palladium(0) (380 mg, 0.33 mmol), a 2 M solution of potassium bicarbonate in water (7.45 mL, 14.9 mmol), and 1,4-dioxane (18 mL) were combined in a sealed tube, and the mixture was stirred and heated at 80 °C overnight. HPLC indicated the complete conversion of the starting material. The product, 4-(3-methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester was isolated by flash chromatography (Silicagel, EtOAc/Hexanes 25 -50 %) in 90% yield. Id) 4-(3-methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester, Intermediate la, was converted to (±)-(3R,4S)-4-{3-methoxy-4-[7-(2-methoxy- phenyl)-pyrrolo[2, 1 -fj [ 1 ,2,4]triazin-2-ylamino]-phenyl} -piperidin-3-ol (Intermediate 1 d) as outlined in Scheme 1 and described in detail in US8,471,005 (Appl. WO2010071885). le) A mixture of (±)-(3R,4S)-4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,l- f][l,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-ol (Intermediate Id, prepared as described in US8,471,005 / Appl. WO2010071885; 60 mg, 0.13 mmol), l-bromo-2-methoxy-ethane, (26 mg, 0.19 mmol), and sodium bicarbonate (13.6 mg, 0.16 mmol) in acetonitrile (1.5 mL) was heated to reflux overnight, then the solvent was evaporated under vacuum and the title product was isolated by preparative reverse phase hplc (on Gilson) as a yellow foam (14.5 mg, 21.4% yield). 1H NMR (CDC13): 8.68 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.46 (br s, 1H), 7.42 (m, 1H), 7.12 (m, 1H), 7.06 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 4.1 Hz, 1H), 6.89 (s, 1H), 6.83 (d, J = 4.1 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 3.90 (br s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.54 (m, 2H), 3.36 (s, 3H), 3.13 (m, 1H), 3.06 (m, 1H), 2.64 (m, 4H), 2.35 (d, J = 11.4 Hz, 1H), 2.22 (br s, 2H), 1.68 (m, 1H); LC/MS (ESI+): 504.1 (M+H).

70%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In water; N,N-dimethyl-formamide at 90℃; for 16h; Inert atmosphere;	8 Preparation 8 tert-butyl 4- (3-methoxy-4-nitrophenyl) -3,6-dihydropyridine- 1 (2H) -carboxylate preparation Chloro-2-methoxy-1-nitrobenzene (8.0 g, 42.6 mmol)And tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6-dihydropyridine- -carboxylate (13.2 g, 42.6 mmol)Was dissolved in a mixed solvent of DMF (50 mL) and water (10 mL)To the system was added potassium carbonate (11.8 g, 85.3 mmol) and Pd (PPh3) 4 (986 mg, 0.85 mmol)The reaction was stirred at 90 & lt; 0 & gt; C for 16 hours under nitrogen.After completion of the reaction, water (100 mL) was added, followed by extraction with ethyl acetate (100 mL × 2)The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated.The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the title compound (10.0 g, yield 70.0%).
70%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In water; N,N-dimethyl-formamide at 90℃; for 16h; Inert atmosphere;	2 Preparation Example 2 Preparation of tert-butyl 4-(3-methoxy-4-nitrophenyl)-3,6-dihydropyridin-1(2H)-carboxylate (0408) 4-Chloro-2-methoxy-1-nitrobenzene (5.0 g, 26.7 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1 (2H)-carboxylat e (9.9 g, 32 mmol) were dissolved in a mixed solvent of N,N-dimethylformamide (50 mL) and water (10 mL), and sodium carbonate (5.66 g, 53.4 mmol) and Pd(dppf)Cl2 (978 mg, 1.3 mmol) were added. Under the protection of nitrogen gas, the reaction was carried out at 90° C. for 16 h. The resultant mixture was cooled to room temperature, and water (100 mL) and ethyl acetate (200 mL) were added, and the water phase and the organic phase were separated. The water phase was extracted with ethyl acetate (100 mL×2), and the organic phases were combined, washed with saturated saline solution, dried with anhydrous sodium sulfate, filtrated, and concentrated to get the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to get the title compound as a yellow powder (6.2 g, yield: 70%).
	With sodium carbonate In 1,2-dimethoxyethane; water at 130℃; for 0.333333h; Irradiation with microwave;	57A Into a 5 niL microwave tube was charged tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (0.247 g, 0.800 mmol), A- chloro-2-methoxy- 1 -nitrobenzene (0.100 g, 0.533 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.019 g, 0.027 mmol), sodium carbonate (0.113 g, 1.066 mmol) in water (0.889 ml) and dimethoxyethane (2.3 ml). The reaction mixture was heated at 130 0C for 20 minutes in a Biotage microwave reactor. The solids were filtered off and the filtrate was purified by reverse phase HPLC using 0.1% ammonium hydroxide. MS (DCI(+)) m/e 335.2 (M+H)+.

Reference： [1]Location in patent: experimental part Mesaros, Eugen F.; Thieu, Tho V.; Wells, Gregory J.; Zificsak, Craig A.; Wagner, Jason C.; Breslin, Henry J.; Tripathy, Rabindranath; Diebold, James L.; McHugh, Robert J.; Wohler, Ashley T.; Quail, Matthew R.; Wan, Weihua; Lu, Lihui; Huang, Zeqi; Albom, Mark S.; Angeles, Thelma S.; Wells-Knecht, Kevin J.; Aimone, Lisa D.; Cheng, Mangeng; Ator, Mark A.; Ott, Gregory R.; Dorsey, Bruce D. [Journal of Medicinal Chemistry, 2012, vol. 55, # 1, p. 115 - 125]
[2]Current Patent Assignee: GUANGZHOU MAXINOVEL PHARMACEUTICALS; GUANGZHOU MAXINOVEL PHARMACEUTICAL - EP3287463, 2018, A1 Location in patent: Paragraph 0104; 0107
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2014/193932, 2014, A1 Location in patent: Page/Page column 21; 22
[4]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - CN105884695, 2016, A Location in patent: Paragraph 0236; 0237; 0238
[5]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - US2017/112833, 2017, A1 Location in patent: Paragraph 0407-0408
[6]Current Patent Assignee: ABBVIE INC - WO2010/138576, 2010, A1 Location in patent: Page/Page column 100

63
[ 110166-26-2 ]
[ 6627-53-8 ]
[ 1296098-66-2 ]

Yield	Reaction Conditions	Operation in experiment
58%	With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 12h;

Reference： [1]Location in patent: experimental part Gellerman, Gary; Waintraub, Sagiv; Albeck, Amnon; Gaisin, Vladimir [European Journal of Organic Chemistry, 2011, # 22, p. 4176 - 4182]

64
[ 6627-53-8 ]
[ 62-53-3 ]
[ 1346682-80-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	Stage #1: 1-chloro-3-methoxy-4-nitrobenzene; aniline With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at -60℃; for 0.583333h; Stage #2: With water; ammonium chloride In N,N-dimethyl-formamide	Preparation of new N-aryl-2-nitrosoanilines 1. General procedure: Procedure A: To a cooled solution of t-BuOK (6 mmol, 672 mg) in DMF (12 mL) was added dropwise at -60 °C a solution of aniline 1 (2 mmol), then nitroarene 2 (2 mmol) in DMF (2 mL each). The mixture was stirred at this temperature for 20-60 min. The reaction mixture was then poured into a concentrated NH4Cl solution (ca. 50 mL) and extracted with AcOEt. The extract was washed thoroughly with water and brine, and dried with Na2SO4. After evaporation, the crude product was subjected to column chromatography (SiO2, hexane/AcOEt, hexane/CH2Cl2 or hexane/toluene).
	With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at -60℃; for 7h;

Reference： [1]Kwast, Andrzej; Stachowska, Karolina; Trawczyński, Adam; Wróbel, Zbigniew [Tetrahedron Letters, 2011, vol. 52, # 48, p. 6484 - 6488]
[2]Yang, Hongfen; Kundra, Shivani; Chojnacki, Michaelle; Liu, Ke; Fuse, Marisa A.; Abouelhassan, Yasmeen; Kallifidas, Dimitris; Zhang, Peilan; Huang, Guangtao; Jin, Shouguang; Ding, Yousong; Luesch, Hendrik; Rohde, Kyle H.; Dunman, Paul M.; Lemos, José A.; Huigens, Robert W. [Journal of Medicinal Chemistry, 2021, vol. 64, # 11, p. 7275 - 7295]

65
[ 6627-53-8 ]
[ 98-80-6 ]
[ 42271-42-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium methanolate; tetrabutylammomium bromide; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In methanol; toluene at 0 - 60℃; for 24h;	5.A A solution of potassium methoxyde (0.56 g, 7.98 mmol) in anhydrous methanol (5 mL) was added at 0° C. to a mixture of 5-chloro-2-nitroanisole (0.5 g, 2.66 mmol), phenylboronic acid (0.42 g, 3.44 mmol), bis(dibenzylideneacetone)palladium (47 mg, 0.082 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (35 mg, 0.082 mmol) and tetrabutylammonium bromide (86 mg, 0.267 mmol) in anhydrous toluene (20 mL). The reaction mixture was stirred at 60° C. for 24 hours, and then was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified on a silica gel plug (EtOAc /hexane, 20/80) to give 0.7 g of 3-methoxy-4-nitro-biphenyl as a yellow oil.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2012/15962, 2012, A1 Location in patent: Page/Page column 61

66
[ 6627-53-8 ]
[ 31682-65-2 ]
Ethyl hydrogen 3-methoxy-4-nitrophenylphosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	Stage #1: 1-chloro-3-methoxy-4-nitrobenzene; diethyl phosphite With potassium phosphate In N,N-dimethyl-formamide for 0.333333h; Inert atmosphere; Stage #2: With 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In N,N-dimethyl-formamide at 130℃; for 4h;	Intermediate 57 Ethyl hydrogen 3-methoxy-4-nitrophenylphosphonate 4-Chloro-2-methoxy-1-nitrobenzene (4.84 g, 25.8 mmol) and diethyl phosphonate (3.92 g, 28.4 mmol) were added in a 250 mL round-bottomed flask. DMF (100 mL) was added to give a yellow solution. Potassium phosphate (6.02 g, 28.4 mmol) and palladium (II) acetate (0.290 g, 1.29 mmol) were added. Nitrogen was bubbled through the solution for 20 min before xantphos (1.045 g, 1.81 mmol) was added. The reaction was heated to 130° C. and stirred at that temperature for 4 h. After it was cooled to RT, the solution was concentrated in vacuo to remove the solvent, and to the residue was added water (60 mL) and DCM (40 mL). After partition, the aqueous layer was washed with DCM (2×20 mL). The aqueous layer was acidified using 12 N HCl (10 mL), and DCM was added (50 mL). After partition and extraction with DCM (2×30 mL), the DCM solution was combined and concentrated to give the product without further purification (2.4 g, 36% yield).1H NMR (300 MHz, DMSO-d6) δ ppm 7.98 (d, 1H), 7.51 (d, 1H), 7.40 (m, 1H), 3.85-4.03 (m, 5H), 1.13-1.28 (m, 3H).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US2012/28924, 2012, A1 Location in patent: Page/Page column 36-37

67
[ 120347-74-2 ]
[ 6627-53-8 ]
[ 1383682-75-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-piperidylboronic acid; 1-chloro-3-methoxy-4-nitrobenzene With sodium carbonate In 1,4-dioxane at 80℃; for 16h; Inert atmosphere; Stage #2: With sodium carbonate In 1,4-dioxane at 85℃; for 4h;	4-chloro-2-methoxy-nitrobenzene (2.0 g, 9.6 mmol) is taken up in 40 ml. anhydrous dioxane in an argon atmosphere. 3-pyridineboric acid (1.77 g, 14.4 mmol) is added to this mixture, followed by degassed sodium carbonate solution (10 ml_, 3 M) and bis- triphenylphosphine-palladium (II) chloride (337 mg, 48 mmol). The reaction mixture is stirred for 16 h at 80°C under an argon atmosphere. After further addition of sodium carbonate (3.2 g) and 0.1 eq palladium catalyst the mixture is stirred again for 4 h at 85 °C. After cooling, the reaction mixture is poured onto water (100 ml_), extracted 3 x with ethyl acetate (20 im L aliquots), the combined organic phases are dried on magnesium sulphate and evaporated down in vacuo. Chromatographic purification through silica gel with cyclohexane/ethyl acetate yields the coupling product.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2012/85126, 2012, A1 Location in patent: Page/Page column 72

68
[ 6627-53-8 ]
[ 60-24-2 ]
[ 100777-49-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile Reflux;	2.j . 5-Chloro-2-nitroanisole (48.3 g, 0.25 mol) is dissolved in 300 ml of acetonitrile. A solution of 2- mercaptoethanol (17.8 ml, 0.25 mol) in 100 ml of acetonitrile and potassium carbonate (69.1 g, 0.5 mol) is added with stirring, and the mixture is stirred under reflux overnight. The reaction mixture is cooled, 500 ml of ice-water are added, and the mixture is then extracted twice with 400 ml of ethyl acetate. The organic phase is washed with 0.2 N NaOH solution and then with water, dried over magnesium sulfate, filtered and evaporated in a rotary evaporator. Crystallisation using diethyl ether gives beige crystals of compound 12.

Reference： [1]Current Patent Assignee: MERCK KGAA - US2012/202827, 2012, A1 Location in patent: Page/Page column 11-12

69
[ 454482-11-2 ]
[ 6627-53-8 ]
[ 1625678-62-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere;	Preparation of 2-methoxy-4-(i -methylpiperidin-4- yl)aniline (1 9b): A 25 mE glass microwave tube was charged with potassium phosphate tribasic (3.00 g, 13.05 mmol), 2-(dicyclohexylphosphino)-2?,4?,6?,-tri-isopropyl- 1,1 ?-biphenyl (Strem Chemicals, Newburyport, Mass., 83 mg, 0.174 mmol), tris(dibenzylideneacetone) dipalladium (0) (Strem Chemicals, Newburyport, Mass., 80mg, 0.O87mmol), 1-methyl- 1 ,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (Acros Organics, New Jersey, 971 mg, 4.35 mmol) followed by 5-chloro-2-nitroanisole (Sigma Aldrich, 816 mg, 4.35 mmol). The solids were purged with argon and treated with 1 ,4-dioxane (12 mE) and water (4 mE), scaled and heated at1100 C. in a heating block for 1 h. The reaction mixture was treated with 1 N NaOH and extracted with EtOAc (3x30 mE), dried over Mg504, filtered and concentrated. The crude resi41due was purified on the ISCO Combiflash RF (80 g Thomson SingleStep column, using a gradient of 0-20percent MeOH in DCM) affording 4-(3-methoxy-4-nitrophenyl)- 1-methyl-i ,2, 3,6-tetrahydropyridine (1 9a; 970 mg, 3.91 mmol, 90percent yield) as a rust-brown solid which crystallized upon standing. mlz (ESI, +ve ion) 249.1 (M+H). ?H NMR (400 MHz, CDC13) oe ppm 7.86 (1H, d, J=8.4 Hz), 6.99-7.08 (2H, m), 6.17-6.24 (1H, m), 3.97 (3H, s), 3.15 (2H, q, J=2.8 Hz), 2.65-2.74 (2H, m), 2.53-2.62 (2H, m), 2.38-2.46 (3H, m). In a 50 mE glass reactor, 4-(3-methoxy-4-nitrophenyl)- i-methyl-i ,2,3,6-tet- rahydropyridine (940 mg, 3.79 mmol) was treated with palladium hydroxide (20 wt percent Pd, dry basis, on wet carbon, degussa type elOl ne/w, 266 mg, 0.38 mmol) and anhydrous EtOH (20 mE). The reactor was purged with hydrogen (5x) and allowed to stir under 50 psi hydrogen at RT for 4 h. The reaction mixture was filtered through a 0.45 urn acrodisc to remove the catalyst residues washing with MeOH and concentrated to dryness under high vacuum affording 2-meth- oxy-4-(i-methylpiperidin-4-yl)aniline (19b; 830 mg, 3.77 mmol, 99percent yield) as a yellow crystalline solid. mlz (ESI, +ve ion) 221.0 (M+H). ?H NMR (400 MHz, CDC13) oe ppm 6.56-6.74 (3H, m), 3.76-3.89 (3H, m), 3.54-3.76 (2H, m),2.97 (2H, d, J=ii.2 Hz), 2.34-2.47 (1H, m), 2.23-2.34 (3H,1.95-2.12 (2H, m), 1.70-1.90 (4H, m).

Reference： [1]Patent: US2014/249131,2014,A1 .Location in patent: Paragraph 0265; 0266

70
[ 6627-53-8 ]
1-chloro-2-iodo-5-methoxy-4-nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With N-iodo-succinimide; trifluoromethylsulfonic anhydride; sulfuric acid at 20℃; for 1h;	1-Chloro-2-iodo-5-methoxy-4-nitrobenzene 1-Chloro-2-iodo-5-methoxy-4-nitrobenzene To a solution of H2SO4 (600 mL, 90%), trifluoromethanesulfonic anhydride (11.3 g, 0.04 mol) and NIS (49.68 g, 0.22 mol) were added and resulting mixture was stirred at room temperature for 1 h. To this mixture, 4-chloro-2-methoxy-1-nitrobenzene (69 g, 0.368 mol) was added quickly. The mixture was stirred for 1 h, and then NIS (33.12 g, 0.148 mol) was slowly added to the mixture. The mixture was stirred at room temperature for 1 h and then was poured into ice-water. The precipitate collected by filtration, rinsed with water, aqueous NaSO3 and NaHCO3 solutions, and then dried in vacuo to afford the desired product (113 g, 98% yield).

Reference： [1]Current Patent Assignee: ARAXES PHARMA LLC - US2014/288045, 2014, A1 Location in patent: Paragraph 0462

71
[ 6627-53-8 ]
[ 71597-85-8 ]
3'-methoxy-4'-nitro-[1,1'-biphenyl]-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With tetrabutylammomium bromide; palladium diacetate; sodium carbonate at 175℃; for 0.166667h; Microwave irradiation;	4.2.30 3′-Methoxy-4′-nitro-[1,1′-biphenyl]-4-ol (27d) A mixture of boronic acid (300mg, 2.18mmol), 4-chloro-2-methoxy-1-nitrobenzene (408mg, 2.18mmol), Pd(OAc)2 (5mg, 0.022mmol), TBAB (723mg, 2.18mmol) and 2M Na2CO3 (3.27mL, 6.54mmol) was irridated by microwave at 175°C for 10min. The reaction mixture was then extracted by ethyl acetate. The organic layer was collected, dried (over Na2SO4) and concentrated under reduced pressure. The brown residue was purified by column chromatography (SiO2, 10:1, EtOAc:Hexane) to afford desired product as a yellowish amorphous solid (95mg, 18%). 1H NMR (400MHz, Chloroform-d) δ 7.93 (d, J=8.5Hz, 1H), 7.48-7.42 (m, 2H), 7.19-7.11 (m, 2H), 6.95-6.87 (m, 2H), 4.00 (s, 3H). 13C NMR (126MHz, CDCl3) δ 156.80, 152.76, 146.98, 136.59, 129.71, 127.71, 125.69, 117.48, 115.07, 110.41, 55.59. Exact Mass, Calculated for C13H11NO4 (M-H): 244.0546; found (M-H): 244.0542.
18%	With tetrabutylammomium bromide; palladium diacetate; sodium carbonate In water at 175℃; for 0.166667h; Microwave irradiation;	2 3'-methoxy-4'-nitro-[1,1'-biphenyl]-4-ol (27d): 3'-methoxy-4'-nitro-[1,1'-biphenyl]-4-ol (27d): A mixture of boronic acid (300 mg, 2.18 mmol), 4-chloro-2-methoxy-1-nitrobenzene (408 mg, 2.18 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), TBAB (723 mg, 2.18 mmol) and 2M Na2CO3 (3.27 ml, 6.54 mmol) was irridated by microwave at 175o C for 10 min. The reaction mixture was then extracted by ethyl acetate. The organic layer was collected, dried (over Na2SO4) and concentrated under reduced pressure. The brown residue was purified by column chromatography (SiO2, 10:1, EtOAc:Hexane) to afford desired product as a yellowish amorphous solid (95 mg, 18 %). 1H NMR (400 MHz, chloroform-d) δ 7.93 (d, J = 8.5 Hz, 1H), 7.48- 7.42 (m, 2H), 7.19- 7.11 (m, 2H), 6.95- 6.87 (m, 2H), 4.00 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 156.80, 152.76, 146.98, 136.59, 129.71, 127.71, 125.69, 117.48, 115.07, 110.41, 55.59. Exact Mass, Calculated for C13H11NO4 (M-H): 244.0546; found (M-H): 244.0542.

Reference： [1]Zhao, Huiping; Garg, Gaurav; Zhao, Jinbo; Moroni, Elisabetta; Girgis, Antwan; Franco, Lucas S.; Singh, Swapnil; Colombo, Giorgio; Blagg, Brian S.J. [European Journal of Medicinal Chemistry, 2015, vol. 89, p. 442 - 466]
[2]Current Patent Assignee: UNIVERSITY OF KANSAS - WO2015/70091, 2015, A1 Location in patent: Page/Page column 108

72
[ 6627-53-8 ]
[ 1197956-03-8 ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 4948 - 4964

73
[ 6627-53-8 ]
[ 762-04-9 ]
diethyl (3-methoxy-4-nitrophenyl)phosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In N,N-dimethyl-formamide at 150℃; for 0.333333h; Inert atmosphere; Microwave irradiation;	57 Diethyl (3-methoxy-4-nitrophenyl)phosphonate Diethyl (3-methoxy-4-nitrophenyl)phosphonate (0569) To a solution of 5-chloro-2-nitroanisole (1.00 g, 5.33 mmol) in 20 mL DMF was added diethyl phosphite (0.809 g, 5.86 mmol), palladium acetate (0.060 g, 0.27 mmol), XantPHOS (0.185 g, 0.320 mmol), and potassium phosphate (1.24 g, 5.86 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-45% ethyl acetate:heptane) to afford the desired product (0.504 g, 33% yield).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2015/225436, 2015, A1 Location in patent: Paragraph 0569; 0766

74
[ 6627-53-8 ]
[ 7211-39-4 ]
(3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In N,N-dimethyl-formamide at 120℃; for 18h; Inert atmosphere;	15 (3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide (3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide (0433) To a solution of 5-Chloro-2-nitroanisole (0.5 g, 2.67 mmol) in 5 mL of DMF was added dimethylphosphine oxide (0.229 g, 2.93 mmol), palladium acetate (30 mg, 0.13 mmol), XANPHOS (0.092 g, 0.16 mmol) and potassium phosphate (0.623 g, 2.93 mmol). The mixture was purged with argon, and heated at 120° C. for 18 h. The reaction mixture was basified with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was concentrated and purified by prep-HPLC to give the final product (0.16 g, 30% yield). MS/ES+: m/z=229.
30%	With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In N,N-dimethyl-formamide at 120℃; for 18h; Inert atmosphere;

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2015/225436, 2015, A1 Location in patent: Paragraph 0433; 0607; 0718
[2]Huang, Wei-Sheng; Liu, Shuangying; Zou, Dong; Thomas, Mathew; Wang, Yihan; Zhou, Tianjun; Romero, Jan; Kohlmann, Anna; Li, Feng; Qi, Jiwei; Cai, Lisi; Dwight, Timothy A.; Xu, Yongjin; Xu, Rongsong; Dodd, Rory; Toms, Angela; Parillon, Lois; Lu, Xiaohui; Anjum, Rana; Zhang, Sen; Wang, Frank; Keats, Jeffrey; Wardwell, Scott D.; Ning, Yaoyu; Xu, Qihong; Moran, Lauren E.; Mohemmad, Qurish K.; Jang, Hyun Gyung; Clackson, Tim; Narasimhan, Narayana I.; Rivera, Victor M.; Zhu, Xiaotian; Dalgarno, David; Shakespeare, William C. [Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 4948 - 4964]

75
[ 6627-53-8 ]
2-bromo-1-chloro-5-methoxy-4-nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With N-Bromosuccinimide; trifluoromethylsulfonic anhydride; sulfuric acid at 20℃; for 2h;	52 To a solution of H2S04 (600 mL, 90%), trifluoromethanesulfonicanhydride (11 .3g, 0.O4mol) and NIS (49.68 g, 0.22 mol) were added and resultingmixture was stirred at room temperature for 1 h. To this mixture, 4-chloro-2-methoxy-1-nitrobenzene (69 g, 0.368 mol) was added quickly. The mixture was stirred for 1 h, and then NIS (33.12 g, 0.148 mol) was slowly added to the mixture. The mixture was stirred at room temperature for 1 h and then was poured into ice-water. The precipitate collected by filtration, rinsed with water, aqueous NaSO3 and NaHCO3 solutions, andthen dried in vacuo to afford the desired product (113 g, 98% yield).

Reference： [1]Current Patent Assignee: ARAXES PHARMA LLC - WO2016/44772, 2016, A1 Location in patent: Paragraph 322; 323

76
[ 6627-53-8 ]
[ 155954-17-9 ]
tert-butyl 6-chloro-8-methoxy-3-(1-pyrrolidinyl)quinoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	Stage #1: (E)-3-pyrrolidin-1-yl-but-2-enoic acid tert-butyl ester With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium In tetrahydrofuran; hexane at -70℃; for 0.5h; Inert atmosphere; Stage #2: 1-chloro-3-methoxy-4-nitrobenzene In tetrahydrofuran; hexane at -70℃; for 0.166667h; Stage #3: With pivaloyl chloride; triethylamine In tetrahydrofuran; hexane at -70℃; for 2h;

Reference： [1]Bujok, Robert; Cmoch, Piotr; Wróbel, Zbigniew; Wojciechowski, Krzysztof [Organic and Biomolecular Chemistry, 2017, vol. 15, # 11, p. 2397 - 2402]

77
[ 6627-53-8 ]
C₂₀H₂₉NO₃ [ No CAS ]
(S)-tert-butyl 3-[2-(benzyloxymethyl)-1-pyrrolidinyl]-6-chloro-8-methoxyquinoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: C₂₀H₂₉NO₃ With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium In tetrahydrofuran; hexane at -70℃; for 0.5h; Inert atmosphere; Stage #2: 1-chloro-3-methoxy-4-nitrobenzene In tetrahydrofuran; hexane at -70℃; for 0.166667h; Stage #3: With pivaloyl chloride; triethylamine In tetrahydrofuran; hexane at -70℃; for 2h;

Reference： [1]Bujok, Robert; Cmoch, Piotr; Wróbel, Zbigniew; Wojciechowski, Krzysztof [Organic and Biomolecular Chemistry, 2017, vol. 15, # 11, p. 2397 - 2402]

78
[ 6627-53-8 ]
C₂₀H₂₉NO₃ [ No CAS ]
(S)-tert-butyl 3-[3-(benzyloxymethyl)-1-pyrrolidinyl]-6-chloro-8-methoxyquinoline-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	Stage #1: C₂₀H₂₉NO₃ With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium In tetrahydrofuran; hexane at -70℃; for 0.5h; Inert atmosphere; Stage #2: 1-chloro-3-methoxy-4-nitrobenzene In tetrahydrofuran; hexane at -70℃; for 0.166667h; Stage #3: With pivaloyl chloride; triethylamine In tetrahydrofuran; hexane at -70℃; for 2h;

Reference： [1]Bujok, Robert; Cmoch, Piotr; Wróbel, Zbigniew; Wojciechowski, Krzysztof [Organic and Biomolecular Chemistry, 2017, vol. 15, # 11, p. 2397 - 2402]

79
[ 6627-53-8 ]
[ 67572-28-5 ]
1-(3-(3-methoxy-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.7%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; XPhos In 1,4-dioxane at 110℃;	6.3 (3) Preparation of 1-(3-(3-methoxy-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)ethan-1-one (0508) 1-(3,8-Diazabicyclo[3.2.1]octan-8-yl)ethan-1-one (100 mg, 0.649 mmol) and 4-chloro-2-methoxy-1-nitrobenzene (121.7 mg, 0.649 mmol) were dissolved in 1,4-dioxane (15 mL), and tris(dibenzylideneacetone)dipalladium (59.5 mg, 0.065 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (62 mg, 0.13 mmol) and cesium carbonate (632.8 mg, 1.95 mmol) were added. The mixture was heated to 110° C., and the reaction was carried out overnight. After the reaction, the reaction solution was filtrated. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to get the title compound (140 mg, yield: 70.7%).

Reference： [1]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - US2017/112833, 2017, A1 Location in patent: Paragraph 0507-0508

80
[ 900503-08-4 ]
[ 6627-53-8 ]
tert-butyl 3-(3-methoxy-4-nitrophenyl)-8-azabicyclo[3.2.1]octan-2-en-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere;	(0523) 4-Chloro-2-methoxy-1-nitrobenzene (2.0 g, 10.7 mmol) and <strong>[900503-08-4]tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]octan-2-en-8-carboxylate</strong> (4.3 g, 12.8 mmol) were dissolved in a mixed solvent of 1,4-dioxane (50 mL) and water (10 mL). Sodium carbonate (2.27 g, 21.4 mmol) and [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (436 mg, 0.54 mmol) were added to the system. Under the protection of nitrogen gas, the reaction was carried out at 90 C. under stirring for 16 h. After the reaction, the mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried with anhydrous sodium sulfate, filtrated, and concentrated to get the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to get the title compound (2.4 g, yield: 62%).

Reference： [1]Patent: US2017/112833,2017,A1 .Location in patent: Paragraph 0522-0523

81
[ 6627-53-8 ]
tert-butyl (cis)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-carboxylate [ No CAS ]
tert-butyl (cis)-5-(3-methoxy-4-nitrophenyl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,4-dioxane; water at 90℃; for 16h; Inert atmosphere;	9.4 (4) Preparation of tert-butyl (cis)-5-(3-methoxy-4-nitrophenyl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)carboxylate (0557) 4-Chloro-2-methoxy-1-nitrobenzene (1.36 g, 7.3 mmol) and tert-butyl (cis)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-carboxylate (2.95 g, 8.8 mmol) were dissolved in a mixed solvent of 1,4-dioxane (30 mL) and water (10 mL). To the reaction system, sodium carbonate (1.55 g, 14.6 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (326 mg, 0.4 mmol) were added. Under the protection of nitrogen gas, the reaction was carried out under stirring at 90° C. for 16 h. After the reaction, the mixture was cooled to room temperature. Water (100 mL) was added, and the resultant mixture was extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried with anhydrous sodium sulfate, filtrated, and concentrated to get the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to get the title compound (1.7 g, yield: 65%).

Reference： [1]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - US2017/112833, 2017, A1 Location in patent: Paragraph 0556-0557

82
[ 6627-53-8 ]
1-(2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one [ No CAS ]
1-(6-(3-methoxy-4-nitrophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; XPhos In 1,4-dioxane at 110℃;	30.3 (3) Preparation of 1-(6-(3-methoxy-4-nitrophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (0803) 1-(2,6-Diazaspiro[3.3]heptan-2-yl)ethan-1-one (140 mg, 1.0 mmol) and 4-chloro-2-methoxy-1-nitrobenzene (187 mg, 1.0 mmol) were dissolved in 1,4-dioxane (15 mL), and tris(dibenzylideneacetone)dipalladium (92 mg, 0.1 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (95 mg, 0.2 mmol) and cesium carbonate (975 mg, 3.0 mmol) were added. The mixture was heated to 110° C., and the reaction was carried out overnight. LC-MS detection showed that the reaction was finished. The reaction solution was filtrated, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to get the title compound (195 mg, yield: 67%).

Reference： [1]Current Patent Assignee: SIHUAN PHARMACEUTICAL HOLDINGS GROUP LTD. - US2017/112833, 2017, A1 Location in patent: Paragraph 0802-0803

83
[ 6627-53-8 ]
[ 755027-21-5 ]

Reference： [1]Patent: EP3486244,2019,A1

84
[ 6627-53-8 ]
[ 95-53-4 ]
C₁₄H₁₃ClN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at -60℃; for 7h;

Reference： [1]Yang, Hongfen; Kundra, Shivani; Chojnacki, Michaelle; Liu, Ke; Fuse, Marisa A.; Abouelhassan, Yasmeen; Kallifidas, Dimitris; Zhang, Peilan; Huang, Guangtao; Jin, Shouguang; Ding, Yousong; Luesch, Hendrik; Rohde, Kyle H.; Dunman, Paul M.; Lemos, José A.; Huigens, Robert W. [Journal of Medicinal Chemistry, 2021, vol. 64, # 11, p. 7275 - 7295]

85
[ 6627-53-8 ]
[ 371-40-4 ]
C₁₃H₁₀ClFN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at -60℃; for 7h;

Reference： [1]Yang, Hongfen; Kundra, Shivani; Chojnacki, Michaelle; Liu, Ke; Fuse, Marisa A.; Abouelhassan, Yasmeen; Kallifidas, Dimitris; Zhang, Peilan; Huang, Guangtao; Jin, Shouguang; Ding, Yousong; Luesch, Hendrik; Rohde, Kyle H.; Dunman, Paul M.; Lemos, José A.; Huigens, Robert W. [Journal of Medicinal Chemistry, 2021, vol. 64, # 11, p. 7275 - 7295]

86
[ 877149-80-9 ]
[ 6627-53-8 ]
2-(4-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)-N,N-dimethylethan-1-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With tetrakis-(triphenylphosphine)-palladium; Cs₂CO₃ In 1,4-dioxane; water monomer at 80℃; for 2h; Inert atmosphere;	113.1 Step 1: 2- (4- (3-methoxy-4-nitrophenyl) -1H-pyrazol-1-yl) -N, N-dimethylethan-1-amine A mixture of 4-chloro-2-methoxy-1-nitrobenzene (500 mg, 2.7 mmol) , N, N-dimethyl-2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethan-1-amine (780 mg, 2.9 mmol) , Pd (PPh3)4(309 mg, 0.27 mmol) and Cs2CO3(1.3 g, 4.0 mmol) in 1, 4-dioxane (30 mL) and H2O (6 mL) was stirred in a round bottom flask at 80 for 2 h under N2. The mixture was evaporated in vacuum to afford the crude product, which was purified with silica gel column chromatography (DCM: MeOH = 100: 0 10: 1 gradient elution) to give the title product (760 mg, 97%) . [M+H]+= 291.2.

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2022/63106, 2022, A1 Location in patent: Page/Page column 100

87
[ 864754-21-2 ]
[ 6627-53-8 ]
3-((4-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)methyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With tetrakis-(triphenylphosphine)-palladium; Cs₂CO₃ In 1,4-dioxane; water monomer at 80℃; for 2h; Inert atmosphere;	114.1 Step 1: 3- ( (4- (3-methoxy-4-nitrophenyl) -1H-pyrazol-1-yl) methyl) pyridine A mixture of 4-chloro-2-methoxy-1-nitrobenzene (500 mg, 2.7 mmol) , 3- ( (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) methyl) pyridine (838 mg, 2.9 mmol) , Pd (PPh3)4(309 mg, 0.27 mmol) and Cs2CO3(1.3 g, 4.0 mmol) in 1, 4-dioxane (30 mL) and H2O (6 mL) was stirred in a round bottom flask at 80 for 2 h under N2. The mixture was evaporated in vacuum to afford the crude product, which was purified with silica gel column chromatography (DCM: MeOH = 100: 0 20: 1 gradient elution) to give the title product (820 mg, 98%) . [M+H]+= 311.2.

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2022/63106, 2022, A1 Location in patent: Page/Page column 101

88
[ 6627-53-8 ]
1-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)piperazine [ No CAS ]
1-(2-(4-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethyl)-4-methylpiperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With tetrakis-(triphenylphosphine)-palladium; Cs₂CO₃ In 1,4-dioxane; water monomer at 80℃; for 2h; Inert atmosphere;	115.1 Step 1: 1- (2- (4- (3-methoxy-4-nitrophenyl) -1H-pyrazol-1-yl) ethyl) -4-methylpiperazine A mixture of 4-chloro-2-methoxy-1-nitrobenzene (200 mg, 1.1 mmol) , 1-methyl-4- (2- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethyl) piperazine (376 mg, 1.2 mmol) , Pd (PPh3)4(123 mg, 0.11 mmol) and Cs2CO3(523 mg, 1.6 mmol) in 1, 4-dioxane (20 mL) and H2O (4 mL) was stirred in a round bottom flask at 80 for 2 h under N2. The mixture was evaporated in vacuum to afford the crude product, which was purified with silica gel column chromatography (DCM: MeOH = 100: 0 10: 1 gradient elution) to give the title product (255 mg, 69%) . [M+H]+= 346.2.

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2022/63106, 2022, A1 Location in patent: Page/Page column 102

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	6627-53-8	MDL No. :	MFCD00007288
Formula :	C₇H₆ClNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ABEUJUYEUCCZQF-UHFFFAOYSA-N
M.W :	187.58	Pubchem ID :	81110
Synonyms :

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	46.77
TPSA :	55.05 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) :	-5.73 cm/s

Log Po/w (iLOGP) :	1.54
Log Po/w (XLOGP3) :	2.41
Log Po/w (WLOGP) :	2.26
Log Po/w (MLOGP) :	1.21
Log Po/w (SILICOS-IT) :	0.32
Consensus Log Po/w :	1.55

[ CAS No. 6627-53-8 ] {[proInfo.proName]}

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[ 6627-53-8 ] Synthesis Path-Upstream 1~14

[ 6627-53-8 ] Synthesis Path-Downstream 1~88

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[ 6627-53-8 ]

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

Log S (ESOL) :	-2.76
Solubility :	0.327 mg/ml ; 0.00174 mol/l
Class :	Soluble
Log S (Ali) :	-3.21
Solubility :	0.116 mg/ml ; 0.000619 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.52
Solubility :	0.561 mg/ml ; 0.00299 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.93

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:

Yield	Reaction Conditions	Operation in experiment
30 g	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h;	4-Chloro-2-methoxy-1-nitrobenzene To a solution of 5-chloro-2-nitrophenol (40 g, 0.23 mol) in DMF (200 mL), K₂CO₃ (47.6 g, 0.345 mol) and iodomethane (49 g, 0.345 mol) were added and the resulting mixture was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether) to afford the desired product (30 g, 70percent yield).
30 g	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h;	To a solution of 5-chloro-2-nitrophenol (40 g, 0.23 mol) in DMF (200mL), K2C03 (47.6 g, 0.345 mol) and iodomethane (49 g, 0.345 mol) were added and the resulting mixture was stirred at room temperature for 1 6h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried overMgSO, filtered and concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (petroleum ether) to afford the desired product (30 g, 70percent yield).

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: With iron; ammonium chloride In water for 0.25 h; Heating / reflux Stage #2: Heating / reflux	A suspension of ferrum (5.0 equiv.), ammonium chloride (0.65 equiv.), and distilled water were refluxed for fifteen minutes. The nitro compound (1.0 equiv.) was added and the resulting reaction mixture was allowed to stir at reflux. When TLC showed that the reaction had stopped the mixture was neutralized by drop wise addition of a 5percent aqueous solution of sodium bicarbonate and it was filtered through Celite. The filtrate was washed thrice with ethyl acetate. The combined organic layers were washed once with brine and once with a 5percent aqueous solution of hydrochloric acid. The combined water layers were neutralized with 20percent aqueous sodium hydroxide and extracted thrice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and the solvent removed in vacuo. The pure product was obtained using column chromatography in ethyl acetate and hexanes but sometimes the product was kept crude. The purity of the product was determined using ¹H- NMR.; 4-Chloro-2-methoxy-phenylamine was obtained from Ferrum (2.23 g, 40 mmol) ammonium chloride (278 mg, 5.2 mmol), water (48 mL) and 5-chloro-2-nitroanisole (1.5 g, 8.0 mmol) as a crude mixture, which was a dark purple oil (1.15g, 91 percent). The reaction was complete in 1.5 hours. ¹H NMR (300 MHz, CDCl₃): δ(ppm) 6.78(m, 2H), 6.65(d, IH), 3.86(s, 3H). EPO <DP n="81"/>4-Chloro-2-methoxy-phenylamine was obtained from Ferrum (4.47 g, 80.0 mmol) ammonium chloride (556 mg, 10.4 mmol), water (80 mL) and 5-chloro-2-nitroanisole (3.0 g, 16.0 mmol) as a crude mixture, which was a dark purple oil (2.35g, 93percent). The reaction was complete in 2 hours. No ¹H-NMR was performed.
76%	With 5%-palladium/activated carbon; hydrogen In methanol for 72 h;	A. A suspension of 5-chloro-2-nitroanisole (7s) (2.67 g, 14.2 mmol) and 5percent Pt/C (200 nig) in methanol (60 niL) was placed under a hydrogen gas atmosphere and stirred 3 days. The suspension was filtered through diatoniaceous earth and concentrated. Purification by column chromatography (40 g), eluting with 15 to 30percent EA/hexanes, gave compound 7b (1.69 g, 76percent). 1H NMR (CHLOROFORM-d) δ: 6.70 - 6.83 (m, 2H), 6.58 - 6.64 (m, 1H), 3.84 (s, 3H), 3.76 (br. s., 2H). ESI-MS (m/z): Calcd. for C7H8ClNO: 158.0 (M+1); found: 158.0.
69.5%	With hydrogen In tetrahydrofuran at 20℃;	5-Chlor-2-nitroanisol in THF are hydrogenated in the presence of H2 and Raney nickel at room temperature overnight. The catalyst is separated by filtration and the filtrate evaporated to dryness. The residue is purified by chromatography (35 g silica gel, eluent : DICHLOROMETHANE : methanol = 99 : 1). Yield : 69.5 percent, brown oil

65%	Stage #1: With water; tin(ll) chloride In ethanol for 18 h; Heating / reflux Stage #2: With sodium hydroxide In ethanol; water at 20℃;	A mixture of 4-chloro-2-methoxy-l -nitrobenzene (938 mg, 5.0 mmol), tin(II) chloride dihydrate (3.38 g, 15 mmol) and EtOH (25 mL) was heated at reflux for 18 h. After cooling to rt, NaOH (aq, 4M, 50 mL) was added. The mixture was extracted with Et₂O (3x20 mL) and the combined extracts dried (Na₂SO₄) and concentrated. Purification by chromatography gave the title compound (511 mg, 65percent) as a red oil which solidified on standing.¹H NMR (DMSO-J₆, 400 MHz) δ 6.78 (IH, d), 6.67 (IH, dd), 6.57 (IH, d), 4.82 (2H, S)₃ 3.75 (3H, s).
64%	Stage #1: With sodium dithionite; potassium hydrogencarbonate In methanol; water at 20℃; for 2 h; Stage #2: With hydrogenchloride In methanol; water at 60℃; for 2 h;	Preparation 91; 4-Chloro-2-methoxy-phenvlamine; To a suspension of 5-chloro-2-nitroanisole (10g, 53mmol) and potassium bicarbonate (28g, 280mol) in methanol (150mL) and water (150mL) was added sodium dithionite (28g, 159 mmol). The mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was acidified to pH1 with concentrated hydrochloric acid and the resulting brown suspension was heated for 2 hours at 60°C before the solvent was evaporated under reduced pressure. The residual aqueous solution was washed with ethyl acetate, basified with sodium hydroxide pellets and re-extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title compound in 64percent yield (5.35g). 'H NMR (DMSO-D6, 400MHz) zu : 3.66 (s, 3H), 4.76 (bs, 2H), 6.52 (m, 1H), 6.65 (m, 1 H), 6.79 (m, 1 H)
64%	With sodium dithionite; potassium hydrogencarbonate In methanol; water at 20℃; for 2 h;	Preparation 37; (4-Chloro-2-methoxyphenyl)amine; Sodium dithionite (28g, 159mmol) was added portionwise to a mixture of 5-chloro-2-nitroanisole (1Og, 53mmol) and potassium hydrogen carbonate (28g, 275.6mmol) in methanol (15OmL) and water (15OmL) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then acidified with concentrated hydrochloric acid and the mixture was heated at 6O⁰C for 2 hours. The reaction mixture was then concentrated in vacuo and the aqueous residue was washed with ethyl acetate. The aqueous solution was then basified with sodium hydroxide and extracted with ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound in 64percent yield, 5.35g. ¹HNMR(400MHz, DMSO-Cl₆) δ: 3.74(s, 3H), 4.78(s, 2H), 6.58(m, 1 H), 6.65(m, 1 H), 6.77(s, 1 H)

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

[ CAS No. 6627-53-8 ] {[proInfo.proName]}

Quality Control of [ 6627-53-8 ]

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[ 6627-53-8 ] Synthesis Path-Upstream 1~14

[ 6627-53-8 ] Synthesis Path-Downstream 1~88

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Aryls

Chlorides

Ethers

Nitroes

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[ 6627-53-8 ]