Name: 21900-54-9|2-Chloro-4-fluorobenzoylchloride|98%
Brand: Ambeed
SKU: A636093
Price: 12.0 USD
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1
[ 2252-51-9 ]
[ 21900-54-9 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride
	With thionyl chloride; N,N-dimethyl-formamide for 2h; Heating;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane Heating;

	With thionyl chloride
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 18h;	8 REFERENCE EXAMPLE 8(2-Chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone REFERENCE EXAMPLE 8 (2-Chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone oxalyl chloride (2.60 g) was added to a suspension of 2-chloro-4-fluorobenzoic acid (3.44 g) in dichloromethane (50 ml).. Two drops of dimethylformamide were added and the mixture was stirred for 18 hours at room temperature.. The resultant solution was evaporated to give the crude 2-chloro-4-fluorobenzoyl chloride as a viscous oil (3.72 g).
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane Heating / reflux;	1.C Step C. 2-Chloro-4-fluorobenzoyl chloride Step C. 2-Chloro-4-fluorobenzoyl chloride A suspension of the 2-chloro-4-fluorobenzoic acid (13.61g, 78 mmol) in dichloromethane (85 ML) containing a few drops of dimethylformamide was treated dropwise under nitrogen with a 2M solution of oxalyl chloride in dichloromethane (1.2 equivalents).. After gas evolution subsided, the reaction mixture was refluxed for an additional 25 minutes and then evaporated to dryness in vacuo.. The crude acid chloride was used as such in the next step.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane Heating / reflux;	16.B Step B. (2-Chloro-4-fluoro-phenyl)-(11H-5-oxa-4,10-diazadibenzo[a,d]cyclohepten-10-yl)-methanone Under anhydrous conditions a mixture of 2-chloro-4-fluorobenzoic acid (0.37 g, 2.12 mmol) and oxalyl chloride (0.303 mL, 2.3 mmol) in 10 mL of dichloromethane containing a catalytic amount of dimethylformamide was stirred at room temperature until gas evolution ceased. The crude acid chloride solution was then added portionwise to a stirred solution of 6H-pyrido[2,3-b][1,5]benzoxazepine of Step A (0.45 g, 2.12 mmol) and triethylamine (0.35 mL, 2.5 mmol) in 15 mL of dichloromethane. The reaction mixture was stirred overnight at ambient temperature, washed with water and dried over sodium sulfate. Evaporation of the solvent provided the crude title compound as a gummy solid which was used as such in the next step. NMR (DMSO-d6, 400 MHz): δ 5.1 (broad, 2H, CH2N), 6.9-7.5 (m, 8H), 7.92 (d, 1H), 8.22 (m, 1H) MS (EI, m/z): 354 [M]+, 319, 198, 157
	With oxalyl dichloride In dichloromethane at 20℃; for 18h;	8 EXAMPLE 8; (2-Chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone Oxalyl chloride (2.60 g) was added to a suspension of 2-chloro-4-fluorobenzoic acid (3.44 g) in dichloromethane (50 ml). Two drops of dimethylformamide were added and the mixture was stirred for 18 hours at room temperature. The resultant solution was evaporated to give the crude 2-chloro-4-fluorobenzoyl chloride as a viscous oil (3.72 g).
	With thionyl chloride Reflux;
	With pyridine; 1,3,5-trichloro-2,4,6-triazine In dichloromethane at 50℃; for 0.25h; Microwave irradiation;	8 Preparation of (2-chloro-4-nitrophenyl)(p-tolyl)methanone (6a). Method A (using AlCl₃): General procedure: 2-Chloro-4-nitrobenzoic acid (201 mg, 1.0 mmol) and cyanuric chloride (368 mg, 2 mmol) in 2 mL CH2Cl2 were treated with pyridine (79 mg, 1.0 mmol) and irradiated in the microwave for 15 min at 50 °C. Then, the resulting mixture was treated with AlCl3 (400 mg, 3.01 mmol) and irradiated in the microwave for 5 min at 30 °C. Finally, 3 mL of toluene was added to the solution and irradiated in the microwave for 15 min at 70 °C. Then the reaction mixture was poured onto the ice and filter from Celite. The filtrate was washed with water followed by brine solution. The separated organic layer was dried on Na2SO4 and concentrated under reduced pressure to give crude product, which is purified by column chromatography (98:2 heptane/ethyl acetate) to give the pure white color product 6a (269.5 mg, 91% yield).
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere;
	With thionyl chloride; N,N-dimethyl-formamide at 60℃; for 0.5h; Inert atmosphere;	6.1. General synthetic procedure for the isocoumarin derivatives 3(a-d) General procedure: 2-Chloro-4-fluorobenzoic acid, 2-chloro-6-fluorobenzoic acid, 3-chloro-4-fluorobenzoic acid and 4-chloro-2-fluorobenzoic acid 1(a-d) (5 g, 28.7 mmol) were converted into their respective acid chlorides 2(a-d) by reaction with thionyl chloride (4.09 g, 2.49 mL and 34 mmol) in the presence of a drop of DMF under reflux for 30 min. Completion of the reaction was indicated by the stoppage of gas evolution. Removal of excess of thionyl chloride was carried out under reduced pressure to afford dihalobenzoyl chlorides 2(a-d). Mixtures of homophthalic acid (1.3 g, 7.2 mmol) and dihalobenzoyl chlorides 2(a-d) (5.516 g, 28.7 mmol) were heated at 200 °C under reflux for 4 h. The mixtures were dissolved in ethyl acetate and aqueous solution of sodium carbonate was added in order to remove the unreacted homophthalic acid. Organic layer was separated and the aqueous layer was extracted with 2× 25 mL ethyl acetate. The combined organic layers were concentrated and chromatographed on silica gel using pet ether (40-80 °C fraction) as eluent which gave 3-(dihalophenyl)isocoumarins 3(a-d) as solids, which were further purified by recrystallization from methanol.
	With thionyl chloride Reflux;
	With thionyl chloride at 90℃; for 1h;	8 Preparation of 2-Chloro-N-(2-chloro-4-{fl-(4-methoxybenzyl)-lH-pyrazolof4,3- b]pyridin-S-yl]amino}phenyl)-4-fluorobenzamide[01 19] Into a vessel containing 10 mL of SO2CI2 was added 174 mg of 2-chloro-4- fluoro-benzoic acid (1 mmol) with stirring at 90 °C. Stirring was continued for 1 hr. then the mixture was concentrated in vacuum yielding crude 2-chloro-4-fluoro-benzoyl chloride. Into 6 mL of a 5: 1 vohvol mixture of dichloromethane (D CM): pyridine was dissolved 50 mg of 2-chloro-7V4-[l-(4-methoxybenzyl)-lH-pyrazolo [4,3-&]pyridin-3-yl] benzene- 1 ,4-diamine (0.13 mmol) at RT. Into this solution was added, dropwise, 50 mg of the crude 2-chloro-4-fluoro-benzoyl chloride previously prepared. The reaction mixture thus provided was stirred overnight at ambient temperature (RT) then the reaction mixture was washed with HQ (aq) and extracted with DCM. The combined organics were washed sequentially with water and brine, dried over Na2S04, filtered, then concentrated under reduced pressure yielding 48 mg of Exp-8-g3 (calculated yield 68.5 %). The crude material was used directly in the next step without purification. The identity of the product was confirmed by mass spectroscopy in accordance with the procedures described herein. MS (ESI) m/z 536, 538 (M+H)+
	With thionyl chloride In 1-methyl-pyrrolidin-2-one; toluene at 75℃; for 1h;
	With sulfuryl dichloride at 90℃; for 1h;	8 EXAMPLE 8: 3-[(3-Chloro-4-[(2-chloro-4-fluorophenyl)carbonyl]amino} iyl)amino] - ΙΗ-pyr azolo [4,3-b] pyridin-4-ium trifluoroacetate Preparation of 2-Chloro-N-(2-chloro-4-ifl-(4-methoxybenzyl)-lH-pyrazolo[4,3- b]pyridin-3-yl]aminojphenyl)-4-fluorobenzam,ide Into a vessel containing 10 mL of SO2CI2 was added 174 mg of 2-chloro-4- fluoro-benzoic acid (1 mmol) with stirring at 90 °C. Stirring was continued for 1 hr. then the mixture was concentrated in vacuum yielding crude 2-chloro-4-fluoro-benzoyl chloride
	With 1-methyl-pyrrolidin-2-one; thionyl chloride In toluene at 78 - 85℃; for 4h; Large scale;
	With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere;	8 General procedure for the preparation of acid chlorides 32-42 General procedure: Under inert atmosphere, a mixture of carboxylic acid 21-31 ( Scheme 1 ) (1 equiv), thionyl chloride (1.5 equiv) and DMF (3-5 drops) in dichloromethane was stirred at rt until the complete consumption of the carboxylic acid (1H NMR control). The pale yellow solution was concentrated in vacuo to give the crude acid chloride 32-42 ( Scheme 1 ) as a yellow pale solid in quantitative yield
	With thionyl chloride for 3h; Reflux;	37-1 2-chloro-4-flu oro-N ,N -dimethylbenzamide The reaction mixture of 2-chloro-4-fluorobenzoic acid (5 g, 28.6 mmol, 1.0 eq) in thionyl5 chloride (10 mL, 137 mmol, 4.7 eq) was refluxed for 3 h. Then the mixture was cooled tort andthe solvent was evaporated under reduced pressure to give 2-chloro-4-fluorobenzoyl chloride.The crude chloride was dissolved in THF ( 5 mL ), then treated with triethylamine ( 16 mL, 115mmol, 4.0 eq) and dimethylamine (42 mL, 84 mmol, 2M in THF, 2.9 eq) at ambient temperature.The reaction mixture was stirred at ambient temperature for 17h. The mixture was diluted with10 ethyl acetate (90 mL), washed with water (10 mL x 3), dried over anhydrous Na2S04, filteredand concentrated. The crude product was purified by column chromatography (silica gel: 300-400 mesh, PE/EtOAc = 3/1, VN) to afford 2-chloro-4-fluoro-N,N-dimethylbenzamide. LRMSm/z (M+H) 202.0 found, 202.0 required.
	With thionyl chloride In dichloromethane at 20 - 38℃; for 2.5h;	59-4 2-Chloro-4-fluorobenzoyl chloride Reference example 59-4 2-Chloro-4-fluorobenzoyl chloride To a mixture of 2-chloro-4-fluorobenzoic acid (159 mg) in dichloromethane (2.0 mL) were added thionyl chloride (332 uL) and a catalytic amount of N-methylpyrrolidone at room temperature, and the mixture was stirred at room temperature for an hour, followed by stirring at 38 °C for 1.5 hours. The solvent was removed under reduced pressure to give 2-chloro-4-fluorobenzoyl chloride (175 mg).
	With thionyl chloride In toluene for 3h; Reflux;	4.2.13. Synthesis of 2-chloro-N-(4-chloro-3-(8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenyl)-4-fluorobenzamide (TPB12) Thionyl chloride (0.356 g; 3 mmol) was added to a mixture of 2-chloro-4-fluorobenzoic acid (0.175 g, 1 mmol) in toluene and themixture was heated at reflux for 3 h. The reaction was cooled to roomtemperature and the solvent was removed under reduced pressure. Theresultant acid chloride was dropwised to a mixture of Compound 4 (0.279 g, 1 mmol) and DIPEA (0.258 g, 2 mmol) in dichloromethane(15 ml) at room temperature. The solution was stirred for overnight,then concentrated in vacuo. The residue was purified by silica gelcolumn (DCM/MeOH = 20/1) to afford TPB12 (0.280 g, yield: 65%);purity: 99%; mp: 237.5-239.2 °C; 1H-NMR (d6-DMSO): δ = 10.95 (s,1H), 8.19-8.13 (m, 1H), 8.11 (d, J = 2.6 Hz, 1H), 8.00 (dd, J = 8.9,2.6 Hz, 1H), 7.81-7.73 (m, 2H), 7.73-7.68 (m, 1H), 7.63 (dd, J = 9.0,2.5 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.06 (t, J = 7.1 Hz, 1H); 13CNMR(d6-DMSO): δ = 164.99 (s), 164.12 (s), 161.63 (s), 148.00 (s),146.14 (s), 138.78 (s), 133.54 (d, J = 3.5 Hz), 131.92 (d, J = 11.0 Hz),131.36 (d, J = 9.6 Hz), 131.12 (s), 127.92 (d, J = 3.8 Hz), 125.89 (s),124.18 (s), 123.84 (d, J = 12.4 Hz), 120.63 (s), 117.81 (s), 117.56 (s),115.22 (s), 114.94 (d, J = 14.1 Hz); HR-ESI-MS for C19H9ON4Cl3F([M-H]+) Calcd: 432.9826; Found: 432.9838.

Reference： [1]Verbeerst,R.; Slootmaekers,R.J. [Bulletin des Societes Chimiques Belges, 1968, vol. 77, p. 287 - 293]
[2]Gabbutt, Christopher D.; Heron, B. Mark; Instone, Alicia C. [Tetrahedron, 2006, vol. 62, # 4, p. 737 - 745]
[3]Failli, Amedeo A.; Shumsky, Jay S.; Steffan, Robert J.; Caggiano, Thomas J.; Williams, David K.; Trybulski, Eugene J.; Ning, Xiaoping; Lock, Yeungwai; Tanikella, Tarak; Hartmann, David; Chan, Peter S.; Park [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 4, p. 954 - 959]
[4]Chatani; Tatamidani; Ie; Kakiuchi; Murai [Journal of the American Chemical Society, 2001, vol. 123, # 20, p. 4849 - 4850]
[5]Current Patent Assignee: PFIZER INC - EP1000062, 2004, B1 Location in patent: Page 32
[6]Current Patent Assignee: PFIZER INC - EP1000059, 2004, B1 Location in patent: Page 29
[7]Current Patent Assignee: PFIZER INC - EP1000059, 2004, B1 Location in patent: Page 37
[8]Current Patent Assignee: PFIZER INC - US6831079, 2004, B1 Location in patent: Page/Page column 38
[9]Balkrishna, Shah Jaimin; Bhakuni, Bhagat Singh; Chopra, Deepak; Kumar, Sangit [Organic Letters, 2010, vol. 12, # 23, p. 5394 - 5397]
[10]Location in patent: experimental part Mahdi, Jasia; Ankati, Haribabu; Gregory, Jill; Tenner, Brian; Biehl, Edward R. [Tetrahedron Letters, 2011, vol. 52, # 20, p. 2594 - 2596]
[11]Ano, Yusuke; Tobisu, Mamoru; Chatani, Naoto [Organic Letters, 2012, vol. 14, # 1, p. 354 - 357]
[12]Location in patent: experimental part Abid, Obaid-Ur-Rahman; Khalid, Muhammad; Hussain, Muhammad T.; Hanif, Muhammad; Qadeer, Ghulam; Rama, Nasim H.; Kornienko, Alexander; Khan, Khalid M. [Journal of Fluorine Chemistry, 2012, vol. 135, p. 240 - 245]
[13]Location in patent: experimental part Balkrishna, Shah Jaimin; Kumar, Sangit [Synthesis, 2012, vol. 44, # 9, p. 1417 - 1426]
[14]Current Patent Assignee: ADDEX THERAPEUTICS SA; MERCK & CO INC - WO2013/60029, 2013, A1 Location in patent: Paragraph 0119
[15]Leroy, Vincent; Lee, George E.; Lin, Jiang; Herman, Sandra H.; Lee, Thomas B. [Organic Process Research and Development, 2001, vol. 5, # 2, p. 179 - 183]
[16]Current Patent Assignee: ADDEX THERAPEUTICS SA; MERCK & CO INC - WO2013/63100, 2013, A1 Location in patent: Paragraph 0119
[17]Watson, Timothy J.; Ayers, Timothy A.; Shah, Nik; Wenstrup, David; Webster, Mark; Freund, David; Horgan, Stephen; Carey, James P. [Organic Process Research and Development, 2003, vol. 7, # 4, p. 521 - 532]
[18]Ghinet, Alina; Moise, Iuliana-Monica; Rigo, Benoît; Homerin, Germain; Farce, Amaury; Dubois, Joëlle; Bîcu, Elena [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 10, p. 2307 - 2317]
[19]Current Patent Assignee: MERCK & CO INC - WO2018/68295, 2018, A1 Location in patent: Page/Page column 143; 144
[20]Current Patent Assignee: KISSEI PHARMACEUTICAL COMPANY LIMITED - EP1867639, 2007, A1 Location in patent: Page/Page column 85
[21]Chen, Mian; Lv, Lin; Quan, Dongling; Schmitz, John C.; Tian, Nannan; Tian, Yuanxin; Wei, Ning; Wu, Huanxian; Wu, Shaoyu; Xie, Ying; Xu, Yimei; Yang, Danni; Yang, Zichao; Zhang, Huiwu; Zhang, Jiajie; Zhang, Tingting; Zhou, Lei [Bioorganic and medicinal chemistry, 2020, vol. 28, # 16]

2
[ 39658-41-8 ]
[ 21900-54-9 ]
[ 201686-69-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1737 - 1740

3
[ 21900-54-9 ]
[ 71-43-2 ]
[ 69943-47-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With aluminium trichloride for 1h; Heating;
	Stage #1: 2-chloro-4-fluorobenzoyl chloride With aluminum (III) chloride In dichloromethane at 30℃; for 0.0833333h; Microwave irradiation; Stage #2: benzene In dichloromethane at 70℃; for 0.25h; Microwave irradiation;	8 Preparation of (2-chloro-4-nitrophenyl)(p-tolyl)methanone (6a). Method A (using AlCl₃): General procedure: 2-Chloro-4-nitrobenzoic acid (201 mg, 1.0 mmol) and cyanuric chloride (368 mg, 2 mmol) in 2 mL CH2Cl2 were treated with pyridine (79 mg, 1.0 mmol) and irradiated in the microwave for 15 min at 50 °C. Then, the resulting mixture was treated with AlCl3 (400 mg, 3.01 mmol) and irradiated in the microwave for 5 min at 30 °C. Finally, 3 mL of toluene was added to the solution and irradiated in the microwave for 15 min at 70 °C. Then the reaction mixture was poured onto the ice and filter from Celite. The filtrate was washed with water followed by brine solution. The separated organic layer was dried on Na2SO4 and concentrated under reduced pressure to give crude product, which is purified by column chromatography (98:2 heptane/ethyl acetate) to give the pure white color product 6a (269.5 mg, 91% yield).

Reference： [1]Gabbutt, Christopher D.; Heron, B. Mark; Instone, Alicia C. [Tetrahedron, 2006, vol. 62, # 4, p. 737 - 745]
[2]Location in patent: experimental part Mahdi, Jasia; Ankati, Haribabu; Gregory, Jill; Tenner, Brian; Biehl, Edward R. [Tetrahedron Letters, 2011, vol. 52, # 20, p. 2594 - 2596]

4
[ 21900-54-9 ]
[ 625-98-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 71 percent Chromat_. / HCOONH₄ / Ru₃(CO)12 / dioxane / 20 h / 160 °C

Reference： [1]Chatani; Tatamidani; Ie; Kakiuchi; Murai [Journal of the American Chemical Society, 2001, vol. 123, # 20, p. 4849 - 4850]

5
[ 181132-29-6 ]
[ 21900-54-9 ]
[ 220603-17-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;	16.B Step B. (2-Chloro-4-fluoro-phenyl)-(11H-5-oxa-4,10-diazadibenzo[a,d]cyclohepten-10-yl)-methanone Under anhydrous conditions a mixture of 2-chloro-4-fluorobenzoic acid (0.37 g, 2.12 mmol) and oxalyl chloride (0.303 mL, 2.3 mmol) in 10 mL of dichloromethane containing a catalytic amount of dimethylformamide was stirred at room temperature until gas evolution ceased. The crude acid chloride solution was then added portionwise to a stirred solution of 6H-pyrido[2,3-b][1,5]benzoxazepine of Step A (0.45 g, 2.12 mmol) and triethylamine (0.35 mL, 2.5 mmol) in 15 mL of dichloromethane. The reaction mixture was stirred overnight at ambient temperature, washed with water and dried over sodium sulfate. Evaporation of the solvent provided the crude title compound as a gummy solid which was used as such in the next step. NMR (DMSO-d6, 400 MHz): δ 5.1 (broad, 2H, CH2N), 6.9-7.5 (m, 8H), 7.92 (d, 1H), 8.22 (m, 1H) MS (EI, m/z): 354 [M]+, 319, 198, 157

Reference： [1]Current Patent Assignee: PFIZER INC - EP1000059, 2004, B1 Location in patent: Page 37

6
[ 21900-54-9 ]
[ 16287-36-8 ]
[ 220603-04-3 ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate In <i>N</i>-methyl-acetamide	1.D Step D. Step D. (2-Chloro-4-fluorophenyl)-(5,11-dihydro-pyrido [2,3-b][1,5]benzodiazepin-6-yl)-methanone To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Step B (12.8 g, 65 mmol) in dimethylformamide (120 mL) under nitrogen was added potassium carbonate (19.76 g, 143 mmol). The mixture was cooled and treated dropwise with a solution of crude 2chloro-4-fluorobenzoyl chloride of Step C (78 mmol) in dimethylformamide (50 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate gradient from 95:5 to 80:20) to provide the pure title compound (14.25 g, 62%) along with some less pure material (2.7 g). The pure material is an off-white crystalline solid, which is used as such in the next step. NMR (DMSO-d6, 400 MHz): δ 4.13 and 5.42 (dd, 2 H, CONCH2), 6.52 (m, 1H), 6.71-6.79 (m, 2H), 6.98-7.16 (2m, 2H), 7.23-7.33 (m, 3H), 7.58 (m, 1H), 8.10 (m, 1H), 9.53 (s, 1H, NH) MS (EI, m/z): 353/355 [M]+, 196
62%	With potassium carbonate In <i>N</i>-methyl-acetamide	1.D Step D. Step D. (2-Chloro-4-fluorophenyl)-(5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Step B (12.8 g, 65 mmol) in dimethylformamide (120 mL) under nitrogen was added potassium carbonate (19.76 g, 143 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-chloro-4-fluorobenzoyl chloride of Step C (78 mmol) in dimethylformamide (50 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate gradient from 95:5 to 80:20) to provide the pure title compound (14.25 g, 62%) along with some less pure material (2.7 g). The pure material is an off-white crystalline solid, which is used as such in the next step. NMR (DMSO-d6, 400 MHz): δ 4.13 and 5.42 (dd, 2 H, CONCH2), 6.52 (m, 1H), 6.71-6.79 (m, 2H), 6.98-7.16 (2 m, 2H), 7.23-7.33 (m, 3H), 7.58 (m, 1H), 8.10 (m, 1H), 9.53 (s, 1H, NH); MS (EI, m/z): 353/355 [M]+, 196.
62%	With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 1.25h;	1.D Step D. (2-Chloro-4-fluorophenyl)-(5,11-dihydro-pyrido [2,3-b] [1,5] benzodiazepin-6-yl)-methanone Step D. (2-Chloro-4-fluorophenyl)-(5,11-dihydro-pyrido [2,3-b] [1,5] benzodiazepin-6-yl)-methanone To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Step B (12.8 g, 65 mmol) in dimethylformamide (120 ML) under nitrogen was added potassium carbonate (19.76 g, 143 mmol).. The mixture was cooled and treated dropwise with a solution of crude 2-chloro-4-fluorobenzoyl chloride of Step C (78 mmol) in dimethylformamide (50 ML).. After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane.. The organic extracts were dried over magnesium sulfate and evaporated to dryness.. The crude material was purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate gradient from 95:5 to 80:20) to provide the pure title compound (14.25 g, 62%) along with some less pure material (2.7 g).. The pure material is an off-white crystalline solid, which is used as such in the next step. NMR (DMSO-d6, 400 MHz): δ 4.13 and 5.42 (dd, 2 H, CONCH2), 6.52 (m, 1H), 6.71-6.79 (m, 2H), 6.98-7.16 (2 m, 2H), 7.23-7.33 (m, 3H), 7.58 (m, 1H), 8.10 (m, 1H), 9.53 (s, 1H, NH) MS (EI, m/z): 353/355 [M]+, 196

With potassium carbonate In N-methyl-acetamide

1.D Step D. Step D. (2-Chloro-4-fluorophenyl)-(6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Step B (12.8 g, 65 mmol) in dimethylformamide (120 mL) under nitrogen was added potassium carbonate (19.76 g, 143 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-chloro-4-fluorobenzoyl chloride of Step C (78 mmol) in dimethylformamide (50 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate gradient from 95:5 to 80:20) to provide the pure title compound (14.25 g) along with some less pure material (2.7 g). The pure material is an off-white crystalline solid, which is used as such in the next step. NMR (DMSO-d6, 400 MHz): δ 4.13 and 5.42 (dd, 2H), 6.52 (m, 1H), 6.71-6.79 (m, 2H), 6.98-7.16 (m, 2H), 7.23-7.33 (m, 3H), 7.58 (m, 1H), 8.10 (m, 1H), 9.53 (s, 1H) MS (EI, m/z): 353/355 [M]+, 196

Reference： [1]Current Patent Assignee: PFIZER INC - US6090803, 2000, A
[2]Current Patent Assignee: PFIZER INC - US6194407, 2001, B1
[3]Current Patent Assignee: PFIZER INC - EP1000059, 2004, B1 Location in patent: Page 29
[4]Current Patent Assignee: PFIZER INC - US6235900, 2001, B1

7
[ 21900-54-9 ]
[ 22162-53-4 ]
[ 220461-65-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In hexane; dichloromethane	8 (2-Chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone The crude 2-chloro-4-fluorobenzoyl chloride (3.68 g) in dichloromethane (25 ml) was added portionwise to a stirred, ice cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.76 g), diisopropylethylamine (2.47 g) and dichloromethane (50 ml). After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried with anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (3.85 g), m.p. 110-112° C.
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h;	8 REFERENCE EXAMPLE 8; (2-Chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone The crude 2-chloro-4-fluorobenzoyl chloride (3.68 g) in dichloromethane (25 ml) was added portionwise to a stirred, ice cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.76 g), diisopropylethylamine (2.47 g) and dichloromethane (50 ml).. After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate.. The dichloromethane solution was dried with anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane.. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred.. After cooling, the crystals were collected by filtration to yield the title compound (3.85 g), m.p. 110-112 °C.
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h;	8 The crude 2-chloro-4-fluorobenzoyl chloride (3.68 g) in dichloromethane (25 ml) was added portionwise to a stirred, ice cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.76 g), diisopropylethylamine (2.47 g) and dichloromethane (50 ml). After 18 hours at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried with anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (3.85 g), m.p. 110-112° C.

Reference： [1]Current Patent Assignee: PFIZER INC - US6511974, 2003, B1
[2]Current Patent Assignee: PFIZER INC - EP1000062, 2004, B1 Location in patent: Page 32-33
[3]Current Patent Assignee: PFIZER INC - US6831079, 2004, B1 Location in patent: Page/Page column 38

8
[ 220461-04-1 ]
[ 21900-54-9 ]
[ 220461-18-7 ]

Yield	Reaction Conditions	Operation in experiment
	With diisopropylamine In dichloromethane	37 {4-[1-(2-Chloro-4-fluoro-benzoyl)-1H-pyrazol-3-yl]-phenyl}-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl}methanone EXAMPLE 37 {4-[1-(2-Chloro-4-fluoro-benzoyl)-1H-pyrazol-3-yl]-phenyl}-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl}methanone Portionwise, 2-chloro-4-fluorobenzoyl chloride (0.82 g) was added to a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g) and diisopropylamine (0.55g) in dichloromethane (25 ml) which was cooled in an ice bath. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was washed with water and saturated sodium bicarbonate and dried over anhydrous sodium sulfate. The dichloromethane solution was passed through a short column of hydrous sodium magnesium silicate, eluding several additional volumes of dichloromethane. The eluent was evaporated to dryness to yield 1.06 g of the product as a solid, m.p. 150-157° C.; MS, m/z: 510 (M)+.
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;	37 EXAMPLE 37; {4-[1-(2-Chloro-4-fluoro-benzoyl)-1H-pyrazol-3-yl]-phenyl}-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone EXAMPLE 37 {4-[1-(2-Chloro-4-fluoro-benzoyl)-1H-pyrazol-3-yl]-phenyl}-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone Portionwise, 2-chloro-4-fluorobenzoyl chloride (0.82 g) was added to a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g) and diisopropylamine (0.55g) in dichloromethane (25 ml) which was cooled in an ice bath.. The reaction mixture was allowed to stir at room temperature overnight.. The reaction mixture was washed with water and saturated sodium bicarbonate and dried over anhydrous sodium sulfate.. The dichloromethane solution was passed through a short column of hydrous sodium magnesium silicate, eluding several additional volumes of dichloromethane.. The eluent was evaporated to dryness to yield 1.06 g of the product as a solid, m.p. 150-157 °C; MS, m/z: 510 (M)+.
	With diisopropylamine In dichloromethane at 0 - 20℃;	37 EXAMPLE 37; {4-[1-(2-Chloro-4-fluoro-benzoyl)-1H-pyrazol-3-yl]-phenyl}-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl}methanone Portionwise, 2-chloro-4-fluorobenzoyl chloride (0.82 g) was added to a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g) and diisopropylamine (0.55g) in dichloromethane (25 ml) which was cooled in an ice bath. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was washed with water and saturated sodium bicarbonate and dried over anhydrous sodium sulfate. The dichloromethane solution was passed through a short column of hydrous sodium magnesium silicate, eluting several additional volumes of dichloromethane. The eluent was evaporated to dryness to yield 1.06 g of the product as a solid, m.p. 150-157° C.; MS, m/z: 510 (M)+.

Reference： [1]Current Patent Assignee: PFIZER INC - US6511974, 2003, B1
[2]Current Patent Assignee: PFIZER INC - EP1000062, 2004, B1 Location in patent: Page 39
[3]Current Patent Assignee: PFIZER INC - US6831079, 2004, B1 Location in patent: Page/Page column 47

9
1-methyl-4-(3-aminophenylamino)piperidine [ No CAS ]
[ 21900-54-9 ]
2-chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With triethylamine In tetrahydrofuran at 20 - 26℃; for 2h;	1 Example 1. 2-Chloro-4-fluoro-N- (3- (1-methylpiperidin-4-ylamino) phenyl) benzamide dihydrochloride Combine 2-chloro-4-fluoro-N- (3-aminophenyl) benzamide (Preparation 1,200 mg, 0.756 mmol), 1-methylpiperidin-4-one (0.093 mL, 0.756 mmol), sodium triacetoxyborohydride (208 mg, 0.982 mmol), acetic acid (0.043 mL, 0.756 mmol) and dichloromethane (8 mL). Stir at room temperature overnight. Dilute with dichloromethane (5 mL) and wash twice with sodium hydroxide (10 mL IN aq. ). Combine the organic layers and wash with saturated aqueous NaCl (10 mL). Dry over magnesium sulfate, filter under reduced pressure and concentrate to dryness. Purify by flash chromatography on a Biotage silica cartridge eluting with a 20/1 mixture of dichloromethane and 2N ammonia in methanol to give the free base of the title compound (239 mg, 87%). Dissolve the residue in diethyl ether and treat with ethereal hydrogen chloride. Triturate the resulting gum with ether to give the title compound as a white solid (31 mg): mp 180°C ; mass spectrum (free base, ion spray): milz = 362.1 (M+1), 1H NMR (free base, CDC13) : 7.80-7. 75 (m, 2H), 7.23 (bs, 1H), 7.19 (dd, J= 2.4 Hz, 8.3 Hz, 1H), 7.13 (t, J= 8.2 Hz, 1H), 7. 08 (dd, J= 2.4 Hz, 8.3 Hz, 1H), 6.67 (d, J= 7.8 Hz, 1H), 6.41 (dd, J= 2.0 Hz, 8. 3 Hz, 1H), 3.68 (bd, J= 7.9 Hz, 1H), 3.36 (bs, 1H), 2.92-2. 81 (bm, 2H), 2.35 (s, 3H), 2.82-2. 17 (bm, 2H), 2.10 (bd, J= 13.0 Hz, 2H), 1.64-1. 51 (bm, 2H). Analysis calc'd for CsClsFNsO : C, 51.95 ; H, 5. 39 ; N, 9.57. Found: C, 52.03 ; H, 5.46 ; N, 9.17. Alternatively, to a solution of 1-methyl-4- (3-aminophenylamino) piperidine (92 g, 17mmol) and triethylamine (156 mL, 39 mmol) in dry THF (1 L), add dropwise 2-chloro- 4-fluorobenzoyl chloride (3.6 g, 18. 6 mmol), under nitrogen, over 1 hr., keeping the Amass between 20°C and 26°C. Agitate the suspension at room temperature for 1 hr. Quench the reaction mixture with water (100 mL) and 30% NaOH (40 mL) to obtain a biphasic solution (pH-8-9). Extract with methyl t-butyl ether (500 mL), wash the organic layer with water (lOOmL), dry over MgS04, and concentrate under reduced pressure to obtain 2-Chloro-4-fluoro-N- (3- (1-methylpiperidin-4-ylamino) phenyl) benzamide as an amorphous solid. Suspend the solid with methyl t-butyl ether (400 mL) and warm the mixture under reflux for 2 hr. Cool the mixture to room temperature, add cyclohexane (100 mL) and methyl t-butyl ether (250 mL). Filter the resulting crystals, rinse with methyl t-butyl ether (160 mL) and dry under reduced pressure at 50°C overnight to obtain 2-Chloro-4-fluoro-N- (3- (1-methylpiperidin-4-ylamino) phenyl) benzamide as a white powder (123 g, 76% yield).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2005/35499, 2005, A1 Location in patent: Page/Page column 50

10
[ 850083-44-2 ]
[ 21900-54-9 ]
2-chloro-4-fluoro-N-(2-fluoro-3-(1-methyl-piperidinylamino)-phenyl)-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 2-fluoro-N-(1-methylpiperidin-4-yl)benzene-1,3-diamine; 2-chloro-4-fluorobenzoyl chloride In 1,4-dioxane for 2h; Heating / reflux; Stage #2: With ammonia In methanol; dichloromethane	43 Example 43. 2-Chloro-4-fluoro-N- (2-fluoro-3- (1-methyl-piperidinylamino)-phenyl)- benzamide Mix 2-fluoro-N-(l-methyl-piperidin-4-yl)-benzene-1, 3-diamine (Preparation 20) (0.08 g) and 2-chloro-4-fluorobenzoyl chloride (83 mg) in 1,4-dioxane (5 mL) and heat at reflux for 2 hr. Partition the reaction mixture between ethyl acetate and saturated saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (10 g) (dichloromethane-2M NH3 in methanol, gradient) to give 0.106 g of the title compound (78% yield): mass spectrum (ion spray) : 7nez = 380 (M+1) ; 1H NMR (CDC13) : 8.19 (br s, 1H), 7.83 (dd, 1H), 7.66 (dd, 1H), 7.19 (dd, 1H), 7.09 (ddd, lH), 7.00 (dd, 1H), 6.52 (ddd, 1H), 3.76 (br d, 1H), 3.29 (m, 1H), 2.81 (br d, 2H), 2.29 (s, 3H), 2.13 (m, 2H), 2.05 (m, 2H), 1.52 (m, 2H). Dissolve the benzamide in methanol, add 0.28 mL of 1 N HCl in ether and evaporate to give its mono-hydrochloric acid salt.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2005/35499, 2005, A1 Location in patent: Page/Page column 73

11
[ 850083-52-2 ]
[ 21900-54-9 ]
2-chloro-4-fluoro-N-(3-fluoro-5-(methyl-(1-methyl-piperidin-4-yl)-amino)-phenyl)-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 1-methyl-4-(N-(3-amino-5-fluorophenyl)methylamino)piperidine; 2-chloro-4-fluorobenzoyl chloride In 1,4-dioxane for 3h; Heating / reflux; Stage #2: With ammonia In methanol	48 Example48. 2-Chloro-4-fluoro-N-(3-fluoro-5-(methyl-(1-metllyl-piperidin-4-yl)-amino)- phenyl)-benzamide; Combine 5-fluoro-N-methyl-N- (l-methyl-piperidin-4-yl)-benzene-1, 3-diamine (Preparation 29,0. 036 g, 0.15 mmol), 2-chloro-4-fluoro-benzoyl chloride (0.044 g, 0.23 mmol) and 1,4-doxane (2 mL), stir and heat at reflux. After 3 hr, cool to ambient temperature. Load on a SCX column (10 g), wash with methanol, elute with 2M ammonia-methanol. Concentrate eluent to obtain 0.059 g (100%) the title compound as a free base. Dissolve this material in dichloromethane (5 mL) and treat with 1M hydrochloric acid in ether (0.15 mL, 0.15 mmol). Concentrate to give the title compound as a brown powder: high resolution mass spectrum: Obs. m/z 394.1495 ; Calc. m/z 394.1497 ; 1H NMR (CDCI3) of free base: 7.8 (bs, 1H), 7.7 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1 H), 6.8 (s, 1H), 6.7 (m, 1H), 6.2 (m, 1 H), 3.5 (m, 1H), 2.9 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.1 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2005/35499, 2005, A1 Location in patent: Page/Page column 75-76

12
[ 364-76-1 ]
[ 21900-54-9 ]
[ 850083-36-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	In 1,4-dioxane at 20℃;	13 Preparation 13. 2-Chloro-4-fluoro-N- (4-fluoro-3- nitrophenyl) benzamide; Combine 4-fluoro-3-nitroaniline (1.0 g, 6.4 mmol) with dioxane (20 mL). Treat mixture with 2-chloro-4-fluorobenzoyl chloride (1.6 g, 8.3 mmol). Stir the reaction overnight at room temperature. Transfer the reaction mixture into ethyl acetate (220 mL), then wash successively with aqueous HCl (1N, 50 mL), aqueous NaOH (1N, 50 mL), saturated aqueous NaCl (50 mL). Dry the organic layer over anhydrous sodium sulfate, then evaporate the solvent under reduced pressure. Further purify the residue by chromatography on silica gel, using a gradient of 10-30% ethyl acetate in hexanes to obtain the title intermediate (1.7 g, 85% yield): mass spectrum (ion spray) : m/z = 313.0 (M+1).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2005/35499, 2005, A1 Location in patent: Page/Page column 31

13
[ 21900-54-9 ]
2-chloro-4-fluoro-N-[3-(1-methylpiperidin-4-ylsulfanyl)phenyl]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: 3-(1-methylpiperidin-4-ylsulfanyl)phenylamine With pyridine In dichloromethane at 0℃; Stage #2: 2-chloro-4-fluorobenzoyl chloride In dichloromethane at 20℃; for 2h;	171 Combine pyridine (0.110 mL, 1.36 MMOL), 3- (1-METHYL-PIPERIDIN-4-YLSULFANYL)- PHENYLAMINE (preparation 76,151 mg, 0.679 mmol) in dichloromethane (6.5 mL) at 0°C. Stir and add 2-CH] ORO-4-FLUOROBENZOYL CHLORIDE (0.105 mL, 0.815 mmol). Allow to warm to ambient temperature and stir. After 2HR., dilute with dichloromethane (10 mL) and wash with sodium hydroxide (1N, 3x10 mL). Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purification by flash chromatography, eluting with DICHLOROMETHANE/AMMONIA (2.0 N in methanol) [20/1] to give the title compound as free base (184 MG, 72%). Dissolve the residue in diethyl ether and treat with ethereal hydrogen chloride (1.0 M). Triturate the resulting gum with ether to give the title compound as the hydrogen chloride SALT. H NMR (free base, CDCI3) : 8. 37 (bs, 1H), 7.65 (s, 1H), 7. 58 (t, J= 6.8 Hz, 1H), 7.42 (d, J= 7.7 Hz, 1H), 7.21 (t, J= 7. 8 Hz, 1H), 7.14-7. 06 (m, 2H), 6.99-6. 93 (m, 1H), 3.05 (bs, 1H), 2. 71 (bd, J= 11. 5 Hz, 2H), 2.19 (s, 3H), 2.03-1. 90 (m, 4H), 1.67-1. 56 (m, 2H). 3C NMR (free base, CDCI3) : 164.9, 162.2 (d, JC-F = 167.7 Hz), 137.9, 135.8, 132.0, 131.7 (d, JC-F= 8.6 HZ), 131.4, 129. 3, 128.0, 123.0, 118.6, 117.5 (D, JCF=25. 0 Hz), 114.5 (D,./C-F=21. 3 Hz), 54.9, 46.0, 43.6, 32.4.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2004/94380, 2004, A1 Location in patent: Page 148-149

14
[ 478366-23-3 ]
[ 21900-54-9 ]
2-chloro-4-fluoro-N-[6-(1-methylpiperidin-4-yloxy)pyridin-2-yl]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With pyridine at 55℃; for 4h;	160 Dissolve 6- (1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 60,150 mg, 0.724 mmol) in pyridine (20 mL). Add 2-chloro-4-fluorobenzoyl chloride (208 mg, 1.08 mmol) and heat at 55 °C. After 4 hr. , cool to room temperature, concentrate and load residue onto a 5 g SCX cartridge. Wash resin with methanol, then remove product with 2 M NH3/METHANOL. Concentrate in vacuo, and silica gel chromatography eluting with 2- 10% methanol/methylene dichloride to give the free base (280 mg, 97%). Dissolve the purified oil in methanol, add NH4CI (1 eq) as a solid, and SONICATE the solution at room temperature for 15 min. Concentration in vacuo provides the title compound (280 MG, 97%). Mass spectrum (ion spray): M/Z 364.0 (M+1) ; Analysis calculated for CL8HL9N302C] 2F-0. 5 H20. Theory: C, 52.82, H, 5. 17, N, 10.27. Found: C, 52.89, H, 5.18, N, 10.37 ; MP = 135-137°C.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2004/94380, 2004, A1 Location in patent: Page 142-143

15
[ 790668-18-7 ]
[ 21900-54-9 ]
2-chloro-N-[6-(1-cyclopropylmethylpiperidin-4-yloxy)pyridin-2-yl]-4-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With pyridine at 55℃; for 15h;	167 Add 2-CHLORO-4-FLUOROBENZOYL chloride (149 mg, 0. 58 mmol) to a solution of 6-(1- CYCLOPROPYLMETHYL-PIPERIDIN-4-YLOXY)-PYRIDIN-2-YLAMINE (preparation 70, 130 mg, 0.53 mmol) in pyridine (7 mL) and heat at 55 °C for 15 hr. Remove pyridine in vacuo, dissolve the residue in CH2CL2, wash with saturated NAHC03 solution, dry over NA2SO4, filter and concentrate to give a residue. Chromatography (silica gel, eluting with 5% 2M NH3-METHANOL in CH2CL2) provides 170 mg (79%) of the title compound: mass spectrum (ion spray): 404.1 (M+1) ; H NMR (CDCI3, PPM) : 8.08 (S, 1H), 7.63 (m, 2H), 7.52 (t, 1H), 7.11 (m, 1H), 6.99 (m, 1H), 6.41 (d, 1H), 4.82 (m, 1H), 2.72 (m, 2H), 2.26 (m, 2H), 2.17 (d, 2H), 1.89 (m, 2H), 1.69 (m, 2H), 0.77 (m, 1H), 0.40 (m, 2H), 0.00 (m, 2H). Hydrochloride salt: Analytical calc. for C2] H23CIFN302-HCI-0. 5H20: C, 56.13 ; H, 5.61 ; N, 9.35. Found: C, 56.12 ; H, 5.30 ; N, 9. 35.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2004/94380, 2004, A1 Location in patent: Page 146

16
[ 21900-54-9 ]
[ 790667-68-4 ]
[ 790668-62-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With pyridine In dichloromethane at 0 - 20℃; for 1.5h;	77 Add pyridine (0.66 mL, 8.21 mmol) to a solution of 4- (3-amino-phenoxy)- PIPERIDINE-1-CARBOXYLIC acid TERT-BUTYL ester (preparation 30,2. 0 g, 6.84 mmol) in dichloromethane (35 mL) at 0°C. Stir and add 2-chloro-4-fluorobenzoyl chloride dropwise (1.45 g, 7. 52 mmol). Stir at 0°C for 30 min and 1 HR. at room temperature. Dilute with dichloromethane (30 mL) and wash with sodium hydroxide (IN, 2x25 mL). Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purification by flash chromatography, eluting with ethyl acetate/hexanes [20- 40%] to give the title compound (3.0 g, 98%). Mass spectrum (ion spray): m/z = 449.0 (M+1) ; H NMR (CDC13) : 7.87 (bs, N-H), 7.80 (dd, J = 6.1 Hz, 8.6 Hz, 1H), 7.48 (s, 1H), 7. 28-7. 24 (m, 1H), 7.21 (dd, J = 2. 5 HZ, 8. 4 Hz, 1H), 7.11 (td, J= 2. 2 HZ, 8. 4 HZ, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.73 (dd, J= 2.2 Hz, 8.4 Hz, 1H), 4.52 (septet, J = 3.6 Hz, 1H), 3.69 (ddd, J= 3.7 Hz, 7. 7 Hz, 13. 6 Hz, 2H), 3. 3-5 (DDD,-J= 3. 9 Hz, 7.7 Hz, 1-3. 6 Hz, 2H), 1.97-1. 89 (m, 2H), 1.81-1. 72 (m, 2H), 1.46 (s, 9H).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2004/94380, 2004, A1 Location in patent: Page 76

17
[ 790667-73-1 ]
[ 21900-54-9 ]
4-[3-(2-chloro-4-fluorobenzoylamino)phenoxy]-2-methylpiperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In 1,4-dioxane for 4h;	78 Combine 4- (3-AMINO-PHENOXY)-2-METHYL-PIPERIDINE-1-CARBOXYLIC acid test-butyl ester cis isomer 1 (preparation 35,0. 40 g, 1.31 MMOL), 1, 4-dioxane (20 mL), triethylamine (0.22 mL, 1.57 mmol) and 2-CHLORO-4-FLUORO-BENZOYL chloride (0.30 g, 1.57 mmol) with stirring. After 4 hr., partition between 4: 1 hexane : ethyl acetate (100. ML) AND 0.5M aqueous sodium hydroxide solution (100 mL). Separate the organic layer, dry over sodium sulfate, filter and concentrate to obtain of the title compound (0.60 g, 100%) : 1H NMR (CDCl3) : 7.9 (bs, 1H), 7. 8 (dd, 1H), 7.45 (m, 1H), 7.25 (m, 1H), 7.2 (dd, 1H), 7. 1 (m, 1H), 7.0 (dd, 1H), 6.7 (dd, 1H), 4.7 (m, 1H), 4. 35 (m, 1H), 3.9 (m, 1H), 3.25 (m, 1H), 2.0 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.45 (s, 9H), 1.3 (d, 3H).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2004/94380, 2004, A1 Location in patent: Page 93

18
[ 790667-82-2 ]
[ 21900-54-9 ]
4-[3-(2-chloro-4-fluorobenzoylamino)phenoxy]-cis-2-methylpiperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In tetrahydrofuran at 20℃; for 18h;	86 Combine 4-(3-amino-phenoxy)-cis-2-methyl-piperidine-1-carboxylic acid tert- butyl ester isomer 2 (preparation 39,0. 29 g), triethyl amine (95 mg), and 2-ch] oro-4- fluorobenzoyl chloride (0.201 g) in THF (10 mL) and stir at room temperature. After 18 hr. , partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and dry in vacuum to give the title compound (0.464 g). Mass spectrum (electrospray) m/z = 461 (M-1) ; H NMR (CDC] 3) : 7.87 (br s, 1H), 7.72 (dd, I H), 7. 37 (t, 1H), 7.19 (DD, 1H), 7.13 (dd, 1H), 7.02 (ddd, 1H), 6.97 (dd, 1H), 6.64 (dd, 1H), 4.63 (m, 1H), 4. 28 (M, 1H), 3.81 (m, 1H), 3.20 (m, 1H), 1. 88 (m, 2H), 1. 81 (m, 1H), 1.67 (m, 1H), 1.40 (s, 9H), 1.24 (d, J= 7.1 Hz, 3H). (file : MN4-A01246-76).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2004/94380, 2004, A1 Location in patent: Page 102-103

19
3-(1-benzyl-3-methylpiperidin-4-yloxy)phenylamine [ No CAS ]
[ 21900-54-9 ]
N-[3-(1-benzyl-3-methylpiperidin-4-yloxy)phenyl]-2-chloro-4-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.7%	In 1,4-dioxane for 2h; Heating / reflux;	80 Combine racemic 3- (I-BENZYL-CIS-3-METHYL-PIPERIDIN-4-YLOXY)-PHENYLAMINE (preparation 41,0. 80 g, 2.7 mmol), 1, 4-dioxane (20 mL), and 2-chloro-4-fluoro-benzoyl chloride (0.625 g, 3.24 MMOL), stir and heat at reflux. After 2 HR., cool to ambient temperature. Dilute with methanol and load the resulting solution on 2 1 Og SCX columns. Wash each with methanol (2X50 ML). Elute product from each column with 2M AMMONIA/METHANO] (2x50 mL). Combine and concentrate the eluent. Purify residue by silica gel flash chromatography eluting with 5% (2M NH3/METHANOL)/METHYLENE dichloride to obtain the title compound as a racemic mixture (1.07 g, 87.7%). Resolve using a CHIRALPAK ADTM 4.6 x 250mm column eluting at 1.0 ML/MIN. with 10% absolute ethanol/90% Heptane with 0.2% DMEA to obtain of the title compound (0.524 g, 49.0%). Mass spectrum (electrospray): M/Z = 453.2 (M+1) ; H NMR (CDC13) : 7.85 (bs, 1H), 7.8 (dd, 1H), 7.45 (S, IH), 7.3 (M, 7H), 7.1 (m, 1H), 7.0 (m, 1H), 6.75 (dd, 1H), 4.4 (m, 1H), 3.5 (m, 2H), 2.5 (m, 2H), 2.4 (m, 2H), 2.1 (m, 2H), 1.8 (m,1H), 1.0 (d, 3H).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2004/94380, 2004, A1 Location in patent: Page 96-97

20
[ 855531-22-5 ]
[ 21900-54-9 ]
2-[(2-chloro-4-fluorobenzoyl)-(4-trifluoromethoxyphenyl)amino]-thiazole-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In tetrahydrofuran at 50℃; for 48h;	1.U A mixture of 2.0 g (6.6 mmol) 2- (4- (trifluoromethoxy) phenylamino) -thiazole-4- carboxylic acid, 3.17 g (16.4 mmol) 2-chloro-4-fluorobenzoyl chloride and 0.92 g (6.6 mmol) potassium carbonate in 50 mL THF was stirred at 50°C for 48 h. After evaporation of the volatiles the residue was partitioned between water and ethyl acetate. Organic phases were pooled, dried with MgS04 and the solvent was removed in vacuo. Crystallisation from n-heptane/ethyl acetate yielded 3.4 g of the title compound which was used without further purification. MS (m/e): 459.0, 461.0 (M-H)

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2005/58887, 2005, A1 Location in patent: Page/Page column 48

21
[ 79-37-8 ]
[ 2252-51-9 ]
[ 21900-54-9 ]

Yield	Reaction Conditions	Operation in experiment
	In <i>N</i>-methyl-acetamide; dichloromethane	8 (2-Chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone EXAMPLE 8 (2-Chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone Oxalyl chloride (2.60 g) was added to a suspension of 2-chloro-4-fluorobenzoic acid (3.44 g) in dichloromethane (50 ml). Two drops of dimethylformamide were added and the mixture was stirred for 18 hours at room temperature. The resultant solution was evaporated to give the crude 2-chloro-4-fluorobenzoyl chloride as a viscous oil (3.72 g).
	In <i>N</i>-methyl-acetamide; dichloromethane	1.C Step C. Step C. 2-Chloro-4-fluorobenzoyl chloride A suspension of the 2-chloro-4-fluorobenzoic acid (13.61 g, 78 mmol) in dichoromethane (85 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with a 2M solution of oxalyl chloride in dichloromethane (1.2 equivalents). After gas evolution subsided, the reaction mixture was refluxed for an additional 25 minutes and then evaporated to dryness in vacuo. The crude acid chloride was used as such in the next step.
	In <i>N</i>-methyl-acetamide; dichloromethane	1.C Step C. Step C. 2-Chloro-4-fluorobenzoyl chloride A suspension of the 2-chloro-4-fluorobenzoic acid (13.61g, 78 mmol) in dichloromethane (85 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with a 2M solution of oxalyl chloride in dichloromethane (1.2 equivalents). After gas evolution subsided, the reaction mixture was refluxed for an additional 25 minutes and then evaporated to dryness in vacuo. The crude acid chloride was used as such in the next step.

	In <i>N</i>-methyl-acetamide; dichloromethane	1.C Step C. Step C. 2-Chloro-4-fluorobenzoyl chloride A suspension of the 2-chloro-4-fluorobenzoic acid (13.61 g, 78 mmol) in dichloromethane (85 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with a 2M solution of oxalyl chloride in dichloromethane (1.2 equivalents). After gas evolution subsided, the reaction mixture was refluxed for an additional 25 minutes and then evaporated to dryness in vacuo. The crude acid chloride was used as such in the next step.
	In <i>N</i>-methyl-acetamide; dichloromethane	1.C Step C. Step C. 2-Chloro-4-fluorobenzoyl chloride A suspension of the 2-chloro-4-fluorobenzoic acid (13.61 g, 78 mmol) in dichloromethane (85 mL) containing a few drops of dimethylformamide was treated dropwise under nitrogen with a 2M solution of oxalyl chloride in dichloromethane (1.2 equivalents). After gas evolution subsided, the reaction mixture was refluxed for an additional 25 minutes and then evaporated to dryness in vacuo. The crude acid chloride was used as such in the next step.

Reference： [1]Current Patent Assignee: PFIZER INC - US6511974, 2003, B1
[2]Current Patent Assignee: PFIZER INC - US6090803, 2000, A
[3]Current Patent Assignee: PFIZER INC - EP1149096, 2002, B1
[4]Current Patent Assignee: PFIZER INC - US6194407, 2001, B1
[5]Current Patent Assignee: PFIZER INC - US6235900, 2001, B1

22
[ 21900-54-9 ]
[ 182564-38-1 ]
5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.921 gm (68.2%)	With sodium hydroxide; triethylamine In tetrahydrofuran; <i>N</i>-methyl-acetamide; ethyl acetate	181 Alternate Synthesis of 5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole EXAMPLE 181 Alternate Synthesis of 5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole To a suspension of 0.804 gm (3.5 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 10 mL tetrahydrofuran and 5.0 mL dimethylformamide were added 0.586 mL (4.2 mMol) triethylamine followed by a solution of 0.744 gm (3.86 mMol) 2-chloro-4-fluorobenzoyl chloride in 5 mL tetrahydrofuran. After 18 hours the reaction mixture was diluted with ethyl acetate followed by 2N sodium hydroxide. The phases were separated and the aqueous extracted with ethyl acetate. The organic extracts were combined then washed sequentially with 2N sodium hydroxide, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography, eluding with 100:10:1 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure. The residue was precipitated from ethyl acetate to give 0.921 gm (68.2%) of the title compound as a light pink powder. m.p.=159°-162° C. MS(m/e): 385(M+) Calculated for C21 H21 N3 OClF: Theory: C, 65.37; H, 5.49; N, 10.89. Found: C, 65.15; H, 5.55; N, 10.74.
0.921 gm (68.2%)	With sodium hydroxide; triethylamine In tetrahydrofuran; <i>N</i>-methyl-acetamide; ethyl acetate	181 Alternate Synthesis of 5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole EXAMPLE 181 Alternate Synthesis of 5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole To a suspension of 0.804 gm (3.5 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 10 mL tetrahydrofuran and 5.0 mL dimethylformamide were added 0.586 mL (4.2 mMol) triethylamine followed by a solution of 0.744 gm (3.86 mMol) 2-chloro-4-fluorobenzoyl chloride in 5 mL tetrahydrofuran. After 18 hours the reaction mixture was diluted with ethyl acetate followed by 2N sodium hydroxide. The phases were separated and the aqueous extracted with ethyl acetate. The organic extracts were combined then washed sequentially with 2N sodium hydroxide, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography, eluding with 100:10:1 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure. The residue was precipitated from ethyl acetate to give 0.921 gm (68.2%) of the title compound as a light pink powder. m.p.=159-162°C MS(m/e): 385(M+) Calculated for C21H21N3OClF: Theory: C, 65.37; H, 5.49; N, 10.89. Found: C, 65.15; H, 5.55; N, 10.74.
0.921 gm (68.2%)	With sodium hydroxide; triethylamine In tetrahydrofuran; <i>N</i>-methyl-acetamide; ethyl acetate	181 Alternate Synthesis of 5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole EXAMPLE 181 Alternate Synthesis of 5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole To a suspension of 0.804 gm (3.5 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 10 mL tetrahydrofuran and 5.0 mL dimethylformamide were added 0.586 mL (4.2 mMol) triethylamine followed by a solution of 0.744 gm (3.86 mMol) 2-chloro-4-fluorobenzoyl chloride in 5 mL tetrahydrofuran. After 18 hours the reaction mixture was diluted with ethyl acetate followed by 2N sodium hydroxide. The phases were separated and the aqueous extracted with ethyl acetate. The organic extracts were combined then washed sequentially with 2N sodium hydroxide, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography, eluding with 100:10:1 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure. The residue was precipitated from ethyl acetate to give 0.921 gm (68.2%) of the title compound as a light pink powder. m.p.=159-162°C MS(m/e): 385(M+) Calculated for C21H21N3OClF: Theory: C, 65.37; H, 5.49; N, 10.89. Found: C, 65.15; H, 5.55; N, 10.74.

0.921 gm (68.2%)

With sodium hydroxide; triethylamine In tetrahydrofuran; N-methyl-acetamide; ethyl acetate

181 Alternate Synthesis of 5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole EXAMPLE 181 Alternate Synthesis of 5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methylpiperidin-4-yl)-1H-indole To a suspension of 0.804 gm (3.5 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 10 mL tetrahydrofuran and 5.0 mL dimethylformamide were added 0.586 mL (4.2 mMol) triethylamine followed by a solution of 0.744 gm (3.86 mMol) 2-chloro-4-fluorobenzoyl chloride in 5 mL tetrahydrofuran. After 18 hours the reaction mixture was diluted with ethyl acetate followed by 2N sodium hydroxide. The phases were separated and the aqueous extracted with ethyl acetate. The organic extracts were combined then washed sequentially with 2N sodium hydroxide, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography, eluding with 100:10:1 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure. The residue was precipitated from ethyl acetate to give 0.921 gm (68.2%) of the title compound as a light pink powder. m.p.=159-162° C. MS(m/e): 385(M+); Calculated for C21 H21 N3 OClF: Theory: C, 65.37; H, 5.49; N, 10.89. Found: C, 65.15; H, 5.55; N, 10.74.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - US5708008, 1998, A
[2]Current Patent Assignee: ELI LILLY & CO - EP824917, 1998, A2
[3]Current Patent Assignee: ELI LILLY & CO - EP832650, 1998, A2
[4]Current Patent Assignee: ELI LILLY & CO - US5962473, 1999, A

23
[ 180340-73-2 ]
[ 21900-54-9 ]
N-[4-[(4,5-Dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(1H)-yl)carbonyl]phenyl]-2-chloro-4-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; sodium hydrogencarbonate; triethylamine; citric acid In methanol; hexane; dichloromethane; water; ethyl acetate	1 N-[4-[(4,5-Dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(1H)-yl)carbonyl]phenyl]-2-chloro-4-fluorobenzamide EXAMPLE 1 N-[4-[(4,5-Dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(1H)-yl)carbonyl]phenyl]-2-chloro-4-fluorobenzamide To an ice bath cooled mixture of 296 mg of 6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine in 3.5 ml of methylene chloride is added 417 μl of triethylamine followed by a solution of 483 mg of 2-chloro-4-fluorobenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. An additional 40 ml of methylene chloride is added followed by 20 ml of water. The organic layer is washed with 20 ml each of 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried (Na2 SO4), filtered through hydrous magnesium silicate and the filtrate evaporated in vacuo to give a residue which is crystallized from ethyl acetate:hexane to give 520 mg of a white solid. To a suspension of 340 mg of the preceding compound in 5 ml methanol is added 1.2 ml of 1N NaOH. The reactants are stirred at room temperature for 1 hour. The reaction mixture is evaporated in vacuo to a residue which is diluted with 100 ml of ethyl acetate and filtered. The filtrate is washed with 30 ml each of water, brine and dried (NaSO4). The organic layer is passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is stirred with ethyl acetate:hexane to give 255 mg of white crystalline solid, m.p. 258°-266° C.
	With sodium hydroxide; sodium hydrogencarbonate; triethylamine; citric acid In methanol; hexane; dichloromethane; water; ethyl acetate	1 N-[4-[(4,5-Dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(1H)-yl)carbonyl]phenyl]-2-chloro-4-fluorobenzamide EXAMPLE 1 N-[4-[(4,5-Dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(1H)-yl)carbonyl]phenyl]-2-chloro-4-fluorobenzamide To an ice bath cooled mixture of 296 mg of 6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]-thieno[3,2-b]azepine in 3.5 ml of methylene chloride is added 417 μ1 of triethylamine followed by a solution of 483 mg of 2-chloro-4-fluorobenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. An additional 40 ml of methylene chloride is added followed by 20 ml of water. The organic layer is washed with 20 ml each of 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried (Na2 SO4), filtered through hydrous magnesium silicate and the filtrate evaporated in vacuo to give a residue which is crystallized from ethyl acetate:hexane to give 520 mg of a white solid. To a suspension of 340 mg of the preceding compound in 5 ml methanol is added 1.2 ml of 1N NaOH. The reactants are stirred at room temperature for 1 hour. The reaction mixture is evaporated in vacuo to a residue which is diluted with 100 ml of ethyl acetate and filtered. The filtrate is washed with 30 ml each of water, brine and dried (NaSO4). The organic layer is passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is stirred with ethyl acetate:hexane to give 255 mg of white crystalline solid, m.p. 258°-266° C.

Reference： [1]Current Patent Assignee: PFIZER INC - US5532235, 1996, A
[2]Current Patent Assignee: PFIZER INC - US5719278, 1998, A

24
[ 21900-54-9 ]
[ 52779-53-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide In thiophene; toluene; benzene	IV EXAMPLE IV EXAMPLE IV To a stirred mixture of 25.25 parts of thiophene, 58.1 parts of 2-chloro-4-fluorobenzoyl chloride and 200 parts of anhydrous benzene are added dropwise 78.16 parts of stannic chloride (fuming) at room temperature (slightly exothermic reaction: the temperature is kept for 3 hours at 25° C). The reaction mixture is poured onto a mixture of crushed ice and concentrated hydrochloric acid solution. The while is stirred for a few minutes and the layers are separated. The organic layer is diluted with 80 parts of toluene, washed successively with 200 parts of sodium hydroxide solution 5% and with 200 parts of water, dried and evaporated. The residue is distilled, yielding 2-chloro-4-fluorophenyl 2-thienyl ketone; bp. 129°-130° C at 0.5 mm pressure.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US4035376, 1977, A

25
[ 150705-53-6 ]
[ 21900-54-9 ]
[ 1146411-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;	3 Example 3 4-[(2-Chloro-4-fluorophenyl)carbonyl]-1-(2-methylphenyl)-2-piperazinone (E3); A solution of 1-(2-methylphenyl)-2-piperazinone (146 mg, 0.77 mmol, prepared as described above for Example 1 ) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.20 ml, 1.15 mmol) in dichloromethane (4 ml) was stirred at O0C under argon. 2-Chloro- 4-fluorobenzoyl chloride (148 mg, 0.77 mmol) was added portionwise. The mixture was allowed to warm to room temperature and was stirred over the weekend. Dichloromethane and aqueous 3N citric acid were added and the resulting mixture was extracted into dichloromethane (x2). The dichloromethane layers were combined and washed sequentially with water (x1 ), saturated aqueous sodium hydrogen carbonate (x1 ), water (x1 ), and brine (x1 ), and then dried over magnesium sulphate. The solvent was evaporated in vacuo and the crude product purified by flash-silica gel chromatography, eluting with 0-60% ethyl acetate in isohexane, to give 4-[(2- chloro-4-fluorophenyl)carbonyl]-1-(2-methylphenyl)-2-piperazinone (54mg) as a white solid. LC/MS [M+H]+ = 347, retention time = 2.51 minutes.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/53459, 2009, A1 Location in patent: Page/Page column 35

26
[ 21900-54-9 ]
[ 1146411-40-6 ]
[ 1146411-39-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;	5 Example 54-[(2-Chloro-4-fluorophenyl)carbonyl]-1-(2-chlorophenyl)-2-piperazinone (E5); 1-(2-Chlorophenyl)-2-piperazinone hydrochloride (100mg, 0.41 mmol) and λ/-ethyl-/V- (1-methylethyl)-2-propanamine (0.11 ml, 0.61 mmol) were added together in dichloromethane (4 ml) at O0C. Subsequently 2-chloro-4-fluorobenzoyl chloride (86 mg, 0.45 mmol) was added portionwise. The reactants were left under argon and in an icebath and allowed to return to room temperature whilst being stirred constantly overnight. Dichloromethane and aqueous 3N citric acid were added and the mixture was extracted into dichloromethane (x2). The dichloromethane layers were combined and washed sequentially with water (x1 ), saturated aqueous sodium hydrogen carbonate (x1 ), water (x1 ), and brine (x1 ), and then dried over magnesium sulphate. The solvent was evaporated in vacuo and the crude product was purified by flash- silica gel chromatography, eluting with 30-100% ethyl acetate in isohexane, to give 4- [(2-chloro-4-fluorophenyl)carbonyl]-1-(2-chlorophenyl)-2-piperazinone (79mg) as a white solid. LC/MS [M+H]+ = 367, retention time = 2.54 minutes.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/53459, 2009, A1 Location in patent: Page/Page column 37

27
[ 21900-54-9 ]
[ 91476-80-1 ]
[ 1253801-39-6 ]

Yield	Reaction Conditions	Operation in experiment
	With diethylaminomethyl polystyrene; In dichloromethane; at 25℃; for 3h;	5.6.7.8-Tetrahydroimidazo[1 ,2-a]pyrazine(l17) (620 mg, 3.07 mmol) and diethylaminomethyl polystyrene (3071 mg, 9.83 mmol) were slurried in dichloromethane (DCM) (20 ml_). 2-Chloro-4-fluorobenzoyl chloride (622 mg, 3.22 mmol, commercially available from e.g. Sigma-Aldrich, Maybridge or Fluorochem) was added and the slurry stirred at 25 0C for 3 h. The resin was removed by filtration, washed with dichloromethane (50 ml) and the filtrate concentrated in vacuo to afford a crude oil. The crude product was purified by flash chromatography (Isolera, 100 g, 0-100% 2M ammonia in methanokdichloromethane (1 :9)/dichloromethane) to afford product. This was further purified by flash chromatography (Isolera, 50 g, 0-100% methanokdichloromethane (1 :9)/dichloromethane), to afford product. The oil was further purified by MDAP to afford clean product as the formate salt. The solid was loaded on to an SCX cartridge (Varian, 5g) and washed with methanol. The product was eluted with 2M ammonia methanol and the filtrate concentrated to afford desired product in 330 mg as a white solid.LC/MS = 280/282 (M+H)+, retention time = 0.52 minutes (2 minute).

Reference： [1]Patent: WO2010/125101,2010,A1 .Location in patent: Page/Page column 59-60

28
[ 126069-70-3 ]
[ 21900-54-9 ]
[ 1253801-40-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 4.0h;	2-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1 ,2-a]pyrazine (I4) (287 mg, 1.5 mmol) and DIPEA (0.314 ml_, 1.800 mmol) were dissolved at 0 0C in dichloromethane (DCM) (15 ml_). 2-chloro-4-fluorobenzoyl chloride (290 mg, 1.500 mmol, commercially available from e.g. Sigma-Aldrich, Maybridge or Apollo ) dissolved in DCM (5 ml.) was added dropwise and the solution stirred to room temperature over 4 h. Solvents were removed in vacuo and the residue was partitioned between dichloromethane (50 ml.) and saturated sodium bicarbonate solution (25 ml_). The aqueous phase was extracted with dichloromethane (3 x 50 ml.) and the combined extracts were washed with water (50 ml_), brine (50 ml_), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil (759 mg). The crude product was purified by flash chromatography (Isolera, 25 g, 0-100% 2M ammonia in methanokdichloromethane (1 :9)/dichloromethane) to afford crude product. Concentration of the waste afforded material which was also identified as product. Samples were combined to afford crude product. This was purified by MDAP, product containing fractions concentrated and loaded directly on to an SCX cartridge (Varian, 10 g). The column was washed with methanol and the product eluted with 2M ammonia methanol. The solvents were evaporated in vacuo to afford the desired product in 318 mg. LC/MS = 348/350 (M+H)+, retention time = 0.94 minutes (2 minute method)

Reference： [1]Patent: WO2010/125101,2010,A1 .Location in patent: Page/Page column 60-61

29
[ 5625-67-2 ]
[ 21900-54-9 ]
[ 1030164-97-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃; Cooling with ice;	2-Piperazinone (4.00 g, 40 mmol, commercially available e.g. from Sigma-Aldrich) was dissolved in Dichloromethane (DCM) (125 ml.) and to this was added triethylamine (6.69 ml_, 48.0 mmol). This solution was then cooled with ice water. 2- Chloro-4-fluorobenzoyl chloride (8.49 g, 44.0 mmol, commercially available e.g. from Maybridge, Alfa Aesar or ABCR) was then diluted down with Dichloromethane (DCM) (25 ml_), before being added via a pressure-equalizing dropping funnel. The solution was allowed to stir at room temperature overnight, and was then washed with sodium bicarbonate (100ml), the solid was removed, and the remaining solution was washed again with sodium bicarbonate (100ml) and brine (100ml), before being dried over magnesium sulphate. The solvent was then removed in vacuo to afford crude product which was triturated with hexane then stirred in ethyl acetate at 80 0C, before being filtered and air-dried to give 4-[(2-chloro-4-fluorophenyl)carbonyl]-2-piperazinone (5.179 g).LC/MS [M+H]+ = 257.02, retention time = 0.61 minutes (2 minute method).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2010/125102, 2010, A1 Location in patent: Page/Page column 66

30
[ 21900-54-9 ]
[ 100-46-9 ]
[ 886624-05-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	In dichloromethane at 0 - 20℃; for 13h;
	In dichloromethane at 0 - 20℃;

Reference： [1]Balkrishna, Shah Jaimin; Bhakuni, Bhagat Singh; Chopra, Deepak; Kumar, Sangit [Organic Letters, 2010, vol. 12, # 23, p. 5394 - 5397]
[2]Location in patent: experimental part Balkrishna, Shah Jaimin; Kumar, Sangit [Synthesis, 2012, vol. 44, # 9, p. 1417 - 1426]

31
6-amino-1-hydroxy-2,1-benzoxaborolane hydrochloride [ No CAS ]
[ 21900-54-9 ]
[ 1222509-03-6 ]

Yield	Reaction Conditions	Operation in experiment
67%	With triethylamine In dichloromethane at 20℃;	E14 E14 2-Chlow-4-fluow-N-(l-hydwxy-l,3-dihydro-benzofcJfl,2Joxaborol-6-yl)- benzamide[0464] A 250 ml round bottom flask was charged with a mixture of 6-amino- 1 - hydroxy-2,l-benzoxaborolane hydrochloride (1 g, 5.4 mmol, 1 eq), triethylamine (2.3 ml, 16.2 mmol, 3 eq) and dichloromethane (100 ml). 2-Chloro-4-fluorobenzoyl chloride (1.14 g, 5.9 mmol, 1.1 eq) was added, and the reaction mixture was allowed to stir at room temperature overnight. Aqueous hydrochloric acid (1 M, 50 ml) was added to the mixture and the suspension was vigorously mixed. The resulting white precipitate was then collected by vacuum filtration and dried under vacuum. LCMS (m/e) 306 (M+H). 1H NMR (400 MHz, DMSO-J6) δ ppm 4.96 (s, 2 H) 7.29 - 7.45 (m, 2 H) 7.59 (dd, J=9.0, 2.3 Hz, 1 H) 7.63 - 7.78 (m, 2 H) 8.15 (d, J=1.8 Hz, 1 H) 9.25 (s, 1 H) 10.53 (s, 1 H). Amount Obtained: 1.1 g, 67% yield.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/19618, 2011, A1 Location in patent: Page/Page column 169-170

32
[ 21900-54-9 ]
[ 100-66-3 ]
[ 1097106-69-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-chloro-4-fluorobenzoyl chloride With aluminum (III) chloride In dichloromethane at 30℃; for 0.0833333h; Microwave irradiation; Stage #2: methoxybenzene In dichloromethane at 70℃; for 0.25h; Microwave irradiation;	8 Preparation of (2-chloro-4-nitrophenyl)(p-tolyl)methanone (6a). Method A (using AlCl₃): General procedure: 2-Chloro-4-nitrobenzoic acid (201 mg, 1.0 mmol) and cyanuric chloride (368 mg, 2 mmol) in 2 mL CH2Cl2 were treated with pyridine (79 mg, 1.0 mmol) and irradiated in the microwave for 15 min at 50 °C. Then, the resulting mixture was treated with AlCl3 (400 mg, 3.01 mmol) and irradiated in the microwave for 5 min at 30 °C. Finally, 3 mL of toluene was added to the solution and irradiated in the microwave for 15 min at 70 °C. Then the reaction mixture was poured onto the ice and filter from Celite. The filtrate was washed with water followed by brine solution. The separated organic layer was dried on Na2SO4 and concentrated under reduced pressure to give crude product, which is purified by column chromatography (98:2 heptane/ethyl acetate) to give the pure white color product 6a (269.5 mg, 91% yield).

Reference： [1]Location in patent: experimental part Mahdi, Jasia; Ankati, Haribabu; Gregory, Jill; Tenner, Brian; Biehl, Edward R. [Tetrahedron Letters, 2011, vol. 52, # 20, p. 2594 - 2596]

33
[ 21900-54-9 ]
[ 13412-12-9 ]
[ 1361018-98-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In toluene; at 0 - 20℃;	To a mixture of methyl 3-(methylamino)-2-butenoate (i.e. the product of Step A) (10.25 g, 79.43 mmol) and triethylamine (13.26 mL, 9.63 g, 95.31 mmol) in toluene (125 mL) at 0 C was added dropwise 2-chloro-4-fluorobenzoyl chloride (15.25 g, 79.48 mol) in toluene (25 mL) over 30 minutes while maintaining the temperature of the reaction mixture between about 0 to 5 C. The reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting dark yellow oil was triturated with hexanes and filtered to provide the title compound as a white solid (15.91 g)..H NMR (CDCI3): delta 12.60 (s, 1H), 7.20-6.90 (m, 3H), 3.30 (s, 3H), 3.11 (s, 3H), 2.35 (s, 3H).

Reference： [1]Patent: WO2012/30922,2012,A1 .Location in patent: Page/Page column 44

34
[ 1361019-09-1 ]
[ 21900-54-9 ]
[ 1361019-75-1 ]

Yield	Reaction Conditions	Operation in experiment
	With aluminum (III) chloride In 1,2-dichloro-ethane at 180℃; for 0.5h; microwave irradiation;	10.C To a mixture of aluminum chloride (0.18 g, 1.36 mmol) in 1 ,2-dichloroethane (2 mL) was added a mixture of 2-chloro-4-fluorobenzoyl chloride (0.26 g, 1.36 mmol) and 5-(2,6- difluorophenyl)-l -methyl- lH-pyrazole-3-carbonitrile (i.e. the product of Step B) (0.15 g, 0.68 mmol) in dichloroethane (1 mL). The reaction mixture was heated at 180 °C in a Biotage Initiator microwave apparatus for 30 minutes. The resulting mixture was poured directly onto a Varian Bond Elute SI column and eluted with methylene chloride followed by 30% ethyl acetate in hexanes to provide the title compound, a compound of the present invention, as a solid (0.07 g)..H NMR (CDCI3): δ 8.12-8.03 (m, 1H), 7.41-7.57 (m, 1H), 7.40-7.33 (m, 1H), 7.12-7.04 (m, 1H), 6.91-7.03 (m, 2H), 3.85 (s, 3H).

Reference： [1]Current Patent Assignee: FMC CORP - WO2012/30922, 2012, A1 Location in patent: Page/Page column 53

35
[ 21900-54-9 ]
(S)-1-((S)-3-methyl-2-(methylamino)butyl)pyrrolidin-3-ol dihydrochloride [ No CAS ]
[ 87-69-4 ]
(3S)-1-((S)-2-(2-chloro-4-fluoro-N-methylbenzamido)-3-methylbutyl)-3-hydroxypyrrolidinium 2,3-dihydroxysuccinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: 2-chloro-4-fluorobenzoyl chloride; (S)-1-((S)-3-methyl-2-(methylamino)butyl)pyrrolidin-3-ol dihydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With ammonia In methanol; N,N-dimethyl-formamide Stage #3: tartaric acid In water; acetonitrile	10.1 Example 10.1: (3S -l-((S -2-(2-Chloro-4-fluoro-N-methylbenzamido -3-methylbutyl -3- hydroxypyrrolidinium 2,3-dihydroxysuccinate; To a solution of (S)-l-((S)-3-methyl-2-(methylamino)butyl)pyrrolidin-3-ol dihydrochloride (0.30 g, 1.16 mmol), which is commercially available, in DMF (2 mL) was DIPEA (0.809 mL, 4.63 mmol) and 2-chloro-4-fluorobenzoyl chloride (0.223 g, 1.16 mmol) added. The resultant mixture was stirred at rt overnight. To the mixture was added NH3 in MeOH (1 mL, 2N). The reaction was concentrated under reduced pressure and the residue purified by preparative HPLC to give the neutral form of the the title compound (280 mg, 58%)). The product was dissolved in MeCN (5 mL) and a solution of DL-tartaric acid (61 mg, 0.41 mmol) in water (5 mL) was added. The resulting mixture was freeze dried in vacuo to give the title compound (280 mg, 58%). Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ 0.85 - 0.93, 1.05, 1.11, 1.93, 2.25, 2.77, 3.14, 3.32 - 3.51, 4.37,4.50, 4.66, 7.12 - 7.28, 7.35. Ratio major:minor: 1 : 0.05. Total no of protons: 23(excluding the tartaric acid peak). HRMS (M+H)+: calculated 343.1588; found 343.1593.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2012/74469, 2012, A1 Location in patent: Page/Page column 106-107

36
[ 21900-54-9 ]
[ 56-40-6 ]
[ 923243-22-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide In water at 20℃;
	With hydrogenchloride; sodium hydroxide In water	General procedure: Compounds 1 were obtained by the acylation reaction with glycine (0.01 mol) and benzoyl chloride or benzoyl chloride derivatives (0.02 mol) as the raw materials in sodium hydroxide solution, which were then reacted with benzaldehyde or benzaldehyde derivatives (0.01mol) in the presence of acetic anhydride (Ac2O) (10 mL) and sodium acetate (AcONa) (0.01 mol) to obtain compounds 2. Next, the intermediates mentioned above were reacted with l-phenylalaninol (0.01mol) to yield the crude products 3, respectively. Finally, the crude products 3 (0.01 mol) were directly brominated with bromine (0.015 mol) and anhydrous calcium carbonate (0.01mol) in CHCl3 to give the crude products, which were purified by column chromatography to yield the title compounds 4Aa-f and 4Ba-t, respectively.

Reference： [1]Hsu, Mei-Yuan; Dietrich, Justin; Hulme, Christopher; Shaw, Arthur Y. [Synthetic Communications, 2013, vol. 43, # 11, p. 1538 - 1542]
[2]Gu, Xiaoke; Zhang, Yinpeng; Zou, Yueting; Li, Xin; Guan, Mingyu; Zhou, Qingqing; Qiu, Jingying [Bioorganic and Medicinal Chemistry, 2021, vol. 29]

37
[ 21900-54-9 ]
[ 1432112-24-7 ]
[ 1432112-28-1 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine In dichloromethane at 20℃;	8 Preparation of 2-Chloro-N-(2-chloro-4-{fl-(4-methoxybenzyl)-lH-pyrazolof4,3- b]pyridin-S-yl]amino}phenyl)-4-fluorobenzamide Preparation of 2-Chloro-N-(2-chloro-4-{fl-(4-methoxybenzyl)-lH-pyrazolof4,3- b]pyridin-S-yl]amino}phenyl)-4-fluorobenzamide[01 19] Into a vessel containing 10 mL of SO2CI2 was added 174 mg of 2-chloro-4- fluoro-benzoic acid (1 mmol) with stirring at 90 °C. Stirring was continued for 1 hr. then the mixture was concentrated in vacuum yielding crude 2-chloro-4-fluoro-benzoyl chloride. Into 6 mL of a 5: 1 vohvol mixture of dichloromethane (D CM): pyridine was dissolved 50 mg of 2-chloro-7V4-[l-(4-methoxybenzyl)-lH-pyrazolo [4,3-&]pyridin-3-yl] benzene- 1 ,4-diamine (0.13 mmol) at RT. Into this solution was added, dropwise, 50 mg of the crude 2-chloro-4-fluoro-benzoyl chloride previously prepared. The reaction mixture thus provided was stirred overnight at ambient temperature (RT) then the reaction mixture was washed with HQ (aq) and extracted with DCM. The combined organics were washed sequentially with water and brine, dried over Na2S04, filtered, then concentrated under reduced pressure yielding 48 mg of Exp-8-g3 (calculated yield 68.5 %). The crude material was used directly in the next step without purification. The identity of the product was confirmed by mass spectroscopy in accordance with the procedures described herein. MS (ESI) m/z 536, 538 (M+H)+
	In pyridine; dichloromethane at 20℃;	8 EXAMPLE 8: 3-[(3-Chloro-4-[(2-chloro-4-fluorophenyl)carbonyl]amino} iyl)amino] - ΙΗ-pyr azolo [4,3-b] pyridin-4-ium trifluoroacetate Preparation of 2-Chloro-N-(2-chloro-4-ifl-(4-methoxybenzyl)-lH-pyrazolo[4,3- b]pyridin-3-yl]aminojphenyl)-4-fluorobenzam,ide Into 6 mL of a 5: 1 vol: vol mixture of dichloromethane (DCM) pyridine was dissolved 50 mg of 2-chloro-N4-[l-(4-methoxybenzyl)-lH-pyrazolo [4,3-&]pyridin-3-yl] benzene- 1,4-diamine (0.13 mmol) at RT. Into this solution was added, dropwise, 50 mg of the crude 2-chloro-4-fluoro-benzoyl chloride previously prepared. The reaction mixture thus provided was stirred overnight at ambient temperature (RT) then the reaction mixture was washed with HC1 (aq) and extracted with DCM. The combined organics were washed sequentially with water and brine, dried over Na2S04, filtered, then concentrated under reduced pressure yielding 48 mg of Exp-8-g3 (calculated yield 68.5 %). The crude material was used directly in the next step without purification. The identity of the product was confirmed by mass spectroscopy in accordance with the procedures described herein. MS (ESI) m/z 536, 538 (M+H)+

Reference： [1]Current Patent Assignee: ADDEX THERAPEUTICS SA; MERCK & CO INC - WO2013/60029, 2013, A1 Location in patent: Paragraph 0119
[2]Current Patent Assignee: ADDEX THERAPEUTICS SA; MERCK & CO INC - WO2013/63100, 2013, A1 Location in patent: Paragraph 0119

38
[ 21900-54-9 ]
[ 108-18-9 ]
[ 1492905-06-2 ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine In diethyl ether at 0 - 20℃; Inert atmosphere; Schlenk technique;

Reference： [1]Wertjes, William C.; Wolfe, Lydia C.; Waller, Peter J.; Kalyani, Dipannita [Organic Letters, 2013, vol. 15, # 23, p. 5986 - 5989]

39
[ 21900-54-9 ]
5-(4-bromo-2,6-difluorophenyl)-1,3-dimethyl-1H-pyrazole [ No CAS ]
[5-(4-bromo-2,6-difluorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl](2-chloro-4-fluorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.5 g	With aluminum (III) chloride In 1,1,2,2-tetrachloroethane at 0 - 150℃; for 12h;	1.D Step D: Preparation of [5-(4-bromo-2,6-difluorophenyl)-l ,3-dimethyl-lH-pyrazol-4- yl](2-chloro-4-fluorophenyl)methanone Step D: Preparation of [5-(4-bromo-2,6-difluorophenyl)-l ,3-dimethyl-lH-pyrazol-4- yl](2-chloro-4-fluorophenyl)methanone To a mixture of 5-(4-bromo-2,6-difluorophenyl)-l ,3-dimethyl-lH-pyrazole (i.e. the product of Step C) (0.6 g, 2.1 mmol) in tetrachloroethane (8 mL) at 0 °C was added aluminum chloride (0.70 g, 5.2 mmol), followed 2-chloro-4-fluorobenzoyl chloride (1.4 g, 7.3 mmol). The reaction mixture was heated at 150 °C for 12 h. After cooling to room temperature, the reaction mixture was quenched with ice water and then extracted with ethyl acetate (4 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting material was purified by column chromatography on silica gel eluting with 10% ethyl acetate in petroleum ether to provide the title compound as an off-white solid (0.5 g). in NMR (DMSO- ): δ 7.47 (d, 2H), 7.32-7.27 (m, 2H), 7.10 (dt, 1H), 3.61 (s, 3H), 2.31 (s, 3H).

Reference： [1]Current Patent Assignee: FMC CORP - WO2015/26646, 2015, A1 Location in patent: Page/Page column 46

40
[ 21900-54-9 ]
methyl 5-[(4-aminophenyl)carbamoyl]-1H-imidazole-4-carboxylate [ No CAS ]
methyl 5-({4-[(2-chloro-4-fluorobenzoyl)amino]phenyl}carbamoyl)-1H-imidazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69 g	With triethylamine In tetrahydrofuran at 20℃; for 2h;	13 Methyl 5-(f4-[ (2-ch loro-4-fluorobenzoyl)amino]phenyl}carbamoyl)- I Himidazole-4-carboxylate To a mixture of 281 mg (1.079 mmo[) methy[ 5-[(4-aminopheny[)carbamoy[]-1H-imidazo[e-4-carboxy[ate (Intermediate 015) in 15.8 mL THF, 0.17 mL (1.187 mmo[)triethy[amine and 0.16 mL (1.187 mmo[) 2-ch[oro-4-f[uorobenzoy[ ch[oride were subsequent[y added and the mixture was stirred for additiona[ 2 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by f[ash co[umn chromatography (dich[oromethane/methano[-gradient) togive after washing with dich[oromethane 69 mg of the tit[e compound as a so[id materia[.1HNMR (300 MHz, DMSO-d6), 6 [ppm]= 13.67-13.50 (m, 1H), 11.94-11.78 (m, 1H),10.51 (br. s., 1H), 7.92 (s, 1H), 7.75-7.64 (m, 5H), 7.61 -7.55 (m, 1H), 7.37-7.29 (m,1H), 3.91 (br. s., 3H).LC-MS (Method 5): R = 0.99 mm; MS (ESIpos) m/z = 417 [M+H]÷.

Reference： [1]Current Patent Assignee: BAYER AG - WO2015/150449, 2015, A2 Location in patent: Page/Page column 226; 227

41
[ 21900-54-9 ]
N5-(6-aminopyridin-3-yl)-N4-methyl-1H-imidazole-4,5-dicarboxamide [ No CAS ]
N⁵-{6-[(2-chloro-4-fluorobenzoyl)amino]pyridin-3-yl}-N⁴-methyl-1H-imidazole-4,5-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11 mg	With triethylamine In tetrahydrofuran at 20℃; for 3h;	16 N5-f6-[ (2-ch loro-4-fluorobenzoyl)ami no]pyridin-3-yl}-N4-methyl- I H-imidazole4, 5-dicarboxamide To a mixture of 180 mg (0.692 mmo[) N5-(6-aminopyridin-3-y[)-N4-methy[-1H- imidazo[e-4,5-dicarboxamide (Intermediate 016) in 10.1 mL THF, 0.11 mL (0.761 mmo[) triethy[amine and 0.10 mL (0.761 mmo[) 2-ch[oro-4-f[uorobenzoy[ ch[oride were subsequent[y added and the mixture was stirred for additiona[ 3 h at roomtemperature. The reaction mixture was concentrated in vacuo and the residue was purified by f[ash co[umn chromatography (dich[oromethane/methano[-gradient) to give after washing with methano[ 11 mg of the tit[e compound as a so[id materia[.1HNMR (300 MHz, DMSO-d6), 6 [ppm]= 13.93-13.80 (m, 1H), 13.58-13.40 (m, 1H),11.13-10.98 (m, 1H), 8.94-8.84 (m, 1H), 8.77-8.63 (m, 1H), 8.32-8.06 (m, 2H), 7.95(s, 1H), 7.69-7.61 (m, 1H), 7.59-7.50 (m, 1H), 7.36-7.23 (m, 1H), 2.90-2.83 (m,3H).LC-MS (Method 5): R = 1.00 mm; MS (ESIpos) m/z = 417 [M+H].

Reference： [1]Current Patent Assignee: BAYER AG - WO2015/150449, 2015, A2 Location in patent: Page/Page column 229

42
[ 21900-54-9 ]
methyl 5-[(4-amino-3-fluorophenyl)carbamoyl]-1H-imidazole-4-carboxylate [ No CAS ]
methyl 5-({4-[(2-chloro-4-fluorobenzoyl)amino]-3-fluorophenyl}carbamoyl)-1H-imidazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
562 mg	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1h;	71 methyl 5- (f4-[ (2-ch loro-4-fluorobenzoyl)amino]-3-fluorophenyl}carbamoyl)- I Himidazole-4-carboxylate 439 mg (1 .58 mmo[) methy[ 5-[(4-amino-3-f[uoropheny[)carbamoy[]- 1 H-imidazo[e-4- carboxy[ate (Intermediate 031) were suspended in 10 mL dry tetrahydrofuran. 1.37 mL (7.89 mmo[) N-ethy[-N,N-diisopropy[amine and 412 j.iL (3.16 mmo[) 2-ch[oro-4- f[uorobenzoy[ ch[oride were added and the mixture was stirred at room temperature for 1 hour. 50 mL water were added and the precipitate was fi[teredoff. The so[id was washed twice with methano[ (3 mL) and twice with diethy[ether (3 mL) to give 562 mg of the tit[e compound as a so[id materia[.1HNMR (400 MHz, DMSO-d6), 6 [ppm] = 13.62 (s, 1H), 11.80 (bs, 1H), 10.29 (s, 1H),7.95 (s, 1H), 7.90-7.74 (m, 2H), 7.68 (t, 1H), 7.61-7.52 (m, 1H), 7.43-7.28 (m, 1H),3.91 (s, 3H).LC-MS (Method 6): R = 3.50 mm; MS (ESIpos) m/z = 435.2 [M+H].

Reference： [1]Current Patent Assignee: BAYER AG - WO2015/150449, 2015, A2 Location in patent: Page/Page column 273

43
[ 21900-54-9 ]
methyl 5-[(4-amino-3-methylphenyl)carbamoyl]-1H-imidazole-4-carboxylate [ No CAS ]
methyl 5-({4-[(2-chloro-4-fluorobenzoyl)amino]-3-methylphenyl}carbamoyl)-1H-imidazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
704 mg	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1h;	83 methyl 5- (f4-[ (2-ch loro-4-fluorobenzoyl)amino]-3-methylphenyl}carbamoyl)- I Himidazole-4-carboxylate 600 mg (2.19 mmo[) methy[ 5-[(4-amino-3-methy[pheny[)carbamoy[]- 1 H-imidazo[e4-carboxy[ate Intermediate 033) and 1.90 mL (10.94 mmo[) N-ethy[-N,Ndiisopropy[amine were suspended in 12 mL tetrahydrofuran. 584 pL (4.38 mmo[) 2-ch[oro-4-f[uorobenzoy[ ch[oride were added and the mixture was stirred at room temperature for 1 hour. 100 mL water were added and the precipitate was fi[tered off. The so[id was washed three times with water, methano[ and diethy[ether to give 704 mg of the tit[e compound as a so[id materia[.1H-NMR (400 MHz, DMSO-d6), 6 [ppm] = 13.57 (s, 1H), 11.61 (s, 1H), 9.94 (s, 1H),7.93 (s, 1H), 7.74-7.67 (m, 1H), 7.62-7.54 (m, 3H), 7.46-7.42 (m, 1H), 7.39-7.31 (m, 1H), 3.92 (s, 3H), 2.31 (s, 3H).LC-MS (Method 6): R = 3.44 mm; MS (ESIpos) m/z = 431.2 [M+H]÷.

Reference： [1]Current Patent Assignee: BAYER AG - WO2015/150449, 2015, A2 Location in patent: Page/Page column 281; 282

44
[ 21900-54-9 ]
methyl 4-[(4-amino-3-methoxyphenyl)carbamoyl]-1H-imidazole-5-carboxylate [ No CAS ]
methyl 5-({4-[(2-chloro-4-fluorobenzoyl)amino]-3-methoxyphenyl}carbamoyl)-1H-imidazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
534 mg	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1h;	94 methyl 5-(f4-[ (2-ch loro-4-fluorobenzoyl)amino]-3-methoxyphenyl}carbamoyl)- I H-imidazole-4-carboxylate 500 mg (1 .72 mmo[) methy[ 4-[(4-amino-3-methoxypheny[)carbamoy[]- 1 Himidazo[e-5-carboxy[ate (Intermediate 037) and 1 .50 mL (8.61 mmo[) N-ethy[-N,N10 diisopropy[amine were suspended in 20 mL tetrahydrofuran. 460 pL (3.45 mmo[) 2-ch[oro-4-f[uorobenzoy[ ch[oride were added and the mixture was stirred at room temperature for 1 hour. 40 mL water were added and the organic so[vent was removed under reduced pressure. The precipitate was fi[tered off and washed with water. After drying in vacuo the crude product was recrysta[[ised to give 534 mg ofthe tit[e compound as a so[id materia[.1H-NMR (400 MHz, DMSO-d6), 6 [ppm] = 13.58 (s, 1H), 11.87 (s, 1H), 9.66 (s, 1H),7.95 (s, 1H), 7.90 (s, 1H), 7.67-7.61 (m, 2H), 7.54 (m, 1H), 7.32 (m, 1H), 7.21 (s,1H), 3.93 (s, 3H), 3.84 (s, 3H).LC-MS (Method 6): R = 3.61 mm; MS (ESIpos) m/z = 447.2 [M+H].

Reference： [1]Current Patent Assignee: BAYER AG - WO2015/150449, 2015, A2 Location in patent: Page/Page column 290

45
[ 21900-54-9 ]
methyl 5-[(6-aminopyridin-3-yl)carbamoyl]-1H-imidazole-4-carboxylate [ No CAS ]
methyl 5-({6-[(2-chloro-4-fluorobenzoyl)amino]pyridin-3-yl}carbamoyl)-1H-imidazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
600 mg	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 50℃; for 1h;	043 methyl 5-(f6-[ (2-ch loro-4-fluorobenzoyl)amino]pyridin- 3-yl}carbamoyl)- I Himidazole-4-carboxylate 496 mg (1 .90 mmo[) methy[ 5-[(6-aminopyridin-3-y[)carbamoy[]- 1 H-imidazo[e-4- carboxy[ate (Intermediate 42) and 1.65 mL (9.5 mmo[) N-ethy[-N,Ndiisopropy[amine were suspended in 300 mL tetrahydrofuran. During 30 minutes 279 pL (2.09 mmo[) 2-ch[oro-4-f[uorobenzoy[ ch[oride di[uted in 5 mL were added dropwise at 50 °C and the mixture was stirred at 50 °C for 1 hour. The so[vent wasremoved under reduced pressure and 20 mL water were added to the residue. The precipitate was fi[tered off and the so[id was washed with water and methano[ to give after drying under vacuum 600 mg of the tit[e compound as a so[id materia[ (contains 20 % of the bisacy[ated product).1HNMR (400 MHz, DMSO-d6), 6 [ppm] = 13.6 (s, 1H), 11.05 (s, 1H), 8.74-8.66 (m,1H), 8.29-8.13 (m, 2H), 7.96 (s, 1H), 7.67-7.63 (m, 1H), 7.57-7.50 (m, 1H), 7.35-7.20 (m, 1H), 3.91 (s, 3H).LC-MS (Method 6): R = 3.44 mm; MS (ESIpos) m/z = 418.2 [M+H]÷.

Reference： [1]Current Patent Assignee: BAYER AG - WO2015/150449, 2015, A2 Location in patent: Page/Page column 195

46
[ 21900-54-9 ]
N5-(4-aminophenyl)-N4-methyl-1H-imidazole-4,5-dicarboxamide [ No CAS ]
N⁵-{4-[(2-chloro-4-fluorobenzoyl)amino]-3-methylphenyl}-N⁴-methyl-1H-imidazole-4,5-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26 mg	With triethylamine In tetrahydrofuran at 20℃; for 72h;	5 N5-f4-[ (2-ch loro-4-fluorobenzoyl)ami no]- 3-methylphenyl}-N4-methyl- I Himidazole-4, 5-dicarboxamide In 14.83 mL THF, a mixture of 200 mg (0.732 mmo[) N5-(4-amino-3-methy[pheny[)-N4-methy[-1H-imidazo[e-4, 5-dicarboxamide (Intermediate 003), 0.10 mL (0.732mmo[) 2-ch[oro-4-f[uorobenzoy[ ch[oride and 0.10 mL (0.732 mmo[) triethy[aminewas stirred for 3 days at room temperature. The resu[ting precipitate was fi[teredoff and purified by preparative HPLC to yie[d 26 mg of the tit[e compound as a so[idmateria[.1HNMR (300 MHz, DMSO-d6), 6 [ppm]= 13.75-13.51 (m, 1H), 13.43-13.33 (m, 1H),9.92 (s, 1H), 8.96-8.68 (m, 1H), 7.91 (s, 1H), 7.75-7.65 (m, 1H), 7.64-7.52 (m, 3H),7.43 (s, 2H), 2.87 (d, 3H), 2.29 (s, 3H).LC-MS (Method 4): R = 1.04 mm; MS (ESIpos) m/z = 430 [M+H]÷.

Reference： [1]Current Patent Assignee: BAYER AG - WO2015/150449, 2015, A2 Location in patent: Page/Page column 221

47
[ 21900-54-9 ]
N5-(4-aminophenyl)-N4-methyl-1H-imidazole-4,5-dicarboxamide [ No CAS ]
N⁵-{4-[(2-chloro-4-fluorobenzoyl)amino]phenyl}-N⁴-methyl-1H-imidazole-4,5-dicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With triethylamine In tetrahydrofuran at 20℃; for 5h;	12 N5-f4-[ (2-ch loro-4-fluorobenzoyl)ami no]phenyl}-N4-methyl- I H-imidazole-4 , 5-di- carboxamide In 720 mL THF, a mixture of 8.09 g (40.7 mmo[) N5-(4-amino-pheny[)-N4-methy[-1H- imidazo[e-4,5-dicarboxamide (Intermediate 003), 5.59 mL (40.7 mmo[) 2-ch[oro-4- f[uoro-benzoy[ ch[oride and 5.15 mL (37 mmo[) triethy[amine was stirred for 2 h atroom temperature.300 mL THF, 3.6 mL triethy[amine and 2.5 mL 2-ch[oro-4-f[uoro-benzoy[ ch[oride were added and stirring was continued to 1 .5 h.2.5 mL triethy[amine and 2.5 mL 2ch[oro-4-f[uoro-benzoy[ ch[oride were added and stirring was continued for another 1 .5 h.The suspension was concentrated and dried in vacuo. The precipitate was suspended in a mixture of 500 mL 1 N aqueous sodium hydroxide so[ution and 300 mL methano[ and stirred for 30 mm at 40 °C (water bath). The pH of the mixture was adjusted to 7 by addition of 3N aqueous hydroch[oric acid. The precipitate was fi[tered off and washed with water and dried.The crude materia[ was purified by f[ash chromatography to give a materia[ which was digested in methano[ to give 7.59 g (49% yie[d) of the tit[e compound as so[id materia[.1H-NMR (500MHz, DMSO-d6): 6 [ppm]= 2.86 (d, 3H), 7.34 (td, 1H), 7.57 (dd, 1H),7.64 - 7.74 (m, 5H), 7.91 (s, 1H), 8.81 (d, 1H), 10.49 (s, 1H), 13.40 (s, 1H), 13.66(s, 1H).LC-MS (Method 1): R = 1.00 mm; MS (ESIpos) m/z = 416 [M+H]÷.

Reference： [1]Current Patent Assignee: BAYER AG - WO2015/150449, 2015, A2 Location in patent: Page/Page column 225; 226

48
[ 21900-54-9 ]
[ 5510-10-1 ]
C₁₆H₁₁ClFNO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-methyl-2H-1,2-benzothiazine-4-(3H)-one-1,1-dioxyde With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 2-chloro-4-fluorobenzoyl chloride In N,N-dimethyl-formamide at 25℃; for 1.33333h; Inert atmosphere;	5.8. General procedure for compounds (4j-4w) General procedure: A solution of compound 8 (1.1 g, 5 mmol) in DMF (10 mL) was added to sodium hydride (0.26 g, 7.5 mmol of a 60% suspension in mineral oil which had been washed with benzene by decantation) at 0 °C. After stirring for 10 min, 4-nitrobenzoyl chloride was added during 20 min. The solution was stirred at 25 °C for 1 h and then evaporated. The residue was suspended in water and extracted with ethyl acetate. The combined organic phase was dried with anhydrous sodium sulfate, filtered and removed by rotary evaporation to yield 9a as brown viscous oil, which was used in the next step without further purification. A solution of compound 9a (1.0 g, 2.7 mmol) in dichloromethane (10 mL) was added to triethylamine (0.4 g, 4 mmol), 18-crown-6 (71 mg, 0.3 mmol) and potassium cyanide (91 mg, 1.4 mmol). The mixture was stirred at 25 °C for 48 h. The mixture was poured into water and extracted with dichloromethane. The combined organic phase was dried with anhydrous sodium sulfate, filtered and removed by rotary evaporation. The residue was scratched from ethyl acetate and ethanol (1/1 by volume) to give desired product to 4j as a yellow solid (734 mg, yield: 41%). The rest of compounds were prepared by the similar procedure to 4j. Data for (4j): Yield 41%; yellow solid; mp 196-197 °C; 1H NMR (400 MHz, CDCl3) δ: 15.45 (s, 1H), 8.42-8.36 (m, 2H), 8.35-8.29 (m, 2H), 8.27-8.18 (m, 1H), 7.98-7.95 (m, 1H), 7.91-7.82 (m, 2H), 2.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 188.3, 170.8, 149.9, 140.2, 136.3, 134.3, 133.2, 130.5, 128.3, 128.0, 124.6, 123.7, 119.1, 40.4; HRMS: calcd for C16H12N2O6S [M+H]+ 361.0416, found 361.0492.

Reference： [1]Lei, Kang; Hua, Xue-Wen; Tao, Yuan-Yuan; Liu, Yang; Liu, Na; Ma, Yi; Li, Yong-Hong; Xu, Xiao-Hua; Kong, Chui-Hua [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 2, p. 92 - 103]

49
[ 21900-54-9 ]
[ 7117-31-9 ]
C₁₆H₁₁ClFNO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-methyl-2,2-dioxo-2,3-dihydro-1H-2λ⁶-benzo[c][1,2]thiazin-4-one With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 2-chloro-4-fluorobenzoyl chloride In N,N-dimethyl-formamide at 25℃; for 1.33333h; Inert atmosphere;	5.12. General procedure for compounds (15a-15j) General procedure: A solution of compound 13 (1.1 g, 5 mmol) in DMF (10 mL) was added to sodium hydride (0.3 g, 7.5 mmol of a 60% suspension in mineral oil which had been washed with benzene by decantation) at 0 °C. After stirring for 10 min, benzoyl chloride (1.4 g, 10 mmol) was added during 20 min. The solution was stirred at 25 °C for 1 h and then evaporated. The residue was suspended in water and extracted with ethyl acetate. The combined organic phase was dried with anhydrous sodium sulfate, filtered and removed by rotary evaporation to yield 14a as brown viscous oil, which was used in the next step without further purification. A solution of compound 14a (0.9 g, 2.8 mmol) in dichloromethane (10 mL) was added to triethylamine (0.4 g, 4 mmol), 18-crown-6 (71 mg, 0.3 mmol) and potassium cyanide (91 mg, 1.4 mmol). The mixture was stirred at 25 °C for 48 h. The mixture was poured into water and extracted with dichloromethane. The combined organic phase was dried with anhydrous sodium sulfate, filtered and removed by rotary evaporation. The residue was scratched from ethyl acetate and ethanol (1/1 by volume) to give desired product 15a as yellow solid (572 mg, yield: 36%). The rest of compounds were prepared by the similar procedure to 15a. Data for (15a): Yield 36%; light yellow solid; mp 208-210 °C; 1H NMR (400 MHz, CDCl3) δ: 8.19 (dd, J = 8.0, 1.4 Hz, 1H), 7.86 (dd, J = 5.2, 3.3 Hz, 2H), 7.73-7.67 (m, 1H), 7.65-7.59 (m, 1H), 7.53 (dd, J = 10.4, 4.7 Hz, 2H), 7.38-7.31 (m, 1H), 7.23 (d, J = 8.3 Hz, 1H), 3.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 193.2, 177.4, 142.1, 137.2, 135.6, 132.5, 128.2, 128.1, 128.1, 123.9, 120.3, 117.9, 115.2, 32.1; HRMS: calcd for C16H13NO4S [M+H]+ 316.0565, found 316.0640.

Reference： [1]Lei, Kang; Hua, Xue-Wen; Tao, Yuan-Yuan; Liu, Yang; Liu, Na; Ma, Yi; Li, Yong-Hong; Xu, Xiao-Hua; Kong, Chui-Hua [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 2, p. 92 - 103]

50
[ 21900-54-9 ]
[ 118-93-4 ]
2-acetylphenyl 2-chloro-4-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	In pyridine at 20℃; for 2h; Inert atmosphere;	General Synthetic Procedure for Compound 11 General procedure: A mixture of 2'-hydroxyacetophenone (10.0 mmol) and 2-chlorobenzoyl chloride (15.0 mmol) were stirred in dry pyridine(10 mL) at room temperature for 2 h. The reaction mixture was then poured into a mixture of crushed ice (15 mL) and concentrated HCl (5 mL), extracted twice with dichloromethane, washed thrice with aqueous K2CO3, and then washed thrice with water. The solvent was removed under reduced pressure. The residue was recrystallized from ethanol to give 2-acetylphenyl 2-chlorobenzoate (11-1). The remaining compounds were prepared using a similar procedure to that used for preparing 11-1.

Reference： [1]Lei, Kang; Sun, Dong-Wei; Tao, Yuan-Yuan; Xu, Xiao-Hua [Australian Journal of Chemistry, 2016, vol. 69, # 1, p. 98 - 106]

51
[ 4414-88-4 ]
[ 21900-54-9 ]
α-(1H-benzimidazol-(3H)-idene)-2-chloro-4-fluoro-γ-oxobenzenepropanenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With pyridine for 1.5h; Reflux;	α-(1H-benzimidazol-(3H)-idene)-2-chloro-4-fluoro-γ-oxobenzenepropanenitrile 13 A solution of (1H-benzimidazol-2-yl)acetonitrile 2 (1.63 g, 10.40 mmol) and 2-chloro-4-fluorobenzoyl chloride 11 (2.00 g, 10.40 mmol) in pyridine (13 ml) was refluxed for 1.5 h. After being cooled to room temperature, the reaction mixture was poured into water (100 ml) and the precipitated solid was filtered off and recrystallized from ethanol to obtain 13 as a brown powder (1.36 g, 49%); m.p. >300°C. 1H NMR (300 MHz, DMSO-d6): δ/ppm 13.10 (bs, 2H, NH), 7.59-7.51 (m, 4H, Harom.), 7.36-7,30 (m, 3H, Harom.); 13C NMR (75 MHz, DMSO-d6): δ/ppm 184.75 (s), 162.40 (s, JCF = 247.17 Hz), 150.84 (s), 137.56 (s, JCF = 3.50 Hz), 131.24 (s, JCF = 10.75 Hz), 130.86 (s), 130.65 (d, JCF = 9.17 Hz), 124.14 (d, 2C), 120.30 (s), 117.46 (d, JCF = 25.01 Hz), 114.83 (d, JCF = 21.13 Hz),112.74 (d, 2C), 67.77 (s).

Reference： [1]Perin, Nataša; Nhili, Raja; Cindrić, Maja; Bertoša, Branimir; Vušak, Darko; Martin-Kleiner, Irena; Laine, William; Karminski-Zamola, Grace; Kralj, Marijeta; David-Cordonnier, Marie-Hélène; Hranjec, Marijana [European Journal of Medicinal Chemistry, 2016, vol. 122, p. 530 - 545]

52
[ 21900-54-9 ]
2,8-dimethyl-1,2,3,4-tetrahydropyrido[1,2-b]indazol-2-amine [ No CAS ]
2-chloro-N-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[1,2-b]indazol-2-yl)-4-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 0.533333h;	2-Chloro-N-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[1,2-b]indazol-2-yl)-4-fluorobenzamide To a solution of 2,8-dimethyl-1,2,3,4-tetrahydropyrido[1,2-b]indazol-2-amine (240 mg, 0.557 mmol) and DIEA (0.3 ml, 1.718 mmol) in DCM (3 ml) cooled at 0oC was added 2-chloro-4- fluorobenzoyl chloride (215 mg, 1.115 mmol) dropwise. It was stirred for 2 min and warmed to room temperature for 30 min. It was directly purified by ISCO (12g, 0-100% ethyl acetate in hexane) to give the title compound. LCMS calc. = 372.13; found = 372.14 (M+H)+.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2016/133793, 2016, A1 Location in patent: Page/Page column 49

53
[ 21900-54-9 ]
8-amino-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-1-one [ No CAS ]
2-chloro-4-fluoro-N-[(trans)-1-oxo-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-8-yl]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With triethylamine In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃;	78 2-chloro-4-fluoro-N-[(trans)-1 -oxo-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-8-yl]benzamide A solution of 2-chloro-4-fluorobenzoyl chloride (42 μΙ, 310 μιηοΙ) in THF (1 .0 ml) was added dropwise at 0 to a mixture of 8-amino-2-(pyridin- 2-yl)-2-azaspiro[4.5]decan-1 -one (isomer 1 , intermediate I66) (75.0 mg, 306 μιηοΙ) and triethylamine (130 μΙ, 920 μιηοΙ) in THF (1 .5 ml) and DMF (0.31 ml) and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with ethyl acetate (3x). The combined organic phases were filtrated through a silicone filter and concentrated under reduced pressure. The crude product was recrystallized from ethanol to give the title compound 40.1 mg (32 % yield).LC-MS (Method 2): Rt= 1 .05 min; MS (ESIneg) : m/z = 400 [M-H]-1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.84), 1 .415 (1 .19), 1 .438 (2.57), 1 .446 (2.73), 1 .458 (2.96), 1 .468 (4.50), 1 .487 (3.37), 1 .498 (2.94), 1 .519 (1 .85), 1 .703 (13.80), 1 .712 (16.00), 1 .728 (10.57), 1 .734 (9.71 ), 1 .929 (4.94), 1 .939 (5.16), 1 .950 (3.06), 1 .962 (4.79), 1 .971 (4.34), 2.056 (9.48), 2.074 (13.72), 2.091 (9.97), 2.389 (0.74), 2.393 (1 .07), 2.398 (0.76), 2.584 (3.70), 2.589 (2.41 ), 2.731 (0.78), 2.735 (1 .09), 2.740 (0.76), 3.225 (0.95), 3.238 (0.99), 3.756 (0.99), 3.767 (1 .1 1 ), 3.776 (2.04), 3.786 (2.51 ), 3.795 (2.06), 3.805 (2.49), 3.815 (1 .95), 3.824 (1 .1 1 ), 3.834 (0.99), 3.994 (10.10), 4.006 (4.34), 4.012 (13.86), 4.016 (4.81 ), 4.029 (9.64), 7.193 (6.03), 7.196 (6.00), 7.205 (5.47), 7.208 (6.05), 7.21 1 (6.40), 7.214 (5.76), 7.224 (6.19), 7.226 (6.31 ), 7.318 (4.09), 7.324 (4.59), 7.339 (8.21 ), 7.346 (9.17), 7.360 (4.81 ), 7.366 (5.35), 7.526 (8.78), 7.541 (8.99), 7.547 (8.06), 7.557 (9.21 ), 7.563 (14.27), 7.580 (8.62), 7.586 (8.23), 7.859 (5.39), 7.864 (5.49), 7.877 (5.49), 7.880 (6.33), 7.882 (5.94), 7.885 (5.94), 7.898 (5.08), 7.903 (5.41 ), 8.379 (6.36), 8.381 (12.55), 8.384 (7.24), 8.400 (6.15), 8.403 (10.39), 8.405 (6.36), 8.446 (10.61 ), 8.449 (13.14), 8.451 (10.90), 8.454 (7.92), 8.459 (7.61 ), 8.461 (8.08), 8.464 (8.90), 8.466 (10.41 )

Reference： [1]Current Patent Assignee: BAYER AG - WO2018/78005, 2018, A1 Location in patent: Page/Page column 189; 190

54
[ 21900-54-9 ]
[ 124-40-3 ]
2-chloro-4-fluoro-N,N-dimethylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In tetrahydrofuran at 20℃; for 17h;	37-1 2-chloro-4-flu oro-N ,N -dimethylbenzamide The reaction mixture of 2-chloro-4-fluorobenzoic acid (5 g, 28.6 mmol, 1.0 eq) in thionyl5 chloride (10 mL, 137 mmol, 4.7 eq) was refluxed for 3 h. Then the mixture was cooled tort andthe solvent was evaporated under reduced pressure to give 2-chloro-4-fluorobenzoyl chloride.The crude chloride was dissolved in THF ( 5 mL ), then treated with triethylamine ( 16 mL, 115mmol, 4.0 eq) and dimethylamine (42 mL, 84 mmol, 2M in THF, 2.9 eq) at ambient temperature.The reaction mixture was stirred at ambient temperature for 17h. The mixture was diluted with10 ethyl acetate (90 mL), washed with water (10 mL x 3), dried over anhydrous Na2S04, filteredand concentrated. The crude product was purified by column chromatography (silica gel: 300-400 mesh, PE/EtOAc = 3/1, VN) to afford 2-chloro-4-fluoro-N,N-dimethylbenzamide. LRMSm/z (M+H) 202.0 found, 202.0 required.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2018/68295, 2018, A1 Location in patent: Page/Page column 143; 144

55
[ 21900-54-9 ]
5-(4-bromothiophen-2-yl)pyridin-3-amine [ No CAS ]
N-(5-(4-bromothiophen-2-yl)pyridin-3-yl)-2-chloro-4-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine In acetone at 20℃; for 2h;	4.1.1.2 Procedure B, general procedure for amide synthesis (4a, 6a-34a) General procedure: A solution of 0.18gm (0.7mmol) of compound D dissolved in acetone was treated with 0.84mmol of the appropriate acid chloride followed by the addition of 0.12gm (1.05mmol) of TEA. The reaction mixture was left to stir at room temperature for 2h which was followed by evaporation of solvent in vacuo and the product was purified by CC.

Reference： [1]Darwish, Sarah S.; Abdel-Halim, Mohammad; Salah, Mohamed; Abadi, Ashraf H.; Becker, Walter; Engel, Matthias [European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1031 - 1050]

56
2,3-O-isopropylidene-D-ribofuranose [ No CAS ]
[ 21900-54-9 ]
C₂₂H₁₈Cl₂F₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 22 - 28℃; for 1.5h;	9.1 1.Preparation of 2,6-0-Di-(2-chloro-4-fluorobenzoyl)-3, 4-0-acetonylidene-D-ribose: The preparation of IM-1 is as described above.By preparing 100 g of D-ribose for reaction, a crude IM-1 product can be obtained. This crude product was dissolved in 800 ml of dichloromethane, added with stirring, 201.8 g of triethylamine, and slowly added 321 g.2-Chloro-4-fluorobenzoyl chloride.After stirring at room temperature for 1.5 hours, the sample was sampled by TLC plate analysis.IM-1 is not obvious and is considered as the end of the reaction; after the reaction is completed,As described above, the extract was concentrated and dried to obtain a crude compound B, which was not purified, and the compound B was also shown to contain a mixture of two configurations of alpha and beta.

Reference： [1]Current Patent Assignee: HONGENE BIOTECHNOLOGY - CN108424431, 2018, A Location in patent: Paragraph 0182; 0184-0186

57
[ 67-56-1 ]
[ 21900-54-9 ]
[ 85953-29-3 ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 8670 - 8692

58
[ 21900-54-9 ]
7-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ No CAS ]
2-chloro-4-fluoro-N-(7-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 2-chloro-4-fluorobenzoyl chloride; 7-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine With pyridine at 0 - 20℃; Stage #2: With ammonia In methanol at 20℃;	1.1.5 General procedure for the synthesis of [1,2,4]triazolo[1,5-a]pyrimidines 6-7 and [1,2,4]triazolo[1,5-a]pyridines 17-18 General procedure: The appropriate acyl chloride (2.5 equiv) was added dropwise to a solution of triazolo[1,5-a]pyrimidin-2-amine 11 or 12 or triazolo[1,5-a]pyridin-2-amine 16 (1 equiv) in pyridine at 0 C. The reaction mixture was allowed to warm up to r.t. and stirred for 1-2 h. EtOAc was added, and the organic layer was washed with HCl 1N (2 X), followed by water or brine. After solvent evaporation, the resultant residue was treated with 7 N methanolic ammonia solution and stirred at r.t. overnight to hydrolyze any potential bis-acylated product formed. The product was then purified by flash chromatography on silica gel using as eluent a gradient of EtOAC (0 - 10%) in DCM or MeOH (0 - 5%) in DCM, washed with MeOH and dried in vacuum to afford the desired compound (adapted from 1).

Reference： [1]Ribeiro, Carlos J.A.; Kankanala, Jayakanth; Xie, Jiashu; Williams, Jessica; Aihara, Hideki; Wang, Zhengqiang [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 2, p. 257 - 261]

59
[ 21900-54-9 ]
[ 1774-47-6 ]
C₁₀H₁₀ClFO₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: trimethylsulfoxonium iodide With potassium <i>tert</i>-butylate In tetrahydrofuran for 2h; Reflux; Stage #2: 2-chloro-4-fluorobenzoyl chloride In tetrahydrofuran at 0 - 20℃; for 3h;	3.2.1. General Procedure for the Preparation of Sulfoxonium Ylides 1a-1p General procedure: Sulfoxonium ylides 1a-1p were prepared according to the reported procedures [28]. To a stirredsolution of potassiumtert-butoxide (3.3 equiv.) in THF was added trimethylsulfoxonium iodide(3.0 equiv.) at room temperature. The resulting mixture is refluxed for 2 h. Then reaction mixturewas cooled to 0 °C, followed by the addition of acyl chlorides (1.0 equiv.) in THF. The reaction was allowed to reach room temperature and stirred for 3 h. Next, the solvent was evaporated, and waterand ethylacetate were added to the resulting slurry. The layers were separated and the aqueous layerwas washed with ethyl acetate and the organic layers were combined. The organic solution was driedover anhydrous sodium sulphate (Na2SO4), filtered over a sintered funnel, and evaporated to dryness.The crude product was purified by flash chromatography over silica gel using DCM/MeOH (95:5) toaord the corresponding sulfoxonium ylides 1a-1p.

Reference： [1]Song, Xiaohan; Han, Xu; Zhang, Rui; Liu, Hong; Wang, Jiang [Molecules, 2019, vol. 24, # 10]

60
[ 21900-54-9 ]
[ 1008-79-3 ]
1-phenyl-1H-pyrazol-3-yl 2-chloro-4-fluorobenzoate [ No CAS ]

Reference： [1]Molecular Diversity,2019

61
[ 21900-54-9 ]
[ 6638-79-5 ]
2-chloro-4-fluoro-N-methoxy-N-methylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.45 g	With trimethylamine In dichloromethane at 20℃; for 3h; Cooling with ice;	4 Synthesis of 2-chloro-4-fluoro-N-methoxy-N-methylbenzamide Reference Example 4 Synthesis of 2-chloro-4-fluoro-N-methoxy-N-methylbenzamide The dichloromethane solution (50 ml) containing 2.53 g of N-methoxy-N-methylamine hydrochloride and 7.22 ml of trimethylamine was added under ice cooling 5.00 g of 2-chloro-4-fluorobenzoyl chloride. The mixture was brought to room temperature and was stirred for 3 hours. The reaction mixture was separated by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer thus obtained was washed sequentially with 1 N hydrochloric acid and saturated brine, and was dried over magnesium sulfate. The mixture was distilled under reduced pressure to remove the solvent, to obtain the title compound (5.45 g). The product was used for the next reaction without further purification. 1H-NMR (CDCl3) δ: 7.34 (1H, dd, J=8.5, 6.0 Hz), 7.17 (1H, dd, J=8.5, 2.4 Hz), 7.04 (1H, td, J=8.3, 2.4 Hz), 3.95-3.06 (6H, m).

Reference： [1]Current Patent Assignee: MITSUI CHEMICALS,INC. - US2020/45963, 2020, A1 Location in patent: Paragraph 1258-1260

62
[ 21900-54-9 ]
C₂₇H₃₀N₂O₅S [ No CAS ]
C₃₄H₃₂ClFN₂O₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49.5%	With triethylamine In tetrahydrofuran; dichloromethane at 60℃; for 24h;	12 [Preparation Example 4: Preparation of Compound 1] General procedure: Compound [A] (1.5 g, 2.94 mmol, 1 eq) was dissolved in a mixture of 5 g of dichloromethane in 25 g of tetrahydrofuran. 4-nitrobenzoyl chloride (2.72g, 14.7mmol, 5eq) and Triethylamine (0.9g, 8.82mmol, 3eq) were added and heated at 60 ° C. After the reaction for about 24 hours, the reaction was terminated by quenching with 1M HCl solution, and filtered under reduced pressure. Purification by column chromatography (Dichloromethane: Metanol = 8: 1) afforded 1.6 g (2.0 mmol) of compound [1]. (Yield 68%)

Reference： [1]Current Patent Assignee: LG CHEM CO.,LTD. - KR2020/7157, 2020, A Location in patent: Paragraph 0213; 0215; 0253-0256

63
[ 21900-54-9 ]
4-chloro-3-(8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)aniline [ No CAS ]
2-chloro-N-(4-chloro-3-(8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenyl)-4-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.28 g	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	4.2.13. Synthesis of 2-chloro-N-(4-chloro-3-(8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenyl)-4-fluorobenzamide (TPB12) Thionyl chloride (0.356 g; 3 mmol) was added to a mixture of 2-chloro-4-fluorobenzoic acid (0.175 g, 1 mmol) in toluene and themixture was heated at reflux for 3 h. The reaction was cooled to roomtemperature and the solvent was removed under reduced pressure. Theresultant acid chloride was dropwised to a mixture of Compound 4 (0.279 g, 1 mmol) and DIPEA (0.258 g, 2 mmol) in dichloromethane(15 ml) at room temperature. The solution was stirred for overnight,then concentrated in vacuo. The residue was purified by silica gelcolumn (DCM/MeOH = 20/1) to afford TPB12 (0.280 g, yield: 65%);purity: 99%; mp: 237.5-239.2 °C; 1H-NMR (d6-DMSO): δ = 10.95 (s,1H), 8.19-8.13 (m, 1H), 8.11 (d, J = 2.6 Hz, 1H), 8.00 (dd, J = 8.9,2.6 Hz, 1H), 7.81-7.73 (m, 2H), 7.73-7.68 (m, 1H), 7.63 (dd, J = 9.0,2.5 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.06 (t, J = 7.1 Hz, 1H); 13CNMR(d6-DMSO): δ = 164.99 (s), 164.12 (s), 161.63 (s), 148.00 (s),146.14 (s), 138.78 (s), 133.54 (d, J = 3.5 Hz), 131.92 (d, J = 11.0 Hz),131.36 (d, J = 9.6 Hz), 131.12 (s), 127.92 (d, J = 3.8 Hz), 125.89 (s),124.18 (s), 123.84 (d, J = 12.4 Hz), 120.63 (s), 117.81 (s), 117.56 (s),115.22 (s), 114.94 (d, J = 14.1 Hz); HR-ESI-MS for C19H9ON4Cl3F([M-H]+) Calcd: 432.9826; Found: 432.9838.

Reference： [1]Chen, Mian; Lv, Lin; Quan, Dongling; Schmitz, John C.; Tian, Nannan; Tian, Yuanxin; Wei, Ning; Wu, Huanxian; Wu, Shaoyu; Xie, Ying; Xu, Yimei; Yang, Danni; Yang, Zichao; Zhang, Huiwu; Zhang, Jiajie; Zhang, Tingting; Zhou, Lei [Bioorganic and medicinal chemistry, 2020, vol. 28, # 16]

64
[ 21900-54-9 ]
[ 100-63-0 ]
2-chloro-4-fluoro-N'-phenylbenzohydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With pyridine In tetrahydrofuran at 5 - 20℃; for 2h;	34 Example 34. 2-chloro-4-fluoro-N'-phenylbenzohydrazide (34) Following the general procedure Route C, 2-chloro-4-fluoro-N'-phenylbenzohydrazide was obtained from the coupling reaction of 2-chloro-4-fluorobenzoyl chloride (2.89 g, 15 mmol) and phenylhydrazine (1 .78 g, 16.5 mmol), in presence of pyridine (2.65 mL, 33 mmol). Phenylhydrazine is solubilized in pyridine in a 50 mL flask and cooled at 5 ° C with an ice bath. In parallel, 2-chloro-4- fluorobenzoyl chloride is dissolved in 5 mL of THF. The acyl chloride solution is then added dropwise at 5 ° C to the phenylhydrazine solution. After addition, the temperature is allowed to warm to room temperature and the medium is stirred during 2 hours. Pyridinium chloride gradually appeared in the medium. After completion of the reaction, water (30 mL) is added, pyridinium chloride dissolved and 2-chloro-4-fluoro-N'-phenylbenzohydrazide precipitated. The precipitate is filtered, washed by diethylether (3x10 mL) and dried. Compound 34 is obtained as a white solid (2.66 g, 67% yield), m.p. 159-160° C (0470) 1H NMR (400 MHz, DMSO-d6): d 10.2 (d, J = 2.8 Hz, 1 H, NH, conformer 1 ), 9.71 (s, 1 H, NH, conformer 2), 8.58 (d, 2H, CHAr, conformer 2), 8.00 (d, J = 3.2 Hz, 1 H, NH, conformer 1 ), 7.91 (s, 1 H, NH, conformer 2), 7.78 (tt, J = 7.6 Hz, J = 2,0 Hz, 1 H, CHAr, conformer 1 ), 7.62 (td, J = 8.4 Hz, J = 6.0 Hz, 1 H, CHAr, conformer 1 ), 7.58 (dd, J = 8.8 Hz, J = 2.4 Hz, 1 H, CHAr, conformer 1 ), 7.44-7.37 (m, 3H, CHAr, conformer 2), 7.34 (td, J = 8.0 Hz, J = 2.4 Hz, 1 H, CHAr, conformer 1 ), 7.15 (td, J = 8.0 Hz, J = 2.0 Hz, 2H, CHAr, conformer 1 ), 715-7.11 (m, 3H, CHAr, conformer 2), 6.84 (d, J = 8.2 Hz, 2H, CHAr, conformer 1 ), 6.81 -6.73 (m, 2H, CHAr, conformer 2), 6.73 (td, J = 8.4 Hz, J = 2.0 Hz, 1 H, CHAr, conformer 2). (0471) 13C{1H}NMR (100 MHz, DMSO-cU): 166.0 (C=0), 162.8 (d, C,v, J = 250 Hz, CF), 149.4 (C,v), 132.3 (d, Civ, J = 3 Hz), 132.3 (d, C,v, J = 1 1 Hz), 131 .8 (d, CH, J = 10 Hz), 129.2 (2CHAr), 119.1 (CH), 1 17.7 (d, CH, J = 26 Hz), 1 15.0 (d, CH, J = 21 Hz), 1 12.7 (2CHAr). (0472) IR v (cm'1): 3231 , 1651 , 1599, 1439, 1269, 1043, 929, 855, 758, 686.

Reference： [1]Current Patent Assignee: NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; UNIVERSITY LILLE 1: SCIENCE AND TECHNOLOGY; YNCRÉA HAUTS-DE-FRANCE; INSTITUT PASTEUR - WO2020/169682, 2020, A1 Location in patent: Page/Page column 45

65
[ 21900-54-9 ]
2-(3H-imidazo[4,5-b]pyridin-2-yl)acetonitrile [ No CAS ]
(Z)-3-(2-chloro-4-fluorophenyl)-3-hydroxy-2-(3H-imidazo[4,5-b]pyridin-2-yl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With pyridine for 1.5h; Reflux;	4.2.3.1 (Z)-3-(2-chloro-4-fluorophenyl)-3-hydroxy-2-(3H-imidazo[4,5-b]pyridin-2-yl)acrylonitrile 17 A solution of 1.000g (6.32mmol) 2-(1H-imidazo[4,5-b]pyridin-2-yl)acetonitrile 2 and 1.220g (6.32mmol) 2-chloro-4-fluorobenzoylchloride 15 in pyridine (7mL) was refluxed for 1.5h. The cooled mixture was poured into water (50mL) and the resulting product was filtered off and recrystallized from ethanol to obtain a brown powder (0.950g, 47%); mp 275-279°C; 1H NMR (300MHz, DMSO-d6): δ/ppm=13.68 (bs, 1H, OH), 13.24 (bs, 1H, Himidazopyridine), 8.28 (dd, 1H, J=5.10Hz, Harom), 7.98 (d, 1H, J=7.77Hz, Harom), 7.57-7.48 (m, 2H, Harom), 7.35-7.27 (m, 2H, Harom); 13C NMR (75MHz, DMSO-d6): δ/ppm=185.6, 163.9 (d, JCF=247.31Hz), 154.7, 146.5, 140.9, 137.6 (d, JCF=3.45Hz), 131.3 (d, JCF=10.81Hz), 130.6 (d, JCF=9.13Hz), 126.2, 121.4, 120.1, 118.6, 117.4 (d, JCF=24.94Hz), 114.9 (d, JCF=21.12Hz), 69.9; Found: C, 57.00; H, 2.66; N, 18.01. Calc. for C15H8ClFN4O: C, 57.25; H, 2.56; N, 17.80%; MS (ESI) m/z 315.0 [M+H]+.

Reference： [1]Lončar, Borka; Perin, Nataša; Mioč, Marija; Boček, Ida; Grgić, Lea; Kralj, Marijeta; Tomić, Sanja; Stojković, Marijana Radić; Hranjec, Marijana [European Journal of Medicinal Chemistry, 2021, vol. 217]

66
[ 21900-54-9 ]
22-((3-amino-1,2,4-triazole-5-yl)-thioacetyl)-22-deoxypleuromutilin [ No CAS ]
22-((3-amino-2-(2-chloro-4-fluorobenzoyl)-1,2,4-triazole-5-yl)-thioacetyl)-22-deoxypleuromutilin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.1%	With potassium carbonate In dichloromethane at 20℃; for 6h;	4.2.2 General procedure for the synthesis of compounds 9-28 General procedure: 22-(3-amino-1,2,4-triazole-5-yl)-thioacetyl)-22-deoxypleuromutilin (compound 6) (1g, 2.10mmol) was dissolved in dichloromethane (20mL). Then added K2CO3 (0.58g, 4.20mmol) and benzoyl chloride derivatives (3.15mmol) to the solution and stirred for 6h at room temperature until reaction was completed. The mixture was washed with dichloromethane (30mL) and water (50mL) 3 times. The organic phase was dried over anhydrous Na2SO4 and evaporated in vacuum. The crude production was purified by column chromatography (dichloromethane: methanol=70:1) using silica gel to give the desired compound.

Reference： [1]Huang, Si-Yu; Wang, Xiao; Shen, Ding-Yi; Chen, Fang; Zhang, Guang-Yu; Zhang, Zhe; Li, Kang; Jin, Zhen; Du, Dan; Tang, You-Zhi [Bioorganic and Medicinal Chemistry, 2021, vol. 38]

67
[ 21900-54-9 ]
[ 536-74-3 ]
1-(2-chloro-4-fluorophenyl)-3-phenylprop-2-yn-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; for 6h;	General procedure for the synthesis of 3a-k General procedure: Compounds 3a-k were prepared according to the literature [6].2-chloro-5-nitrobenzolyl chloride (500 mg, 1.0 equiv.) was solvedin a solution of Pd(PPh3)2Cl2 (16 mg, 0.10 equiv.) and of CuI (9 mg,0.05 equiv.) in dry THF (10 mL). Then triethylamine (0.41 mL, 1.3equiv.) and alkyne (0.325 mL, 1.3 equiv.) were added via syringe.The reaction mixture was stirred for 6 h at room temperature untilthe alkyne was completely cunsumed (monitored by TLC). Solventswere evaporated, and the residue was washed with water. Theproduct was purified by chromatography on silica gel using heptaneand ethyl acetate as eluents.

Reference： [1]Dang, Tuan T.; Ehlers, Peter; Langer, Peter; Miliutina, Mariia; Nguyen Tien, Tuan Anh; Radolko, Jan; Thom, Richard [Tetrahedron, 2022, vol. 104]

68
[ 21900-54-9 ]
C₁₄H₁₃BrN₄O₂ [ No CAS ]
5-bromo-N-{2-[2-(2-chloro-4-fluorobenzoyl)hydrazinecarbonyl]-6-methylphenyl}nicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.4%	With potassium carbonate In tetrahydrofuran for 4h;	Synthesis of compounds 5a-5f and 10a-10i. General procedure: Tothe desired intermediate 4 or 9 (1 mmol), anhydrousTHF (10 mL) and anhydrous potassium carbonate(1.5 mmol) were added. Then substituted benzoyl chloride(1 mmol) was added dropwise to the reaction mixture, andit was stirred for 4 h. Upon completion of the process, themixture was poured into 50 mL of water, the residue wasfiltered off and recrystallized from anhydrous ethanol togive the corresponding compounds 5a-5f and 10a-10ias white solids.

Reference： [1]Li, Pei; Wang, Xiang; Yang, Zaibo [Russian Journal of General Chemistry, 2022, vol. 92, # 1, p. 132 - 140][Zh. Obshch. Khim., p. 8]

Type	HazMat fee for 500 gram (Estimated)
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CAS No. :	21900-54-9	MDL No. :	MFCD00084954
Formula :	C₇H₃Cl₂FO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	POIAZJJVWRVLBO-UHFFFAOYSA-N
M.W :	193.00	Pubchem ID :	2736546
Synonyms :

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	3265
Hazard Statements:	H302-H314	Packing Group:	Ⅱ
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[ CAS No. 21900-54-9 ]

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[ 21900-54-9 ] Synthesis Path-Upstream 1~1

[ 21900-54-9 ] Synthesis Path-Downstream 1~68

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