Name: 55117-15-2|1-Chloro-2-(chloromethyl)-3-fluorobenzene|98%
Brand: Ambeed
SKU: A480433
Price: 9.0 USD
Availability: InStock
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1
[ 56456-50-9 ]
[ 55117-15-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride

Reference： [1]Butler; Alexander; McLean; Strand [Journal of medicinal chemistry, 1971, vol. 14, # 11, p. 1052 - 1054]

2
[ 5446-37-7 ]
[ 55117-15-2 ]
[ 70091-33-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium carbonate In 1,2-dimethoxyethane
58%	With potassium carbonate In N,N-dimethyl acetamide	14 EXAMPLE 14 EXAMPLE 14 In a procedure analogous to that of Example 9, by using 1.75 g of 6-allylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride, there was obtained 1.84 g of 6-allylamino-9-(2-chloro-6-fluorobenzyl)purine as colorless needles (yield: 58%), m.p. 163°-164° C. Elemental analysis, for C15 H13 ClFN5: Calcd. C, 56.70; H, 4.12; N, 22.04. Found C, 56.43; H, 3.92; N, 22.09.

Reference： [1]Imai; Seo [European Journal of Medicinal Chemistry, 1980, vol. 15, # 3, p. 207 - 210]
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED; NIPPON SEIBUTSU KAGAKU KENKYUSHO; NIPPON SEIBUTSU KAGAKU KENKIYU - US4189485, 1980, A

3
[ 16370-58-4 ]
[ 55117-15-2 ]
[ 70091-32-6 ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate In 1,2-dimethoxyethane
59%	With potassium carbonate In N,N-dimethyl acetamide	13 EXAMPLE 13 EXAMPLE 13 In a procedure analogous to that of Example 9, by using 1.77 g of 6-n-propylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride, there was obtained 1.89 g of 9-(2-chloro-6-fluorobenzyl)-6-n-propylaminopurine as colorless needles (yield: 59%), m.p. 166°-167° C. Elemental analysis, for C15 H15 ClFN5: Calcd. C, 56.34; H, 4.73; N, 21.90. Found C, 56.12; H, 4.59; N, 21.67.

Reference： [1]Imai; Seo [European Journal of Medicinal Chemistry, 1980, vol. 15, # 3, p. 207 - 210]
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED; NIPPON SEIBUTSU KAGAKU KENKYUSHO; NIPPON SEIBUTSU KAGAKU KENKIYU - US4189485, 1980, A

4
[ 55117-15-2 ]
[ 443-72-1 ]
[ 70091-21-3 ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium carbonate; In N,N-dimethyl acetamide; water;	3. To a mixture of <strong>[443-72-1]6-methylaminopurine</strong> (7.45 g, 50 mmols), potassium carbonate (6.9 g, 50 mmols) and N,N-dimethylacetamide (250 ml) was added 2-chloro-6-fluorobenzyl chloride (17.9 g, 100 mmols), and the resultant mixture was allowed to react at 110 C. for 6 hours with stirring. After cooling, the reaction mixture was filtered to remove insoluble materials and the filtrate was concentrated to dryness under reduced pressure. Upon addition of water to the resultant residue, the formed precipitate was collected by filtration and recrystallized from ethanol to give 9-(2-chloro-6-fluorobenzyl)-<strong>[443-72-1]6-methylaminopurine</strong> as colorless needles (9.08 g, yield 63%), m.p. 188-190 C.
63%	With potassium carbonate; In N,N-dimethyl acetamide; water;	EXAMPLE 9 To a mixture of 7.45 g of <strong>[443-72-1]6-methylaminopurine</strong>, 6.9 g of potassium carbonate and 250 ml of N,N-dimethylacetamide was added 17.9 g of 2-chloro-6-fluorobenzyl chloride, and the resultant mixture was allowed to react at 110 C. for 6 hours with stirring. After cooling, the reaction mixture was filtered to remove insoluble materials and the filtrate was concentrated to dryness under reduced pressure. Upon addition of water to the resultant residue, the formed precipitate was collected by filtration and recrystallized from ethanol to give 9.08 g of 9-(2-chloro-6-fluorobenzyl)-<strong>[443-72-1]6-methylaminopurine</strong> as colorless needles (yield: 63%), m.p. 188-190 C.

Reference： [1]Patent: US4423219,1983,A
[2]Patent: US4189485,1980,A
[3]European Journal of Medicinal Chemistry,1980,vol. 15,p. 207 - 210

5
[ 55117-15-2 ]
[ 443-72-1 ]
[ 76099-78-0 ]

Reference： [1]European Journal of Medicinal Chemistry,1980,vol. 15,p. 207 - 210

6
[ 55117-15-2 ]
[ 16370-43-7 ]
[ 70091-31-5 ]

Yield	Reaction Conditions	Operation in experiment
34%	With potassium carbonate In 1,2-dimethoxyethane
34%	With potassium carbonate In N,N-dimethyl acetamide	12 EXAMPLE 12 EXAMPLE 12 In a procedure analogous to that of Example 9, by using 1.63 g of 6-ethylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride, there was obtained 1.04 g of 9-(2-chloro-6-fluorobenzyl)-6-ethylaminopurine as colorless needles (yield: 34%), m.p. 175°-176° C. Elemental analysis, for C14 H13 ClFN5: Calcd. C, 55.00; H, 4.29; N, 22.91. Found C, 54.66; H, 4.05; N, 22.90.

Reference： [1]Imai; Seo [European Journal of Medicinal Chemistry, 1980, vol. 15, # 3, p. 207 - 210]
[2]Current Patent Assignee: NIPPON SEIBUTSU KAGAKU KENKIYU; TAKEDA PHARMACEUTICAL COMPANY LIMITED; NIPPON SEIBUTSU KAGAKU KENKYUSHO - US4189485, 1980, A

7
[ 55117-15-2 ]
[ 938-55-6 ]
[ 70091-23-5 ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate; In N,N-dimethyl acetamide;	EXAMPLE 11 In a procedure analogous to that of Example 9, by using 1.63 g of 6-dimethylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride, there was obtained 1.9 g of 9-(2-chloro-6-fluorobenzyl)-6-dimethylaminopurine as colorless needles (yield: 62%); m.p. 134-135 C. Elemental analysis, for C14 H13 ClFN5: Calcd. C, 55.00; H, 4.29; N, 22.91. Found C, 54.91; H, 4.23; N, 22.86.

Reference： [1]Patent: US4189485,1980,A
[2]European Journal of Medicinal Chemistry,1980,vol. 15,p. 207 - 210

8
[ 55117-15-2 ]
[ 2898-08-0 ]
[ 713518-29-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In N,N-dimethyl-formamide at 20℃;

Reference： [1]Bolli, Martin H.; Marfurt, Judith; Grisostomi, Corinna; Boss, Christoph; Binkert, Christoph; Hess, Patrick; Treiber, Alexander; Thorin, Eric; Morrison, Keith; Buchmann, Stephan; Bur, Daniel; Ramuz, Henri; Clozel, Martine; Fischli, Walter; Weller, Thomas [Journal of Medicinal Chemistry, 2004, vol. 47, # 11, p. 2776 - 2795]

9
[ 55117-15-2 ]
9b-(3-butyl-phenyl)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione [ No CAS ]
9b-(3-butyl-phenyl)-5-(2-chloro-6-fluoro-benzyl)-1-(4,6-dimethyl-pyrimidin-2-yloxy)-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate In N,N-dimethyl-formamide at 50 - 60℃;

Reference： [1]Bolli, Martin H.; Marfurt, Judith; Grisostomi, Corinna; Boss, Christoph; Binkert, Christoph; Hess, Patrick; Treiber, Alexander; Thorin, Eric; Morrison, Keith; Buchmann, Stephan; Bur, Daniel; Ramuz, Henri; Clozel, Martine; Fischli, Walter; Weller, Thomas [Journal of Medicinal Chemistry, 2004, vol. 47, # 11, p. 2776 - 2795]

10
[ 888738-15-6 ]
[ 55117-15-2 ]
[ 888739-50-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	With hydrogenchloride In N,N-dimethyl-formamide	R.133 Reference Example 133 Reference Example 133 To a solution of ethyl 3-(3-isopropoxy-1H-pyrazol-5-yl)propionate (1.00 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (190 mg, 60% in oil) at room temperature, and the mixture was stirred for 10 min. To the reaction mixture was added 2-chloro-6-fluorobenzyl chloride (1.19 g), and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:49 to 1:4, v/v) to give ethyl 3-[1-(2-chloro-6-fluorobenzyl)-3-isopropoxy-1H-pyrazol-5-yl]propionate (730 mg, yield 45%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ:1.25 (6 H, t, J = 6.2 Hz), 1.27 (3 H, d, J = 6.9 Hz), 2.59 - 2.66 (2 H, m), 2.94 - 3.01 (2 H, m), 4.15 (2 H, q, J = 6.9 Hz), 4.48 - 4.60 (1 H, m), 5.20 (2 H, d, J = 1.5 Hz), 5.40 (1 H, s), 6.95 - 7.04 (1 H, m), 7.15 - 7.30 (2 H, m).
45%	With sodium hydride In N,N-dimethyl-formamide at 20℃; for 4h;

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1829863, 2007, A1
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2006/57448, 2006, A1 Location in patent: Page/Page column 165

11
[ 55117-15-2 ]
[ 94318-23-7 ]
[ 300659-77-2 ]

Yield	Reaction Conditions	Operation in experiment
61.2%	With ammonium chloride; magnesium	56 1-(2-chloro-6-fluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride Example 56 1-(2-chloro-6-fluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride 0.38 g (15.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.79 g (15.6 mmole) of 2-chloro-6-fluorobenzyl chloride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for one hour at RT. 3.00 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 30 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.92 g of crude base (101% of theory) were obtained, from which 3.28 g of 1-(2-chloro-6-fluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (61.2% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone.

Reference： [1]Current Patent Assignee: Gruenenthal Pharma GmbH & Co. Kommanditgesellschaft - US6410790, 2002, B1

12
[ 55117-15-2 ]
[ 20348-16-7 ]
2-amino-3-(2-chloro-6-fluorobenzyloxy)-6-methylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In dichloromethane;	(a) 2-Amino- 3-(2-chloro-6-fluorobenzyloxy)-6-methylpyridine A mixture of <strong>[20348-16-7]2-amino-3-hydroxy-6-methylpyridine</strong> (4.3 g, 0.035 mol), dichloromethane (26 ml) and 40% aqueous sodium hydroxide solution (26 ml) was stirred for five minutes at room temperature, then 2-chloro-6-fluorobenzyl chloride (6.8 g, 0.038 mol) and Adogen 464 (2.5 ml) were added and stirring continued for 16 hours. The mixture was diluted with water and extracted with dichloromethane. Drying and evaporation of the organic extracts and trituration with ethanol gave the desired product. Yield 6.3 g (67%), m.p. 108-109 C.

Reference： [1]Patent: US5409943,1995,A

13
[ 55117-15-2 ]
[ 107-21-1 ]
[ 443-72-1 ]
[ 70091-21-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In acetone;	Example 27 To 100 ml. of acetone were added 6.5 g. (0.0435 mole) of N6 -methyladenine and 3.5 g. (0.0435 mole) of a 50% by weight aqueous solution of sodium hydroxide. The mixture was heated under reflux for 1.5 hours. To the suspension was added a solution prepared by dissolving 7.8 g. (0.0435 mole) of 2-chloro-6-fluorobenzyl chloride and 2.61 g. (0.00435 mole) of polyethylene glycol (average molecular weight: 600) into 20 ml. of acetone. The mixture was heated under reflux for 6 hours. After evaporating the resulting acetone, the powdery residue was taken out and dried at 70 C. for 20 hours to give 15.79 g. of a crude 9-(2-chloro-6-fluorobenzyl)-N6 -methyladenine in crystal form. The purity was 67.5% by weight and the content of the 3-isomer was 6.7% by weight.

Reference： [1]Patent: US4900826,1990,A

14
[ 55117-15-2 ]
[ 5137-55-3 ]
[ 443-72-1 ]
[ 70091-21-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium hydroxide; In acetone;	(1) Alkylation To 744 ml. of acetone were added 50 g. of N6 -methyladenine (purity: 92.6% by weight) and 24.9 g. of a 50% by weight aqueous solution of sodium hydroxide. The mixture was heated under reflux for 3 hours. To the mixture was added a solution prepared by dissolving 55.9 g. of 2-chloro-6-fluorobenzyl chloride and 8.4 g. of tri-n-octylmethylammonium chloride (90% by weight aqueous solution) into 124 ml. of acetone. The resultant was heated under reflux for 6 hours. After completing the reaction, the acetone was recovered by distillation and 750 ml. of 0.1N sodium hydroxide was added to the residue. The resultant was agitated for about 15 minutes at a room temperature. The resulting precipitate was filtered and repeatedly washed with water until the filtrate became neutral. The obtained crystals were dried in a hot air drier at 70 C. for 20 hours to give 88.3 g. of a crude 9-(2-chloro-6-fluorobenzyl)-N6 -methyladenine. The yield was 98 %, and the purity was 76.6% by weight and the content of the 3-isomer was 23.4% by weight.

Reference： [1]Patent: US4900826,1990,A

15
tricaprylylmethyl ammoniumchloride [ No CAS ]
[ 55117-15-2 ]
[ 443-72-1 ]
[ 70091-21-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In ethanol; acetone;	EXAMPLE 18 To 100 ml. of acetone were added 6.5 g. (0.0435 mole) of N6 -methyladenine which had a purity of 99.8% by weight and was prepared by recrystallizing the product obtained in Example 1 from ethanol, and 3.5 g. (0.0435 mole) of a 50% by weight aqueous solution of sodium hydroxide. The mixture was heated under reflux for 1.5 hours. A solution prepared by dissolving 7.8 g. (0.0435 mole) of 2-chloro-6-fluorobenzyl chloride and 1.17 g. (0.0026 mole) of a 90% by weight trioctylmethyl ammonium chloride as a phase transfer catalyst into 17 ml. of acetone was added thereto and the resultant was heated under reflux for 6 hours. After completing the reaction, the acetone was removed by distillation and the resulting powdery residue was taken out and dried at 70 C. for 15 hours to give 12.4 g. of a crude 9-(2-chloro-6-fluorobenzyl)-N6 -methyladenine in crystal form. The purity was 79.4% by weight and the content of the 3-isomer was 20.6% by weight.

Reference： [1]Patent: US4900826,1990,A

16
[ 55117-15-2 ]
[ 7239-81-8 ]
2-[[(2-Chloro-6-fluorophenyl)methyl]thio]-1H-imidazo[4,5-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium In ethanol; N,N-dimethyl-formamide	9 2-[[(2-Chloro-6-fluorophenyl)methyl]thio]-1H-imidazo[4,5-c]pyridine EXAMPLE 9 2-[[(2-Chloro-6-fluorophenyl)methyl]thio]-1H-imidazo[4,5-c]pyridine To a solution of 0.34 g (0.015 g atom) of sodium in 70 mL of ethanol was added 2.0 g (0.013 mol) of 2-mercapto-1H-imidazo[4,5-c]pyridine. After stirring at room temperature for 25 minutes, the reaction mixture was evaporated to dryness in a rotary evaporator. To the residue was added 40 mL of DMF. To the resulting solution was added dropwise 2.33 g (0.013 mol) of 2-chloro-6-fluorobenzyl chloride in 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and was then poured into 400 mL of chilled water. The precipitate that formed was collected by filtration and amounted to 3.11 g. An analytical sample (m.p. 224°-226° C.) was obtained by recrystallization from ethanol. Anal. Calcd. for C13 H9 ClFN3 S: C, 53.15; H, 3.09; N, 14.30. Found: C, 53.29; H, 3.30; N, 13.95.

Reference： [1]Current Patent Assignee: PFIZER INC - US5081253, 1992, A

17
[ 55117-15-2 ]
2-(azidomethyl)-1-chloro-3-fluorobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide	37 EXAMPLE 37 123 g of (0.687 mole) of 6-chloro-2-fluorobenzyl chloride are added dropwise at 20°-40° C. to a suspension of 47 g (0.722 mole) of sodium azide in 400 ml of dimethylsulfoxide. The mixture is stirred for 4 hours at room temperature, then diluted with ice-water and extracted with cyclohexane. The solvent is removed by distillation and the residue is distilled, affording 6-chloro-2-fluorobenzyl azide; bp15 =99°-100° C.
	With sodium azide; triethylamine In water; <i>tert</i>-butyl alcohol at 20℃; for 0.5h;	6.1.2. General procedure for the synthesis of compounds 3a-n General procedure: A mixture of 1.3 mmol of Et3N, 0.9 mmol of sodium azide and 1.1 mmol of appropriate benzyl chloride 6 in 4 mL of water and 4 mL of t-BuOH was stirred vigorously for 30 min at room temperature. Then, 0.5 mmol of compound 5 and 7% mol of CuI were added into the mixture and stirred for 24-56 h at room temperature. The completion of reaction was detected by TLC. The reaction mixture was diluted with water, cooled in ice. A brown precipitate was formed, filtrated and washed three times with 20 mL of cold water. The resulting product was purified using silica gel column chromatography.

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US4789680, 1988, A
[2]Location in patent: experimental part Tahghighi, Azar; Razmi, Sepideh; Mahdavi, Mohammad; Foroumadi, Parham; Ardestani, Sussan K.; Emami, Saeed; Kobarfard, Farzad; Dastmalchi, Siavoush; Shafiee, Abbas; Foroumadi, Alireza [European Journal of Medicinal Chemistry, 2012, vol. 50, p. 124 - 128]

18
[ 55117-15-2 ]
[ 5137-55-3 ]
[ 938-55-6 ]
[ 70091-23-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; nitric acid; In nitrogen; water; acetone;	EXAMPLE 24 In water (0.28 ml) was dissolved sodium hydroxide (280 mg, 7 mmols) followed by addition of acetone (14 ml) and 6-dimethylaminopurine (1.142 g, 7 mmols). The mixture was refluxed in a nitrogen gas stream with stirring for 1.5 hours. After cooling, a solution of 2-chloro-6-fluorobenzyl chloride (1.253 g, 7 mmols) and trioctylmethylammonium chloride (141 mg, 0.35 mmol) in acetone (5 ml) was added to the mixture. Thereafter the same procedure as that described in Example 22 was followed to obtain crystals of 2-chloro-6-fluorobenzyl-substituted 6-dimethylaminopurine (1.146 g, yield 54%). 9-isomer 79%. From the mother liquor, there was obtained 2-chloro-6-fluorobenzyl substituted 6-dimethylaminopurine (847 mg, yield 40%). 9-isomer 29%. To the crystals (9-isomer 79%) (500 mg) obtained as above were added water (8 ml) and 1 N nitric acid (0.32 ml) and the mixture was refluxed with stirring for 2 hours. When hot, the insoluble crystals were recovered by filtration and washed with hot water, 28% aqueous ammonia, and hot water in that order to give 9-(2-chloro-6-fluorobenzyl)-6-dimethylaminopurine as colorless crystals (385 mg), m.p. 135-136 C.

Reference： [1]Patent: US4423219,1983,A

19
[ 17455-13-9 ]
[ 55117-15-2 ]
[ 81778-07-6 ]
2-[(2-chloro-6-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dichloromethane; acetonitrile	33 2-[(2-Chloro-6-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone EXAMPLE 33 2-[(2-Chloro-6-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone To a stirred suspension of 3.6 grams (0.026 mole) of potassium carbonate and 0.14 gram (0.0005 mole) of 1,4,7,10,13,16-hexaoxacyclooctadecane in 50 ml of acetonitrile was added dropwise a solution of 3.0 grams (0.026 mole) of 4,4-dimethyl-3-isoxazolidinone (Example 30, Step B) and 4.7 grams (0.025 mole) of (2-chloro-6-fluorophenyl)methyl chloride in 25 ml of acetonitrile. The complete addition required 30 minutes. Upon completion of addition the reaction mixture was stirred at ambient temperature for 18 hours, and then filtered. The filtrate was diluted with 200 ml of methylene chloride and washed with three 100-ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. The oil solidified and was recrystallized from petroleum ether to give 3.0 grams of 2-[(2-chloro-6-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone; mp 49°-51°. The nmr and the ir spectra were consistent with the assigned structure. Analysis calc'd for C12 H13 ClFNO3: C 55.93; H 5.08; N 5.44; Found: C 55.65; H 5.17; N 5.25.

Reference： [1]Current Patent Assignee: FMC CORP - US4405357, 1983, A

20
[ 55117-15-2 ]
[ 15205-15-9 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; In benzene;	EXAMPLE 2 Preparation of 2 -Chloro-6 -fluorobenzylamine An autoclave was charged with 89.0 g. (0.5 mole) of 2-chloro-6-fluorobenzyl chloride, 170.0 g. (10 mole) ammonia and 50 ml. benzene. The reaction vessel was sealed and the contents heated at 100 C. for 15 hours. The excess ammonia was carefully evaporated off from the cooled contents of the autoclave with a stream of nitrogen. The residue was washed with water, and the organic phase after drying with anhydrous MgSO4, fractionated to afford 72.4 g. (90%) of product as a clear liquid; b.p. 99-100 C./20 mm; NMR (CDCl3) delta 1.46 (s, 2H); 3.88 (d, 2H); 7.00 (m, 3H).

Reference： [1]Patent: US4098787,1978,A

21
[ 19335-11-6 ]
[ 55117-15-2 ]
[ 40064-34-4 ]
[ 144-55-8 ]
N-[1-(2-Chloro-6-fluorobenzyl)-4-piperidyl]-N-(1H-5-indazolyl)amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate; In methanol; acetonitrile;	Example 150 N-[1-(2-Chloro-6-fluorobenzyl)-4-piperidyl]-N-(1H-5-indazolyl)amine 2-Chloro-6-fluorobenzyl chloride (89 mg), <strong>[40064-34-4]4-piperidone monohydrate hydrochloride</strong> (77 mg), and potassium carbonate (138 mg) were dissolved in acetonitrile (1 ml), and the mixture was then stirred at room temperature for 18 hr. The reaction mixture was filtered through Celite, and the filtrate was then concentrated to give an intermediate. This intermediate, 5-aminoindazole (53 mg), andacetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (89 mg, yield 62%). 1H-NMR (CDCl3, 400 MHz): 1.42 - 1.55 (m, 2H), 2.03 - 2.12 (m, 2H), 2.30 - 2.40 (m, 2H), 2.91 - 3.00 (m, 2H), 3.25 - 3.34 (m, 1H), 3.75 (s, 2H), 6.76 - 6.81 (m, 2H), 6.93 - 7.03 (m, 1H), 7.17 - 7.23 (m, 2H), 7.25 - 7.33 (m, 1H), 7.87 (s, 1H) Mass spectrum (ESI-MS, m/z): 359 (M++1)

Reference： [1]Patent: EP1256574,2002,A1

22
[ 20232-57-9 ]
[ 55117-15-2 ]
1-propyl-2-(2-chloro-6-fluorophenyl)methyl-6,7-dimethoxy-isoquinolinium chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In acetonitrile for 12h;	139 Preparation of 1-propyl-2-(2-chloro-6-fluorophenyl)methyl-6,7-dimethoxy-isoquinolinium chloride (Compound No. 139) 2.33 g of 1-propyl-3,4-dihydro-6,7-dimethoxyisoquinoline thus obtained was dissolved in 40 ml of tetrahydrofuran and 2.2 g of potassium t-butoxide was added thereto. The resulting mixture was heated to proceed the reaction for 24 hours at reflux temperature.The resulting mixture was cooled to room temperature and washed with water then extracted with ethyl acetate. The concentrated reaction mixture thus obtained was separated through silica-gel column chromatography eluting with dichloromethane and methanol (40:1), to give 2.08 g of 6,7-dimethoxyisoquinoline (yield: 90%) 231 Mg of 6,7-dimethoxyisoquinoline thus obtained was dissolved in 10 ml of acetonitrile and 214 mg of 2'-chloro-6'-fluorobenzyl chloride was added thereto to proceed the reaction for 12 hours. The reaction mixture was cooled to room temperature and the solvent was removed from the reaction mixture under reduced pressure. The concentrated reaction mixture was separated through silica-gel column chromatography eluting with dichloromethane and methanol (10:1), to give 350 mg of 1-propyl-2-(2-chloro-6-fluorophenyl)methyl-6,7-dimethoxy-isoquinolinium chloride (yield: 85%) (m.p. 78° C.).1H-NMR (CDCl3, 300 MHz): δ 1.16 (t, 3H, J=7.5 Hz), 1.31 (s, 9H), 1.61.8 (m, 2H), 3.52 (t, 2H, J=7.5), 4.13 (s, 3H), 4.20 (s, 3H), 6.27 (s, 2H), 7.15 (d, 2H, J=6.9 Hz), 7.35 (d, 2H, J=6.9 Hz), 7.40 (s, 1H), 7.60 (s, 1H), 8.34 (d, 1H, J=6.9 Hz), 8.17 (d, 1H, J=6.9 Hz)
85%	In acetonitrile for 12h;	139 231Mg of 6,7-dimethoxyisoquinoline thus obtained was dissolved in 10ml of acetonitrile and 214mg of 2'-chloro-6'-fluorobenzyl chloride was added thereto to proceed the reaction for 12 hours. The reaction mixture was cooled to room temperature and the solvent was removed from the reaction mixture under reduced pressure. The concentrated reaction mixture was separated through silica-gel column chromatography eluting with dichloromethane and methanol(10: l), to give 350mg of l-propyl-2-(2-chloro-6-fluorophenyl)methyl-6,7-dimethoxy-isoquinolinium chloride(yield: 85%)(m.p.78°C).[859] 1H-NMR (CDCl , 300MHz):δ 1.16(t, 3H, /=7.5Hz), 1.31(s, 9H), 1.6~1.8(m, 2H),3.52(t, 2H, J=7.5), 4.13(s, 3H), 4.20(s, 3H), 6.27 (s, 2H), 7.15(d, 2H, /=6.9Hz), 7.35(d, 2H, /=6.9Hz), 7.40(s, IH), 7.60(s, IH), 8.34(d, IH, /=6.9Hz), 8.17(d, IH, /=6.9Hz)

Reference： [1]Current Patent Assignee: HANWHA SOLUTIONS CORPORATION - US2009/221829, 2009, A1 Location in patent: Page/Page column 35
[2]Current Patent Assignee: HANWHA SOLUTIONS CORPORATION - WO2006/129978, 2006, A1 Location in patent: Page/Page column 75

23
[ 903468-73-5 ]
[ 55117-15-2 ]
[ 1215289-40-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In N,N-dimethyl-formamide at 90 - 100℃; regioselective reaction;

Reference： [1]Location in patent: experimental part Sirko, Svetlana M.; Gorobets, Nikolay Yu.; Musatov, Vladimir I.; Desenko, Sergey M. [Molecules, 2009, vol. 14, # 12, p. 5223 - 5234]

24
[ 1239964-46-5 ]
[ 55117-15-2 ]
[ 1239956-62-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 3-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-1H-1,2,4-triazole-5(4H)-thione With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: 2-chloro-6 fluorobenzyl chloride In acetone for 2h; Reflux;	A mixture of 3-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-lH- l,2,4-triazole-5(4H)-thione (200 mg, 0.54 mmol) and K2CO3 (111 mg, 0.80 mmol) in acetone (15 mL) was stirred for 30 min at room temperature. 2-Chloro-6-fluorobenzyl chloride (206 μL, 1.61 mmol) was added to the reaction mixture, and the resulting mixture was refluxed for 2 h. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated. Purification by flash chromatography [Hex/EtOAc, 1 :4 to 1 :1] afforded the title product (230 mg, 0.45 mmol, 83%). 1H NMR (400 MHz, CDCl3) δ 12USD - 7.12 (m, 2H), 6.95 - 6.91 (m, IH), 6.84 - 6.80 (m, 2H), 6.68 (d, IH), 6.54 (d, IH), 6.50 (dd, IH), 6.45 - 6.40 (m, 2H), 4.45 (s, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 1.65 (s, 6H); MS (EI) m/z 516 (MH+).

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2010/93845, 2010, A1 Location in patent: Page/Page column 84-85

25
[ 1239963-77-9 ]
[ 55117-15-2 ]
[ 1239956-60-5 ]

Yield	Reaction Conditions	Operation in experiment
33%	With potassium carbonate In acetone for 2h;	To a mixture of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2(3H)-thione (138 mg, 0.362 mmol) and K2CO3 (76 mg, 0.543 mmol) in acetone (6 rnL) was added 2-chloro-6-fluorobenzyl chloride (79 mg, 0.434 mmol). After stirring 2h, the reaction mixture was filtered, concentrated and purified by flash chromatography to provide the title product (77 mg, 33 %). 1H NMR (400 MHz, CDCl3) δ 7.25 (m, IH), 7.22 (s, IH), 7.16-7.11 (m, 2H), 7.03 (d, IH), 6.91 (m, IH), 6.83 (dd, IH), 6.78 (t, 2H), 6.34 (m, 2H), 4.25 (s, 2H), 1.49 (s, 6H); MS (EI) m/z 523, 525 (MH+).

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2010/93845, 2010, A1 Location in patent: Page/Page column 84

26
[ 26278-79-5 ]
[ 55117-15-2 ]
[ 1146853-03-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-amino-6-hydroxybenzothiazole With potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 2-chloro-6 fluorobenzyl chloride In N,N-dimethyl-formamide at 20℃; for 20h;	8 add 337 mg of anhydrous potassium hydroxide to a solution of 1g of 2-amino-1,3-benzothiazol-6-ol in 5 cm3 of N,N-dimethylformamide. After stirring for one hour at a temperature close to 20° C., a solution of 1.08 g of 1-chloro-2-(chloromethyl)-3-fluorobenzene in 2 cm3 of N,N-dimethylformamide is added dropwise. Stir the resultant mixture for about twenty hours at about 20° C. The reaction mixture is poured into 30 cm3 of water, and extracted three times with 50 cm3 of dichloromethane. The organic phases are combined and washed three times with 50 cm3 of a 0.1N aqueous solution of sodium hydroxide, then dried over magnesium sulphate, filtered and concentrated under reduced pressure (0.2 kPa). The residue is taken up in 10 cm3 of a dichloromethane/methanol mixture (98/2 by volume), drained and then washed twice with 5 cm3 of the same mixture, stove-dried under reduced pressure (0.2 kPa) and at a temperature close to 35° C. We obtain 339 mg of 6-[(2-chloro-6-fluorobenzyl)oxy]-1,3-benzothiazol-2-amine in the form of a white solid, which has the following characteristics:Melting point: 175° C. (Köfler)1H NMR spectrum (400 MHz, DMSO-d6) δ ppm: 5.12 (d, J=2.0 Hz, 2H) 6.90 (dd, J=8.5, 2.7 Hz, 1H) 7.24 (m, 3H) 7.31 (t, J=8.8 Hz, 1H) 7.41 (m, 2H) 7.51 (td, J=8.8, 6.4 Hz, 1H)Mass spectrum: LC-MS-DAD-ELSD: 309(+)=(M+H)(+)

Reference： [1]Current Patent Assignee: SANOFI - US2010/273793, 2010, A1 Location in patent: Page/Page column 21

27
[ 110-85-0 ]
[ 55117-15-2 ]
1-(2-chloro-6-fluorobenzyl)piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	In tetrahydrofuran for 4h; Reflux;	5.1.3. General procedure for the synthesis of various substituted benzylpiperazines (3a-s) General procedure: Anhydrous piperazine (6.89 g, 80 mmol) was dissolved in 40 mL of freshly distilled THF. Once the piperazine was fully dissolved, 2.303 mL (20 mmol) of benzyl chloride was added dropwise. The reaction mixture was then refluxed for about 4 h until benzyl chloride disappeared, as assessed by TLC. The stirring mixture was allowed to cool, and then filtered. The filtrate was concentrated in a rotary evaporator and then diluted with EtOAc (100 mL) and water (50 mL), which was then made basic (pH>12) with a saturated 1 N NaOH aqueous solution and separated. The organic phase was washed with water (4 × 100 mL), brine (2 × 100 mL), dried over Na2SO4 and concentrated to yield an oil. Column chromatography (PE/EtOAc = 1:1 to EtOAc/MeOH = 5:1) afforded a pale yellow liquid.
77%	In tetrahydrofuran for 2.5h; Reflux;	2 General Procedure A: Synthesis of 1-benzylpiperazines. General procedure: General Procedure A: Synthesis of 1-benzylpiperazines.[0088]Anhydrous piperazine (6.0 equiv.) was suspended in THF (0.45 M benzyl halide). The mixture was heated to reflux until piperazine fully dissolved. Upon dissolution, the substituted benzyl halide (1.0 equiv.) was added to the reaction mixture. A white solid immediately formed. The reaction mixture was stirred at reflux for 2.5 hours. The mixture was cooled to room temperature. The solid was filtered and washed with THF and EtOAc. The combined filtrates were concentrated to 10% of the original volume. The concentrate was poured into a separatory funnel with 5% brine/H2O made basic (pH>12) with KOH. The aqueous layer was extracted with DCM and EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography to yield pure 1-benzylpiperazine
	With triethylamine In ethanol at 55℃; for 12h;

Reference： [1]Location in patent: experimental part Zhang, Cunlong; Tan, Chunyan; Zu, Xuyu; Zhai, Xin; Liu, Feng; Chu, Bizhu; Ma, Xiaohua; Chen, Yuzong; Gong, Ping; Jiang, Yuyang [European Journal of Medicinal Chemistry, 2011, vol. 46, # 4, p. 1404 - 1414]
[2]Current Patent Assignee: UNIVERSITY OF ILLINOIS (SYSTEM) - US2013/96133, 2013, A1 Location in patent: Paragraph 0088; 0093-0094
[3]Location in patent: experimental part Cai, Mingyi; Li, Zhong; Fan, Feng; Huang, Qingchun; Shao, Xusheng; Song, Gonghua [Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 5, p. 2624 - 2629]

28
[ 117011-70-8 ]
[ 55117-15-2 ]
[ 1338359-21-9 ]

Yield	Reaction Conditions	Operation in experiment
~ 80%	With potassium carbonate; In ethanol; for 24h;Reflux;	Example 44-(2-chloro, 6-fluoro)benzylamino-phenoxyisobutyric acidA mixture of 1.28 ml (10 mole) of 2-chloro, 6-fluorobenzylchloride, 1.95 g (10 mole) <strong>[117011-70-8]4-aminophenoxyisobutyric acid</strong>, 2.76 g (20 mole) potassium carbonate and 25 ml ethanol was refluxed and stirred for 24 hours. The mixture was treated as in example 1 giving a solid with a melting point of 173-175 C. The structure (shown below as Formula EX4) was confirmed by NMR spectroscopy. The yield was approximately 80%

Reference： [1]Patent: US8034966,2011,B1 .Location in patent: Page/Page column 13

29
[ 1338223-47-4 ]
[ 55117-15-2 ]
[ 1338222-28-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N'-(2,3-dimethyl-1H-indol-5-yl)-N-ethyl-N-methyl-formamidine With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: 2-chloro-6 fluorobenzyl chloride In dimethyl sulfoxide	18.18b Under argon, N'-(2,3-dimethyl-1 H-indol-5-yl)-N-ethyl-N-methyl-formamidine (650 mg) was dissolved in dry DMSO (5ml) at room temperature and potassium tert-butylate (318 mg) and 18-crown-6 (37 mg) were added and stirred for 5 minutes. Then 2-chloro- 6-fluorobenzylchloride (597 mg) dissolved in 5 ml of dry DMSO were added dropwise and the reaction mixture was stirred over night. Water (40 ml) was added and the mixture was extracted with MTBE (3x40 ml). The combined organic phases were washed with water (2x30 ml) and dried over sodium sulfate. After evaporation of the solvents, the residue was purified by column chromatography with a gradient of DCM and MeOH which yielded 200 mg of the product.

Reference： [1]Current Patent Assignee: BASF SE - WO2011/120912, 2011, A1 Location in patent: Page/Page column 67

30
methyl 2-(3-methyl-1H-indazole-6-yl)acetate [ No CAS ]
[ 55117-15-2 ]
C₁₈H₁₆ClFN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 18h;	104 Example 104 Synthesis of 2-[1-(2-chloro-6-fluorobenzyl)-3-methyl-1H-indazole-6-yl]ac etic acid [104] (hereinafter referred to as a compound [104]) To a solution of the compound [102-4] obtained in the process (4) of Example 102 (60.9 mg) in N,N-dimethylformamide (1.6 mL) were added potassium carbonate (221.2 mg) and 2-chloro-6-fluorobenzyl chloride (0.16 mL) at room temperature, and then the reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was quenched with water, and extracted with diethyl ether. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography. To a solution of the purified compound in methanol (1 mL) were added 1N-sodium hydroxide (1 mL) and tetrahydrofuran (1 mL), and then the reaction mixture was stirred at 65°C for 16 hours. The reaction mixture was added 1 N-hydrochloric acid for acidification, and extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative liquid chromatography to give the titled compound 4.5 mg as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 7.59 (1H, d, J = 8.3 Hz), 7.39 (1H, s), 7.23-7.19 (2H, m), 7.07-6.98 (2H, m), 5.64 (2H, s), 3.79 (2H, s), 2.53 (3H, s). ESI-MS found: 333 [M+H]+

Reference： [1]Current Patent Assignee: SATO PHARMACEUTICAL CO., LTD. - EP2669270, 2013, A1 Location in patent: Paragraph 0692-0693

31
[ 1613166-28-1 ]
[ 55117-15-2 ]
[ 1613165-84-6 ]

Yield	Reaction Conditions	Operation in experiment
15%	With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 20℃;	12 3-[4-(2-Chloro-6-fluoro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide 3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 2-Chloro-6-fluorobenzyl chloride (45 mg, 0.24 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(2-chloro-6-fluoro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (12.3 mg, 15%). HRMS Calcd. for C17H13ClFN2O3 (M+H)+, 347.0593. Found: 347.0591.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86704, 2014, A1 Location in patent: Page/Page column 40

32
[ 55117-15-2 ]
[ 106-93-4 ]
[ 7440-66-6 ]
[ 501435-60-5 ]

Yield	Reaction Conditions	Operation in experiment
	With chloro-trimethyl-silane In tetrahydrofuran at 65℃; for 3.5h;	16F (2-chloro-6-fluorobenzyl)zinc(II) bromide To a suspension of zinc powder (322 mg, 4.95 mmol) in tetrahydrofuran (3 mL) at 65°C. under nitrogen was added 1 ,2-dibromoethane (9 mg, 0.05 mmol) and trimethylsilylchloride (10mg, 0.09 mmol), and the mixture was stirred at 65° C. for 30 minutes. A solution of 2-chloro-6-fluoroben- zyl bromide (1 g, 4.50 mmol) in tetrahydrofuran (10 mL) was added dropwise and the mixture was stirred with heating at 65° C. for 3 hours. The mixture was cooled to ambient temperature to give a solution of (2-chloro-6-fluorobenzyl)zinc (II) bromide in tetrahydrofuran (about 0.5 M).

Reference： [1]Current Patent Assignee: ABBVIE INC - US2014/171429, 2014, A1 Location in patent: Paragraph 0367

33
[ 55117-15-2 ]
[ 128564-78-3 ]
[ 1621102-47-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	In acetonitrile at 60 - 70℃;	General procedure for the preparation of compounds 3a-u General procedure: To a mixture of (E)-3-(pyridin-4-ylmethylene)indolin-2-one (2,1 mmol) in dry acetonitrile (5 mL), proper benzyl bromide or chloride (1.5 mmol) was added and the mixture was stirred at 60-70 °C for 6-24 h. Then, the mixture was cooled and the precipitated solid was filtrated off and washed with diethyl ether or n-hexane. The product was recrystallized from ethanol-water (1:1) to give pure compounds 3a-u.

Reference： [1]Akrami, Hamidreza; Mirjalili, Bibi Fatemeh; Khoobi, Mehdi; Nadri, Hamid; Moradi, Alireza; Sakhteman, Amirhossein; Emami, Saeed; Foroumadi, Alireza; Shafiee, Abbas [European Journal of Medicinal Chemistry, 2014, vol. 84, p. 375 - 381]

34
[ 55117-15-2 ]
[ 536-74-3 ]
1-(2-chloro-6-fluorobenzyl)-4-phenyl-1H-1,2,3-triazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium azide; sodium L-ascorbate In water; <i>tert</i>-butyl alcohol at 70℃; for 2h; Green chemistry; regioselective reaction;
90%	With sodium azide In water at 70℃; for 7h; Green chemistry; regioselective reaction;	4.2. General process for the synthesis of dierent 1,4-disubstituted 1,2,3-triazoles General procedure: A mixture of sodium azide (1 mmol), benzyl or alkyl halide (1 mmol), and corresponding acetylene (1 mmolof phenyl acetylene or 2 mmol of alkyl acetylene) and catalyst (5 mg of catalyst equal to 0.1 mol % of copper)was taken in a round bottomed ask containing 1 mL of H 2 O and 0.2 mL of PEG 300 and heated at 70C for3 h under vigorous stirring. After completion of the reaction (monitored by TLC), the catalyst was removedby external magnet, washed with EtOH, and dried under vacuum. The collected solvent was concentratedunder vacuum and the product was allowed to crystalize, which did not require any further purication.The obtained products were conrmed and completely characterized by physical and spectral data (see theSupporting Information).
84%	With sodium azide In ethanol; water at 20℃; for 0.183333h; Sonication;	2.4. A typical procedure for the sonication synthesis of 1,2,3-triazoles General procedure: A mixture of alkyne (1 mmol), alkyl halide (1 mmol), NaN3 (1.2 mmol) and functionalized graphene oxide Cu(I) complex (0.005 g) as a catalyst were added to a mixture of water and EtOH (1:1) (6 mL) as solvent and the reaction mixture was soncated in ultrasonic apparatus with 70W power. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and the isolated catalyst was washed three times with ethanol (3 10 mL). The organic layer was separated and dried by rotary evaporator until the solid product precipitated. In order to further purification, recrystallization of the product was performed at 5:1 EtOAc:MeOH to yield the pure desired products. The products were characterized by 1H NMR, 13C NMR, FT-IR and melting points and the spectral data of synthesized compounds were compared with authentic samples as followed.

83%

With sodium azide In water at 60℃; for 3h;

4.1. General procedure for the synthesis of 1,2,3-triazoles using Cu/PMO NCs General procedure: The click reaction of organohalides and alkynes was carried out with treatment of NaN3 (72 mg, 1.1 mmol), organohalide (1 mmol), alkyne (1 mmol), and Cu/PMO NCs (10 mg, 0.47 mol %) in H2O (3 mL). The reaction mixture was warmed to 60 °C and monitored by TLC until total conversion of the starting materials. After completion of the reaction, the reaction mixture was filtered off. In order to separate the catalyst from the products, the reaction mixture was dissolved in hot ethanol; subsequently, the whole mixture was directly passed through a sintered glass filter funnel and the excess of solvent was removed under reduced pressure to give the corresponding 1,2,3-triazole compounds (Table 1). Most of the products are known and all of the isolated products gave satisfactory IR and NMR spectra (see Supporting Information).

Reference： [1]Karimi Zarchi, Mohammad Ali; Nazem, Fatemeh [Journal of the Iranian Chemical Society, 2014, vol. 11, # 6, p. 1731 - 1742]
[2]Hasanpour, Zeinab; Maleki, Aziz; Hosseini, Morteza; Gorgannezhad, Lena; Nejadshafiee, Vajihe; Ramazani, Ali; Haririan, Ismaeil; Shafiee, Abbas; Khoobi, Mehdi [Turkish Journal of Chemistry, 2017, vol. 41, # 2, p. 294 - 307]
[3]Naeimi, Hossein; Shaabani, Rahele [Ultrasonics Sonochemistry, 2017, vol. 34, p. 246 - 254]
[4]Nejadshafiee, Vajihe; Naeimi, Hossein [Turkish Journal of Chemistry, 2017, vol. 41, # 5, p. 700 - 709]

35
N-methyl-N-{1-[(2-ethoxythiazol-5-yl)methyl]piperidin-4-yl}amine [ No CAS ]
[ 55117-15-2 ]
N-methyl-N-(2-fluoro-6-chlorobenzyl)-N-{1-[(2-ethoxythiazol-5-yl)methyl]piperidin-4-yl}amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h;	5 4.2.1. General procedure for the synthesis of compounds HSP70-(1-20) General procedure: A solution of compound 5a (0.2 mmol) was dissolved in DMF (5 ml). Anhydrous K2CO3 (0.2 mmol) and benzyl chloride (0.2 mmol) were added, and the mixture was stirred at room temperature for 4 h. Water (40 ml) was added, and the compound was extracted with dichloromethane, dried with Na2SO4, and the solvent was removed to produce a colorless oily substance, HSP70-(1-20). 4.2.1.5 N-(2-chloro-6-fluorobenzyl)-1-((2-ethoxythiazol-5-yl)methyl)-N-methylpiperidin-4-amine (HSP70-5) 1H NMR (300 MHz, CDCl3-d) δ1.43-1.46 (t,3H); δ1.72-1.75 (m,2H); δ1.84-1.87 (d,2H); δ2.00-2.03 (t,2H); δ2.26 (s,3H); δ2.53 (m,1H); δ3.01-3.04 (d,2H); δ3.58 (s,2H); δ3.73 (s,2H); δ4.41-4.46 (m,2H); δ6.91 (s,1H); δ6.98-6.99 (m,1H); δ7.18-7.28 (m,2H). MS(TOF) 397.9 (M+).