Name: 27469-61-0|1-(Bis(4-chlorophenyl)methyl)piperazine|98%
Brand: Ambeed
SKU: A162981
Price: 10.0 USD
Availability: InStock
Rating: 91 (35 reviews)

1
[ 110-85-0 ]
[ 782-08-1 ]
[ 27469-61-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	In acetonitrile at 90℃; for 16h;
68%	In acetonitrile Reflux;	1-(bis(4-chlorophenyl)methyl)piperazine (9y) General procedure: 4,4'-(Chloromethylene)bis(chlorobenzene) (3.0 g, 11.05 mmol) was dissolved in acetonitrile (100 ml) at room temperature. Piperazine (8.6 g, 100 mmol) was added, and the mixture was refluxed overnight. Acetonitrile was evaporated. The mixture was dissolved in ethyl acetate and washed three times with water to remove the excess piperazine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude mixture was purified on silica gelusing a gradient of (7N NH3 in methanol) in dichloromethane to afford 2.4 g of 9 as an off-white solid (7.51 mmol, 68%).
60%	In acetonitrile for 2h; Heating;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]
[2]Weïwer, Michel; Bittker, Joshua A.; Lewis, Timothy A.; Shimada, Kenichi; Yang, Wan Seok; MacPherson, Lawrence; Dandapani, Sivaraman; Palmer, Michelle; Stockwell, Brent R.; Schreiber, Stuart L.; Munoz, Benito [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1822 - 1826]
[3]Jones, C. David; Winter, Mark A.; Hirsch, Kenneth S.; Stamm, Nancy; Taylor, Harold M.; et al. [Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 416 - 429]
[4]Morren et al. [Industrie Chimique Belge, 1957, vol. 22, p. 409,416]

2
[ 27469-61-0 ]
[ 628-89-7 ]
[ 103508-78-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; toluene

Reference： [1]Morren et al. [Industrie Chimique Belge, 1957, vol. 22, p. 409,416]

3
[ 4298-52-6 ]
[ 50-00-0 ]
[ 27469-61-0 ]
[ 105314-56-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	In tetrahydrofuran for 5.75h; Heating;

Reference： [1]Alivert; Canals; Bonet; Gomez-Parra; Sanchez-Alonso [Archiv der Pharmazie, 1991, vol. 324, # 9, p. 559 - 561]

4
[ 5394-18-3 ]
[ 27469-61-0 ]
[ 118419-78-6 ]

Yield	Reaction Conditions	Operation in experiment
	Yield given. Multistep reaction;

Reference： [1]Nishikawa; Shindo; Ishii; Nakamura; Kon; Uno [Journal of Medicinal Chemistry, 1989, vol. 32, # 3, p. 583 - 593]

5
[ 15468-86-7 ]
[ 27469-61-0 ]
[ 47762-78-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide In butan-1-ol for 8h; Heating;

Reference： [1]Dhainaut, Alain; Regnier, Gilbert; Atassi, Ghanem; Pierre, Alain; Leonce, Stephane; et al. [Journal of Medicinal Chemistry, 1992, vol. 35, # 13, p. 2481 - 2496]

6
[ 50-00-0 ]
Diethyl phosphonate [ No CAS ]
[ 27469-61-0 ]
diethyl <(4-(bis(4-chlorophenyl) methyl)-1-piperazinyl) methyl> phosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	In water for 12h; Heating;

Reference： [1]Younes, S.; Baziard-Mouysset, G.; Saqui-Sannes, G. de; Stigliani, J. L.; Payard, M.; et al. [European Journal of Medicinal Chemistry, 1993, vol. 28, # 12, p. 943 - 948]

7
[ 27469-61-0 ]
[ 25596-72-9 ]
diethyl <4-((4-(bis(4-chlorophenyl) methyl) 1-piperazinyl) methyl) phenylmethyl> phosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	With potassium carbonate In tetrahydrofuran for 18h; Heating;

Reference： [1]Younes, S.; Baziard-Mouysset, G.; Saqui-Sannes, G. de; Stigliani, J. L.; Payard, M.; et al. [European Journal of Medicinal Chemistry, 1993, vol. 28, # 12, p. 943 - 948]

8
[ 27469-61-0 ]
[ 1794-48-5 ]
[ 137242-74-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium carbonate In toluene for 1.5h;

Reference： [1]Alivert; Canals; Bonet; Gomez-Parra; Sanchez-Alonso [Archiv der Pharmazie, 1991, vol. 324, # 9, p. 559 - 561]

9
[ 154544-61-3 ]
[ 27469-61-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium hydroxide In methanol for 72h; Heating;

Reference： [1]Younes, S.; Baziard-Mouysset, G.; Saqui-Sannes, G. de; Stigliani, J. L.; Payard, M.; et al. [European Journal of Medicinal Chemistry, 1993, vol. 28, # 12, p. 943 - 948]

10
[ 27469-61-0 ]
[ 106-89-8 ]
[ 125345-86-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In ethanol for 18h; Ambient temperature;

Reference： [1]Press; Falotico; Hajos; Sawyers; Kanojia; Williams; Haertlein; Kauffman; Lakas-Weiss; Salata [Journal of Medicinal Chemistry, 1992, vol. 35, # 24, p. 4509 - 4515]

11
[ 27469-61-0 ]
[ 91950-00-4 ]
[ 1025840-02-1 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol for 2h; Heating;

Reference： [1]Sugiyama; Akahoshi; Kuwahara; Kajii; Sakaue; Yakumaru; Sugiura; Fukaya [Journal of Medicinal Chemistry, 1994, vol. 37, # 13, p. 1977 - 1982]

12
[ 27469-61-0 ]
[ 241823-42-7 ]
1-{4-[(4-Chloro-phenyl)-(3-chloro-phenyl)-methyl]-piperazin-1-yl}-3-(6-pyrrol-1-yl-purin-9-yl)-propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol for 3h; Heating; Yield given;

Reference： [1]Estep; Josef; Bacon; Carabateas; Rumney IV; Pilling; Krafte; Volberg; Dillon; Dugrenier; Briggs; Canniff; Gorczyca; Stankus; Ezrin [Journal of Medicinal Chemistry, 1995, vol. 38, # 14, p. 2582 - 2595]

13
[ 27469-61-0 ]
[ 60971-82-6 ]
7-(4-{4-[Bis-(4-chloro-phenyl)-methyl]-piperazin-1-yl}-butyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 140℃; Heating;

Reference： [1]Abou-Gharbia; Moyer; Nielsen; Webb; Patel [Journal of Medicinal Chemistry, 1995, vol. 38, # 20, p. 4026 - 4032]

Yield	Reaction Conditions	Operation in experiment
	4.4'-Dichlor-benzhydrylchlorid, Piperazin;
	entspr. Chlorid, Piperazin;

15
[ 27469-61-0 ]
[ 145600-66-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: ethanol / 2 h / Heating 2: BH₃-SMe₂ / tetrahydrofuran / 2 h / Heating

Reference： [1]Sugiyama; Akahoshi; Kuwahara; Kajii; Sakaue; Yakumaru; Sugiura; Fukaya [Journal of Medicinal Chemistry, 1994, vol. 37, # 13, p. 1977 - 1982]

16
[ 27469-61-0 ]
2-[N-[3-[4-(4,4'-dichlorobenzhydryl)piperazino]propyl]-N-isopropyl]amino-4-methylphenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: ethanol / 2 h / Heating 2: BH₃-SMe₂ / tetrahydrofuran / 2 h / Heating 3: sodium cyanoborohydride / methanol; tetrahydrofuran / 5 h / 60 °C

Reference： [1]Sugiyama; Akahoshi; Kuwahara; Kajii; Sakaue; Yakumaru; Sugiura; Fukaya [Journal of Medicinal Chemistry, 1994, vol. 37, # 13, p. 1977 - 1982]

17
[ 90-97-1 ]
[ 27469-61-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 98 percent / SOCl₂ / cyclohexane / 24 h / Heating 2: 19 percent / K₂CO₃ / tetrahydrofuran / 14 h / Heating 3: 96 percent / 10percent aq. NaOH / methanol / 72 h / Heating
	Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 20 °C 2: acetonitrile / Reflux

Reference： [1]Younes, S.; Baziard-Mouysset, G.; Saqui-Sannes, G. de; Stigliani, J. L.; Payard, M.; et al. [European Journal of Medicinal Chemistry, 1993, vol. 28, # 12, p. 943 - 948]
[2]Weïwer, Michel; Bittker, Joshua A.; Lewis, Timothy A.; Shimada, Kenichi; Yang, Wan Seok; MacPherson, Lawrence; Dandapani, Sivaraman; Palmer, Michelle; Stockwell, Brent R.; Schreiber, Stuart L.; Munoz, Benito [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1822 - 1826]

18
[ 782-08-1 ]
[ 27469-61-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 19 percent / K₂CO₃ / tetrahydrofuran / 14 h / Heating 2: 96 percent / 10percent aq. NaOH / methanol / 72 h / Heating

Reference： [1]Younes, S.; Baziard-Mouysset, G.; Saqui-Sannes, G. de; Stigliani, J. L.; Payard, M.; et al. [European Journal of Medicinal Chemistry, 1993, vol. 28, # 12, p. 943 - 948]

19
[ 90-98-2 ]
[ 27469-61-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: NaBH₄ / methanol 2: 98 percent / SOCl₂ / cyclohexane / 24 h / Heating 3: 19 percent / K₂CO₃ / tetrahydrofuran / 14 h / Heating 4: 96 percent / 10percent aq. NaOH / methanol / 72 h / Heating
	Multi-step reaction with 3 steps 1: sodium tetrahydroborate / tetrahydrofuran; methanol / 0.5 h / 0 °C 2: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 20 °C 3: acetonitrile / Reflux

Reference： [1]Younes, S.; Baziard-Mouysset, G.; Saqui-Sannes, G. de; Stigliani, J. L.; Payard, M.; et al. [European Journal of Medicinal Chemistry, 1993, vol. 28, # 12, p. 943 - 948]
[2]Weïwer, Michel; Bittker, Joshua A.; Lewis, Timothy A.; Shimada, Kenichi; Yang, Wan Seok; MacPherson, Lawrence; Dandapani, Sivaraman; Palmer, Michelle; Stockwell, Brent R.; Schreiber, Stuart L.; Munoz, Benito [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1822 - 1826]

20
[ 27469-61-0 ]
[ 118420-30-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 2: 1.) ethyl chlorocarbonate

Reference： [1]Nishikawa; Shindo; Ishii; Nakamura; Kon; Uno [Journal of Medicinal Chemistry, 1989, vol. 32, # 3, p. 583 - 593]

21
[ 27469-61-0 ]
1-{4-[Bis-(4-chloro-phenyl)-methyl]-piperazin-1-yl}-3-(7H-purin-6-ylsulfanyl)-propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NaHCO₃ / ethanol / 18 h / Ambient temperature 2: 22.3 percent / Et₃N / dimethylformamide / 22 h / Ambient temperature

Reference： [1]Press; Falotico; Hajos; Sawyers; Kanojia; Williams; Haertlein; Kauffman; Lakas-Weiss; Salata [Journal of Medicinal Chemistry, 1992, vol. 35, # 24, p. 4509 - 4515]

22
[ 27469-61-0 ]
[ 105314-63-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 91 percent / anhydrous CuSO₄ / tetrahydrofuran / 5.75 h / Heating 2: 84 percent / LiAlH₄ / tetrahydrofuran / 7 h / Heating

Reference： [1]Alivert; Canals; Bonet; Gomez-Parra; Sanchez-Alonso [Archiv der Pharmazie, 1991, vol. 324, # 9, p. 559 - 561]

23
[ 27469-61-0 ]
[ 125345-86-0 ]

Yield	Reaction Conditions	Operation in experiment
		1-(1-Chloro-2-hydroxy-3-propanyl)-4-[bis(4-chlorophenyl)methyl]piperazine 1-(1-Chloro-2-hydroxy-3-propanyl)-4-[bis(4-chlorophenyl)methyl]piperazine 4,4'-Dichlorobenzhydrylpiperazine (6.0 g, 18.7 mmol) was reacted as above with epichlorohydrin to give the title compound as an amber oil, 3.67 g (49.8%). 100 MHZ 1 H NMR (CDCl3) δ: 7.3 (s, 8H), 4.2 (s, 1H), 3.9 (m, 1H), 3.6 (d, 2H, J=10 Hz), 2.9 (m, 2H), 2.7-2.4 (m, 10H).
		1-(1-Chloro-2-hydroxy-3-propanyl)-4-[bis(4-chlorophenyl)methyl]piperazine 1-(1-Chloro-2-hydroxy-3-propanyl)-4-[bis(4-chlorophenyl)methyl]piperazine 4,4'-Dichlorobenzhydrylpiperazine ((6.0 g, 18.7 mmol) was reacted as above with epichlorohydrin to give the title compound as an amber oil, 3.67 g (49.8%). 100 MHz 1 H NMR (CDCl) δ: 7.3 (s, 8H), 4.2 (s, 1H), 3.9 (m, 1H), 3.6 (d, 2H, J=10 Hz), 2.9 (m, 2H), 2.7-2.4 (m, 10H).
		1-(1-Chloro-2-hydroxy-3-propanyl)-4-[bis(4-chlorophenyl)methyl]piperazine 1-(1-Chloro-2-hydroxy-3-propanyl)-4-[bis(4-chlorophenyl)methyl]piperazine 4,4'-Dichlorobenzhydrylpiperazine ((6.0 g, 18.7 mmol) was reacted as above with epichlorohydrin to give the title compound as an amber oil, 3.67 g (49.8%). 100 MHz 1 H NMR (CDCl3) δ: 7.3 (s, 8H), 4.2 (s, 1H), 3.9 (m, 1H), 3.6 (d, 2H, J=10 Hz), 2.9 (m, 2H), 2.7-2.4 (m, 10H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US5252569, 1993, A
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US5001127, 1991, A
[3]Current Patent Assignee: AGC INC; JOHNSON & JOHNSON INC - US4876257, 1989, A Current Patent Assignee: JOHNSON & JOHNSON INC - US4885300, 1989, A Current Patent Assignee: JOHNSON & JOHNSON INC - US5164390, 1992, A

24
[ 169807-49-2 ]
[ 27469-61-0 ]
7-(4-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)butyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium iodide; potassium carbonate In water; N,N-dimethyl-formamide; toluene	7 EXAMPLE 7 EXAMPLE 7 The mixture of 2.4 g of 4-(bis(4-chlorophenyl)methyl)piperazine, 2.0 g of 7-(4-chlorobutyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one, 1.9 g of potassium carbonate and 1.2 g of potassium iodide in 15 ml of N,N-dimethylformamide and 15 ml of toluene was stirred at 60° C. for 5 hours. After the mixture was cooled in a water bath, water was added thereto. The precipitated crystals were filtered off and the filtrate was extracted with toluene. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and the resulting crystals were recrystallized from isopropyl alcohol-isopropyl ether to give 0.18 g of 7-(4-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)butyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one as white crystals, m.p. 185°-187° C. (decomposition).

Reference： [1]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - US5532240, 1996, A

25
[ 119-56-2 ]
[ 27469-61-0 ]

Yield	Reaction Conditions	Operation in experiment
88.4%	In dichloromethane	1-[Bis(4-chlorophenyl)methyl]piperazine 1-[Bis(4-chlorophenyl)methyl]piperazine To 4-chlorobenzhydrol (12.66 g, 50 mmol) in CH2 Cl2 (200 mL) under nitrogen, thionyl chloride (10 mL, 137 mmol) was added dropwise over 15 min. After 18 h and removal of the solvent in vacuo, the crude product was dissolved in CH2 Cl2 (100 mL) and washed with saturated NAHCO3 (3*), dried over Na2 SO4, and concentrated in vacuo to a thin, amber oil (12.53 g). Upon standing at room temperature for 1 h, crystallization occured to give pure product (12.5 g, 88.4%) as a white solid, mp 61°-64° C. DCI/MS (M+1) 235. 400 MHz 1 H NMR (CDCl3) δ: 7.35 (m, 8H), 6.05 (s, 1H). Anal. Calcd. for C13 H9 C13:C, 57.49; H, 3.34. Found: C, 57.69; H, 3.46.
88.4%	In dichloromethane	1-[Bis(4-chlorophenyl)methyl]piperazine 1-[Bis(4-chlorophenyl)methyl]piperazine To 4-chlorobenzhydrol (12.66 g, 50 mmol) in CH2 Cl2 (200 mL) under nitrogen, thionyl chloride (10 mL, 137 mmol) was added dropwise over 15 min. After 18 h and removal of the solvent in vacuo, the crude product was dissolved in CH2 Cl2 (100 mL) and washed with saturated NaHCO3 (3*), dried over Na2 SO4, and concentrated in vacuo to a thin, amber oil (12.53 g). Upon standing at room temperature for 1 h, crystallization occured to give pure product (12.5 g, 88.4%) as a white solid, mp 61°-64° C. DCI/MS (M+1) 235. 400 MHz 1 H NMR (CDCl3) δ: 7.35 (m, 8H), 6.05 (s, 1H). Anal. Calcd. for C13 H9 C13: C, 57.49; H, 3.34 Found: C, 57.69; H, 3.46.
88.4%	In dichloromethane	1-[Bis(4-chlorophenyl)methyl]piperazine 1-[Bis(4-chlorophenyl)methyl]piperazine To 4-chlorobenzhydrol (12.66 g, 50 mmol) in CH2 Cl2 (200 mL) under nitrogen, thionyl chloride (10 mL, 137 mmol) was added dropwise over 15 min. After 18 h and removal of the solvent in vacuo, the crude product was dissolved in CH2 Cl2 (100 mL) and washed with saturated NaHCO3 (3*), dried over Na, and concentrated in vacuo to a thin, amber oil (12.53 g). Upon standing at room temperature for 1 h, crystallization occured to give pure Product (12.5 g, 88.4%) as a white solid, mp 61°-64° C. DCI/MS (M+1) 235. 400 MHz 1 H NMR (CDCl3) δ: 7.35 (m, 8H), 6.05 (s, 1H). Anal. Calcd. for C13 H9 C13: C, 57.49; H, 3.34. Found: C, 57.69; H, 3.46.

88.4%	In dichloromethane	1-[Bis(4-chlorophenyl)methyl]piperazine 1-[Bis(4-chlorophenyl)methyl]piperazine To 4-chlorobenzhydrol (12.66 g, 50 mmol) in CH2 Cl2 (200 mL) under nitrogen, thionyl chloride (10 mL, 137 mmol) was added dropwise over 15 min. After 18 h and removal of the solvent in vacuo, the crude product was dissolved in CH2 Cl2 (100 mL) and washed with saturated NaHCO3 (3*), dried over Na2 SO4, and concentrated in vacuo to a thin, amber oil (12.53 g). Upon standing at room temperature for 1 h, crystallization occured to give pure product (12.5 g, 88.4%) as a white solid, mp 61°-64° C. DCI/MS (M+1) 235. 400 MHz 1 H NMR (CDCl3) δ: 7.35 (m, 8H), 6.05 (s, 1H). Anal. Calcd. for C13 H9 C13: C, 57.49; H, 3.34. Found: C, 57.69; H, 3.46.
88.4%	In dichloromethane	1-[Bis(4-chlorophenyl)methyl]piperazine 1-[Bis(4-chlorophenyl)methyl]piperazine To 4-chlorobenzhydrol (12.66 g, 50 mmol) in CH2 Cl2 (200 mL) under nitrogen, thionyl chloride (10 mL, 137 mmol) was added dropwise over 15 min. After 18 h and removal of the solvent in vacuo, the crude product was dissolved in CH2 Cl2 (100 mL) and washed with saturated NaHCO3 (3*), dried over Na2 SO4, and concentrated in vacuo to a thin, amber oil (12.53 g). Upon standing at room temperature for 1 h, crystallization occured to give pure product (12.5 g, 88.4%) as a white solid, mp 61°-64° C. DCI/MS (M+1) 235. 400 MHz 1 H NMR (CDCl3) δ: 7.35 (m, 8H), 6.05 (s, 1H). Anal. Calcd. for C13 H9 C13: C, 57.49; H, 3.34. Found: C, 57.69; H, 3.46.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US5164390, 1992, A
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US5001127, 1991, A
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - US5021574, 1991, A
[4]Current Patent Assignee: AGC INC; JOHNSON & JOHNSON INC - US4876257, 1989, A
[5]Current Patent Assignee: JOHNSON & JOHNSON INC - US4885300, 1989, A

26
[ 213774-10-8 ]
[ 7285-11-2 ]
[ 27469-61-0 ]
N-cyclopropyl-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; N-ethyl-N,N-diisopropylamine	5 [Preparation of N-Cyclopropyl-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesulfonamide] Example 5 [Preparation of N-Cyclopropyl-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesulfonamide] 1-[Bis(4-chlorophenyl)methyl]piperazine (10.00 g, 31.13 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (8.30 g, 34.63 mmol) were refluxed in N-ethyldiisopropylamine (50 ml) for 7 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesulfonamide (14.70 g) as an oil (yield based on 1-[bis(4-chlorophenyl)methyl]piperazine: 95.3%).

Reference： [1]Current Patent Assignee: Azwell Inc. - US6172228, 2001, B2

27
[ 213774-30-2 ]
[ 7285-11-2 ]
[ 27469-61-0 ]
N-(2-hydroxyethyl)-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.2%	In water; N-ethyl-N,N-diisopropylamine	33 [Preparation of N-(2-Hydroxyethyl)-6-[4-[bis(4-chlorophenyl)methyl]-1-Piperazinyl]hexanesulfonamide] Example 33 [Preparation of N-(2-Hydroxyethyl)-6-[4-[bis(4-chlorophenyl)methyl]-1-Piperazinyl]hexanesulfonamide] 1-[Bis(4-chlorophenyl)methyl]piperazine (642.5 mg, 2.00 mmol) and N-(2-hydroxyethyl)-6-chlorohexanesulfonamide (487.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesulfonamide (975.0 mg) as a pale brown oil (92.2%).

Reference： [1]Current Patent Assignee: Azwell Inc. - US6172228, 2001, B2

28
[ 213774-42-6 ]
[ 7285-11-2 ]
[ 27469-61-0 ]
N-(2-hydroxyethyl)-5-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]pentanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.5%	In water; N-ethyl-N,N-diisopropylamine	34 [Ppreparation of N-(2-Hydroxyethyl)-5-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]pentanesulfonamide] Example 34 [Ppreparation of N-(2-Hydroxyethyl)-5-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]pentanesulfonamide] 1-[Bis(4-chlorophenyl)methyl]piperazine (642.5 mg, 2.00 mmol) and N-(2-hydroxyethyl)-5-chloropentanesulfonamide (459.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-5-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]pentanesulfonamide (1003.0 mg) as a pale brown oil (97.5%).

Reference： [1]Current Patent Assignee: Azwell Inc. - US6172228, 2001, B2

29
[ 35730-09-7 ]
[ 27469-61-0 ]
{4-[bis-(4-chlorophenyl)-methyl]piperazin-1-yl}-(2,5-difluorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; triethylamine In 1,2-dichloro-ethane at 20℃;	8 To a 0.075 M 1,2-dicholoroethane solution of l-(4,4'-dichlorobenzhydryl)piperazine (450 μL, 33.8 μmol), triethylamine (4 mg, 40.5 μmol), and DMAP (0.4 mg, 3.4 μmol) was added 300 μL of a 0.125 M solution of 2,5-diflourobenzoyl chloride (37.5 μmol) in 1,2- dichloroethane. The mixture was stirred overnight at room temperature then filtered on hydromatrix-filled filter pre-treated with 500 μL of 2 N NaOH solution. The hydromatrix was washed with 500 μL of dichloromethane and evaporated to dryness in the Genevac. Estimated yield from combichem plate: 14.0 mg (90%). 1H NMR (500 MHz, DMSO-d6) δ EPO 2.26 (s, br, 2H), 2.36 (s, br, 2H), 3.26 (s, br, 2H), 3.67 (s, br 2H), 4.48 (s, IH), 7.27-7.34 (m, 3H), 7.38 (d, J= 8.0 Hz, 4H), 7.44 (d, J= 8.0 Hz, 4H); +ES MS (M+l) 460.1.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/18459, 2007, A1 Location in patent: Page/Page column 36-37

30
[ 27469-61-0 ]
[ 403-43-0 ]
{4-[bis-(4-chlorophenyl)methyl]piperazin-1-yl}-(4-fluorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; triethylamine In 1,2-dichloro-ethane at 20℃;	4 To a 0.075 M 1,2-dicholoroethane solution of l-(4,4'-dichlorobenzhydryl)piperazine (450 μL, 33.8 μmol), triethylamine (1.2 eq, 4 mg, 40.5 μmol), and DMAP (10 mol%, 0.4 mg, 3.4 μmol) was added 300 μL of a 0.125 M solution of 4-fluorobenzoyl chloride (37.5 μmol) in 1,2-dichloroethane. The mixture was stirred overnight at room temperature, then filtered on hydromatrix-filled filter pre-treated with 500 μL of 2 N NaOH solution. The hydromatrix was washed with 500 μL of dichloromethane and evaporated to dryness in the Genevac. Estimated yield from combichem plates: 13.4 mg (90%). 1H NMR (500 MHz, DMSO-de) δ 2.20-2.40 (m, 4H), 3.30-3.50 (m, 4H), 4.46 (s, IH), 7.25 (dd, J= 8.5, 8.5 Hz5 2H), 7.38 (d, J= 8.0 Hz, 4H), 7.43-7.45 (m, 6H); +ES MS (M+l) 442.1.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/18459, 2007, A1 Location in patent: Page/Page column 33-34

31
[ 785-56-8 ]
[ 27469-61-0 ]
{4-[bis-(4-chlorophenyl)methyl]piperazin-1-yl}-(3,5-ditrifluoromethylphenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With dmap; triethylamine In 1,2-dichloro-ethane at 20℃;	12 To a 0.075 M 1,2-dicholoroethane solution of l-(4,4'-dichlorobenzhydtyl)piperazine (450 μL, 33.8 μmol), triethylamine (4 mg, 40.5 μmol), and DMAP (0.4 mg, 3.4 μmol) was added 300 μL of a 0.125 M solution of 3,5-bis(trifluoromethyl)benzoyl chloride (37.5 μmol) in 1 ,2-dichloroethane. The mixture was stirred overnight at room temperature, then filtered on hydromatrix-filled filter pre-treated with 500 μL of 2 N NaOH solution. The hydromatrix was washed with 500 μL of dichloromethane and evaporated to dryness in the Genevac. Estimated yield from combichem plate: 13.6 mg (72%). 1H NMR (SOO MHZ, DMSO-d6) 52.27 (s, 2H), 2.40 (s, br, 2H), 3.4 (s, br, 4H), 4.47 (s, IH), 7.39 (d, J= 8.0 Hz, 4H), 7.44 (d, 7= 8.0 Hz, 4H), 8.10 (s, 2H), 8.21 (s, IH); +ES MS (M+l) 560.1

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/18459, 2007, A1 Location in patent: Page/Page column 38-39

32
[ 27469-61-0 ]
[ 1711-07-5 ]
{4-[bis-(4-chlorophenyl)methyl]piperazin-1-yl}-(3-fluorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; triethylamine In 1,2-dichloro-ethane at 20℃;	5 To a 0.075 M 1,2-dicholoroethane solution of l-(4,4'-dichlorobenzhydryl)piperazine (450 μL, 33.8 μmol), triethylamine (1.2 eq, 4 mg, 40.5 μmol), and DMAP (10 mol%, 0.4 mg, 3.4 μmol) was added 300 μL of a 0.125 M solution of 3-fluorobenzoyl chloride (37.5 μmol) in 1,2-dichloroethane. The mixture was stirred overnight at room temperature, then filtered on hydromatrix-filled filter pre-treated with 500 μL of 2N NaOH solution. The hydromatrix was washed with 500 μL of dichloromethane and evaporated to dryness in the Genevac. Estimated yield from combichem plates: 13.5 mg (90%). 1H NMR (500 MHz, EPO DMSO-(I6) δ 2.20-2.40 (m, 4H), 3.30-3.50 (m, 4H), 4.46 (s, IH), 7.21 (dd, J= 7.5, 7.5 Hz, 2H), 7.25-7.30 (m, IH), 7.38 (d, J= 8.0 Hz, 4H), 7.32-7 '.47 (m, 6H); +ES MS (M+l) 442.1.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/18459, 2007, A1 Location in patent: Page/Page column 34-35

33
[ 27469-61-0 ]
[ 393-52-2 ]
{4-[bis-(4-chlorophenyl)methyl]piperazin-1-yl}-(2-fluorophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; triethylamine In 1,2-dichloro-ethane at 20℃;	9 To a 0.075 M 1,2-dicholoroethane solution of l-(4,4'-dichlorobenzhydryl)piperazine (450 μL, 33.8 μmol), triethylamine (4 mg, 40.5 μmol), and DMAP (0.4 mg, 3.4 μmol) was added 300 μL of a 0.125 M solution of 2-fluorobenzoyl chloride (37.5 μmol) in 1,2- dichloroethane. The mixture was stirred overnight at room temperature, then filtered on hydromatrix-filled filter pre-treated with 500 μL of 2N NaOH solution. The hydromatrix was washed with 500 μL of dichloromethane and evaporated to dryness in the Genevac. Estimated yield from combichem plate: 13.5 mg (90%). 1H NMR (500 MHz, DMSOd5) δ 2.26 (s, br, 2H), 2.37 (s, br, 2H), 3.25 (s, br, 2H), 3.68 (s, br, 2H), 4.48 (s, IH), 7.25-7.29 (m, 2H), 7.36-7.39 (m, 5H), 7.43-7.49 (m, 5H); +ES MS (M+l) 442.1.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/18459, 2007, A1 Location in patent: Page/Page column 37

34
[ 27469-61-0 ]
[ 2251-65-2 ]
{4-[bis-(4-chlorophenyl)methyl]piperazin-1-yl}-(3-trifluoromethylphenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With dmap; triethylamine In 1,2-dichloro-ethane at 20℃;	7 To a 0.075 M 1,2-dicholoroethane solution of l-(4,4'-dichlorobenzhydryl)piperazine (450 μL, 33.8 μmol), triethylamine (4 mg, 40.5 μmol), and DMAP (0.4 mg, 3.4 μmol) was added 300 μL of 0.125 M solution of a 3-trifluoromethylbenzoyl chloride (37.5 μmol) in 1,2-dichloroethane. The mixture was stirred overnight at room temperature, then filtered on hydromatrix-filled filter pre-treated with 500 μL of 2N NaOH solution. The hydromatrix was washed with 500 μL of dichloromethane and evaporated to dryness in the Genevac. Estimated yield from combichem plate: 13.5 mg (81%). 1H NMR (500 MHz, DMSOd6) δ 2.20-2.45 (m, 4H), 4.47 (s, IH), 7.38 (d, J= 8.0 Hz, 4H), 7.44 (d, J= 8.0 Hz, 4H), 7.65-7.71 (m, 3H), 7.81 (d, J= 5.0 Hz, IH); +ES MS (M+l) 492.1.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/18459, 2007, A1 Location in patent: Page/Page column 35-36

35
[ 27469-61-0 ]
[ 638-29-9 ]
1-{4-[bis-(4-chlorophenyl)methyl]piperazin-1-yl}pentan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With dmap; triethylamine In 1,2-dichloro-ethane at 20℃;	11 To a 0.075 M 1,2-dicholoroethane solution of l-(4,4'-dichIorobenzhydryl)piperazine (450 μL, 33.8 μmol), triethylamine (4 mg, 40.5 μmol), and DMAP (0.4 mg, 3.4 μmol) was added 300 μL of a 0.125 M solution of n-pentanoyl chloride (37.5 μmol) in 1,2- dichloroethane. The mixture was stirred overnight at room temperature, then filtered on hydromatrix-filled filter pre-treated with 500 μL of 2N NaOH solution. The hydromatrix was washed with 500 μL of dichloromethane and evaporated to dryness in the Genevac. Estimated yield from combichem plate: 11.6 mg (85%). 1H NMR (500 MHz, DMSO-d6) δ 0.86 (t, J= 5.0 Hz, 3H), 1.26 (m, 4H), 1.44 (t, J= 5.0 Hz, 2H), 2.25 (m, 6H), 3.46 (s, br, 2H), 4.43 (s, IH), 7.39 (d, J= 10.0 Hz, 4H), 7.44 (d, J= 10.0 Hz, 4H); +ES MS (M+l) 404.1.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/18459, 2007, A1 Location in patent: Page/Page column 38

36
[ 27469-61-0 ]
[ 5006-22-4 ]
{4-[bis-(4-chlorophenyl)methyl]piperazin-1-yl}cyclobutylmethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With dmap; triethylamine In 1,2-dichloro-ethane at 20℃;	10 To a 0.075 M 1,2-dicholoroethane solution of l-(4)4'-dichlorobenzhydryl)piperazine (450 μL, 33.8 μmol), triethylamine (1.2 eq, 4 mg, 40.5 μmol), and DMAP (10 mol%, 0.4 mg, 3.4 μmol) was added 300 μL of a 0.125 M solution of cyclobutanecarbonyl chloride (37.5 μmol) in 1,2-dichloroethane. The mixture was stirred overnight at room temperature, then EPO filtered on hydromatrix-filled filter pre-treated with 500 μL of 2N NaOH solution. The hydromatrix was washed with 500 μL of dichloromethane and evaporated to dryness in the Genevac. Estimated yield from combichem plate: 11.8 mg (88%). 1H NMR (SOO MHZ, DMSO-de) 50.87 (m, IH), 1.30 (m, IH), 1.46 (m, IH), 1.71 (m, IH), 1.85 (m, IH), 2.04 (d, J= 9.0 Hz, IH), 2.11 (m, IH), 2.23 (s, 4H), 3.30 (s, br, 2H), 3,45 (s, br, 2H), 4.41 (s, IH), 7.38 (d, /= 8.5 Hz, 4H), 7.43 (d, /= 8.5 Hz, 4H); +ES MS (M+l) 402.1.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/18459, 2007, A1 Location in patent: Page/Page column 37-38

37
[ 49609-84-9 ]
[ 27469-61-0 ]
(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)(2-chloropyridin-3-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With dmap; triethylamine In 1,2-dichloro-ethane at 20℃;	3 To a 0.075 M 1,2-dicholoroethane solution of l-(4,4'-dichlorobenzhydryl)piperazine (450 μL, 33.8 μmol), triethylamine (1.2 eq, 4 mg, 40.5 μmol), and DMAP (10 mol%, 0.4 mg,3.4 μmol) was added 300 μL of a 0.125 M solution of 2-chloronicotinoyl chloride (37.5 μmol) in 1,2-dichloroethane. The mixture was stirred overnight at room temperature, then filtered on hydromatrix-filled filter pre-treated with 500 μL of 2 N NaOH solution. The hydromatrix was washed with 500 μL of dichloromethane and evaporated to dryness in the Genevac. Estimated yield from combichem plate: 12.3 mg (79%). 1H NMR (SOO MHZ, DMSO-dg) δ 2.27 (s, 2H), 2.3-2.45 m, 2H), 3.19 (s, 2H), 3.60-3.75 (m, 2H), 7.38 (d, J=8.5 Hz, 4H), 7.44 (d, J= 8.5 Hz, 4H), 7.50 (dd, J= 6.5, 6.5 Hz, IH), 7.86 (d, J= 7.0 Hz, IH), 8.45 (s, IH); +ES MS (M+l) 459.1.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/18459, 2007, A1 Location in patent: Page/Page column 33

38
[3-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]acetic acid [ No CAS ]
[ 27469-61-0 ]
1-benzhydryl-3-(2-{4-[bis-(4-chlorophenyl)methyl]piperazin-1-yl}-2-oxoethyl)imidazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: [3-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]acetic acid; 1-(4,4'-dichloro-benzhydryl)-piperazine With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 5h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water	2 -[Bis(4-chlorophenyl)methyl]piperazine (343 mg, 1.07 mmol) was added to a solution of [3-(diphenylmethyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl]acetic acid (300 mg, 0.97 mmol) EPO and EDC (205 mg, 1.07 mmol) in DMF (50 mL) at ambient temperature. The reaction mixture was stirred for 5 hours and the solvent was concentrated. The residue was recovered in DCM and washed with water, sat. NaHCCb solution, and brine. The solution was dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified on silica gel by flash chromatography using 2.5% MeOH in DCM as eluent to provide the title compound as a white powder: 532 mg (89%). 1H NMR (400 MHz, CDCl3) δ 2.26 - 2.41 (m, 4H), 3.46 - 3.55 (m, 2H), 3.56 - 3.68 (m, 2H), 4.18 (s, IH), 4.45 (s, 2H), 6.09 (d, J= 3.1 Hz, IH), 6.35 (d, J= 3.1 Hz, IH), 6.54 - 6.62 (m, IH), 7.09 - 7.19 (m, 3H), 7.21 - 7.39 (m, 15H); +ES MS (M+l) 611.2.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/18459, 2007, A1 Location in patent: Page/Page column 32-33

39
[ 88-09-5 ]
[ 27469-61-0 ]
[ 922423-90-3 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

40
[ 88-14-2 ]
[ 27469-61-0 ]
[ 1028991-77-6 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

41
[ 527-72-0 ]
[ 27469-61-0 ]
[ 1028991-78-7 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

42
[ 16629-19-9 ]
[ 27469-61-0 ]
[ 1028991-90-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

43
[ 10147-37-2 ]
[ 27469-61-0 ]
[ 1028991-85-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

44
[ 2386-60-9 ]
[ 27469-61-0 ]
[ 1028991-86-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

45
[ 7795-95-1 ]
[ 27469-61-0 ]
[ 1028991-87-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

46
[ 3721-95-7 ]
[ 27469-61-0 ]
{4-[bis-(4-chlorophenyl)methyl]piperazin-1-yl}cyclobutylmethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

47
[ 3400-45-1 ]
[ 27469-61-0 ]
[ 1028991-75-4 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

48
[ 27469-61-0 ]
[ 104-12-1 ]
[ 1028991-73-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

49
[ 27469-61-0 ]
[ 103-71-9 ]
[ 1028991-72-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

50
[ 27469-61-0 ]
[ 24608-52-4 ]
[ 918161-24-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

51
[ 27469-61-0 ]
[ 20412-38-8 ]
[ 1028991-82-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

52
[ 27469-61-0 ]
[ 3173-53-3 ]
[ 1028991-40-3 ]

Yield	Reaction Conditions	Operation in experiment
44%	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

53
[ 27469-61-0 ]
[ 501-53-1 ]
[ 1028991-80-1 ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

54
[ 27469-61-0 ]
[ 98-60-2 ]
[ 1028991-89-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

55
[ 27469-61-0 ]
[ 592-34-7 ]
[ 1028991-83-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

56
[ 27469-61-0 ]
[ 1885-14-9 ]
[ 1028991-81-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

57
[ 27469-61-0 ]
[ 98-59-9 ]
[ 1028991-88-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

58
[ 27469-61-0 ]
[ 79-31-2 ]
[ 922366-37-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

59
[ 27469-61-0 ]
[ 3173-56-6 ]
[ 1028991-71-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

60
[ 27469-61-0 ]
[ 142-62-1 ]
[ 1028991-50-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

61
[ 27469-61-0 ]
[ 594-44-5 ]
[ 1028991-84-5 ]

Yield	Reaction Conditions	Operation in experiment
43%	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

62
[ 27469-61-0 ]
[ 107-92-6 ]
[ 922361-67-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

63
[ 27469-61-0 ]
[ 1609-86-5 ]
[ 1028991-74-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

64
[ 27469-61-0 ]
[ 1759-53-1 ]
[ 1028991-76-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

65
[ 27469-61-0 ]
[ 98-89-5 ]
[ 1028991-49-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃;

Reference： [1]Song, Kwang-Seop; Lee, Sung-Han; Chun, Hyun Ji; Kim, Jong Yup; Jung, Myung Eun; Ahn, Kwangwoo; Kim, Soo-Un; Kim, Jeongmin; Lee, Jinhwa [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 4035 - 4051]

66
5-methyl-4-nitroisoxazole-3-carbonyl chloride [ No CAS ]
[ 27469-61-0 ]
[ 1360705-96-9 ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine In dichloromethane at 20℃; for 2h;	(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)(5-methyl-4-nitroisoxazol-3-yl)methanone (2y) General procedure: 5-methyl-4-nitroisoxazole-3-carbonyl chloride 5 (33 mg, 0.17 mmol) was dissolved in dichloromethane (1ml) at room temperature and 1-(bis(4-chlorophenyl)methyl)piperazine 9 (55 mg, 0.17 mmol) was added, along with one drop of triethylamine. After stirring for 2 hours, TLC shows complete conversion. The mixture was dissolved in dichloromethane and washed with a saturated aqueous solution of sodium bicarbonate (2 x 10 ml). The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude mixture was purified on silica gel using a gradient of ethyl acetate in hexanes to afford the final product 2y (61 mg) as a white solid (0.128 mmol, 74%).

Reference： [1]Weïwer, Michel; Bittker, Joshua A.; Lewis, Timothy A.; Shimada, Kenichi; Yang, Wan Seok; MacPherson, Lawrence; Dandapani, Sivaraman; Palmer, Michelle; Stockwell, Brent R.; Schreiber, Stuart L.; Munoz, Benito [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1822 - 1826]

67
[ 32315-10-9 ]
[ 27469-61-0 ]
[ 93496-85-6 ]
[ 1446817-38-4 ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: bis(trichloromethyl) carbonate; methyl d,l-2-hydroxy-3,3,3-trifluoropropionate With N-ethyl-N,N-diisopropylamine In dichloromethane for 2h; Stage #2: 1-(4,4'-dichloro-benzhydryl)-piperazine In dichloromethane for 2h;	36 Example 36: l,l,l-trifluoro-3-methoxy-3-oxopropan-2-yl 4-(bis(4- chlorophenyl)methyl)piperazine-l-carboxylate (6h) To a stirring solution of triphosgene (65 mg, 0.22 mmol) in (( (5.0 mL) was added methyl-3,3,3-trifluoro-DL-lactate (116 mg, 0.73 mmol) followed by N,N- diisopropylethylamine (0.38 mL, 2.19 mmol). After 2 h, l-(bis(4- chlorophenyl)methyl)piperazine (160 mg, 0.50 mmol) was added as a solution in (( (2 mL) and stirred for another 2 h. The mixture was concentrated under reduced pressure and purified directly by S1O2 flash chromatography (25% EtOAc/hexanes) to provide the titled compound (156 mg, 62%): 'H NMR 500 MHz (CDC13) δ 7.31 (d, J= 8.47 Hz, 4H), 7.26 (d, J = 8.41 Hz, 4H), 5.43 (q, J= 7.03 Hz, 1H), 4.23 (s, 1H), 3.85 (s, 3H), 3.66 - 3.46 (m, 4H), 2.44 - 2.32 (m, 4H); HRMS m/z calc'd for [M+H]+ C22H21Cl2F3 204: 505.0903, found 505.0905.

Reference： [1]Current Patent Assignee: H. LUNDBECK A/S; SCRIPPS RESEARCH - WO2013/103973, 2013, A1 Location in patent: Paragraph 00175

68
[ 27469-61-0 ]
[ 1446817-39-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h 1.2: 2 h 2.1: sodium hydroxide; water / 1,4-dioxane / 20 °C

Reference： [1]Current Patent Assignee: H. LUNDBECK A/S; SCRIPPS RESEARCH - WO2013/103973, 2013, A1

69
[ 27469-61-0 ]
[ 1446817-40-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h 1.2: 2 h 2.1: tetrahydrofuran / 24 h / 20 °C

Reference： [1]Current Patent Assignee: H. LUNDBECK A/S; SCRIPPS RESEARCH - WO2013/103973, 2013, A1

70
[ 32315-10-9 ]
[ 27469-61-0 ]
[ 1072850-67-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine In dichloromethane at 0 - 20℃; for 5.33333h; Inert atmosphere;	41.3 Step 3: Pre aration of 4-(bis(4-chlorophenyl)methyl)piperazine-l-carbonyl chloride Step 3: Pre aration of 4-(bis(4-chlorophenyl)methyl)piperazine-l-carbonyl chloride [00175] To a stirring solution of triphosgene (460 mg, 1.56 mmol, 0.5 equiv) in anhydrous (( (25 mL) at 0 °C under 2 was added pyridine (0.25 mL, 3.11 mmol, 1.0 equiv). After stirring for 5 min, l-(bis(4-chlorophenyl)methyl)piperazine (3.11 mmol, 1.0 equiv) was added in small portions over 15 min. The reaction mixture was stirred for 1 h and then allowed to warm to room temperature. After stirring for an additional 4 h, the reaction mixture was quenched with cold HC1 (10 mL, 1.0 N), and the product was extracted with CH2CI2 (3 x 20 mL). The combined organic layers were washed with saturated aHC03 (2 x 20 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure. The crude 4- (bis(4-chlorophenyl)methyl)piperazine-l-carbonyl chloride was used without further purification.

Reference： [1]Current Patent Assignee: H. LUNDBECK A/S; SCRIPPS RESEARCH - WO2013/142307, 2013, A1 Location in patent: Paragraph 00175

71
[ 27469-61-0 ]
[ 1460028-84-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 5.33 h / 0 - 20 °C / Inert atmosphere 2: 4-methyl-morpholine; dmap / dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: H. LUNDBECK A/S; SCRIPPS RESEARCH - WO2013/142307, 2013, A1

72
[ 27469-61-0 ]
14-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)-3,6,9,12-tetraoxatetradecan-1-amine trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: tetrabutyl-ammonium chloride; potassium carbonate / water / 0.25 h / 20 °C 1.2: 2 h / 100 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0 - 20 °C 2.3: 0 - 20 °C

Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES - WO2015/80949, 2015, A1

73
[ 27469-61-0 ]
[ 628-89-7 ]
[ 76-05-1 ]
2-(2-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)ethoxy)ethanol trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-(4,4'-dichloro-benzhydryl)-piperazine With tetrabutyl-ammonium chloride; potassium carbonate In water at 20℃; for 0.25h; Stage #2: 2-(2-Chloroethoxy)ethanol In water; acetonitrile at 100℃; for 2h; Stage #3: trifluoroacetic acid In water; acetonitrile	2-(2-(4-(bis(4-Chlorophenyl)methyl)piperazin- 1 -yl)ethoxy)ethanol . A solution of l-(bis(4-chlorophenyl)methyl)piperazine (100 mg, 0.31 1 mmol) in H20 (1.50 mL) was treated with K2C03 (86.0 mg, 0.623 mmol) and tetrabutylammonium chloride (87.0 mg, 0.31 1 mmol). The resulting mixture was stirred at room temperature for 15 min, then 2-(2-chloroethoxy)ethanol (38.8 mg, 0.31 1 mmol) in acetonitrile (1.50 mL) was added to the mixture. The resulting reaction mixture was heated to 100 °C for 2 h, after which LCMS analysis showed completion. The reaction mixture was diluted with EtOAc and washed with H20 and brine. The organic layer was separated, dried over MgS04, filtered and concentrated. Residue was purified by preparative HPLC to afford the title compound as the TFA salt. NMR (400 MHz, DMSO-d6) δ ppm 9.34 (s, 1H), 7.47 - 7.36 (m, 8H), 4.58 (s, 1H), 3.72 (t, J = 4.9 Hz, 2H), 3.55 - 3.49 (m, 4H), 3.49 - 3.42 (m, 4H), 3.13 (d, J = 1 1.5 Hz, 3H), 2.80 (d, J = 12.9 Hz, 2H), 2.27 (t, J = 12.2 Hz, 2H). LCMS RT (Method 1) = 4.716 min, m/z 410.4 [M+H+].

Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES - WO2015/80949, 2015, A1 Location in patent: Paragraph 0324; 0325

74
[ 27469-61-0 ]
[ 628-89-7 ]
[ 76-05-1 ]
2-(2-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)ethoxy)ethanol trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-(4,4'-dichloro-benzhydryl)-piperazine With tetrabutyl-ammonium chloride; potassium carbonate In water at 20℃; for 0.25h; Stage #2: 2-(2-Chloroethoxy)ethanol In water; acetonitrile at 100℃; for 2h; Stage #3: trifluoroacetic acid In water; acetonitrile

Reference： [1]He, Shanshan; Xiao, Jingbo; Dulcey, Andrés E.; Lin, Billy; Rolt, Adam; Hu, Zongyi; Hu, Xin; Wang, Amy Q.; Xu, Xin; Southall, Noel; Ferrer, Marc; Zheng, Wei; Liang, T. Jake; Marugan, Juan J. [Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 841 - 853]

75
[ 625-38-7 ]
[ 27469-61-0 ]
1-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)but-3-en-1-one [ No CAS ]