Name: 17403-09-7|3-(Piperidin-4-yl)-1H-indole|98%
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SKU: A680030
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1
[ 52548-84-2 ]
[ 17403-09-7 ]
1-{2-[4-(1H-Indol-3-yl)-piperidin-1-yl]-ethyl}-1,3-dihydro-benzoimidazol-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydrogencarbonate In tetrahydrofuran; N,N-dimethyl-formamide for 48h; Heating;

Reference： [1]Freter; Fuchs; Barsumian; Oliver [Arzneimittel-Forschung/Drug Research, 1985, vol. 35, # 1 A, p. 272 - 276]

2
[ 7460-59-5 ]
[ 17403-09-7 ]
[ 111622-09-4 ]

Yield	Reaction Conditions	Operation in experiment
30.2%	With sodium hydrogencarbonate In tetrahydrofuran; N,N-dimethyl-formamide for 1.7h; Heating;
	With sodium bicarbonate; sodium chloride In tetrahydrofuran; methanol; chloroform; water; N,N-dimethyl-formamide	1 EXAMPLE 1 EXAMPLE 1 2-Acetylamino-4-chloromethylthiazole (480 mg), 3-(4-piperidyl)indole (500 mg) and sodium hydrogen carbonate (310 mg) was refluxed in a mixture of N,N-dimethylformamide (5 ml) and tetrahydrofuran (7 ml) for 1 hour and 40 minutes. After the reaction mixture cooled to ambient temperature, it was concentrated under reduced pressure. After addition of water (50 ml), the residue was extracted with ethyl acetate (50 ml) twice. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol (30:1 V/V). The elude gave 2-acetylamino-4-[4-(3-indolyl)piperidinomethyl]thiazole (270 mg). mp: 204°-207° C. (recrystallized from ethanol). IR (Nujol): 3400, 3165, 1686, 1263, 1004, 758, 747 cm-1. NMR (DMSO-d6, δ): 2.32 (3H, s), 1.4-3.2 (9H, m), 3.52 (2H, s), 6.8-7.65 (6H, m), 10.70 (1H, s), 12.08 (1H, s). Mass: 354 (M+). Elemental analysis: C19 H22 N4 OS: Calcd.: C 64.38, H 6.26, N 15.81, Found: C 64.40, H 6.06, N 15.67.
	With sodium bicarbonate; sodium chloride In tetrahydrofuran; methanol; chloroform; water; N,N-dimethyl-formamide	1 Example 1 Example 1 2-Acetylamino-4-chloromethylthiazole (480 mg), 3-(4-piperidyl)indole (500 mg) and sodium hydrogen carbonate (310 mg) was refluxed in a mixture of N,N-dimethylformamide (5 ml) and tetrahydrofuran (7 ml) for 1 hour and 40 minutes. After the reaction mixture was cooled to ambient temperature, it was concentrated under reduced pressure. After addition of water (50 ml), the residue was extracted with ethyl acetate (50 ml) twice. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol (30:1 V/V). The elude gave 2-acetylamino-4-[4-(3-indolyl)piperidinomethyl]thiazole (270 mg).

Reference： [1]Shigenaga; Manabe; Matsuda; Fujii; Hiroi; Matsuo [Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 9, p. 1589 - 1595]
[2]Current Patent Assignee: ASTELLAS PHARMA INC. - US4742057, 1988, A
[3]Current Patent Assignee: ASTELLAS PHARMA INC. - EP224919, 1991, B1

3
[ 26493-13-0 ]
[ 17403-09-7 ]
[ 111608-42-5 ]

Yield	Reaction Conditions	Operation in experiment
27.8%	With sodium hydrogencarbonate In tetrahydrofuran; N,N-dimethyl-formamide for 1.7h; Heating;
	With potassium iodide; sodium bicarbonate In tetrahydrofuran; methanol; chloroform; N,N-dimethyl-formamide	2 EXAMPLE 2 EXAMPLE 2 2-Acetylamino-4-(2-chloroethyl)thiazole (1 g), 3-(4-piperidyl)indole (0.98 g), sodium hydrogen carbonate (620 mg) and potassium iodide (810 mg) were refluxed in a mixture of tetrahydrofuran (14 ml) and N,N-dimethylformamide (10 ml) for 4 hours and 10 minutes. Thereafter, with additions of 2-acetylamino-4-(2-chloroethyl)thiazole (0.5 g) three times, the mixture was further refluxed for 2 hours and 20 minutes. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was extracted with a mixture of chloroform and methanol (100 ml, 10:1 V/V) and the extract was washed successively with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol (10:1 V/V). The elude gave 2-acetylamino-4-[2-[4-(3-indolyl)piperidino]ethyl]thiazole (500 mg). mp: 203°-204° C. (recrystallized from ethanol). Mass: 368 (M+). IR (Nujol): 3275, 1663, 1560, 1305, 1106, 740 cm31 1. NMR (DMSO-d6, δ): 2.13 (3H, s), 1.4-3.4 (13H, m), 6.80 (1H, s), 6.8-7.7 (5H, m), 10.79 (1H, s), 12.03 (1H, br s). Elemental analysis: C20 H24 N4 OS: Calcd.: C 65.19, H 6.56, N 15.20, Found: C 65.30, H 6.77, N 15.21.
	With potassium iodide; sodium bicarbonate In tetrahydrofuran; methanol; chloroform; N,N-dimethyl-formamide	2 Example 2 Example 2 2-Acetylamino-4-(2-chloroethyl)thiazole (1 g), 3-(4-piperidyl)indole (0.98 g), sodium hydrogen carbonate (620 mg) and potassium iodide (810 mg) were refluxed in a mixture of tetrahydrofuran (14 ml) and N,N-dimethylformamide (10 ml) for 4 hours and 10 minutes. Thereafter, with additions of 2-acetylamino-4-(2-chloroethyl)thiazole (0.5 g) three times, the mixture was further refluxed for 2 hours and 20 minutes. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was extractedwith a mixture of chloroform and methanol (100 ml, 10:1 V/V) and the extract was washed successively with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol (10:1 V/V). The elude gave 2-acetylamino-4-[2-[4-(3-indolyl)piperidino]ethyl]-thiazole (500 mg).

Reference： [1]Shigenaga; Manabe; Matsuda; Fujii; Hiroi; Matsuo [Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 9, p. 1589 - 1595]
[2]Current Patent Assignee: ASTELLAS PHARMA INC. - US4742057, 1988, A
[3]Current Patent Assignee: ASTELLAS PHARMA INC. - EP224919, 1991, B1

4
[ 65347-55-9 ]
[ 17403-09-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; hydrogen In methanol for 1h;
100%	With hydrogen In methanol for 8h;
87%	In methanol; palladium-carbon	1.B B. B. Preparation of 3-piperidin-4-yl-1H-indole 19.03 g (0.096 mol) of 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole were hydrogenated in a Parr apparatus during 18 h at 40 psi with 2.2 g of Pd/C 10% in 600 ml of methanol. After usual work-up, 16.76 g (87% of yield) of the desired product were obtained. Melting point=210-212° C.

87%	In methanol; palladium-carbon	1.B B. B. Preparation of 3-piperidin-4-yl-1H-indole 19.03 g (0.096 mol) of 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole were hydrogenated in a Parr apparatus during 18 h at 40 psi with 2.2 g of Pd/C 10% in 600 ml of methanol. After standard work-up, 16.76 g (87% of yield) of the desired product were obtained. Melting point=210-212° C.
87%	With hydrogen In methanol for 18h;	1.B Example 1; B. Preparation of 3-piperidin-4-yl-1H-indole 19.03 G (0.096 mol) of 3- (1, 2, 3, 6-TETRAHYDRO-PYRIDIN-4-YL)-1 H-INDOLE WERE hydrogenated in a Parr apparatus during 18 h at 3 bar with 2.2 G of Pd/C 10% in 600 mi of methanol. After standard work-up, 16.76 G (87% of yield) of the desired product were obtained. Melting point: 210-212°C C
71%	With hydrogen In ethanol
	With hydrogen In ethanol at 20℃;	2 Example 2 ~ Synthesis and SAR of Diphenylbutylpiperidines Autophagy Inducers Based on Pimozide (2)Diphenylbutylpiperidines compounds, such as those described herein, can be prepared by SN2 substitution of halodiphenylbutyl compounds with piperidines (as described in Janneke, W.; Hulshof, H. F.; Vischer, H.P.; Verheij, S. A.; Fratantoni, Martine, J. S.; Iwan, J. P. Bioorg. Med. Chem. Lett. 2006, 14, 7213).As part of structure-activity relationship studies, modification of left-hand side of compound 2 were explored (Figures 13 and 14). Interestingly, compound 109 showed 2- fold increase in the activity of inducing autophagyModifications of the right-hand side of compound 2 were also explored. For example, synthetic variations on the P-1-56 fused ring scaffold are described in Figures 15 and 16. Reductive amination of N-Bocpiperidone with o-aminophenol was followed by cyclization with triphosgene and removal the Boc group. Substitution of the MsO group of piperidine 114 with compounds 113, 116 or 118 (6,5-fused heterocycles) followed by deprotection of Boc group by TFA afforded the desired compound 115, 117 or 119 (He, Y.; Yang, J., et al. Bioorg. Med. Chem. Lett. 2004, 14, 695). Reductive amination of N- Bocpiperidone 121 with o-aminophenol 120 followed by cyclization of 122 withtriphosgene and deprotection the Boc group yielded compound 123 (Flyren, K.; Bergquist, L. O.; et al. Bioorg. Med. Chem. Lett. 2007, 17, 3421). Treatment of piperidone 125 with indole gave compound 126, which was converted to compound 127 by hydrogenation. Reductive amination of 121 with indoline, prepared by reduction of indole, anddeprotection gave compound 130.Cyclization of compounds 120, 131 or 132 with 4-piperidinecarboxylic acid 133 give the desired compounds 134, 135 or 136 (He, Y.; Yang, J., etal. Bioorg. Med. Chem. Lett. 2004, 14, 695). Reductive amination of N-Boc piperidone with isoindoline prepared by reduction of phthalimide 137 and deprotection of the Boc group gave compound 138. Substitution of MsO group of piperidine 141 with phthalimide potassium salt followed by deprotection of Boc group afforded the desired compound 142. Treatment of 4-hydroxy piperidine 144 with 1,2,3-benzotriazole by Mitsunobu reaction followed by deprotection afforded two compounds 145 and 146 (Ruckle, T.; Biamonte, M., et al. J. Med. Chem. 2004, 47, 6921). Cyclization of compounds 121, 131 or 132 wuth 4-piperidine carboxylic acid gave compounds 134, 135 or 136 (respectively).Figures 18 and 19 showed the biological activity of selected P-l-56 compounds. As mentioned above, compound 109 showed 2-fold increased potent activity comparable to compound 2. A series of compounds with CN group have also been prepared; interestingly, some showed good results (147 vs 155, 151 vs 159, 153 vs 161) while some did not (149 vs 157, 150 vs 158, 152 vs 160). In the left series, compounds 149, 150, 152 and 153 showed 3 to 5-fold increased activity comparable to compound 2, while compounds 148, 151 and 154 showed no activity. In the right series, compounds 157, 158 and 160 showed 3 to 7-fold increased activity comparable to compound 2, while compounds 156 and 162 showed no activity. All of the above results indicate that the 4-position of piperidine ring can tolerate 6,5-fused heterocycle groups.The biological activity results of P-2-56 compounds is shown in Figure 20. These results suggested that compounds 163 and 166 are comparable to compound 2, while compounds 169 and 178 showed about a 4-fold increase in activity. However, compounds 164, 165, 170 and 177 showed no activity. Comparing the three isoelectronic compounds at the bottom of Figure 20, compound 166 showed the best result, while compounds 167 and 168 showed the same results. In contrast, compound 178 also showed the best result, while compounds 179 and 180 showed no activity.Encouraged by the biological activity results of DPBPs with 6,5-fused ring linked to the piperidine ring, compounds with 6,6-fused ring shown in Figures 21-24 were also prepared. Reductive amination of N-Boc piperidone with compound 182, prepared by reduction of isoquinoline 137, and deprotection of the Boc group gave compound 183. Cyclization of anthranilamide 184 with N-benzylpiperidone 185 followed by reduction of compound 186 afforded intermediate compound 187 (Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.; Kasuya, Y.; Shigenobl, K.; Hashikami, M.; Karashima, N. Chem. Pharm. Bull. 1985, 33, 1116). Cyclization 187 with CDI and deprotection of the Boc group gave compound 189. Cyclization 187 with different regents gave compounds 191, 193, 195 and 197 (Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.; Kasuya, Y.; Shigenobl, K.; Hashikami, M.; Karashima, N. Chem. Pharm. Bull. 1985, 33, 1116; and Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.; Hashimoto, T. Chem. Pharm. Bull. 1985, 33, 1104).The biological activity results of P-2-66 compounds is shown in Figures 23 and 24. Reductive amination of N-Boc piperidone with compound 199, prepared by reduction of quinoline 198, and deprotection of the Boc group gave compound 200. Treatment of salicylaldehyde 201 with compound 202, followed cyclization with CDI and deprotection of Bn group gave compound 205 (Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.; Hashimoto, T. Chem. Pharm. Bull. 1985, 33, 1104). Ring opening of compound 206 with 202 afforded intermediate 203 (Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Karasawa, A.; Kubo, K.; Shuto, K.; Kasuya, T. Chem. Pharm. Bull. 1986, 34, 1907). Cyclization 203 with different regents gave compounds 205, 207 and 209.Reductive amination of compound 210 with 211, followed by deprotection of the Boc group, gave compound 212. Cyclization 212 with different regents gave compounds 213- 217 (Takai, H.; Obase, H.; Nakamizo, N.; Teranishi, M.; Kubo, K.; Shuto, K.; Hashimoto, T. Chem. Pharm. Bull. 1985, 33, 1104).Compounds 234-237, which combined variations in both the left-hand side and right-hand side, we prepared and tested (Figure 28). Compounds 238 and 239 were also prepared and tested (Figure 29). Compound 239 (with a spiro structure) showed better results than Fluspirilene; this compound was easily prepared and has good solubility properties.
	With palladium 10% on activated carbon; ammonium formate In methanol Reflux;	1 The product (1.1 g) was dissolved in CH3OH (100 ml) and treated with 10% Pd/C (250 mg) and ammonium formate (2.8 g). The mixture was reflu ed overnight. The reaction mixture was then filtered through celite and concentrated to produce crude product 2, which was then purified.

Reference： [1]Fonquerna, Silvia; Miralpeix, Montse; Pagès, Lluís; Puig, Carles; Cardús, Arantxa; Antón, Francisca; Cárdenas, Álvaro; Vilella, Dolors; Aparici, Mónica; Calaf, Elena; Prieto, José; Gras, Jordi; Huerta, Josep M.; Warrellow, Graham; Beleta, Jorge; Ryder, Hamish [Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6326 - 6337]
[2]Current Patent Assignee: MERCEDES-BENZ GROUP AG; FCA (in: Stellantis); STELLANTIS NV - WO2004/43949, 2004, A1 Location in patent: Page/Page column 30
[3]Current Patent Assignee: ALMIRALL SA - US2002/147344, 2002, A1
[4]Current Patent Assignee: ALMIRALL SA - US2004/116471, 2004, A1
[5]Current Patent Assignee: ALMIRALL SA - WO2003/99807, 2003, A1 Location in patent: Page 9
[6]Freter; Fuchs; Barsumian; Oliver [Arzneimittel-Forschung/Drug Research, 1985, vol. 35, # 1 A, p. 272 - 276]
[7]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; HARVARD UNIVERSITY - WO2011/143444, 2011, A2 Location in patent: Page/Page column 7; 87-90
[8]Current Patent Assignee: MERCK & CO INC; UNIVERSITY OF DUNDEE - WO2015/82499, 2015, A2 Location in patent: Page/Page column 142-143

5
[ 17403-09-7 ]
[ 92926-65-3 ]
N-<4-<4-(1H-indol-3-yl)piperidinomethyl>-2-thiazolyl>propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.7%	With sodium hydrogencarbonate; sodium iodide In N,N-dimethyl-formamide at 50℃; for 2h;
	With sodium bicarbonate; nitrogen In methanol; ethanol; chloroform; N,N-dimethyl-formamide	6 EXAMPLE 6 EXAMPLE 6 A mixture of 2-propionylamino-4-chloromethylthiazol (5.11 g), 3-(4-piperidyl)indole (5 g), sodium hydrogen carbonate (2.31 g) and N,N-dimethylformamide (25 ml) was heated at 102° to 103° C. with bubbling nitrogen gas and stirring for 6 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was subjected to column chromatography on silica gel and the column was eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the desired compound were combined and concentrated and ethanol was added thereto. The solution was concentrated again and the residue was triturated with diisopropyl ether to give 4-[4-(3-indolyl)piperidinomethyl]-2-propionylaminothiazole (6.50 g). mp: 191.5°-195° C. IR (Nujol): 3380, 1673, 1540, 1180, 738 cm31 1. NMR (DMSO-d6, δ): 1.07 (3H, t, J=7.2 Hz), 1.2-3.8 (13H, m), 6.8-7.7 (6H, m), 10.66 (1H, br s), 12.05 (1H, br s).
	With sodium bicarbonate; nitrogen In methanol; ethanol; chloroform; N,N-dimethyl-formamide	6 Example 6 Example 6 A mixture of 2-propionylamino-4-chloromethylthiazol (5.11 g), 3-(4-piperidyl)indole (5 g), sodium hydrogen carbonate (2.31 g) and N,N-dimethylformamide (25 ml) was heated at 102 to 103°C with bubbling nitrogen gas and stirring for 6 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was subjected to column chromatography on silica gel and the column was eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the desired compound were combined and concentrated and ethanol was added thereto. The solution was concentrated again and the residue was triturated with diisopropyl ether to give 4-[4-(3-indolyl)piperidinomethyl]-2-propionylaminothiazole (6.50 g).

Reference： [1]Shigenaga; Manabe; Matsuda; Fujii; Matsuo [Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 9, p. 1822 - 1827]
[2]Current Patent Assignee: ASTELLAS PHARMA INC. - US4742057, 1988, A
[3]Current Patent Assignee: ASTELLAS PHARMA INC. - EP224919, 1991, B1

6
[ 17403-09-7 ]
[ 111608-44-7 ]
4-[4-(3-indolyl)piperidinomethyl]-2-pivaloylaminothiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38.9%	With sodium hydrogencarbonate; sodium iodide In N,N-dimethyl-formamide at 50℃; for 2h;
	With sodium iodide; sodium bicarbonate In methanol; chloroform; N,N-dimethyl-formamide	3 EXAMPLE 3 EXAMPLE 3 A mixture of 2-pivaloylamino-4-chloromethylthiazole (0.42 g), 3-(4-piperidyl)indole (0.34 g), sodium hydrogen carbonate (0.23 g), N,N-dimethylformamide (4.2 ml) and a trace amount of sodium iodide was stirred at 50° C. for 2 hours. The insoluble material was filtered off and the filtrate was washed with a mixture of chloroform and methanol (10:1 V/V). The washings and the filtrate were combined and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and recrystallized from ethanol to give 4-[4-(3-indolyl)piperidinomethyl]-2-pivaloylaminothiazole (280 mg). mp: 93°-96° C. IR (Nujol): 3235, 1684, 1165, 1148, 1045, 750 cm-1. NMR (CDCl3, δ): 1.33 (9H, s), 1.5-3.4 (9H, m), 3.56 (2H, s), 6.73 (1H, s), 6.9-7.8 (5H, m), 8.10 (1H, br s), 9.00 (1H, br s). Elemental analysis: C22 H28 N4 OS.C2 H5 OH: Calcd.: C 65.12, H 7.74, N 12.65, Found: C 65.11, H 7.77, N 12.60.
	With sodium iodide; sodium bicarbonate In methanol; chloroform; N,N-dimethyl-formamide	3 Example 3 Example 3 A mixture of 2-pivaloylamino-4-chloromethylthiazole (0.42 g), 3-(4-piperidyl)indole (0.34 g), sodium hydrogen carbonate (0.23 g), N,N-dimethylformamide (4.2 ml) and a trace amount of sodium iodide was stirred at 50°C for 2 hours. The insoluble material was filtered off and the filtrate was washed with a mixture of chloroform and methanol (10:1 V/V). The washings and the filtrate were combined and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and recrystallized from ethanol to give 4-[4-(3-indolyl)piperidinomethyl]-2-pivaloylaminothiazole (280 mg).

Reference： [1]Shigenaga; Manabe; Matsuda; Fujii; Matsuo [Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 9, p. 1822 - 1827]
[2]Current Patent Assignee: ASTELLAS PHARMA INC. - US4742057, 1988, A
[3]Current Patent Assignee: ASTELLAS PHARMA INC. - EP224919, 1991, B1

7
[ 574-98-1 ]
[ 17403-09-7 ]
[ 57311-64-5 ]

Yield	Reaction Conditions	Operation in experiment
37.6%	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 68 - 74℃; for 4h;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 80℃;
	With potassium iodide; sodium carbonate In water; 4-methyl-2-pentanone	1.A STEP A STEP A 4-(3'-indolyl)-N-(β-phthalimidoethyl)-piperidine A mixture of 10 g of 3-(4'-piperidyl)-indole and 12.7 g of N-(2-bromoethyl)-phthalimide in 250 ml of isobutyl methyl ketone was heated to 80°-90°C with stirring and the 10.6 g of sodium carbonate and a few crystals of potassium iodide were added thereto. The mixture was refluxed for 21/2 hours and after cooling, the mixture was added to water. The mixture was extracted with ethyl acetate and the organic phase was washed with water containing sodium chloride, was dried, concentrated to dryness. The residue was crystallized from ethyl acetate to obtain 8 g of 4-(3'-indolyl)-N-(β-phthalimido ethyl)-piperidine melting at 193°C.

Reference： [1]Shigenaga; Manabe; Matsuda; Fujii; Matsuo [Archiv der Pharmazie, 1996, vol. 329, # 1, p. 3 - 10]
[2]Forbes, Ian T; Cooper, David G.; Dodds, Emma K.; Hickey, Deirdre M.B.; Ife, Robert J.; Meeson, Malcolm; Stockley, Martin; Berkhout, Theo A.; Gohil, Jayneeta; Groot, Pieter H.E.; Moores, Kitty [Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 16, p. 1803 - 1806]
[3]Current Patent Assignee: SANOFI - US3950527, 1976, A

8
[ 5460-29-7 ]
[ 17403-09-7 ]
[ 57311-65-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 68 - 74℃;
	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 80℃;
	With sodium bicarbonate In methanol; chloroform; N,N-dimethyl-formamide	2 PREPARATION 2 PREPARATION 2 A mixture of 4-(3-indolyl)piperidine (7.47 g), N-(3-bromopropyl)phthalimide (10.0 g) and sodium hydrogen carbonate (3.45 g) in dry N, N-dimethylformamide (88 ml) was heated at 70° C. for 2 hours. After cooling, the reaction mixture was poured into water (880 ml) and extracted with a mixture of chloroform and methanol (10:1 V/V). The organic layer was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (290 g) and eluted with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with diethyl ether to give pale yellow crystals of 1-(3-phthalimidopropyl)-4-(3-indolyl)piperidine (5.83 g). IR (Nujol): 3360, 1770, 1704, 1040, 735, 712 cm-1 NMR (DMSO-d6, δ): 1.0-3.1 (13H, m), 3.67 (2H, t, J=6.0 Hz), 6.8-7.6 (5H, m), 7.6-8.0 (4H, m), 10.63 (1H, s)

Reference： [1]Shigenaga; Manabe; Matsuda; Fujii; Matsuo [Archiv der Pharmazie, 1996, vol. 329, # 1, p. 3 - 10]
[2]Forbes, Ian T; Cooper, David G.; Dodds, Emma K.; Hickey, Deirdre M.B.; Ife, Robert J.; Meeson, Malcolm; Stockley, Martin; Berkhout, Theo A.; Gohil, Jayneeta; Groot, Pieter H.E.; Moores, Kitty [Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 16, p. 1803 - 1806]
[3]Current Patent Assignee: NATIVELLE ETS; ASTELLAS PHARMA INC. - US5017703, 1991, A

9
[ 120-72-9 ]
[ 3612-20-2 ]
[ 17403-09-7 ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: indole; 1-phenylmethyl-4-piperidone With sodium methylate In methanol Stage #2: With hydrogen In ethanol; acetic acid
	Stage #1: indole; 1-phenylmethyl-4-piperidone With potassium hydroxide In methanol at 20℃; for 16h; Reflux; Inert atmosphere; Stage #2: With palladium 10% on activated carbon; hydrogen In methanol at 45℃; for 8h;	3-piperidin-4-yl-1H-indoles (3a-c) General procedure: The starting compounds 3a-cwere obtained according to previously described [6-9]A mixture of 0.1 mol of appropriate indole, 0.2mol of N-benzyl-4-piperidone and 150ml of 2 N KOH/MeOH was refluxed while stirring under an atmosphere of nitrogenfor 8 h. The mixture was further stirred for 8 h at room temperature and pouredonto ice/water. The crude product was extracted with CHCl3. Organiclayers were combined and dried with MgSO4. The mixture was thenfiltered and the filtrate was evaporated to dryness. The crude residue was purifiedwith diethyl ether. The obtained yellow solid was dissolved in 300 ml ofmethanol, hydrogenated for 8 h in 45 C and 1 atm on 10% Pd/C as catalyst. Thecatalyst was then filtered off and the filtrate was The starting compounds 3a-cwere obtained according to previously described [6-9]A mixture of 0.1 mol of appropriate indole, 0.2mol of N-benzyl-4-piperidone and 150ml of 2 N KOH/MeOH was refluxed while stirring under an atmosphere of nitrogenfor 8 h. The mixture was further stirred for 8 h at room temperature and pouredonto ice/water. The crude product was extracted with CHCl3. Organiclayers were combined and dried with MgSO4. The mixture was thenfiltered and the filtrate was evaporated to dryness. The crude residue was purifiedwith diethyl ether. The obtained yellow solid was dissolved in 300 ml ofmethanol, hydrogenated for 8 h in 45 C and 1 atm on 10% Pd/C as catalyst. Thecatalyst was then filtered off and the filtrate was 3-piperidin-4-yl-1H-indole (3a). The title compound 3a was isolated as a yellow powder (220-225C)1H NMR (DMSO-d6, 200 MHz, δ[ppm]): 1.46-1.64(m, 2H), 1.83-1.89 (m, 2H), 2.57-2.69 (dt, 2J ) 12.1 Hz, 3J ) 2.3 Hz, 2H),2.76-2.82 (tt, J ) 11.70, 3.51 Hz, 1H), 2.98-3.04 (d, J ) 12.1 Hz, 2H),6.90-7.07 (m, 3H), 7.31-7.34 (d, J ) 7.8 Hz, 1H), 7.53-7.57 (d, J ) 7.4 Hz,1H), 10.79 (s, 1H)[8].

Reference： [1]Burm, Brigitte E.A; Gremmen, Christiaan; Wanner, Martin J; Koomen, Gerrit-Jan [Tetrahedron, 2001, vol. 57, # 10, p. 2039 - 2049]
[2]Wróbel, Martyna Z.; Chodkowski, Andrzej; Herold, Franciszek; Marciniak, Monika; Dawidowski, Maciej; Siwek, Agata; Starowicz, Gabriela; Stachowicz, Katarzyna; Szewczyk, Bernadeta; Nowak, Gabriel; Belka, Mariusz; Bączek, Tomasz; Satała, Grzegorz; Bojarski, Andrzej J.; Turło, Jadwiga [European Journal of Medicinal Chemistry, 2019, vol. 183]

10
[ 17403-09-7 ]
[ 72831-89-1 ]

Reference： [1]Tetrahedron,2001,vol. 57,p. 2039 - 2049

11
[ 7560-50-1 ]
[ 17403-09-7 ]
(2E)-3-[4-[4-(1H-indol-3-yl)piperidin-1-ylmethyl]phenyl]-2-propenoic acid methyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 4609 - 4624

12
[ 541-41-3 ]
[ 17403-09-7 ]
[ 312631-12-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	In dichloromethane; water	13.A A. A. Preparation of 4-(1H-indol-3-yl)-piperidine-1-carboxylic Acid Ethyl Ester To a suspension of 30 g (0.15 mol) of 3-piperidin-4-yl-1H-indole and 28 mL (0.2 mol) in 185 mL of anhydrous dichloromethane, 17 mL (0.18 mol) of ethyl chloroformate was added dropwise keeping the temperature of the reaction below 20° C. After 2 h at room temperature, the crude mixture was poured into 100 mL of water. The organic layer was separated and dried with sodium sulfate. After filtration, the solvent was removed under reduced pressure affording 39 g (95% of yield) of the expected product. ESI/MS m/e=272 [(M+1)+, C16 H20 N2 O2] NMR (300 MHz, DMSO) δ=1.16-1.23 (t, 2H), 1.41-1.65 (m, 2H), 1.92-1.99 (m, 2H), 2.90-23.10 (m, 3H), 3.99-4.10 (m, 4H), 6.95-7.10 (m, 3H), 7.31-7.34 (d, 1H), 7.53-7.57 (d, 1H), 10.81 (a, 1H).
95%	In dichloromethane at 20℃; for 2h;	1.C Example 1; C. Preparation of 4- (1 H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester To a suspension of 30 G (0.15 mol) of 3-PIPERIDIN4-YL-1H-INDOLE and 28 mL (0.2 mol) in 185 ML of anhydrous DICHLOROMETHANE, 17 mi (0.18 mol) of ethyl chloroformate were added dropwise keeping the temperature of the reaction BELOW 20°C. After 2h at room temperature, the crude mixture was poured into 100 ML of water. The organic layer was separated and dried with sodium sulphate. After filtration, the solvent was removed under reduced pressure affording 39 g (95% of yield) of the expected product. ESI/MS m/e = 272 [(M+1) +, C16 H20 N2 02] 'H-NMR (300 MHz, DMSO) 8 =1. 16-1.23 (t, 2H), 1.41-1. 65 (m, 2H), 1.92-1. 99 (m, 2H), 2.90-3. 10 (m, 3H), 3. 99-4. 10 (m, 4H), 6.95-7. 10 (m, 3H), 7.31-7. 34 (d, 1 H), 7.53-7. 57 (d, 1 H), 10.81 (s, 1H).
93%	With triethylamine In dichloromethane at 0℃; for 1h;

Reference： [1]Current Patent Assignee: ALMIRALL SA - US2004/116471, 2004, A1
[2]Current Patent Assignee: ALMIRALL SA - WO2003/99807, 2003, A1 Location in patent: Page 9
[3]Fonquerna, Silvia; Miralpeix, Montse; Pagès, Lluís; Puig, Carles; Cardús, Arantxa; Antón, Francisca; Cárdenas, Álvaro; Vilella, Dolors; Aparici, Mónica; Calaf, Elena; Prieto, José; Gras, Jordi; Huerta, Josep M.; Warrellow, Graham; Beleta, Jorge; Ryder, Hamish [Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6326 - 6337]

13
[ 312631-02-0 ]
[ 17403-09-7 ]
[ 312631-03-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate; potassium iodide In various solvent(s) at 90℃; for 18h;
51%	With potassium iodide; potassium carbonate In dichloromethane; 4-methyl-2-pentanone	138.A A. A. Preparation of methyl 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoate 10 g (0.05 mol) of 4-(3-indolyl)-piperidine, 16.1 g (0.075 mol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester both prepared in Example 1 (parts A and B), 31.1 g (0.225 mol) of potassium carbonate and 1.33 g (0.008 mol) of potassium iodide were suspended in 90 ml of methyl isobutyl ketone. This mixture was refluxed for 24 h. Once the reaction was completed, the inorganic salts were filtered and the liquid phase evaporated to dryness. The remaining material was redissolved in dichloromethane and water and worked-up as usual. The crude mixture was purified by flash-chromatography over silica gel affording 9.58 g (51% of yield) of methyl 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoate. Melting point=124-125° C.

Reference： [1]Fonquerna, Silvia; Miralpeix, Montse; Pagès, Lluís; Puig, Carles; Cardús, Arantxa; Antón, Francisca; Cárdenas, Álvaro; Vilella, Dolors; Aparici, Mónica; Calaf, Elena; Prieto, José; Gras, Jordi; Huerta, Josep M.; Warrellow, Graham; Beleta, Jorge; Ryder, Hamish [Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6326 - 6337]
[2]Current Patent Assignee: ALMIRALL SA - US2002/147344, 2002, A1

14
8-(2-chloro-ethyl)-7,9-difluoro-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one [ No CAS ]
[ 17403-09-7 ]
7,9-difluoro-8-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethyl}-6,6-dimethyl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium carbonate In water at 100℃; for 16h;	46 A mixture of 8-(2-chloro-ethyl)-7,9-difluoro-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//]quinolin-4-one (100 mg, 0.368 mmol), 3-piperidin-4-yl-1H-indole (73 mg, 0.364 mmol), Kl (61 mg, 0.367 mmol), K2CO3 (61 mg, 0.441 mmol) and water (5 ml_) was stirred at 10O0C for 16 h. After completion of the reaction, the mixture was allowed to cool to RT and was filtered. The filtered solid was triturated in acetone and filtered to obtain the title compound as a yellowish white solid (109 mg, 68%). 1H NMR (400 MHz, DMSOd6) δ iθ.75 (1 H, s), 10.75 (1 H, s), 7.52 (1 H, d, J=8.0 Hz), 7.32 (1 H, d, J=8.2 Hz), 7.07 (1 H, d, J=2.1 Hz), 7.03 (1 H, m), 6.94 (1 H, m), 3.98 (2H, t, J=8λ Hz), 3.31 (2H, s), 3.13 (1 H, t, J=8.2 Hz), 2.88 (2H, t, J=7.7 Hz), 2.74 (2H, s), 2.56 (2H, t, J=7.8 Hz), 2.51 (7H, d, J=I .9 Hz), 2.14 (1 H, s), 1.92 (1 H, s), 1.68 (1 H, s).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2008/15516, 2008, A1 Location in patent: Page/Page column 43-44

15
8-(2-chloro-ethyl)-7-fluoro-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one [ No CAS ]
[ 17403-09-7 ]
7-fluoro-8-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethyl}-6,6-dimethyl-1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With potassium carbonate In water at 100℃; for 16h;	47 A mixture of 8-(2-chloro-ethyl)-7-fluoro-1 ,2,5,6-tetrahydro-pyrrolo[3,2,1-//\|quinolin-4-one (100 mg, 0.394 mmol), 3-piperidin-4-yl-1 H-indole (79 mg, 0.394 mmol), Kl (65 mg, 0.392 mmol), K2CO3 (65 mg,0.470 mmol) and water (5 ml_) was stirred at 1000C for 16 h. After completion of the reaction, the mixture was allowed to cool to RT and was filtered. The filtered solid was triturated in acetone and filtered to obtain title compound as a yellowish white solid (130 mg, 79%). 1H NMR (400 MHz, DMSOd6) δ 10.74 (1 H, s), 7.53 (1 H, d, J=7.8 Hz), 7.32 (1 H, d, J=8.0 Hz), 7.05 (3H, m), 6.94 (1 H, m), 3.94 (2H, t, J=8.5 Hz), 3.31 (3H, s), 3.07 (2H, t, J=8.5 Hz), 3.02 (2H, d, J=11.5 Hz), 2.90 (2H, t, J=7.8 Hz), 2.70 (2H, m), 2.55 (2H, t, J=7.8 Hz), 2.13 (2H, s), 1.92 (2H, s), 1.67 (1 H, dd, J=12.3, 3.1 Hz)

Reference： [1]Current Patent Assignee: PFIZER INC - WO2008/15516, 2008, A1 Location in patent: Page/Page column 44

16
[ 881016-89-3 ]
[ 17403-09-7 ]
[ 881016-90-6 ]

Yield	Reaction Conditions	Operation in experiment
27%	With TEA In acetonitrile for 5h; Heating;
27%	With triethylamine In acetonitrile for 5h; Heating / reflux;	5 A solution of Compound 5c (0.335 g, 1.040 mmol), 3-piperidin-4-yl-1H-indole Compound 1f (0.208 g, 1.040 mmol) and TEA (0.29 mL, 2.080 mmol) in CH3CN was refluxed for 5 hrs. The solvent was removed in vacuo to provide a yellow solid. The product was washed with a minimal amount of methanol to removing residual starting material to obtain 4-{carboxy-[4-(1H-indol-3-yl)-piperidin-1-yl]-methyl}-piperidine-1-carboxylic acid tert-butyl ester Compound 5d (27%, 0.459 g) as a white solid. MS m/z 442 (M+H)+.

Reference： [1]Xia, Mingde; Hou, Cuifen; DeMong, Duane E.; Pollack, Scott R.; Pan, Meng; Brackley, James A.; Jain, Nareshkumar; Gerchak, Chrissy; Singer, Monica; Malaviya, Ravi; Matheis, Michele; Olini, Gil; Cavender, Druie; Wachter, Michael [Journal of Medicinal Chemistry, 2007, vol. 50, # 23, p. 5561 - 5563]
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2006/69123, 2006, A1 Location in patent: Page/Page column 83

17
[ 120-72-9 ]
[ 17403-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 63 percent / KOH / methanol / 5 h / 70 °C 2: 100 percent / H₂; HCl / Pd/C / methanol / 1 h / 2250.18 Torr
	Multi-step reaction with 2 steps 1: sodium methylate / methanol 2: palladium 10% on activated carbon; hydrogen / methanol
	Multi-step reaction with 2 steps 1: potassium hydroxide / isopropyl alcohol / 6 h / Reflux 2: acetic acid; palladium 10% on activated carbon; hydrogen / ethyl acetate / 20 °C / 760.05 Torr

	Multi-step reaction with 3 steps 1: potassium hydroxide / methanol / 8 h / 70 °C 2: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 15 h / 25 °C / 760.05 Torr 3: hydrogenchloride / dichloromethane; ethyl acetate / 3 h
	Multi-step reaction with 3 steps 1: potassium hydroxide / methanol / 8 h / 70 °C 2: palladium 10% on activated carbon; hydrogen / methanol; tetrahydrofuran / 15 h / 25 °C / 760.05 Torr 3: hydrogenchloride / dichloromethane; ethyl acetate / 3 h
	Multi-step reaction with 2 steps 1: potassium hydroxide / methanol; water / 8 h / 65 °C 2: hydrogen / 5%-palladium/activated carbon / methanol / 8 h / 1500.15 Torr

Reference： [1]Fonquerna, Silvia; Miralpeix, Montse; Pagès, Lluís; Puig, Carles; Cardús, Arantxa; Antón, Francisca; Cárdenas, Álvaro; Vilella, Dolors; Aparici, Mónica; Calaf, Elena; Prieto, José; Gras, Jordi; Huerta, Josep M.; Warrellow, Graham; Beleta, Jorge; Ryder, Hamish [Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6326 - 6337]
[2]Wróbel, Martyna Z.; Chodkowski, Andrzej; Herold, Franciszek; Gomółka, Anna; Kleps, Jerzy; Mazurek, Aleksander P.; Pluciński, Franciszek; Mazurek, Andrzej; Nowak, Gabriel; Siwek, Agata; Stachowicz, Katarzyna; Sławińska, Anna; Wolak, Małgorzata; Szewczyk, Bernadeta; Satała, Grzegorz; Bojarski, Andrzej J.; Turło, Jadwiga [European Journal of Medicinal Chemistry, 2013, vol. 63, p. 484 - 500]
[3]Santos, Sofia A.; Lukens, Amanda K.; Coelho, Lis; Nogueira, Fátima; Wirth, Dyann F.; Mazitschek, Ralph; Moreira, Rui; Paulo, Alexandra [European Journal of Medicinal Chemistry, 2015, vol. 102, p. 320 - 333]
[4]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN106045966, 2016, A
[5]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN106045967, 2016, A
[6]Current Patent Assignee: MERCEDES-BENZ GROUP AG; FCA (in: Stellantis); STELLANTIS NV - WO2004/43949, 2004, A1

18
[ 41979-39-9 ]
[ 17403-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 63 percent / KOH / methanol / 5 h / 70 °C 2: 100 percent / H₂; HCl / Pd/C / methanol / 1 h / 2250.18 Torr
	Multi-step reaction with 2 steps 1: 32 percent / ammonium acetate / acetic acid; tetrahydrofuran / 336 h / Ambient temperature 2: 71 percent / H₂ / 5percent Pd/C / ethanol / 2327.2 Torr
	Multi-step reaction with 2 steps 1: potassium hydroxide / methanol; water / 8 h / 65 °C 2: hydrogen / 5%-palladium/activated carbon / methanol / 8 h / 1500.15 Torr

Reference： [1]Fonquerna, Silvia; Miralpeix, Montse; Pagès, Lluís; Puig, Carles; Cardús, Arantxa; Antón, Francisca; Cárdenas, Álvaro; Vilella, Dolors; Aparici, Mónica; Calaf, Elena; Prieto, José; Gras, Jordi; Huerta, Josep M.; Warrellow, Graham; Beleta, Jorge; Ryder, Hamish [Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6326 - 6337]
[2]Freter; Fuchs; Barsumian; Oliver [Arzneimittel-Forschung/Drug Research, 1985, vol. 35, # 1 A, p. 272 - 276]
[3]Current Patent Assignee: MERCEDES-BENZ GROUP AG; FCA (in: Stellantis); STELLANTIS NV - WO2004/43949, 2004, A1

19
[ 247915-89-5 ]
[ 17403-09-7 ]
1-(5-fluoro-indol-1-yl)-3-[4-(1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	In methanol for 15h; Heating / reflux;	9 1-(5-Fluoro-indol-1-yl)-3-[4-(1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol Example 9 1-(5-Fluoro-indol-1-yl)-3-[4-(1H-indol-3-yl)-piperidin-1-yl]-propan-2-ol A methanolic solution of 1-N-glycidyl-5-fluoroindole (0.52 g, 3.0 mmole) from example 1 and 3-(4-piperidinyl)indole (0.6 g, 3.0 mmole) was refluxed under nitrogen for 15 hours. The reaction mixture was concentrated in vacuo and the product purified by flash silica gel chromatography (ethyl acetate) to afford the titled compound as an oil (0.599 g, 50% yield). Treatment with a 0.25M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as a white solid. The product was recrystallized twice from ethanol. mp 215-216°C Elemental Analysis for: C24H26FN3O 0.5C4H4O4 0.8CH2Cl2 Calculated: C, 68.65; H, 6.22; N, 9.21 Found: C. 68.44; H, 6.36; N, 9.14 ãã--3ãã

Reference： [1]Current Patent Assignee: PFIZER INC - EP1075471, 2004, B1 Location in patent: Page 7

20
[ 24424-99-5 ]
[ 17403-09-7 ]
[ 155302-28-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In tetrahydrofuran; water; at 60℃; for 27h;	A. 4-(1H-Indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester. A solution of 4-(3-indo)piperidine (compound 2a) (purchased from Tyger Scientific Inc.) (1.0 g, 5 mmol), di-tert-butyl dicarbonate (1.36 g, 6.25 mmol) and K2CO3 (2.19 g, 15.9 mmol) in THF (80 mL) and H2O (40 mL) was stirred at 60 C. for 22 h. Another batch of di-tert-butyl dicarbonate (1.1 g, 5 mmol) and K2CO3 (0.7 g, 5 mmol) was added and the mixture was stirred at 60 C. for another 5 h. After cooling to rt, the two phases were separated and the aqueous phase was extracted with EtOAc, washed with brine and dried over Na2SO4. Removal of solvent gave the product as a white solid 2b. 1H-NMR (400 MHz, CDCl3): δ 8.01 (1H, s), 7.62-7.64 (1H, d), 7.36-7.38 (1H, d), 7.17-7.21 (1H, td), 7.09-7.13 (1H, td), 6.95-6.96 (1H, d), 4.18-4.30 (2H, m), 2.85-3.20 (3H, m), 2.02-2.06 (2H, d), 1.65-1.68 (2H, m), 1.53 (9H, s); LC/MS: C18H24N2O2: m/z 300.7 (M+1).
	With triethylamine; In DMF (N,N-dimethyl-formamide); dichloromethane; at 0℃; for 2.5h;	DMF (500ml), 3- (4-piperidinyl)-lH-indole (50g) and triethylamine (45. 5ml) were combined. A solution of di-tert-butyl dicarbonate (71g) in methylene chloride (70ml) was dropwise added to the reaction mixture in ice bath. After that, the reaction mixture was stirred for 2.5h. The mixture was poured into ice water (1500ml) and the mixture was stirred for lh. Sodium chloride was added to the mixture and the mixture was stirred for 30 min. The crystalline precipitate was collected by filtration and washed with water and the solution of IPE and hexane (1 : 1). The residue was dried in vacuo to give tert-butyl 4-(lH-indol-3-yl)-l-piperidinecarboxylate (74.32g). tert-butyl 4- (lH-indol-3-yl)-l-piperidinecarboxylate (74.32g). mp: 159-160C
	In tetrahydrofuran; at 20℃;	Example 192 43.1 tert-butyl 4-(1H-indol-3-yl)-piperidine-1-carboxylate 10 g 3-piperidin-4-yl-1H-indole are placed in 300 mL THF and 10.9 g di-tert-butyl-dicarbonate are added. The reaction mixture is stirred overnight at ambient temperature and evaporated to dryness. The residue is mixed with water and the product is extracted with diethyl ether and purified by chromatography. 9 g of the product are obtained as a solid.

9 g

In tetrahydrofuran; at 20℃;

26.1 tert.butyl 4-(1H-indol-3-yl)-piperidine-1-carboxylate 10 g 3-piperidin-4-yl-1H-indole are placed in 300 mL THF and 10.9 g di-tert-butyl-dicarbonate are added. The reaction mixture is stirred overnight at ambient temperature and evaporated to dryness. The residue is mixed with water and the product is extracted with diethyl ether and purified by chromatography. 9 g of the product are obtained as a solid.

Reference： [1]Patent: US2009/318498,2009,A1 .Location in patent: Page/Page column 11-12
[2]Patent: WO2005/56012,2005,A1 .Location in patent: Page/Page column 44-45
[3]Patent: US2011/21501,2011,A1 .Location in patent: Page/Page column 82
[4]Patent: US2013/225609,2013,A1 .Location in patent: Paragraph 0384; 0385

21
[ 109-64-8 ]
[ 17403-09-7 ]
3-(1-(3-(4-indol-3-ylpiperidyl)propyl)-4-piperidyl)indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 4h;	17 3-(1-(3-(4-Indol-3-ylpiperidyl)propyl)-4-piperidyl)indole Hydrochloride Example 17 3-(1-(3-(4-Indol-3-ylpiperidyl)propyl)-4-piperidyl)indole Hydrochloride To a suspended solution of 4-(3-indolyl)piperidine (165 mg, 0.82 mmol) and 1,3-dibromopropane (76 mg, 0.37 mmol) in DMF (6 mL) was added potassium carbonate (216 mg, 1.6 mmol), and the resulting mixture was stirred at 80° C. for 4 hours. After the precipitated salt was filtered off, and the filtrate was then concentrated, water (20 mL) was added to the filtrate and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated, and the resulting crude crystals were recrystallized from ethanol to afford a free form (107 mg, yield: 66%) of the title compound as pale yellow crystals. After adding hydrochloric acid/methanol to a solution of the free form (98 mg) in chloroform, the mixture was concentrated and was then recrystallized from methanol/ether to afford the title compound (103 mg) as pale red crystals.

Reference： [1]Current Patent Assignee: TORAY INDUSTRIES INC - US6642228, 2003, B1 Location in patent: Page/Page column 83-84

22
[ 5407-04-5 ]
[ 17403-09-7 ]
(3-(4-indol-3-ylpiperidinyl)propyl)dimethylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; sodium iodide In acetonitrile for 5h; Heating / reflux;	4 (3-(4-Indol-3-ylpiperidyl)propyl)dimethylamine Hydrochloride Example 4 (3-(4-Indol-3-ylpiperidyl)propyl)dimethylamine Hydrochloride To a suspended solution of 4-(3-indolyl)piperidine (1.0 g, 5.0 mmol) and a 96% 3-dimethylaminopropyl chloride hydrochloride (0.91 g, 5.5 mmol) in acetonitrile (50 mL) was added potassium carbonate (2.07 g, 15 mmol) and sodium iodide (0.82 g, 5.5 mmol), and the resulting mixture was refluxed for 5 hours. After the precipitated salt was filtered off, the filtrate was concentrated, and water (40 mL) was added to the filtrate and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated, and the resulting crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; ethyl acetate) to afford a free form (1.2 g) of the title compound as pale red crystals. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then recrystallized from methanol/ether to afford the title compound (1.2 g, yield: 69%) as pale yellow crystals.

Reference： [1]Current Patent Assignee: TORAY INDUSTRIES INC - US6642228, 2003, B1 Location in patent: Page/Page column 80

23
[ 314083-23-3 ]
[ 17403-09-7 ]
1-(1-(3-(4-indol-3-ylpiperidinyl)propyl)-3-piperidyl)-4-methoxybenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile for 12h; Heating / reflux;	2 1-(1-(3-(4-Indol-3-ylpiperidyl)propyl)-3-piperidyl)-4-methoxybenzene Hydrochloride Example 2 1-(1-(3-(4-Indol-3-ylpiperidyl)propyl)-3-piperidyl)-4-methoxybenzene Hydrochloride To a suspended solution of 4-(3-indolyl)piperidine (48 mg, 0.24 mmol) and 1-(3-chloropropyl)-3-(4-methoxyphenyl)piperidine hydrochloride (61 mg, 0.2 mmol) in acetonitrile (13 mL) was added potassium carbonate (111 mg, 0.8 mmol), and the resulting mixture was refluxed for 12 hours. After the precipitated salt was filtered off, the filtrate was concentrated, and the resulting crude product was purified by column chromatography on a silica gel (eluent; chloroform:ammonia-saturated chloroform=10:1→3:1→1:2) to afford a free form (92 mg) of the title compound as a colorless viscous oil. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then freeze-dried to afford the title compound (81 mg, yield: 80%) as a white amorphous solid.

Reference： [1]Current Patent Assignee: TORAY INDUSTRIES INC - US6642228, 2003, B1 Location in patent: Page/Page column 79

24
[ 365413-00-9 ]
[ 17403-09-7 ]
4-{4-[4-(1H-indol-3-yl)-piperidin-1-carbonyl]-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h;	4-(4-Carboxy-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1 eq) was dissolved under inert conditions in dry dimethylacetamide (0.03 mmol/ml). To this solution aryl- or alkylamine (1 eq), diisopropylethylamine (2 eq) and O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (2 eq) was added. The reaction mixture was stirred for 12 h at r.t. The solvent was removed in vacuo and the residue was dissolved in ethylacetate. The organic layer was extracted 3 times with 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with brine, dried over, MgSO4 and filtred. The solvent was removed and the residue was purified by silica gel chromatography using a DCM/MeOH 95:5 gradient. Yield; 40-80%

Reference： [1]Current Patent Assignee: BIONTECH AG - US2006/69102, 2006, A1 Location in patent: Page/Page column 17

25
1-(3-chloropropyl)-4-phenyl-piperidine hydrochloride [ No CAS ]
[ 17403-09-7 ]
3-(1-(3-(4-phenylpiperidinyl)propyl)-4-piperidyl)indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 4h;	1 3-(1-(3-(4-Phenylpiperidyl)propyl)-4-piperidyl)indole Hydrochloride Example 1 3-(1-(3-(4-Phenylpiperidyl)propyl)-4-piperidyl)indole Hydrochloride To a suspended solution of 4-(3-indolyl)piperidine (2.0 g, 10 mmol) and 1-(3-chloropropyl)-4-phenylpiperidine hydrochloride (3.1 g, 11.2 mmol) in DMF (60 mL) was added potassium carbonate (5.5 g, 40 mmol), and the mixture was stirred at 100° C. for 4 hours. After the precipitated salt was filtered off, the filtrate was concentrated, water (50 mL) was added to the filtrate, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the chloroform layer was concentrated to afford a crude product. The crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform) and was then recrystallized from ethyl acetate to afford a free form (1.6 g, yield: 40%) of the title compound as white crystals. After adding hydrochloric acid/methanol to a solution of the free form (1.6 g) in methanol, the mixture was concentrated and was then recrystallized from methanol/ether to afford the title compound (1.8 g) as white crystals.

Reference： [1]Current Patent Assignee: TORAY INDUSTRIES INC - US6642228, 2003, B1 Location in patent: Page/Page column 79

26
[ 881016-09-7 ]
[ 17403-09-7 ]
[4-(1H-indol-3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With triethylamine In acetonitrile for 5h; Heating / reflux;	1 To a solution of Compound 1e (0.26 g, 0.64 mmol) in acetonitrile (10 mL) was added 3-piperidin-4-yl-1H-indole Compound 1f (152 mg, 0.64 mmol) and TEA (0.18 mL, 1.29 mmol). The resulting reaction mixture was refluxed for 5 hrs, then concentrated and cooled to provide a white precipitate. The precipitate was washed with EtOAc and water to give Compound 6 (0.23 g, 67%) as a racemate. MS m/z 526 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ 12.11 (br s, 1H), 10.85 (s, 1H), 7.81 (q, J=7.2 Hz, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.37 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.04 (m, 2H), 6.95 (q, J=7.0 Hz, 1H), 4.47 (m, 1H), 4.31 (m, 1H), 3.10 (m, 1H), 2.96 (d, J=10.8 Hz, 1H), 2.88 (m, 2H), 2.65 (m, 3H), 2.35 (m, 1H), 2.06 (m, 1H), 1.94 (m, 1H), 1.61 (m, 2H), 1.09 (m, 2H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2006/69123, 2006, A1 Location in patent: Page/Page column 77

27
[ 881016-80-4 ]
[ 17403-09-7 ]
[4-(1H-indol-3-yl)-piperidin-1-yl]-{1-[(2E)-3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With triethylamine In acetonitrile for 48h; Heating / reflux;	3 [4-(1H-indol-3-yl)-piperidin-1-yl]-{1-[(2E)-3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid methyl ester (Cpd 87) EXAMPLE 3 [4-(1H-indol-3-yl)-piperidin-1-yl]-{1-[(2E)-3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid methyl ester (Cpd 87) The procedure of Example 1 and piperidin-4-yl-acetic acid methyl ester was used in place of piperidin-4-yl-acetic acid ethyl ester Compound 1f to provide bromo-{1-[(2E)3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid methyl ester Compound 3a. 3-piperidin-4-yl-1H-indole Compound 1f (1.0 g, 5.0 mmol) and TEA (0.6 g, 5.9 mmol) were added to a solution of Compound 3a (2.1 g, 5.0 mmol) in acetonitrile (70 mL). The mixture was refluxed for 48 hrs and then concentrated in vacuo. The residue was chromatographed (5% CH3OH/CHCl3) to give Compound 87 (1.5 g, 56%). MS m/z 540 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 7.98 (br s, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.48 (d, J=15.4 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.10 (m, 4H), 6.96 (br s, 1H), 6.81 (m, 1H), 4.69 (m, 1H), 4.08 (m, 1H), 3.76 (s, 3H), 3.13 (m, 1H), 2.93 (m, 2H), 2.82 (m, 3H), 2.59 (m, 1H), 2.29 (m, 1H), 2.08 (m, 4H), 1.79 (m, 1H), 1.65 (m, 2H), 1.21 (m, 2H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2006/69123, 2006, A1 Location in patent: Page/Page column 80-81

28
[ 881016-85-9 ]
[ 17403-09-7 ]
2-[4-(1H-indol-3-yl)-piperidin-1-yl]-2-{1-[(2E)-3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With triethylamine In N,N-dimethyl-formamide for 4h; Heating / reflux;	4 To a solution of Compound 4a (25 mg, 0.065 mmol) in DMF (4 mL) was added 3-piperidin-4-yl-1H-indole Compound 1f (13 mg, 0.065 mmol) and TEA (0.05 mL, 0.36 mmol). The reaction mixture was refluxed for 4 hrs and then concentrated in vacuo. The residue was purified using preparative TLC (70% CH3CO2Et/hexane) to give Compound 107 (8 mg, 25%). MS m/z 525 (M+H)+; 1H NMR (CD3OD, 300 MHz) δ: 7.38-7.61 (m, 5H), 7.18-7.31 (m, 2H), 6.92-7.10 (m, 4H), 4.62 (m, 1H), 4.39 (m, 1H), 4.12 (m, 1H), 3.79 (m, 1H), 3.10-3.40 (m, 4H), 2.79 (m, 1H), 2.61 (m, 1H), 2.08-2.39 (m, 4H), 1.81 (m, 2H), 1.25-1.49 (m, 2H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2006/69123, 2006, A1 Location in patent: Page/Page column 82

29
[ 881017-93-2 ]
[ 17403-09-7 ]
4-{ethoxycarbonyl-[4-(1H-indol-3-yl)-piperidin-1-yl]-methyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With N-ethyl-N,N-diisopropylamine In acetonitrile for 48h; Heating / reflux;	9 Compound 9b (7.25 g, 20.7 mmol, 1 eq), 3-piperidin-4-yl-1H-indole Compound 1f (4.14 g, 20.7 mmol, 1 eq) and diisopropylethylamine (10.8 mL, 62.1 mmol, 3 eq) were added to MeCN (60 mL) and the resulting solution was heated at reflux for 48 hrs. The reaction was then cooled to room temperature to precipitate unreacted Compound 1f from the solution. The precipitate was removed by filtration and the filtrate evaporated. Silica gel chromatography (3:2:1 to 3:1.5:1 CH2Cl2:hexanes:EtOAc) provided 4-{ethoxycarbonyl-[4-(1H-indol-3-yl)-piperidin-1-yl]-methyl}-piperidine-1-carboxylic acid tert-butyl ester Compound 9c (4.73 g, 49%) as a pale foam. MS: m/z 470 (M+H)+, 492 (M+Na)+.
	With N-ethyl-N,N-diisopropylamine In acetonitrile Reflux;

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2006/69123, 2006, A1 Location in patent: Page/Page column 88
[2]Location in patent: scheme or table Xia, Mingde; Hou, Cuifen; DeMong, Duane; Pollack, Scott; Pan, Meng; Brackley, James; Singer, Monica; Matheis, Michele; Cavender, Druie; Wachter, Michael [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 12, p. 3562 - 3564]

30
C₁₃H₁₃NO₅ [ No CAS ]
[ 17403-09-7 ]
C₂₆H₂₉N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	With sodium cyanoborohydride In tetrahydrofuran; acetic acid at 20℃; for 16h;	B2 A mixture of intermediate compound 5 (prepared according to A3) (0.00095 mol), 3- (4-piperidinyl)-lH-indol (0.00085 mol) and sodium cyanoborohydride (0.00142 mol) in TΗ;F/AcOΗ; (8/2) (10 ml) was stirred for 16 hours at room temperature, then the reaction mixture was diluted with CΗ;2CI2 and extracted with a 10 % aqueous citric acid solution. The aqueous layer was alkalised with a saturated. Na2CO3 solution and extracted with CH2Cl2. The organic layer was separated, dried (Na2SO4), filtered off and the solvent was evaporated. The residue was purified by CC-LC on Chromatotron (eluent gradient: CH2C12/(CH3OH/NH3) 98/2, 97/3, 96/4). The product fractions were collected and the solvent was evaporated. The residue was crystallised from CH2C12/DIPE, then the resulting precipitate was filtered off and dried. Yield: 0.035 g of final compound 54 (8%; (3α;, 3aα;) racemic mixture)).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2006/56600, 2006, A1 Location in patent: Page/Page column 30

31
[ 76315-65-6 ]
[ 17403-09-7 ]
C₂₄H₂₆N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With sodium carbonate In 4-methyl-2-pentanone for 24h; Heating / reflux;	B3 A mixture of l-(3-chloropropyl)- 2,4(lNo.,3,H)-quinazo]inedione (0.015 mol), 3-(4-piperidinyl)- l/f-indole (0.015 mol) and sodium carbonate (0.030 mol) in 4-methyl-2-pentanone (150 ml) was stirred and refluxed for 24 hours, then the reaction mixture wascooled and water was added. The separated organic layer was dried and the solvent wasevaporated. The residue was purified by column chromatography over silica gel(eluent: CHC13/CH3OH 95/5). The product fractions were collected and the solvent wasevaporated. The residue was crystallised from EtOH and the resulting precipitate wascollected, yielding 2 g (33 %) of compound 3, melting point 216.8°C.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2006/3148, 2006, A1 Location in patent: Page/Page column 22

32
[ 17229-14-0 ]
[ 459-46-1 ]
[ 17403-09-7 ]
(2-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		EXAMPLE 37 Preparation of (2-{4-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-acetic acid The procedure described in Example 1 was performed using 0.2 g (1 mmol) of 3-piperidin-4-yl-1H-indole and 0.18 g (1.1 mmol) of <strong>[17229-14-0](2-chloro-ethoxy)-acetic acid ethyl ester</strong>. 0.06 g (0.18 mmol) of the crude, obtained as in step D, were then alkylated with 0.03 mL (0.27 mmol) of 4-fluorobenzyl bromide affording 0.059 g (80% yield) of (2-{4-[1-(4-fluoro -benzyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-acetic acid. ESI/MS m/e=411 [(M+1)+, C24 H27 F N2 O3] NMR (300 MHz, CDCl3) d=2.25-2.40 (m, 4H), 2.96-3.10 (m, 5H), 3.58-3.63 (m, 2H), 3.87-3.91 (t, 2H), 4.07 (s, 2H), 5.24 (s, 2H), 6.97-7.28 (m, 8H), 7.57-7.60 (d, 1H)

Reference： [1]Patent: US2002/147344,2002,A1

33
[ 17229-14-0 ]
[ 54149-17-6 ]
[ 17403-09-7 ]
[2-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-ethoxy]-acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		EXAMPLE 36 Preparation of [2-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-ethoxy]-acetic acid The procedure described in Example 1 was performed using 0.2 g (1 mmol) of 3-piperidin-4-yl-1H-indole and 0.18 g (1.1 mmol) of <strong>[17229-14-0](2-chloro-ethoxy)-acetic acid ethyl ester</strong>. 0.06 g (0.18 mmol) of the crude, obtained as in step D, were then alkylated with 0.03 mL (0.27 mmol) of 1-bromo-2-(2-methoxy-ethoxy)-ethane affording 0.056 g (77% yield) of [2-(4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-3-yl}-piperidin-1-yl)-ethoxy]-acetic acid. ESI/MS m/e=405 [(M+1)+, C22 H32 N2 O5] NMR (300 MHz, CDCl3) d=2.05-2.40 (m, 4H), 2.89-3.05 (m, 5H), 3.36 (s, 3H), 3.47-3.57 (m, 4H), 3.67-3.81 (m, 4H), 3.87-3.91 (t, 2H), 4.10 (s, 2H), 4.24-4.28 (t, 2H), 7.02-7.27 (m, 3H), 7.35-7.37 (d, 1H), 7.56-7.58 (d, 1H)

Reference： [1]Patent: US2002/147344,2002,A1

34
[ 628-17-1 ]
[ 17229-14-0 ]
[ 17403-09-7 ]
{2-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%		EXAMPLE 38 Preparation of {2-[4-(1-pentyl-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-acetic acid The procedure described in Example 1 was performed using 0.2 g (1 mmol) of 3-piperidin-4-yl-1H-indole and 0.18 g (1.1 mmol) of <strong>[17229-14-0](2-chloro-ethoxy)-acetic acid ethyl ester</strong>. 0.06 g (0.18 mmol) of the crude, obtained as in step D, were then alkylated with 0.03 mL (0.27 mmol) of pentyl iodide affording 0.047 g (74% yield) of {2-[4-(1-pentyl-1H-indol-3 -yl)-piperidin-1-yl]-ethoxy}-acetic acid. ESI/MS m/e=373 [(M+1)+, C22 H32 N2 O3] NMR (300 MHz, CDCl3) d=0.87-0.91 (t, 3H), 1.28-1.36 (m, 4H), 1.79-1.84 (m, 2H), 2.21-2.32 (m, 4H), 2.89-2.96 (m, 2H), 3.04-3.07 (m, 3H), 3.55-3.59 (d, 2H), 3.88-3.92 (t, 2H), 4.02-4.07 (t, 2H), 4.11 (s, 2H), 4.40-4.80 (bs, 1H), 6.97-7.34 (m, 4H), 7.56-7.58 (d, 1H)

Reference： [1]Patent: US2002/147344,2002,A1

35
polystyrene methyl isocyanate [ No CAS ]
[ 312631-02-0 ]
[ 17403-09-7 ]
[ 312631-03-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium iodide; ammonia; potassium carbonate In methanol; dichloromethane; 4-methyl-2-pentanone	1.D D. D. Preparation of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester 0.22 g (0.5 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester were added to a mixture of 0.1 g (0.5 mmol) of 3-piperidin-4-yl-1H-indole, 0.08 g (0.6 mmol) of potassium carbonate and 0.04 g (0.2 mmol) of potassium iodide in 1.5 mL of isobutyl methyl ketone under nitrogen atmosphere and the reaction mixture was refluxed for 18 hours. After cooling at room temperature 1.5 mL of dichloromethane and 0.08 g (0.1 mmol) of polystyrene methyl isocyanate were added and the mixture was stirred at this temperature for 3 hours. After filtering, the solution was placed directly on a 500 mg Varian SCX ion exchange column. The columns were washed with 5 mL of methanol and the product was eluted with 5 mL of methanol/ammonia 20:1 affording, after removal of the solvent at reduced pressure, 0.113 g (60% yield) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester as a yellow oil.

Reference： [1]Current Patent Assignee: ALMIRALL SA - US2002/147344, 2002, A1

36
4-(2-chloro-ethoxy)-benzoic acid tert-butyl ester [ No CAS ]
[ 17403-09-7 ]
4-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid [ No CAS ]
4-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With potassium iodide; potassium carbonate In 4-methyl-2-pentanone	137.B B. B. Preparation of 4-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid 4-(2-{4-[1-(2-ethoxy-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid was prepared using the general procedure described in Example 1 (part D), starting with 0.1 g (0.5 mmol) of 3-piperidin-4-yl-1H-indole, 0.26 g (0.5 mmol) of 4-(2-chloro-ethoxy)-benzoic acid tert-butyl ester, 0.08 g (0.6 mmol) of potassium carbonate and 0.04 g (0.2 mmol) of potassium iodide in 1.5 mL of isobutyl methyl ketone for the first alkylation step affording 0.09 g (44% yield) of 4-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid.

Reference： [1]Current Patent Assignee: ALMIRALL SA - US2002/147344, 2002, A1

37
ethyl chloroformiate [ No CAS ]
[ 17403-09-7 ]
[ 312631-12-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine In dichloromethane; water	157.A A. A. Preparation of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester 17 mL (0.18 mol) of ethyl chloroformiate were added to a suspension of 30 g (0.15 mol) of 4-(3-indolyl)-piperidine and 28 mL (0.18 mol) of triethylamine in 185 mL of dichloromethane, keeping the temperature between 20 and 25° C. The mixture was stirred at room temperature for 2 hours and 150 mL of water were added. The organic layer was separated and the solvent was removed under reduced pressure affording 36 g (88% of yield)of the desired product.

Reference： [1]Current Patent Assignee: ALMIRALL SA - US2002/147344, 2002, A1

38
[ 90097-61-3 ]
[ 17403-09-7 ]
4-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-(1H)-quinolinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In <i>N</i>-methyl-acetamide	1.A Example 1 A. Preparation of 4-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-(1H)-quinolinone (III-2) A suspension of 4-(2-bromethyl)-2-(1H)-quinolinone (II-2) (500 mg, 1.98 mmol), 3-(4-piperidinyl)-1H-indole (396.5 mg, 1.98 mmol) and sodium hydrogencarbonate (249.5 mg, 2.97 mmol) in dry dimethylformamide (5 ml) was react at 80 ° C. for 5 hours. The reaction mixture was poured into ice-water and the separated solid was filtered by aspiration. The residue was washed with water and recrystallized from methanol/tetrahydrofuran/water to give the desired product (336 mg) (III-2) as pale yellow crystals (mp 259°-260 ° C. (methanol/tetrahydrofuran/water)).