Name: 13916-99-9|4-Fluoro-1-naphthonitrile|97%
Brand: Ambeed
SKU: A562260
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1
[ 13916-99-9 ]
[ 573-03-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; acetic acid

Reference： [1]Adcock,W.; Dewar,M.J.S. [Journal of the American Chemical Society, 1967, vol. 89, p. 386 - 390]

2
[ 341-41-3 ]
[ 544-92-3 ]
[ 13916-99-9 ]

Reference： [1]Journal of the American Chemical Society,1967,vol. 89,p. 386 - 390

3
[ 13916-99-9 ]
[ 3367-95-1 ]
1-(4-cyanonaphthalen-1-yl)piperidine-3-carboxylic acid diethylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine at 220℃; for 0.166667h; microwave irradiation;	A solution of 1-cyano-4-fluoronaphthalene in pyridine (0.6 M, 1 mL) was transferred to a Pyrex tube and N, N-diethylnipecotamide (447 mg, 2.4 mmol) was added. The tube was capped and the reaction tube was exposed to microwave irradiation (220 °C, 10 min). The reaction mixture was concentrated and purified according to Purification Method A. [0178] LCMS m/z 336 [M+H]+. HPLC tR = 9.0 min (method I). 'H-NMR (CD30D, 400 MHz) No. 8.15 (d, J = 8.2, 1H), 8.00 (d, J = 8.2, 1H), 7.77 (d, J = 7.8, 1H), 7.60-7.52 (m, 2H), 7.05 (d, J= 7.8, 1H), 3.60-3.36 (m, 4H), 3.36-3.21 (m, 1H), 3.21-3.10 (m, 1H), 3.03-2.92 (m, 1H), 2.78-2.65 (m, 1H), 2.08-1.83 (m, 4H), 1.78-1.60 (m, 1H), 1.30- 1.16 (m, 3H), 1.07 (t, J = 7.04,3H). ¹3C-NMR (CD30D, 100 MHz) 173.9,155.1, 133,7, 133.6,128.4, 128.1,126.6, 125.1,124.5, 118.1,114.1, 103.6,56.1, 53.7, 42.3, 40.4,39.9, 27.8, 25.0, 14.2, 12.2. Purification Method A [0179] The concentrated crude material was taken up in ethyl acetate and extracted with 2 M HCI. The organic phase was then dried over Na2S04, filtered and concentrated in vacuo.

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 51-52

4
[ 13916-99-9 ]
[ 23356-96-9 ]
4-((S)-2-hydroxymethylpyrrolidin-1-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	In toluene at 180℃; for 0.0833333h; microwave irradiation;	1-Cyano-4-fluoronaphthalene (86 mg, 0.5 mmol) was transferred to a Pyrex tube and L-prolinol (197 µL, 2.0 mmol) was added followed by toluene (0.5 mL). The tube was capped and the reaction tube was exposed to microwave irradiation (180 °C, 5 min). The reaction mixture was concentrated and purified by flash chromatography on silica gel (eluent: 0-3% methanol in dichloromethane). Yield: 23 mg (18%). [0203] LCMS m/z 253 [M+H]+. HPLC tR = 7.3 min (method I). ¹H-NMR (CD30D, 400 MHz) 8 8.30 (d, J= 8.6, 1H), 8.08-8.05 (m, 1H), 7.80 (d, J= 8.2, 1H), 7.67- 7.63 (m, 1H), 7.56-7.51 (m, 1H), 7.07 (d, J = 8.2, 1H), 4.21-4.15 (m, 1H), 4.10-4.00 (m, 1H), 3.68-3.64 (m, 1H), 3.55-3.50 (m, 1H), 3.36-3.30 (m, 1H), 2.40-2.29 (m, 1H), 2.10- 1.98 (m, 2H), 1.90-1.71 (m, 1H). ¹3C-NMR (CD30D, 100 MHz) No. 153.5,135.7, 134,6, 129.3, 128.6, 127.4, 126.1, 125.9, 120.1, 111.5, 100.4, 63.8, 62.4, 57.6, 30.2, 26.1.

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 55

5
[ 123-75-1 ]
[ 13916-99-9 ]
4-pyrrolidin-1-ylnaphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	for 0.25h;	1-Cyano-4-fluoronaphthalene (2.0 g, 11.7 mmol) was transferred to a 25 mL flask and pyrrolidine (4.0 mL) was added. The reaction mixture was stirred for 15 min where after the product precipitated out. The reaction mixture was concentrated in vacuo. The solid was then re-crystallized with MeOH and the crystals washed with EtOH. Yield: 1.6 g (62%). [0205] LCMS m/z 223 [M+H]+. HPLC tR = 9.7 min (method I). ¹H-NMR (CD30D, 400 MHz) No. 8.38-8.35 (m, 1H), 8.05-8.02 (m, 1H), 7.75 (d, J = 8.2, 1H), 7.64- 7.60 (m, 1H), 7.51-7.45 (m, 1H), 6.80 (d, J= 8.2, 1H), 3.65-3.61 (m, 4H), 2.07-2.03 (m, 4H). ¹3C-NMR (CD30D, 100 MHz) No. 152.6,135.2, 134.1,128.2, 126.6,125.8, 125.0, 124.6, 119.6, 108.0, 97.4, 53.0, 25.9.
62%	for 0.25h;

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 55-56
[2]Schlienger, Nathalie; Lund, Birgitte W.; Pawlas, Jan; Badalassi, Fabrizio; Bertozzi, Fabio; Lewinsky, Rasmus; Fejzic, Alma; Thygesen, Mikkel B.; Tabatabaei, Ali; Bradley, Stefania Risso; Gardell, Luis R.; Piu, Fabrice; Olsson, Roger [Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7186 - 7191]

6
8-azabicyclo[3.2.1]octan-(3-exo)-ol [ No CAS ]
[ 13916-99-9 ]
4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With pyridine at 220℃; for 0.0833333h; microwave irradiation;	1-Cyano-4-fluoronapthalene (104 mg, 0.6 mmol), nortropanol (305 mg, 2.4 mmol) and pyridine (93 µL, 0.6 mmol) were transferred to a Pyrex tube. The tube was capped and the reaction tube was exposed to microwave irradiation (220 °C, 5 min). The mixture was transferred to a separation funnel with ethyl acetate and with 2 M HCI and the organic phases were then washed with brine. The organic layer was collected, dried over Na2S04, filtered and concentrated to yield 157 mg (92%) of the title compound. [0213] LCMS m/z 279 [M+H]+. HPLC tR = 6.8 min (method I). (at)H-NMR (CDC13, 400 MHz) 8 8.21-8.16 (m, 2H), 7.75 (d, J= 8.0, 1H), 7.66-7.62 (m, 1H), 7.56-7.52 (m, 1H), 6.90 (d, J= 8.0, 1H), 4.32 (t, J= 5.1, 1H), 4.14-4.11 (m, 2H), 2.51-2.45 (m, 2H), 2.34-2.28 (m, 2H), 2.02-1.96 (m, 4H). ¹3C-NMR (CDCl3,100 MHz) 8 153.1, 134.5, 133,7, 128.4, 127.9, 126.0, 125.9, 125.4, 119.1, 111.0, 102.0, 65.2, 60.1, 40.7, 27.4.

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 57

7
N-nortropine [ No CAS ]
[ 13916-99-9 ]
4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: N-nortropine; 4-fluoronaphthalene-1-carbonitrile In pyridine for 20h; Heating / reflux; Stage #2: With hydrogenchloride In pyridine; water	Alternatively, 154BG31 was prepared by the following procedure: 1- Cyano-4-fluoronaphthalene (20.0 g, 117 mmol) was dissolved in pyridine (100 mL). A solution of nortropine (59.4 g, 467 mmol) in pyridine (100 mL) was added, and the reaction mixture was heated to reflux for 20 hours. The resulting black solution was concentrated, and water (800 mL) was added. The pH was adjusted to 1 by addition of 2 M HCI. The product was extracted into dichloromethane (2 x 800 mL), and the combined organic phases were washed with 0.5 M NaOH (400 mL), dried over sodium sulfate, filtered and evaporated. The crude product was dissolved in hot ethyl acetate (200 mL), and crystallization occurred upon cooling to rt. Crystallization was continued at 5 °C for 20 hours. Filtration afforded a first crop of the title compound (21.2 g, 65% yield) as a white solid. The mother liquors contained more product (as shown by LC-MS), but re- crystallization of the mother liquors was not pursued further.

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 57-58

8
[ 473541-96-7 ]
[ 13916-99-9 ]
4-(3,4-dihydroxypyrrolidin-1-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%	In N,N-dimethyl-formamide at 20℃; for 48h;	1-Boc-3,4-pyrrolidindiol (178 mg, 0.88 mmol) was stirred in a 2 M solution of hydrochloride acid in diethyl ether (3 mL). After 2 hours stirring at rt hydrochloride form of 3,4-pyrrolidindiol was isolated from the mixture by filtration. The product was dissolved in methanol and left on standing overnight with PS-trisamine resin (3.38 mmol/g, 0.5 g). The resin was removed by filtration and the solution was concentrated in vacuo affording 3,4-pyrrolidindiol as colourless oil. This material was dissolved in DMF (3 mL) and 1-cyano-4-fluoronaphthalene (66 mg, 0.39 mmol) was added to the solution. After 48 hour stirring at rt the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a stepwise gradient of 5-10 % methanol in dichloromethane, afforded the desired compound (14 mg, 14%). [0272] Rf = 0.38 (MeOH/CH2C12 10: 90). LCMS m/z 255 [M+H]+. HPLC tR = 2.13 min (method III). ¹H NMR (CDC13, 300 MHz) 6 8.21-8.12 (m, 2H, Ar-H), 7.69 (d, 1H, J = 8.0, Ar-H), 7.60 (m, 1H, Ar-H), 7.49 (m, 1H, Ar-H), 6.68 (d, 1H, J = 8.0, Ar-H), 4.50-4.41 (m, 2H, pyrrolidine-H), 3.94-3.80 (m, 2H, pyrrolidine-H), 3.72-3.51 (m, 2H, pyrrolidine-H), 2.88 (broad s, 2H, OH).

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 68-69

9
[ 13916-99-9 ]
[ 113451-59-5 ]
(1S,4S)-5-(4-cyanonaphthalen-1-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene at 60℃; for 40h;	1-Cyano-4-fluoronaphthalene (50 mg, 0.29 mmol) and t-butyl(1S,4S)-(- )-2,5-diazobicyclo- [2.2.1]heptane-2-carboxylate (86 mg, 0.44 mmol) was dissolved in pyridine (1 mL). DBU (18 µL, 0.12 mmol) was added and the mixture was shaken in a vial at 60 °C for 40 hours. After cooling to rt hydrochloric acid (1 M, 10 mL) was added and the mixture was extracted with dichloromethane (3 x 5 mL). The combined organic layers was washed with sodium hydrogen carbonate, dried over sodium sulfate and evaporated to dryness. The solid was purified by column chromatography on silica gel using ethyl acetate/n-heptane (1:1) giving a white solid (42 mg, 41 %). [0280] Rf = 0.40 (EtOAc/n-heptane 1:1). LCMS m/z 350 [M+H]+. HPLC tR = 12.4 min (method III). ¹H-NMR (CDC13, 300 MHz) No. 8.09 (d, 1H, J= 7.9 Hz, Ar-H), 8.01 (d, 1H, J = 7.9 Hz, Ar-H), 7.65 (d, 1 H, J = 7.9 Hz, Ar-H), 7.54 (m, 1H, Ar-H), 7.39 (m, 1H, Ar-H), 6.65 (d, 1H, J= 7.9 Hz, Ar-H), 4.60-4.48 (m, 2H, pip-H), 3.92-3.39 (m, 4H, pip-H), 2.01-1.82 (m, 2H, pip-H), 1.36 (s, 9H, CH3 t-butyl).

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 70-71

10
[ 40807-61-2 ]
[ 13916-99-9 ]
4-(4-hydroxy-4-phenylpiperidin-1-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With pyridine at 110℃; for 72h;	1-Cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) was dissolved in pyridine (1 mL). 4-Hydroxy-4-phenylpiperidine (83 mg, 0.467 mmol) was added and the reaction mixture was shaken at 110 °C for 3 days in a sealed vial. The reaction mixture was concentrated and re-suspended in 2 M HCl (1 mL). The product mixture was extracted with ethyl acetate (2 x 1 mL), and the combined organic phases were concentrated. The residue was purified by preparative reversed phase HPLC to give the title compound (14 mg, 36% yield) as a white solid. [0329] LCMS m/z 329 [M+H]+.

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 82

11
[ 252723-22-1 ]
[ 13916-99-9 ]
4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With pyridine In N,N-dimethyl-formamide at 100℃;	A solution of methyl magnesium bromide in diethyl ether (3 M, 3.7 mL, 11.09 mmol) was diluted with anhydrous THF (5 mL). Lithium bromide (1.93 g, 22.1 mmol) was slowly added to the solution at rt, followed by addition of a solution of Boc- nortropinone (500 mg, 2.21 mmol) in anhydrous THF (5 mL). The reaction mixture was stirred at 50 °C for 2 hours and stirring was continued overnight at rt. The reaction was quenched with water and the mixture partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a mixture of ethyl acetate and n-heptane (50: 50), afforded 3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (168 mg, 31%). The obtained product was dissolved in 2 M HCl in diethyl ether (5 mL). After 4 hours stirring at rt the mixture was left on standing overnight. The formed participate, 3-methyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride, was isolated by filtration and dissolved in a mixture of dichloromethane and methanol (90:10). PS-Trisamine was added to the solution and it was left standing overnight. The resin was removed by filtration and washed with dichloromethane. The filtrate was evaporated to dryness affording pure 3-methyl-8-azabicyclo[3.2.1]octan-3-ol. 1-Cyano-4- fluoronaphthalene (37.1 mg, 0.22 mmol) was added to a solution of 3-methyl-8- azabicyclo [3.2.1]octan-3-ol (91 mg, 0.64 mmol) in DMF (1 mL), followed by addition of pyridine (1 mL). The reaction mixture was stirred overnight at 100 °C, cooled down to rt and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with a mixture of ethyl acetate and n-heptane (50: 50), and by reverse phase preparative HPLC afforded the title compound (58 mg, 90 %). [0357] Rf = 0.31 (Ethyl acetate/n-Heptane 50: 50). ¹H NMR (CDC13, 300 MHz) 8 8.26-8.15 (m, 2H, Ar-H), 7.78 (d, 1H, J= 8.0, Ar-H), 7.71-7.51 (m, 2H, Ar-H), 6.91 (d, 1H, J = 8.0, Ar-H), 4.21-4.10 (m, 2H, Tr-H), 2.39-2.28 (m, 4H, Tr-H), 2.02-1.89 (m, 4H, Tr-H), 1.39 (m, 3H, CH3). LCMS m/z 293 [M+H]+, HPLC tR= 4.1 (method A).

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 85

12
endo-3-exo-methyl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride [ No CAS ]
[ 13916-99-9 ]
4-(3-endo-hydroxy-3-exo-methyl-8-azabicyclo[3.2.1]oct-8-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 18h;	Alternatively, the title compound was obtained using the following procedure: To a solution of 197FBA20a (2.375 g, 13.42 mmol) in DMSO (35 mL) was added 1-cyano-4-fluonaphthalene (1.767 g, 10.32 mmol) and potassium carbonate (4.636 g, 33.54 mmol) and the reaction was allowed to stir at 100°C for 18 h. The mixture was cooled, diluted with ethyl acetate (200 mL) and washed with water (3 x 35 mL). The organic phase was dried over sodium sulfate, filtered and evaporated to give a crude product which was purified by filtration over silica gel. Elution with a stepwise gradient of 30-50% ethyl acetate in heptane afforded the title compound as a white solid (2.539 g, 84%). [0359] LCMS m/z 293 [M+H] +. ¹H-NMR (CDC13,300 MHz) No. 8.19 (d, J= 8.5, 2H), 7.76 (d, J = 8.1, 1H), 7.70-7.60 (m, 1H), 7.60-7.50 (m, 1H), 6.92 (d, J = 8.1, 1H), 4.27-4.08 (m, 2H), 2.43-2.26 (m, 4H), 2.06-1.86 (m, 4H), 1.37 (s, 3H). ¹3C-NMR (CDCl3, 75 MHz) 153.0,134.6, 133.8,128.5, 128.0,126.2, 126.1,125.6, 119.3,111.2, 102.2,69.9, 60.6,46.2, 34.7, 26.9.

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 85-86

13
[ 13916-99-9 ]
[ 2577-48-2 ]
[ 870889-33-1 ]

Yield	Reaction Conditions	Operation in experiment
1.7%	at 60℃; for 48h;	1-Cyano-4-fluoronaphthalene (109 mg, 0.64 mmol) and L-proline methyl ester (380 mg, 2.95 mmol) were heated to 60 °C for 2 days in a sealed vial. The crude product was concentrated in vacuo and purified by preparative TLC (ethyl acetate/n- heptane 1: 3, 3 x eluted) to afford the title compound (2.9 mg, 1.7 %) as an off-white solid. [0385] Rf = 0.42 (ethyl acetate/n-heptane 1: 1). LCMS m/z 281 [M+H] +. ¹H- NMR (CDC13, 300 MHz) 8 8.18-8.08 (m, 2H), 7.68 (d, 1H, J = 8.2), 7.60-7.41 (m, 2H), 6.78 (d, 1H, J= 8.2), 4.58 (t, 1H, J= 5.8), 4.05 (m, 1H), 3.55 (s, 3H), 3.22 (m, 1H), 2.42- 1.88 (m, 4H). HPLC tR = 4.0 min (method III).

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 91-92

14
[ 280-05-7 ]
[ 13916-99-9 ]
[ 870889-35-3 ]

Yield	Reaction Conditions	Operation in experiment
4%	With pyridine at 100℃;	Alternatively, the title compound was also obtained using the following procedure: 8-Azabicyclo[3,2,1]octane (20 mg, 0.18 mmol), 1-cyano-4-fluoronaphthalene (46 mg, 0.27 mmol) and pyridine (0.5 mL) were heated overnight at 100 °C, concentrated in vacuo and the residue purified by preparative TLC (dichloromethane, 3 x eluted) to afford the title compound (1.8 mg, 4.0 %) as a yellow oil.

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 92-93

15
[ 13916-99-9 ]
[ 135682-88-1 ]
[ 870889-47-7 ]

Yield	Reaction Conditions	Operation in experiment
6%	With pyridine at 110℃; for 48h;	8-Azabicyclo[3.2.1]oct-2-ene-2-carboxylic acid methyl ester (225 mg, 1.35 mmol, Davies H. M. L. et al., J. Org. Chem. 1991,56, 5696-5700), 1-cyano-4- fluoronaphthalene (230 mg, 1.35 mmol) and pyridine (1.0 mL) were heated to 110 °C for 2 days and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate/n-heptane 1: 4, 5 x eluted) to afford the title compound (25 mg, 6 %) as a colorless oil. [0406] Rf = 0.49 (ethyl acetate/n-heptane, 1: 1). LCMS m/z 319 [M+H]+. ¹H- NMR (CDC13, 300 MHz) 8.13-8.05 (m, 2H), 7.66 (d, 1H, J= 8.0), 7.61-7.48 (m, 2H), 6.78 (d, 1H, J= 8.0), 4.58 (d, 1H, J= 5.8), 4.43 (t, 1H, J= 6.0), 3.78 (s, 3H), 2.39 (m, 2H), 2.22 (m, 1H), 2.05-1.91 (m, 2H), 1.72 (m, 1H), 1.51 (m, 1H). HPLC tR = 4.8 min (method III).

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 96

16
[ 13916-99-9 ]
[ 71962-74-8 ]
1-(4-cyanonaphthalen-1-yl)piperidine-3-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With pyridine at 115℃; for 20h;	1-Cyano-4-fluoronaphthalene(1.0 g, 5.84 mmol) and ethyl nipecotate (3.63 mL, 23.4 mmol) were dissolved in pyridine (5 mL) and stirred at 115 °C for 20 hours. After cooling to rt ethyl acetate (50 mL) was added and the solution washed with HCl (0.4 M, 2 x 30 mL). The combined aqueous layers were extracted with ethyl acetate (30 mL). The combined organic layers were washed with sat. sodium hydrogen carbonate (30 mL), brine (30 mL), dried and evaporated. The crude product was purified by silica gel column chromatography eluted with a stepwise gradient of 0-70% ethyl acetate in n-heptane to give the title compound (1.23 g, 68 %) as a yellowish oil [0446] LCMS m/z 309 [M+H]+. (at)H-NMR (CDCl3,300 MHz) 8 8.20 (m, 2H), 7.83 (d, 1H, J = 7.9), 7.63 (m, 2H), 7.06 (d, 1H, J = 7.9), 4.18 (q, 2H, J = 7.1), 3.59 (m, 1 H), 3.38 (m, 1 H), 3.07 (m, 1 H), 2.89 (m, 2H), 2.17 (m, 1 H), 2.02 (m, 2H), 1.71 (m, 1 H), 1.25 (t, 3H, J= 7.1).

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 105

17
[ 13916-99-9 ]
[ 3000-79-1 ]
4-(2-methylpiperidin-1-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene at 60 - 110℃; for 312h;	1-Cyano-4-fluoronaphthalene (100 mg, 0.58 mmol), 2-methylpiperidine (0.28 mL, 2.3 mmol) and DBU (0.01 mL, 59 µmol) were dissolved in pyridine (2 mL) and stirred at 60 °C for 3 days. The temperature was raised to 110 °C and the stirring was continued for 10 days. The reaction was worked up in the same way as for 198RL60. The crude compound was purified by preparative TLC followed by preparative HPLC to give the title compound (27.4 mg, 19 %) as a colourless oil, which was stored under argon atmosphere. [0448] LCMS m/z 251 [M+H]+. (at)H-NMR (CDC13, 300 MHz) No. 8.33 (d, 1H, J= 8.2), 8.19 (d, 1H, J= 8.2), 7.84 (d, 1H, J= 7.8), 7.59 (m, 2H), 7.10 (d, 1H, J= 7.8), 3.53 (m, 1H), 3.28 (m, 1H), 2.75 (m, 1H), 2.01 (m, 1H), 1.88-1.53 (m, 5H), 0.92 (d, 3H, J = 6.3).

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 105

18
[ 13916-99-9 ]
[ 142643-29-6 ]
[1-(4-cyanonaphthalen-1-yl)piperidin-3-ylmethyl]carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene; at 60℃; for 96h;	1-Cyano-4-fluoronaphthalene (273 mg, 1.60 mmol), <strong>[142643-29-6]tert-butyl (piperidin-3-ylmethyl)carbamate</strong> (411 mg, 1.92 mmol) and DBU (25 mul, 0.16 mmol) were dissolved in pyridine (4 mL) and stirred at 60 C for 4 days. The reaction was worked up in the same way as for 198RL60 followed by purification using silica gel column chromatography eluted with a stepwise gradient of 0 - 70% ethyl acetate in n-heptane, giving the desired compound (416 mg, 71 %) as a white solid. [0452] ¹H-NMR (CDCl3, 300 MHz) No. 8.18 (m, 2H, Ar-H), 7.81 (d, 1H, J= 7.9, Ar-H), 7.61 (m, 2H, Ar-H), 7.00 (d, 1H, J = 7.9, Ar-H), 4.62 (m, 1H), 3.45 (m, 2H), 3.14 (m, 2H), 2.81 (m, 1H), 2.59 (m, 1H), 2.14 (m, 1H), 1.93 (m, 3H), 1.42 (s, 9H), 1.24 (m, 1H).

Reference： [1]Patent: WO2005/115361,2005,A2 .Location in patent: Page/Page column 106

19
trans-4-hydroxycyclohexylamine hydrochloride [ No CAS ]
[ 13916-99-9 ]
trans-4-(4-hydroxycyclohexylamino)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate In dimethyl sulfoxide at 120℃;	1-Cyano-4-fluoronaphthalene (1.00 g, 5.84 mmol), trans-4-amino cyclohexanol hydrochloride (1.33 g, 8.76 mmol) and potassium carbonate (4.0 g, 29 mmol) were stirred in DMSO (20 mL) at 120 °C overnight. The reaction mixture was then diluted with dichloromethane (100 mL) and washed with water (3 x 50 mL). The solution was dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluted with a stepwise gradient of 0 - 70% ethyl acetate in n- heptane, giving the title compound (1.187 g, 92 %) as a colorless solid. [0466] Rf = 0.74 (ethyl acetate). LCMS m/z 267 [M+H] +. (at)H-NMR (CDCl3,300 MHz) No. 8.16 (m, 1H), 7.75 (m, 2H), 7.64 (m, 1H), 7.52 (m, 1H), 6.58 (m, 1H), 3.76 (m, 1H), 3.54 (m, 1H), 2.27 (m, 2H), 2.10 (m, 2H), 1.70-1.30 (m, 5H), 2.26 (m, 1H).

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 109

20
[ 13916-99-9 ]
[ 3433-37-2 ]
4-[2-(hydroxymethyl)piperidin-1-yl]naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%	With pyridine at 200℃; for 1h; microwave irradiation;	A solution of 1-cyano-4-fluoronaphthalene (200 mg, 1.168 mmol) in pyridine (0.5 mL) was transferred to a Pyrex tube and 2-piperidinemethanol (538 mg, 4.67 mmol) was added. The tube was capped and exposed to microwave irradiation (200 °C, 60 min). The reaction mixture was diluted with ethyl acetate , washed with 0.4 N HCl and saturated aqueous NaHC03. The organic phase was dried and evaporated to give a crude product which was purified by preparative TLC (65:35 n-heptane/ethyl acetate), followed by further purification by preparative HPLC to give 173FBA70e (15 mg, 5%). [0473] LCMS m/z 267 [M+H] (at). ¹H-NR4R (CDC13, 300 MHz) No. 8.30 (d, J= 8.1, 1 H), 8.20 (d, J = 7.8,1H), 7.83 (d, J = 7.8,1H), 7.72-7.53 (m, 2H), 7.22 (d, J = 8.0,1H), 3.67-3.48 (m, 3H), 3.41-3.26 (m, 1H), 3.00-2.82 (m, 1H), 2.10-1.55 (m, 6H).

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 110-111

21
[ 13916-99-9 ]
[ 13772-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aq. H₂SO₄, AcOH 2: H₂SO₄

Reference： [1]Adcock,W.; Dewar,M.J.S. [Journal of the American Chemical Society, 1967, vol. 89, p. 386 - 390]

22
[ 110-91-8 ]
[ 13916-99-9 ]
4-(4-morpholinyl)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	7 Example 7 A mixture of 4-fluoro-1-naphthonitrile (100 mg), morpholine (0.10 mL), potassium carbonate (162 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(4-morpholinyl)-1-naphthonitrile (113 mg) (Compound 7). mp 128 - 129 C.1H-NMR (300 MHz, CDCl3) ?: 3.17-3.20 (4H, m), 3.99-4.02 (4H, m), 7.05 (1H, d, J=7.8 Hz), 7.57-7.70 (2H, m), 7.86 (1H, d, J=7.8 Hz), 8.19-8.24 (2H, m). IR (KBr) 2216, 1574 cm-1[]

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 60

23
[ 35794-11-7 ]
[ 13916-99-9 ]
4-(3,5-dimethyl-1-piperidinyl)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	58 Example 58 A mixture of 4-fluoro-1-naphthonitrile (150 mg), 3,5-dimethylpiperidine (198 mg), potassium carbonate (362 mg), and dimethylsulfoxide (2.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(3,5-dimethyl-1-piperidinyl)-1-naphthonitrile (223 mg) (Compound 58).1H-NMR (300 MHz, CDCl3) ?: 0.72-0.84 (1H, m), 0.95 (6H, d, J=6.6 Hz), 1.91-2.12 (3H, m), 2.32 (2H, t, J=11.4 Hz), 3.39-3.44 (2H, m), 6.98 (1H, d, J=7.8 Hz), 7.55 (1H, ddd, J=8.4, 6.6 and 1.5 Hz), 7.63 (1H, ddd, J=8.4, 6.6 and 1.5 Hz), 7.80 (1H, d, J=7.8 Hz), 8.11-8.14 (1H, m), 8.16-8.19 (1H, m). IR (KBr) 2953, 2216, 1574 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 73

24
[ 111-49-9 ]
[ 13916-99-9 ]
4-azepan-1-ylnaphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	10 Example 10 A mixture of 4-fluoro-1-naphthonitrile (100 mg), azepane (116 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(1-azepaneyl)-1-naphthonitrile (116 mg) (Compound 10).1H-NMR (300 MHz, CDCl3) ?: 1.77-1.92 (8H, m), 3.40-3.44 (4H, m),7.02 (1H, d, J=8.1 Hz), 7.52 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.62 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.77 (1H, d, J=8.1 Hz), 8.15-8.18 (1H, m), 8.19-8.23 (1H, m). IR (KBr) 2930, 2213, 1568 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 61

25
[ 109-01-3 ]
[ 13916-99-9 ]
4-(4-methyl-1-piperazinyl)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	17 Example 17 A mixture of 4-fluoro-1-naphthonitrile (100 mg), 1-methylpiperazine (117 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(4-methyl-1-piperazinyl)-1-naphthonitrile (100 mg) (Compound 17). mp 128 - 129 C.1H-NMR (300 MHz, CDCl3) ?: 2.43 (3H, s), 2.73 (4H, br. s), 3.22 (4H, br.s), 7.03 (1H, d, J=7.8 Hz), 7.56 (1H, ddd, J=8.4, 6.6 and 1.2 Hz), 7.65 (1H, ddd, J=8.4, 6.6 and 1.2 Hz), 7.83 (1H, d, J=7.8 Hz), 8.16-8.21 (2H, m). IR (KBr) 2795, 2215, 1574 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 63

26
[ 123-90-0 ]
[ 13916-99-9 ]
[ 664362-60-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	8 Example 8 Examle 8 (Preparation of Compound 8) A mixture 4-fluoro-1-naphthonitrile (500 mg), thiomorpholine (0.57 mL), potassium carbonate (808 mg), and dimethylsulfoxide (5.0 mL) was stirred at 100°C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(4-thiomorpholinyl)-1-naphthonitrile (560 mg) (Compound 8). mp 130 - 131°C. 1H-NMR (300 MHz, CDCl3) δ: 2.94-2.97 (4H, m), 3.41-3.45 (4H, m), 7.06 (1H, d, J=8.1 Hz), 7.60 (1H, ddd, J=8.4, 6.6 and 1.2 Hz), 7.68 (1H, ddd, J=8.4, 6.6 and 1.2 Hz), 7.85 (1H, d, J=8.1 Hz), 8.13-8.17 (1H, m), 8.20-8.23 (1H, m). IR (KBr) 2216, 1574 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 60-61

27
[ 13916-99-9 ]
[ 177-11-7 ]
4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	In tetrahydrofuran at 20℃; for 48h;	1.4-dioxa-8-azaspiro [4.5]decane mg, 2.32 mmol) was added to a solution of 1-cyano-1-fluoronaphthalene (120 mg, 0.70 mmol) in anhydrous THF (1 mL). After 48 hours stirring at rt the mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The residue was washed with a mixture of ethyl acetate and n-heptane (50: 50). Purification by silica gel column chromatography, eluting with 5% methanol in dichloromethane afforded the desired compound (126 mg, 43 %). The compound was converted to the corresponding hydrochloride salt as described above. [0244] Rf = 0.45 (ethyl acetate/n-heptane 50: 50). LCMS m/z 295 [M+H]+. HPLC tR = 12.3 min (method I). ¹H NMR (CDC13, 400 MHz) No. 8.21-8.15 (m, 2H, Ar-H), 7.82 (d, 1H, J = 8.0, Ar-H), 7.65 (m, 1H, Ar-H), 7.58 (m, 1H, Ar-H), 7.04 (d, 1H, J = 8.0, Ar-H), 4.03 (m, 4H, dioxolane-H), 3.27 (m, 4H, pip-H), 2.01 (m, 4H, pip-H).
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	13 Example 13 A mixture of 4-fluoro-1-naphthonitrile (1.00 g), 1,4-dioxane-8-azaspiro[4,5]decane (1.67 g), potassium carbonate (1.62 g), and dimethylsulfoxide (10 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(1,4-dioxane-8-azaspiro[4,5]deca-8-yl)-1-naphthonitrile (1.42 g) (Compound 13). mp 142 - 143 C.1H-NMR (300 MHz, CDCl3) ?: 2.02 (4H, t, J=5.7 Hz), 3.26-3.29 (4H, m), 4.04 (4H, s), 7.05 (1H, d, J=7.8 Hz), 7.59 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.65 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.83 (1H, d, J=7. 8 Hz), 8.16-8.22 (2H, m). IR (KBr) 2216, 1574 cm-1

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 63
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 62

28
[ 91-21-4 ]
[ 13916-99-9 ]
4-(3,4-dihydro-2(1H)-isoquinolinyl)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	69 Example 69 Example 69 (Preparation of Compound 70) A mixture of 4-fluoro-1-naphthonitrile (100 mg), 1,2,3,4-tetrahydroisoquinoline (150 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.5 mL) was stirred at 100°C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(3,4-dihydro-2(1H)-isoquinolinyl)-1-naphthonitrile (140 mg) (Compound 70). 1H-NMR (300 MHz, CDCl3) δ: 3.15 (2H, t, J=6.0 Hz), 3.55 (2H, t, J=6.0 Hz), 4.39 (2H, s), 7.10-7.14 (2H, m), 7.18-7.26 (3H, m), 7.57 (1H, ddd, J=8.1, 6.9 and 1.2 Hz), 7.66 (1H, ddd, J=8.1, 6.9 and 1.2 Hz), 7.84 (1H, d, J=7.8 Hz), 8.20-8.24 (2H, m). IR (KBr) 2216, 1572 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 75-76

29
[ 13916-99-9 ]
[ 79286-87-6 ]
N-[1-(4-cyanonaphthalen-1-yl)pyrrolidin-3-yl]-N-methylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 15h;	49 Example 49 A mixture of 4-fluoro-1-naphthonitrile (100 mg), N-methyl-N-pyrrolidin-3-yl acetamide (249 mg), potassium carbonate (87 mg) and dimethylsulfoxide (2.0 mL) was stirred at 100 C for 15 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane : ethyl acetate = 1 : 2) and crystallized from hexane : ethyl acetate = 1 : 1, to obtain N-[1-(4-cyano-1-naphthyl)pyrrolidin-3-yl]-N-methylacetamide (130 mg) (Compound 49). mp 144 - 145 C.1H-NMR (200 MHz, CDCl3) ?: 2.00-2.40 (2H, m), 2.15(2.1H, s), 2.20(0.9H, s), 3.03(0.9H, s), 3.08(2.1H, s), 3.40-3.78(4H, m), 4.52-4.62(0.3H, m), 5.28-5.50(0.7H, m), 6.80(0.7H, d, J=8.4Hz),6.84(0.3H, d, J=8.4Hz), 7.45-7.70(2H, m), 7.77(0.7H, J-=8.4Hz), 7.79(0.3H, d, J=8.4Hz), 8.12(2H, d, J=8.4Hz). IR (KBr) 2199, 1655, 1565 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 71

30
[ 6859-99-0 ]
[ 13916-99-9 ]
4-(3-hydroxypiperidin-1-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	40 Example 40 A mixture of 4-fluoro-1-naphthonitrile (200 mg), 3-hydroxypiperidine (236 mg), potassium carbonate (322 mg), and dimethylsulfoxide (2.5 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(3-hydroxy-1-piperidinyl)-1-naphthonitrile (259 mg) (Compound 40).1H-NMR (300 MHz, CDCl3) ?: 1.66-2.28 (5H, m), 3.02-3.16 (3H, m), 3.22-3.36 (1H, m), 4.08-4.15 (1H, m), 7.03 (1H, d, J=7.8 Hz), 7.59 (1H, ddd, J=8.1, 6.6 and 1.5 Hz), 7.66 (1H, ddd, J=8.1, 6.6 and 1.5 Hz), 7.82 (1H, d, J=7.8 Hz), 8.18-8.21 (2H, m). IR (KBr) 2216, 1572 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 68

31
[ 622-26-4 ]
[ 13916-99-9 ]
4-[4-(2-hydroxyethyl)piperidin-1-yl]naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	77 Example 77 Example 77 (Preparation of Compound 78) A mixture of 4-fluoro-1-naphthonitrile (100 mg), 4-piperidine ethanol (151 mg), potassium carbonate (161 mg) and dimethylsulfoxide (1.5 mL) was stirred at 100°C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[4-(2-hydroxyethyl)-1-piperidinyl]-1-naphthonitrile (149 mg) (Compound 78). mp 128 - 129°C. 1H-NMR (300 MHz, CDCl3) δ: 1.30 (1H, t, J=5.1 Hz), 1.59-1.73 (5H, m), 1.90-1.94 (2H, m), 2.78-2.86 (2H, m), 3.49-3.53 (2H, m), 3.77-3.83 (2H, m), 7.01 (1H, d, J=8.1 Hz), 7.56 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.65 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.82 (1H, d, J=8.1 Hz), 8.14-8.20 (2H, m). IR (KBr) 2924, 2216, 1572 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 77-78

32
[ 4606-65-9 ]
[ 13916-99-9 ]
[ 664362-71-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	19 Example 19 A mixture of 4-fluoro-1-naphthonitrile (400 mg), 3-(hydroxymethyl) piperidine (539 mg), potassium carbonate (646 mg), and dimethylsulfoxide (4.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[3-(hydroxymethyl)-1-piperidinyl]-1-naphthonitrile (560 mg) (Compound 19).1H-NMR (300 Hz, CDCl3) ?: 1.20-1.32 (1H, m), 1.59 (1H, br.s), 1.86-1.96 (3H, m), 2.09-2.20 (1H, m), 2.66 (1H, t, J=10.5 Hz), 2.77-2.86 (1H, m), 3.38-3.42 (1H, m), 3.54-3.68 (3H, m), 7.01 (1H, d, J=7.8 Hz), 7.56 (1H, ddd, J=8.1, 6.9 and 1.2 Hz), 7.62 (1H, ddd, J=8.1, 6.9 and 1.2 Hz), 7.79 (1H, d, J=7.8 Hz), 8.13-8.18 (2H, m). IR (KBr) 2932, 2216, 1572 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 63

33
[ 6457-49-4 ]
[ 13916-99-9 ]
4-(4-hydroxymethylpiperidin-1-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	31 Example 31 A mixture of 4-fluoro-1-naphthonitrile (100 mg), 4-(hydroxymethyl) piperidine (135 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[4-(hydroxymethyl)-1-piperidinyl]-1-naphthonitrile (150 mg) (Compound 30). mp 135 - 136 C.1H-NMR (300 MHz, CDCl3) ?: 1.47 (1H, t-like), 1.58-1.80 (3H, m), 1.93-1.98 (2H, m), 2.79-2.87 (2H, m), 3.55 (1H, d.t-like, J=12.3 Hz), 3.65 (2H, t, J=5.4 Hz), 7.01 (1H, d, J=7.8 Hz), 7.56 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.64 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.81 (1H, d, J=7.8 Hz), 8.13-8.20 (2H, m). IR (KBr) 2915, 2216, 1572 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 66

34
[ 13916-99-9 ]
[ 25137-01-3 ]
ethyl (3R)-1-(4-cyano-1-naphthyl)-3-piperidinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	33 Example 33 A mixture of 4-fluoro-1-naphthonitrile (300 mg), (R)-ethyl nipecotate (551 mg), potassium carbonate (485 mg), and dimethylsulfoxide (3.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl (3R)-1-(4-cyano-1-naphthyl)-3-piperidinecarboxylate (451 mg) (Compound 32). [?]D=-56.4 (c=0.475, MeOH).1H-NMR (200 MHz, CDCl3) ?: 1.26 (3H, t, J=7.0 Hz), 1.70-2.03 (3H, m), 2.14-2.20 (1H, m), 2.79-2.95 (2H, m), 3.07 (1H, t, J=10.6 Hz), 3.35-3.41 (1H, m), 3.57-3.62 (1H, m), 4.17 (2H, q, J=7.0 Hz), 7.06 (1H, d, J=8.2 Hz), 7.54-7.70 (2H, m), 7.84 (1H, d, J=8.2 Hz), 8.13-8.23 (2H, m). IR (KBr) 2216, 1730, 1574 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 66-67

35
[ 496-12-8 ]
[ 13916-99-9 ]
4-(1,3-dihydro-2H-isoindole-2-yl)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 5h;	129 Example 129 Example 129 (Preparation of Compound 131) A mixture of 4-fluoro-1-naphthonitrile (300 mg), isoindoline (250 mg), potassium carbonate (270 mg), and dimethylsulfoxide (6.0 mL) was stirred at 100°C for 5 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(1,3-dihydro-2H-isoindole-2-yl)-1-naphthonitrile (195mg) (Compound 131). mp 156 - 158°C. 1H-NMR (200 MHz, CDCl3) δ: 5.00 (4H, s), 6.94 (1H, d, J=8.2 Hz), 7.30-7.41 (4H, m), 7.48-7.72 (2H, m), 7.82 (1H, d, J=8.2 Hz), 8.22 (1H, d, J=8.0 Hz), 8.48 (1H, d, J=8.0Hz). IR (KBr) 2201, 1561, 1413 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 93

36
[ 13916-99-9 ]
[ 79286-74-1 ]
N-[1-(4-cyano-1-naphthyl)pyrrolidin-3-yl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 16h;	42 Example 42 A mixture of 4-fluoro-1-naphthonitrile (100 mg), N-pyrrolidin-3-yl acetamide (240 mg), potassium carbonate (87 mg) and dimethylsulfoxide (2.0 mL) was stirred at 100 C for 16 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate) and crystallized from hexane : ethyl acetate = 4 : 1, to obtain N-[1-(4-cyano-1-naphthyl)pyrrolidin-3-yl]acetamide (136 mg) (Compound 42). mp 154 - 155 C.1H-NMR (200 MHz, CDCl3) ?: 1.90-2.15(1H, m), 2.02 (3H, s), 2.35-2.48(1H, m), 3.40-3.60(2H, m), 3.70-3.92(2H, m),4.55-4.78(1H,m),5.90(1H, d, J=5.0 Hz), 6.72(1H, d,J=5.0Hz),7.42-7.68(2H, m). IR (KBr) 2203, 1649, 1563, 1518 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 69

37
[ 4138-26-5 ]
[ 13916-99-9 ]
1-(4-cyano-1-naphthyl)-3-piperidinecarboxylic acid amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 3h;	Example 73 (Preparation of Compound 74) A mixture of 4-fluoro-1-naphthonitrile (100 mg), <strong>[4138-26-5]nipecotamide</strong> (150 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.5 mL) was stirred at 100°C for 3 hours. After cooling to room temperature, the reactact was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 1-(4-cyano-1-naphthyl)-3-piperidinecarboxylic acid amide (140 mg) (Compound 74). mp 187 - 18°C. 1H-NMR (300 MHz, DMSO-d6) delta: 1.51-1.64 (1H, m), 1.76-1.87 (2H, m), 1.96-2.02 (1H, m), 2.65-2.81 (2H, m), 2.90 (1H, t, J=11.1 Hz), 3.38-3.48 (2H, m), 6.90 (1H, br.s), 7.17 (1H, d, J=8.4 Hz), 7.40 (1H, br.s), 7.68 (1H, ddd, J=8.1, 6.6 and 1.2 Hz), 7.76 (1H, ddd, J=8.1, 6.6 and 1.2 Hz), 8.02-8.07 (1H, m), 8.15-8.17 (1H, m). IR (KBr) 3422, 2216, 1661 cm-1

Reference： [1]Patent: EP1553074,2005,A1 .Location in patent: Page/Page column 76-77

38
[ 59184-90-6 ]
[ 13916-99-9 ]
ethyl [1-(4-cyano-1-naphthyl)-4-piperidinyl]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 0.5h;	Example 101 (Preparation of Compound 105) A mixture of tert-butyl 4-(2-ethoxy-2-oxoethyl)-1-piperidinecarboxylate (450 mg) and 4 N hydrogen chloride - ethyl acetate (1.5 mL) was stirred at room temperature for 1 hour. The reactant was concentrated to obtain a colorless solid matter (330 mg). A mixture of the obtained matter (146 mg), 4-fluoro-1-naphthonitrile (100 mg), potassium carbonate (218 mg), and dimethylsulfoxide (2.0 mL) was stirred at 100C for 30 minutes. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl [1-(4-cyano-1-naphthyl)-4-piperidinyl]acetate (113 mg) (Compound 105). 1H-NMR (CDCl3) delta: 1.29 (3H, t, J=7.2 Hz), 1.60-1.72 (2H, m), 1.92-2.12 (3H, m), 2.38 (2H, d, J=6.9 Hz), 2.84 (2H, td, J=12.0 amd 1.8 Hz), 3.48-3.52 (2H, m), 4.17 (2H, q, J=7.2 Hz), 7.00 (1H, d, J=8.1 Hz), 7.55 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.64 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.81 (1H, d, J=8.1 Hz), 8.11-8.20 (2H, m). IR (KBr) 2216, 1732, 1574 cm-1

Reference： [1]Patent: EP1553074,2005,A1 .Location in patent: Page/Page column 85

39
[ 13916-99-9 ]
[ 37675-18-6 ]
ethyl (3S)-1-(4-cyano-1-naphthyl)-3-piperidinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 3h;	A mixture of 4-fluoro-1-naphthonitrile (300 mg), (S)-ethyl nipecotate (551 mg), potassium carbonate (485 mg), and dimethylsulfoxide (3.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl (3S)-1-(4-cyano-1-naphthyl)-3-piperidinecarboxylate (508 mg) (Compound 31). [?]D=+49.6 (c=0.580, MeOH).1H-NMR (200 MHz, CDCl3) ?: 1.26 (3H, t, J=7.0 Hz), 1.70-2.03 (3H, m), 2.14-2.20 (1H, m), 2.79-2.95 (2H, m), 3.07 (1H, t, J=10.6 Hz), 3.35-3.41 (1H, m), 3.57-3.62 (1H, m), 4.17 (2H, q, J=7.0 Hz), 7.06 (1H, d, J=8.2 Hz), 7.54-7.70 (2H, m), 7.84 (1H, d, J=8.2 Hz), 8.13-8.23 (2H, m). IR (KBr) 2216, 1730, 1574 cm-1

Reference： [1]Patent: EP1553074,2005,A1 .Location in patent: Page/Page column 66

40
[ 13916-99-9 ]
[ 99724-19-3 ]
tert-butyl 1-(4-cyano-1-naphthyl)-3-pyrrolidinyl carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	26 Example 26 Example 26 (Preparation of Compound 25) A mixture of 4-fluoro-1-naphthonitrile (500 mg), tert-butyl 3-pyrrolidinyl carbamate (1.09 g), potassium carbonate (808 mg), and dimethylsulfoxide (10 mL) was stirred at 100°C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl 1-(4-cyano-1-naphthyl)-3-pyrrolidinyl carbamate (765 mg) (Compound 25). mp 157 - 158°C. 1H-NMR (300 MHz, CDCl3) δ: 1.46 (9H, s), 1.92-2.08 (1H, m), 2.26-2.43 (1H, m), 3.41-3.61 (2H, m), 3.72-3.87 (2H, m), 4.35-4.45 (1H, m), 4.78 (1H, br.s), 6.74 (1H, d, J=8.0 Hz), 7.48 (1H, ddd, J=8.8, 6.8 and 1.2 Hz), 7.62 (1H, ddd, J=8.8, 6.8 and 1.2 Hz), 7.75 (1H, d, J=8.0 Hz), 8.15-8.22 (2H, m). IR (KBr) 2978, 2209, 1694 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 65

41
3-fluoropyrrolidine hydrochloride [ No CAS ]
[ 13916-99-9 ]
4-(3-fluoro-1-pyrrolidinyl)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 2h;	95 Example 95 Example 95 (Preparation of Compound 99) A mixture of 4-fluoro-1-naphthonitrile (40 mg), 3-fluoropyrrolidine hydrochloride (29 mg), potassium carbonate (81 mg) and dimethylsulfoxide (1.0 mL) was stirred at 100°C for 2 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts o were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(3-fluoro-1-pyrrolidinyl)-1-naphthonitrile (32 mg) (Compound 99). 1H-NMR (300 MHz, CDCl3) δ: 2.11-2.46 (2H, m), 3.48-3.55 (1H, m), 3.66-4.00 (3H, m), 5.39 (1H, dt, J=53.7 and 3.9 Hz), 6.78 (1H, d, J=8.1 Hz), 7.49 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.62 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.75 (1H, d, J=8.1 Hz), 8.16-8.22 (2H, m). IR (KBr) 2207, 1566 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 83

42
[ 221298-00-6 ]
[ 13916-99-9 ]
4-[3-(hydroxymethyl)-3-methyl-1-piperidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	56 Example 56 A mixture of 4-fluoro-1-naphthonitrile (200 mg), 3-(hydroxymethyl)-3-methylpiperidine (301 mg), potassium carbonate (322 mg) and dimethylsulfoxide (2.5 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[3-(hydroxymethyl)-3-methyl-1-piperidinyl]-1-naphthonitrile (264 mg) (Compound 56).1H-NMR (300 MHz, CDCl3) ?: 1.13 (3H, s), 1.40-1.48 (1H, m), 1.63-2.04 (4H, m), 2.86-3.20 (4H, m), 3.63-3.76 (2H, m), 7.03 (1H, d, J=8.1 Hz), 7.54-7.67 (2H, m), 7.81 (1H, d, J=8.1 Hz), 8.17-8.22 (2H, m). IR (KBr) 2216, 1572 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 72

43
[ 40499-83-0 ]
[ 13916-99-9 ]
[ 664362-70-3 ]

Yield	Reaction Conditions	Operation in experiment
43%	In toluene at 180℃; for 0.0833333h; microwave irradiation;	1-Cyano-4-fluoronaphthalene (86 mg, 0.5 mmol) was transferred to a Pyrex tube and 3-pyrrolidinol (162 µL, 2.0 mmol) was added followed by toluene (0.5 mL). The tube was capped and the reaction tube was exposed to microwave irradiation (180 °C, 5 min). The reaction mixture was concentrated and purified by re-crystallization with EtOH. Yield: 51 mg (43%). [0201] LCMS m/z 239 [M+H]+. HPLC tR = 6.0 min (method I). (at)H-NMR (CD30D, 400 MHz) No. 8.36-8.33 (m, 1H), 7.97-7.95 (m, 1H), 7.83 (d, J= 8.4, 1H), 7.70- 7.65 (m, 1H), 7.53-7.48 (m, 1 H), 6.74 (d, J = 8.4, 1 H), 5.05 (d, J = 3.2, 1 H), 4.10 (s, 1 H), 3.93-3.89 (m, 1H), 3,85-3,78 (m, 1H), 3,55-3,49 (m, 1H), 2,10-2,02 (m, 1H), 2,02-1,90 (m, 1H). ¹3C-NMR (CD30D, 100 MHz) 8 152.4,135.1, 135.0,129.3, 127.3,125.4, 125.4, 125.1, 120.4, 108.3, 96.5, 70.1,62.0, 51.0,34.5.
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	18 Example 18 A mixture of 4-fluoro-1-naphthonitrile (400 mg), 3-hydroxypyrrolidine (467 mg), potassium carbonate (646 mg), and dimethylsulfoxide (4.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(3-hydroxy-1-pyrrolidinyl)-1-naphthonitrile (447 mg) (Compound 18). mp 138 - 139 C.1H-NMR (300 MHz, CDCl3) ?: 1.93 (1H, d, J=6.6 Hz),2.08-2.29 (2H, m), 3.49-3.56 (2H, m), 3.84-3.98 (2H, m), 4.62-4.68 (1H, m), 6.73 (1H, d, J=8.1 Hz), 7.46 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.60 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.72 (1H, d, J=8.1 Hz), 8.13-8.16 (1H, m), 8.22-8.25 (1H, m). IR (KBr) 3434, 2205, 1561 cm-1

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 55
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 63

44
[ 36652-42-3 ]
[ 13916-99-9 ]
4-(1,2-oxazinane-2-yl)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 27h;	74 Example 74 Example 74 (Preparation of Compound 75) A mixture of 1,2-oxazinane hydrochloride (300 mg), 2-tert-butyl imino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphospholine (polystyrene-carried, about 2.2 mmol/g) (1.20 g) and dichloromethane (6.0 mL) was stirred at room temperature for 3 hours. Resin was filtered off, washed with dichloromethane, and then concentrated to obtain a colorless oily matter. A mixture of the obtained matter, 4-fluoro-1-naphthonitrile (225 mg), potassium carbonate (336 mg), and dimethylsulfoxide (3.0 mL) was stirred at 100°C for 27 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(1,2-oxazinane-2-yl)-1-naphthonitrile (34 mg) (Compound 75). mp 111 - 112°C. 1H-NMR (300 MHz, CDCl3) δ: 1.77-1.85 (2H, m), 2.03-2.10 (2H, m), 3.32-3.36 (2H, m), 4.28 (2H, t, J=5.4 Hz), 7.44 (1H, d, J=7.8 Hz), 7.57 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.65 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.86 (1H, d, J=7.8 Hz), 8.09-8.12 (1H, m), 8.17-8.20 (1H, m). IR (KBr) 2220, 1576 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 77

45
[ 13916-99-9 ]
[ 7531-52-4 ]
1-(4-cyano-1-naphthyl)-L-prolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 15h;	46 Example 46 A mixture of 4-fluoro-1-naphthonitrile (100 mg), L-prolinamide (200 mg), potassium carbonate (87 mg), and dimethylsulfoxide (2.0 mL) was stirred at 100 C for 15 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane : ethyl acetate = 1 : 2) and crystallized from hexane : ethyl acetate = 1 : 2, to obtain 1-(4-cyano-1-naphthyl)-L-prolinamide (101 mg) (Compound 46). mp 177 - 178 C. [?]D =+218.7 (c=0.608, MeOH).1H-NMR (200 MHz, CDCl3) ?: 1.80-2.30 (3H, m), 2.30-2.72(1H, m), 3.28-3.46(1H, m), 4.10-4.30(1H, m), 4.38(1H, t, J=8.0Hz), 5.32(1H, brs), 6.39(1H, brs), 6.97(1H, d, J=8.0Hz), 7.52-7.75 (2H, m), 7.78(1H, d, J=8.0Hz), 8.18-8.32(2H, m). IR (KBr) 2210, 1691, 1323 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 70

46
[ 5382-16-1 ]
[ 13916-99-9 ]
4-(4-hydroxypiperidin-1-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	11 Example 11 A mixture of 4-fluoro-1-naphthonitrile (300 mg), 4-hydroxypiperidine (355 mg), potassium carbonate (485 mg), and dimethylsulfoxide (3.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(4-hydroxy-1-piperidinyl)-1-naphthonitrile (380 mg) (Compound 11). mp 126 - 127 C.1H-NMR (300 MHz, CDCl3) ?: 1.85-1.96 (2H, m), 2.05-2.20 (2H, m), 2.94-3.02 (2H, m), 3.40-3.47 (2H, m), 3.95-4.03 (1H, m), 7.02 (1H, d, J=7.8 Hz), 7.58 (1H, ddd, J=8.1, 6.6 and 1.5 Hz), 7.65 (1H, ddd, J=8.1, 6.6 and 1.5 Hz), 7.81 (1H, d, J=7.8 Hz), 8.13-8.21 (2H, m). IR (KBr) 2216, 1574 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 61

47
[ 13916-99-9 ]
[ 163457-23-6 ]
4-(3,3-difluoro-1-pyrrolidinyl)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 1h;	99 Example 99 Example 99 (Preparation of Compound 103) A mixture of 4-fluoro-1-naphthonitrile (100 mg), 3,3-difluoropyrrolidine hydrochloride (92 mg), potassium carbonate (202 mg) and dimethylsulfoxide (1.0 mL) was stirred at 100°C for 1 hour. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(3,3-difluoro-1-pyrrolidinyl)-1-naphthonitrile (39 mg) (Compound 103). mp 68 - 69°C. 1H-NMR (300 MHz, CDCl3) δ: 2.50-2.64 (2H, m), 3.64 (2H, t, J=7.2 Hz), 3.81 (2H, t, J=12.6 Hz), 6.90 (1H, d, J=8.1 Hz), 7.58 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.68 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.82 (1H, d, J=8.1 Hz), 8.14-8.17 (1H, m), 8.21-8.24 (1H, m). IR (KBr) 2213, 1574 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 84

48
[ 13916-99-9 ]
(S)-(hydroxymethyl)piperidine [ No CAS ]
4-[(3S)-3-(hydroxymethyl)-1-piperidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	21 Example 21 A mixture of 4-fluoro-1-naphthonitrile (100 mg), (S)-3-(hydroxymethyl)piperidine (135 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(3S)-3-(hydroxymethyl)-1-piperidinyl]-1-naphthonitrile (133 mg) (Compound 21). [?]D=+4.9 (c=0.460, MeOH).1H-NMR (300 Hz, CDCl3) ?: 1.20-1.32 (1H, m), 1. 59 (1H, br. s), 1.86-1.96 (3H, m), 2.09-2.20 (1H, m), 2.66 (1H, t, J=10.5 Hz), 2.77-2.86 (1H, m), 3.38-3.42 (1H, m), 3.54-3.68 (3H, m), 7.01 (1H, d, J=7.8 Hz), 7.56 (1H, ddd, J=8.1, 6.9 and 1.2 Hz), 7.62 (1H, ddd, J=8.1, 6.9 and 1.2 Hz), 7.79 (1H, d, J=7.8 Hz), 8.13-8.18 (2H, m).Compound 21 was obtained using optical resolution as shown in Example 23 as an alternative method.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 64

49
[ 473730-88-0 ]
[ 13916-99-9 ]
4-(3-hydroxy-3-methyl-1-piperidinyl)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 1h;	67 Example 67 Example 67 (Preparation of Compound 68) To a mixture of 1-benzyl-5-hydroxy-5-methyl-2-piperidinone (95 mg) and tetrahydrofuran (2.5 mL) was added lithium aluminum hydride (16 mg) at room temperature, and the mixture was stirred at 75°C for 5 hours. After cooling to room temperature, water (16 μl), a 25% potassium hydroxide solution (16 μl) and water (48 μl) were sequentially added, and the mixture was stirred for 1 hour. Insolubles were filtered off using celite and mother liquor was concentrated to obtain a yellow oily matter. A mixture of the obtained matter, 10% palladium carbon (50% water content, 92 mg), 4 N hydrochloric acid (0.12 mL) and methanol (1.4 mL) was stirred under hydrogen atmosphere at room temperature for 12 hours. Palladium carbon was filtered off using celite. Mother liquor was concentrated to obtain a pale orange oily matter. A mixture of the obtained matter, 4-fluoro-1-naphthonitrile (50 mg), potassium carbonate (120 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100°C for 1 hour. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(3-hydroxy-3-methyl-1-piperidinyl)-1-naphthonitrile (15 mg) (Compound 68). 1H-NMR (300 MHz, CDCl3) δ: 1.33 (3H, s), 1.49-1.59 (1H, m), 1.78-1.89 (2H, m), 2.05-2.22 (1H, m), 2.70-2.85 (2H, m), 3.02 (1H, br.s), 3.22-3.26 (1H, m), 3.40-3.53 (1H, m), 7.05 (1H, d, J=7.8 Hz), 7.60-7.70 (2H, m), 7.83 (1H, d, J=7.8 Hz), 8.20-8.29 (2H, m). IR (KBr) 2216, 1574 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 75

50
[ 13916-99-9 ]
[ 62937-45-5 ]
1-(4-cyano-1-naphthyl)-D-prolineamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 23h;	Example 133 (Preparation of Compound 135) D-prolinamide (800 mg), 4-fluoro-1-naphthonitrile (1000 mg) and potassium carbonate (1000 mg) was added dimethylsulfoxide (15.0 mL), and the mixture was stirred at 100C for 23 hours. After cooling to room temperature, water was poured into the reactant, and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. To the obtained residue was added hexane: ethyl acetate = 1: 2 and crystallized to obtain 1-(4-cyano-1-naphthyl)-D-prolinamide (570 mg) (Compound 135). mp 176 - 177C. [alpha]D=-194.6 (c=0.380, MeOH). 1H-NMR (200 MHz, CDCl3) delta: 1.82-2.30 (3H, m), 2.50-2.72 (1H, m), 3.30-3.42(1H, m), 4.10-4.48(2H, m), 5.29(1H, br.s), 6.38(1H, br.s), 6.97(1H, d, J=8.0 Hz), 7.50-7.75 (2H, m), 7.78 (1H, d, J=8.0 Hz), 8.20-8.32 (2H, m). IR (KBr) 2210, 1690, 1568 cm-1

Reference： [1]Patent: EP1553074,2005,A1 .Location in patent: Page/Page column 94

51
[ 297172-16-8 ]
[ 13916-99-9 ]
4-[4-(hydroxymethyl)-4-methyl-1-piperidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 3h;	Example 76 (Preparation of Compound 77) A mixture of 4-fluoro-1-naphthonitrile (200 mg) (4-methyl-4-piperidinyl) methanol (242 mg), potassium carbonate (332 mg) and dimethylsulfoxide (3.0 mL) was stirred at 100C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[4-(hydroxymethyl)-4-methyl-1-piperidinyl]-1-naphthonitrile (256 mg) (Compound 77). mp 136 - 137C. 1H-NMR (300 MHz, CDCl3) delta: 1.10 (3H, s), 1.48 (1H, t, J=6.0 Hz), 1.55-1.61 (2H, m), 1.90 (2H, ddd, J=13.2, 10.2 and 4.2 Hz), 3.04-3.12 (2H, m), 3.24-3.31 (2H, m), 3.53 (2H, d, J=6.0 Hz), 7.04 (1H, d, J=8.1 Hz), 7.57 (1H, ddd, J=8.1, 6.9 and 1.5 Hz), 7.65 (1H, ddd, J=8.1, 6.9 and 1.5 Hz), 7.83 (1H, d, J=8.1 Hz), 8.15-8.21 (2H, m). IR (KBr) 2216, 1574 cm-1

Reference： [1]Patent: EP1553074,2005,A1 .Location in patent: Page/Page column 77

52
[ 13916-99-9 ]
[ 37675-20-0 ]
4-[(3R)-3-(hydroxymethyl)-1-piperidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of 4-fluoro-1-naphthonitrile (100 mg), (R)-3-(hydroxymethyl)piperidine (135 mg), potassium carbonate (161 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(3R)-3-(hydroxymethyl)-1-piperidinyl]-1-naphthonitrile (139 mg) (Compound 22). [?]D=-4.4 (c=0.460, MeOH).1H-NMR (300 Hz, CDCl3) ?: 1.20-1.32 (1H, m), 1. 59 (1H, br. s), 1.86-1.96 (3H, m), 2.09-2.20 (1H, m), 2.66 (1H, t, J=10.5 Hz), 2.77-2.86 (1H, m), 3.38-3.42 (1H, m), 3.54-3.68 (3H, m), 7.01 (1H, d, J=7.8 Hz), 7.56 (1H, ddd, J=8.1, 6.9 and 1.2 Hz), 7.62 (1H, ddd, J=8.1, 6.9 and 1.2 Hz), 7.79 (1H, d, J=7.8 Hz), 8.13-8.18 (2H, m). Compound 22 was obtained using optical resolution as shown in Example 23 as an alternative method. Example 23 (preparation of compounds 21 and 22) 4-[3-(hydroxymethyl)-1-piperidinyl]-1-naphthonitrile (3.53 g) was optically resolved by CHILALCEL OD (50 x 500 mm), to obtain 4-[(3S)-3-(hydroxymethyl)-1-piperidinyl]-1-naphthonitrile (Compound 21, 1.77 g) and 4-[(3R)-3-(hydroxymethyl)-1-piperidinyl]-1-naphthonitrile (Compound 22, 1.77 g).

Reference： [1]Patent: EP1553074,2005,A1 .Location in patent: Page/Page column 64

53
[ 13916-99-9 ]
4-hydrazino-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine In N,N-dimethyl acetamide at 30℃; for 0.666667h;	75 Reference Example 75 Reference Example 75 To a mixture of 4-fluoro-1-naphthonitrile (865 mg) and N,N-dimethylacetamide (5.0 mL) was added hydrazine monohydrate (0.45 mL), and the mixture was stirred at 30°C for 40 minutes. Water was added to the reactant and the produced precipitate was taken by filtration. After washing with water, the precipitate was dissolved in ethyl acetate, dried and concentrated to obtain 4-hydrazino-1-naphthonitrile (530 mg). 1H-NMR (300 MHz, DMSO-d6) δ: 4.47 (2H, br.s), 7.05 (1H, d, J=8.4 Hz), 7.49 (1H, ddd, J=8.1, 6.9 and 1.5 Hz), 7.66 (1H, ddd, J=8.1, 6.9 and 1.5 Hz), 7.86 (1H, d, J=8.4 Hz), 7.89-7.92 (1H, m), 8.23-8.26 (1H, m), 8.59 (1H, br.s). IR (KBr) 3312, 2205, 1578 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 50

54
[ 664364-19-6 ]
[ 13916-99-9 ]
4-[(2S,3S)-3-(hydroxymethyl)-2-methyl-1-pyrrolidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 0.5h;	103 Example 103 Example 103 (Preparation of Compound 107) To a mixture of sodium triacetoxyhydroborate (2.02 g), acetic acid (4.7 mL), and acetonitrile (3.0 mL) was added a mixture of methyl 2-methyl-1-[(1S)-1-phenylethyl]-4,5-dihydro-1H-pyrrole-3-carboxylate (780 mg) and acetonitrile (1.7 mL) at 0°C, and the mixture was stirred for 3 hours. The reactant was poured into a sodium carbonate solution and extracted with ethyl acetate. The extracts were washed with a sodium carbonate solution and brine, dried and concentrated to obtain a colorless oily matter (778 mg). To a mixture of the obtained oily matter (740 mg) and tetrahydrofuran (8.0 mL) was added lithium aluminum hydride (114 mg) at 0°C, and the mixture was stirred for 3 hours. Water (0.11 mL), a 25% potassium hydroxide solution (0.11 mL) and water (0.33 mL) were sequentially added, and the resulting mixture was stirred at room temperature for 15 hours. Insolubles were filtered off using celite and mother liquor was concentrated to obtain a pale yellow oily matter (656 mg). A mixture of the obtained matter (581 mg), 10% palladium carbon (50% water content, 564 mg), and methanol (9.0 mL) was stirred under hydrogen atmosphere at room temperature for 20 hours. Palladium carbon was filtered off using celite and washed with methanol. Mother liquor was concentrated, and then ethyl acetate was added to the residue. The mixture was dried and concentrated to obtain a pale yellow oily matter (260 mg). A mixture of the obtained oily matter (117 mg), 4-fluoro-1-naphthonitrile (171 mg), potassium carbonate (207 mg), and dimethylsulfoxide (2.0 mL) was stirred at 100°C for 30 minutes. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was washed with dichloromethane to obtain 4-[(2S,3S)-3-(hydroxymethyl)-2-methyl-1-pyrrolidinyl]-1-naphthonitrile (80 mg) (Compound 107). mp 158 - 159°C. [α]D=-258.9° (c=0.320, MeOH). 1H-NMR (300 MHz, CDCl3) δ: 1.44 (3H, d, J=6.3 Hz), 1.99-2.20 (3H, m), 2.55-2.66 (1H, m), 3.01-3.09 (1H, m), 3.79-4.02 (3H, m), 4.11 (1H, qui, J=6.3 Hz), 6.96 (1H, d, J=8.4 Hz), 7.54 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.65 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.82 (1H, d, J=8.4 Hz), 8.14-8.21 (2H, m). IR (KBr) 2211, 1568, 1323 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 85-86

55
[ 664364-48-1 ]
[ 13916-99-9 ]
4-[(2S,3S)-3-hydroxy-2-methyl-1-pyrrolidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 0.666667h;	113 Example 113 Example 113 (Preparation of Compound 116) A mixture of 4-fluoro-1-naphthonitrile (166 mg), (2S,3S)-2-methyl-3-pyrrolidinol (98 mg), potassium carbonate (202 mg) and dimethylsulfoxide (1.5 mL) was stirred at 100°C for 40 minutes. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S,3S)-3-hydroxy-2-methyl-1-pyrrolidinyl]-1-naphthonitrile (160 mg) (Compound 116). NMR values were identical to those of Compound 116 in Example 111.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 89

56
(2R,3R)-2-methylpyrrolidin-3-ol [ No CAS ]
[ 13916-99-9 ]
4-[(2R,3R)-3-hydroxy-2-methyl-1-pyrrolidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 0.5h;	120 Example 120 Example 120 (Preparation of Compound 122) To a mixture of tert-butyl (2R,3R)-3-hydroxy-2-methyl-5-oxopyrrolidine-1-carboxylate (2.20 g) and ethyl acetate (18 mL) was added 4 N hydrogen chloride - ethyl acetate (6.0 mL) and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain a pale yellow oily matter. To a mixture of the obtained matter and tetrahydrofuran (50 mL) was added lithium aluminum hydride (1.15 g) at room temperature, and the mixture was heated under reflux for 18 hours. After cooling to 0°C, water (1.0 mL), a 25% potassium hydroxide solution (1.0 mL) and water (3.0 mL) were sequentially added, and the mixture was stirred for 1 hour. Insolubles were filtered off using celite and mother liquor was concentrated to obtain a light brown oily matter (1.0 g). A mixture of the obtained matter (330 mg), 4-fluoro-1-naphthonitrile (500 mg), potassium carbonate (606 mg) and dimethylsulfoxide (5.0 mL) was stirred at 100°C for 30 minutes. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2R,3R)-3-hydroxy-2-methyl-1-pyrrolidinyl]-1-naphthonitrile (473 mg) (Compound 122). [α]D=+271.5° (c=0.555, MeOH). 1H-NMR (200 MHz, CDCl3) δ: 1.25(3H, d, J=6.2 Hz), 1.93 (1H, d-like), 2.00-2.20 (2H, m), 3.18-4.02 (1H, m), 4.20-4.40 (1H, m), 4.40-4.58 (1H, m), 6.86 (1H, d, J=8.0 Hz), 7.46-7.70 (2H, m), 7.78 (1H, d, J=8.0 Hz), 8.12-8.28 (2H, m). IR (KBr) 2211, 1565, 1515 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 91

57
[ 664364-26-5 ]
[ 13916-99-9 ]
4-[4-(hydroxymethyl)-2,4-dimethyl-1-pyrrolidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; hydrogen; potassium carbonate In methanol; water; dimethyl sulfoxide at 100℃; for 4h;	128 Example 128 Example 128 (Preparation of Compound 130) A mixture of (1-benzyl-3,5-dimethylpyrrolidin-3-yl) methanol (1.88 g), methanol (60 mL), 1 N-hydrochloric acid (8.6 mL) and 10% palladium carbon (containing water) (1.10 g) was stirred under hydrogen atmosphere for 16 hours. The catalyst was filted off, the filtrate was concentrated and dried. To the residue was added 4-fluoro-1-naphthonitrile (1.10 g), potassium carbonate (3.55 g) and dimethylsulfoxide (30.0 mL) were added, and the mixture was stirred at 100°C for 4 hours. After cooling to room temperature, water was poured into the reactant, and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[4-(hydroxymethyl)-2,4-dimethyl-1-pyrrolidinyl]-1-naphthonitrile (480 mg) (Compound 130). mp 100 - 101°C. 1H-NMR (200 MHz, CDCl3) δ: 1.02(3H, s), 1.20(3H, d, J=5.8 Hz), 1.65-2.04(3H, m), 2.98 (1H, dd, J=1.0 Hz and 9.8 Hz), 3.66(2H, d, J=5.4 Hz), 4.00-4.26(2H, m), 6.88(1H, d, J=8.4 Hz), 7.42-7.70(2H, m), 7.23 (1H, d, J=8.0 Hz), 8.12-8.26 (2H, m). IR (KBr) 2211, 1564, 1515cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 93

58
[ 1026-59-1 ]
[ 13916-99-9 ]
4-(3-phenyl-1-pyrrolidinyl)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; hydrogen; potassium carbonate In methanol; water; dimethyl sulfoxide at 100℃; for 30h;	135 Example 135 Example 135 (Preparation of Compound 137) 1-Benzyl-3-phenylpyrrolidine (2.35 g) was dissolved in methyl alcohol (30 mL), 1 N-hydrochloric acid (10 mL) and 10% palladium carbon (containing water) (1200 mg) were added, and the mixture was stirred under hydrogen atmorsphere for 15 hours. The catalyst was filtered off, the filtrate was concentrated and dried. To the residue was added 4-fluoro-1-naphthonitrile (600 mg), potassium carbonate (1500 mg) and dimethylsulfoxide (15.0 mL) and the mixture was stirred at 100°C for 15 hours. After cooling to room temperature, water was poured into the reactant and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(3-phenyl-1-pyrrolidinyl)-1-naphthonitrile (628 mg) (Compound 137). 1H-NMR (200 MHz, CDCl3) δ: 2.01-2.57 (2H, m), 3.40-4.02 (5H, m), 6.73 (1H, d, J=8.4 Hz), 7.20-7.50 (5H, m), 7.57-7.70 (1H, m), 7.75 (1H, d, J=8.4 Hz), 8.12-8.32 (2H, m). IR (KBr) 2205, 1563, 1518 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 95

59
[ 644971-22-2 ]
[ 13916-99-9 ]
4-[3-(hydroxymethyl)-1-pyrrolidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide;	A mixture of 4-fluoro-1-naphthonitrile (100 mg), <strong>[644971-22-2]pyrrolidin-3-yl methanol hydrochloride</strong> (240 mg), potassium carbonate (330 mg) and dimethylsulfoxide (2.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane : ethyl acetate =1 : 1). The residue was dissolved in ethyl acetate and a 4N-hydrochloric acid / ethyl acetate solution (0.3 mL) was added thereto. The resulting solution was concentrated and dried to obtain 4-[3-(hydroxymethyl)pyrrolidin-1-yl]-1-naphthonitrile hydrochloride (153 mg) as hygroscopic amorphous matter (Compound 50).1H-NMR (200 MHz, CDCl3 + CD3OD + D2O) ?: 1.75-2.00(1H, m), 2.05-2.38(1H, m), 2.45-2.80(1H, m), 3.40-3.90(6H, m), 6.81(1H, d, J=8.4Hz), 7.40-7.80(3H, m), 8.14(1H, d, J=8.4Hz), 8.29(1H, d, J=8.4Hz). IR (KBr) 2205, 1561 cm-1

Reference： [1]Patent: EP1553074,2005,A1 .Location in patent: Page/Page column 71

60
[ 13916-99-9 ]
[ 220024-87-3 ]
4-(2,2-dimethyl-1-pyrrolidinyl)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-fluoronaphthalene-1-carbonitrile; 1-benzyl-2,2-dimethylpyrrolidine With hydrogenchloride; hydrogen; potassium carbonate In methanol; water; dimethyl sulfoxide at 100℃; for 20h; Stage #2: With 1H-imidazole In methanol; water; dimethyl sulfoxide at 100℃; for 3h;	132 Example 132 Example 132 (Preparation of Compound 134) 1-Benzyl-2,2-dimethylpyrrolidine (1.00 g) was dissolved in methyl alcohol (30 mL), 1 N-hydrochloric acid (5.5 mL) and 10% palladium carbon (containing water) (500mg) were added, and the mixture was stirred under hydrogen atmosphere for 15 hours. The catalyst was filtered off, the filtrate was concentrated and dried. To the residue was added 4-fluoro-1-naphthonitrile (256 mg), potassium carbonate (825mg) and dimethylsulfoxide (6.0 mL), and the mixture was stirred at 100°C for 20 hours. Then, imidazole (210 mg) and potassium carbonate (280 mg) were added, and the mixture was stirred at 100°C for 3 hours. After cooling to room temperature, water was poured into the reactant and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-(2,2-dimethyl-1-pyrrolidinyl)-1-naphthonitrile (46 mg) (Compound 134). 1H-NMR (200 MHz, CDCl3) δ: 1.17 (6H, s), 1.90-2.15 (4H, m), 7.34(1H, d, J=8.0 Hz), 7.48-7.70 (2H, m), 7.83 (1H, d, J=8.0 Hz), 8.14-8.22 (1H, m), 8.42-8.49(1H, m). IR (KBr) 2218, 1570 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 94

61
[ 664364-29-8 ]
[ 13916-99-9 ]
ethyl [1-(4-cyano-1-naphthyl)pyrrolidin-3-yl]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; trifluoroacetic acid In dimethyl sulfoxide; toluene at 20 - 100℃; for 2.5h;	138 Example 138 Example 138 (Preparation of Compound 140) Tert-butyl 3-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate (510 mg) was dissolved in toluene (2.0 mL), trifluoroacetic acid (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and dried. To the residue was added 4-fluoro-1-naphthonitrile (171 mg), potassium carbonate (410 mg) and dimethylsulfoxide (4.0 mL) were added, and the mixture was stirred at 100°C for 1.5 hours. After cooling to room temperature, water was poured into the reactant and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl [1-(4-cyano-1-naphthyl)pyrrolidin-3-yl]acetate (300 mg) (Compound 140). 1H-NMR (200 MHz, CDCl3) δ: 1.28(3H, d, J=7.2 Hz), 1.64-1.88 (1H, m), 2.20-2.40 (1H, m), 2.53(2H, d, J=7.8Hz), 2.62-2.70 (1H, m), 3.40(1H, dd, J=7.6Hz and 7.7Hz), 3.55-3.84 (3H, m), 4.17(2H, q, J=7.2 Hz), 6.70 (1H, d, J=8.4 Hz), 7.40-7.68 (2H, m), 7.72 (1H, d, J=8.4 Hz), 8.12-8.28 (2H, m). IR (KBr) 2199, 1732, 1556, 1522 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 95

62
(2S,3R)-2-methylpyrrolidin-3-ol [ No CAS ]
[ 13916-99-9 ]
[ 664363-64-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 15h;	109 Example 109 Example 109 (Preparation of Compound 113) (2S,3R)-1-benzyl-2-methylpyrrolidin-3-ol (820 mg) was dissolved in methyl alcohol (30 mL), 1 N-hydrochloric acid (4.3 mL) and 10% palladium carbon (containing water) (500 mg) were added, and the mixture was stirred under hydrogen atmosphere for 15 hours. The catalyst was filtered off, and the filtrate was concentrated and dried. To the residue was added 4-fluoro-1-naphthonitrile (582 mg), potassium carbonate (890 mg), and dimethylsulfoxide (12.0 mL), and the mixture was stirred at 100°C for 15 hours. After cooling to room temperature, water was poured into the reactant, and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography and basic silica gel column chromatography (Chromatorex NH, a product made in Fuji Silysia Chemical Ltd.) to obtain 4-[(2S,3R)-3-hydroxy-2-methyl-1-pyrrolidinyl]-1-naphthonitrile (540 mg) (Compound 113). [α]D=-268.6° (c=0.515, MeOH). 1H-NMR (200 MHz, CDCl3) δ: 1.15(3H, d, J=6.2 Hz), 1.80-2.20 (2H, m), 2.30-2.50 (1H, m), 3.20-3.38 (1H, m), 3.77-4.00 (2H, m), 4.10-4.30 (1H, m), 6.89 (1H, d, J=8.0 Hz), 7.46-7.68 (2H, m), 7.19 (1H, d, J=8.0 Hz), 8.14-8.26 (2H, m). IR (KBr) 2211, 1567, 1514 cm-1.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 88

63
[ 664364-54-9 ]
[ 13916-99-9 ]
C₁₈H₂₀N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 60h;	36 Example 36 A mixture of 4-fluoro-1-naphthonitrile (400 mg), 2-(methoxymethoxymethyl)piperidine (744 mg), potassium carbonate (646 mg), and dimethylsulfoxide (4.0 mL) was stirred at 100 C for 60 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated, to obtain a yellowish-brown oily matter. A mixture of the obtained matter and trifluoroacetic acid (2.0 mL) was stirred at room temperature for 10 hours. The reaction solution was alkalified with a 1 N sodium hydroxide solution, and extracted with diethyl ether. The extracts were washed with brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[2-(hydroxymethyl)-1-piperidinyl]-1-naphthonitrile (37 mg) (Compound 35).1H-NMR (300 MHz, CDCl3) ?: 1.42-1.92 (6H, m), 1.96-2.06 (1H, m), 2.88-2.96 (1H, m), 3.30-3.37 (1H, m), 3.52-3.62 (3H, m), 7.21 (1H, d, J=8.1 Hz), 7.55-7.67 (2H, m), 7.82 (1H, d, J=8.1 Hz), 8.17 (1H, d, J=8.1 Hz), 8.29 (1H, d, J=8.1 Hz). IR (KBr) 2935, 2216, 1570, 1508 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 67

64
cis-(5-methylpyrrolidin-3-yl)methanol hydrochloride [ No CAS ]
[ 13916-99-9 ]
cis-4-[4-(hydroxymethyl)-2-methylpyrrolidin-1-yl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	52 Example 52 A mixture of 4-fluoro-1-naphthonitrile (100 mg), cis-(5-methylpyrrolidin-3-yl) methanol hydrochloride (220 mg), potassium carbonate (330 mg) and dimethylsulfoxide (2.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain cis-4-[4-(hydroxymethyl)-2-methylpyrrolidin-1-yl]-1-naphthonitrile (139 mg) (Compound 52).1H-NMR (200 MHz, CDCl3) ?: 1.25(3H, d, J=6.2Hz), 1.40-1.70(1H, m), 2.28-2.58(2H, m), 3.30-3.45(1H, m), 3.62-4.20(4H, m), 6.85(1H, d, J=8.4Hz), 7.44-7.68(2H, m), 7.77(1H, d, J=8.4Hz), 8.18(2H, t, J=8.4Hz). IR (KBr) 2209, 1566, 1514, 1327 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 71

65
trans-(5-methylpyrrolidin-3-yl)methanol hydrochloride [ No CAS ]
[ 13916-99-9 ]
trans-4-[4-(hydroxymethyl)-2-methylpyrrolidin-1-yl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	53 Example 53 A mixture of 4-fluoro-1-naphthonitrile (100 mg), trans-(5-methylpyrrolidin-3-yl) methanol hydrochloride (220 mg), potassium carbonate (330 mg) and dimethylsulfoxide (2.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain trans-4-[4-(hydroxymethyl)-2-methylpyrrolidin-1-yl]-1-naphthonitrile (148 mg) (Compound 53).1H-NMR (200 MHz, CDCl3) ?: 1.10(3H, d, J=5.8Hz), 1.18-1.99(1H, m), 2.10-2.30(1H, m), 2.40-2.70(1H, m), 3.10-3.20(1H, m), 3.40-3.70(2H, m), 4.00-4.20 (2H, m), 6.86(1H, d, J=8.0Hz), 7.48-7.70 (2H, m), 7.76(1H, d, J=8.0Hz), 8.12-8.24 (2H, m). IR (KBr) 2210, 1566, 1514, 1327 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 72

66
[ 850306-71-7 ]
[ 13916-99-9 ]
4-[(2R)-2-vinyl-1-pyrrolidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24.8%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	80 Example 80 A mixture of tert-butyl (2R)-2-vinyl-1-pyrrolidine carboxylate (70 mg) and 4 N hydrogen chloride - ethyl acetate (1.0 mL) was stirred at room temperature for 1.5 hours. The reactant was concentrated and processed with diethyl ether to obtain a colorless solid matter. A mixture of the obtained solid, 4-fluoro-1-naphthonitrile (50 mg), potassium carbonate (104 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2R)-2-vinyl-1-pyrrolidinyl]-1-naphthonitrile (36 mg). The enantiomer excess of the obtained compound was 24.8% e.e. A mixture of tert-butyl (2S)-2-vinyl-1-pyrrolidine carboxylate (185 mg) and 4 N hydrogen chloride - ethyl acetate (1.0 mL) was stirred at room temperature for 1.5 hours. The reactant was concentrated and processed with diethyl ether to obtain a colorless solid matter. A mixture of the obtained solid, 4-fluoro-1-naphthonitrile (100 mg), potassium carbonate (242 mg), and dimethylsulfoxide (1.5 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S)-2-vinyl-1-pyrrolidinyl]-1-naphthonitrile (90 mg). The enantiomer excess of the obtained compound was 22.7% e.e. 4-[(2R)-2-vinylpyrrolidinyl]-1-naphthonitrile (25 mg) and 4-[(2S)-2-vinylpyrrolidinyl]-1-naphthonitrile (70 mg) were combined and the combination was optically resolved using CHIRALPAK AS (50 x 500 mm), to obtain 4-[(2R)-2-vinyl-1-pyrrolidinyl]-1-naphthonitrile (Compound 81) (43 mg) and 4-[(2S)-2-vinyl-1-pyrrolidinyl]-1-naphthonitrile (Compound 82) (50 mg). Compound 81 [?]D=-267.0 (c=0.295, MeOH).1H-NMR (300 MHz, CDCl3) ?: 1.80-1.98 (2H, m), 2.02-2.10 (1H, m), 2.27-2.35 (1H, m), 3.37-3.43 (1H, m), 4.05-4.13 (1H, m), 4.32-4.40 (1H, m), 5.08 (1H, dt, J=10.2 and 1.2 Hz), 5.23 (1H, dt, J=17.1 and 1.2 Hz), 5.70 (1H, ddd, J=17.1, 10.2 and 7.2 Hz), 6.78 (1H, d, J=8.4 Hz), 7.46 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.59 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.71 (1H, d, J=8.4 Hz), 8.13-8.16 (1H, m), 8.21-8.24 (1H, m). IR (KBr) 2209, 1566 cm-1 Compound 82 [?]D=+267.9 (c=0.345, MeOH).1H-NMR (300 MHz, CDCl3) ?: 1.80-1.98 (2H, m), 2.02-2.10 (1H, m), 2.27-2.35 (1H, m), 3.37-3.43 (1H, m), 4.05-4.13 (1H, m), 4.32-4.40 (1H, m), 5.08 (1H, dt, J=10.2 and 1.2 Hz), 5.23 (1H, dt, J=17.1 and 1.2 Hz), 5.70 (1H, ddd, J=17.1, 10.2 and 7.2 Hz), 6.78 (1H, d, J=8.4 Hz), 7.46 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.59 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.71 (1H, d, J=8.4 Hz), 8.13-8.16 (1H, m), 8.21-8.24 (1H, m). IR (KBr) 2209, 1566 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 78-79

67
[ 13916-99-9 ]
[ 146405-59-6 ]
4-[(2S)-2-vinyl-1-pyrrolidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22.7%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	80 Example 80 A mixture of tert-butyl (2R)-2-vinyl-1-pyrrolidine carboxylate (70 mg) and 4 N hydrogen chloride - ethyl acetate (1.0 mL) was stirred at room temperature for 1.5 hours. The reactant was concentrated and processed with diethyl ether to obtain a colorless solid matter. A mixture of the obtained solid, 4-fluoro-1-naphthonitrile (50 mg), potassium carbonate (104 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2R)-2-vinyl-1-pyrrolidinyl]-1-naphthonitrile (36 mg). The enantiomer excess of the obtained compound was 24.8% e.e. A mixture of tert-butyl (2S)-2-vinyl-1-pyrrolidine carboxylate (185 mg) and 4 N hydrogen chloride - ethyl acetate (1.0 mL) was stirred at room temperature for 1.5 hours. The reactant was concentrated and processed with diethyl ether to obtain a colorless solid matter. A mixture of the obtained solid, 4-fluoro-1-naphthonitrile (100 mg), potassium carbonate (242 mg), and dimethylsulfoxide (1.5 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S)-2-vinyl-1-pyrrolidinyl]-1-naphthonitrile (90 mg). The enantiomer excess of the obtained compound was 22.7% e.e. 4-[(2R)-2-vinylpyrrolidinyl]-1-naphthonitrile (25 mg) and 4-[(2S)-2-vinylpyrrolidinyl]-1-naphthonitrile (70 mg) were combined and the combination was optically resolved using CHIRALPAK AS (50 x 500 mm), to obtain 4-[(2R)-2-vinyl-1-pyrrolidinyl]-1-naphthonitrile (Compound 81) (43 mg) and 4-[(2S)-2-vinyl-1-pyrrolidinyl]-1-naphthonitrile (Compound 82) (50 mg). Compound 81 [?]D=-267.0 (c=0.295, MeOH).1H-NMR (300 MHz, CDCl3) ?: 1.80-1.98 (2H, m), 2.02-2.10 (1H, m), 2.27-2.35 (1H, m), 3.37-3.43 (1H, m), 4.05-4.13 (1H, m), 4.32-4.40 (1H, m), 5.08 (1H, dt, J=10.2 and 1.2 Hz), 5.23 (1H, dt, J=17.1 and 1.2 Hz), 5.70 (1H, ddd, J=17.1, 10.2 and 7.2 Hz), 6.78 (1H, d, J=8.4 Hz), 7.46 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.59 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.71 (1H, d, J=8.4 Hz), 8.13-8.16 (1H, m), 8.21-8.24 (1H, m). IR (KBr) 2209, 1566 cm-1 Compound 82 [?]D=+267.9 (c=0.345, MeOH).1H-NMR (300 MHz, CDCl3) ?: 1.80-1.98 (2H, m), 2.02-2.10 (1H, m), 2.27-2.35 (1H, m), 3.37-3.43 (1H, m), 4.05-4.13 (1H, m), 4.32-4.40 (1H, m), 5.08 (1H, dt, J=10.2 and 1.2 Hz), 5.23 (1H, dt, J=17.1 and 1.2 Hz), 5.70 (1H, ddd, J=17.1, 10.2 and 7.2 Hz), 6.78 (1H, d, J=8.4 Hz), 7.46 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.59 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.71 (1H, d, J=8.4 Hz), 8.13-8.16 (1H, m), 8.21-8.24 (1H, m). IR (KBr) 2209, 1566 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 78-79

68
[ 753447-35-7 ]
[ 13916-99-9 ]
4-[(2S)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24.4%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	81 Example 81 A mixture of tert-butyl (2S)-2-ethyl-1-pyrrolidine carboxylate (70 mg) and 4 N hydrogen chloride - ethyl acetate (1.0 mL) was stirred at room temperature for 1.5 hours. The reactant was concentrated and processed with diethyl ether to obtain a colorless solid matter. A mixture of the obtained matter, 4-fluoro-1-naphthonitrile (50 mg), potassium carbonate (104 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile (33 mg). The enantiomer excess of the obtained compound was 24.4%e.e. A mixture of tert-butyl (2R)-2-ethyl-1-pyrrolidine carboxylate (130 mg) and 4 N hydrogen chloride - ethyl acetate (1.5 mL) was stirred at room temperature for 1.5 hours. The reactant was concentrated and processed with diethyl ether to obtain a colorless solid matter. A mixture of the obtained matter, 4-fluoro-1-naphthonitrile (75 mg), potassium carbonate (182 mg), and dimethylsulfoxide (1.5 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2R)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile (85 mg). The enantiomer excess of the obtained compound was 21.0%e.e. 4-[(2S)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile (80 mg) and 4-[(2R)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile (19 mg) were combined and the combination was optically resolved using CHIRALPAK AS (50 x 500 mm), to obtain 4-[(2S)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile (Compound 83) (44 mg) and 4-[(2R)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile (Compound 84 (51 mg). Compound 83 [?]D=-294.6 (c=0.330, MeOH).1H-NMR (300 MHz, CDCl3) ?: 0.90 (3H, t, J=7.8 Hz), 1.30-1.45 (1H, m), 1.68-1.86 (3H, m), 1.95-2.05 (1H, m), 2.26-2.34 (1H, m), 3.32-3.38 (1H, m), 3.83-3.92 (1H, m), 3.95-4.03 (1H, m), 6.79 (1H, d, J=8.1 Hz), 7.45 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.59 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.73 (1H, d, J=8.1 Hz), 8.13-8.18 (2H, m). IR (KBr) 2963, 2209, 1564 cm-1 Compound 84 [?]D=+294.9 (c=0.380, MeOH).1H-NMR (300 MHz, CDCl3) ?: 0.90 (3H, t, J=7.8 Hz), 1.30-1.45 (1H, m), 1.68-1.86 (3H, m), 1.95-2.05 (1H, m), 2.26-2.34 (1H, m), 3.32-3.38 (1H, m), 3.83-3.92 (1H, m), 3.95-4.03 (1H, m), 6.79 (1H, d, J=8.1 Hz), 7.45 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.59 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.73 (1H, d, J=8.1 Hz), 8.13-8.18 (2H, m). IR (KBr) 2963, 2209, 1564 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 79

69
[ 13916-99-9 ]
[ 123168-37-6 ]
4-[(2R)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	81 Example 81 A mixture of tert-butyl (2S)-2-ethyl-1-pyrrolidine carboxylate (70 mg) and 4 N hydrogen chloride - ethyl acetate (1.0 mL) was stirred at room temperature for 1.5 hours. The reactant was concentrated and processed with diethyl ether to obtain a colorless solid matter. A mixture of the obtained matter, 4-fluoro-1-naphthonitrile (50 mg), potassium carbonate (104 mg), and dimethylsulfoxide (1.0 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile (33 mg). The enantiomer excess of the obtained compound was 24.4%e.e. A mixture of tert-butyl (2R)-2-ethyl-1-pyrrolidine carboxylate (130 mg) and 4 N hydrogen chloride - ethyl acetate (1.5 mL) was stirred at room temperature for 1.5 hours. The reactant was concentrated and processed with diethyl ether to obtain a colorless solid matter. A mixture of the obtained matter, 4-fluoro-1-naphthonitrile (75 mg), potassium carbonate (182 mg), and dimethylsulfoxide (1.5 mL) was stirred at 100 C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2R)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile (85 mg). The enantiomer excess of the obtained compound was 21.0%e.e. 4-[(2S)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile (80 mg) and 4-[(2R)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile (19 mg) were combined and the combination was optically resolved using CHIRALPAK AS (50 x 500 mm), to obtain 4-[(2S)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile (Compound 83) (44 mg) and 4-[(2R)-2-ethyl-1-pyrrolidinyl]-1-naphthonitrile (Compound 84 (51 mg). Compound 83 [?]D=-294.6 (c=0.330, MeOH).1H-NMR (300 MHz, CDCl3) ?: 0.90 (3H, t, J=7.8 Hz), 1.30-1.45 (1H, m), 1.68-1.86 (3H, m), 1.95-2.05 (1H, m), 2.26-2.34 (1H, m), 3.32-3.38 (1H, m), 3.83-3.92 (1H, m), 3.95-4.03 (1H, m), 6.79 (1H, d, J=8.1 Hz), 7.45 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.59 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.73 (1H, d, J=8.1 Hz), 8.13-8.18 (2H, m). IR (KBr) 2963, 2209, 1564 cm-1 Compound 84 [?]D=+294.9 (c=0.380, MeOH).1H-NMR (300 MHz, CDCl3) ?: 0.90 (3H, t, J=7.8 Hz), 1.30-1.45 (1H, m), 1.68-1.86 (3H, m), 1.95-2.05 (1H, m), 2.26-2.34 (1H, m), 3.32-3.38 (1H, m), 3.83-3.92 (1H, m), 3.95-4.03 (1H, m), 6.79 (1H, d, J=8.1 Hz), 7.45 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.59 (1H, ddd, J=8.4, 6.9 and 1.2 Hz), 7.73 (1H, d, J=8.1 Hz), 8.13-8.18 (2H, m). IR (KBr) 2963, 2209, 1564 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 79

70
C₆H₁₂N₂O [ No CAS ]
[ 13916-99-9 ]
(2S,3S)-1-(4-cyano-1-naphthyl)-2-methylpyrrolidine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 5h;	157 Example 157 Example 157 (Preparation of Compound 160) Tert-butyl (2S,3S)-3-(aminocarbonyl)-2-methylpyrrolidine-1-carboxylate (760 mg) was dissolved in toluene (4.0 mL), trifluoroacetic acid (4.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and dried. To the residue was added 4-fluoro-1-naphthonitrile (570 mg), potassium carbonate (1370 mg) and dimethylsulfoxide (12 mL), and the mixture was stirred at 100°C for 5 hours. After cooling to room temperature, water was poured into the reactant and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. To the residue was added hexane: ethyl acetate = 1: 2 and crystallized, to obtain (2S,3S)-1-(4-cyano-1-naphthyl)-2-methylpyrrolidine-3-carboxamide (158 mg). Mother liquor was purified by silica gel column chromatography, to obtain the same compound (289 mg) (Compound 160). mp 204 - 206°C. [α]D=-276.7° (c=0.388, MeOH). 1H-NMR (200 MHz, CDCl3+DMSO-d6) δ: 1.17(3H, d, J=6.2 Hz), 2.00-2.50 (2H, m), 3.06-3.30 (2H, m), 4.05-4.30 (2H, m), 5.84 (1H, br.s), 6.51 (1H, br.s), 6.98 (1H, d, J=8.0 Hz), 7.50-7.71 (2H, m), 7.82 (1H, d, J=8.0 Hz), 8.12-8.30 (2H, m). IR (KBr) 2210, 1664, 1567 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 100

71
[ 13916-99-9 ]
[ 765-38-8 ]
4-(2-methyl-1-pyrrolidinyl)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 15h;	47 Example 47 A mixture of 4-fluoro-1-naphthonitrile (100 mg), 2-methylpyrrolidine (150 mg), potassium carbonate (87 mg) and dimethylsulfoxide (2.0 mL) was stirred at 100 C for 15 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane : ethyl acetate = 8 : 1). The residue was dissolved in ethyl acetate and a 4N-hydrochloric acid / ethyl acetate solution (0.3 mL) was added thereto. The resulting solution was concentrated and dried, to obtain 4-(2-methylpyrrolidin-1-yl)-1-naphthonitrile hydrochloride (150 mg) as a hygroscopic amorphous matter (Compound 47).1H-NMR (200 MHz, DMSO-d6) ?: 1.13(3H, d, J=5.8Hz), 1.58-2.10(3H, m), 2.20-2.40(1H, m), 3.20-3.60(1H, m), 3.95-4.20(2H, m), 6.92(1H, d, J=8.4Hz), 7.49-7.76(2H, m), 7.90(1H, d, J=8.4Hz), 7.99(1H, d, J=8.4Hz), 8.25(1H, d, J=8.4Hz). IR (KBr) 2209, 1566, 1515, 1328,764 cm-1
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 5h;	48 Example 48 A mixture of 4-fluoro-1-naphthonitrile (400 mg), 2-methylpyrrolidine (410 mg), potassium carbonate (350 mg) and dimethylsulfoxide (8.0 mL) was stirred at 100 C for 5 hours. After cooling to room temperature, the reactant was poured into water, and then extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane : ethyl acetate = 8 : 1), to obtain 4-(2-methylpyrrolidin-1-yl)-1-naphthonitrile (516 mg) (Compound 48).1H-NMR (200 MHz, CDCl3) ?: 1.18 (3H, d, J=5.8Hz), 1.60-2.15 (3H, m), 2.20-2.40 (1H, m), 3.25-3.40 (1H, m), 3.90-4.15 (2H, m), 6.82 (1H, d, J=8.0 Hz), 7.40-7.70 (2H, m) 7.76(1H, d, J=8.0 Hz), 8.15-8.25(2H, m). IR (KBr) 2209, 1565, 1514, 1327, 763 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 70
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 70-71

72
[ 7037-49-2 ]
[ 13916-99-9 ]
4-[4-(3-hydroxypropyl)-1-piperidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; water; dimethyl sulfoxide; at 100℃; for 3h;	Example 85 (Preparation of Compound 88) To a mixture of ethyl 3-(4-piperidinyl)butyrate (870 mg) and tetrahydrofuran (10 mL) was added lithium aluminum hydride (178 mg) at 0°C, and the mixture was stirred for 6 hours. Water (0.18 mL), a 25percent potassium hydroxide solution (0.18 mL) and water (0.54 mL) were sequentially added and the mixture was stirred for 14 hours. Insolubles were filtered off using celite and mother liquor was concentrated to obtain a pale yellow oily matter (590 mg). A mixture of the obtained matter (167 mg), 4-fluoro-1-naphthonitrile (100 mg), potassium carbonate (202 mg) and dimethylsulfoxide (1.0 mL) was stirred at 100°C for 3 hours. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[4-(3-hydroxypropyl)-1-piperidinyl]-1-naphthonitrile (105 mg) (Compound 88). mp 114 - 115°C. 1H-NMR (300 MHz, CDCl3) delta: 1.30 (1H, t, J=5.4 Hz), 1.43-1.54 (4H, m), 1.57-1.72 (3H, m), 1.90-1.92 (2H, m), 2.80 (2H, t, J=11.7 Hz), 3.49-3.54 (2H, m), 3.70 (2H, td, J=6.6 and 5.4 Hz), 7.00 (1H, d, J=8.1 Hz), 7.56 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.65 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.82 (1H, d, J=8.1 Hz), 8.14-8.20 (2H, m). IR (KBr) 2932, 2216, 1572 cm-1

Reference： [1]Patent: EP1553074,2005,A1 .Location in patent: Page/Page column 80-81

73
[ 71879-55-5 ]
[ 13916-99-9 ]
ethyl 3-[1-(4-cyano-1-naphthyl)-4-piperidinyl]butyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 1h;	84 Example 84 Example 84 (Preparation of Compound 87) A mixture of 4-fluoro-1-naphthonitrile (70 mg), ethyl 3-(4-piperidinyl)butyrate (91 mg), potassium carbonate (78 mg) and dimethylsulfoxide (1.0 mL) was stirred at 100°C for 1 hour. After cooling to room temperature, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain ethyl 3-[1-(4-cyano-1-naphthyl)-4-piperidinyl]butyrate (110 mg) (Compound 87). mp 106 - 107°C. 1H-NMR (300 MHz, CDCl3) δ: 1.28 (3H, t, J=7.2 Hz), 1.54-1.62 (2H, m), 1.69-1.77 (2H, m), 1.88-1.91 (2H, m), 2.41 (2H, t, J=7.5 Hz), 2.79 (2H, t, J=11.1 Hz), 3.46-3.52 (2H, m), 4.16 (2H, q, J=7.2 Hz), 6.99 (1H, d, J=7.8 Hz), 7.55 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.64 (1H, ddd, J=8.4, 6.9 and 1.5 Hz), 7.80 (1H, d, J=7.8 Hz), 8.12-8.19 (2H, m). IR (KBr) 2216, 1732, 1574 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 80

74
[ 13916-99-9 ]
(4-fluoronaphthalen-1-yl)methanamine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With hydrogenchloride; hydrogen In ethanol	A solution of 1-cyano-4-fluoronapthalene (1.05 g, 6.12 mmol) and 1.5 mL of HCl (aq.) in absolute ethanol (50 mL) was stirred under a hydrogen atmosphere (balloon) with 10% palladium on carbon (0.20 g) for 16 hours. The catalyst was removed by filtration through Celite, and the filtrate concentrated under vacuum. The resulting solid was triturated with ether and collected by filtration to give the title compound (0.575 g, 44% yield) as an off white solid.
44%	With hydrogenchloride; hydrogen In ethanol; water for 16h;	(4-Fluoronaphthalen-1-yl)methanamine hydrochloride. A solution of 1-cyano-4-fluoronapthalene (1.05 g, 6.12 mmol) and 1.5 mL of HCl (aq.) in absolute ethanol (50 mL) was stirred under a hydrogen atmosphere (balloon) with 10% palladium on carbon (0.20 g) for 16 hours. The catalyst was removed by filtration through Celite, and the filtrate concentrated under vacuum. The resulting solid was triturated with ether and collected by filtration to give the title compound (0.575 g, 44% yield) as an off white solid.
44%	With hydrogenchloride; hydrogen In ethanol; water for 16h;	(4-Fluoronaphthalen-1-yl)methanamine hydrochloride. A solution of 1-cyano-4-fluoronapthalene (1.05 g, 6.12 mmol) and 1.5 mL of HCl (aq.) in absolute ethanol (50 mL) was stirred under a hydrogen atmosphere (balloon) with 10% palladium on carbon (0.20 g) for 16 hours. The catalyst was removed by filtration through Celite, and the filtrate concentrated under vacuum. The resulting solid was triturated with ether and collected by filtration to give the title compound (0.575 g, 44% yield) as an off white solid.

44%	With hydrogenchloride; hydrogen In ethanol for 16h;	(4-Fluoronaphthalen-l-yl)methanωninβ hydrochloride. A solution of 1- cyano-4-fluoronapthalene (1.05 g, 6.12 mmol) and 1.5 mL of HCl (aq.) in absolute ethanol (50 mL) was stirred under a hydrogen atmosphere (balloon) with 10% palladium on carbon (0.20 g) for 16 hours. The catalyst was removed by filtration through Celite, and the filtrate concentrated under vacuum. The resulting solid was triturated with ether and collected by filtration to give the title compound (0.575 g, 44% yield) as an off white solid.
44%	With hydrogenchloride; hydrogen In ethanol; water for 16h;	(4-Fluoronaphthalen-l-yl)methanωninβ hydrochloride. A solution of 1- cyano-4-fluoronapthalene (1.05 g, 6.12 mmol) and 1.5 mL of HCl (aq.) in absolute ethanol (50 mL) was stirred under a hydrogen atmosphere (balloon) with 10% palladium on carbon (0.20 g) for 16 hours. The catalyst was removed by filtration through Celite, and the filtrate concentrated under vacuum. The resulting solid was triturated with ether and collected by filtration to give the title compound (0.575 g, 44% yield) as an off white solid.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2005/267105, 2005, A1 Location in patent: Page/Page column 51
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/111984, 2007, A1 Location in patent: Page/Page column 13
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/129379, 2007, A1 Location in patent: Page/Page column 9-10
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2007/64316, 2007, A1 Location in patent: Page/Page column 107
[5]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2007/64316, 2007, A1 Location in patent: Page/Page column 107

75
[ 905724-78-9 ]
[ 13916-99-9 ]
C₂₄H₁₈N₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl acetamide at 150℃; for 1h;	30 INTERMEDIATE 1 (132 mg, 0.50 mmol) was combined with 4-fluoronaphthonitrile (76 mg, 0.5 mmol) and Cs2CO3 (1.0 g, 3 mmol) in 5 mL of N,N-dimethylacetamide. The reaction mixture was stirred at 150 0C for 1 h, then was dumped into water and acidified with 2N aq. HCl to pH <2. The resulting solid precipitate was extracted with ethyl acetate and washed with water followed by brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexane gradient) gave the product. LC-MS calc. for C24H18N2O3S: 414; Found: 415 (M+H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2006/83781, 2006, A1 Location in patent: Page/Page column 72

76
[ 905724-75-6 ]
[ 13916-99-9 ]
C₂₃H₁₆N₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl acetamide at 150℃; for 1h;	10 INTERMEDIATE 1 (125 mg, 0.50 mmol) was combined with 4-fluoronaphthonitrile (76 mg, 0.5 mmol) and Cs2CO3 (1.0 g, 3 mmol) in 5 mL of N,N-dimethylacetamide. The reaction mixture was stirred at 150 0C for 1 h, then was dumped into water and acidified with 2N aq. HCl to pH <2. The resulting solid precipitate was extracted with ethyl acetate and washed with water followed by brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by Combi-Flash (silica, 5-30% ethyl acetate/hexane gradient) gave the product.LC-MS calc. for C23H16N2O3S: 400; Found: 401 (M+H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2006/83781, 2006, A1 Location in patent: Page/Page column 64

77
[ 13916-99-9 ]
[ 2386-64-3 ]
[ 1427-77-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-fluoronaphthalene-1-carbonitrile; ethylmagnesium chloride In diethyl ether for 16h; Heating / reflux; Stage #2: With hydrogenchloride In diethyl ether; water	21 Preparation 21: l-(4-Fluoronaphthalcn-l-yl)propan-l-oncl-Cyano-4-fluoronaphthalene (Ig, 5.8mmol) was dissolved in Et2O (1OmL) followed by addition of ethylmagnesium chloride (2.0M in Et2O, 2.9mL, 5.8mmol) and the reaction was heated to reflux for 16hr. The reaction was quenched with 2N HCl (2OmL) then extracted into DCM (3 x 4OmL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with EtOAc:hexanes (1:9) to afford the title compound. δH (CDCl3): 1.29 (3H, t), 3.08 (2H, q), 7.16 (IH, m), 7.60 (IH, m), 7.66 (IH, m), 7.89 (IH, m), 8.16 (IH, d), 8.74 (IH, d).

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2006/85118, 2006, A2 Location in patent: Page/Page column 25

78
[ 13916-99-9 ]
[ 89990-53-4 ]
[ 908267-39-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With caesium carbonate; In dimethyl sulfoxide; at 80℃;	B. 4-(tetrahydro-1 (2H)-pyridazinyl)-1 -naphthalenecarbonitrile (B1) To a 500ml round bottom flask equipped with a magnetic stirbar, an addition funnel, and nitrogen flow was added 7.Og <strong>[89990-53-4]hexahydropyridazine dihydrochloride</strong> (43.18 mmoles, 1.5eq) in 100ml dry DMSO, then 33g cesium carbonate (0.102 moles, 3.5eq) was added all at once. The reaction mixture was heated to 80 0C via an oil bath, at which point, 5g 4-fluoro-1 -naphthalenecarbonitrile (29.21 mmoles, 1eq) in 20ml DMSO was added dropwise. The reaction was stirred at 80 0C overnight. After cooling to ambient EPO <DP n="48"/>6 00609647 temperature, 100ml distilled water was added, which resulted in the precipitation of a5.6g (80% yield) of the title compound as a yellow solid.1 H NMR (400 MHz, DMSO-D6) delta ppm 1.6 (m, 2 H) 1.9 (m, 2 H) 3.1 (m, 2 H) 3.4 (m, 2 H) 4.5 (m, 1 H) 7.2 (d, J=8.6 Hz, 1 H) 7.6 (m, 1 H) 7.7 (m, 1 H) 8.3 (m, 2 H) 8.5 (d, J=8.1 Hz, 1 H)

Reference： [1]Patent: WO2006/91592,2006,A1 .Location in patent: Page/Page column 46-47

79
[ 24830-94-2 ]
[ 13916-99-9 ]
[ 1182368-47-3 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: D-allo-threonine; 4-fluoronaphthalene-1-carbonitrile With potassium carbonate In dimethyl sulfoxide at 20 - 80℃; Stage #2: With citric acid In water	51.51a Example 51; 4-((1R,2R)-1-(5-(4-Cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino) 1-naphthonitrile; Intermediate 51a; (2R,3R)-2-(4-Cyanonaphthalen-1-ylamino)-3-hydroxybutanoic acid; To a suspension of D-allo-threonine (2.09 g, 17.53 mmol) and K2CO3 (4.04 g, 29.21 mmol) in DMSO (40 mL) was added 4-fluoro-1-naphthonitrile (CAS 13916-99-9, 2.50 g, 14.61 mmol) at room temperature. The reaction mixture was heated to 80° C. and stirred for 89 h. The reaction mixture was allowed to cool to room temperature, quenched with H2O (150 mL) and extracted with EtOAc (3×100 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The later organic extracts were combined, washed with H2O (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a light brown solid (3.0 g, 76%): 1H NMR (400 MHz, DMSO-d6, δ in ppm) 8.46 (d, J=8.8 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.74 (t, J=7.0 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 4.29-4.20 (m, 1H), 4.08-3.99 (m, 1H), 1.28 (d, J=6.1 Hz, 3H).

Reference： [1]Current Patent Assignee: ELLIPSES PHARMA LIMITED - US2009/253758, 2009, A1 Location in patent: Page/Page column 98

80
[ 632-20-2 ]
[ 13916-99-9 ]
[ 1182367-26-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: D-Threonine; 4-fluoronaphthalene-1-carbonitrile With potassium carbonate In dimethyl sulfoxide at 75℃; for 24h; Stage #2: With citric acid In water; dimethyl sulfoxide at 20℃;	13.13a Example 13; 4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-1-naphthonitrile; Intermediate 13a; (2R,3S)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoic acid; 4-fluoro-1-naphthonitrile (13916-99-9) (1.0 g, 5.84 mmol) was mixed together with H-D-Thr-OH (835 mg, 7.01 mmol) in DMSO (20 mL). K2CO3 (1.61 g, 11.68 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexane/EtOAc and then with EtOAc, 100% to get the pure final product (1.1 g): 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.25 (d, J=9 Hz, 1H), 8.09 (d, J=9 Hz, 1H), 7.84 (d, J=9 Hz, 1H), 7.75 (t, J=9 Hz, 1H), 7.65 (t, J=9 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 6.32 (d, J=9 Hz, 1H), 4.53 (m, 1H), 4.38 (m, 1H), 1.40 (d, J=6 Hz, 3H).

Reference： [1]Current Patent Assignee: ELLIPSES PHARMA LIMITED - US2009/253758, 2009, A1 Location in patent: Page/Page column 45

81
[ 664364-31-2 ]
[ 13916-99-9 ]
4-[(2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methyl-1-pyrrolidinyl]-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-[(2S,3S)-2-methyl-1-[(1S)-1-phenylethyl]pyrrolidine-3-yl]propane-2-ol With hydrogen; acetic acid In methanol for 3h; Stage #2: 4-fluoronaphthalene-1-carbonitrile With potassium carbonate In dimethyl sulfoxide at 100℃; for 3h;	155 Example 155 Example 155 (Preparation of Compound 158) 2-{(2S,3S)-2-methyl-1-[(1S)-1-phenylethyl]-pyrrolidin-3-yl}propan-2-ol (1.08 g) was dissolved in methanol (20 mL), acetic acid (1.0 mL) and 10% palladium carbon (containing water) (500 mg) were added, and the mixture was stirred under hydrogen atmosphere for 3 hours. The catalyst was filtered off, the filtrate was concentrated and dried. To the residue was added 4-fluoro-1-naphthonitrile (750 mg), potassium carbonate (1.81 g) and dimethylsulfoxide (20.0 mL) were added, and the mixture was stirred at 100°C for 3.0 hours. After cooling to room temperature, water was poured into the reactant and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4-[(2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methyl-1-pyrrolidinyl]-1-naphthonitrile (543 mg) (Compound 158). [α]D=-225.5° (c=0.20, MeOH). 1H-NMR (200 MHz, CDCl3) δ: 0.98(3H, d, J=6.6 Hz), 1.34 (3H, s), 1.39 (3H, s), 1.57 (1H, s), 2.05-2.16 (2H, m), 2.45-2.65 (1H, m), 3.20-3.40 (1H, m), 3.70-3.92 (1H, s), 4.35-4.55 (1H, m), 6.89 (1H, d, J=8.0 Hz), 7.45-7.70 (2H, m), 7.77 (1H, d, J=8.0 Hz), 8.06-8.24 (2H, m). IR (KBr) 2211, 1569 cm-1

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1553074, 2005, A1 Location in patent: Page/Page column 100

82
[ 13916-99-9 ]
(3RS)-3-fluoropiperidine hydrochloride [ No CAS ]
4-(3-fluoropiperidin-1-yl)naphthalene-1-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	Stage #1: (3RS)-3-fluoropiperidine hydrochloride With sodium hydroxide Stage #2: 4-fluoronaphthalene-1-carbonitrile With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene at 110℃; for 336h;	3-Fluoropiperidine hydrochloride (106 mg, 0.76 mol) was dissolved in sodium hydroxide (1 M, 10 mL) and extracted with dichloromethane (4 x 10 mL), the combined extracts were dried over sodium sulfate, filtered and evaporated. Pyridine (2 mL) was added, followed by 1-cyano-4-fluoronaphthalene (108 mg, 0.63 mmol) and the vial was shaken at 110 °C overnight. GC-MS and TLC showed only very little conversion. DBU (10 µL) was added and the shaking was continued for 2 weeks at 110 °C, after which GC-MS showed -50% conversion. The reaction was worked up in the same way as 165RL60 and purified by silica gel column chromatography eluted with a stepwise gradient of 0 - 60% ethyl acetate in n-heptane to give the title compound (29.3 mg, 12 %) as a solid. [0464] LCMS m/z 255 [M+H] (at). (at)H-NMR (CDCl3,300 NMz) No. 8.22 (m, 2H), 7.83 (d, 1H, J= 7.9), 7.63 (m, 2H), 7.03 (d, 1H, J= 7.9), 4.92 (dm, 1H, JH-F = 48), 3.45- 3.04 (m, 4H), 2.23-1.79 (m, 4H).

Reference： [1]Current Patent Assignee: ACADIA PHARMACEUTICALS INC - WO2005/115361, 2005, A2 Location in patent: Page/Page column 108-109

83
[ 13916-99-9 ]
[ 538-09-0 ]
[ 870888-46-3 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7186 - 7191

84
[ 13916-99-9 ]
[ 1236124-75-6 ]
[ 1236124-53-0 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide	3.5 Example 3, Step S Reaction of compound 3-5 with 4-fluoronaphthonitriIe 3-6 and cesium carbonate in DMF affords Example 3 after workup and purification.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2010/85528, 2010, A1 Location in patent: Page/Page column 83-84

85
[ 13916-99-9 ]
[ 123-08-0 ]
[ 1202577-02-3 ]

Yield	Reaction Conditions	Operation in experiment
81.6%	Stage #1: 4-hydroxy-benzaldehyde With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 4-fluoronaphthalene-1-carbonitrile In N,N-dimethyl-formamide at 140℃; for 12h; Inert atmosphere;	To a solution of 4-hydroxybenzaldehyde (4.78 g, 39.1 mmol) inDMF (100 mL) was added K2CO3 powder (10.8 g, 78.3 mmol). Afterstirring at room temperature for 0.5 h, intermediate 12 (6.7 g,39.1 mmol) was added and the mixture was heated to 140 C for12 h under nitrogen protection. After cooling to room temperature,the reaction mixture was filtered and washed with ethyl acetate(50 mL 3), then the filtrate was washed with water (100 mL 2)and brine (100 mL 2). The organic layer was dried and concentratedto give the crude product, which was recrystallized inethanol-water mixed solvent to give intermediate 13 (8.78 g) aswhite solid in 81.6% yield.
77%	With caesium carbonate In N,N-dimethyl acetamide at 20 - 120℃; Inert atmosphere;	23.A (23A) 4-(4-Formylphenoxy)-1-naphthonitrile (23A) 4-(4-Formylphenoxy)-1-naphthonitrile 4-Hydroxybenzaldehyde (300 mg, 2.46 mmol) was dissolved in dimethylacetoamide (8.0 mL), and 4-fluoro-naphthalene-1-carbonitrile (463 mg, 0.420 mmol) and cesium carbonate (1.20 g, 3.69 mmol) were sequentially added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 120° C. for 2 hours. After the temperature of the reaction solution was returned to room temperature, water was added thereto, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 70:30 (v/v)), whereby the objective title compound was obtained (515 mg, yield: 77%). 1H NMR (CDCl3, 400 MHz): δ7.00 (1H, d, J=7.8 Hz), 7.24 (2H, d, J=8.6 Hz), 7.72-7.66 (1H, m), 7.83-7.78 (1H, m), 7.89 (1H, d, J=8.2 Hz), 7.97 (2H, d, J=8.6 Hz), 8.31 (2H, d, J=9.4 Hz), 10.0 (1H, s)

Reference： [1]Wang, Junwei; Song, Qiao; Xu, Anhua; Bao, Yu; Xu, Yungen; Zhu, Qihua [European Journal of Medicinal Chemistry, 2017, vol. 130, p. 15 - 25]
[2]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2011/53974, 2011, A1 Location in patent: Page/Page column 32

86
[ 13916-99-9 ]
[ 121-33-5 ]
[ 1055361-84-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate In N,N-dimethyl-formamide at 95℃; for 5h;
85%	Stage #1: vanillin With lithium carbonate In dimethyl sulfoxide at 20℃; for 0.5h; Stage #2: 4-fluoronaphthalene-1-carbonitrile In dimethyl sulfoxide at 100℃; for 48h;	36 Reference Example 36 4-(4-formyl-2-methoxyphenoxy)naphthalene-l-carbonitrile; [Show Image] To a solution (700 mL) of 4-hydroxy-3-methoxybenzaldehyde (63.5 g) in dimethyl sulfoxide was added lithium carbonate (45.8 g), and the mixture was stirred at room temperature for 0.5 hr. To the reaction mixture was added 4-fluoronaphthalene-1-carbonitrile (70.0 g), and the mixture was stirred at 100°C for 2 days. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was recrystallized from tetrahydrofuran to give the title compound as a white solid (yield: 106 g, 85%). 1H-NMR (DMSO-d6, 300 MHz):δ3.84 (3H, s), 6.75 (1H, d, J = 8.1 Hz), 7.46 (1H, d, J = 8.1 Hz), 7.67 (1H, dd, J = 8.1, 1.9 Hz), 7.75 (1H, d, J = 1.9 Hz), 7.77-7.84 (1H, m), 7.87-7.94 (1H, m), 8.06 (1H, d, J = 8.3 Hz), 8.15 (1H, d, J = 8.3 Hz), 8.42 (1H, d, J = 8.3 Hz), 10.03 (1H, s).

Reference： [1]Location in patent: experimental part Patch, Raymond J.; Searle, Lily L.; Kim, Alexander J.; De, Debyendu; Zhu, Xizhen; Askari, Hossein B.; O'Neill, John C.; Abad, Marta C.; Rentzeperis, Dionisios; Liu, Jianying; Kemmerer, Michael; Lin, Ling; Kasturi, Jyotsna; Geisler, John G.; Lenhard, James M.; Player, Mark R.; Gaul, Micheal D. [Journal of Medicinal Chemistry, 2011, vol. 54, # 3, p. 788 - 808]
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2450352, 2012, A1 Location in patent: Page/Page column 72

87
[ 13916-99-9 ]
[ 1264753-83-4 ]
[ 1264751-34-9 ]

Yield	Reaction Conditions	Operation in experiment
9%	With lithium carbonate In dimethyl sulfoxide at 80℃; for 24h;	26 Example 26 4-{4-[(Z)-(1-ethyl-5-imino-2-oxoimidazolidin-4-ylidene)methyl]-2-methoxyphenoxy}naphthalene-1-carbonitrile; [Show Image] To a solution (3 mL) of (4Z)-1-ethyl-4-[(4-hydroxy-3-methoxyphenyl)methylidene]-5-iminoimidazolidin-2-one (200 mg) in DMSO were added 4-fluoronaphthalene-1-carbonitrile (131 mg) and lithium carbonate (114 mg), and the mixture was stirred at 80°C for 1 day. Water (30 mL) was added at room temperature, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with 1 mol/L aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30 - 60%) to give the title compound as a white powder (yield: 26.9 mg, 9%), which was recrystallized from ethyl acetate/n-heptane to give the title compound as colorless crystals (yield: 13.5 mg, 4%). 1H-NMR (DMSO-d6, 300 MHz):δ1.14 (3H, brs), 3.58 (2H, q, J = 6.4 Hz), 3.79 (3H, s), 6.58-6.72 (2H, m), 7.13-7.39 (3H, m), 7.75-7.84 (1H, m), 7.85-7.95 (1H, m), 8.04 (1H, dd, J = 8.0, 1.8 Hz), 8.13 (1H, d, J = 8.3 Hz), 8.47 (1H, d, J = 8.3 Hz), 8.89 (1H, brs), 10.39 (1H, brs).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2450352, 2012, A1 Location in patent: Page/Page column 98-99

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
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CAS No. :	13916-99-9	MDL No. :	MFCD00236656
Formula :	C₁₁H₆FN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XQSGYYNFKIQWAC-UHFFFAOYSA-N
M.W :	171.17	Pubchem ID :	2736734
Synonyms :

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P233-P260-P261-P264-P270-P271-P280-P301+P310-P302+P352-P304-P304+P340-P305+P351+P338-P312-P321-P322-P330-P332+P313-P337+P313-P340-P361-P362-P363-P403-P403+P233-P405-P501	UN#:	2811
Hazard Statements:	H301-H311-H315-H319-H335	Packing Group:	Ⅲ
GHS Pictogram:

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P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 13916-99-9 ] {[proInfo.proName]}

Quality Control of [ 13916-99-9 ]

Related Doc. of [ 13916-99-9 ]

Product Details of [ 13916-99-9 ]

Safety of [ 13916-99-9 ]

Application In Synthesis of [ 13916-99-9 ]

[ 13916-99-9 ] Synthesis Path-Downstream 1~87

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry