[ CAS No. 39512-49-7 ] {[proInfo.proName]}

Name: 39512-49-7|4-(4-Chlorophenyl)piperidin-4-ol|98%
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SKU: A160694
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Quality Control of [ 39512-49-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 39512-49-7 ]

CAS No. :	39512-49-7	MDL No. :	MFCD00006001
Formula :	C₁₁H₁₄ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LZAYOZUFUAMFLD-UHFFFAOYSA-N
M.W :	211.69	Pubchem ID :	38282
Synonyms :

Calculated chemistry of [ 39512-49-7 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.45
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	61.29
TPSA :	32.26 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.47 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.18
Log Po/w (XLOGP3) :	1.58
Log Po/w (WLOGP) :	1.42
Log Po/w (MLOGP) :	2.01
Log Po/w (SILICOS-IT) :	2.83
Consensus Log Po/w :	2.0

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.4
Solubility :	0.845 mg/ml ; 0.00399 mol/l
Class :	Soluble
Log S (Ali) :	-1.87
Solubility :	2.87 mg/ml ; 0.0135 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.87
Solubility :	0.0284 mg/ml ; 0.000134 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.39

Safety of [ 39512-49-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 39512-49-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 39512-49-7 ]
Downstream synthetic route of [ 39512-49-7 ]

[ 39512-49-7 ] Synthesis Path-Upstream 1~9

1
[ 235109-63-4 ]
[ 39512-49-7 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 234 - 239
[2] Patent: WO2015/112441, 2015, A1, . Location in patent: Page/Page column 220
[3] Patent: US2016/333021, 2016, A1, . Location in patent: Paragraph 0795

2
[ 26905-02-2 ]
[ 39512-49-7 ]

Reference： [1] Organic Letters, 2017, vol. 19, # 3, p. 572 - 575

3
[ 873-77-8 ]
[ 39512-49-7 ]

Reference： [1] Patent: WO2015/112441, 2015, A1,
[2] Patent: US2016/333021, 2016, A1,

4
[ 79099-07-3 ]
[ 39512-49-7 ]

Reference： [1] Patent: WO2015/112441, 2015, A1,
[2] Patent: US2016/333021, 2016, A1,

5
[ 91335-13-6 ]
[ 39512-49-7 ]

Reference： [1] Journal of Medicinal and Pharmaceutical Chemistry, 1959, vol. 1, p. 281,284

6
[ 39512-49-7 ]
[ 3874-54-2 ]
[ 52-86-8 ]

Reference： [1] Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11353 - 11356
[2] Chemistry - A European Journal, 2012, vol. 18, # 35, p. 11107 - 11114
[3] ACS Catalysis, 2014, vol. 4, # 3, p. 722 - 731
[4] Journal of Medicinal and Pharmaceutical Chemistry, 1959, vol. 1, p. 281,284

7
[ 39512-49-7 ]
[ 52-86-8 ]

Reference： [1] Advanced Synthesis and Catalysis, 2004, vol. 346, # 11, p. 1329 - 1334
[2] Journal of Medicinal Chemistry, 1985, vol. 28, # 9, p. 1319 - 1324

8
[ 39512-49-7 ]
[ 37743-18-3 ]
[ 34552-83-5 ]

Yield	Reaction Conditions	Operation in experiment
67%	Stage #1: With sodium carbonate In 1,3-dioxolane-4-methanol for 0.25 h; Stage #2: at 60℃; for 2 h; Stage #3: With hydrogenchloride In 1,3-dioxolane-4-methanol; isopropyl alcohol for 0.333333 h;	Example 1 : Preparation of 4-[4-(4-diphenyl)-4-hvdroxypiperidino1-N,N- dimethyl-2,2-diphenylbutyramide hydrochloride (loperamide)0.111 g (5.2-10-4 mol, 1 eq) of 4,4-chlorophenyl-4-hydroxypiperidine, 0.062 g (5.8-10-4 mol, 1.11 eq) of sodium carbonate, 0.0009 g (0.24percent by weight) of potassium iodide were weighed and dissolved in 0.5 ml_ of glycerol formal. The resulting mixture was stirred for 15 minutes. Afterwards 0.2089 g (6.03-10-4 mol, 1.15 eq) of N,N-dimethyl-(3,3-diphenyltetrahydro-2- furyliden)ammonium bromide were added and heated at 6O⁰C. After 2 hours, the reaction mixture was left to cool to room temperature. The crude product was centrifuged at 18000 rpm for 30 minutes at 4O⁰C. The two phases were separated. To the supernatant 0.65 ml_ of isopropanol saturated with hydrochloric acid (7.8-10-4 mol of HCI, 1.5 eq) was added by stirring for 20 minutes. Then, 1 mL of H2O was added by stirring for 15 minutes. After this time, it was centrifuged at 9000 rpm for 1 hour at 21⁰C and the supernatant was removed. It was washed with water. The obtained solid was decanted and dried under vacuum. The title compound was obtained as a white solid. Yield: 67percent. Rf (AcNH^Dioxane/MeOH; 20/40/40) =0.86. ¹H NMR (300 MHz,CDCI₃) δ 11.7 (1H, s, OH), 7.3-7.5 (14 H, m, Ar), 3 (1 H, s, CH₃), 2.36 (2H, t, CH₂, J=6 MHz), 2.25 (2H, t, CH₂, J=6 MHz), 14.94 (4H, t, J=6 MHz).

Reference： [1] Patent: WO2008/80601, 2008, A2, . Location in patent: Page/Page column 10

9
[ 39512-49-7 ]
[ 37743-18-3 ]
[ 108-10-1 ]
[ 34552-83-5 ]

Reference： [1] Patent: US5798093, 1998, A,

[ 39512-49-7 ] Synthesis Path-Downstream 1~84

1
[ 39512-49-7 ]
[ 3874-54-2 ]
[ 52-86-8 ]

Yield	Reaction Conditions	Operation in experiment
30%	With sodium carbonate; sodium iodide; In acetonitrile; for 12h;Reflux; Inert atmosphere;	Compound 7 was prepared following a previously published protocol for a similar molecule.? Sodium iodide (0.039 g, 0.260 mmol) and sodium carbonate (0.050 g, 0.472 mmol) were added to a stirred mixture of 4?-fluoro-4- chiorobutyrophenone (0.047 g, 0.236 mmol) and 4-(4-chlo- rophenyl)-4-hydroxypiperidine (0.050 g, 0.236 mmol) in MeCN (2 mE). The reaction mixture was refluxed for 12 h. The mixture was diluted with H20, and extracted with CH2C12 (3x10 mE), dried over Mg504, and concentrated under reduced pressure. The residue was purified by column chromatography (5i02, MeOH:EtOAc/i:9, R10.19), to give compound 7 (0.027 g, 30% yield) as a white solid: ?H NMR (400 MHz, CDC13, FIG. 22) oe 7.99-7.96 (m, 2H), 7.38 (d, J=7.6 Hz, 2H), 7.27 (dd, J=8.4, 1.6 Hz, 2H), 7.11 (app. t, J=8.4 Hz, 2H), 3.04-2.98 (m, 4H), 2.72 (t, J=ii.6 Hz, 2H), 2.67 (t, J=6.8 Hz, 2H), 2.30-2.17 (m, 2H), 2.07 (p, J=6.8 Hz, 2H), 1.75 (m, 2H); ?3C NMR (100 MHz, CDC13, FIG. 23) oe 197.8, 167.0, 164.5, 146.0, 133.2, 133.0, 130.7, 130.6, 128.4, 126.0, 115.8, 115.6, 70.4, 57.4, 49.1, 37.2, 35.9, 20.6; ERMS mlz calcd for C2,H24C1FN02 [M+H]: 376.1; found 376.7. Purity of the compound was thrther confirmed by RP-HPEC by using method 1: Rt=7.62 mm (100% pure; FIG. 24).

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 11353 - 11356
[2]Chemistry - A European Journal,2012,vol. 18,p. 11107 - 11114
[3]ACS Catalysis,2014,vol. 4,p. 722 - 731
[4]Patent: US2019/15400,2019,A1 .Location in patent: Paragraph 0171; 0199-0200
[5]Journal of medicinal and pharmaceutical chemistry,1959,vol. 1,p. 281,284

2
[ 39512-49-7 ]
[ 939-52-6 ]
[ 31293-71-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	With Sodium hydrogenocarbonate; potassium iodide In toluene for 24h; Reflux;
17%	With anhydrous sodium carbonate; sodium iodide In acetonitrile for 12h; Reflux; Inert atmosphere;
	With toluene

Reference： [1]Fyfe, Tim J.; Kellam, Barrie; Sykes, David A.; Capuano, Ben; Scammells, Peter J.; Lane, J. Robert; Charlton, Steven J.; Mistry, Shailesh N. [Journal of Medicinal Chemistry, 2019, vol. 62, # 21, p. 9488 - 9520]
[2]Garneau-Tsodikova, Sylvie; Garzan, Atefeh; Green, Keith D.; Holbrook, Selina Y. L.; Hou, Caixia; Krieger, Kyle; Pang, Allan H.; Parish, Tanya; Posey, James E.; Punetha, Ankita; Thamban Chandrika, Nishad; Tsodikov, Oleg V.; Willby, Melisa J. [2021, vol. 12, # 11, p. 1894 - 1909]
[3]Janssen et al. [Journal of medicinal and pharmaceutical chemistry, 1959, vol. 1, p. 281,284]

3
[ 290-87-9 ]
[ 39512-49-7 ]
[ 420-04-2 ]
[ 91126-04-4 ]

Reference： [1]Archiv der Pharmazie,1984,vol. 317,p. 417 - 420

4
[ 39512-49-7 ]
[ 42205-96-9 ]
[ 80775-82-2 ]

Yield	Reaction Conditions	Operation in experiment
48.5%	at 160℃; for 40h;

Reference： [1]Sato; Uchimaru [Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 11, p. 3134 - 3144]

5
[ 39512-49-7 ]
[ 3308-94-9 ]
[ 56660-99-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 100℃; for 17.5h;

Reference： [1]Moerlein, Stephen M.; Stoecklin, Gerhard L. [Journal of Medicinal Chemistry, 1985, vol. 28, # 9, p. 1319 - 1324]

6
[ 39512-49-7 ]
[ 30005-58-4 ]

Yield	Reaction Conditions	Operation in experiment
74.8%	With triethylsilane; trifluoroacetic acid; at 60℃; for 4h;	(1) Weigh 4-(4-chlorophenyl)-piperidin-4-ol (300 mg, 1.42 mmol,a compound of the formula VI), triethylsilane (434 mg, 4.26 mmol) in a reaction flask,Add 10 mL of dry TFA and stir at 60 C for 4 h under nitrogen.The solvent was concentrated under reduced pressure, and the reaction mixture was diluted with ethyl acetate and water.The liquid phase was separated, and the aqueous phase was extracted with ethyl acetate.Wash with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn,Add anhydrous sodium sulfate and concentrate under reduced pressure.Crude chromatography by column chromatography (dichloromethane / methanol = 100:5)Obtained a pale yellow solid(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine, compound of formula VI-2) 205 mg,Yield: 74.8%.

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 9488 - 9520
[2]Journal of the American Chemical Society,1996,vol. 118,p. 5846 - 5856
[3]Patent: CN109384707,2019,A .Location in patent: Paragraph 0135-0139

7
[ 39512-49-7 ]
[ 39186-58-8 ]
[ 63959-33-1 ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 40h;Inert atmosphere; Reflux;	Under inert conditions, 4-(4-Chlorophenyl)-4-hydroxypiperidine (27a) (1.78g, 8.41mmol, 1.0equiv.) was suspended in 28mL MeCN and DIPEA (4.30mL, 23.2mmol, 3.0equiv.) was added. 4-Bromo-2,2-diphenylbutyronitrile (26) (2.52g, 8.41mmol, 1.0equiv.) was then added and the reaction mixture was stirred at reflux for 40h. After concentration under reduced pressure, the crude residue was purified by flash chromatography (eluent DCM/MeOH=98/2 to 9/1), yielding 2.78g (77%) of diphenylbutanenitrile ( 25a) as a white solid. (0076) Rf (DCM/MeOH=9/1)=0.38; 1H NMR (400MHz, CDCl3) delta (ppm)=7.28-7.46 (14H, m, Ar-H), 2.40-2.90 (8H, m, H-2, H-3 and H-4), 2.00-2.21 (2H, m, H-5a), 1.71 (2H, d, H-5b, J=12.9Hz), 1.57 (1H, bs, OH).
70%	With sodium carbonate; sodium iodide; In acetonitrile;Reflux;	Method B. A mixture of 4-bromo-2,2-diphenylbutyronitrile (8.0g, 26.7mmol), <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (5.92g, 28.0mmol), NaI (4.40g, 29.4mmol) and Na2CO3 (5.65g, 53.3mmol) in CH3CN (50mL) was heated and refluxed overnight. The solvent was removed in vacuo. The residue was dissolved in CH2Cl2 and washed with water, brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with ammonium hydroxide solution (2M) in MeOH/CH2Cl2 (from 0 to 3:125) to afford compound 1 (8.05g, 70%) as a white solid, mp 106-108C (lit.8 108-109C). 1H NMR (CDCl3): delta 7.43-7.28 (m, 14H), 2.76 (d, J=11.5Hz, 2H), 2.66-2.63 (m, 2H), 2.54-2.51 (m, 2H), 2.44 (dt, J=2.0, 12.0Hz, 2H), 2.08 (dt, J=4.0, 13.0Hz, 2H), 1.69 (dd, J=2.0, 14.0Hz, 2H), 1.61 (br s, 1H).

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 8503 - 8519
[2]European Journal of Medicinal Chemistry,2016,vol. 119,p. 231 - 249
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5259 - 5263
[4]Journal of Medicinal Chemistry,2008,vol. 51,p. 6034 - 6043
[5]Molecules,2012,vol. 17,p. 14288 - 14297
[6]Tetrahedron Letters,2013,vol. 54,p. 1412 - 1415
[7]Journal of Medicinal Chemistry,1999,vol. 42,p. 4680 - 4694

8
[ 39512-49-7 ]
[ 100-39-0 ]
[ 56108-25-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In methanol; dichloromethane; N,N-dimethyl-formamide;	Step 1 N-benzyl-<strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong>: a To a stirred solution of commercially available <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (10 g, 47 mmol., 1) in anhydrous DMF (10 mL) was added benzyl bromide (5.6 mL, 47 mmol) and K2CO3 (7.4 g, 94 mmol.) and stirred at RT overnight. Excess solvent was removed under reduced pressure, brought up into CH2Cl2 (100 mL) washed with H2O (2*50 mL). Organic layer separated, dried over Na2SO4 and charged on a silica gel flash column. Eluding off with 2% MeOH/CH2Cl2 10 g 2 (80% yield) was obtained as a viscous liquid. MS m/z: (M+303)
80%	With potassium carbonate; In methanol; dichloromethane; N,N-dimethyl-formamide;	Step 1 N-benzyl-<strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong>: a To a stirred solution of commercially available <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (10 g, 47 mmol., 1) in anhydrous DMF (10 mL) was added benzyl bromide (5.6 mL, 47 mmol) and K2CO3 (7.4 g, 94 mmol.) and stirred at RT overnight. Excess solvent was removed under reduced pressure, brought up into CH2Cl2 (100 mL) washed with H2O (2*50 mL). Organic layer separated, dried over Na2SO4 and charged on a silica gel flash column. Eluding off with 2% MeOH/CH2Cl2 10 g 2 (80% yield) was obtained as a viscous liquid. MS m/z: (M+303)
80%	With potassium carbonate; In methanol; dichloromethane; N,N-dimethyl-formamide;	Step 1 N-benzyl-<strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong>: FIG. 8a To a stirred solution of commercially available <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (10 g, 47 mmol., 1) in anhydrous DMF (10 mL) was added benzyl bromide (5.6 mL, 47 mmol) and K2CO3 (7.4 g, 94 mmol.) and stirred at RT overnight. Excess solvent was removed under reduced pressure, brought up into CH2Cl2 (100 mL) washed with H2O (2*50 mL). Organic layer separated, dried over Na2SO4 and charged on a silica gel flash column. Eluding off with 2% MeOH/CH2Cl2 10 g 2 (80% yield) was obtained as a viscous liquid. MS m/z: (M+303).

80%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	10828] To a stirred solution of commercially available 4-(4- chlorophenyl)-4-hydroxypiperidine (10 g, 47 mmol., 1) in anhydrous DMF (10 mE) was added benzyl bromide (5.6 mE, 47 mmol) and K2C03 (7.4 g, 94 mmol.) and stirred at RT overnight. Excess solvent was removed under reduced pressure, brought up into CH2C12 (100 mE) washed with H20 (2x50 mE). Organic layer separated, dried over Na2504 and charged on a silica gel flash column. Eluting off with 2% MeOHCH2C12 10 g 2 (80% yield) was obtained as a viscous liquid. MS mz: (M+303)
73%	With sodium carbonate; sodium iodide; In acetonitrile; for 2h;Reflux; Inert atmosphere;	Sodium carbonate (372 mg, 3.51 mmol) was added to the solution of benzyl bromide (5a) (300 mg, 1.75 mmol), (p-chlorophenyl)piperidin-4-ol (6) (447 mg, 2.11 mmol) and sodium iodide (316 mg, 2.11 mmol) in dry MeCN (2.0 mL) at room temperature under atmosphere of argon, and the mixture was refluxed for indicated hours. The reaction quenched with water and extracted with CHCl3. The extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography with CHCl3/MeOH (50:1) to give N-benzyl-4-(p-chlorophenyl)piperidin-4-ol (7a) as a yellow oil in 73% yield. The analytical data were identical with those of a literature compound.13 IR (neat): nu = 3390 (OH), 2942 (CH2), 1095 (Ar-Cl); 1H NMR (500 MHz, CDCl3): delta = 1.62-1.80 (3H, m), 2.12 (2H, dt, J = 4.4, 13.0 Hz), 2.45 (2H, dt, J = 2.5, 12.0 Hz), 2.78 (2H, dd, J = 2.4, 8.9 Hz), 3.57 (2H, s), 7.23-7.37 (7H, m), 7.41-7.47 (2H, m); 13C NMR (125 MHz, CDCl3): delta= 38.5, 49.4, 63.2, 71.1, 126.2, 127.1, 128.2, 128.4, 129.2, 132.7, 138.4, 147.0; MS (EI) m/z301 ([M]+); HR-MS (EI) Calcd for C18H20ClNO: 301.1233. Found: 301.1225.

Reference： [1]Synthetic Communications,2009,vol. 39,p. 2297 - 2303
[2]Tetrahedron Letters,2000,vol. 41,p. 8853 - 8856
[3]Patent: US2002/169155,2002,A1
[4]Patent: US2002/119973,2002,A1
[5]Patent: US6509346,2003,B2
[6]Patent: US2016/31908,2016,A1 .Location in patent: Paragraph 0828
[7]Heterocycles,2018,vol. 97,p. 560 - 568

9
[ 39512-49-7 ]
[ 37743-18-3 ]
[ 53179-11-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium carbonate In N,N-dimethyl-formamide at 80℃;
38%	With sodium carbonate; 4-methyl-2-pentanone at 80℃; Dean-Stark; Reflux;	4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-N,N-dimethyl-2,2-diphenylbutanamide(loperamide, 9). A mixture of 4-(4-chlorophenyl)-4-hydroxypiperidine (123mg, 0.58mmol), Na2CO3 (231mg, 2.18mmol) in iBuCOMe (18mL) was distilled azeotropically to dry with the aid of a Dean-Stark trap. After cooling to 80°C, compound 8 (200mg, 0.58mmol) was added. The reaction mixture was heated and refluxed overnight. The solvent was removed in vacuo. The residue was diluted with water, and extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was first purified by column chromatography with ammonium hydroxide solution (2M) in MeOH/CH2Cl2 (1:10). Then the product purified by silica gel column was injected onto onto a Luna C18 column (5μm, 100A, 10×250mm), and eluted at 5.0mL/min 40% solvent A (water/0.1% TFA) and 60% solvent B (acetonitrile/0.1% TFA) to afford compound 9 (126mg, 38%, TFA salt) as a white solid, mp 103-104°C. 1H NMR (CDCl3): δ 11.10 (s, 1H), 7.43-7.40 (m, 4H), 7.37-7.26 (m, 10H), 5.44 (s, 1H), 3.34 (d, J=10.0Hz, 2H), 3.20 (q, J=10.5Hz, 2H), 2.94 (s, 3H), 2.76-2.75 (m, 2H), 2.64-2.61 (m, 2H), 2.44-2.40 (m, 2H), 2.29 (s, 3H), 1.83 (d, J=14.5Hz, 2H). 13C NMR (CDCl3): δ 144.7, 138.9 133.6, 129.2, 128.8, 128.0, 127.9, 126.1, 69.1, 60.2, 55.6, 49.2, 39.6, 39.4, 37.4, 35.6. LC-MS (ESI, m/z): Calcd for C29H34ClN2O2 ([M+H]+) 477.2, found: 477.2.

Reference： [1]Chen, Zhengming; Davies, Ellen; Miller, Wendy S.; Shan, Shen; Valenzano, Kenneth J.; Kyle, Donald J. [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 21, p. 5275 - 5279]
[2]Wang, Min; Gao, Mingzhang; Zheng, Qi-Huang [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 19, p. 5259 - 5263]

10
[ 39512-49-7 ]
[ 4559-96-0 ]
1-(4''-bromobutyrophenone)-4-(4'-chlorophenyl)-4-hydroxypiperidine hydrochloride [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2005,vol. 53,p. 64 - 66

11
[ 39512-49-7 ]
[ 4830-93-7 ]
VUF 5746 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium carbonate; sodium iodide; In acetonitrile; for 6h;Reflux; Inert atmosphere;	General procedure: Sodium carbonate (372 mg, 3.51 mmol) was added to the solution of benzyl bromide (5a) (300 mg, 1.75 mmol), (p-chlorophenyl)piperidin-4-ol (6) (447 mg, 2.11 mmol) and sodium iodide (316 mg, 2.11 mmol) in dry MeCN (2.0 mL) at room temperature under atmosphere of argon, and the mixture was refluxed for indicated hours. The reaction quenched with water and extracted with CHCl3. The extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography with CHCl3/MeOH (50:1) to give N-benzyl-4-(p-chlorophenyl)piperidin-4-ol (7a) as a yellow oil in 73% yield.
		EXAMPLE 88 4-(4-Chlorophenyl)-4-hydroxyl-1-(4-phenylbutyl)piperidine STR125 From 1-chloro-4-phenylbutane (203 mg, 1.2 mmol) and <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (514 mg, 2.4 mmol) there was obtained 30 mg (7%) of the amine as a yellowish powder, mp 110-111 C. 1 H NMR (CDCl3): 1.56-1.74 (m, 7H), 2.08-2.18 (m, 2H), 2.36-2.46 ((, 4H), 2.62-2.67 (m, 2H), 2.80-2.84 (m, 2H), 7.187 (d, 2H, J=7), 7.26-7.33 (m, 5H), 7.445 (d, 2H, J=7). Anal. Calcd. for C21 H26 ClNO: C 73.35, H 7.62, N 4.07; Found: C 73.59, H 7.54, N 4.12.

Reference： [1]Heterocycles,2018,vol. 97,p. 560 - 568
[2]Journal of Medicinal Chemistry,2005,vol. 48,p. 6461 - 6471
[3]Patent: US6124323,2000,A

12
[ 14469-83-1 ]
[ 39512-49-7 ]
VUF 5752 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium carbonate; sodium iodide In acetonitrile Heating;

Reference： [1]Hulshof, Janneke W.; Vischer, Henry F.; Verheij, Mark H.P.; Fratantoni, Silvina A.; Smit, Martine J.; de Esch, Iwan J.P.; Leurs, Rob [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 21, p. 7213 - 7230]

13
[ 39512-49-7 ]
[ 637-59-2 ]
VUF 5745 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium carbonate; sodium iodide; In acetonitrile; for 2h;Reflux; Inert atmosphere;	General procedure: Sodium carbonate (372 mg, 3.51 mmol) was added to the solution of benzyl bromide (5a) (300 mg, 1.75 mmol), (p-chlorophenyl)piperidin-4-ol (6) (447 mg, 2.11 mmol) and sodium iodide (316 mg, 2.11 mmol) in dry MeCN (2.0 mL) at room temperature under atmosphere of argon, and the mixture was refluxed for indicated hours. The reaction quenched with water and extracted with CHCl3. The extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography with CHCl3/MeOH (50:1) to give N-benzyl-4-(p-chlorophenyl)piperidin-4-ol (7a) as a yellow oil in 73% yield.
		EXAMPLE 86 4-(4-Chlorophenyl)-4-hydroxyl-1-(3-phenylpropyl)piperidine STR123 From 3-phenylpropyl bromide (200 mg, 1.0 mmol) and <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (212 mg, 1.0 mmol) there was obtained 100 mg (30%) of the amine as a yellowish powder, mp 107-8 C. 1 H NMR (CDCl3): 1.52-1.75(m, 5H), 1.84-1.96 (m, 2H), 2.12-2.19 (m, 2H), 2.40-2.49 (m, 2H), 2.661 (t, 2H, J=7.6), 2.83-2.86 (m, 2H), 7.19-7.33 (m, 6H), 7.43-7.46 (m, 3H). Anal. Calcd. for C20 H24 ClNO: C 72.82, H 7.33, N 4.25; Found: C 72.54, H 7.18, N 4.23.

Reference： [1]Heterocycles,2018,vol. 97,p. 560 - 568
[2]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7213 - 7230
[3]Patent: US6124323,2000,A

14
[ 67713-99-9 ]
[ 39512-49-7 ]
1-benzofuran-3-ylmethyl-4-(4-chloro-phenyl)-piperidin-4-ol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 745 - 749

15
[ 39512-49-7 ]
[ 24424-99-5 ]
[ 235109-63-4 ]

Yield	Reaction Conditions	Operation in experiment
81%		Example 1: Preparation of 4-(4-Chlorophenyl)-l-(3,3-diphenylpropyl)-4- fluoropiperidine Hydrochloride[0053] Step 1 : Preparation of tert- utyl 4-(4-Chlorophenyl)-4-hydroxypiperidine-l- carboxylate. To a solution of 4-(4-chlorophenyl)-4-hydroxypiperdine (1.75 g, 8.22 mmol) in methylene chloride (100 mL) was added di-tert-butyldicarbonate (1.98 g, 9.10 mmol) followed by diisopropylethylamine (1.17 g, 9.10 mmol) and the resulting solution stirred at room temperature for 6 hours. After this time the reaction was quenched by the addition of 25% aqueous ammonium chloride (250 mL) and the layers separated. The organic layer was washed with water (100 mL) and brine (100 mL) and dried over magnesium sulfate.Subsequent filtration and concentration under reduced pressure afforded tert-butyl 4-(4- chlorophenyl)-4-hydroxypiperidine-l-carboxylate in 81% yield as a viscous clear oil which solidified on standing.1H NMR (CDC13): delta = 7.41 (d, J = 6.8 Hz, 2H), 7.32 (d, J = 6.8 Hz, 2H), 3.99 (m, 2H), 3.22 (m, 2H), 2.15 (bs, 1H), 1.94 (dd, J= 12.1, 9.5Hz, 2H), 1.70 (bd, J= 14.4Hz, 2H) and 1.47 ppm (s, 9H).
	With triethylamine; In dichloromethane;	PREPARATION 195 To a suspension of <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (8 g) and triethylamine (5.8 ml) in dichloromethane (80 ml) was added di-tert-butyldicarbonate (9.07 g) under ice-cooling. The suspension was then stirred for 5 hours at ambient temperature. The reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with water, washed with brine, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica using n-hexane/ethyl acetate (3:1) as the elution to give <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong>-1-carboxylic acid tert-butyl ester (11.76 g). IR (KBr): 3461.6, 1675.8, 1662.3, 1166.7 cm-1. NMR (CDCl3, delta): 1.48 (9H, s), 1.62-2.04 (5H, m), 3.16-3.28 (2H, m), 3.97-4.09 (2H, m), 7.30-7.44 (4H, m).
790 mg	With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 12h;	42.1 tert.butyl <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong>-1-carboxylate 500 mg 4-(4-chlorophenyl)-piperidin-4-ol are placed in 6 ml dioxane, then 0.9 ml of water and 400 mg sodium carbonate are added. After 5 min 530 mg di-tert-butyl-dicarbonate are added. The reaction mixture is stirred for 12 hours at ambient temperature, then mixed with water and the product is extracted with dichloromethane. 790 mg product are obtained as an oil. Analytical HPLC-MS (method B): RT=1.65 min.

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 14054 - 14058
[2]Patent: WO2011/137331,2011,A2 .Location in patent: Page/Page column 19-20
[3]Patent: US6884868,2005,B1
[4]Patent: US2013/225609,2013,A1 .Location in patent: Paragraph 0452; 0453
[5]Journal of Medicinal Chemistry,2019,vol. 62,p. 9488 - 9520

16
[ 39512-49-7 ]
[ 52-86-8 ]

Reference： [1]Advanced Synthesis and Catalysis,2004,vol. 346,p. 1329 - 1334
[2]Journal of Medicinal Chemistry,1985,vol. 28,p. 1319 - 1324
[3]Journal of the American Chemical Society,2019

17
[ 39512-49-7 ]
[ 201609-25-8 ]
2a-[4-{4-(4-chlorophenyl)-4-hydroxy-piperidyl}butyl]-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 3h;	2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (390 mg, 1.3 mmol), 4-(4-chlorophenyl) -4-hydroxypiperidine (290 mg, 1.4 mmol) and potassium carbonate (260 mg, 1.9 mmol) were stirred in anhydrous N,N-dimethylformamide (10 ml) at 60 C. for 3 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate and water. The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 490 mg of the title compound (1.1 mmol, 90% in yield). 1H-NMR (CDCl3) delta 1.01-1.16 (1 H, m), 1.27-1.40 (2 H, m), 1.41-1.58 (1 H, m), 1.67-1.92 (6 H, m), 2.05-2.23 (4 H, m), 2.32-2.52 (4 H, m), 2.60-2.70 (1 H, m), 2.77-2.90 (3 H, m), 6.68 (1 H, d, J=8.0 Hz), 6.80 (1 H, d, J=7.6 Hz), 7.11 (1 H, dd), 7.30 (2 H, d, J=8.0 Hz), 7.42 (2 H, d), 7.68 (1 H, br s); MW 439.00 (C26H31ClN2O2); Mass spectrum EI m/z 438:440 (intensity ratio 3:1) (M)+ The thus obtained free compound was dissolved in hydrochloric acid-saturated methanol to obtain its hydrochloric acid salt. MW (C26H32Cl2N2O2) 475.46; Mass spectrum EI m/z 438:440 (intensity ratio: 3:1) (M-HCl)+

Reference： [1]Patent: US6355642,2002,B1 .Location in patent: Page column 29

18
6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate [ No CAS ]
[ 39512-49-7 ]
[ 501377-46-4 ]

Yield	Reaction Conditions	Operation in experiment
49%	With triethylamine; In DMF (N,N-dimethyl-formamide); at 70℃; for 18h;	Example 269 2-(6-[4-(4-Chlorophenyl)-4-hydroxy-1-piperidyl]methyl}-2-pyridyl)-4H-1,3-benzothiazine-4-one 6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.30 g, 0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (0.20 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at 70 C for 18 hrs.. The reaction mixture was combined with ethyl acetate and water.. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.20 g, 49 %) as pale yellow crystals. mp. 151.0-153.0 C1H-NMR (CDCl3) delta: 1.75-1.79 (2H, m), 2.14-2.24 (2H, m), 2. 66-2.73 (2H, m), 2.87-2.95 (2H, m), 3.89 (2H, s), 7.33 (2H, d, J = 8.6 Hz), 7.47 (2H, d, J = 8.6 Hz), 7.60-7.75 (4H, m), 7.88 (1H, t, J = 7.8 Hz), 8.42 (1H, d, J = 7.7 Hz), 8.53-8.57 (1H, m). IR(KBr): 1651, 1572, 1537, 1439, 1302, 1097, 910, 734 cm-1.

Reference： [1]Patent: EP1424336,2004,A1 .Location in patent: Page 200

19
[ 39512-49-7 ]
[ 3436-04-2 ]
4-(4-chlorophenyl)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)propyl]piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium iodide; potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 1 4-(4-Chlorophenyl)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)propyl]piperidin-4-ol To a solution of 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (described in JP 48-030064)(200 mg) in DMF (10 ml) were added <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (230 mg), potassium carbonate (360 mg), and potassium iodide (50 mg). The mixture was stirred at 70 C. for 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluding with ethyl acetate-hexane (1:1) to give the titled compound (250 mg). 1H-NMR (CDCl3) d: 1.65-2.11 (5H, m), 2.32-3.10(8H, m), 3.22-3.67(4H, m), 5.87(1H, t), 7.03-7.44(12H, m). MS m/z: 444(M+1).
	With potassium iodide; potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 1 4-(4-Chlorophenyl)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)propyl]piperidin-4-ol To a solution of 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (described in JP 48-030064)(200 mg) in DMF (10 ml) were added <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (230 mg), potassium carbonate (360 mg), and potassium iodide (50 mg). The mixture was stirred at 70 C. for 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluding with ethyl acetate-hexane (1:1) to give the titled compound (250 mg). 1H-NMR (CDCl3) d: 1.65-2.11 (5H,m), 2.32-3.10 (8H,m), 3.22-3.67 (4H,m), 5.87 (1H,t), 7.03-7.44 (12H,m). MS m/z: 444 (M+1).
	With potassium iodide; potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 1 4-(4-Chlorophenyl)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)propyl]piperidin-4-ol To a solution of 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (described in JP 48-030064)(200 mg) in DMF (10 ml) were added <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (230 mg), potassium carbonate (360 mg), and potassium iodide (50 mg). The mixture was stirred at 70 C. for 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluding with ethyl acetate-hexane (1:1) to give the titled compound (250 mg). 1H-NMR (CDCl3) delta: 1.65-2.11 (5H, m), 2.32-3.10 (8H, m), 3.22-3.67 (4H, m), 5.87 (1H, t), 7.03-7.44 (12H, m). MS m/z: 444 (M+1).

	With potassium iodide; potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide;	Example 1 4-(4-Chlorophenyl)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)propyl]piperidin-4-ol To a solution of 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (described in JP 48-030064) (200 mg) in DMF (10 ml) were added <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (230 mg), potassium carbonate (360 mg), and potassium iodide (50 mg). The mixture was stirred at 70 C. for 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluding with ethyl acetate-hexane (1:1) to give the titled compound (250 mg). 1H-NMR (CDCl3) delta: 1.65-2.11 (5H, m) 2.32-3.10 (8H, m) 3.22-3.67 (4H, m), 5.87 (1H, t), 7.03-7.44 (12H, m). MS m/z: 444 (M+1).
	With potassium iodide; potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide;	Example 1 4-(4-Chlorophenyl)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)propyl]piperidin-4-ol To a solution of 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (described in JP 48-030064)(200 mg) in DMF (10 ml) were added <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (230 mg), potassium carbonate (360 mg), and potassium iodide (50 mg). The mixture was stirred at 70 C. for 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluding with ethyl acetate-hexane (1:1) to give the titled compound (250 mg). 1H-NMR (CDCl3) delta: 1.65-2.11 (5H,m), 2.32-3.10 (8H,m), 3.22-3.67(4H,m), 5.87(1H,t), 7.03-7.44(12H,m). MS m/z: 444(M+1).
	With potassium iodide; potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide;	Example 1 4-(4-Chlorophenyl)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)propyl]piperidin-4-ol To a solution of 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (described in JP 48-030064) (200 mg) in DMF (10 ml) were added <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (230 mg), potassium carbonate (360 mg), and potassium iodide (50 mg). The mixture was stirred at 70 C. for 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluding with ethyl acetate-hexane (1:1) to give the titled compound (250 mg). 1H-NMR (CDCl3) d: 1.65-2.11(5H,m), 2.32-3.10(8H,m), 3.22-3.67(4H,m), 5.87(1H,t), 7.03-7.44(12H,m). MS m/z: 444(M+1).
250 mg	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; for 24h;	Example 1 4-(4-Chlorophenyl)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)propyl]piperidin-4-ol To a solution of 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (described in JP 48-030064)(200 mg) in DMF (10 ml) were added <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (230 mg), potassium carbonate (360 mg), and potassium iodide (50 mg). The mixture was stirred at 70 C. for 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (250 mg). 1H-NMR (CDCl3) d: 1.65-2.11 (5H, m), 2.32-3.10 (8H, m), 3.22-3.67 (4H, m), 5.87 (1H, t), 7.03-7.44 (12H, m). MS m/z: 444 (M+1).

Reference： [1]Patent: US2002/169155,2002,A1
[2]Patent: US2002/119973,2002,A1
[3]Patent: US6509346,2003,B2
[4]Patent: US6613905,2003,B1
[5]Patent: US6329385,2001,B1
[6]Patent: US2005/70549,2005,A1
[7]Patent: US2016/31908,2016,A1 .Location in patent: Paragraph 0174

20
[ 39512-49-7 ]
[ 432505-59-4 ]
[ 432505-58-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine; In N,N-dimethyl-formamide;	Example 44 3-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-propionamide 4-(4-Chlorophenyl)-4-hydroxypiperidine (229 mg, 1.1 mmol, 1.5 equiv) was added in one portion to a solution of 3-bromo-N-(9-ethyl-9H-carbazol-3-yl)-propionamide (250 mg, 0.72 mmol, 1 equiv) and triethylamine (0.301 mL, 219 mg, 2.2 mmol) in DMF (2 mL). The resultant solution was maintained at room temperature for 21 hours and then diluted with ethyl acetate (25 mL). The mixture was washed with water (25 mL) and saturated aqueous sodium chloride (2*25 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by rotary chromatography (5% MeOH/CH2Cl2) to afford 3-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-propionamide (278 mg, 81%) as a white solid.

Reference： [1]Patent: US6399631,2002,B1

21
[ 23499-01-6 ]
[ 39512-49-7 ]
[ 144872-20-8 ]

Yield	Reaction Conditions	Operation in experiment
18%	With sodium cyanoborohydride; acetic acid;	EXAMPLE 5 4-(4-Chlorophenyl)-1-[1-(4-nitrophenyl)-4-piperidinyl]-4-piperidinol STR23 3.0 g (13.6 mmol) of <strong>[23499-01-6]1-(4-nitrophenyl)-4-piperidone</strong> (cf. Taylor et al. Synthesis (1981) 606], 2.9 g (13.6 mmol) of 4-(4-chlorophenyl)-4-hydroxypiperidine, 0.8 g (13.6 mmol) of acetic acid and 0.9 g (13.6 mmol) of sodium cyanoborohydride were reacted as in Example 1. Yield: 18%; melting point 225-226 C.

Reference： [1]Patent: US5296485,1994,A

22
N-(2-chloropropyl)-N-(2-phenylethyl)benzylamine [ No CAS ]
[ 39512-49-7 ]
[ 497-19-8 ]
3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]-N-benzyl-N-(2-phenyl-ethyl)-propylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium chloride; In ethyl acetate;	EXAMPLE 48 For the synthesis of 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]-N-benzyl-N-(2-phenyl-ethyl)-propylamine (UCSF61), a reaction flask was charged with N-(2-chloropropyl)-N-(2-phenylethyl)benzylamine (125 mg, 0.411 mmol), <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (120 mg, 0.561 mmol) and Na2 CO3 (110 mg). Xylenes (6 mL) were refluxed in under argon over two days. The resulting mixture was cooled to room temperature, then diluted with ether (30 mL). The ether layer was washed with saturated NaHCO3 (30 mL) followed by saturated NaCl (30 mL). The aqueous layers were back-extracted with ether (30 mL). The ether layers were combined, then dried over Na2 SO4, and evaporated to a brown oil (240 mg). This material was purified on a silica-gel column (6.2 g) with a gradient system (50% ethyl acetate in hexanes to 100% ethyl acetate), to yield 171 mg of an oil (89% yield), Rf =0.11 in 100% ethyl acetate. The identity of the product was continued as that of 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]-N-benzyl-N-(2-phenyl-ethyl)-propylamine by proton NMR.

Reference： [1]Patent: US5583000,1996,A

23
[ 68884-48-0 ]
[ 558-43-0 ]
[ 39512-49-7 ]
4-[4-(4-Chlorophenyl)-4-hydroxy-1-piperidinyl]methyl}-1-methyl-3,3-diphenyl-2-pyrrolidinone Fumarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	In ethanol; di-isopropyl ether; isopropyl alcohol;	EXAMPLE 23 4-[4-(4-Chlorophenyl)-4-hydroxy-1-piperidinyl]methyl}-1-methyl-3,3-diphenyl-2-pyrrolidinone Fumarate To a steel bomb was added 17.0 g. (0.057 mole) of 4-chloromethyl-1-methyl-3,3-diphenyl-2-pyrrolidinone in 150 ml. of ethanol, 12.0 g. (0.057 mole) of 4-(p-chlorophenyl)-4-hydroxypiperidine and 21.2 g. (0.17 mole) of finely ground potassium carbonate. The mixture was heated with stirring to 200 C. for 48 hours. After concentrating the mixture in vacuo, the residue was partitioned between dilute hydrochloric acid solution and isopropyl ether. The ether was discarded, the acid solution was made basic with 50 percent sodium hydroxide solution and the base insoluble material was extracted with chloroform. The chloroform was dried, filtered and concentrated in vacuo. The residue was dissolved in a mixture of isopropyl ether and isopropanol and treated with an equivalent of fumaric acid. The fumarate salt was recrystallized twice from ethanol and once from isopropanol-methanol. The fumarate salt (2.0 g., 10%) melted at 213-215 C. Analysis: Calcd for C33 H35 ClN2 O6: C, 67.06; H, 5.97; N, 4.74; Found: C, 67.44; H, 5.93; N, 4.79.
10%	In ethanol; di-isopropyl ether; isopropyl alcohol;	EXAMPLE 23 4-[4-(4-Chlorophenyl)-4-hydroxy-1-piperidinyl]methyl}-1-methyl-3,3-diphenyl-2-pyrrolidinone Fumarate To a steel bomb was added 17.0 g. (0.057 mole) of 4-chloromethyl-1-methyl-3,3-diphenyl-2-pyrrolidinone in 150 ml. of ethanol, 12.0 g. (0.057 mole) of 4-(p-chlorophenyl)-4-hydroxypiperidine and 21.2 g. (0.17 mole) of finely ground potassium carbonate. The mixture was heated with stirring to 200 C. for 48 hours. After concentrating the mixture in vacuo, the residue was partitioned between dilute hydrochloric acid solution and isopropyl ether. The ether was discarded, the acid solution was made basic with 50 percent sodium hydroxide solution and the base insoluble material was extracted with chloroform. The chloroform was dried, filtered and concentrated in vacuo. The residue was dissolved in a mixture of isopropyl ether and isopropanol and treated with an equivalent of fumaric acid. The fumarate salt was recrystallized twice from ethanol and once from isopropanol-methanol. The fumarate salt (2.0 g., 10%) melted at 213-215 C. Analysis: Calcd. for C33 H35 ClN2 O6: C, 67.06; H, 5.97; N, 4.74. Found: C, 67.44; H, 5.93; N, 4.79.

Reference： [1]Patent: US4324791,1982,A
[2]Patent: US4120969,1978,A

24
[ 39512-49-7 ]
[ 1716-42-3 ]
[ 54094-09-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In N-methyl-acetamide;	EXAMPLE 1 A mixture of 2.83 g of 1-chloro-3-(p-fluorophenoxy)-propane, 3.18 g of 4-(p-chlorophenyl)-4-hydroxypiperidine, 0.8 g of sodium carbonate and 60 ml of dimethylformamide is heated at a temperature of 80° - 90°C for 10 hours. After cooling, the reaction mixture is poured into water. The precipitate is collected by filtration and dried to give 1-[3-(p-fluorophenoxy)-propyl]-4-(p-chlorophenyl)-4-hydroxypiperidine, M.P. 134 - 135°C. Recrystallization from benzene gives the purified product, M.P. 136° - 137°C.

Reference： [1]Patent: US3965106,1976,A

25
[ 39512-49-7 ]
[ 50528-16-0 ]
γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; potassium iodide; potassium carbonate; In N-methyl-acetamide; methanol;	EXAMPLE 1 A mixture of gamma-chloro-2,4-difluorobutyrophenone (14.2 g), 4-(4-chlorophenyl)-4-hydroxypiperidine (13.8 g), anhydrous potassium carbonate (9.0 g), potassium iodide (0.5 g) and dimethylformamide (170 ml) was heated for 20 hours at 90 - 110C. After cooling, the reaction mixture was diluted with water and extracted with ether. The ethereal extract was sufficiently washed with water, dried over anhydrous sodium sulfate, treated with hydrogen chloride and then concentrated. Trituration and recrystallization of the residue from methanol gave gamma-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride. M.P. 245C (decomposition).

Reference： [1]Patent: US3979390,1976,A

26
[ 39512-49-7 ]
[ 39186-58-8 ]
[ 60-29-7 ]
2,2-diphenyl-4-[4-(4-chlorophenyl)-4-hydroxypiperidino]butyronitrile hydrochloride [ No CAS ]
[ 63959-33-1 ]

Yield	Reaction Conditions	Operation in experiment
90.7%	With hydrogenchloride; potassium hydroxide; potassium iodide; In water; isopropyl alcohol;	EXAMPLE 21 A solution of 4.87 parts of 4-(4-chlorophenyl)piperidin-4-ol and 1.91 parts of potassium iodide in 25 parts of deionized water is heated and stirred under a nitrogen atmosphere. When the temperature reaches about 30 - 35 C., 1.65 parts of potassium hydroxide is added. The heating is continued to a temperature of about 45 - 55 C., at which time 7.51 parts of 2,2-diphenyl-4-bromobutyronitrile is added. The temperature is raised to reflux and maintained thereat for 4.5 hours. After cooling to about 30 C., 29 parts of ethyl ether is added with stirring. The ether and water layers are separated and the water layer re-extracted with 7 parts of ethyl ether. The ether extracts are combined and washed twice with 12 part portions of dilute acetic acid. A solution of hydrochloric acid in isopropanol is added to form a precipitate which is filtered, washed with ethyl ether, and air-dried. The dried soild, 2,2-diphenyl-4-[4-(4-chlorophenyl)-4-hydroxypiperidino]butyronitrile hydrochloride is obtained in 90.7% yield. The solid is dissolved in dilute ammonium hydroxide and extracted with ethyl ether. The solvent is removed from the ether extract under reduced pressure to afford as a white glass, 2,2-diphenyl-4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-butyronitrile, represented by the following structural formula. STR15

Reference： [1]Patent: US4086234,1978,A

27
acetone-toluene-methanol [ No CAS ]
[ 39512-49-7 ]
[ 590-90-9 ]
[ 57390-39-3 ]
[ 1511-16-6 ]

Yield	Reaction Conditions	Operation in experiment
80.1%	With hydrogenchloride; potassium iodide; potassium hydrogencarbonate; In methanol; water; toluene;	EXAMPLE 2 4.87 Parts of 4-(4-chlorophenyl)piperidin-4-ol, 1.91 parts of potassium iodide and 25 parts of deionized water is stirred together and gently warmed under a nitrogen atmosphere. Then, 2.75 parts of potassium bicarbonate and 6.17 parts of 1,1-dimethoxy-1-(4-fluorophenyl)-4-chlorobutane is added and the mixture is heated to reflux. After heating for 4.5 hours, the reaction mixture is allowed to cool to room temperature and 55 parts of toluene is added. The aqueous and organic layers are separated, and the aqueous layer discarded. 5.1 Parts of methanol is added to the organic layer. Then, 2.5 parts of concentrated hydrochloric acid is added with vigorous stirring. The resulting precipitate is cooled to about 25 C., filtered, washed twice with 22 parts by volume portions of a 10:9:1 mixture of acetone-toluene-methanol, and twice with 20 parts by volume portions of a 10:1 mixture of acetone-methanol. After air-drying, the product, 4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-4' -fluorobutyrophenone hydrochloride, melts at about 227-229 C. and is obtained in 80.1% yield. This compound is the hydrochloride salt of the product of Example 1.

Reference： [1]Patent: US4086234,1978,A

28
[ 401564-36-1 ]
[ 39512-49-7 ]
3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride; acetic acid; In methanol; water;	(1) The title compound (593 mg) of Reference Example 12 was dissolved in methanol (10 mL), and 4-(4-chlorophenyl)-4-hydroxypiperidine (500 mg), acetic acid (113 muL) and sodium cyanoborohydride (124 mg) were added thereto at room temperature. The mixture was stirred for 21 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with brine and dried. The solvent was evaporated under reduced pressure to give 3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (428 mg) as a white solid.

Reference： [1]Patent: EP1308439,2003,A1

29
[ 39512-49-7 ]
[ 740789-75-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	With hydrogen fluoride; In pyridine; methanol; dichloromethane;	Step 1 To a cooled (0 C.) solution of hydrogen fluoride (65-70%) in pyridine (4 mL) was added 4-(4-chloro-phenyl)-piperidin-4-ol (500 mg, 2.36 mmol). The resulting solution was stirred at 0 C. for 15 min and then warmed to rt and stirred 1 h. The mixture was slowly poured into a saturated aqueous sodium bicarbonate solution (30 mL) and extracted with methylene chloride (100 mL; ADD SOLVENT AND EXTRACT SLOWLY AND WITH CAUTION). Excess hydrogen fluoride was neutralized with solid sodium carbonate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography, eluding with a methylene chloride to methylene chloride/methanol/ammonium hydroxide (8.5/1/0.5) gradient to give 4-(4-Chloro-phenyl)-4-fluoro-piperidine (260 mg, 52%). 1H-NMR (CDCl3, 300 MHz) delta: 2.98-3.14 (m, 4H), 1.87-2.10 (m, 4H), 7.33-7.36 (m, 4H). 19F-NMR (CDCl3, 282 MHz) d: -160.40--160.20 (m). MS m/z: 214 (M+1).
52%	With hydrogen fluoride; In pyridine; methanol; dichloromethane; at 0 - 20℃; for 1.25h;	Step 1 To a cooled (0 C.) solution of hydrogen fluoride (65-70%) in pyridine (4 mL) was added 4-(4-chloro-phenyl)-piperidin-4-ol (500 mg, 2.36 mmol). The resulting solution was stirred at 0 C. for 15 min and then warmed to rt and stirred 1 h. The mixture was slowly poured into a saturated aqueous sodium bicarbonate solution (30 mL) and extracted with methylene chloride (100 mL; ADD SOLVENT AND EXTRACT SLOWLY AND WITH CAUTION). Excess hydrogen fluoride was neutralized with solid sodium carbonate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography, eluting with a methylene chloride to methylene chloride/methanol/ammonium hydroxide (8.5/1/0.5) gradient to give 4-(4-Chloro-phenyl)-4-fluoro-piperidine (260 mg, 52%). 1H-NMR (CDCl3, 300 MHz) delta: 2.98-3.14 (m, 4H), 1.87-2.10 (m, 4H), 7.33-7.36 (m, 4H). 19F-NMR (CDCl3, 282 MHz) d: -160.40--160.20 (m). MS m/z: 214 (M+1).

Reference： [1]Patent: US2005/70549,2005,A1
[2]Patent: US2016/31908,2016,A1 .Location in patent: Paragraph 1285; 1286; 1287; 1288; 1289

30
CH₂Cl₂Cl₂ [ No CAS ]
[ 39512-49-7 ]
[ 100-39-0 ]
[ 56108-25-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In methanol; dichloromethane; N,N-dimethyl-formamide;	Step 1. N-benzyl-<strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong>: FIG. 8a To a stirred solution of commercially available <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (10 g, 47 mmol., 1) in anhydrous DMF (10 mL) was added benzyl bromide (5.6 mL, 47 mmol) and K2CO3 (7.4 g, 94 mmol.) and stirred at RT overnight. Excess solvent was removed under reduced pressure, brought up into CH2Cl2 (100 mL) washed with H2O (2*50 mL). Organic layer separated, dried over Na2SO4 and charged on a silica gel flash column. Eluding off with 2% MeOH/CH2Cl2Cl2 10 g 2 (80% yield) was obtained as a viscous liquid. MS m/z: (M+303).

Reference： [1]Patent: US2005/70549,2005,A1

31
[ 39512-49-7 ]
[ 100986-89-8 ]
C₂₄H₂₂ClFN₂O₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1229 - 1236

32
[ 39512-49-7 ]
[ 112811-72-0 ]
[ 1018937-82-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 2558 - 2569

33
[ 39512-49-7 ]
[ 37743-18-3 ]
[ 34552-83-5 ]

Yield	Reaction Conditions	Operation in experiment
67%		Example 1 : Preparation of 4-[4-(4-diphenyl)-4-hvdroxypiperidino1-N,N- dimethyl-2,2-diphenylbutyramide hydrochloride (loperamide)0.111 g (5.2-10-4 mol, 1 eq) of 4,4-chlorophenyl-4-hydroxypiperidine, 0.062 g (5.8-10-4 mol, 1.11 eq) of sodium carbonate, 0.0009 g (0.24% by weight) of potassium iodide were weighed and dissolved in 0.5 ml_ of glycerol formal. The resulting mixture was stirred for 15 minutes. Afterwards 0.2089 g (6.03-10-4 mol, 1.15 eq) of N,N-dimethyl-(3,3-diphenyltetrahydro-2- furyliden)ammonium bromide were added and heated at 6O0C. After 2 hours, the reaction mixture was left to cool to room temperature. The crude product was centrifuged at 18000 rpm for 30 minutes at 4O0C. The two phases were separated. To the supernatant 0.65 ml_ of isopropanol saturated with hydrochloric acid (7.8-10-4 mol of HCI, 1.5 eq) was added by stirring for 20 minutes. Then, 1 mL of H2O was added by stirring for 15 minutes. After this time, it was centrifuged at 9000 rpm for 1 hour at 210C and the supernatant was removed. It was washed with water. The obtained solid was decanted and dried under vacuum. The title compound was obtained as a white solid. Yield: 67%. Rf (AcNH^Dioxane/MeOH; 20/40/40) =0.86. 1H NMR (300 MHz,CDCI3) delta 11.7 (1H, s, OH), 7.3-7.5 (14 H, m, Ar), 3 (1 H, s, CH3), 2.36 (2H, t, CH2, J=6 MHz), 2.25 (2H, t, CH2, J=6 MHz), 14.94 (4H, t, J=6 MHz).

Reference： [1]Patent: WO2008/80601,2008,A2 .Location in patent: Page/Page column 10

34
[ 940890-90-4 ]
[ 39512-49-7 ]
(3'R)-4-(4-chlorophenyl)-1,3'-bipiperidin-4-ol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2215 - 2221

35
[ 404577-34-0 ]
[ 39512-49-7 ]
(3'S)-4-(4-chlorophenyl)-1,3'-bipiperidin-4-ol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2215 - 2221

36
[ 39512-49-7 ]
[ 39186-58-8 ]
4-(4-chlorophenyl)-4-hydroxylpiperidine [ No CAS ]
[ 63959-33-1 ]

Yield	Reaction Conditions	Operation in experiment
	N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane; acetonitrile;	Reaction i: 4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanenitrile (Compound 1) The synthesis of compound 1 was accomplished by a new route in two steps from commercially available materials. Briefly, the amide precursor (4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanenitrile; compound 1 in the scheme above) was obtained in 69% yield by alkylation of 4-(4-chlorophenyl)-4-hydroxylpiperidine with <strong>[39186-58-8]4-bromo-2,2-diphenylbutyronitrile</strong> in the presence of DIPEA (diisopropylethyl amine; 2 eq.) in MeCN at 70 C. for 31 hours. Specifically, 4-(4-Chlorophenyl)-4-hydroxypiperidine (2.12 g, 10.0 mmol) was suspended in acetonitrile (15 mL) and DIPEA (3.5 mL, 30 mmol) was added. 4-Bromo-2,2-diphenylbutyronitrile (3.00 g, 10.0 mmol) in acetonitrile (15 mL) was then added. The reaction mixture was stirred under argon at 70 C. for 31 h. After concentration under vacuum, the crude material was re-dissolved in dichloromethane and introduced onto a silica gel column. The product was eluted with ammonium hydroxide solution (2 M) in MeOH:CH2Cl2 (6:94 v/v) to yield compound 1 as a pale orange solid (3.10 g, 7.21 mmol, 69% yield). M.p. 108-109 C. (n=3). TLC (silica gel; CH2Cl2:2 M NH4OH in MeOH (95:5 v/v); Rf=0.60. 1H NMR (CDCl3): delta 7.36 (m, 14H), 2.76 (d, J=11.20 Hz, 2H), 2.65 (m, 4H), 2.48 (t, J=6.9 Hz, 2H), 2.08 (t, J=12.5 Hz, 2H), 1.68 (d, J=11.58 Hz, 2H), 1.60 (br s, 1H).

Reference： [1]Patent: US2009/274624,2009,A1

37
[ 235109-63-4 ]
[ 39512-49-7 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In dichloromethane; at 20℃; for 2h;	To the solution of tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-l- carboxylate (2.83 g, 9.08 mmol) in CH2CI2 (20 mL) was added trifluoroacetic acid (7.0 mL, 91 mmol) and the resulting solution was stirred at rt for 2 hr. The reaction solution was concentrated to give 4-(4-chlorophenyl)piperidin-4-ol. LC/MS: (M+l)+: 212.16 (100%), 214.1 1(30%).
	With trifluoroacetic acid; In dichloromethane; at 20℃; for 2h;	Step B: 4-(4-chlorophenyl)piperidin-4-ol (0795) To the solution of tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (2.83 g, 9.08 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid (7.0 mL, 91 mmol) and the resulting solution was stirred at rt for 2 hr. The reaction solution was concentrated to give 4-(4-chlorophenyl)piperidin-4-ol. LC/MS: (M+1)+: 212.16 (100%), 214.11 (30%).

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 9488 - 9520
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 234 - 239
[3]Patent: WO2015/112441,2015,A1 .Location in patent: Page/Page column 220
[4]Patent: US2016/333021,2016,A1 .Location in patent: Paragraph 0795

38
[ 39512-49-7 ]
[ 1266676-21-4 ]
[ 1266696-21-2 ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 75℃; for 12h;	A mixture of 4-(4-chlorophenyl)piperidin-4-ol (0.217 g, 1.026 mmol), NaHCO3 (0.086 g, 1.026 mmol) and compound (3) (0.179 g, 0.513 mmol) in anhydrous DMF was stirred at 75 C for 12 h. The organic solvent was evaporated under vacuum and the residue was dissolved in water (50 mL) followed by an extraction with CH2Cl2 (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in a vacuum to obtain a crude yellow oil product. Purification by flash chromatography (20-80% AcOEt in cyclohexane) yielded (+/-)-MRJF4 (0.113 g, 43% of yield) as colorless oil, which was transformed into an oxalate salt: mp: 132.5-135.2 C; 1H NMR (200 MHz, DMSO-d6): delta = 7.46-7.07 (m, 13H), 6.36 (br s, 3H), 5.67 (t, J = 6.0 Hz, 1H), 3.28-3.03 (m, 6H), 2.53-2.12 (m, 6H), 1.79-1.66 ppm (m, 8H); 13C NMR (50 MHz, [D6]DMSO): delta 172.35, 164.8, 161.5 (d, JCF = 242.45 Hz), 147.01, 141.35, 136.63, 131.48, 128.49, 128.33, 128.06, 126.71, 125.91, 115.50, 115-07, 73.91, 67.98, 48.03, 34.74, 34.26, 33.04, 32.84, 26.29, 19.97 ppm; Anal. Calcd for C31H35ClFNO3·C2H2O4: C 64.54, H 6.07, N 2.28, found: C 64.21, H 6.28, N 2.55.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 433 - 438

39
[ 39512-49-7 ]
[ 129722-34-5 ]
[ 1314032-10-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate; potassium iodide; In acetonitrile;Reflux; Inert atmosphere;	A mixture of <strong>[129722-34-5]7-(4-bromobutoxy)-3,4-dihydroquinolin-2(1H)-one</strong> (20, 1.7 mmol), 4-(chlorophenyl)-4-hydroxypiperidine (1.7 mmol), potassium carbonate (5 equiv) and potassium iodide (1 equiv) in acetonitrile (20 mL) was stirred at reflux overnight. The reaction mixture was evaporated. The resulting residue was suspended in water (25 mL) and filtered. The solid was washed with water and air dried to give the product as white powder (96percent yield). The oxalate salt was prepared using 1 equiv of oxalic acid in ethanol and recrystallized from ethanol to give 2 as an off-white powder, mp 178-179 °C; 1H NMR (free base, CDCl3 + DMSO-d6) delta 9.08 (br s, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.2 Hz, 1H), 6.49 (dd, J = 8.7 and 2.5 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H), 3.95 (t, J = 6.0 Hz, 2H), 3.50-3.60 (m, 1H), 2.78-2.89 (m, 4H), 2.43-2.62 (m, 6H), 2.02-2.10 (m, 2H), 1.70-1.80 (m, 6H). Anal. (C24H29ClN2O3C2H2O40.5H2O) C, H, N.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3502 - 3511

40
[ 39512-49-7 ]
[ 129722-34-5 ]
7-(4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3502 - 3511

41
[ 39512-49-7 ]
[ 1357348-83-4 ]
[ 34933-71-6 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium carbonate; potassium iodide; In 1,2-dimethoxyethane; for 12h;Inert atmosphere; Reflux;	A mixture of 3-(4-fluorophenylthio)propyl methanesulfonate (4b) (1.0 g, 3.79 mmol), 4-(4-chloro-phenyl)-piperidin-4-ol (0.8 g, 3.79 mmol), KI (120 mg), K2CO3 (1.2 g, 8.7 mmol) in DME (10 mL) was heated to reflux under N2 for 12 h. The cooled mixture was then diluted with EtOAc (400 mL) and washed with H2O (200 mL). The organic layers were pooled, dried with Na2SO4, and filtered. The filtrate was concentrated in vacuo, then followed by purification through column chromatography on silica gel, to afford 4-(4-chlorophenyl)-1-(3-((4-fluorophenyl)thio)propyl)piperidin-4-ol (6); yield 74%, mp 121-122 C. 1H NMR (CDCl3): delta 7.43 (2H, d, J = 8.4 Hz), 7.35 (2H, dd, J = 4.8, 8.7 Hz), 7.31 (2H, d, J = 8.4 Hz), 6.99 (2H, t, J = 8.4 Hz), 2.92 (2H, t, J = 7.5 Hz), 2.75 (2H, m), 2.51 (2H, t, J = 7.8 Hz), 2.41 (2H, m), 2.08 (2H, m), 1.82 (2H, m), 1.70 (2H, m). Calcd for C20H23ClFNOS: C 63.23, H 6.10, N 3.69; Found: C 63.08, H 6.12, N 3.71.

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 9488 - 9520
[2]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 1291 - 1297

42
[ 39512-49-7 ]
[ 1380392-06-2 ]
[ 1380392-04-0 ]

Yield	Reaction Conditions	Operation in experiment
29%	With potassium carbonate; In acetonitrile; at 140℃; for 1h;Sealed tube; Microwave irradiation;	5-(3-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one 5-(3-chloropropyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (100 mg; 0.38 mmol) was added to a 5 mL microwave vessel containing a magnetic stir bar. 4-(4-Chlorophenyl)piperidin-4-ol (89.3 mg; 0.42 mmol), potassium carbonate (78.77 mg; 0.57 mmol), and 2 mL of acetonitrile were added to the vessel. The vessel was sealed and heated to 140 C. for 1 hour, after which the solvent was evaporated and the reaction mixture was purified by flash chromatography to yield 5-(3-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (48.5 mg; 0.11 mmol; 29%). [M+1]+=436.
	With potassium carbonate; In acetonitrile;	5-(3-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one 5-(3-chloropropyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (100 mg; 0.38 mmol) was added to a 5 mL microwave vessel containing a magnetic stir bar. 4-(4-Chlorophenyl)piperidin-4-ol (89.3 mg; 0.42 mmol), potassium carbonate (78.77 mg; 0.57 mmol), and 2 mL of acetonitrile were added to the vessel. The vessel was sealed and heated to 140 C. for 1 hour, after which the solvent was evaporated and the reaction mixture was purified by flash chromatography to yield 5-(3-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (48.5 mg; 0.11 mmol; 29%). [M+1]+=436.

Reference： [1]Patent: US9375474,2016,B2 .Location in patent: Paragraph 119; 120
[2]Patent: US2012/141471,2012,A1

43
[ 470-17-7 ]
[ 39512-49-7 ]
[ 1401324-89-7 ]

Reference： [1]Chemistry of Heterocyclic Compounds,2012,vol. 48,p. 698 - 703,6

44
[ 39512-49-7 ]
[ 2901-80-6 ]
[ 946581-64-2 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 9643 - 9653

45
[ 39512-49-7 ]
[ 37742-98-6 ]
4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 105℃; for 30h; Inert atmosphere; Schlenk technique;

Reference： [1]Bao, Xiaofeng; Liu, Duliang; Jin, Yanyan; Yang, Yao [Molecules, 2012, vol. 17, # 12, p. 14288 - 14297]

46
[ 39512-49-7 ]
[ 37742-98-6 ]
1,4-bis(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenyl butan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile / 30 h / 105 °C / Inert atmosphere; Schlenk technique 2: titanium tetrachloride / toluene / 20 h / Inert atmosphere; Schlenk technique; Reflux

Reference： [1]Bao, Xiaofeng; Liu, Duliang; Jin, Yanyan; Yang, Yao [Molecules, 2012, vol. 17, # 12, p. 14288 - 14297]

47
[ 39512-49-7 ]
[ 39186-58-8 ]
[ 66164-06-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5259 - 5263

48
[ 30030-91-2 ]
[ 39512-49-7 ]
[ 1531588-07-4 ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.166667h;Microwave irradiation;	General procedure: Pathway A: To a solution of (2-chloro-1-(5-methoxy-1H-indol-3-yl)ethanone) (9) (223mg, 1mmol) in DMF dry (2mL) the appropriate piperidine fragments (1mmol) and K2CO3 (70.0mg, 0.5mmol) were added. The mixture was placed in a cylindrical quartz tube (2cm), then stirred and irradiated in a microwave oven at 200W at 100C for 10min. Then the reaction mixture was cooled, quenched with NaHCO3 saturated aqueous solution (10mL) and extracted with EtOAc (3×10mL). The organic layer was washed with brine (3×3mL), dried over Na2SO4 and concentrated until dryness under reduced pressure. The crude compounds were purified by flash chromatography DCM/CH3OH (90:10) and they were recrystallized from ethanol to give derivatives 6a-f. Then the appropriate derivatives 6a-f were dissolved in methylene chloride (DCM) (5mL), treated with BBr3 (1M in DCM), (6mL, 0.006mol) and stirred overnight. Successively, methanol (7mL) was carefully added at 0C and the solvents removed under reduced pressure. The residue was dissolved in ethyl acetate (10mL) and washed with water (3×10mL). The organic layer was dried (Na2SO4), combined and concentrated in vacuo. The crude products were purified by flash chromatography (DCM/MeOH 90:10) and recrystallized from ethanol to give the desired compounds (7a-f).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 393 - 397

49
[ 39512-49-7 ]
[ 1531588-03-0 ]
[ 1531588-13-2 ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.166667h;Microwave irradiation;	General procedure: Pathway A: To a solution of (2-chloro-1-(5-methoxy-1H-indol-3-yl)ethanone) (9) (223mg, 1mmol) in DMF dry (2mL) the appropriate piperidine fragments (1mmol) and K2CO3 (70.0mg, 0.5mmol) were added. The mixture was placed in a cylindrical quartz tube (2cm), then stirred and irradiated in a microwave oven at 200W at 100C for 10min. Then the reaction mixture was cooled, quenched with NaHCO3 saturated aqueous solution (10mL) and extracted with EtOAc (3×10mL). The organic layer was washed with brine (3×3mL), dried over Na2SO4 and concentrated until dryness under reduced pressure. The crude compounds were purified by flash chromatography DCM/CH3OH (90:10) and they were recrystallized from ethanol to give derivatives 6a-f. Then the appropriate derivatives 6a-f were dissolved in methylene chloride (DCM) (5mL), treated with BBr3 (1M in DCM), (6mL, 0.006mol) and stirred overnight. Successively, methanol (7mL) was carefully added at 0C and the solvents removed under reduced pressure. The residue was dissolved in ethyl acetate (10mL) and washed with water (3×10mL). The organic layer was dried (Na2SO4), combined and concentrated in vacuo. The crude products were purified by flash chromatography (DCM/MeOH 90:10) and recrystallized from ethanol to give the desired compounds (7a-f).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 393 - 397

50
[ 39512-49-7 ]
[ 2823-19-0 ]
[ 1391052-53-1 ]

Reference： [1]ACS Catalysis,2014,vol. 4,p. 722 - 731

51
[ 39512-49-7 ]
[ 898761-12-1 ]
[ 1551099-68-3 ]

Reference： [1]ACS Catalysis,2014,vol. 4,p. 722 - 731

52
[ 39512-49-7 ]
4-chloro-1-(3,4-difluorophenyl)butan-1-one [ No CAS ]
[ 21937-79-1 ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 9488 - 9520
[2]ACS Catalysis,2014,vol. 4,p. 722 - 731

53
[ 39512-49-7 ]
[ 462094-45-7 ]
4-(2-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2-oxoethoxy)-2H-chromen-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		General procedure: Compound 3 (1mmol), EDC (1mmol) and HBT (1mmol) were dissolved in dry acetonitrile (5ml). The solution was stirred at room temperature for 30min and then appropriate amine (1mmol) was added to the mixture. The solution was stirred at room temperature for 24h. After completion of the reaction (monitored by TLC), the mixture was diluted with water and the precipitate was filtered and washed with saturated sodium carbonate. The resulting crude product was purified by flash chromatography (Silica gel) eluting with ethyl acetate/petroleum ether (1:1) to give compounds 4a-s.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 64,p. 252 - 259

54
[ 39512-49-7 ]
[ 1444012-07-0 ]
4-(4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-4-oxobutoxy)-2H-chromen-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		General procedure: Compound 3 (1mmol), EDC (1mmol) and HBT (1mmol) were dissolved in dry acetonitrile (5ml). The solution was stirred at room temperature for 30min and then appropriate amine (1mmol) was added to the mixture. The solution was stirred at room temperature for 24h. After completion of the reaction (monitored by TLC), the mixture was diluted with water and the precipitate was filtered and washed with saturated sodium carbonate. The resulting crude product was purified by flash chromatography (Silica gel) eluting with ethyl acetate/petroleum ether (1:1) to give compounds 4a-s.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 64,p. 252 - 259

55
[ 39512-49-7 ]
4-(8-bromo-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino)benzoic acid ethyl ester [ No CAS ]
4-{8-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-benzoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 18h;Sealed tube; Inert atmosphere; Sonication;	Step 1. A microwave vial was charged with 4-(8-bromo-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzoic acid ethyl ester (1.00 g, 2.77 mmol), 4-(4-chloro-phenyl)- piperidin-4-ol (879 mg, 4.15 mmol), tris(dibenzylideneacetone)dipalladium(0) (256 mg,0.28 mmol), cesium carbonate (1.81 g, 5.54 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (321 mg, 0.55 mmol) and dioxane (12 mL). The vessel was sealed, evacuated and refilled with argon three times before being purged with argon whilst being sonicated for 5 minutes. The reaction mixture was stirred at 110C for 18 hours then cooled to room temperature before being filtered through a pad of Celite, elutingwith ethyl acetate. The filtrate was concentrated in vacuo before being purified by flash chromatography on silica eluting with 0-4% MeOH in dichloromethane. 4-{8-[4-(4- chloro-phenyl)-4-hydroxy-piperidin- 1 -yl]- [1 ,2,4]triazolo [1, 5-a]pyridin-2-ylamino} -benzoic acid ethyl ester was obtained as a pale yellow solid (1.13 g, 83%). LCMS (Method 1) [M+H]b 492.4, RT = 4.07 mm. ?H NIVIR (400 MHz, DMSO-d6) oe 10.14 (s,1H), 8.35 (dd, J = 6.0, 1.5 Hz, 1H), 7.92-7.86 (m, 2H), 7.82-7.76 (m, 2H), 7.60-7.53(m, 2H), 7.43 - 7.34 (m, 2H), 6.99-6.88 (m, 2H), 5.21 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H),4.12 (d, J = 11.8 Hz, 2H), 3.22 (t, J = 11.4 Hz, 2H), 2.13 (td, J = 12.9, 4.3 Hz, 2H), 1.76(d, J = 12.7 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).

Reference： [1]Patent: WO2015/32286,2015,A1 .Location in patent: Page/Page column 307; 308

56
[ 117-80-6 ]
[ 39512-49-7 ]
2-chloro-3-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl][1,4]naphthoquinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With sodium carbonate; In dichloromethane; at 20℃;	General procedure: An appropriate amount 2,3-dichloro-1,4-naphthoquinone 1and the corresponding nucleophile were stirred in dichloromethane (30 mL) with Na2CO3(1.56 g) solution for 2-3 h at room temperature. The color of the solution quickly changedand the reaction was monitored by TLC. Chloroform (30 mL) was added to the reactionmixture. The organic layer was washed with water (4 × 30 mL), and dried over Na2SO4.After the solvent was evaporated the residue was purified by column chromatography onsilica gel.

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2015,vol. 190,p. 1422 - 1433

57
[ 39512-49-7 ]
[ 118-75-2 ]
2,3,5-trichloro-6-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)cyclohexa-2,5-diene-1,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium carbonate; In dichloromethane; at 20℃;	General procedure: Appropriate amounts of chloranil, 1, and the correspondingnucleophile were stirred in dichloromethane (30 mL) with Na2CO3 (1.56 g) for 2-3 h atroom temperature. The color of the solution quickly changed and the reactionwas monitoredby TLC. Chloroform (30 mL) was added to the reaction mixture. The organic layer waswashed with water (4 × 30 mL), and dried over Na2SO4. After the solvent was evaporated,the residue was purified by column chromatography on silica gel.

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2015,vol. 190,p. 2273 - 2282

58
[ 39512-49-7 ]
p-toluenesulfonic acid 3-hydroxy-3,3-diphenylpropyl ester [ No CAS ]
1,1-diphenyl-3-[4-hydroxy-4-(4-chlorophenyl)piperidin-1-yl]-1-propanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium carbonate; In acetonitrile; for 16h;Inert atmosphere; Reflux;	General procedure: Sodium carbonate (95.4 mg, 0.9 mmol) was added to the solution of(3-hydroxy-3,3-diphenyl)propyl p-toluenesulfonate 5 (114.7 mg, 0.3 mmol) and4-(4-chlorophenyl)-4-piperidinol (63.5 mg, 0.3 mmol) in dry MeCN (1.0 mL) at room temperature underatmosphere of Argon, and the mixture was refluxed for 16 h. The reaction quenched with water andextracted with CHCl3. The extracts were washed with brine, dried over Na2SO4, and concentrated underreduced pressure. The residue was purified by column chromatography with CHCl3/MeOH (30:1) togive 1,1-diphenyl-3-[4-hydroxy-4-(4-chlorophenyl)piperidin-1-yl]-1-propanol 10a as a white solid in84% yield. IR (KBr): = 3384 (OH), 1095 (Ar-Cl); 1H NMR (400 MHz, CDCl3): " = 1.59 (1H, s), 1.73(2H, brd, J = 12.2 Hz), 2.09-2.16 (2H, m), 2.40-2.53 (6H, m), 2.82 (2H, brd, J = 10.7 Hz), 7.16-7.21 (2H,m), 7.28-7.33 (6H, m), 7.40-7.43 (2H, m), 7.45-7.48 (4H, m), 8.28 (1H, brs); 13C NMR (100 MHz,CDCl3): " = 35.3, 38.5, 49.2, 54.9, 70.8, 79.1, 125.8, 126.0, 126.4, 128.1, 128.5, 133.0, 146.4, 147.8; MS(EI) m/z 421 ([M]+). The hydrochloride salts as white powders, mp 220 C (dec.); Anal. Calcd forC26H28NO2Cl·HCl: C, 68.12, H, 6.38, N, 3.06. Found: C, 68.11, H, 6.32, N, 2.99

Reference： [1]Heterocycles,2014,vol. 88,p. 663 - 673
[2]Organic and Biomolecular Chemistry,2016,vol. 14,p. 8503 - 8519

59
[ 39512-49-7 ]
[ 68664-23-3 ]
4-(4-chlorophenyl)-4-hydroxy-N-(3-phenylpropyl)piperidine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	In tetrahydrofuran; at 40 - 45℃; for 24h;	(3-isocyanatopropyl) benzene (2.01 mmol)And a THF solution (20 ml) of 4- (4-chlorophenyl) piperidin-4-ol (2.01 mmol) were stirred at 40-45 C for 24 hours. The next day, the completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. The organic layer was treated with brine and dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.
68%	In tetrahydrofuran; at 40 - 45℃; for 24h;	(20 ml) of (3-isocyanatopropyl) benzene (2.01 mmol) and 4- (4-chlorophenyl) piperidin-4-ol (2.01 mmol); The next day completion of the reaction was confirmed by TLC. The solvent was distilled off and ammonium chloride (100 ml), water (50 ml) and ethyl acetate (100 ml) were added to the remaining residue. After treating the organic layer with brine And dried over sodium sulfate. The solvent was distilled off and the resulting concentrate was adsorbed onto silica gel using methylene chloride. The mixture was purified by column chromatography using ethyl acetate in hexane to give the title compound.

Reference： [1]Patent: KR2016/108281,2016,A .Location in patent: Paragraph 1152-1155
[2]Patent: KR2015/111825,2015,A .Location in patent: Paragraph 1152-1155

60
[ 39512-49-7 ]
[ 106-94-5 ]
N-propyl-4-(4-chlorophenyl)-4-piperidinol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With sodium carbonate; In acetonitrile; at 20℃; for 3h;Inert atmosphere;	General procedure: Sodium carbonate (95.4 mg, 0.9 mmol) was addedto the solution of 1-bromopropane (43.0 mg, 0.6 mmol) and 4-(4-chlorophenyl)-4-piperidinol (63.5 mg,0.3 mmol) in dry MeCN (1.0 mL) at room temperature under atmosphere of Argon, and the mixture wasstirred for 3 h at room temperature. The reaction quenched with water and extracted with CHCl3. Theextracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Theresidue was purified by column chromatography with CHCl3/MeOH (30:1) to give 12a as a colorless670 HETEROCYCLES, Vol. 88, No. 1, 2014crystal in 49% yield, mp 99-100 C. IR (KBr): = 3168 (OH) , 1095 (Ar-Cl); 1H NMR (400 MHz,CDCl3): " = 0.94 (3H, t, J = 7.3 Hz), 1.56-1.65 (2H, m), 1.70 (1H, brs), 1.74 (2H, dd, J = 2.1 and 14.3 Hz),2.19-2.26 (2H, m), 2.42-2.53 (4H, m), 2.90 (2H, d, J = 10.4 Hz), 7.31 (2H, d, J = 8.5 Hz), 7.45 (2H, d, J =8.5 Hz); 13C NMR (100 MHz, CDCl3): " = 12.0, 20.0, 38.3, 49.4, 60.7, 71.0, 126.1, 128.4, 132.7, 146.7;MS (ESI) m/z 254 ([M+H]+); HRMS (ESI) m/z 254.1301 (calcd for C14H21ClNO, 254.1312).

Reference： [1]Heterocycles,2014,vol. 88,p. 663 - 673

61
[ 882-59-7 ]
[ 39512-49-7 ]
1,1-diphenyl-2-[4-hydroxy-4-(4-chlorophenyl)piperidin-1-yl]-1-ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With lithium perchlorate; In acetonitrile; for 10h;Inert atmosphere; Reflux;	The solution ofoxirane 7 (785 mg, 4.0 mmol), 4-(4-chlorophenyl)-4-piperidinol (846 mg, 4.0 mmol) lithium perchlorate(851 mg, 8.0 mmol) was refluxed for 16 h under atmosphere of Argon. The reaction quenched withwater and extracted with CHCl3. The extracts were washed with brine, dried over Na2SO4, andconcentrated under reduced pressure. The residue was purified by column chromatography withCHCl3/MeOH (30:1) to give 11a as a white solid in 81% yield. IR (KBr): = 3420 (OH), 1094 (Ar-Cl);1H NMR (400 MHz, CDCl3): " = 1.47 (1H, s), 1.56-1.60 (2H, m), 1.97 (2H, dt, J = 3.9, 12.7 Hz), 2.43(2H, brd, J = 11.2 Hz), 2.65-2.70 (2H, m), 3.33 (2H, s), 5.38 (1H, brs), 7.16-7.20 (2H, m), 7.27-7.31 (6H,m), 7.36-7.40 (2H, m), 7.50-7.53 (4H, m); 13C NMR (100 MHz, CDCl3): " = 38.6, 50.6, 67.8, 70.4, 74.1,125.6, 126.1, 126.6, 128.1, 128.4, 132.9, 146.5, 147.1; MS (FAB, glycerol) m/z 408 ([M+H]+). Thehydrochloride salts as colorless prisms, mp 195 C (dec.); Anal. Calcd for C25H26NO2Cl·HCl: C, 67.57, H,6.12, N, 3.10. Found: C, 67.56, H, 6.06, N, 3.17

Reference： [1]Heterocycles,2014,vol. 88,p. 663 - 673

62
[ 26905-02-2 ]
[ 39512-49-7 ]

Reference： [1]Organic Letters,2017,vol. 19,p. 572 - 575

63
[ 39512-49-7 ]
((2-(3-bromopropyl)-1,3-dioxolan-2-yl)ethynyl)trimethylsilane [ No CAS ]
4-(4-chlorophenyl)-1-(3-(2-((trimethylsilyl)ethynyl)-1,3-dioxolan-2-yl)propyl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-ethyl-N,N-diisopropylamine; potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 13h;	Compound 18 (0.20 g, 0.69 mmol) and amine 6 (0.73 g,3.4 mmol) were dissolved in 2.0 mL anhydrous DMF. Potassiumiodide (23 mg, 0.14 mmol) and DIPEA (0.60 mL, 3.4 mmol) wereadded to the reaction mixture and stirred for 13 h at room temperature.The solvent was evaporated under reduced pressure and thecrude product was purified by flash column chromatography onsilica gel (eluents: CH2Cl2/MeOH 95/5) to give product 19 (0.28 g,97%) as a pale yellow oil. 1H NMR (600 MHz, CDCl3) d 7.51-7.44(m, 2H), 7.35-7.30 (m, 2H), 4.12-4.03 (m, 2H), 4.06-3.97 (m,2H), 3.38-3.29 (m, 2H), 3.18 (t, J = 12.4 Hz, 2H), 3.04-2.97 (m,2H), 2.77 (t, J = 14.4 Hz, 2H), 2.16-2.06 (m, 2H), 1.99 (t, J = 7.1 Hz,2H), 1.95-1.87 (m, 2H), 0.19 (s, 9H) 13C NMR (151 MHz, CDCl3) d144.77, 133.73, 128.90, 126.16, 102.32, 101.94, 89.65, 69.86,64.88, 57.33, 48.95, 36.07, 35.83, 19.12, -0.04. HPLC (system 1,210 nm): tR = 18.2 min, purity: 86%, (system 2, 210 nm): tR = 17.4 -min, purity: 86%; ESI-MS m/z 422.17 [M+H]+; HR-ESI-MS m/z [M+H]+ calcd for C22H33ClNO3Si, 422.191275; found, 422.190363.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5084 - 5094

64
[ 39512-49-7 ]
[ 138-41-0 ]
4-[4-(4-chlorophenyl)-4-hydroxypiperidine-1-carbonyl]benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%		Pathway ii: A mixture of 4-(aminosulfonyl)benzoic acid (4)(2 mmol) and N,N,N,N-tetramethyl-O-(1H-benzotriazol-1-yl)uraniumhexafluorophosphate (HBTU) (2 mmol) in DMF(2 mL) was stirred at room temperature for 1 h. Then, a solution of the appropriate amine derivative (2 mmol) in TEA (2 mmol) was added dropwise. The reaction mixture was left overnight and then quenched with water (10 mL) and extracted with EtOAc (3 5 mL).The organic phase was dried with Na2SO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography(DCM/MeOH 96:4), crystallized by treatment with a mixtureof Et2O and EtOH (1:1) to give the desired final compounds 5b, 5c,6a, 7a-f and 8a-d as white crystals. For compounds 5 a-d, 6a, 8a and 8d registered CAS numbers have been already assigned. However,their synthetic procedures, chemical properties and structural characterization are not available in literature.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 163,p. 443 - 452
[2]Journal of Enzyme Inhibition and Medicinal Chemistry,2019,vol. 34,p. 1186 - 1192

65
[ 39512-49-7 ]
[ 456-04-2 ]
C₁₉H₁₉ClFNO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In ethanol;Inert atmosphere;	Compound 7 was prepared following a previously published protocol for a similar molecule.? Sodium iodide (0.039 g, 0.260 mmol) and sodium carbonate (0.050 g, 0.472 mmol) were added to a stirred mixture of 4?-fluoro-4- chiorobutyrophenone (0.047 g, 0.236 mmol) and 4-(4-chlo- rophenyl)-4-hydroxypiperidine (0.050 g, 0.236 mmol) in MeCN (2 mE). The reaction mixture was refluxed for 12 h. The mixture was diluted with H20, and extracted with CH2C12 (3x10 mE), dried over Mg504, and concentrated under reduced pressure. The residue was purified by column chromatography (5i02, MeOH:EtOAc/i:9, R10.19), to give compound 7 (0.027 g, 30% yield) as a white solid: ?H NMR (400 MHz, CDC13, FIG. 22) oe 7.99-7.96 (m, 2H), 7.38 (d, J=7.6 Hz, 2H), 7.27 (dd, J=8.4, 1.6 Hz, 2H), 7.11 (app. t, J=8.4 Hz, 2H), 3.04-2.98 (m, 4H), 2.72 (t, J=ii.6 Hz, 2H), 2.67 (t, J=6.8 Hz, 2H), 2.30-2.17 (m, 2H), 2.07 (p, J=6.8 Hz, 2H), 1.75 (m, 2H); ?3C NMR (100 MHz, CDC13, FIG. 23) oe 197.8, 167.0, 164.5, 146.0, 133.2, 133.0, 130.7, 130.6, 128.4, 126.0, 115.8, 115.6, 70.4, 57.4, 49.1, 37.2, 35.9, 20.6; ERMS mlz calcd for C2,H24C1FN02 [M+H]: 376.1; found 376.7. Purity of the compound was thrther confirmed by RP-HPEC by using method 1: Rt=7.62 mm (100% pure; FIG. 24); Following the general procedure described for the synthesis of compound 7, potassium carbonate (0.05 g, 0.36 mmol), 4?-fluoro-2-chloroacetophenone (0.04 g, 0.23 mmol), and <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong> (0.05 g, 0.23 mmol) in EtOH (10 mL) were used to afford compound 23 (0.067 g, 100%, Rf 0.33 in MeOH:CH2Cl2/5:95) as a white solid: 1H NMR (400 MHz, CDCl3, FIG. 66) delta 8.05 (dd, J=7.6, 5.6 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.30 (d, J=7.6 Hz, 2H), 7.12 (app. t, J=8.4 Hz, 2H), 3.83 (s, 2H), 2.88 (m, 2H), 2.62 (t, J=11.6 Hz, 2H), 2.21 (td, J=11.6, 4.4 Hz, 2H), 1.72 (m, 2H), 1.71 (br s, 1H); 13C NMR (100 MHz, CDCl3, FIG. 67) delta 195.0, 167.1, 164.5, 146.7, 132.9, 132.4, 130.9, 130.8, 128.4, 126.1, 115.8, 115.6, 70.7, 64.5, 49.7, 38.3; LRMS m/z calcd for C19H20ClFNO2 [M+H]+: 348.1; found 348.7. Purity of the compound was further confirmed by RP-HPLC by using method 1: Rt=6.85 min (95% pure; FIG. 68)

Reference： [1]Patent: US2019/15400,2019,A1 .Location in patent: Paragraph 0171; 0199-0200; 0231-0232

66
[ 39512-49-7 ]
C₁₄H₁₇ClO [ No CAS ]
3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43.1%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 16h;	3) Weigh the compound of formula Va-2 (70 mg, 0.30 mmol), 4-(4-chlorophenyl)piperidin-4-ol (95 mg,0.45 mmol of the compound of formula VI-1) in a reaction flask, 10 mL of dry DMF was added, followed by N,N-diisopropyl BAmine (116mg, 0.90mmol), heated to 60 C for 16h, add ethyl acetate and water to dilute the reaction solution, liquid separation, water phase with BExtracted with ethyl acetate, combined with organic phase, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfateReduction, crude column chromatography (dichloromethane / methanol = 100:2)Obtained a white solid (compound of formula IA-6) 53 mg, yield:43.1%.

Reference： [1]Patent: CN109384707,2019,A .Location in patent: Paragraph 0091-0093; 0098-0100

67
[ 39512-49-7 ]
[ 92581-66-3 ]
1-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)butane-1,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.7%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 5h;	(3) Weighing the compound of the formula Vb-1-OH (120 mg, 0.49 mmol),4-(4-chlorophenyl)-piperidin-4-ol(125 mg, 0.59 mmol, compound of formula VI-1), HATU (281 mg, 0.74 mmol) and TEA (148 mg, 1.47 mmol) in a reaction flask.Add 15 mL of dry DMF as the reaction solvent and stir at room temperature for 5 h.The reaction solution was diluted with an appropriate amount of ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate.The organic phases are combined and washed successively with water and a saturated sodium chloride solution.Add anhydrous sodium sulfate and concentrate under reduced pressure.165 mg of a pale yellow solid (compound of formula IA-11) was obtained, yield: 76.7%.

Reference： [1]ACS Infectious Diseases,2019
[2]Patent: CN109384707,2019,A .Location in patent: Paragraph 0125-0127; 0130; 0131

68
[ 39512-49-7 ]
C₁₄H₁₉Cl [ No CAS ]
4-(4-chlorophenyl)-1-(3-(6,7,8,9-tetrahydro-5H-benzo[7]-annulen-2-yl)propyl)piperidin-4-ol hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38.1%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 16h;	(3) The compound of the formula Vaa-1 (142 mg, 0.64 mmol), 4-(4-chlorophenyl)piperidin-4-ol (203 mg, 0.96 mmol, compound of the formula VI-1) was weighed. Add 10 mL of dry DMF to the bottle, then add N,N-diisopropylethylamine (248 mg, 1.92 mmol), heat to 60 C for 16 h, add the ethyl acetate and water to dilute the reaction solution, and dispense.The aqueous phase was extracted with ethyl acetate and the organic phases were combined.Wash with water and saturated sodium chloride solution successively, and dry over anhydrous sodium sulfate.Concentrated under reduced pressure, the crude was purified by column chromatography (dichloromethane / methanol = 100:2)Get a white solid(hydrochloride of the compound of formula IC-1)97 mg, yield: 38.1%.

Reference： [1]Patent: CN109384707,2019,A .Location in patent: Paragraph 0203-0205; 0210-0212

69
[ 39512-49-7 ]
C₁₂H₁₃ClO₂ [ No CAS ]
4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(2,3-dihydrobenzofuran-5-yl)butan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44.9%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 16h;	(2) Weighing the compound of the formula Va-1 (200 mg, 0.89 mmol),4-(4-chlorophenyl)piperidin-4-ol (283 mg,1.335 mmol of the compound of formula VI-1) in a reaction flask, 15 mL of dry DMF was added, followed by N,N-diisopropylethylamine (344 mg, 2.67 mmol).Heat to 60 C for 16 h, add ethyl acetate and water to dilute the reaction solution, and dispense.The aqueous phase was extracted with ethyl acetate. The organic phase was combined, washed sequentially with water and saturated sodium chloride and dried over anhydrous sodium sulfate.Concentrated under reduced pressure,The crude product was subjected to silica gel column chromatography (dichloromethane / methanol = 100:2)A white solid (compound of formula IA-1) 160 mg was obtained in a yield: 44.9%.

Reference： [1]Patent: CN109384707,2019,A .Location in patent: Paragraph 0054-0056; 0059-0061

70
[ 39512-49-7 ]
[ 75489-97-3 ]
1-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)butan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.5%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 5h;	(3) Weigh the compound of the formula Vbb-1-OH (129 mg, 0.56 mmol), 4-(4-chlorophenyl)-piperidin-4-ol(142 mg, 0.67 mmol, compound of formula VI-1), 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethylurea hexafluoroPhosphate (HATU, 319 mg, 0.84 mmol) and TEA (170 mg, 1.68 mmol) in a reaction flask, adding 15 mL of dry DMFAs a reaction solvent, stir at room temperature for 5 h, dilute the reaction solution by adding appropriate amount of ethyl acetate and water, and separate the liquid.The organic phase was combined, washed successively with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated.Yellow solid (compound represented by formula IC-6) 192 mg, yield: 80.5%.

Reference： [1]Patent: CN109384707,2019,A .Location in patent: Paragraph 0237-0239; 0242-0244
[2]ACS Infectious Diseases,2019

71
[ 39512-49-7 ]
5-cyano-2-(difluoromethyl)-6-(4-(trifluoromethyl)phenyl)nicotinic acid [ No CAS ]
5-(4-(4-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-6-(difluoromethyl)-2-(4-(trifluoromethyl)phenyl)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With dmap; N-[3-(diethylamino)propyl]-N'-ethylcarbodiimide hydrochloride; In dichloromethane; at 20℃;	0.16 g of 5-cyano-2-(difluoromethyl)-6-(4-(trifluoromethyl)phenyl) nicotinic acid was suspended in 10 ml of dichloromethane, 0.2 g of <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong>, 0.11 g of 4-(N,N-dimethylamino) pyridine and 0.18 g of 1-[3-(diethylamino)propyl]-3-ethylcarbodiimide hydrochloride were added thereto, and the resulting mixture was stirred at room temperature overnight. The reaction solution was poured into ice water and extracted with chloroform. The resultant was washed sequentially with water and saturated brine. Thereafter, the resultant was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 0.1 g of a target compound. Yield: 40% 1H-NMR (CDCl3, delta ppm) 1.66-2.16 (4H, m), 3.34-3.43 (2H, m), 3.65-3.73 (1H, m), 4.67-4.77 (1H, m), 6.86 (1H, t), 7.33-7.42 (4H, m), 7.82 (2H, d), 8.10-8.12 (3H, m)

Reference： [1]Patent: US2019/191702,2019,A1 .Location in patent: Paragraph 0434-0437

72
[ 39512-49-7 ]
6-[4-(trifluoromethyl)phenoxy]pyridine-3-carboxylic acid [ No CAS ]
(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)(6-(4-(trifluoromethyl)phenoxy)pyridin-3-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With dmap; N-[3-(diethylamino)propyl]-N'-ethylcarbodiimide hydrochloride; In dichloromethane; at 20℃;	0.3 g of 6-(4-(trifluoromethyl)phenoxy) nicotinic acid was suspended in 15 ml of dichloromethane, to which 0.34 g of <strong>[39512-49-7]4-(4-chlorophenyl)-4-hydroxypiperidine</strong>, 0.19 g of 4-(N,N-dimethylamino) pyridine and 0.3 g of 1-[3-(diethylamino)propyl]-3-ethylcarbodiimide hydrochloride were added, and the resulting mixture was stirred at room temperature overnight. The reaction solution was poured into ice water and extracted with chloroform. The resultant was washed sequentially with water and saturated brine. Thereafter, the resultant was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 0.46 g of a target compound. Yield: 91% 1H-NMR (CDCl3, delta ppm) 1.66-2.19 (4H, m), 3.23-3.79 (3H, m), 4.56-4.71 (1H, m), 7.03 (1H, d), 7.25-7.40 (6H, m) , 7.67 (2H, d), 7.86 (1H, d), 8.27 (1H, s)

Reference： [1]Patent: US2019/191702,2019,A1 .Location in patent: Paragraph 0446-0449

73
[ 39512-49-7 ]
[ 78573-85-0 ]
4-(p-chlorophenyl)-1-(7-phenylheptyl)piperidin-4-ol [ No CAS ]