[ CAS No. 4897-50-1 ] {[proInfo.proName]}

Name: 4897-50-1|4-Piperidinopiperidine|98%
Brand: Ambeed
SKU: A197582
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Quality Control of [ 4897-50-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 4897-50-1 ]

Product Details of [ 4897-50-1 ]

CAS No. :	4897-50-1	MDL No. :	MFCD00006475
Formula :	C₁₀H₂₀N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QDVBKXJMLILLLB-UHFFFAOYSA-N
M.W :	168.28	Pubchem ID :	78607
Synonyms :

Calculated chemistry of [ 4897-50-1 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	59.48
TPSA :	15.27 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.45 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.35
Log Po/w (XLOGP3) :	1.23
Log Po/w (WLOGP) :	0.46
Log Po/w (MLOGP) :	1.52
Log Po/w (SILICOS-IT) :	1.81
Consensus Log Po/w :	1.47

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.59
Solubility :	4.3 mg/ml ; 0.0256 mol/l
Class :	Very soluble
Log S (Ali) :	-1.15
Solubility :	12.0 mg/ml ; 0.0711 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.81
Solubility :	2.62 mg/ml ; 0.0156 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.43

Safety of [ 4897-50-1 ]

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 [ 4897-50-1 ]

* 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 [ 4897-50-1 ]
Downstream synthetic route of [ 4897-50-1 ]

[ 4897-50-1 ] Synthesis Path-Upstream 1~13

1
[ 110-89-4 ]
[ 79099-07-3 ]
[ 4897-50-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 0 - 20℃; for 16 h;	Piperidine (1.549 g, 18.19 mmol), sodium triacetoxyborohydride (3.85 g, 19.2 mmol), and acetic acid (0.0910 g, 1.52 mmol) were added to a solution of 1-tert-butoxycarbonyl-4-piperidinone (3.02 g, 15.2 mmol) in dichloromethane (25.0 mL) at 0° C., and the resulting mixture was stirred at room temperature for 16 hours. The reaction liquid was cooled to 0° C. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction liquid, and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hydrochloric acid (1.0 N), and the resulting mixture was extracted with ethyl acetate. A 48percent aqueous solution of sodium hydroxide was added to the aqueous layer for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (25.0 mL), and concentrated hydrochloric acid (5.0 mL) was added, and then the resulting mixture was stirred at 40° C. for 12 hours. The reaction liquid was concentrated and exsiccated, and then the residue was dissolved in distilled water. A 48percent aqueous solution of sodium hydroxide was added for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. 4-(Piperidin-1-yl)piperidine (2.04 g, 12.1 mmol, 80percent) was obtained as a white solid.

Reference： [1] Patent: TW2016/2093, 2016, A, . Location in patent: Paragraph 0317

2
[ 125541-12-0 ]
[ 4897-50-1 ]

Yield	Reaction Conditions	Operation in experiment
2.04 g	With hydrogenchloride In methanol at 40℃; for 12 h;	Reference Example 19 Synthesis of 4-(piperidin-1-yl)piperidine (0391) (0392) Piperidine (1.549 g, 18.19 mmol), sodium triacetoxyborohydride (3.85 g, 19.2 mmol), and acetic acid (0.0910 g, 1.52 mmol) were added to a solution of 1-tert-butoxycarbonyl-4-piperidinone (3.02 g, 15.2 mmol) in dichloromethane (25.0 mL) at 0° C., and the resulting mixture was stirred at room temperature for 16 hours. The reaction liquid was cooled to 0° C. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction liquid, and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hydrochloric acid (1.0 N), and the resulting mixture was extracted with ethyl acetate. A 48percent aqueous solution of sodium hydroxide was added to the aqueous layer for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (25.0 mL), and concentrated hydrochloric acid (5.0 mL) was added, and then the resulting mixture was stirred at 40° C. for 12 hours. The reaction liquid was concentrated and exsiccated, and then the residue was dissolved in distilled water. A 48percent aqueous solution of sodium hydroxide was added for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. 4-(Piperidin-1-yl)piperidine (2.04 g, 12.1 mmol, 80percent) was obtained as a white solid. (0393) ¹H-NMR (400 MHz, CDCl₃) δ: 1.35-1.50 (4H, m), 1.53-1.67 (4H, m), 1.82 (2H, d, J=12.4 Hz), 2.34 (1H, tt, J=11.2, 4.0 Hz), 2.45-2.65 (6H, m), 3.13 (2H, d, J=12.4 Hz). (0394) ESI-MS: m/z=169 (M+H)⁺.

Reference： [1] Patent: US2016/194302, 2016, A1, . Location in patent: Paragraph 0391; 0392; 0393; 0394

3
[ 383865-57-4 ]
[ 4897-50-1 ]

Reference： [1] Patent: US2002/45615, 2002, A1,

4
[ 97682-44-5 ]
[ 4897-50-1 ]
[ 86639-52-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 12, p. 3742 - 3752

5
[ 79099-07-3 ]
[ 4897-50-1 ]

Reference： [1] Patent: US2016/194302, 2016, A1,

6
[ 110-89-4 ]
[ 4897-50-1 ]

Reference： [1] Patent: US2016/194302, 2016, A1,

7
[ 944411-93-2 ]
[ 4897-50-1 ]
[ 1608129-84-5 ]
[ 106-40-1 ]

Reference： [1] European Journal of Medicinal Chemistry, 2014, vol. 78, p. 401 - 418

8
[ 4897-50-1 ]
[ 32315-10-9 ]
[ 103816-19-9 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	Stage #1: at 20 - 70℃; Stage #2: With potassium carbonate In dichloromethane at 20℃;	Example 1 [1,4']bipiperidinyl-1'-carbonyl chloride (II) In a solution of Triphosgene (16.48 gm) in methylene chloride (200 ml) was added a solution of 4-piperidinopiperidine (20 g) in methylene chloride (200 ml) at 20-25° C. within 1-2 hours. Part of the methylene chloride was distilled off and acetonitrile was added. Further, methylene chloride and acetonitrile was distilled off completely until the temperature rises to 70° C. At room temperature fresh methylene chloride was added to the reaction mixture to make homogenous slurry followed by potassium carbonate (30-35 gm) and reaction mixture was stirred for 1-2 hours. The reaction mixture was filtered and subsequently the filtrate was concentrated. Hexane was added slowly into the reaction mixture under stirring. Solid compound so obtained was filtered, washed with hexane and dried under reduced pressure at about 40° C. Yield-27 g (98.5percent); GC purity: 99.80percent; Dimeric Impurity: Not Detected
98.5%	Stage #1: at 20 - 25℃; Stage #2: With potassium carbonate In dichloromethane at 20℃;	Example 1 [1,4']bipiperidinyl-1'-carbonyl chloride (II) In a solution of Triphosgene (16.48gm) in methylene chloride (200ml) was added a solution of 4-piperidinopiperidine (20 g) in methylene chloride (200ml) at 20-25 °C within 1-2 hours. Part of the methylene chloride was distilled off and acetonitrile was added. Further, methylene chloride and acetonitrile was distilled off completely until the temperature rises to 70 °C. At room temperature fresh methylene chloride was added to the reaction mixture to make homogenous slurry followed by potassium carbonate (30-35 gm) and reaction mixture was stirred for 1-2 hours. The reaction mixture was filtered and subsequently the filtrate was concentrated. Hexane was added slowly into the reaction mixture under stirring. Solid compound so obtained was filtered, washed with hexane and dried under reduced pressure at about 40 °C. Yield- 27 g (98.5percent); GC purity: 99.80percent; Dimeric Impurity: Not Detected

Reference： [1] Patent: US2011/144342, 2011, A1, . Location in patent: Page/Page column 7
[2] Patent: EP2341046, 2011, A2, . Location in patent: Page/Page column 9
[3] Patent: US2007/208050, 2007, A1, . Location in patent: Page/Page column 7
[4] Patent: WO2009/97695, 2009, A1, . Location in patent: Page/Page column 114-115
[5] Patent: WO2006/16203, 2006, A1, . Location in patent: Page/Page column 8-9
[6] European Journal of Medicinal Chemistry, 2011, vol. 46, # 6, p. 2490 - 2502
[7] MedChemComm, 2016, vol. 7, # 4, p. 658 - 666
[8] Patent: WO2017/74325, 2017, A1, . Location in patent: Paragraph 0104-0105
[9] Patent: US2017/114076, 2017, A1, . Location in patent: Paragraph 0116
[10] Patent: WO2017/123809, 2017, A1, . Location in patent: Paragraph 0078

9
[ 4897-50-1 ]
[ 503-38-8 ]
[ 103816-19-9 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 6, p. 1446 - 1454

10
[ 4897-50-1 ]
[ 86639-52-3 ]
[ 100286-90-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: With triethylamine In pyridine; dichloromethane at 30 - 40℃; for 1.5 h; Stage #2: for 0.5 h;	7-Ethyl-lO-hydroxycamptothecin (4.5 g) and pyridine (60 ml) were charged in a reaction vessel. A solution of [l,4']-bipiperidinyl-r-carbonyl chloride hydrochloride (3.44 g) and triethylamine (4.8 ml) in 75 ml of methylene chloride was added at 30-40 °C. The mixture was stirred for 1.5 hours at 30-40 °C. 4- piperidinopiperidine (0.58 g) was added and the mixture was stirred for 0.5 hour. Methylene chloride and pyridine were distilled off until the volume of the residue was about 25 ml. Acetonitrile (100 ml) was added and the mixture was heated to about 60 °C. The mixture was cooled to room temperature and 15 ml of 5 percent aqueous hydrochloric acid was added. The mixture was stirred about 20 hours at room temperature. The mixture was cooled to 0 +/- 5. The crystalline compound was filtered and washed with acetonitrile: water 10:1 mixture (10 ml) and acetonitrile (10 ml). The product was dried under reduced pressure. The yield was 6.4 g (90 percent).

Reference： [1] Patent: WO2006/84940, 2006, A1, . Location in patent: Page/Page column 5-6

11
[ 4897-50-1 ]
[ 100286-90-6 ]

Reference： [1] Patent: US2011/144342, 2011, A1,
[2] Patent: EP2341046, 2011, A2,
[3] Patent: WO2012/32531, 2012, A1,

12
[ 4897-50-1 ]
[ 97682-44-5 ]

Reference： [1] Chemistry - A European Journal, 1998, vol. 4, # 1, p. 67 - 83
[2] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 6, p. 1446 - 1454
[3] Patent: US2011/144342, 2011, A1,
[4] Patent: EP2341046, 2011, A2,
[5] Patent: WO2012/7952, 2012, A1,
[6] Patent: WO2012/32531, 2012, A1,

13
[ 4897-50-1 ]
[ 32315-10-9 ]
[ 86639-52-3 ]
[ 97682-44-5 ]

Yield	Reaction Conditions	Operation in experiment
85.2%	Stage #1: With 1,4-diaza-bicyclo[2.2.2]octane; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.583333 h; Stage #2: at 22 - 25℃; for 2.25 - 4.25 h;	EXAMPLE 2 4.00 g (10.2 mmol) 7-Ethyl-10-hydroxycamptothecin (purity 80percent) are dissolved in 60 ml CH₂Cl₂. 2.15 g (16.3 mmol) diisopropylethylamine, dissolved in 10 ml CH₂Cl₂, 0.16 g (1 mmol) DABCO and 1.1 g (36 mmol) bis(trichloromethyl)carbonate, dissolved in 10 ml CH₂Cl₂are added at a temperature of 20° C. within 15 min. The solution is stirred for a further 20 min. Then 1.80 g (16 mmol) piperidinopiperidine, dissolved in 10 ml CH₂Cl₂, and 2.15 g (16.2 mmol) diisopropylethylamine, dissolved in 10 ml CH₂Cl₂, are added simultaneously within 15 min at 22° C. The resulting clear solution is stirred for 2-4 h at 25° C. The organic layer is extracted with 2.x.80 ml saturated NaHCO₃solution and 3.x.60 ml H₂O. The aqueous layers are collected and extracted with 2.x.40 ml CH₂Cl₂. The combined organic layers are extracted again with 2.x.60 ml H₂O, dried over 2 g Na₂SO₄, filtered and concentrated. The residue is recrystallized from 2-methoxyethanol and dried in vacuo. Yield: 5.1 g 85.2percent of theory Appearance: yellow powder

Reference： [1] Patent: US2007/135471, 2007, A1, . Location in patent: Page/Page column 4

[ 4897-50-1 ] Synthesis Path-Downstream 1~87

1
[ 4897-50-1 ]
[ 82419-35-0 ]
[ 86794-27-6 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1984,vol. 32,p. 4907 - 4913

2
[ 4897-50-1 ]
[ 503-38-8 ]
[ 103816-19-9 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1446 - 1454

3
[ 4897-50-1 ]
[ 272104-64-0 ]
[ 270574-03-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 50℃; for 18h;	methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-2-phenyl-4-quinolinecarboxylateMethyl 3-(bromomethyl)-2-phenyl-4-quinolinecarboxylate (1 .00 g, 2.81 mmol), 1 ,4'- bipiperidine (0.497 g, 2.81 mmol), and A/JV-diisopropylethylamine (0.540 mL, 3.09 mmol) were dissolved in anhydrous tetrahydrofuran (20.0 mL). The mixture was stirred for 18 h at 50 °C. The resulting thick suspension was concentrated in vacuo and the solid residue was triturated with water (-20 mL) and collected by filtration. The solids were washed with water and air-dried to provide the crude product. This material was purified via columnchromatography (ISCO, 120 g column, 0-10percent methanol/methylene chloride) to afford methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-2-phenyl-4-quinolinecarboxylate (0.89 g, 72percent yield) as a foam. MS (m/z) 444.14 (M+H+).

Reference： [1]Patent: WO2011/119704,2011,A1 .Location in patent: Page/Page column 51
[2]Journal of Medicinal Chemistry,2001,vol. 44,p. 1675 - 1689
[3]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 549 - 554

4
[ 656233-42-0 ]
[ 4897-50-1 ]
[ 103816-16-6 ]

Yield	Reaction Conditions	Operation in experiment
73%	With triethylamine; In tetrahydrofuran; at 20℃; for 2h;	Example 6 Synthesis of PP-HCPT 10-[4-(1-Piperidino)-1-piperidino]carbonyloxycamptothecin (PP-HCPT). Carbonate 8 (0.53 g, 1 mmol) in THF (55 mL) was treated with <strong>[4897-50-1]4-piperidinopiperidin</strong>e (0.17 g, 1 mmol), and triethylamine (1 mL), and the reaction was stirred at room temperature for 2 h. Solvent was removed in vacuo, and the product was purified by column chromatography, eluding with dichloromethane and methanol (5:1, v/v) to afford PP-HCPT as a yellow solid (0.41 g, 73percent yield). 1H NMR (DMSO-d6): 8.66 (s, 1H), 8.19-8.17 (d, 1H, J=9.2 Hz), 7.92-7.91 (d, 1H, J=2.8 Hz), 7.70-7.67 (dd, 1H, J=3.2, 9.6 Hz), 7.35 (s, 1H), 6.54 (s, 1H), 5.44 (s, 2H), 5.30 (s, 2H), 4.29-4.26 (br d, 1H), 4.12-4.08 (br d, 1H), 3.08-3.05 (br t, 1H), 2.94-2.91 (br t, 1H), 1.91-1.82 (m, 4H), 1.53-1.42 (br d, 8H), 0.91-0.87 (t, 3H, J=7.4 Hz). MS m/z (M++H): 559.64.

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 5592 - 5599
[2]Patent: US2004/34033,2004,A1 .Location in patent: Page/Page column 13

5
[ 4897-50-1 ]
[ 3895-92-9 ]
6-N-(4-piperidinopiperidin-1-yl)-5,6-dihydrochelerythrine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	In acetonitrile; at 20℃;	A reaction mixture of <strong>[3895-92-9]chelerythrine chloride</strong> (40 mg, 0.10 mmol) and 4-piperidinopiperidine (175 mg, 1.0 rnmol) in acetonitrile (2 mL) is stirred at room temperature overnight. The off-white solid is filtered, washed with acetonitrile and dried to afford 6-N-(4- piperidinopiperidin-lyl)-5,6-dihydrochelerythrine (35.9 mg, 67%).

Reference： [1]Patent: WO2008/16596,2008,A2 .Location in patent: Page/Page column 30

6
[ 4897-50-1 ]
[ 97682-44-5 ]

Reference： [1]Chemistry - A European Journal,1998,vol. 4,p. 67 - 83
[2]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 1446 - 1454
[3]Patent: US2011/144342,2011,A1
[4]Patent: EP2341046,2011,A2
[5]Patent: WO2012/7952,2012,A1
[6]Patent: WO2012/32531,2012,A1
[7]Patent: CN109796462,2019,A

7
[ 4897-50-1 ]
[ 97-08-5 ]
C₁₆H₂₂ClN₃O₄S [ No CAS ]

Reference： [1]Patent: US6362351,2002,B1 .Location in patent: Example 1

8
[ 4897-50-1 ]
[ 635710-31-5 ]
(+/-)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidinyl-1'-yl-1-(7-methyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); dichloromethane; at 0 - 20℃;	A stirred solution of (~)-3-(7-methyl-1H-indazol-5-yl)-2-[4-(2-oxo-1,4- [DIHYDRO-2H-QUINAZOLIN-3-YL)-PIPERIDINE-1-CARBONYL]-AMINO}-PROPIONIC] acid (65.7 mg, 0. [138] mmol) in 2: 1 dimethylformamide/methylene chloride (1.5 [ML)] at [0°C] was treated with [4- (1-PIPERIDYL)-PIPERIDNE] (46.5 mg, 2 equiv), diisopropylethylamine (0.048 mL, 2 equiv) and [PYBOPE] (75.5 mg, 1.05 equiv). The ice bath was allowed to melt and the mixture was stirred at room temperature overnight. The solvents were removed under high vacuum and the residue was purified by flash chromatography on silica gel, eluting with 18: 1 methylene chloride/methanol containing 1percent triethylamine, to give the product as a pale-yellow solid [(80.] 4 mg, [93percent). 1H-NMR] (CD30D, 500 MHz) [8-0.] 28 [(1H,] m), 0.75 [(1H,] m), 1.2-2. 0 (12H, m), 2. 08 (2H, m), 2.4-2. 5 (3H, m), 2.59 (3H, s), 2.68 (2H, m), 2.90 (4H, m), 3. 08 (4H, m), 3.9-5. 1 (4H, several m), 6.81 [(1H,] d), 6.96 [(1H,] t), 7.16 (3H, m), 7.49 [(1H,] s), 8.03 [(1H,] s). Mass spec.: 627.29 [(MH)] [+.]

Reference： [1]Patent: WO2003/104236,2003,A1 .Location in patent: Page 103-104

9
[ 4897-50-1 ]
C₂₆H₃₀N₆O₄ [ No CAS ]
(+/-)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidinyl-1'-yl-1-(7-ethyl-1H-indazol-5-ylmethyl)-2-oxo-ethyl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In DMF (N,N-dimethyl-formamide); dichloromethane; at 0 - 20℃; for 1.75h;	To a solution of [(+)-3-(7-ETHYL-LH-INDAZOL-5-YL)-2-{ [4-(2-OXO-1, 4-DIHYDRO-] [2H-QUINAZOLIN-3-YL)-PIPERIDINE-1-CARBONYL]-AMINO}-PROPIONIC] acid methyl ester (15 mg, 0.03 mmol) in methanol (0.6 mL) was added a solution of lithium hydroxide monohydrate (3.0 mg, 2.5 equiv) in water (0.1 mL), and the resulting solution was stirred for 6 h. The solution was cooled to [0°C,] treated with aqueous 1 M potassium hydrogen sulfate (60 muL, 2.0 equiv), and concentrated to give the crude acid which was immediately used without purification. The crude acid was dissolved in dimethylformamide (0.4 mL), cooled to [0°C,] and sequentially treated with methylene chloride (0.2 mL), 4-piperidyl-piperidine (11 mg, 2.2 equiv), diisopropylethylamine [(12 GEL,] 2.3 equiv. ), and [PYBOPO] (19 mg, 1.2 equiv). The solution was stirred for 15 min at [0°C,] warmed to room temperature, stirred 1.5 h, and concentrated. The product was purified by column chromatography to give 14.5 mg (76percent, 2 [STEPS).APOS;H-] NMR [(CDC13,] 500 [MHZ) O 1.] 28-1.48 (m, [10H),] 1.52 (m, 2H), 1.60-1. 82 (m, 6H), 1.95 (m, 1.4H), 2.06 (m, 1. 6H), 2.20-2. 50 (m, 5H), 2.77-2. 93 (m, [5H),] 2.96-3. 17 (m, 2H), 3.76 (d, J=13.4, [0.] 4H), 3. 86 (d, J=13. 7,0. 6H), 4.10-4. 20 (m, 2H), 4.26 (s, 2H), 4.57 (m, 2H), 5.10-5. 24 (m, 1H), 5.67 (d, J=8. 2,0. 6H), 5.74 (d, J=7. 9,0. 4H), 6.67 (d, [J=7.] 9,1H), 5.67 (d, J=8. 2,0. 6H), 5.74 (d, J=7. 9,0. 4H), 6.67 (d, J=7. 9, 1H), 6.93 (dd, J=7. 6,7. 3, 1H), 6.96 (s, 0.4H), 7.03 (dd, J=7. 0,6. 7, 1H), 7.09 (m, 1. [6H),] 7.15 (dd, J=7. 0,6. 7, 1H), 7.31 (s, 0.4H), 7.38 (s, 0.6H), 7.94 (s, 0.4H), 7.95 (s, 0.6H). Mass spec.: 641.50 [(MH)] [+.]

Reference： [1]Patent: WO2003/104236,2003,A1 .Location in patent: Page 129-130

10
[ 4897-50-1 ]
(+/-)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[1',2'-dihydro-2'-oxospiro-[4H]-3',1-benzoxazine-4,4'-piperidinyl]-butyric acid [ No CAS ]
(+/-)-1-[1,4']bipiperidinyl-1'-yl-2-(7-methyl-1H-indazol-5-ylmethyl)-4-[1',2'-dihydro-2'-oxospiro-[4H]-3',1-benzoxazine-4,4'-piperidinyl]-butane-1,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With triethylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one; In dichloromethane; at 20℃;	A solution of [2- (7-METHYL-LH-INDAZOL-5-YLMETHYL)-4-OXO-4- [LAPOS;,] 2'-dihydro-2'- [OXOSPIRO- [4H-3APOS;, L-BENZOXAZINE-4, 4APOS;-PIPERIDINYL]-BUTYRIC] acid (0.020 g, 0.04 mmol), piperidylpiperidine (0.0087 g, 0.05 mmol) and triethylamine (0.09 g, 0.08 mmol) in methylene chloride (5 [ML)] at room temperature was treated with 3- [(DIETHOXYPHOSPHORYLOXY)-1,] 2,3-benzotriain-4 [(3H)-ONE] (DEPBT, 0.0155 g, 0.05 mmol). The mixture was stirred overnight and then washed with water [(3 X 5 ML).] The organic layer was dried and the solvents were removed [IN VACUO.] The crude product was purified by preparative TLC on silica gel (10percent 2 M ammonium hydroxide/methanol in methylene chloride) to give the desired product (36percent). [LC/MS] : tR=1.18 min, 613.47 (MH) [+.]

Reference： [1]Patent: WO2003/104236,2003,A1 .Location in patent: Page 185-186
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2912 - 2916

11
[ 4897-50-1 ]
[ 635713-19-8 ]
(L)-{1-([1,4']bipiperidmyl-1'-carbonyl)-3-oxo-3-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-propyl}-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With triethylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one; In dichloromethane; at 20℃; for 15h;	To a stirred solution of 2-tert-butoxycarbonylamino-4-oxo-4- [4- (2-oxo-1, 4- dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyric acid (1.14 g, 2.55 mmol) and 4- [PIPERIDINYL-PIPERIDINE] (525 mg, 2.81 mmol) in methylene chloride (20 [ML)] was added [3- (DIETHOXYPHOSPHORYLOXY)-1,] 2,3-benzotriain-4 [(3H)-ONE] (DEPBT, 840 mg, 2.81 mmol) in one portion followed by dropwise addition of triethylamine (0.427 [ML,] 3.06 mmol). The resulted mixture was stirred at room temperature overnight (15 h). The mixture was diluted with methylene chloride and washed with sodium hydroxide (0.5 N) solution and water. The layers were separated and the organic layer was dried with sodium sulfate and concentrated [IN VACUO] to give a light yellow foam. The crude product was purified by flash column chromatography (10percent [(1M] ammonia in methanol) in methylene chloride) to give a colorless foam (1.08 g, [71percent).] [APOS;H-NMR] (400 MHz, [CDC13)] [8] 8.86-8. 55 [(1H,] br), 7.05 [(1H,] br), 6.93 [(1H,] br), 6.82 [(1H,] br), 6.72 [(1H,] d, J = 7.6 Hz), 6.10-5. 68 [(1H,] br), 5.20 [(1H,] m), 54.70-4. 40 (2H, br), 4.20 (2H, br), 4. [01-3. 82] (2H, br. ), 3.10-2. 88 (3H, br), 2.99 (3H, br), 2.53 (6H, br), 1.90-1. 10 (23H, m). Mass spec.: 597 [(MH) +.]

Reference： [1]Patent: WO2003/104236,2003,A1 .Location in patent: Page 195-196

12
[ 4897-50-1 ]
[ 635709-95-4 ]
[ 635709-99-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;	To a solution of (R)-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)- [ PIPERIDINE-I-CARBONYL]-AMINO 1-3- [I- (2-TRIMETHYLSILANYL-ETHANESULFONYL)- IH-INDAZOL-] 5-yl]-propionic acid (554 mg, 0.88 mmol) and N,N-diisopropylethylamine (0.62 mL, 3.54 mmol) in methylene chloride (20 mL) was added a solution of 4- piperidinopiperidine (164 mg, 0.97 mmol) and [PYBOPO] (460 mg, 0.88 mmol) in methylene chloride (15 mL). The reaction mixture was stirred for 16 h at room temperature. It was then concentrated to approximately 2 mL and subjected to flash column chromatography using methylene chloride/methanol/triethylamine (94: 5: 1) as eluent to give 599 mg (87percent) of the title compound as a white [SOLID. 1H-NMR] [(CD3CN,] 300 MHz) 8 8.37 (s, 0.5H), 8.36 (s, 0.5H), 8.02-7. 96 (m, 1H), 7.74 (s, [0.] [5H),] 7.71 (s, 0.5H), 7.55-7. 46 (m, 1H), 7.21-7. 12 (m, 2H), 6.97-6. 92 (m, 1H), 6.79 (d, [J=8. 1HZ, LH),] 5.71 (t, J = 8.1 Hz, 1H), 5.00 (dd, [J = 15.] 0, [8. 1 HZ, 1H),] 4.63- 4.51 (m, [1H),] 4.39-4. 29 (m, 1H), 4.29 (s, 2H), 4.10-3. 96 (m, 3H), 3.46-3. 40 (m, 2H), 2.92-2. 70 (m, 8H), 2.58-2. 37 (m, [5H),] 1.74-1. 40 (m, 13H), 0.80-0. 74 (m, 2H), -0. 04 (s, 9H). Mass spec.: 778 [(MH)] +.

Reference： [1]Patent: WO2003/104236,2003,A1 .Location in patent: Page 82-83

13
[ 4897-50-1 ]
[ 380844-49-5 ]
[ 863030-25-5 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,2-dimethoxyethane; at 85℃; for 16h;	A mixture of 260 mg (0.56 mmol) of <strong>[380844-49-5]7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxyquinoline-3-carbonitrile</strong> (Boschelli, Diane H.; Ye, Fei; Wang, Yanong D.; Dutia, Minu; Johnson, Steve L.; Wu, Biqi; Miller, Karen; Powell, Dennis W.; Yaczko, Deanna; Young, Mairead; Tischler, Mark; Arndt, Kim; Discafani, Carolyn; Etienne, Carlo; Gibbons, Jay; Grod, Janet; Lucas, Judy; Weber, Jennifer M.; Boschelli, Frank. J. Med. Chem. 2001, 44, 3965-3977) and 380 mg (2.24 mmol) of [1,4']bipiperidinyl are heated in 3 mL of ethylene glycol dimethyl ether at 85 C. for sixteen hours to yield the crude product. Following removal of the solvent in vacuo, the crude product is purified by silica gel chromatography (eluting with 7:3 methylene chloride/methanol) to give 35 mg of 7-(3-[1,4'-bipiperidin]-1'-ylpropoxy)-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-quinolinecarbonitrile as a white solid, mp 130-132 C. MS (ES, positive ion mode): m/z calcd for C31H37Cl2N5O3: 598.6, found: 598.3; 600.3 (M+1)

Reference： [1]Patent: US2005/187247,2005,A1 .Location in patent: Page/Page column 27-28

14
[ 4897-50-1 ]
[ 865626-89-7 ]
[ 865626-90-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;	To a solution of (O)-2-hydroxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)propanoic acid (100 mg, 0.29 mmol), <strong>[4897-50-1]4-piperidinopiperidin</strong>e (96.0 mg, 2.0 equiv), and diisopropylethylamine (0.10 mL, 0.57 mmol) in dichloromethane (3.6 mL) at 0° C. was added PyBOP.(R). (156 mg, 0.30 mmol) in two portions. The reaction was stirred at 0° C. for 15 minutes and at room temperature overnight. The reaction was diluted with ethyl acetate, washed with water (2.x.), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (4percent to 10percent methanol/dichloromethane) gave 130 mg (91percent) as an oil. Mass spec.: 501.36 (MH)+.

Reference： [1]Patent: US2005/215576,2005,A1 .Location in patent: Page/Page column 42-43

15
[ 4897-50-1 ]
[ 868707-75-9 ]
4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidine-1-carboxylic acid (R)-1-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-[1,4']bipiperidinyl-1'-yl-ethylester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃;	A solution of 70 mg (0.13 mmol) (R)-1-carboxy-2-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 50 mg (0.16 mmol) TBTU, 25 muL (0.18 mmol) triethylamine and 59 mg (0.16 mmol) [1,4']bipiperidinyl in 1.0 mL DMF were shaken overnight at RT. The reaction mixture was purified by HPLC without any further working up, the fractions containing the product were combined and lyophilised. Yield: 68 mg (75percent of theory) ESI-MS: (M+H)+=673 Rf=0.78 (silica gel, DCM/Cyc/MeOH/NH3 70:15:15:2)

Reference： [1]Patent: US2005/256099,2005,A1 .Location in patent: Page/Page column 181-182
[2]Patent: WO2005/103037,2005,A2 .Location in patent: Page/Page column 208-209

16
[ 4897-50-1 ]
C₂₅H₂₇N₅O₅ [ No CAS ]
3-(7-Methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-(1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); dichloromethane; at 0℃; for 1h;	To a solution of the crude acid, <strong>[4897-50-1]4-piperidinopiperidin</strong>e (9.9 mg, 2 equiv), and diisopropylethylamine (10 muL, 2 equiv) in dimethylformamide (1 mL) and dichloromethane (1 mL) at 0° C. was added PyBOP.(R). (16 mg, 1.05 equiv). The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by preparative HPLC to give the title compound (16 mg, 73percent) as its trifluoroacetic acid salt. 1H-NMR (CD3OD) delta 0.10 (m, 0.5), 1.11 (m, 0.5H), 1.50-2.35 (m, 13H), 2.45-3.30 (m, 10H), 3.38 (m, 2H), 3.55 (m, 2H), 4.15-4.70 (m, 6H), 4.85 (m, 1H), 5.76 (m, 1H), 6.98 (d, J=7.6, 1H), 7.14 (dd, J=7.6, 7.3, 1H), 7.20-7.55 (m, 3H), 7.71 (m, 1H), 8.25 (m, 1H). Mass spec.: 628.29 (MH)+.

Reference： [1]Patent: US2005/215576,2005,A1 .Location in patent: Page/Page column 26

17
[ 4897-50-1 ]
[ 1194-02-1 ]
4-[(4-piperidin-1-yl)piperidin-1-yl]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; In dimethyl sulfoxide; at 95℃; for 3h;	Potassium carbonate (4.14 g, 30 mmols) and (4-piperidin-1-yl)piperidine (6.05 g, 36 mmols) were added to dimethylsulfoxide solution (10 ml) of 4-fluorobenzonitrile (3.63 g, 30 mmols), and stirred at 95°C for 3 hours. The reaction mixture was cooled to room temperature, and poured into ice-water (300 ml) and stirred. The insoluble matter formed was taken out through filtration, and dried to obtain the entitled compound (635 g, 81 percent).

Reference： [1]Patent: EP1669350,2006,A1 .Location in patent: Page/Page column 58

18
[ 4897-50-1 ]
[ 86639-52-3 ]
[ 100286-90-6 ]

Yield	Reaction Conditions	Operation in experiment
90%		7-Ethyl-lO-hydroxycamptothecin (4.5 g) and pyridine (60 ml) were charged in a reaction vessel. A solution of [l,4']-bipiperidinyl-r-carbonyl chloride hydrochloride (3.44 g) and triethylamine (4.8 ml) in 75 ml of methylene chloride was added at 30-40 C. The mixture was stirred for 1.5 hours at 30-40 C. 4- piperidinopiperidine (0.58 g) was added and the mixture was stirred for 0.5 hour. Methylene chloride and pyridine were distilled off until the volume of the residue was about 25 ml. Acetonitrile (100 ml) was added and the mixture was heated to about 60 C. The mixture was cooled to room temperature and 15 ml of 5 % aqueous hydrochloric acid was added. The mixture was stirred about 20 hours at room temperature. The mixture was cooled to 0 +/- 5. The crystalline compound was filtered and washed with acetonitrile: water 10:1 mixture (10 ml) and acetonitrile (10 ml). The product was dried under reduced pressure. The yield was 6.4 g (90 %).

Reference： [1]Patent: WO2006/84940,2006,A1 .Location in patent: Page/Page column 5-6

19
[ 4897-50-1 ]
[ 32779-36-5 ]
2-[4-(piperidin-1-yl)piperidin-1-yl]-5-bromopyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	4-(Piperidin-1-yl)piperidine (342 mg, 2.03 mmols) and cesium carbonate (764 mg, 2.34 mmols) were added to DMF solution (10 ml) of 2-chloro-5-bromopyrimidine (300 mg, 1.56 mmols), and stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, chloroform/methanol = 100/3) to obtain the entitled compound (349 mg, 69 %).

Reference： [1]Patent: EP1669350,2006,A1 .Location in patent: Page/Page column 55

20
[ 383865-57-4 ]
[ 4897-50-1 ]
[1,4']Bipiperidinyl-1'-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%		[1,4']Bipiperidinyl-1'-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide Using <strong>[383865-57-4]4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine</strong> and [1,4']bipiperidinyl the title compound was obtained as white solid (35%). MS: m/e=461 (M+H+).

Reference： [1]Patent: US2002/45615,2002,A1

21
[ 4897-50-1 ]
4-bromo-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide [ No CAS ]
4-[1,4']Bipiperidinyl-1'-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 172 mg (1.02 mmol) of <strong>[4897-50-1]4-piperidinopiperidin</strong>e in 5.0 ml dimethylformamide was stirred at room temperature for 4 hr and at 60°C for 1 hr. After the mixture was cooled, the suspension was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were evaporated to an oil and purified by preparative TLC to yield 100 mg (40percent) yellow solid: mp 140-144°C.
100 mg (40%)	In N-methyl-acetamide;	EXAMPLE 112 4-[1,4']Bipiperidinyl-1'-yl-but-2-enoic Acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 172 mg (1.02 mmol) of <strong>[4897-50-1]4-piperidinopiperidin</strong>e in 5.0 ml dimethylformamide was stirred at room temperature for 4 hr and at 60° C. for 1 hr. After the mixture was cooled, the suspension was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were evaporated to an oil and purified by preparative TLC to yield 100 mg (40percent) yellow solid: mp 140-144° C.

Reference： [1]Patent: EP1950201,2008,A1 .Location in patent: Page/Page column 66
[2]Patent: US6297258,2001,B1

22
[ 4897-50-1 ]
[ 32315-10-9 ]
[ 103816-19-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In dichloromethane; at -10 - 20℃; for 4h;	Dissolve triphosgene (882mg, 2.97mmol) in 30mL of dichloromethane, and then dropwiseadd 1,4'-bipiperidine (500mg, 2.97mmol) and triethylamine (900mg, 8.91mmol)at -10 C.Dichloromethane solution (20 mL). After the dropwise addition was continued, the reaction was stirred at -10 C for 2 hours, and then transferredto room temperature for 2 hours.It was concentrated under reduced pressure, 20 mL of tetrahydrofuran was added to the residue, and the mother liquid was concentrated under reduced pressure to obtain the white title compound(680 mg, yield: 99%).
98.5%		Example 1 [1,4']bipiperidinyl-1'-carbonyl chloride (II) In a solution of Triphosgene (16.48 gm) in methylene chloride (200 ml) was added a solution of 4-piperidinopiperidine (20 g) in methylene chloride (200 ml) at 20-25 C. within 1-2 hours. Part of the methylene chloride was distilled off and acetonitrile was added. Further, methylene chloride and acetonitrile was distilled off completely until the temperature rises to 70 C. At room temperature fresh methylene chloride was added to the reaction mixture to make homogenous slurry followed by potassium carbonate (30-35 gm) and reaction mixture was stirred for 1-2 hours. The reaction mixture was filtered and subsequently the filtrate was concentrated. Hexane was added slowly into the reaction mixture under stirring. Solid compound so obtained was filtered, washed with hexane and dried under reduced pressure at about 40 C. Yield-27 g (98.5%); GC purity: 99.80%; Dimeric Impurity: Not Detected
98.5%		Example 1 [1,4']bipiperidinyl-1'-carbonyl chloride (II) In a solution of Triphosgene (16.48gm) in methylene chloride (200ml) was added a solution of 4-piperidinopiperidine (20 g) in methylene chloride (200ml) at 20-25 C within 1-2 hours. Part of the methylene chloride was distilled off and acetonitrile was added. Further, methylene chloride and acetonitrile was distilled off completely until the temperature rises to 70 C. At room temperature fresh methylene chloride was added to the reaction mixture to make homogenous slurry followed by potassium carbonate (30-35 gm) and reaction mixture was stirred for 1-2 hours. The reaction mixture was filtered and subsequently the filtrate was concentrated. Hexane was added slowly into the reaction mixture under stirring. Solid compound so obtained was filtered, washed with hexane and dried under reduced pressure at about 40 C. Yield- 27 g (98.5%); GC purity: 99.80%; Dimeric Impurity: Not Detected

98%	With triethylamine; In dichloromethane; at -15 - 20℃; for 1h;Inert atmosphere;	(D) In equipped with a thermometer, a dropping funnel, 250ml reaction flask three drying tube, was added triphosgene 1.8g (6mmol), dry dichloromethane 50ml, stirred to dissolution, the reaction was cooled to -15 deg.] C, stirred was added dropwise 4-piperidinyl piperidine 2g (11.9mmol), 50ml dichloromethane solution was dried 5.3ml of triethylamine was added dropwise while the reaction temperature was controlled at -15 ~ -10 , dropwise, warmed to room temperature stirring continued for 1 h, TLC determined reaction end point detection plate.Completion of the reaction, saturated sodium bicarbonate solution was added to the chilled reaction flask PH = 8, separation and extraction, the organic phase was washed with saturated brine precooled to neutral, dried over anhydrous magnesium sulfate, filtered, 35 water bath and concentrated under reduced pressure to an oil, yielding intermediate 4-piperidinyl piperidine carboxylic acid chloride (2.7 g, 98% yield).
		EXAMPLE 3 PREPARATION OF 4-PIPERIDINOPIPERIDINE CARBAMOYL CHLORIDE 150 g of 4-piperidinopiperidine was dissolved in 10.5 L of dichloromethane and the solution was cooled to about 0 C. A solution of triphosgene (94.8 g of triphosgene in 1.2 L of dichloromethane) was added slowly to the solution at about 5 C. over a period of 45 minutes under a nitrogen atmosphere with simultaneous stirring. The resultant reaction mixture was stirred at 27 C. for 12 hours. The reaction mixture was filtered and then the filtrate was washed with 1.2 L of 7% sodium bicarbonate solution. The organic layer was separated and concentrated completely at about 40 C. under a vacuum of 580 mm Hg to afford title compound. Purity: 97.2% by GC.
	In dichloromethane; at 0 - 20℃;	Example 101: 2-[(5E)-2-(l,2-diazinan-l-yl)-4-oxo-4,5-dihydro-l,3-thiazol-5- ylidene]methyl}-5-fluorophenyl 4-(piperidin-l-yl)piperidine-l-carboxylate dihydrochloride; To a solution of 4-piperidinepiperidine (2.O g, 11.9 mmol) in anhydrous CH2Cl2 (50 mL) at 0 0C was added a triphosgene solution (1.3 g, 4.3 mmol) in anhydrous CH2Cl2 (10 mL)by syringe pump addition (1 hour). The mixture was stirred at room temperature overnight. The solid material was removed by filtration. The mixture was extracted with 10% NaHCO3 (2 x 50 mL) and brine (1 x 50 mL). The organic phase was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording the 4-piperidinopiperidinecarbonyl chloride (1.6 g, 59%). The product was used without further purification.To a mixture of (5Z)-2-(l,2-diazinan-l-yl)-5-[(4-fluoro-2-hydroxyphenyl)methylidene]- 4,5-dihydro-l,3-thiazol-4-one (1.0 g, 3.3 mmol) in anhydrous acetonitrile (15 mL) was added potassium carbonate (900 mg, 6.6 mmol), followed by a solution of 4- piperidinopiperidinecarbonyl chloride (1.07 g, 4.6 mmol) in anhydrous acetonitrile (5 mL). The reaction mixture was stirred at reflux for 60 hours. After cooling the mixture to room temperature, the solid material was removed by filtration. The filtrate was recovered and evaporated under reduced pressure. The crude product was purified by flash chromatography (Combiflash Rf, 0-20% MeOH/CH2Cl2). The residue was triturated with diethyl ether (50 mL x 2). The solid material was recovered by filtration and dried in vacuo, affording 2-[(5E)-2-(l,2- diazinan-l-yl)-4-oxo-4,5-dihydro-l,3-thiazol-5-ylidene]methyl}-5-fluorophenyl 4-(piperidin-l- yl)piperidine-l-carboxylate (954 mg, 57%).To a mixture of 2-[(5E)-2-(l,2-diazinan-l-yl)-4-oxo-4,5-dihydro-l,3-thiazol-5- ylidene]methyl}-5-fluorophenyl 4-(piperidin-l-yl)piperidine-l-carboxylate (954 mg, 1.9 mmol) in methanol (5 mL) was added a solution of 4M HCl/ dioxane (3 mL, 12.0 mmol). The resultant solution was filtered, and the filtrate was recovered and evaporated. The solid was triturated with diethyl ether (50 mL). The solid material was recovered by filtration and dried in vacuo, affording the final compound (931mg, 91%). 1H NMR (400 MHz, DMSO-J6) 1-45 (m, IH), <n="116"/>1.81 (m, HH), 2.16 (m, 2H), 2.96 (m, 5H), 3.15 (m, IH), 3.44 (m, 3H), 3.88 (m, 2H), 4.11 (m, IH), 4.35 (m,lH) 6.17 (t, IH, J= 6.7 Hz), 7.32 (m, 2H), 7.47 (s, IH), 7.67 (t, IH, J= 6.3 Hz); M+ 502. HPLC purity: 99.1%.
		Example 1.; Preparation of 1-chlorocarbonyl-4-piperidinopiperidine base (IRT-4):; Dissolving 4-piperdinoperidine (100g) in benzene (1580ml) under stirring for 15 to 30 minutes at room temperature, adding a solution of triphosgene (150g) in benzene (660 ml) over a period of 1 to 3 hours at a temperature of 20- 25C. Filtering the solid, washing it with benzene and drying, then dissolve the dried solid in chloroform (5900 ml) by stirring at room temperature for about 30 minutes. Charging aqueous sodium bicarbonate solution (400 ml), stirring and separating chloroform layer, washing the chloroform layer with water (1800 ml), separating chloroform layer anddistilling off chloroform under vacuum at a temperature up to below 45C to obtain 1-chlorocorbonyl-4-piperidopiperidine base (60 g).
	With triethylamine; In dichloromethane; at -7 - 20℃;	To a solution of triphosgene (8 g, 26.9 mmol) in dry dichloromethane (40 mL) at -7 C were added dry triethylamine (1 mL, 7.1 mmol) and dropwise a solution of 1,4'-dipiperidine (5 g, 29.7 mmol) in dry dichloromethane (35 mL) over a period of 50 min. Then the solution was stirred at room temperature for 8 h, at which time the reaction was completed, the solution was filtered, the filtrate was concentrated, the residue was reacted with 23-hydroxybetulinic acid directly without further purification.
	In dichloromethane; at 0 - 20℃; for 17h;	The 4- piperidinopiperidinecarbamyl chloride reagent was prepared according to the literature condition (US patent 6,121,451. Briefly, To a solution of 4-piperidinopiperidine (35g, 208 mmol) in DCM (2.6L) at OoC was added a solution of triphosgene (22. lg, 83.2 mmol) in DCM (300 mL) slowly. The mixture was stirred from 0C to rt for 17 hr. Celite was added and the solution was filtered. The filtrate was washed with 7%> wt/v NaHC03 solution and dried over MgS04 (100g). The mixture was filtered and the solvent evaporated. The remaining residue was dissolved in anhydrous DCM (208 mL) to make 1M solution. The solution was used as is without further purification.
	In dichloromethane; at 0 - 20℃; for 17h;	The 4-piperidinopiperidinecarbamyl chloride reagent was prepared according to the literature condition (U.S. Pat. No. 6,121,451. Briefly, To a solution of 4-piperidinopiperidine (35 g, 208 mmol) in DCM (2.6 L) at 0 C. was added a solution of triphosgene (22.1 g, 83.2 mmol) in DCM (300 mL) slowly. The mixture was stirred from 0 C. to rt for 17 hr. Celite was added and the solution was filtered. The filtrate was washed with 7% wt/v NaHCO3 solution and dried over MgSO4(100 g). The mixture was filtered and the solvent evaporated. The remaining residue was dissolved in anhydrous DCM (208 mL) to make 1M solution. The solution was used as is without further purification.
	In dichloromethane; at 0 - 20℃;	A solution 4-piperidinopiperidine (2.00 g, 11.88 mmol) in anhydrous DCM (50 mL) at 0 C was added a solution of triphosgene (1.30 g, 4.38 mmol) in anhydrous DCM (10 mL). The mixture was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was concentrated in vacuo to afford a white solid (1.35 g). The solid (1.35 g) was added to a suspension of niclosamide (22) (1.94 g, 5.93 mmol), DMAP (0.15 g, 1.23 mmol) in pyridine (15 mL) at room temperature, and stirred at 80 C. After the reaction had completed, the solution was cooled to room temperature and neutralized to pH 7. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel with EtOAc/w-Hexane to afford compound 34 (0.87 g, 14%, two steps) as a pale white solid: mp 216.3-217.9 C; -NMR (300 MHz, CDCh) delta 1.54-1.84 (m, 8H), 2.02-2.17 (m, 4H), 2.72-3.06 (m, 8H), 4.28-4.40 (m, 2H), 5.30 (s, 1H), 7.14 (d, J = 8.7 Hz, 1H), 7.53 (dd, J= 2.4, 8.7 Hz, 1H), 7.82 (d, J= 2.7 Hz, 1H), 8.20 (dd, J= 2.4, 9.0 Hz, 1H), 8.33 (d, J= 2.4 Hz, 1H), 8.50-8.80 (m, 2H); 13C-NMR (75 MHz, DMSO-c e) delta 22.2, 23.2, 25.5, 43.0, 43.3, 48.9, 61.8, 123.1, 125.1, 125.5, 126.2, 127.4, 128.9, 129.5, 130.3, 131.8, 140.9, 144.5, 147.6, 152.1, 163.5; HRMS (ESI) for C24H25CI2N4O5 (M-H+) calcd 519.1202, found 519.1206; HPLC purity of 100.00% (retention time = 25.09)

Reference： [1]Patent: CN104387358,2016,B .Location in patent: Paragraph 0161-0164
[2]Patent: US2011/144342,2011,A1 .Location in patent: Page/Page column 7
[3]Patent: EP2341046,2011,A2 .Location in patent: Page/Page column 9
[4]Patent: CN110041318,2019,A .Location in patent: Paragraph 0104-0106; 0112-0113
[5]Patent: US2007/208050,2007,A1 .Location in patent: Page/Page column 7
[6]Patent: WO2009/97695,2009,A1 .Location in patent: Page/Page column 114-115
[7]Patent: WO2006/16203,2006,A1 .Location in patent: Page/Page column 8-9
[8]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2490 - 2502
[9]MedChemComm,2016,vol. 7,p. 658 - 666
[10]Patent: WO2017/74325,2017,A1 .Location in patent: Paragraph 0104-0105
[11]Patent: US2017/114076,2017,A1 .Location in patent: Paragraph 0116
[12]Patent: WO2017/123809,2017,A1 .Location in patent: Paragraph 0078

23
[ 4897-50-1 ]
[ 911370-61-1 ]
7-(1,4'-bipiperidin-1'-yl)-5-chloro-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]-pyrimidin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	Example 61; 7-(l,4'-bipiperidin-r-ylV5-chloro-l-(2,6-difluorophenylV3,4-dihvdropyrimido[4.5- ^pyrimidin-2('l.H)-one )To a solution of 5-chloro- 1 -(2,6-difluorophenyl)-7-(methylsulfinyl)-3 ,A- dihydropyrimido[4,5-d]pvrimidin-2(lH)-one (200 mg, 0.56 mmol) in DCM (10 mL) were added 1 ,4'-bipiperidine (270 mg, 1.61 mmol) and AzetaN-diisopropylethylamine (0.3 mL, 1.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NuH4OH[3]) provided the title compound as a white solid (298 mg, 83 percent). LC-MS m/z 463 (M + H)+.
83%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	Example 87; S-beta-d^'-bipiperidin-r-ylVdelta-alpha.-difluorophenvD^-oxo-S^J.delta- tetrahydropyrimidor4,5-cpipyrimidin-4-yl]-N-(4-fluorophenyl')-4-methylbenzamide; 87a) 7-C1 ,4'-bipiperidin- 1 '-ylV 5-chloro- 1 -(2.6-difluorophenyr)-3.4-; To a solution of 5-chloro- l-(2,6-difluorophenyl)-7-(methylsulfmyi)-3, 4- dihydrorhoyrimido[4,5-^pyrimidin-2(l/f)-one (200 mg, 0.56 mmol) in DCM (10 mL) were added l,4'-bipiperidine (270 mg, 1.61 mmol) and iV,N-diisopropylethylamine (0.3 mL, 1.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOEta[7]+NEta4OEta[3]) provided the title compound as a white solid (298 mg, 83 percent). LC-MS m/z 463 (M + H)+.
83%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	To a solution of 5-chloro-l-(2,6-difluorophenyl)-7-(methylsulfnyl)-3,4- dihydropyrimido[4,5-d]pyrimidin-2(lH)-one (200 mg, 0.56 mmol) in DCM (10 niL) were added 1 ,4'-bipiperidine (270 mg, 1.61 mmol) and iV,jV-diisopropylethylamme (0.3 mL, 1.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phaseDCM/DCM[90]+MeOeta[7]+Neta4Oeta[3]) provided the title compound as a white solid (298 mg, 83 percent). LC-MS m/z 463 (M + H)+.

83%

With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;

To a solution of 5-chloro-l-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4- dihydropyrimido[4,5-(i]pyrimidin-2(lH)-one (200 mg, 0.56 mmol) in DCM (10 mL) were added 1 ,4'-bipiperidine (270 mg, 1.61 mmol) and JV,jV-diisopropylethylamine (0.3 mL, 1.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOeta[7]+Neta4Oeta[3]) provided the title compound as a white solid (298 mg, 83 percent). LC-MS m/z 463 (M + H)+.

Reference： [1]Patent: WO2006/104917,2006,A2 .Location in patent: Page/Page column 85
[2]Patent: WO2006/104889,2006,A2 .Location in patent: Page/Page column 188
[3]Patent: WO2007/147104,2007,A2 .Location in patent: Page/Page column 81-82
[4]Patent: WO2007/147109,2007,A2 .Location in patent: Page/Page column 169

24
[ 4897-50-1 ]
[ 83948-53-2 ]
[ 942613-39-0 ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	Reference Example 3 Q-fl^'lBipiperidnyl-l'-yD-propylamine trihydrochloride a) O-ri^'IBipiperidinyl-r-yl-propylVcarbamic acid ferf-butyl esterA mixture of <strong>[4897-50-1]4-piperidinopiperidin</strong>e (Aldrich) (2.0 g, 11.88 mmol), (3-bromo-propyl)- carbamic acid tert-butyl ester [Eur. J. Med. Chem. Chim. Ther. 37 (2002) 573-584] (3.96 g, 16.63 mmol), dimethyl formamide (130 mL) and potassium carbonate (1.64 g, 11.88 mmol) was stirred at room temperature overnight, then concentrated in vacou. The residue was dissolved in water (150 mL), extracted with dichloromethane (3x150 mL), the combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated. The crude product was submitted to column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and cWoroform:methanol:NH4OH = 10:1:0.1 as eluent to yield 2.27 g (59 percent) of the title compound as an oil.
59%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	A mixture of <strong>[4897-50-1]4-piperidinopiperidin</strong>e (Aldrich) (2.0 g, 11.88 mmol), (3-bromo- propyl)-carbamic acid tert-butyl ester [Eur. J. Med. Chem. Chim. Ther. 37 (2002) 573- EPO <DP n="25"/>584] (3.96 g, 16.63 mmol), dimethylfopinamide (130 mL) and potassium carbonate (1.64 g, 11.88 mmol) was stirred at room temperature overnight, then concentrated in vacou. The residue was dissolved in water (150 mL), extracted with dichloromethane (3x150 mL), the combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated. The crude product was submitted to column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol:ammonium hydroxide = 10:1:0.1 as eluent to yield 2.27 g (59 percent) of the title compound as an oil.
59%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	A mixture of <strong>[4897-50-1]4-piperidinopiperidin</strong>e (Aldrich) (2.0 g, 11.88 mmol), (3-bromo-propyl)- carbamic acid tert-butyl ester [Eur. J. Med. Chem. Chim. Ther. 37 (2002) 573-584] (3.96 g,16.63 mmol), dimethylformamide (130 mL) and potassium carbonate (1.64 g, 11.88 mmol) was stirred at room temperature overnight, then concentrated in vacou. The residue was dissolved in water (150 mL), extracted with dichloromethane (3x150 mL), the combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated. The crude product was submitted to column chromatography using Kieselgel 60(0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol:ammonium hydroxide =10:1:0.1 as eluent to yield 2.27 g (59 percent) of the title compound as an oil.

59%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	A mixture of <strong>[4897-50-1]4-piperidinopiperidin</strong>e (Aldrich) (2.0 g, 11.88 mmol), (3-bromo- propyl)-carbamic acid tert-butyl ester [Eur. J. Med. Chem. CHm. Ther. 37 (2002) 573-584] (3.96 g, 16.63 mmol), dimethylformamide (130 mL) and potassium carbonate(1.64 g, 11.88 mmol) was stirred at room temperature overnight, then concentrated in vacou. The residue was dissolved in water (150 mL), extracted with dichloromethane(3x150 mL), the combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated. The crude product was submitted to column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform methanol: ammonium hydroxide = 10:1:0.1 as eluent to yield 2.27 g (59 percent) of the title compound as an oil.
59%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	a) (3-[1,4']Bipiperidinyl-1'-yl-propyl)-carbamic acid tert-butyl ester A mixture of <strong>[4897-50-1]4-piperidinopiperidin</strong>e (Aldrich) (2.0 g, 11.88 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester [Eur. J. Med. Chem. Chim. Ther. 37 (2002) 573-584](3.96 g, 16.63 mmol), dimethylformamide (130 mL) and potassium carbonate (1.64 g, 11.88 mmol) was stirred at room temperature overnight, then concentrated in vacou. The residue was dissolved in water (150 mL), extracted with dichloromethane (3*150 mL), the combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated. The crude product was submitted to column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol:ammonium hydroxide=10:1:0.1 as eluent to yield 2.27 g (59percent) of the title compound as an oil.

Reference： [1]Patent: WO2007/72092,2007,A2 .Location in patent: Page/Page column 21
[2]Patent: WO2008/50167,2008,A1 .Location in patent: Page/Page column 23-24
[3]Patent: WO2008/50168,2008,A1 .Location in patent: Page/Page column 22
[4]Patent: WO2009/53763,2009,A1 .Location in patent: Page/Page column 26
[5]Patent: US2010/298299,2010,A1 .Location in patent: Page/Page column 10

25
[ 4897-50-1 ]
4-(4-carboxypiperidin-1-yl)-1-(3-ethoxybenzyl)-1H-pyrazolo[3,4-d] pyrimidine hydrochloride [ No CAS ]
1-(3-ethoxybenzyl)-4-[4-[(4-piperidino-piperidin-1-yl)carbonyl]piperidin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In chloroform; at 20℃; for 17h;	(1) To 4-(4-carboxypiperidin-1-yl)-1-(3-ethoxybenzyl)-1H-pyrazolo[3,4-d] pyrimidine hydrochloride (50 mg; compound obtained in Reference Example A9-(3)) was added successively chloroform (1 mL), <strong>[4897-50-1]4-piperidinopiperidin</strong>e (26 mg), 1-hydroxybenzotriazole (24 mg), triethylamine (17 muL) and 1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride (35 mg) and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with chloroform (5 mL) and thereto was added an aqueous saturated sodium hydrogencarbonate solution (10 mL). After stirring, the organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by HPLC (Solvent; 10 mM ammonium carbonate/methanol = 80: 20 --> 5: 95) to give 1-(3-ethoxybenzyl)-4-[4-[(4-piperidino-piperidin-1-yl)carbonyl]piperidin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine (44 mg, yield: 69 percent) as an amorphous solid. MS(APCI)m/z; 532 [M+H]+

Reference： [1]Patent: EP1772454,2007,A1 .Location in patent: Page/Page column 27

26
[ 4897-50-1 ]
[ 635710-95-1 ]
[ 128625-52-5 ]
(+/-)-4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidinyl-1'-yl-1-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-ylmethyl)-2-oxo-ethyl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydrogen sulphate; lithium hydroxide monohydrate; N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide; methanol; dichloromethane; water;	EXAMPLE 56 (+-)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-[1,4']bipiperidinyl-1'-yl-1-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5ylmethyl)-2-oxo-ethyl]-amide To a solution of 3-(7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (20 mg, 1.0 equiv) in methanol (0.6 mL) was added lithium hydroxide monohydrate (4 mg, 2.2 equiv) in water (0.1 mL) and stirred for 4 h at room temperature. The solution was cooled to 0 C., treated with aqueous 1M potassium hydrogen sulfate (75 mul, 1.8 equiv), and concentrated to give the crude acid which was immediately used without purification. The crude acid was dissolved in dimethylformamide (0.3 mL) and sequentially treated with methylene chloride (0.15 mL), 4-piperidyl-piperidine (13 mg, 2 equiv), diisopropylethylamine (14 muL, 2 equiv), and PyBOP (22 mg, 1.1 equiv). The solution was stirred 1.5 h and concentrated. The product was purified by column chromatography to give a product which was tainted with HOBT. The HOBT was removed by passing the product through a plug of basic alumina, eluding with 10% methanol in methylene chloride. Concentration gave 18.3 mg (72%, 2 steps). 1H-NMR (CDCl3, 500 MHz) delta 1.25-1.32 (m, 6H), 1.40 (m, 4H), 1.54 (m, 5H), 1.65 (m, 4H), 1.83 (m, 2H), 2.30-2.56 (m, 8H), 2.81 (m, 4H), 3.04 (dt, J=57.1, 12.2, 1H), 3.43-3.60 (m, 2H), 4.00-4.17 (m, 2H), 4.18-4.26 (m, 3H), 4.49 (m, 1H), 4.62 (m, 1H), 5.03 (m, 1H), 5.80 (dd, J=16.8, 9.9, 1H), 6.69 (d, J=7.9, 1H), 6.90 (dd, J=7.3, 7.3, 1H), 6.99 (dd, J=7.6, 7.3, 1H), 7.13 (dd, J=7.6, 7.6, 1H), 7.19 (s, 1H), 7.66 (bd, J=12.8, 1H). Mass spec.: 646.43 (MH)+.

Reference： [1]Patent: US2004/204397,2004,A1

27
[ 4897-50-1 ]
[ 635709-95-4 ]
[ 128625-52-5 ]
[ 635710-03-1 ]

Yield	Reaction Conditions	Operation in experiment
599 mg (87%)	With triethylamine; N-ethyl-N,N-diisopropylamine; In methanol; dichloromethane;	(R)-4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid {2-[1,4']bipiperidinyl-1'-yl-2-oxo-1-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-ylmethyl]-ethyl}-amide To a solution of (R)-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid (554 mg, 0.88 mmol) and N,N-diisopropylethylamine (0.62 mL, 3.54 mmol) in methylene chloride (20 mL) was added a solution of 4-piperidinopiperidine (164 mg, 0.97 mmol) and PyBOP (460 mg, 0.88 mmol) in methylene chloride (15 mL). The reaction mixture was stirred for 16 h at room temperature. It was then concentrated to approximately 2 mL and subjected to flash column chromatography using methylene chloride/methanol/triethylamine (94:5:1) as eluent to give 599 mg (87%) of the title compound as a white solid. 1H-NMR (CD3CN, 300 MHz) delta 8.37 (s, 0.5H), 8.36 (s, 0.5H), 8.02-7.96 (m, 1H), 7.74 (s, 0.5H), 7.71 (s, 0.5H), 7.55-7.46 (m, 1H), 7.21-7.12 (m, 2H), 6.97-6.92 (m, 1H), 6.79 (d, J=8.1 Hz, 1H), 5.71 (t, J=8.1 Hz, 1H), 5.00 (dd, J=15.0, 8.1 Hz, 1H), 4.63-4.51 (m, 1H), 4.39-4.29 (m, 1H), 4.29 (s, 2H), 4.10-3.96 (m, 3H), 3.46-3.40 (m, 2H), 2.92-2.70 (m, 8H), 2.58-2.37 (m, 5H), 1.74-1.40 (m, 13H), 0.80-0.74 (m, 2H), -0.04 (s, 9H). Mass spec.: 778 (MH)+.

Reference： [1]Patent: US2004/204397,2004,A1

28
[ 4897-50-1 ]
[ 112811-72-0 ]
[ 1018937-76-2 ]

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

29
[ 505-66-8 ]
[ 109-01-3 ]
[ 4318-37-0 ]
[ 103-76-4 ]
[ 13349-82-1 ]
[ 4897-50-1 ]
[ 4397-53-9 ]
[ 2759-28-6 ]
[ 303-26-4 ]
[ 51207-66-0 ]
[ 103-55-9 ]
[ 5004-07-9 ]
[ 2252-63-3 ]
[ 1011-15-0 ]
[ 108-49-6 ]
[ 32231-06-4 ]
1-benzyl-4-(4-benzyloxy-benzyl)-piperazine [ No CAS ]
1,4-bis-(4-benzyloxy-benzyl)-[1,4]diazepane [ No CAS ]
[ 416893-26-0 ]
[ 415929-58-7 ]
[ 280560-77-2 ]
[ 849908-91-4 ]
[ 415925-00-7 ]
C₂₃H₃₀N₂O [ No CAS ]
[ 415924-66-2 ]
C₂₃H₃₀N₂O [ No CAS ]
C₂₂H₃₀N₂O₃ [ No CAS ]
[ 849908-83-4 ]
C₂₆H₂₈N₂O₃ [ No CAS ]
C₃₁H₃₁ClN₂O [ No CAS ]
C₃₄H₃₈N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With polymer-bound trimethyl ammonium cyanoborohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 24 - 36h;Combinatorial reaction / High throughput screening (HTS);	All sixty diamines were separated in four groups based on their steric and electronic characteristics, Figures 1-4. Each diamine was measured in the amount of 0.05 g (approximately 0.3 mmol) and pooled together with the others in the group. Obtained diamine mixtures were dissolved in 5 ml of 1,2-dichloroethane and used for the syntheses. Each well of the 96-well filterplates was loaded with 0.2 ml of 1: 10 mixture of acetic acid: DCE, 0.03 ml of the diamine mixture in DCE (group 1, group 2, group 3, or group 4) to assure 0.04 mmol of the diamines per well, and shaken for 5 min at room temperature. Appropriate carbonyl compounds from the master plate (0.1 ml of 1.2 M solution) were added into corresponding wells of the reaction plates followed by the addition of (polystyrylmethyl) trimethylammonium cyanoborohydride, (0.020 g, 0.08 mmol per well). The reaction plates were sealed and placed on a shaker. The reaction was allowed to proceed 24-36 hours at room temperature. At the end, the reaction mixtures were filtered using a filtration manifold, and products were collected into four (one per group) collection plates. Solvents were evaporated in SpeedVac and formed residues were analyzed by mass spectrometry prior to biological screening. Mono and double alkylated products were observed in 1: 0.5 to 1: 2 ratios by mass spectral analysis.

Reference： [1]Patent: WO2005/34857,2005,A2 .Location in patent: Page/Page column 15; 22

30
[ 4897-50-1 ]
[ 448-19-1 ]
[ 761440-29-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 72h;	To 5-fluoro-2-nitrophenyl methyl ether (26.0 g, 152 mmol), 1,4'-bipiperidine (25.5 g, 152 mmol) and K2CO3 (22.9 g, 166 mmol) was added DMSO (260 mL). The mixture was stirred at room temperature for 3 days. The mixture was poured into H2O (1000 mL) and the H2O washed with EtOAc (2.x.500 mL). The EtOAc washes were combined and washed with H2O (2.x.500 mL). The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound (47.9 g, 150 mmol, 99percent) as a yellow solid.1H NMR (400 MHz, CDCl3) delta 7.98 (d, J=9.5 Hz, 1H), 6.40 (dd, J=9.5 and 2.6 Hz, 1H), 6.29 (d, J=2.6 Hz, 1H), 3.99-3.93 (m, 2H), 3.93 (s, 3H), 2.98-2.89 (m, 2H), 2.58-2.48 (m, 5H), 1.99-1.90 (m, 2H), 1.70-1.55 (m, 8H), 1.48-1.40 (m, 2H).

Reference： [1]Patent: US2008/300242,2008,A1 .Location in patent: Page/Page column 51

31
[ 4897-50-1 ]
[ 1089280-66-9 ]
[ 1089280-67-0 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; In dimethyl sulfoxide; at 20℃;	4-Chloro-5-fluoro-2-nitrophenyl methyl ether (2.19 g, 10.7 mmol) was dissolved in DMSO (10 mL). K2CO3 (2.2 g, 16 mmol) and 1,4'-bipiperidine (1.8 g, 11 mmol) were added and the reaction mixture was allowed to stir overnight at rt. The mixture was then poured into H2O and extracted with EtOAc (2×) and then the combined organics were extracted with H2O (5×). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The resulting residue was adsorbed onto silica gel and flash chromatographed to give the title compound of step C (2.69 g, 71%). MS (M+H, ES+) 354.

Reference： [1]Patent: US2008/300242,2008,A1 .Location in patent: Page/Page column 115

32
[ 4897-50-1 ]
[ 33696-00-3 ]
[ 1021426-59-4 ]

Yield	Reaction Conditions	Operation in experiment
26%		To 4-bromo-2-nitroanisole (2.02 g, 8.72 mmol) and 1,4'-bipiperidine (3.49 g, 20.7 mmol) in dioxane (80 mL) was added sequentially, cesium carbonate (6.74 g, 20.7 mmol), palladium (II) acetate (0.196 g, 0.870 mmol) and di-tert-butylphosphino-biphenyl (0.527 g, 1.77 mmol). The reaction was heated at 100° C. for 24 hours, filtered through Celite.(R)., concentrated and purified by flash chromatography. The residue was taken up in EtOAc (100 mL) and Pd on carbon was added in one portion. The mixture was stirred at rt under H2 (1 atm.) until complete by TLC. The reaction was filtered through Celite.(R). and concentrated to provide the title compound of step A (0.667 g, 2.31 mmol, 26percent over two steps). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.32-1.40 (m, 2H), 1.43-1.54 (m, 6H), 1.73 (d, J=12.1 Hz, 2H), 2.18-2.28 (m, 1H), 2.41-2.47 (m, 6H), 3.43 (d, J=12.5 Hz, 2H), 3.65 (s, 3H), 4.52 (s, 2H), 6.06 (dd, J=8.6, 2.7 Hz, 1H), 6.28 (d, J=2.9 Hz, 1H), 6.60 (d, J=8.8 Hz, 1H).

Reference： [1]Patent: US2008/300242,2008,A1 .Location in patent: Page/Page column 56

33
[ 4897-50-1 ]
[ 369-34-6 ]
[ 1160625-54-6 ]

Yield	Reaction Conditions	Operation in experiment
68%	With triethylamine; In tetrahydrofuran; at 20℃;	Step A: 1 '-(2-Fluoro-4-nitrophenyl)-1 ,4'-bipiperidine; <n="236"/>To a solution containing 2.0 ml_ (18.1 mmol) of 1 ,2-difluoro-4-nitrobenzene and 20 ml. of THF was added 3.3 g (19.9 mmol) of 1 ,4'-bipiperidine and 5.8 mL (41.6 mmol) of TEA. The reaction mixture was allowed to stir at rt overnight and partitioned between EtOAc and H2O. The aqueous layer was further extracted with EtOAc and the combined organic layers were dried over MgSO4. The solvent was removed under reduced pressure and the residue was subjected to silica gel chromatography to give 3.9 g (68percent) of 1'-(2-fluoro-4-nitrophenyl)-1 ,4'-bipiperidine as a bright yellow solid: 1H-NMR (400 MHz, DMSO-d6) delta 7.98 (d, J = 11.4 Hz, 2 H), 7.15 (t, J = 9.1 Hz, 1 H), 3.72 (d, J = 12.1 Hz, 2 H), 2.90 (t, J = 12.2 Hz, 2 H), 2.40 - 2.48 (m, 5 H), 1.81 (d, J = 14.1 Hz, 2 H), 1.55 (dd, J = 12.1 and 3.3 Hz, 2 H), 1.45 - 1.51 (m, 4 H), and 1.37 (dt, J = 10.7 and 5.3 Hz, 2 H); MS (ESI): 308.17 (M+H+).

Reference： [1]Patent: WO2009/76140,2009,A1 .Location in patent: Page/Page column 234-235

34
[ 4897-50-1 ]
[ 865626-93-3 ]
[ 865626-94-4 ]

Yield	Reaction Conditions	Operation in experiment
96%		(R)-2-(4-(8-Fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)propanoic acid (105 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (3 mL). N,N-Diisopropylethylamine (100 muL, 0.57 mmol) was added to the mixture followed by o-benzotriazol-1-yl-N,N,N'-tetramethyluronium tetrafluoroborate (65 mg, 0.20 mmol). The reaction was stirred at room temperature for 5 min. 4-Piperidinopiperidine (41 mg, 0.22 mmol) was added to the mixture. The reaction was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetae (25 mL), washed successively with water (3.x.), and brine. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The title compound was obtained without further purification as white solid in 96percent yield. Mass spec.: 773.3 (MH)+.

Reference： [1]Patent: US2005/215576,2005,A1 .Location in patent: Page/Page column 44

35
[ 4897-50-1 ]
[ 749860-66-0 ]
4-(2,4-difluorobenzylamino)-5-(2-fluorophenyl)-2-(4-piperidinopiperidino)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%		Compound F1b (33 mg, 0.091 mmol) obtained in the above step was suspended in toluene (0.66 mL) and mCPBA (24 mg, 0.14 mmol) was added to the suspension, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution added to the reaction mixture, followed by the separation of the two liquids. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, followed by evaporation of the solvent. To the residue, <strong>[4897-50-1]4-piperidinopiperidin</strong>e (30 mg, 0.18 mmol) and ethanol (0.60 mL) were added. The mixture was heated to 110°C and ethanol was evaporated. The reaction mixture was heated and stirred for 2 hours and then cooled. The reaction mixture was purified by preparative thin-layer chromatography (hexane : ethyl acetate : triethylamine = 30:10:1) to obtain Compound 51 (38 mg, 86percent).1H NMR (CDCl3) ? (ppm): 1.35-1.78 (m, 8H), 1.80-1.92 (m, 2H), 2.39-2.63 (m, 5H), 2.79 (dt, J = 2.0, 13.0 Hz, 2H), 4.63 (d, J = 5.9 Hz, 2H), 4.73-4.95 (m, 3H), 6.70-6.89 (m, 2H), 7.08-7.41 (m, 5H), 7.80 (s, 1H). APCIMS m/z: [M + H]+ 482

Reference： [1]Patent: EP1595869,2005,A1 .Location in patent: Page/Page column 41

36
[ 97682-44-5 ]
[ 4897-50-1 ]
[ 86639-52-3 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 3742 - 3752

37
[ 4897-50-1 ]
[ 55981-29-8 ]
[ 1222997-44-5 ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 120℃; for 2h;Inert atmosphere;	To a solution of 2,5-dibromo-l ,3,4-thiadiazole (3B, 10 g, 41 mmol) and 4- piperidinopiperidine (3C, 8.3 g, 1.2 eq) in 1,4-dioxane (150 mL, 0.3 mM) was added N,N- diisopropylethylamine (8.6 mL, d=0.742, 1.2 eq). The resulting reaction was heated to 1200C under N2 and allowed to stir at this temperature for 2 hours, then cooled to room temperature. The cooled solution was filtered and the collected solid was dried under vacuum to provide compound 3D (8.6 g, 63%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 861 - 864
[2]Patent: WO2010/45303,2010,A2 .Location in patent: Page/Page column 97
[3]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 198 - 202

38
[ 4897-50-1 ]
[ 57709-53-2 ]
[ 1222993-52-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 170℃; for 0.75h;Sealed tube; Microwave irradiation;	A solution of 2-bromo-5-(3-methoxyphenyl)-l ,3 ,4- thadiazole (2A, 100 mg, 0.37 mmol), <strong>[4897-50-1]4-piperidinopiperidin</strong>e (75 mg, 1.2 eq) and NaHCpsi3 (46 mg, 1.5 eq) in DMF (2 mL, 0.2 mM) was sealed in microwave tube, heated to 170 QC and allowed to react at this temperature for 45 minutes. The reaction mixture was then cooled to room temperature and diluted with water. The resulting suspended solid was filtered and washed with water to provide compound 168 (93 mg, 70percent).

Reference： [1]Patent: WO2010/45303,2010,A2 .Location in patent: Page/Page column 96-97

39
[ 4897-50-1 ]
[ 1198759-26-0 ]
[ 1198759-27-1 ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; alpha,alpha,alpha-trifluorotoluene; at 160℃; for 0.5h;microwave irradiation;	Starting material 164b (42 mg, 0.17 mmoi) and DIPEA (0.12 mL) were dissolved in 0.8 mL PhCF3-dioxane mixture (1 :4, v/v). To the mixture, a solution of piperidinopiperidine (1M, 0.2 mL, 0.2 mmol) in PhCF3-dioxane (1:4) was added. The mixture was heated at 160°C in a microwave oven for 30 min. The mixture was concentrated and the residue was purified by preparative TLC, eluted with 1 :10 7 N NH3ZMeOH-DCM, to give a white solid (40 mg, 70percent) as desired product 164.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6176 - 6180
[2]Patent: WO2010/71819,2010,A1 .Location in patent: Page/Page column 104

40
[ 4897-50-1 ]
[ 152170-30-4 ]
[ 1198759-23-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	To a solution of 1c (166 mg, 0.97 mmol) in DMF (1 mL) was added K2CO3 (268 mg, 1.94 mmol, 2 equiv) and 4-piperidi?opiperidine (206 mg, 1.2 mmol, 1.2 equiv). The reaction mixture was allowed to stir at room temperature overnight after which it was diluted with H2O and extracted with EtOAc (2 x 10 mL). The combined organic iayer was washed with brine, dried over Na2SO4, filtered and concentrated to yleld after purification by flash chromatography (2 % MeOH/ CH2CI2) 1 (129 mg) as a brown powder.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6176 - 6180
[2]Patent: WO2010/71819,2010,A1 .Location in patent: Page/Page column 50

41
[ 4897-50-1 ]
[ 169205-95-2 ]
[ 1231933-81-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	In N,N-dimethyl-formamide; at 100℃;	A solution of 116A (8g, 47.6 mmoi) and 116B (5g, 30 mmol) in DMF was heated at 100 C for overnight. The reaction mixture was concentrated under vacuum and purified by column chromatography to give 116 as syrup (9 g, 99%).

Reference： [1]Patent: WO2010/71819,2010,A1 .Location in patent: Page/Page column 87
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2075 - 2078

42
[ 4897-50-1 ]
[ 32315-10-9 ]
[ 86639-52-3 ]
[ 97682-44-5 ]

Yield	Reaction Conditions	Operation in experiment
85.2%		EXAMPLE 2 4.00 g (10.2 mmol) 7-Ethyl-10-hydroxycamptothecin (purity 80percent) are dissolved in 60 ml CH2Cl2. 2.15 g (16.3 mmol) diisopropylethylamine, dissolved in 10 ml CH2Cl2, 0.16 g (1 mmol) DABCO and 1.1 g (36 mmol) bis(trichloromethyl)carbonate, dissolved in 10 ml CH2Cl2 are added at a temperature of 20° C. within 15 min. The solution is stirred for a further 20 min. Then 1.80 g (16 mmol) piperidinopiperidine, dissolved in 10 ml CH2Cl2, and 2.15 g (16.2 mmol) diisopropylethylamine, dissolved in 10 ml CH2Cl2, are added simultaneously within 15 min at 22° C. The resulting clear solution is stirred for 2-4 h at 25° C. The organic layer is extracted with 2.x.80 ml saturated NaHCO3 solution and 3.x.60 ml H2O. The aqueous layers are collected and extracted with 2.x.40 ml CH2Cl2. The combined organic layers are extracted again with 2.x.60 ml H2O, dried over 2 g Na2SO4, filtered and concentrated. The residue is recrystallized from 2-methoxyethanol and dried in vacuo. Yield: 5.1 g 85.2percent of theory Appearance: yellow powder

Reference： [1]Patent: US2007/135471,2007,A1 .Location in patent: Page/Page column 4

43
[ 4897-50-1 ]
[ 1262789-83-2 ]
1-[4-(bis(2-chloroethyl)amino)phenyl]-3-[3-(4-(piperidin-1-yl)piperidine-1-carbonyl)phenyl]urea hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		General procedure: A mixture of 7a (0.792 g, 2 mmol), DCC (0.618 g, 3 mmol), HOBT (0.505 g, 3 mmol), TEA (0.4 mL) and N,N-dimethylethylenediamine (8a', 0.264 g, 3 mmol) in dry DMF (25 mL) was stirred at room temperature for 72 h. The reaction mixture was filtered to remove the by-product urea and the filtrate was evaporated in vacuo to dryness. The residue was dissolved in CH2Cl2 (250 mL) and successively washed with water (100 mL), satd NaHCO3 aqueous solution (100 mL) and brine (100 mL), dried over Na2SO4 and filtered. The filtrate was evaporated to dryness and the residue was chromatographed over a silica gel column using CH2Cl2/MeOH (100:9) as an eluent. The fractions containing the main product were combined and evaporated in vacuo to dryness. The residue was crystallized from ethyl acetate to give white solid. The solid was suspended in ethyl acetate (50 mL) and treated with 2.5 M HCl in ethyl acetate (5.0 mL) at 0 °C. The excess solvent was evaporated to dryness and solid separated was dried in vacuo to give desired product 9aa'

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 471 - 485

44
[ 4897-50-1 ]
[ 47502-65-8 ]
1-[4-(bis(2-chloroethyl)amino)phenyl]-3-[4-(4-(piperidin-1-yl)piperidine-1-carbonyl)phenyl]urea hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		General procedure: A mixture of 7a (0.792 g, 2 mmol), DCC (0.618 g, 3 mmol), HOBT (0.505 g, 3 mmol), TEA (0.4 mL) and N,N-dimethylethylenediamine (8a', 0.264 g, 3 mmol) in dry DMF (25 mL) was stirred at room temperature for 72 h. The reaction mixture was filtered to remove the by-product urea and the filtrate was evaporated in vacuo to dryness. The residue was dissolved in CH2Cl2 (250 mL) and successively washed with water (100 mL), satd NaHCO3 aqueous solution (100 mL) and brine (100 mL), dried over Na2SO4 and filtered. The filtrate was evaporated to dryness and the residue was chromatographed over a silica gel column using CH2Cl2/MeOH (100:9) as an eluent. The fractions containing the main product were combined and evaporated in vacuo to dryness. The residue was crystallized from ethyl acetate to give white solid. The solid was suspended in ethyl acetate (50 mL) and treated with 2.5 M HCl in ethyl acetate (5.0 mL) at 0 °C. The excess solvent was evaporated to dryness and solid separated was dried in vacuo to give desired product 9aa'

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 471 - 485

45
[ 4897-50-1 ]
[ 100286-90-6 ]

Reference： [1]Patent: US2011/144342,2011,A1
[2]Patent: EP2341046,2011,A2
[3]Patent: WO2012/32531,2012,A1
[4]Patent: CN109796462,2019,A

46
[ 4897-50-1 ]
[ 1361214-53-0 ]
[ 1361214-54-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;	General procedure: (R)-tert-Butyl 3-(((benzyloxy)carbonyl)amino)-4-oxo-4-(((R)-1-phenylethyl)amino)butanoate (5).18 A solution of 0.6 g (1.75 mmol) of N-benzyloxycarbonyl-d-aspartic acid beta-t-butyl ester monohydrate in 10 mL dichloromethane was treated by sequential addition of 0.238 mL (1.84 mmol) of (R)-alpha-methylbenzylamine, 0.237 g (1.84 mmol) of 1-hydroxy-7-benzotriazole, and 0.337 g (1.84 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. After 18 h stirring at ambient temperature, the reaction mixture was washed sequentially with a saturated sodium bicarbonate solution and with saturated sodium chloride solution. The organic layer was evaporated to give 0.726 g (97percent) of compound 5 as an off-white solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 1337 - 1345

47
[ 4897-50-1 ]
[ 1361214-47-2 ]
[ 1354566-03-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;	General procedure: (R)-tert-Butyl 3-(((benzyloxy)carbonyl)amino)-4-oxo-4-(((R)-1-phenylethyl)amino)butanoate (5).18 A solution of 0.6 g (1.75 mmol) of N-benzyloxycarbonyl-d-aspartic acid beta-t-butyl ester monohydrate in 10 mL dichloromethane was treated by sequential addition of 0.238 mL (1.84 mmol) of (R)-alpha-methylbenzylamine, 0.237 g (1.84 mmol) of 1-hydroxy-7-benzotriazole, and 0.337 g (1.84 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. After 18 h stirring at ambient temperature, the reaction mixture was washed sequentially with a saturated sodium bicarbonate solution and with saturated sodium chloride solution. The organic layer was evaporated to give 0.726 g (97percent) of compound 5 as an off-white solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 1337 - 1345

48
[ 4897-50-1 ]
[ 1361214-48-3 ]
[ 1361214-50-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;	General procedure: (R)-tert-Butyl 3-(((benzyloxy)carbonyl)amino)-4-oxo-4-(((R)-1-phenylethyl)amino)butanoate (5).18 A solution of 0.6 g (1.75 mmol) of N-benzyloxycarbonyl-d-aspartic acid beta-t-butyl ester monohydrate in 10 mL dichloromethane was treated by sequential addition of 0.238 mL (1.84 mmol) of (R)-alpha-methylbenzylamine, 0.237 g (1.84 mmol) of 1-hydroxy-7-benzotriazole, and 0.337 g (1.84 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. After 18 h stirring at ambient temperature, the reaction mixture was washed sequentially with a saturated sodium bicarbonate solution and with saturated sodium chloride solution. The organic layer was evaporated to give 0.726 g (97percent) of compound 5 as an off-white solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 1337 - 1345

49
[ 4897-50-1 ]
[ 169205-95-2 ]
[ 1231933-82-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2075 - 2078

50
[ 61929-24-6 ]
[ 4897-50-1 ]
[ 1222996-43-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3354 - 3357

51
[ 4897-50-1 ]
[ 1400928-15-5 ]
[ 1400928-18-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In tetrahydrofuran; at 60℃; for 36h;Inert atmosphere;	A solution of 1,4'-bipiperidine (Sigma-Aldrich, 33.7 mg, 0.200 mmol), compound (rac)-3 (48.9 mg, 0.200 mmol), and dry Et3N (45 muL, 0.32 mmol) in anhydrous THF (3.0 mL) was stirred at 60 °C under N2 for 36 h, cooled to room temperature, then concentrated in vacuo. PTLC purification (silica gel, CH2Cl2/MeOH/25percent aqueous ammonia = 10:1:0.5) was performed to afford 71.9 mg of the title product 5b in 87percent yield. 1H NMR (300 MHz, CDCl3) delta 8.28 (0.4H, d, 8.25 Hz, Ar H that is a peak for an amide-bond conformer), 7.26-7.08 (2.6H, m, Ar H including a peak for an amide-bond conformer), 6.99 (1H, ddd, J = 7.32 Hz, J = 7.14 Hz, J = 1.11 Hz, Ar H), 5.47-5.44 (0.6H, CH-CO that is a peak for an amide-bond conformer), 5.21 (0.4H, d, 8.61 Hz, CH-CO that is a peak for an amide-bond conformer), 3.72-1.76 (23H, m, NCH(CH2)2, CH2, and N(CH3)2), 1.69-1.38 (8H, m, CH2).

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 55,p. 228 - 242

52
[ 4897-50-1 ]
[ 39856-50-3 ]
[ 1374635-47-8 ]

Yield	Reaction Conditions	Operation in experiment
457 mg	With triethylamine; In dimethyl sulfoxide; at 120℃; for 3h;Microwave irradiation;	Example 3 Synthesis of Substituted 2-Aminopyridines To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmol) in DMSO (4 mL) was added 1-(4-piperidyl)piperidine (1.0 g, 5.9 mmole) and triethyl amine (0.99 mL, 7.1 mmole). The contents were heated to 120 degrees in a CEM Discovery microwave system for 3 hours. The crude reaction was then loaded over a silica gel column and eluted with DCM/methanol (0-20%) to afford 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine as an oil (457 mg). 1H NMR (600 MHz, DMSO-d6) delta ppm 1.26-1.36 (m, 2H) 1.43 (m, 6H) 1.76 (m, 2H) 2.37 (m, 5H) 2.94 (t, J=12.74 Hz, 2H) 4.06 (d, J=13.47 Hz, 2H) 7.41 (dd, J=9.37, 2.64 Hz, 1H) 8.08 (d, J=9.37 Hz, 1H) 8.20 (d, J=2.64 Hz, 1H).
457 mg	With triethylamine; In dimethyl sulfoxide; at 120℃; for 3h;Microwave irradiation;	Example 24 Synthesis of 2-nitro-5-[4-(l-piperidyl)-l-piperidyl]pyridine, Compound 24 To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmol) in DMSO (4 mL) was added l-(4- piperidyl)piperidine (1.0 g, 5.9 mmole ) and triethylamine (0.99 mL, 7.1 mmole). The contents were heated to 120 C in a CEM Discovery microwave system for 3 hours. The crude reaction was then purified by silica gel column chromatography with DCM/methanol (0-20% ) to afford 2-nitro-5-[4-(l-piperidyl)-l-piperidyl]pyridine as an oil (457 mg). 1HNMR (600 MHz, DMSO- d6) delta ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76 (m, 2 H) 2.37 (m, 5 H) 2.94 (t, J=12.74 Hz, 2 H) 4.06 (d, J=13.47 Hz, 2 H) 7.41 (dd, J=9.37, 2.64 Hz, 1 H) 8.08 (d, J=9.37 Hz, 1 H) 8.20 (d, J=2.64 Hz, 1 H).
457 mg	With triethylamine; In dimethyl sulfoxide; at 120℃; for 3h;Microwave irradiation;	To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmol) in DMSO (4 mL) was added l-(4- piperidyl)piperidine (1.0 g, 5.9 mmole ) and triethylamine (0.99 mL, 7.1 mmole). The contents were heated to 120 C in a CEM Discovery microwave system for 3 hours. The crude reaction was then purified by silica gel column chromatography with DCM/methanol (0-20% ) to afford 2-nitro-5-[4-(l-piperidyl)-l-piperidyl]pyridine as an oil (457 mg). 1HNMR (600 MHz, DMSO- de) delta ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76 (m, 2 H) 2.37 (m, 5 H) 2.94 (t, J=12.74 Hz, 2 H) 4.06 (d, J=13.47 Hz, 2 H) 7.41 (dd, J=9.37, 2.64 Hz, 1 H) 8.08 (d, J=9.37 Hz, 1 H) 8.20 (d, J=2.64 Hz, 1 H).

457 mg	With triethylamine; In dimethyl sulfoxide; at 120℃; for 3h;Microwave irradiation;	To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmol) in DMSO (4 mL) was added 1-(4- piperidyl)piperidine (1.0 g, 5.9 mmole ) and triethylamine (0.99 mL, 7.1 mmole). The contents were heated to 120 C in a CEM Discovery microwave system for 3 hours. The crude reactionwas then purified by silica gel column chromatography with DCM/methanol (0-20% ) to afford2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine as an oil (457 mg). ?HNMR (600 MHz, DMSOd 6) oe ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76 (m, 2 H) 2.37 (m, 5 H) 2.94 (t, J=12.74 Hz, 2 H) 4.06 (d, J=13.47 Hz, 2 H) 7.41 (dd, J=9.37, 2.64 Hz, 1 H) 8.08 (d, J9.37 Hz, 1 H) 8.20 (d, J2.64 Hz, 1 H).
457 mg	With triethylamine; In dimethyl sulfoxide; at 120℃; for 3h;Microwave irradiation;	To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmole) in DMSO (4 mL) was added l-(4- piperidyl)piperidine (1.0 g, 5.9 mmole) and triethylamine (0.99 mL, 7.1 mmole). The contents were heated to 120 C in a CEM Discovery microwave system for 3 hours. The cmde reactionwas then loaded over a silica gel column and eluted with DCMlmethanol (0-20%) to afford 2-nitro-5- [4-( 1 -piperidyl)- 1 -piperidyll pyridine as an oil (457 mg).?H NMR (600 MHz, DMSO-d6) ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76 (m, 2 H) 2.37(m, 5 H) 2.94 (t, J=12.74 Hz, 2 H) 4.06 (d, J=13.47 Hz, 2 H) 7.41 (dd, J=9.37, 2.64 Hz, 1 H)8.08 (d, J9.37 Hz, 1 H) 8.20 (d, J=2.64 Hz, 1 H).
457 mg	With triethylamine; In dimethyl sulfoxide; at 120℃; for 3h;Microwave irradiation;	To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmole) in DMSO (4 mL) was added l-(4- piperidyl)piperidine (1.0 g, 5.9 mmole) and triethylamine (0.99 mL, 7.1 mmole). The contents were heated to 120 C in a CEM Discovery microwave system for 3 hours. The cmde reaction was then loaded over a silica gel column and eluted with DCMlmethanol (0-20%) to afford 2-nitro-5- [4-( 1 -piperidyl)- 1 -piperidyll pyridine as an oil (457 mg).?H NMR (600 MHz, DMSO-d6) ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76 (m, 2 H) 2.37(m, 5 H) 2.94 (t, J=12.74 Hz, 2 H) 4.06 (d, J=13.47 Hz, 2 H) 7.41 (dd, J9.37, 2.64 Hz, 1 H)8.08 (d, J9.37 Hz, 1 H) 8.20 (d, J2.64 Hz, 1 H).
457 mg	With triethylamine; In dimethyl sulfoxide; at 120℃; for 3h;Microwave irradiation;	tert-Butyi 4-(6-ami -3-pyridyl)piperazine-l-carboxylate (0500) The compound was prepared as described in WO 2010/020675 Al . (0501) (0502) To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmole) in DMSO (4 mL) was added l -(4- piperidyl)piperidine (1.0 g, 5.9 mmole) and triethylamine (0.99 mL, 7.1 mmole). The contents were heated to 120 C in a CEM Discovery microwave system for 3 hours. The crude reaction was then loaded over a silica gel column and eluted with DCM/methanol (0-20%) to afford 2- nitro-5-[4-(l-piperidyl)-l -piperidyl]pyridine as an oil (457 mg). NMR (600 MHz, DMSO-c e) delta ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76 (m, 2 H) 2.37 (m, 5 H) 2.94 (t, J=12.74 Hz, 2 H) 4.06 (d, J=13.47 Hz, 2 H) 7.41 (dd, J=9.37, 2.64 Hz, 1 H) 8.08 (d, J=9.37 Hz, 1 H) 8.20 (d, J=2.64 Hz, 1 H)
457 mg	With triethylamine; In dimethyl sulfoxide; at 120℃; for 3h;Microwave irradiation;	To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmole) in DMSO (4 raL) was added 1~(4~ piperidyl)piperidme (1.0 g, 5.9 mmole) and triethylamine (0.99 mL, 7.1 mmole). The contents were heated to 120 °C m a CEM Discover ' microwave system for 3 horns. The crude reaction was then loaded over a silica gel column and eluted with DCM/methanol (0-20percent) to afford 2- nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridme as an oil (457 mg). NMR (600 MHz, DMSO-rfe) d ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76 (m, 2 H) 2.37 (m, 5 H) 2 94 (t, J= 12.74 Hz, 2 1 1} 4.06 (d,./ 13.47 Hz, 2 H) 7.41 (dd,.7=9 37, 2.64 Hz, 1H) 8.08 (d,,7=9.37 Hz, 1H) 8.20 (d,./ 2.6-1Hz, 1H).

Reference： [1]Patent: US2013/237534,2013,A1 .Location in patent: Paragraph 0193-0194
[2]Patent: WO2014/144326,2014,A1 .Location in patent: Page/Page column 118
[3]Patent: WO2016/40858,2016,A1 .Location in patent: Page/Page column 111
[4]Patent: WO2016/40848,2016,A1 .Location in patent: Page/Page column 106
[5]Patent: WO2018/5533,2018,A1 .Location in patent: Page/Page column 147; 148; 149
[6]Patent: WO2018/5860,2018,A1 .Location in patent: Page/Page column 161; 162
[7]Patent: WO2018/5863,2018,A1 .Location in patent: Page/Page column 105-106
[8]Patent: WO2019/136244,2019,A1 .Location in patent: Page/Page column 121

53
[ 4897-50-1 ]
[ 51323-43-4 ]
5-(3-([1,4'-bipiperidin]-1'-ylmethyl)phenyl)quinoline-8-carbonitrile [ No CAS ]

Reference： [1]Patent: US2015/105370,2015,A1

54
[ 4897-50-1 ]
[ 51323-43-4 ]
(3-([1,4′-bipiperidin]-1′-ylmethyl)phenyl)boronic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl acetamide; at 150℃; for 0.166667h;Microwave irradiation;	A solution of <strong>[51323-43-4](3-(bromomethyl)phenyl)boronic acid</strong> (129.5 mg, 0.603 mmol) and 1,4?-bipiperidine (190 mg, 1.129 mmol) in DMAC (1 mL) was microwaved at 150 C. for 10 min after which time the reaction was cooled and concentrated to dryness to be used in the next step as crude (3-([1,4?-bipiperidin]-1?-ylmethyl)phenyl)boronic acid.

Reference： [1]Patent: US2015/105370,2015,A1 .Location in patent: Paragraph 0709

55
[ 4897-50-1 ]
[ 139756-22-2 ]
5-(5-([1,4’-bipiperidin]-1‘-ylsulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		Synthesis of Al; Step 9: Dissolve 1,4-bipiperidine (1 eq) dry acetone and added K2C03 (3 eq) stirred the reaction mixture for 10 minutes at 25 C, added 4-ethoxy-3-(1 -methyl25 7-oxo-3-propyl-6,7-dihydro- 1 H-pyrazolo[4,3 -d]pyrimidin-5-yl)benzene- 1 -sulfonylchloride (1 eq) and stirred the reaction for 4.5 hours at 25 C. After completion of the reaction, remove the acetone under vacuum add 30 ml DCM, 30 ml water organic layer was separated. Water layer was re-extracted with 20 ml DCM and the combined organic layer are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Al as a white solid; yield 90%. 1H NMR (400 MHz, CDC13) 6 10.83 (s, 1H), 8.84 (d, J= 2.2 Hz, lH), 7.87 (dd, J= 8.8, 2.2 Hz, 1H), 7.17 (d, J= 8.8 Hz, 1H), 4.40 (q, J= 7.0 Hz, 2H), 4.30 (s,3H), 3.94 (d, J= 11.5 Hz, 2H), 2.95 (t, J 7.5 Hz, 2H), 2.50 (br s, 4H), 2.35 (s, 2H),1.88 (mHz, 4H), 1.75-1.27 (m, 12H), 1.05 (t, J= 7.3 Hz, 3H). MASS: ES [M + H] :543.15. Elemental anal. calcd. for C27H38N604S; C, 59.76; H, 7.06; N, 15.49; 0, 11.79;S, 5.91; found C, 59.74; H, 7.08; N, 15.59; 0, 11.68; S, 5.90
65%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 15 - 25℃;	General procedure: Piperidin-4-one (18.0mg, 0.18mmol) was dissolved in dry DCM and added DIPEA (95.0muL, 0.54mmol) stirred the reaction mixture 10min at 15C added 4-ethoxy-3-(1- methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzene-1-sulfonyl chloride (75mg, 0.18mmol) and stirred the reaction for 6h at 25C. After completion of reaction, added 30mL DCM, 30mL water and organic layer was separated. Water layer re-extracted with 20mL DCM and the combined organic layer washed with brine solution, concentrated under vacuum and purified by using Column chromatography afforded the title compound as a white solid. Yield 90%.

Reference： [1]Patent: WO2015/114647,2015,A1 .Location in patent: Page/Page column 55; 56
[2]Bioorganic Chemistry,2019,vol. 89

56
[ 4897-50-1 ]
6,10-dichloro-12H-thiochromeno[2,3-c]quinolin-12-one [ No CAS ]
6-([1,4'-bipiperidin]-1'-yl)-10-chloro-12H-thiochromeno[2,3-c]quinolin-12-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium carbonate; In dimethyl sulfoxide; at 150℃; for 10h;	General procedure: Compound 3 (0.33 g, 1.0 mmol), appropriate secondary amines (1.1 mmol) and sodium carbonate (5 mmol) in DMSO (20 mL) was refluxed for 10 h (TLC monitored). After 30 min, the reaction was added ice-water (100 mL). The precipitate was filtered, washed with water/methanol and collected to get the yellow solid.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 103,p. 615 - 627

57
[ 4897-50-1 ]
[ 936-59-4 ]
C₁₉H₂₈N₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium carbonate; In acetone; at 45 - 47℃; for 20h;	General procedure: To 3-chloro-1-phenyl-1-propanone (253 mg, 1.5 mmol) in acetone (20 mL), anhydrous potassium carbonate (414 mg, 3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, a solution of <strong>[4897-50-1]4-piperidinopiperidin</strong>e (1.5 mmol) in acetone (10 mL) was then added, and the mixture was reacted for 20 hours by heating to 45 to 47° C. The completion of the reaction was confirmed by thin-layer chromatography, and the solvent was then distilled off under reduced pressure. To the residue, water (20 ml) was added. The aqueous layer was subjected to extraction with ethyl acetate (50 mL) three times. The organic layer was washed with water and saline and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow solid at a yield of 77percent. (0296) 1H NMR (300 MHz, CDCl3) delta 2.24-2.33 (m, 5H), 2.50-2.61 (m, 10H), 2.82-2.92 (m, 2H), 3.16-3.26 (m, 2H), 7.44-7.62 (m, 3H), 7.94-8.03 (m, 2H) (0297) MS (TOF Mass): m/z calcd for C19H28N2O (M+1) 301.22. found: 301.23

Reference： [1]Patent: US2016/60235,2016,A1 .Location in patent: Paragraph 0295-0297

58
[ 4897-50-1 ]
C₁₈H₁₇Cl₃N₆ [ No CAS ]
5-(4-(piperidin-1-yl)piperidin-1-yl)methyl-7-(3-(bis(2-chloroethyl)amino)phenylamino)-3-cyanopyrazolo[1,5-a]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.5%	With potassium carbonate; In N,N-dimethyl-formamide; at 40℃;	General procedure: Compound 3a (3b) (0.5mmol, 96mg) was mixed with corresponding amines (mmol) and K2CO3 in 2mL of DMF and stirred at 40°C for 2?3h. The mixture was poured into 10mL cold water and the solid was filtered, dried and recrystallized from methanol to give the title compounds 4-15a (4-15b).

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 119,p. 183 - 196

59
[ 4897-50-1 ]
C₁₈H₁₇Cl₃N₆ [ No CAS ]
5-(4-(piperidin-1-yl)piperidin-1-yl)methyl-7-(4-(bis(2-chloroethyl)amino)phenylamino)-3-cyanopyrazolo[1,5-a]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.3%	With potassium carbonate; In N,N-dimethyl-formamide; at 40℃;	General procedure: Compound 3a (3b) (0.5mmol, 96mg) was mixed with corresponding amines (mmol) and K2CO3 in 2mL of DMF and stirred at 40°C for 2?3h. The mixture was poured into 10mL cold water and the solid was filtered, dried and recrystallized from methanol to give the title compounds 4-15a (4-15b).

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 119,p. 183 - 196

60
[ 110-89-4 ]
[ 79099-07-3 ]
[ 4897-50-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 0 - 20℃; for 16h;	Piperidine (1.549 g, 18.19 mmol), sodium triacetoxyborohydride (3.85 g, 19.2 mmol), and acetic acid (0.0910 g, 1.52 mmol) were added to a solution of 1-tert-butoxycarbonyl-4-piperidinone (3.02 g, 15.2 mmol) in dichloromethane (25.0 mL) at 0° C., and the resulting mixture was stirred at room temperature for 16 hours. The reaction liquid was cooled to 0° C. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction liquid, and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hydrochloric acid (1.0 N), and the resulting mixture was extracted with ethyl acetate. A 48percent aqueous solution of sodium hydroxide was added to the aqueous layer for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (25.0 mL), and concentrated hydrochloric acid (5.0 mL) was added, and then the resulting mixture was stirred at 40° C. for 12 hours. The reaction liquid was concentrated and exsiccated, and then the residue was dissolved in distilled water. A 48percent aqueous solution of sodium hydroxide was added for basification, and then the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. 4-(Piperidin-1-yl)piperidine (2.04 g, 12.1 mmol, 80percent) was obtained as a white solid.

Reference： [1]Patent: TW2016/2093,2016,A .Location in patent: Paragraph 0317

61
[ 4897-50-1 ]
3-(1-(2-ethoxy-2-oxoethyl)-1H-imidazol-2-yl)propanoic acid [ No CAS ]
ethyl 2-(2-(3-(4-(piperidin-1-yl)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 12h;	Example 23 Synthesis of ethyl 2-(2-(3-(4-(piperidin-1-yl)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate (0525) (0526) Diisopropylethylamine (0.171 g, 1.33 mmol), HBTU (0.402 g, 1.06 mmol), and 4-(piperidin-1-yl)piperidine (0.149 g, 0.884 mmol) were added to a solution of crude 3-(1-(2-ethoxy-2-oxoethyl)-1H-imidazol-2-yl)propanoic acid (0.200 g, 0.884 mmol) in dichloromethane (10.0 mL) at room temperature, and the reaction liquid was stirred at the same temperature for 12 hours. The reaction liquid was concentrated under reduced pressure. The residue was purified by flash chromatography (NH silica gel, hexane/ethyl acetate and chloroform/methanol) to obtain ethyl 2-(2-(3-(4-(piperidin-1-yl)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate (0.266 g, 0.708 mmol, 80percent) (hereinafter referred to as a ?compound of Example 23?) as a reddish brown oil. (0527) 1H-NMR (400 MHz, CDCl3) delta: 1.29 (3H, t, J=7.2 Hz), 1.36-1.48 (4H, m), 1.54-1.63 (4H, m), 1.7-1.86 (2H, m), 2.40-2.58 (6H, m), 2.85-3.00 (1H, m), 2.91 (4H, s), 3.96-4.03 (1H, m), 4.23 (2H, t, J=7.2 Hz), 4.57-4.65 (1H, m), 4.75 (2H, q, J=7.2 Hz), 6.82 (1H, d, J=1.2 Hz), 6.97 (1H, d, J=1.2 Hz). (0528) ESI-MS: m/z=377 (M+H)+.
0.266 g	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 12h;	Diisopropylethylamine (0.171 g, 1.33 mmol), HBTU (0.402 g, 1.06 mmol), and 4-(piperidin-1-yl)piperidine (0.149 g, 0.884 mmol) were added to a solution of crude 3-(1-(2-ethoxy-2-oxoethyl)-1H-imidazol-2-yl)propanoic acid (0.200 g, 0.884 mmol) in dichloromethane (10.0 mL) at room temperature, and the reaction liquid was stirred at the same temperature for 12 hours. The reaction liquid was concentrated under reduced pressure. The residue was purified by flash chromatography (NH silica gel, hexane/ethyl acetate and chloroform/methanol) to obtain ethyl 2-(2-(3-(4-(piperidin-1-yl)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate (0.266 g, 0.708 mmol, 80percent) (hereinafter referred to as a ?compound of Example 23?) as a reddish brown oil.

Reference： [1]Patent: US2016/194302,2016,A1 .Location in patent: Paragraph 0525; 0526; 0527; 0528
[2]Patent: TW2016/2093,2016,A .Location in patent: Paragraph 0353

62
[ 4897-50-1 ]
[ 854382-06-2 ]
[1,4'-bipiperidin]-1'-yl(2-((pyridin-4-ylmethyl)amino)pyridin-3-yl)methanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 2930 - 2943

63
[ 4897-50-1 ]
4-((7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl)amino)benzonitrile [ No CAS ]
N-(4-cyanophenyl)-6-methoxy-7-(3-((4-piperid-1-yl)piperidin-1-yl)propoxy)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 60 - 80℃;	General procedure: To a stirred solution of compounds 7a-c (0.25g, 0.68mmol) in DMF (5mL) was added K2CO3 (1.5:1), KI (0.01:1) and various substituted aniline (1.5:1). The solution was heated at 80°C for 6?10h. Then the reaction mixture was cooled to room temperature, diluted with water (200mL) and extracted with ethyl acetate (3×20mL), combined organic layer, washed with brine, dried with anhydrous Na2SO4 and concentrated under vacuum to afford the target products as a solid. Compounds 8?41 were characterized as follows.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 138,p. 669 - 688

64
[ 4897-50-1 ]
[ 38194-50-2 ]
(Z)-1-([1,4'-bipiperidin]-1'-yl)-2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 20℃;Inert atmosphere;	General procedure: (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), (HATU) (1.2 equivalents) was added to a solution of acid (1 equivalent), the appropriate amine (1.5 equivalents) and DIEA (2 equivalents) in dry acetonitrile (10 mL) at room temperature under argon atmosphere. The reaction mixture was stirred at room temperature for 1-2 h. Solvent was evaporated under reduced pressure and the crude product was purified using a Teledyne Isco Combiflash Rf purification machine to provide the desired amide in excellent yield.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4614 - 4621

65
[ 4897-50-1 ]
[ 49627-27-2 ]
(Z)-1-([1,4'-bipiperidin]-1'-yl)-2-(5-fluoro-2-methyl-1-(4-(methylthio)benzylidene)-1H-inden-3-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃;Inert atmosphere;	General procedure: O-(Benzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluoro phosphate, (HBTU) (1.2 equivalents) was added to a solution of sulindac (1 equivalent), the appropriate amine (1.5 equivalents) and Et3N (2 equivalents) in dry acetonitrile (10 mL) at room temperature under argon atmosphere. Reaction mixture was stirred at room temperature for 1-2 h. Solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (60-200 mesh) to afford amide in excellent yield.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4614 - 4621

66
[ 4897-50-1 ]
[ 29679-58-1 ]
C₂₅H₃₂N₂O₂ [ No CAS ]

Reference： [1]Medicinal Chemistry Research,2017,vol. 26,p. 3038 - 3045

67
[ 4897-50-1 ]
[ 13710-19-5 ]
C₂₄H₃₀ClN₃O [ No CAS ]

Reference： [1]Medicinal Chemistry Research,2017,vol. 26,p. 3038 - 3045

68
[ 75-15-0 ]
[ 4897-50-1 ]
[ 7471-76-3 ]
2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)ethyl [1,4'-bipiperidine]-1'-carbodithioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%		General procedure: CS2 (99 mg, 1.3 mmol) was added dropwise to the mixture of thesecondary amine (1.2 mmol) and TEA (131 mg, 1.3 mmol) in DMF(2 mL). After stirring for 5 min, a solution of the correspondingcoumarin derivatives 3a-f (1.2 mmol) in DMF (3 mL) was added.Then, the reaction mixture was stirred at room temperature for12 h. When the reaction was completed, water (20 mL) was addedand the mixture was extracted with ethyl acetate (10mL x 3), thecombined organic phase was washed with water (15 mL x 3), driedover anhydrous Na2SO4 and concentrated under vacuum to affordthe crude product. The crude product was purified by silica gelchromatography with PE/EA (10:1) as eluent to obtain the targetcompounds 4a-q.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 146,p. 287 - 298

69
[ 4897-50-1 ]
[ 89336-46-9 ]
2-(2-amino-1,3-thiazol-4-yl)-1-(1,4’-bipiperidin-1‘-yl)ethanone dihydrochioride [ No CAS ]

Reference： [1]Patent: WO2018/19681,2018,A1

70
[ 4897-50-1 ]
[ 89336-46-9 ]
tert-butyl {4-[2-(1,4’-bipiperidin-1‘-yl)-2-oxoethyl]-1,3-thiazol-2-yl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20℃;	A solution of {2-[(tert-butoxycarbonyl)amino]-1 ,3-thiazol-4-yl}acetic acid (250 mg, 0.968 mmol), TBTU (326 mg, 1.016mmol), 1,4-bipiperidine (257 mg, 1.452 mmol) and DIPEA (0.331 mL, 1.936 mmol) in DMA (8 mL) was let understirring at rt overnight. The mixture was diluted with EtOAc, washed with a saturated solution of NaHCO3, water and brine, dried over Na2SO4 and filtered. The title compound was purified by column chromatography (eluant DCM:7N NH3 in MeOH = 95:5) and isolated as white solid (356 mg, 96percent).1H NMR (500 MHz, DMSO-d6) ppm 1.12-1.28 (m, 2 H) 1.30?1.39 (m, 2 H) 1.41 ?1.49 (m, 4 H) 1.47 (s, 9 H)1.56 - 1.76 (m, 2 H) 2.27 - 2.44 (m, 5 H) 2.46 ?2.54 (m, 1 H) 2.86 ?2.97 (m, 1 H) 3.64 (d, J=3.5 Hz, 2 H) 3.93 (d,J=13.42 Hz, 1 H) 4.37 (d, J=12.81 Hz, 1 H) 6.80 (s, 1 H) 11.39 (br. s., 1 H).HRMS (ESI+): calcd. for C20H33N4O3S [M + H] 409.2268; found 409.2275.

Reference： [1]Patent: WO2018/19681,2018,A1 .Location in patent: Page/Page column 119

71
[ 4897-50-1 ]
[ 1266480-90-3 ]
([1,4′-bipiperidin]-1′-yl)-6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65.3%	With N-ethyl-N,N-diisopropylamine; potassium iodide; In N,N-dimethyl-formamide; at 60℃;	General procedure: The corresponding piperazine or piperidine (1.1 mmol), KI (0.18 g, 1.1 mmol), and DIEA (0.21 mL, 1.3 mmol) was added to a solution of compound 5 (0.32 g, 1 mmol) in DMF (10 mL). The reaction mixture was stirred at 60 °C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature and poured over ice water. The solid was collected by filtration and purified by chromatography on silica gel (dichloromethane/methanol, 30:1) to give the title compounds 6a,b, 7a?i, 8a?e, 9a?c in moderate yields.

Reference： [1]Molecules,2018,vol. 23

72
[ 4897-50-1 ]
C₂₁H₁₉FO₂S [ No CAS ]
(Z)-1-([1,4'-bipiperidin]-1'-yl)-2-(5-fluoro-2-methyl-1-(4-(methylthio)benzylidene)-1H-inden-3-yl)propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 20℃;Inert atmosphere;	General procedure: 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU; 1.2 equivalents) was added to a solution of the corresponding alpha-methyl carboxylic acid (2) (1 equiv), the appropriate amine (1.5 equiv) and DIEA (2 equiv) in dry acetonitrile (10 mL) at room temperature under argon atmosphere. The reaction mixture was stirred at room temperature overnight. Solvent was evaporated under reduced pressure, and the crude product was purified using a Teledyne Isco Combiflash® Rf purification machine using 0-10percent CHCl3/methanol as eluent to provide the desired amides 3-59 in 68-95percent yields.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2136 - 2142

73
[ 4897-50-1 ]
C₂₁H₁₉FO₃S [ No CAS ]
(Z)-1-([1,4'-bipiperidin]-1'-yl)-2-(5-fluoro-2-methyl-1-(4-(methylsulfinyl)benzylidene)-1H-inden-3-yl)propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 20℃;Inert atmosphere;	General procedure: 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU; 1.2 equivalents) was added to a solution of the corresponding alpha-methyl carboxylic acid (2) (1 equiv), the appropriate amine (1.5 equiv) and DIEA (2 equiv) in dry acetonitrile (10 mL) at room temperature under argon atmosphere. The reaction mixture was stirred at room temperature overnight. Solvent was evaporated under reduced pressure, and the crude product was purified using a Teledyne Isco Combiflash® Rf purification machine using 0-10percent CHCl3/methanol as eluent to provide the desired amides 3-59 in 68-95percent yields.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2136 - 2142

74
[ 4897-50-1 ]
N-(3-fluorobenzyl)-4,6-bis(perfluorophenoxy)-1,3,5-triazin-2-amine [ No CAS ]
4-([1,4’-bipiperidin]-1’-yl)-N-(3-fluorobenzyl)-6-(perfluorophenoxy)-1,3,5-triazin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		DIPEA (30 mg, 0.22 mmol, 1.1 eq) was added to a solution of triazine 4a (113.68 mg, 0.2 mmol, 1 eq) in CH2Cl2 (3 mL) cooled in an ice water bath. After 5 min, a solution of 1-(1-methylpiperidin-4-yl) piperidine (37.03mg, 0.22mmol, 1.1eq) in CH2Cl2 (1 ml) was added dropwise for 5 min at 0°C. The mixture was then stirred for 5 days at room temperature, concentrated under reduced pressure and purified by column chromatography on silica gel (CH2Cl2/AcOEt: 85/15), to afford 72 mg (65 percent) of Mel9. 1H NMR: (400 MHz, CDCl3) delta 7.31 (1H, brs, CHar), 7.14-6.78 (3H,m, CHar), 5.42 (1H,brs, NH), 4.76 (1Ha, brs, CH2), 4.57 (2H, d, J=6 HZ, CH2), 4.41 (Hb, d, J=6.5, CH2), 2.77 (2H, qd, J=10.9.Hz, -N-CH2), 2.49 (4H,brs,CH2-N-CH2). 1.63 (2H, d, J=12.7Hz, CH2-CH2-CH2), 1.67-1.36 (8H, m, CH2-CH2-N-CH2-CH2), 1.26 (1H, m, CH). LC-MS: m/z calcd. for C26 H26 F6 N6 O(M+H)+:553.2070; found: 553.2143.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 155,p. 880 - 888

75
[ 4897-50-1 ]
4,6-bis(perfluorophenoxy)-1,3,5-triazin-2,3,4,5-tetrahydro-1H-benzo[c]azepine [ No CAS ]
2-(4-([1,4'-bipiperidin]-1'-yl)-6-(perfluorophenoxy)-1,3,5-triazin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		DIPEA (96 mg, 0.74 mmol, 1.1 eq) was added to a solution of triazine 4e (400 mg, 0.67 mmol, 1 eq) in CH2Cl2 (10 mL) cooled in an ice water bath. After 5 min, a solution of 1,4'-bipiperidine (125.4 mg, 0.74 mmol, 1.1 eq) in CH2Cl2 (3 ml) was added dropwise for 5 min at 0°C. The mixture was then stirred and heated to 40°C for 24 h, concentrated under reduced pressure and purified by column chromatography on silica gel, (CH2Cl2/MeOH: 90/10), to afford 300 mg (77percent) of Mel55. 1H NMR: 1H NMR (400 MHz, CDCl3) delta 7.35-6.48 (4H, m, CHar), 4.77 (1Ha, d, J=13.2 Hz, CH2), 4.68 (1Hb, d, J=13.7 Hz, CH2), 4.60-4.32 (2H,m, CH2), 4.13-3.78 (2H,m, CH2), 2.97 (2H, qt, J=4.8Hz, CH2), 2.86 (1H, m, CH), 2.79-2.64 (2H, m, CH2), 2.51 (4H, s, 2CH2), 1.88-1.70 (4H, m, 2CH2), 1.59 (4H, s, 2CH2) 1.44 (4H, s, 2CH2). LC-MS: LC-MS: m/z calcd. for C29 H31 F5 N6 O (M+H)+: 575.2480; found: 575.163.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 155,p. 880 - 888

76
[ 4897-50-1 ]
7-benzyl-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]
4-([1,4'-bipiperidin]-1'-yl)-7-benzyl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine; In ethanol; at 80℃; for 0.25h;Microwave irradiation; Sealed tube;	General procedure: The N-alkyl pyrrolo[2,3-d]pyrimidine 2a-c(1.0 mmol), amines (3.0 mmol), triethylamine (4.5 mmol) and ethanol (3 mL) were added to a microwave reaction flask and the reactionmixture was irradiated for 15 min at 80 °C. Then the solvent was evaporatedunder vacuum and the crude product was purified by columnchromatographic on silica gel using chloroform/methanol (10:1) mixture

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2890 - 2893

77
[ 4897-50-1 ]
2,4-dichloro-7-(naphthalen-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]
4-([1,4'-bipiperidin]-1'-yl)-2-chloro-7-(naphthalen-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine; In ethanol; at 80℃; for 0.25h;Microwave irradiation; Sealed tube;	General procedure: The N-alkyl pyrrolo[2,3-d]pyrimidine 2a-c(1.0 mmol), amines (3.0 mmol), triethylamine (4.5 mmol) and ethanol (3 mL) were added to a microwave reaction flask and the reactionmixture was irradiated for 15 min at 80 °C. Then the solvent was evaporatedunder vacuum and the crude product was purified by columnchromatographic on silica gel using chloroform/methanol (10:1) mixture

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2890 - 2893

78
[ 4897-50-1 ]
2,4-dichloro-7-(naphthalen-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]
4-([1,4'-bipiperidin]-1'-yl)-2-chloro-7-(naphthalen-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With triethylamine; In ethanol; at 80℃; for 0.25h;Microwave irradiation; Sealed tube;	General procedure: The N-alkyl pyrrolo[2,3-d]pyrimidine 2a-c(1.0 mmol), amines (3.0 mmol), triethylamine (4.5 mmol) and ethanol (3 mL) were added to a microwave reaction flask and the reactionmixture was irradiated for 15 min at 80 °C. Then the solvent was evaporatedunder vacuum and the crude product was purified by columnchromatographic on silica gel using chloroform/methanol (10:1) mixture

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2890 - 2893

79
[ 75-15-0 ]
[ 4897-50-1 ]
7-(4-bromobutoxy)-3-chloro-4-methyl-2H-chromen-2-one [ No CAS ]
4-((3-chloro-4-methyl-2-oxo-2H-chromen-7-yl)oxy)butyl [1,4'-bipiperidine]-1'-carbodithioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		General procedure: To a mixture of piperidine (1.69 mmol) and triethylamine

Reference： [1]Bioorganic Chemistry,2018,vol. 81,p. 512 - 528

80
[ 4897-50-1 ]
14-O-(((4-(2-chloroacetamido)-1H-pyrrolo[2,3-d]pyrimidin-6-yl)thio)acetyl)mutilin [ No CAS ]
14-O-(((4-(2-([1,4'-bipiperidin]-1'-yl)acetamido)-1H-pyrrolo[2,3-d]pyrimidin-6-yl)thio)acetyl)mutilin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium carbonate; sodium iodide; In tetrahydrofuran; at 20 - 60℃; for 4h;Inert atmosphere;	General procedure: To a stirred solution of compound 14 (1mmol) in THF (10mL) was added K2CO3 (207.0mg, 1mmol), R1H (1mmol) and NaI (3mg, 0.02mmol) at rt. The mixture was warmed to 60C and remained for 4h. Then the mixture was added H2O (5mL) and extracted with EtOAc (10mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuum. The crude product was purified by Prep-TLC or Prep-HPLC to give the target.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 162,p. 194 - 202

81
[ 4897-50-1 ]
[ 5784-45-2 ]
1-([1,4′-bipiperidin]-1′-yl)phthalazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine; In ethanol; at 20℃; for 48h;	l,4'-Bipiperidine (20.0 g, 120.0 mmol) was added slowly to a solution of 1- chloropthalazine (10.0 g, 60.0 mmol) in ethanol (200 mL) containing TEA (34 mL, 240.0 mmol). The reaction mixture was stirred at rt for 48 h. After completion of reaction, the solvent was evaporated and the residue was diluted with water and then extracted with DCM (2 x 200 mL). The organic layer was dried over sodium sulfate and evaporated in vacuo to give the desired product l-([l,4'-bipiperidin]-T-yl)phthalazine. Yield 10.2 g (57%); mp 140-142 C. (0271) [0184] NMR (DMSO-i) d 1.37-1.42 (2H, m, CEE), 1.48-1.53 (4H, m, CEE), 1.75- l .81 (2H, m, CH2), 1.88-1.91 (2H, m, CEE), 2.43 (1H, s, CH), 2.57 (4H, s, 2 x CEE), 2.94-3.00 (2H, m, CEE), 3.87-3.90 (2H, m, CEE), 7.92-7.94 (2H, m, ArH), 8.04-8.06 (2H, m, ArH), 9.25 (1H, s, ArH). HRMS [ESI+]: calculated for CI8H24N4, 297.2079 [M+H]+, found 297.2092.

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 2404 - 2418
[2]Patent: WO2019/99755,2019,A1 .Location in patent: Page/Page column 0182-0184

82
[ 4897-50-1 ]
[ 37886-47-8 ]
(E)-1-([1,4'-bipiperidin]-1'-yl)-5-((1R,4aS,6R,8aS)-6-hydroxy-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)-3-methylpent-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 2h;	32mg of powdered ferric acid and 5mL of dichloromethane were dissolved, adding 19mL of diisopropylethylamine, 47mg of condensing agent HATU, and finally adding 25.3mg of 4-piperidylpiperidine, mixing and stirring at room temperature for 2h, to be reacted The reaction was quenched by the addition of water and then extracted with dichloromethane.The dichloromethane phase was rotary evaporated to dryness, and the title compound was obtained.

Reference： [1]Patent: CN109810017,2019,A .Location in patent: Paragraph 0066; 0067; 0068; 0069; 0070
[2]Bioorganic Chemistry,2020,vol. 98

83
[ 4897-50-1 ]
4-((2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzonitrile [ No CAS ]
4-((4-([1,4′-bipiperidin]-1′-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With triethylamine; In ethanol; at 80℃; for 0.25h;Microwave irradiation;	General procedure: The N-benzyl-pyrrolo[2,3-d]pyrimidine 5a-8a or 5b-8b (1.0 mmol), <strong>[4897-50-1]4-piperidinopiperidin</strong>e(3.0 mmol), triethylamine (4.5 mmol) and ethanol (5 mL) were added to a microwave reaction flask and the reaction mixture was irradiated for 15 min at 80 C. Then the solvent was evaporated under vacuum and the crude product was purified by column chromatographic on silica gelusing chloroform/methanol (10:1) mixture.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 3194 - 3200

84
[ 4897-50-1 ]
2,4-dichloro-7-(2,6-dichlorobenzyl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]
4-([1,4′-bipiperidin]-1′-yl)-2-chloro-7-(2,6-dichlorobenzyl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With triethylamine; In ethanol; at 80℃; for 0.25h;Microwave irradiation;	General procedure: The N-benzyl-pyrrolo[2,3-d]pyrimidine 5a-8a or 5b-8b (1.0 mmol), <strong>[4897-50-1]4-piperidinopiperidin</strong>e(3.0 mmol), triethylamine (4.5 mmol) and ethanol (5 mL) were added to a microwave reaction flask and the reaction mixture was irradiated for 15 min at 80 C. Then the solvent was evaporated under vacuum and the crude product was purified by column chromatographic on silica gelusing chloroform/methanol (10:1) mixture.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 3194 - 3200

85
[ 4897-50-1 ]
4-(2-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)morpholine [ No CAS ]
4-(2-(4-([1,4′-bipiperidin]-1′-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In ethanol; at 80℃; for 0.25h;Microwave irradiation;	General procedure: Compounds 2a-c and (1.0 mmol), <strong>[4897-50-1]4-piperidinopiperidin</strong>e or4-(piperidin-4-yl)morpholine (3.0 mmol), triethylamine (4.5 mmol) and ethanol (5 mL) were added to a microwave reaction flask and the reaction mixture was irradiated for 15 min at 80 C. Then the solvent was evaporated under vacuum and the crude product was purified bycolumn chromatography on silica gel using chloroform/methanol(10:1) mixture.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 3194 - 3200

86
[ 4897-50-1 ]
4-(2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)morpholine [ No CAS ]
4-(2-(4-([1,4′-bipiperidin]-1′-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine; In ethanol; at 80℃; for 0.25h;Microwave irradiation;	General procedure: Compounds 2a-c and (1.0 mmol), <strong>[4897-50-1]4-piperidinopiperidin</strong>e or4-(piperidin-4-yl)morpholine (3.0 mmol), triethylamine (4.5 mmol) and ethanol (5 mL) were added to a microwave reaction flask and the reaction mixture was irradiated for 15 min at 80 C. Then the solvent was evaporated under vacuum and the crude product was purified bycolumn chromatography on silica gel using chloroform/methanol(10:1) mixture.

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 3194 - 3200

87
[ 4897-50-1 ]
[ 50-00-0 ]
[ 518-82-1 ]
C₂₆H₃₀N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With acetic acid; In 1,4-dioxane; water; at 85℃; for 12h;	5 mmol of emodin was dissolved in 15 mL of dioxane, 10 mmol of formaldehyde aqueous solution, 40 mmol of acetic acid and 10 mmol of 4-piperidylpiperidine were added, and the mixture was heated to 85 C for 12 hours, and the solvent was evaporated under reduced pressure. 15 mL of saturated aqueous sodium hydrogen carbonate solution was added. Then, it was extracted three times with 15 mL of dichloromethane, the organic phases were combined, 15 mL of water was washed once, and ethyl acetate was recrystallized to give compound 3 in a yield of 41%.

Reference： [1]Patent: CN109748810,2019,A .Location in patent: Paragraph 0063-0065

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Code	Phrase
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Code	Phrase
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Code	Phrase
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P322
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P378
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P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
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P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
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P401
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P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 4897-50-1 ] {[proInfo.proName]}

Quality Control of [ 4897-50-1 ]

Related Doc. of [ 4897-50-1 ]

Product Details of [ 4897-50-1 ]

Calculated chemistry of [ 4897-50-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 4897-50-1 ]

Application In Synthesis of [ 4897-50-1 ]

[ 4897-50-1 ] Synthesis Path-Upstream 1~13

[ 4897-50-1 ] Synthesis Path-Downstream 1~87

Related Parent Nucleus of [ 4897-50-1 ]

Aliphatic Heterocycles

Piperidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Parent Nucleus of
[ 4897-50-1 ]