[ CAS No. 182223-54-7 ] {[proInfo.proName]}

Name: 182223-54-7|4-Cbz-Aminopiperidine|97%
Brand: Ambeed
SKU: A331228
Price: 8.0 USD
Availability: InStock
Rating: 94 (28 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 182223-54-7

Structure of 182223-54-7 * Storage: {[proInfo.prStorage]}

Please Login or Create an Account to: See VIP prices and availability

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

* Shipping: {[proInfo.prShipping]}

For Research Only 120K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 182223-54-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 182223-54-7 ]

SDS Specification

Alternatived Products of [ 182223-54-7 ]

Product Details of [ 182223-54-7 ]

CAS No. :	182223-54-7	MDL No. :	MFCD04038571
Formula :	C₁₃H₁₈N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WWGUAFRTAYMNHU-UHFFFAOYSA-N
M.W :	234.29	Pubchem ID :	1514304
Synonyms :

Calculated chemistry of [ 182223-54-7 ] Expand+

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.46
Num. rotatable bonds :	5
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	69.33
TPSA :	50.36 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.62 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.59
Log Po/w (XLOGP3) :	1.56
Log Po/w (WLOGP) :	1.13
Log Po/w (MLOGP) :	1.41
Log Po/w (SILICOS-IT) :	1.65
Consensus Log Po/w :	1.67

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.21
Solubility :	1.46 mg/ml ; 0.00621 mol/l
Class :	Soluble
Log S (Ali) :	-2.23
Solubility :	1.39 mg/ml ; 0.00592 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.76
Solubility :	0.0408 mg/ml ; 0.000174 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.14

Safety of [ 182223-54-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 182223-54-7 ]

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

Upstream synthesis route of [ 182223-54-7 ]
Downstream synthetic route of [ 182223-54-7 ]

[ 182223-54-7 ] Synthesis Path-Upstream 1~5

1
[ 220394-97-8 ]
[ 182223-54-7 ]

Yield	Reaction Conditions	Operation in experiment
99.1%	With hydrogenchloride In methanol; water at 20℃; for 23 h;	A mixture of tert-butyl 4-[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate obtained in Example 1a (13.1 g, 39.2 mmol), a 5 N aqueous hydrochloric acid solution (40 ml, 200 mmol) and methanol (40 ml) was stirred at mom temperature for 23 hours. A 5 N aqueous sodium hydroxide solution (40 ml) was added to the reaction mixture under ice-cooling. Water and the solvent were distilled off from the reaction mixture while the mixture was azeotropically distilled with ethanol. Ethanol was added to the residue, the insoluble matter was removed by filtration, and the filtrate was concentrated to give the title compound (9.10 g, yield 99.1percent). ¹H-NMR (400 MHz, CDCl₃) δ ppm; 1.31-1.42 (2H, m), 1.92-2.04 (2H, br), 2.70 (2H, d, J=12 Hz), 3.10 (2H, d, J=12 Hz), 3.56-3.68 (1H, br), 4.72-4.81 (1H, br), 5.09 (2H, s), 7.26-7.40 (5H, m).
99.1%	With hydrogenchloride In methanol; water at 20℃; for 23 h;	(Example 1b) Benzyl N-(piperidin-4-yl)carbamate A mixture of tert-butyl 4-[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate obtained in Example 1a (13.1 g, 39.2 mmol), a 5 N aqueous hydrochloric acid solution (40 ml, 200 mmol) and methanol (40 ml) was stirred at room temperature for 23 hours. A 5 N aqueous sodium hydroxide solution (40 ml) was added to the reaction mixture under ice-cooling. Water and the solvent were distilled off from the reaction mixture while the mixture was azeotropically distilled with ethanol. Ethanol was added to the residue, the insoluble matter was removed by filtration, and the filtrate was concentrated to give the title compound (9.10 g, yield 99.1percent). ¹H-NMR (400 MHz, CDCl₃) δ ppm; 1.31-1.42 (2H, m), 1.92-2.04 (2H, br), 2.70 (2H, d, J=12 Hz), 3.10 (2H, d, J=12 Hz), 3.56-3.68 (1H, br), 4.72-4.81 (1H, br), 5.09 (2H, s), 7.26-7.40 (5H, m).
88%	With hydrogenchloride In 1,4-dioxane at 20℃; for 3 h; Inert atmosphere	Piperidin-4-yl-carbamic acid benzyl ester[00457] HCl (10ml, 4M solution in dioxane) was added in one portstirred solution of 4-benzyloxycarbonylamino-piperidine-1 -carboxylic acid te/f-butyl ester (1 .2g, 3.6mmol) in dioxane (5ml) and the suspension was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the reaction was concentrated under vacuum and the resulting solid was collected by filtration, washed with TBME (3 x 100ml) and dried under vacuum to give the title compound (0.74g, 88percent yield) as a white solid.

Reference： [1] Patent: US2013/65925, 2013, A1, . Location in patent: Paragraph 0197; 0198
[2] Patent: EP2757103, 2014, A1, . Location in patent: Paragraph 0149
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 3, p. 1021 - 1046
[4] Patent: WO2011/60321, 2011, A1, . Location in patent: Page/Page column 115
[5] Patent: WO2006/99884, 2006, A1, . Location in patent: Page/Page column 18
[6] European Journal of Medicinal Chemistry, 2017, vol. 132, p. 26 - 41
[7] Patent: CN102250075, 2016, B, . Location in patent: Paragraph 0706; 0707

2
[ 182223-53-6 ]
[ 182223-54-7 ]

Reference： [1] Patent: US2003/232847, 2003, A1, . Location in patent: Page 14

3
[ 87120-72-7 ]
[ 182223-54-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 3, p. 1021 - 1046
[2] Patent: WO2011/60321, 2011, A1,
[3] Patent: US2013/65925, 2013, A1,
[4] Patent: EP2757103, 2014, A1,
[5] European Journal of Medicinal Chemistry, 2017, vol. 132, p. 26 - 41
[6] Patent: CN102250075, 2016, B,

4
[ 501-53-1 ]
[ 182223-54-7 ]

Reference： [1] Patent: WO2011/60321, 2011, A1,
[2] Patent: US2013/65925, 2013, A1,
[3] Patent: EP2757103, 2014, A1,
[4] European Journal of Medicinal Chemistry, 2017, vol. 132, p. 26 - 41
[5] Patent: CN102250075, 2016, B,

5
[ 182223-54-7 ]
[ 127285-08-9 ]

Reference： [1] European Journal of Medicinal Chemistry, 2017, vol. 132, p. 26 - 41

[ 182223-54-7 ] Synthesis Path-Downstream 1~109

1
[ 124-63-0 ]
[ 182223-54-7 ]
[ 402927-96-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 3h;	The protected piperidine 13 (10 g, 42.7 mmol) and triethylamine (12 mL, 86.7 mmol) was dissolved in 500 mL of methylene chloride at room temperature. Methane sulfo-nylchloride (4.3 mL, 55.5 mmol) in 20 mL of methylene chloride was added dropwise via addition funnel. After addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The solvent and volatiles were removed under reduced pressure. Ethyl acetate (500 mL) and an aqueous solution of hydrochloric acid (0.5M, 350 mL) was added. The reaction was partitioned between the two phases and the aqueous layer was removed. The organic layer was washed again with an aqueous solution of hydrochloric acid (0.5M, 2x, 100 mL) and then with saturated aqueous sodium bicarbonate solution (3x, 100 mL). The reaction solvent was then dried (brine, MgSO4) and evaporated at reduced pressure to provide 9.2 g of the methane sulfonamide 14 (MP=148.6-152.8 C.).

Reference： [1]Patent: US2003/232847,2003,A1 .Location in patent: Page 14-15

2
[ 182223-53-6 ]
[ 182223-54-7 ]

Yield	Reaction Conditions	Operation in experiment
	With carbonochloridic acid 1-chloro-ethyl ester; In dichloromethane; at 20℃; for 3h;	The benzyl amine 12 (27.8 g, 85.7 mmol) was dissolved in 400 mL of methylene chloride at room temperature and 1-chloro-ethylchloroformate (25.4 g, 178 mmol) in 50 mL of methylene chloride was added dropwise via addition funnel. After addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The solvent and volatiles were removed under reduced pressure and methanol (500 mL) was added. The reaction was heated to reflux with stirring for 1 hour and then cooled to room temperature. Removal of the reaction solution via evaporation yielded 26.3 g of the piperidine 13 as an off-white solid (mass spec. M+l=235, MP=190.7-192.2 C.).

Reference： [1]Patent: US2003/232847,2003,A1 .Location in patent: Page 14

Yield	Reaction Conditions	Operation in experiment
		Step B Preparation of Benzyl Piperidin-4-ylcarbamate The benzyl amine (27.8 g, 85.7 mmol) was dissolved in 400 mL of methylene chloride at room temperature and 1-chloro-ethylchloroformate (25.4 g, 178 mmol) in 50 mL of methylene chloride was added dropwise via addition funnel. After addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The solvent and volatiles were removed under reduced pressure and methanol 500 mL) was added. The reaction was heated to reflux with stirring for 1 hour and then cooled to room temperature. Removal of the reaction solution via evaporation yielded 26.3 g of the piperidine as an off-white solid (mass spec. M+1=235, MP=190.7-192.2 C.).

4
[ 220394-97-8 ]
[ 182223-54-7 ]

Yield	Reaction Conditions	Operation in experiment
99.1%	With hydrogenchloride; In methanol; water; at 20℃; for 23h;	A mixture of tert-butyl 4-[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate obtained in Example 1a (13.1 g, 39.2 mmol), a 5 N aqueous hydrochloric acid solution (40 ml, 200 mmol) and methanol (40 ml) was stirred at mom temperature for 23 hours. A 5 N aqueous sodium hydroxide solution (40 ml) was added to the reaction mixture under ice-cooling. Water and the solvent were distilled off from the reaction mixture while the mixture was azeotropically distilled with ethanol. Ethanol was added to the residue, the insoluble matter was removed by filtration, and the filtrate was concentrated to give the title compound (9.10 g, yield 99.1%). 1H-NMR (400 MHz, CDCl3) delta ppm; 1.31-1.42 (2H, m), 1.92-2.04 (2H, br), 2.70 (2H, d, J=12 Hz), 3.10 (2H, d, J=12 Hz), 3.56-3.68 (1H, br), 4.72-4.81 (1H, br), 5.09 (2H, s), 7.26-7.40 (5H, m).
99.1%	With hydrogenchloride; In methanol; water; at 20℃; for 23h;	(Example 1b) Benzyl N-(piperidin-4-yl)carbamate A mixture of tert-butyl 4-[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate obtained in Example 1a (13.1 g, 39.2 mmol), a 5 N aqueous hydrochloric acid solution (40 ml, 200 mmol) and methanol (40 ml) was stirred at room temperature for 23 hours. A 5 N aqueous sodium hydroxide solution (40 ml) was added to the reaction mixture under ice-cooling. Water and the solvent were distilled off from the reaction mixture while the mixture was azeotropically distilled with ethanol. Ethanol was added to the residue, the insoluble matter was removed by filtration, and the filtrate was concentrated to give the title compound (9.10 g, yield 99.1%). 1H-NMR (400 MHz, CDCl3) delta ppm; 1.31-1.42 (2H, m), 1.92-2.04 (2H, br), 2.70 (2H, d, J=12 Hz), 3.10 (2H, d, J=12 Hz), 3.56-3.68 (1H, br), 4.72-4.81 (1H, br), 5.09 (2H, s), 7.26-7.40 (5H, m).
88%	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 3h;Inert atmosphere;	Piperidin-4-yl-carbamic acid benzyl ester[00457] HCl (10ml, 4M solution in dioxane) was added in one portstirred solution of 4-benzyloxycarbonylamino-piperidine-1 -carboxylic acid te/f-butyl ester (1 .2g, 3.6mmol) in dioxane (5ml) and the suspension was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the reaction was concentrated under vacuum and the resulting solid was collected by filtration, washed with TBME (3 x 100ml) and dried under vacuum to give the title compound (0.74g, 88% yield) as a white solid.

		A solution of 4-benzyloxycarbonylamino-piperidine-l-carboxylic acid tert-butyl ester (17.73 g, 53 mmol) in trifluoroacetic acid (30 ml) was stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between IN aq, sodium hydroxide (30 ml) and a DCM-MeOH mixture (9-1, 100 ml). The aq. layer was extracted four more times with the same mixture. The combined extracts were dried over sodium sulfate, filtered and concentrated to dryness. The residue was chromatographed (DCM-MeOH 9-1 1% aq. ammonium hydroxide then DCM-MeOH 4-1) to afford the title piperidine (11.03 g, 47.07 mmol). .H NMR (CDC13) 8: 7.40-7.29 (m, 5H); 6.19 (br. s, 1H); 5.10 (s, 2H); 5.04 (s, 1H); 3.47 (m, 1H); 3.25 (br. d, J= 12.8 Hz, 2H); 2.81 (t, J= 12 Hz, 2H); 2.04 (m, 2H); 1.58 (m,2H).
	With trifluoroacetic acid; In dichloromethane; at 20℃; for 2h;	To a solution of compound I-4 (470 mg, 1.47 mmol) in DCM, TFA (2.5 mL, 29 mmol) was addedand then the reaction mixture was stirred at room temperature for 2 h and then was evaporated togive the crude product directly used in the next step A mixture of the amine, DIEA (3.84 mL,22.05mmol) and cyclohexanone (1.5 mL) in THF (10 mL) was stirred at room temperature for 1.5h and then NaBH(OAc)3 (1.6 g, 7.35 mmol) was added into the solution. The reaction mixture wasstirred at room temperature for overnight and then H2O was added to quench the reaction. Thesolution was extracted with ethyl acetate (30 mL × 2). The organic layer was washed with brine(15 mL × 2) and then was dried over anhydrous MgSO4. After filtration and concentration, thecrude product I-5 was obtained and purified with column chromatography ( methylene chloride/methanol = 45:1 to 30:1) to give compound I-5 as light yellow oil (350 mg, 78%).
	With trifluoroacetic acid; In chloroform; at 20℃; for 1h;	Benzyloxycarboxamide-tert-butyl piperidine-1-carboxylate (0.334 g, 1 mmol),Was dissolved in 5 mL of chloroform, TFA (3.42 g, 30 mmol) was dropped at room temperature,The reaction was stirred for 1h, the excess TFA was distilled off under reduced pressure,Add DIEA (0.258g, 2mmol), cyclopentanone 1mL, sodium triacetoxyborohydride (0.636g, 3mmol), the reaction at room temperature for 1h, add a small amount of water quenched reaction, saturated sodium bicarbonate to adjust pH = 6 ~ 7, The mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. After concentration, the residue was subjected to column chromatography to obtain 0.314 g of a white solid in a yield of 104%.

Reference： [1]Patent: US2013/65925,2013,A1 .Location in patent: Paragraph 0197; 0198
[2]Patent: EP2757103,2014,A1 .Location in patent: Paragraph 0149
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 1021 - 1046
[4]Patent: WO2011/60321,2011,A1 .Location in patent: Page/Page column 115
[5]Patent: WO2006/99884,2006,A1 .Location in patent: Page/Page column 18
[6]European Journal of Medicinal Chemistry,2017,vol. 132,p. 26 - 41
[7]Patent: CN102250075,2016,B .Location in patent: Paragraph 0706; 0707

5
[ 881656-57-1 ]
[ 182223-54-7 ]
[ 910858-80-9 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium perchlorate; potassium carbonate; In N,N-dimethyl-formamide; at 80℃;	To a solution of 3-methoxy-5-[(2i?)-oxiran-2-yl]quinoline (1.6 g, 7.95 mmol) and piperidin-4-yl-carbamic acid benzyl ester (1.77 g, 7.54 mmol) in DMF (15 ml) were added potassium carbonate (1.54 g, 11.13 mmol) and lithium perchlorate (0.99 g, 8.35 mmol). The reaction mixture was stirred at 80C overnight. The solids were filtered off and the filtrate was concentrated to dryness. The residue was purified by chromatography (DCM-MeOH 19-1) to afford the title alcohol (1.5 g, 3.56 mmol) as a yellow oil. MS (ESI, m/z): 436.4[M+H+].

Reference： [1]Patent: WO2006/99884,2006,A1 .Location in patent: Page/Page column 22

6
[ 724788-70-9 ]
[ 182223-54-7 ]
[ 1072828-03-5 ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium phosphate;palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In 1,4-dioxane; at 85℃;Inert atmosphere;	122.i) [1-(3-Fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-piperidin-4-yl]-carbamic acid benzyl esterAn oven-dried vial was charged with 8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine (797 mg, 3.40 mmol), palladium(II) acetate (31 mg, 0.136 mmol), DPEphos (146 mg, 0.272 mmol), K3PO4 (1.81 g, 8.50 mmol) and piperidin-4-yl-carbamic acid benzyl ester (875 mg, 3.40 mmol). The resulting mixture was purged with argon for several min. Dioxane (11 mL) was then added via syringe and the resulting suspension was purged with argon for 3 min. The mixture was then heated at 85 C. overnight. The solvent was removed in vacuo and the residue was extracted with EA/water. The org. layer was washed with brine, dried over MgSO4 and concentrated. To the resulting solid TBME and a few drops of DCM and MeOH were added and the mixture was sonicated for 5 min and filtered to afford the title intermediate as a pale yellow foam (293 mg, 21%).LCMS (ESI, m/z): 411.1 [M+H+].
21%	With potassium phosphate;palladium diacetate; bis[(2-diphenylphosphino)ethyl]ether; In 1,4-dioxane; at 85℃;	122. i) [ l-(3-Fluoro-6-methoxy- [ 1 ,5] naphthyridin-4-yl)-piperidin-4-yl] -carbamic acid benzyl esterAn oven-dried vial was charged with 8-bromo-7-fluoro-2-methoxy-[l,5]naphthyridine (797 mg, 3.40 mmol), palladium(II)acetate (31 mg, 0.136 mmol), DPEphos (146 mg, 0.272 mmol), K3PO4 (1.81 g, 8.50 mmol) and piperidin-4-yl-carbamic acid benzyl ester (875 mg, 3.40 mmol). The resulting mixture was purged with argon for several min. Dioxane (11 mL) was then added via syringe and the resulting suspension was purged with argon for 3 min. The mixture was then heated at 85 0C overnight. The solvent was removed in vacuo and the residue was extracted with EA/water. The org. layer was washed with brine, dried over MgSO4 and concentrated. To the resulting solid TBME and a few drops of DCM and MeOH were added and the mixture was sonicated for 5 min and filtered to afford the title intermediate as a pale yellow foam (293 mg, 21%). MS (ESI, m/z): 411.1 [M+H+].

Reference： [1]Patent: US2011/39823,2011,A1 .Location in patent: Page/Page column 57
[2]Patent: WO2008/126034,2008,A2 .Location in patent: Page/Page column 144

7
[ 1187321-60-3 ]
[ 182223-54-7 ]
[ 1187321-61-4 ]

Yield	Reaction Conditions	Operation in experiment
		Step Il; Scheme: N,N-Diisopropylethylamine (0.16 mL, 0.0009 mol) is added to a solution of piperidin-4-yl-carbamic acid benzyl ester (0.209 g, 0.0008 mol) in acetonitrile (5 mL) at room temperature and stirred for 15 minutes. A solution of 2,3:4,5-di-0-isopropylidene-l-(4-nitrophenoxycarbonyl)-beta-D-fructopyranose (0.3 g, 0.0007 mol) in acetonitrile (5 mL) is introduced into the reaction mixture and stirred at room temperature for 45 minutes. Reaction mixture is concentrated under reduced pressure, D.M. water (20 mL) is added to the residue and aqueous layer is extracted with ethyl acetate (3x20 mL). Combined organic layer is washed with 5% cold aqueous sodium hydroxide solution (1x10 mL) followed by D. M. water (1x10 mL) and brine <n="70"/>solution ( I xI O mL) and finally dried over anhydrous sodium sulphate. Removal of ethyl acetate under reduced pressure gives crude solid which is purified by column chromatography (silica gel 230-400 mesh, toluene:ethyl acetate, 70:30) to yield 2,3:4,5-di-0-isopropylidene-l-[piperidin-{4- benzy loxycarbonylamino} - 1 -carbonyl- 1 -yl]-beta-D-fructopyranose.

Reference： [1]Patent: WO2009/116067,2009,A2 .Location in patent: Page/Page column 68-69

8
[ 1187321-80-7 ]
[ 182223-54-7 ]
[ 1187321-81-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 0.5h;	Step Il; Scheme: N,N-Diisopropylethylamine (0.4 mL, 0.002 mol) is added to a solution of piperidin-4-yl-carbamic acid benzyl ester (0.531 g, 0.002 mol) in acetonitrile (5 mL) at room temperature and stirred for 15 minutes. A solution of l ,2:3,4-di-O-isopropylidene-(4-nitrophenoxycarbonyl)-D-glactopyranose (0.76 g, 0.002 mol) in acetonitrile (5 mL) is introduced into the reaction mixture and stirred at room temperature for 30 minutes. Reaction mixture is concentrated under reduced pressure, D.M.water (20 mL) is added to the residue and aqueous layer is extracted with ethyl acetate (3x20 mL). Combined ethyl acetate layer is washed with 5% cold aqueous sodium hydroxide solution (1x10 mL) followed by D. M. water (1x10 mL) and brine solution ( I x IO mL) and finally dried over anhydrous sodium sulphate. Removal of ethyl acetate layer under reduced pressure gives crude material which is purified by column chromatography (silica gel 230-400 mesh, n- hexane:ethyl acetate, 50:50) to yield l ,2:3,4-di-O-isopropylidene-6-[piperidin-{4- benzyloxycarbonylamino)-(l -carbonyl)-l-yl]-D-galactopyranose.

Reference： [1]Patent: WO2009/116067,2009,A2 .Location in patent: Page/Page column 86

9
[ 74925-15-8 ]
[ 182223-54-7 ]
[ 1187321-38-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1Preparation of 2.3:4.5-di-Q-isopropylidene-l-\|piperidin-(4-aminoacetyl pyrrolidine-2-(SV carbonitrileH-yll-1-deoxy-ri-D-fructopyranoseStep I; Scheme: Pyridine (3.6 mL, 0.046 mol) is added to a stirred solution of 2,3:4,5-di-O-isopropylidene-beta-D- fructopyranose (7.0 g, 0.027 mol) in dichloromethane (70 mL) at room temperature. Reaction mixture is cooled to 0-50C, trifluoromethanesulphonic anhydride (5.3 mL, 0.032 mol) is introduced drop wise over a period of 10 minutes and then stirred at room temperature for 45 minutes. D.M. water (30 mL) is added, dichloromethane layer is separated and aqueous layer is exctrated with dichloromethane (2x25 mL). Combined organic layer is washed with brine solution (1x20 mL) and dried over anhydrous sodium <n="48"/>sulphate. Removal of dichloromethane under reduced pressure furnish the triflate derivative of 2,3:4,5-di- O-isopropylidene-beta-D-fructopyranose which is used directly for the next step.N,N-Diisopropylethylamine (4.46 mL, 0.026 mol) is added to a stirred heterogenous mixture of piperidin- 4-yl carbamic acid benzyl ester (5.52 g, 0.02 mol) in acetonitrile (50 mL) at room temperature and stirred for 15 minutes. A solution of the triflate derivative of 2,3:4,5-di-0-isopropylidene-beta-D-fructopyranose (5.0 g, 0.013 mol) in acetronitrile (10 mL) is introduced and heated at reflux for 4 hrs. Reaction mixture is concentrated under reduced pressure, D. M. water (4OmL) is added to the residue and aqueous layer is extracted with ethyl acetate (2x25 mL). Combined organic layer is washed with brine solution (1x20 mL) and dried over anhydrous sodium sulphate. Removal of ethyl acetate under reduced pressure gives viscous liquid which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate, 60:40) to get 2,3:4,5-di-0-isopropylidene-l-[piperidin-(4-benzyloxycarbonylamino)-l-yl]-l-deoxy-beta-D- fructopyranose.

Reference： [1]Patent: WO2009/116067,2009,A2 .Location in patent: Page/Page column 46-47

10
[ 1622-32-8 ]
[ 124-40-3 ]
[ 182223-54-7 ]
C₁₇H₂₇N₃O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Triethylamine (3.4 mL) was added to a dichloromethane (300 mL) solution of 1-<strong>[182223-54-7]benzyl piperidin-4-ylcarbamate</strong> (2.2 g) at 0 C. followed by the dropwise addition of 2-chloroethanesulfonyl chloride (2.6 mL; TCI) and the resulting mixture was slowly stirred overnight with raising to room temperature. 1 N Hydrochloric acid (90 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minutes, then the reaction mixture was extracted with chloroform, the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). 30 mg of this purified compound was dissolved in methanol (1 mL) followed by the addition of dimethylamine (2 M, 0.2 mL; Ald), the resulting mixture was stirred at 100 C. for 2 hours with microwave irradiation, and then the solvent was evaporated under reduced pressure. The title compound was obtained from this residue according to the method described in Step c of Reference Example N-14.(LCMS: 236.2 (MH+); retention time: 0.27 min; LCMS; condition A)

Reference： [1]Patent: US2010/261701,2010,A1 .Location in patent: Page/Page column 123

11
[ 124-63-0 ]
[ 182223-54-7 ]
C₁₄H₁₉FN₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Triethylamine (10 mL) was added to a dichloromethane (90 mL) solution of 1-<strong>[182223-54-7]benzyl piperidin-4-ylcarbamate</strong> (5.09 g) at 0 C. followed by the dropwise addition of methanesulfonyl chloride (which may be referred to as sbo1; 3 mL; TCI) and the resulting mixture was slowly stirred overnight with raising to room temperature. 1 N Hydrochloric acid (90 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minute, the resulting mixture was extracted with chloroform, the organic layer was dried, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). 200 mg of this purified compound was dissolved in THF (4 mL) and the resulting mixture was added dropwise to a THF (5 mL) solution of LDA prepared from diisopropylamine (0.2 mL; WAKO) and normal butyllithium (1.6 M, 1 mL; KANTO) at -78 C. The resulting mixture was stirred for 30 minutes followed by the dropwise addition of THF (3 mL) solution of N-fluorobenzenesulfonimide (320 mg) and the resulting mixture was slowly stirred overnight with raising to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture solution and the resulting mixture was extracted with ethyl acetate. The organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). The title compound (10 mg) was obtained from this purified product according to the method described in Step c of Reference Example N-14.

Reference： [1]Patent: US2010/261701,2010,A1 .Location in patent: Page/Page column 123

12
[ 594-44-5 ]
[ 182223-54-7 ]
1-(ethanesulfonyl)piperidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Triethylamine (10 mL) was added to a dichloromethane (90 mL) solution of 1-<strong>[182223-54-7]benzyl piperidin-4-ylcarbamate</strong> (5.09 g) at 0 C. followed by the dropwise addition of ethane sulfonylchloride (which may be referred to as sso10; 3.2 mL; TCI) and the resulting mixture was stirred overnight slowly raising to room temperature. 1 N Hydrochloric acid (90 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minutes, then the reaction mixture was extracted with chloroform, the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). Palladium hydroxide (20% by weight, Wet-type, 5 g; NECHEM) was added to a methanol (90 mL) solution of this product under a nitrogen atmosphere. The atmosphere in a reaction vessel was replaced with hydrogen at room temperature, the resulting mixture was stirred overnight, the atmosphere in the reaction vessel was returned to a nitrogen atmosphere, the residue was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was dried to give the title compound (3.32 g).(Intermediate N-2 LCMS: 193.1 (MH+); retention time: 0.28 min; LCMS; condition A)

Reference： [1]Patent: US2010/261701,2010,A1 .Location in patent: Page/Page column 121

13
[ 74-89-5 ]
[ 182223-54-7 ]
benzyl [1-(methylsulfamoyl)piperidin-4-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Triethylamine (1.5 mL) was added to a dichloromethane (30 mL) solution of 1-<strong>[182223-54-7]benzylpiperidin-4-ylcarbamate</strong> (580 mg) at 0 C. followed by the dropwise addition of chlorosulfonic acid (290 muL; TCI), the resulting mixture was stirred at room temperature for 4 hours, and the solvent was evaporated under reduced pressure. Benzene (32 mL) and phosphorus pentachloride (0.7 g; WAKO) were added to this residue and the resulting mixture was stirred at 80 C. for 1.5 hours. The reaction mixture solution was cooled to room temperature followed by the addition of 1 N aqueous sodium hydroxide solution (10 mL), the resulting mixture was extracted with dichloromethane, the organic layer was dried, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; hexane/ethyl acetate). 30 mg of this purified compound was dissolved in dichloromethane (0.4 mL) followed by the addition of 3,5-lutidine (0.4 mL; WAKO) and methylamine (2 M, 70 muL; Ald) and the resulting mixture was stirred at room temperature for 24 hours. 1 N hydrochloric acid (2 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minutes, then the reaction mixture was extracted with dichloromethane, the organic layer was dried, and then the solvent was evaporated under reduced pressure. The title compound was obtained from this residue according to the method described in Step c of Reference Example N-14.(LCMS: 194.1 (MH+); retention time: 0.27 min; LCMS; condition A)

Reference： [1]Patent: US2010/261701,2010,A1 .Location in patent: Page/Page column 123

14
[ 3222-47-7 ]
[ 182223-54-7 ]
[ 954266-45-6 ]

Yield	Reaction Conditions	Operation in experiment
		Triethylamine (14 mL; WAKO) was added to a dichloromethane (98 mL) solution of 1-<strong>[182223-54-7]benzyl piperidin-4-ylcarbamate</strong> (5.33 g), 6-methylnicotinic acid (which may be referred to as sco100; 4.0 g; Ald), HOAt (4.0 g; Wata) and WSC.HCl (5.7 g; Wata) and the resulting mixture was stirred overnight at room temperature. Saturated sodium hydrogencarbonate solution (50 mL) was added to the reaction mixture solution, the resulting mixture was extracted, the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). Palladium carbon (10% by weight, Pe-type, 3.45 g; NECHEM) was added to a methanol (90 mL) solution of this product under a nitrogen atmosphere. The atmosphere in a reaction vessel was replaced with hydrogen at room temperature, the resulting mixture was stirred overnight, the atmosphere in the reaction vessel was returned to a nitrogen atmosphere, the residue was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was dried to give the title compound (4.05 g).

Reference： [1]Patent: US2010/261701,2010,A1 .Location in patent: Page/Page column 121

15
[ 1633-82-5 ]
[ 182223-54-7 ]
[ 1220695-10-2 ]

Yield	Reaction Conditions	Operation in experiment
		Triethylamine (3 mL) was added to a dichloromethane (200 mL) solution of 1-<strong>[182223-54-7]benzyl piperidin-4-ylcarbamate</strong> (1.2 g) at 0 C. followed by the dropwise addition of 3-chloropropane sulfonylchloride (4.3 mL; TCI) and the resulting mixture was slowly stirred overnight with raising to room temperature. 1 N Hydrochloric acid (90 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minutes, then the reaction mixture was extracted with chloroform, the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). 100 mg of this purified compound was dissolved in acetone (10 mL) followed by the addition of sodium iodide (KANTO; 44 mg) and the resulting mixture was stirred at room temperature for 12 hours. Sodium iodide (KANTO; 44 mg) was further added, the resulting mixture was stirred at 40 C. for 24 hours followed by the addition of sodium iodide (KANTO; 132 mg), and the resulting mixture was stirred at 60 C. for 24 hours. The reaction mixture solution was cooled to room temperature, the residue was collected by filtration using a Kiriyama funnel to give the title compound (64 mg).(LCMS: 467.2 (MH+); retention time: 1.68 min; LCMS; condition A)

Reference： [1]Patent: US2010/261701,2010,A1 .Location in patent: Page/Page column 122

16
[ 87120-72-7 ]
[ 182223-54-7 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1021 - 1046
[2]Patent: WO2011/60321,2011,A1
[3]Patent: US2013/65925,2013,A1
[4]European Journal of Medicinal Chemistry,2017,vol. 132,p. 26 - 41
[5]Patent: CN102250075,2016,B

17
[ 98-74-8 ]
[ 182223-54-7 ]
[ 1306723-05-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere;	[1 -(4-Nitro-benzenesulfonyl)-piperidin-4-yl]-carbamic acid benzyl ester[00458] Diisopropylethylamine (1 .04ml, 7.0mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid benzyl ester (0.74g, 3.1 mmol) in THF (10ml) at room temperature. To this mixture was added 4-nitrophenyl sulfonyl chloride (0.77g, 3.5mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the solvent was removed under vacuum and the resulting residue was partitioned between ethyl acetate (50ml) and HCl (50ml, 1 M solution), the organic layer was separated and washed with brine (50ml) before being dried (MgSO4), filtered and concentrated under vacuum. The resulting white solid was suspended in heptane and collected by filtration, washed with water (50ml), heptane (50ml) and TBME (50ml) before being dried under vacuum to afford the title compound (1 .3g, 100% yield) as a white solid. Tr = 2.09 min m/z (ES+) (M+H+) 420.

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1021 - 1046
[2]Patent: WO2011/60321,2011,A1 .Location in patent: Page/Page column 115-116

18
[ 182223-54-7 ]
[ 1306723-06-7 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1021 - 1046
[2]Patent: WO2011/60321,2011,A1

19
[ 182223-54-7 ]
[ 1306720-02-4 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1021 - 1046
[2]Patent: WO2011/60321,2011,A1

20
[ 501-53-1 ]
[ 182223-54-7 ]

Reference： [1]Patent: WO2011/60321,2011,A1
[2]Patent: US2013/65925,2013,A1
[3]European Journal of Medicinal Chemistry,2017,vol. 132,p. 26 - 41
[4]Patent: CN102250075,2016,B

21
[ 182223-54-7 ]
[ 1427058-44-3 ]

Reference： [1]Patent: US2013/65925,2013,A1

22
[ 182223-54-7 ]
C₂₂H₄₀FN₃O₃ [ No CAS ]

Reference： [1]Patent: US2013/65925,2013,A1

23
[ 182223-54-7 ]
[ 1427058-31-8 ]

Reference： [1]Patent: US2013/65925,2013,A1
[2]Patent: EP2757103,2014,A1

24
[ 182223-54-7 ]
[ 1427309-25-8 ]

Reference： [1]Patent: US2013/65925,2013,A1
[2]Patent: EP2757103,2014,A1

25
[ 182223-54-7 ]
[ 1427309-26-9 ]

Reference： [1]Patent: US2013/65925,2013,A1
[2]Patent: EP2757103,2014,A1

26
[ 110-62-3 ]
[ 182223-54-7 ]
[ 1427058-43-2 ]

Yield	Reaction Conditions	Operation in experiment
10.5%		(5S)-(-)-2,2,3-Trimethyl-5-benzyl-4-imidazolidinone dichloroacetic acid (90 mg, 0.259 mmol), N-fluorobenzenesulfonimide (484 mg, 1.53 mmol), 2-propanol (0.4 ml) and tetrahydrofuran (dehydrated) (3.6 ml) were mixed at room temperature. The reaction mixture was cooled to -10 C., and pentanal (0.175 ml, 1.67 mmol) was then added, followed by stirring for three hours and 20 minutes while naturally warming from -10 C. to room temperature. Benzyl N-(piperidin-4-yl)carbamate obtained in Example 1b (304 mg, 1.3 mmol) and sodium triacetoxyborohydride (600 mg, 2.83 mmol) were added to the reaction mixture, which was stirred at room temperature for 15 hours and 40 minutes. Water and an aqueous sodium bicarbonate solution were added to the reaction mixture, the insoluble matter was removed by filtration, and the resulting filtrate was extracted with ethyl acetate twice. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (silica gel, elution solvent: ethyl acetate/heptane) to give a chiral form mixture of the title compound (44 mg, yield 10.5%). 1H-NMR (400 MHz, CDCl3) delta ppm; 0.94 (3H, t, J=7 Hz), 1.38-1.70 (6H, m), 1.85-2.00 (2H, br), 2.14-2.24 (2H, m), 2.35-2.48 (1H, m), 2.55-2.64 (1H, m), 2.80-3.00 (2H, m), 3.48-3.60 (1H, m), 4.59-4.72 (2H, m), 5.09 (2H, s), 7.26-7.37 (5H, m). Optical resolution by HPLC (Analysis conditions) Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.) (0.46 cm diameter×15 cm), eluent: hexane/ethanol=9/1 (v/v), flow rate: 1 ml/min., detection: UV (210 nm) (Analysis result) The resulting chiral form mixture was analyzed under the above analysis conditions, and a peak with a retention time of 7.30 minutes (enantiomeric excess: 80% ee) and a peak with a retention time of 8.28 minutes were observed. Further two lots of the chiral form mixture were obtained by a method similar to the above method. Three lots in total of the chiral form mixture (451 mg, 1.4 mmol) were dissolved in ethanol (18 ml) and optically resolved repeatedly under the following fractionation conditions, and the peak with a shorter retention time was fractionated to give the title compound (318 mg). (Fractionation conditions) Column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.) (2 cm diameter×25 cm), eluent: hexane/ethanol=9/1 (v/v), flow rate: 10 ml/min., detection: UV (220 nm) 1H-NMR (400 MHz, CDCl3) delta ppm; 0.94 (3H, t, J=7 Hz), 1.38-1.70 (6H, m), 1.85-2.00 (2H, br), 2.14-2.24 (2H, m), 2.35-2.48 (1H, m), 2.55-2.64 (1H, m), 2.80-3.00 (2H, m), 3.48-3.60 (1H, m), 4.59-4.72 (2H, m), 5.09 (2H, s), 7.26-7.37 (5H, m). The resulting title compound was analyzed under the above analysis conditions to find that the retention time was 7.41 minutes and the enantiomeric excess was >99% ee.

Reference： [1]Patent: US2013/65925,2013,A1 .Location in patent: Paragraph 0199; 0200; 0201; 0202; 0203

27
C₁₂H₂₀ClNO₃ [ No CAS ]
[ 182223-54-7 ]
C₂₅H₃₇N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; In acetonitrile; at 20℃;	The intermediate of stage 1 (1 .60 g; 6.83 mmol), <strong>[182223-54-7]4-benzyloxycarbonylamino-piperidine</strong> (2.18 g; 7.51 mmol) and potassium carbonate (1 .42g ; 10.24 mmol) in ACN (40 mL) are stirred at r.t. After stirring over night the insoluble material is filtered off and the filtrate is evaporated to dryness. Yield: 3.10 g (84% of theory) C25H37N3O5 ESI Mass spectrum: m/z = 460 [M+H]+

Reference： [1]Patent: WO2013/174757,2013,A1 .Location in patent: Page/Page column 33

28
C₁₁H₁₉ClN₂O₃ [ No CAS ]
[ 182223-54-7 ]
C₂₄H₃₆N₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; In acetonitrile; at 20℃;	The intermediate of stage 1 (1.60 g; 6.83 mmol), <strong>[182223-54-7]4-benzyloxycarbonylamino-piperidine</strong> (2.18 g; 7.51 mmol) and potassium carbonate (1.42 g; 10.24 mmol) in ACN (40 mL) are stirred at r.t. After stirring over night the insoluble material is filtered off and the filtrate is evaporated to dryness. Yield: 3.10 g (84% of theory) C25H37N3O5 ESI Mass spectrum: m/z=460 [M+H]+

Reference： [1]Patent: US2013/316981,2013,A1 .Location in patent: Paragraph 0349; 0350; 0351; 0352

29
[ 182223-54-7 ]
benzyl N-[1-(2-fluoropentyl)piperidin-4-yl]carbamate [ No CAS ]

Reference： [1]Patent: EP2757103,2014,A1

30
[ 182223-54-7 ]
C₂₂H₄₀FN₃O₃ [ No CAS ]

Reference： [1]Patent: EP2757103,2014,A1

31
[ 182223-54-7 ]
1-(2-fluoropentyl)piperidin-4-amine [ No CAS ]

Reference： [1]Patent: EP2757103,2014,A1

32
[ 817-70-9 ]
[ 182223-54-7 ]
[ 1427058-43-2 ]

Yield	Reaction Conditions	Operation in experiment
10.5%	With sodium tris(acetoxy)borohydride; isopropyl alcohol; In tetrahydrofuran; at 20℃; for 15.66h;	(Example 1c) Chiral form of benzyl N-[1-(2-fluoropentyl)piperidin-4-yl]carbamate (5S)-(-)-2,2,3-Trimethyl-5-benzyl-4-imidazolidinone dichloroacetic acid (90 mg, 0.259 mmol), N-fluorobenzenesulfonimide (484 mg, 1.53 mmol), 2-propanol (0.4 ml) and tetrahydrofuran (dehydrated) (3.6 ml) were mixed at room temperature. The reaction mixture was cooled to -10C, and pentanal (0.175 ml, 1.67 mmol) was then added, followed by stirring for three hours and 20 minutes while naturally warming from -10C to room temperature. Benzyl N-(piperidin-4-yl)carbamate obtained in Example 1b (304 mg, 1.3 mmol) and sodium triacetoxyborohydride (600 mg, 2.83 mmol) were added to the reaction mixture, which was stirred at room temperature for 15 hours and 40 minutes. Water and an aqueous sodium bicarbonate solution were added to the reaction mixture, the insoluble matter was removed by filtration, and the resulting filtrate was extracted with ethyl acetate twice. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (silica gel, elution solvent: ethyl acetate/heptane) to give a chiral form mixture of the title compound (44 mg, yield 10.5%). 1H-NMR (400 MHz, CDCl3) delta ppm; 0.94 (3H, t, J=7 Hz), 1.38-1.70 (6H, m), 1.85-2.00 (2H, br), 2.14-2.24 (2H, m), 2.35-2.48 (1H, m), 2.55-2.64 (1H, m), 2.80-3.00 (2H, m), 3.48-3.60 (1H, m), 4.59-4.72 (2H, m), 5.09 (2H, s), 7.26-7.37 (5H, m). Optical resolution by HPLC (Analysis conditions) Column: CHIRALRAK AD-H (manufactured by Daicel Chemical Industries, Ltd.) (0.46 cm diameter x 15 cm), eluent: hexane/ethanol = 9/1 (v/v), flow rate: 1 ml/min., detection: UV (210 nm) (Analysis result) The resulting chiral form mixture was analyzed under the above analysis conditions, and a peak with a retention time of 7.30 minutes (enantiomeric excess: 80% ee) and a peak with a retention time of 8.28 minutes were observed

Reference： [1]Patent: EP2757103,2014,A1 .Location in patent: Paragraph 0150

33
[ 66493-39-8 ]
[ 182223-54-7 ]
p-[4-(benzyloxycarbonylamino)-1-piperidyl]carbonyl}phenylamino 2,2-dimethylpropionate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.8%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dimethyl sulfoxide; at 20℃; for 12h;	p-[4-(benzyloxycarbonylamino)-1-piperidyl]carbonyl}phenylamino 2,2-dimethylpropionateTo a solution of 4-(tert-butoxycarbonylamino)benzoic acid (500mg, 2mmol), 4-CBz- aminopiperidine (500mg, 2mmol) and Et3N (0.89ml, 6mmol) in DMSO (10mL) was added HBTU (1.2g, 3mmol) and the mixture was stirred 12h at rt. The reaction was then diluted with EtOAc (100ml) and water (100mL). The layers were separated and the organic layer was washed with brine (3x100mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (DCM/MeOH, 0 to 10% gradient) and afforded the title compound as a white solid (850 mg, 87.8%)

Reference： [1]Patent: WO2015/58163,2015,A2 .Location in patent: Paragraph 163

34
[ 182223-54-7 ]
C₂₄H₂₈ClN₇O₃ [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

35
[ 182223-54-7 ]
C₁₉H₂₀ClN₇O*ClH [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

36
[ 182223-54-7 ]
C₂₃H₂₃BrClN₇O₂ [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

37
[ 182223-54-7 ]
tert-butyl 4-(4-aminopiperidine-1-carbonyl)phenylcarbamate [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

38
[ 182223-54-7 ]
(E)-N-(4-(4-((5-chloro-4-(1H-pyrazol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

39
[ 182223-54-7 ]
C₂₆H₃₁ClN₆O₃S [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

40
[ 182223-54-7 ]
C₂₁H₂₃ClN₆OS*ClH [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

41
[ 182223-54-7 ]
C₂₅H₂₆BrClN₆O₂S [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

42
[ 182223-54-7 ]
(E)-N-(4-(4-((5-chloro-4-(2,4-dimethylthiazol-5-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

43
[ 182223-54-7 ]
C₂₆H₃₁ClN₆O₄ [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

44
[ 182223-54-7 ]
C₂₁H₂₃ClN₆O₂*ClH [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

45
[ 182223-54-7 ]
C₂₅H₂₆Cl₂N₆O₃ [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

46
[ 182223-54-7 ]
(E)-N-(4-(4-((5-chloro-4-(3,5-dimethylisoxazol-4-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

47
[ 182223-54-7 ]
tert-butyl 4-(4-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)phenylcarbamate [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

48
[ 182223-54-7 ]
C₃₇H₃₉ClN₆O₅S [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

49
[ 182223-54-7 ]
C₃₂H₃₁ClN₆O₃S*ClH [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

50
[ 182223-54-7 ]
(4-aminophenyl)(4-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidin-1-yl)methanone trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

51
[ 182223-54-7 ]
C₂₅H₂₅ClN₆O [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

52
[ 182223-54-7 ]
(E)-N-(4-(4-((5-chloro-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

53
[ 182223-54-7 ]
(E)-N-(4-(4-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

54
[ 182223-54-7 ]
(E)-N-(4-(4-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

55
[ 182223-54-7 ]
tert-butyl (4-(4-((5-chloro-4-(pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2015/58163,2015,A2

56
[ 182223-54-7 ]
benzyl N-(1-sulfamoylpiperidin-4-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With SULFAMIDE; In 1,2-dimethoxyethane; at 100℃; for 72h;	Step 1: Synthesis of benzyl N-(l-sulfamoylpiperidin-4-yl)carbamate 42.1 [00497] To a solution of <strong>[182223-54-7]benzyl piperidin-4-ylcarbamate</strong> (l .OOg, 4.27 mmol) in 1,2- dimethoxyethane (20 ml) was added sulfuric diamide (0.46g, 4.79 mmol) and the resulting mixture was stirred at 100C for 72 hours. The reaction mixture was concentrated in vacuo and taken up in DCM (100ml) and MeOH (10ml). This was washed with IN aqueous HC1 (10ml). DCM (100ml) and MeOH (10ml) were added to the organic layer. The organic layer was again washed with IN aqueous HC1 (2 x 10ml), dried over Na2S04 and concentrated in vacuo to afford as 1.05g (78%) of benzyl N-(l-sulfamoylpiperidin-4-yl)carbamate 42.1 as a white powder.

Reference： [1]Patent: WO2016/40449,2016,A1 .Location in patent: Paragraph 00496-00497

57
[ 182223-54-7 ]
benzyl N-{1-[(pyrimidin-2-yl)sulfamoyl]piperidin-4-yl}carbamate [ No CAS ]

Reference： [1]Patent: WO2016/40449,2016,A1

58
[ 108-94-1 ]
[ 182223-54-7 ]
benzyl (1-cyclohexylpiperidin-4-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
450 mg		General procedure: To a solution of compound I-4 (470 mg, 1.47 mmol) in DCM, TFA (2.5 mL, 29 mmol) was addedand then the reaction mixture was stirred at room temperature for 2 h and then was evaporated togive the crude product directly used in the next step A mixture of the amine, DIEA (3.84 mL,22.05mmol) and cyclohexanone (1.5 mL) in THF (10 mL) was stirred at room temperature for 1.5h and then NaBH(OAc)3 (1.6 g, 7.35 mmol) was added into the solution. The reaction mixture wasstirred at room temperature for overnight and then H2O was added to quench the reaction. Thesolution was extracted with ethyl acetate (30 mL × 2). The organic layer was washed with brine(15 mL × 2) and then was dried over anhydrous MgSO4. After filtration and concentration, thecrude product I-5 was obtained and purified with column chromatography ( methylene chloride/methanol = 45:1 to 30:1) to give compound I-5 as light yellow oil (350 mg, 78%).