[ CAS No. 140447-78-5 ] {[proInfo.proName]}

Name: 140447-78-5|1-(2-N-Boc-Aminoethyl)piperazine|97%
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SKU: A327041
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Quality Control of [ 140447-78-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 140447-78-5 ]

Product Details of [ 140447-78-5 ]

CAS No. :	140447-78-5	MDL No. :	MFCD02683050
Formula :	C₁₁H₂₃N₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VPOIPCJBJNWHSJ-UHFFFAOYSA-N
M.W :	229.32	Pubchem ID :	1514401
Synonyms :

Calculated chemistry of [ 140447-78-5 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.91
Num. rotatable bonds :	6
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	70.92
TPSA :	53.6 Å²

Pharmacokinetics

GI absorption :	High
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) :	-7.48 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.62
Log Po/w (XLOGP3) :	0.31
Log Po/w (WLOGP) :	-0.35
Log Po/w (MLOGP) :	0.32
Log Po/w (SILICOS-IT) :	0.5
Consensus Log Po/w :	0.68

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.06
Solubility :	19.9 mg/ml ; 0.0869 mol/l
Class :	Very soluble
Log S (Ali) :	-1.0
Solubility :	23.0 mg/ml ; 0.1 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.15
Solubility :	1.64 mg/ml ; 0.00714 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.48

Safety of [ 140447-78-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 140447-78-5 ]

* 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 [ 140447-78-5 ]
Downstream synthetic route of [ 140447-78-5 ]

[ 140447-78-5 ] Synthesis Path-Upstream 1~9

1
[ 500013-42-3 ]
[ 140447-78-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogen In methanol for 2 h;	Hydrogen was passed through a degassed solution of benzyl 4-(2-(tert-butyloxycarbonylamino)ethyl)piperazine-1-carboxylate (2.60 g, 7.16 mmol) in methanol (50 ml) containing 10percent palladium on carbon (500 mg) for 2 h. The reaction mixture was filtered through Celite.(R). and the filtrate was concentratedin vacuo to give a yellow gum identified as tert-butyl 2-(1-piperazinyl)ethylcarbamate (1.60 g, 97percent).

Reference： [1] Patent: EP1449844, 2004, A1, . Location in patent: Page 34
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 18, p. 5147 - 5157

2
[ 1007869-45-5 ]
[ 140447-78-5 ]

Reference： [1] Patent: US2011/294775, 2011, A1, . Location in patent: Page/Page column 168

3
[ 140-31-8 ]
[ 24424-99-5 ]
[ 140447-78-5 ]

Reference： [1] Patent: US6518286, 2003, B1,

4
[ 24424-99-5 ]
[ 140447-78-5 ]

Reference： [1] Patent: US2011/294775, 2011, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7345 - 7350
[3] Organic and Biomolecular Chemistry, 2015, vol. 13, # 18, p. 5147 - 5157

5
[ 110-85-0 ]
[ 39684-80-5 ]
[ 140447-78-5 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7345 - 7350

6
[ 4553-21-3 ]
[ 140447-78-5 ]

Reference： [1] Patent: US2011/294775, 2011, A1,

7
[ 104740-55-8 ]
[ 140447-78-5 ]

Reference： [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 18, p. 5147 - 5157

8
[ 100450-84-8 ]
[ 140447-78-5 ]

Reference： [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 18, p. 5147 - 5157

9
[ 140-31-8 ]
[ 140447-78-5 ]

Reference： [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 18, p. 5147 - 5157

[ 140447-78-5 ] Synthesis Path-Downstream 1~88

1
[ 140447-78-5 ]
[ 1675-46-3 ]
[ 1009797-49-2 ]

Yield	Reaction Conditions	Operation in experiment
64%	With potassium carbonate; sodium iodide; In butanone; for 24h;Heating / reflux;	Compound 5 10- { 3-[4-(N-Boc-2-amino)ethylpiperazinyl]propyl } -2-trifluoromethylphenothiazineTo a stirred suspension of the chloropropyl derivative 2 (1.2 g, 3.5 mmol) , potassium carbonate (1.5 g, 10.86 mmol), l-(2-N-Boc- aminoethyl)piperazine (0.78g, 3.5 mmol) in methyl ethyl ketone (30 mL), was added sodium Iodide (0.9 g, 6 mmol). The reaction mixture was stirred for 24 h at reflux under an atmosphere of argon. The reaction mixture was filtered, and filtrate was concentrated under vacuum.The residue was partitioned between ethyl acetate (30 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated. The resulting residue was purified by silica gel chromatography (9:1 CH2C^MeOH) to give 5 (1.2 g, 64%) as a foam. MS(ESI): m/z 537 (M+H).

Reference： [1]Patent: WO2008/27521,2008,A1 .Location in patent: Page/Page column 56

2
[ 140447-78-5 ]
[ 1675-46-3 ]
[ 1009797-51-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; sodium iodide; In butanone; for 24h;Heating / reflux;	Compound 10 10- { 3 -[4-(N-Boc-2 -amino)ethylpiperazinyl] propyl } -2- dimethylsulfamidolphenothiazineTo a stirred solution of the phenothiazine chloro derivative 9 (382 mg, 1.0 mmol), potassium carbonate (500 mg,3.62 mmol), and l-(2-N-Boc- aminoethyl)piperazine (229 mg, 1.0 mmol) in methyl ethyl ketone (20 mL) was added sodium iodide (150 mg, 1 mmol). The reaction mixture was stirred for 24 h at reflux under an atmosphere of argon. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was partitioned between ethyl acetate (20 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2:MeOH) to give 10 (410 mg, 71%) as a foam. MS(ESI): m/z 576 (M+H).

Reference： [1]Patent: WO2008/27521,2008,A1 .Location in patent: Page/Page column 58

3
[ 140447-78-5 ]
[ 3870-95-9 ]
[ 1009797-56-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium iodide; In butanone; for 24h;Heating / reflux;	Compound 22; 10- {4-[4-(N-Boc-2-amino)ethylpiperazinyl]butyl } -2-trifluoromethylphenothiazine ; To a stirred suspension of the chlorobutyl derivative 21 (3.57 g, 10 mmol), potassium carbonate (4.0 g, 28.98 mmol), l-(2-N-Boc- aminoethyl)piperazine (2.6 g, 11.35 mmol) in methyl ethyl ketone (40 mL) was added sodium Iodide 2.5 g, 16 mmol). The reaction mixture was stirred for 24 h at reflux under an atmosphere of argon. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was partitioned between ethyl acetate (50 mL) and brine (25 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated. The resulting residue was purified by silica gel chromatography (9: 1 CH2Cl2MeOH) to give 22 (4,0 g, 72%) as a foam. MS(ESI): m/z 551 (M+H).

Reference： [1]Patent: WO2008/27521,2008,A1 .Location in patent: Page/Page column 62

4
[ 500013-42-3 ]
[ 140447-78-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogen;palladium 10% on activated carbon; In methanol; for 2h;	Hydrogen was passed through a degassed solution of benzyl 4-(2-(tert-butyloxycarbonylamino)ethyl)piperazine-1-carboxylate (2.60 g, 7.16 mmol) in methanol (50 ml) containing 10% palladium on carbon (500 mg) for 2 h. The reaction mixture was filtered through Celite and the filtrate was concentratedin vacuo to give a yellow gum identified as tert-butyl 2-(1-piperazinyl)ethylcarbamate (1.60 g, 97%).

Reference： [1]ChemMedChem,2019
[2]Patent: EP1449844,2004,A1 .Location in patent: Page 34
[3]Organic and Biomolecular Chemistry,2015,vol. 13,p. 5147 - 5157

5
[ 140447-78-5 ]
[ 724788-70-9 ]
[ 903587-78-0 ]

Yield	Reaction Conditions	Operation in experiment
41%	With 18-crown-6 ether; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 12.25h;	In a sealed tube, 8-bromo-7-fluoro-2-(methyloxy)-1 ,5-naphthyridine (1.1 g, 4.3 mmol), 1 ,1 -dimethylethyl [2-(1-piperazinyl)ethyl]carbamate (1 g, 4.3 mmol), Pd2dba3 (271 mg, 0.262 mmol), rac-Binap (163 mg, 0.262 mmol), Cs2CO3 (2.98 mg, 9.2 mmol) and 18- C-6 (115 mg, 0.436 mmol) in dioxane (22 ml_) were combined and flushed with N2. After 15min, the tube was sealed and heated to 1000C while stirring rapidly. After 12h, the solution was filtered, concentrated and the residue purified via column chromatography (silica,.1% MeOH in DCM (1% NH4OH)) yielding the title compound (725 mg, 41%) as an orange oil: LCMS (ES) m/e 406 (M+H)+.

Reference： [1]Patent: WO2006/81289,2006,A2 .Location in patent: Page/Page column 25

6
[ 140-31-8 ]
aqueous KHSO₄ [ No CAS ]
[ 24424-99-5 ]
[ 140447-78-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; benzaldehyde; In dichloromethane;	(i) tert-Butyl 2-(1-piperazinyl)ethylcarbamate A mixture of benzaldehyde (21 g) and 1-(2-aminoethyl)piperazine (25.8 g) was stirred and heated under a Dean and Stark water separator for 20 hours. The cooled solution was treated portionwise with di-tert-butyldicarbonate (48 g), stirred for 72 hours and concentrated. The residue was treated with 1M aqueous KHSO4 solution (220 ml), stirred for 24 hours, ether was added and the organic phase separated. The aqueous phase was treated with 2M NaOH solution, dichloromethane was added and the organic phase separated. The combined organic phase was washed with brine, dried and concentrated to give the sub-titled product as an oil (30 g). MS: APCI(+ve) 230(M+H) 1H NMR delta(CDCl3) 3.43 (t, 4H), 2.8 (t, 2H), 2.45 (m, 6H), 1.5 (s, 9H).

Reference： [1]Patent: US6518286,2003,B1

7
[ 89891-65-6 ]
[ 140447-78-5 ]
[ 1083325-92-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	In N,N-dimethyl-formamide; at 80℃; for 1h;	Example 194; Preparation of 1,1-dimethylethyl [2-(4-{7-[5-(aminosulfonyl)-3-pyridinyl]-2-quinoxalinyl}-1-piperazinyl)ethyl]carbamate; a) 1,1-dimethylethyl {2-[4-(7-bromo-2-quinoxalinyl)-1-piperazinyl]ethyl}carbamate; A solution of 7-bromo-2-chloroquinoxaline (1.20 mmol) in N,N-dimethylformamide (5 ml) was treated with an amine (or an alcohol) such as 1,1-dimethylethyl [2-(1-piperazinyl)ethyl]carbamate (3.60 mmol) then heated at 80 C. for 1 hour. The reaction was cooled to ambient temperature then poured into water (25 ml). Product precipitated out of solution, which was filtered and dried. Alternatively, after the reaction is cooled to ambient temperature and poured into water (25 ml), it was extracted into ethyl acetate (3×25 ml). The extracts were washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (520 mg, 80%) as a yellow solid. MS (ES)+ m/e 297.2 [M+]+.

Reference： [1]Patent: US2008/293706,2008,A1 .Location in patent: Page/Page column 63

8
[ 140447-78-5 ]
[ 13991-36-1 ]
[ 1022150-13-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 20℃; for 2h;	To a solution of 4-bromocrotonic acid (72 mg, 0.44 mmoles) in THF (3 mL) was added a solution of TEA (0.18 mL, 1.3 mmoles) and 1-(2-N-Boc-aminoethyl)piperazine (0.1 g, 0.44 mmoles) in THF (1 mL). After stirring the solution for 2 hr at room temperature the solvent was removed to provide crude Intermediate 5 which was used without further purification.

Reference： [1]Patent: US2008/214501,2008,A1 .Location in patent: Page/Page column 13

9
[ 140447-78-5 ]
C₂₅H₂₂Cl₂FN₂O₅Pol [ No CAS ]
C₃₆H₄₄Cl₂N₅O₇Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 1-methyl-pyrrolidin-2-one; at 65℃; for 48h;	Step 3: Fluorine substitution is accomplished via treatment of resin using 0.5M solution of boc-4-(2-amino-ethyl)-piperazine in NMP for 48h at 65C. The resin is washed 3x DMF, 2x DCM, 2xDMF, (ending up with swollen resin in DMF).

Reference： [1]Patent: WO2009/105435,2009,A1 .Location in patent: Page/Page column 50

10
[ 140447-78-5 ]
[ 530-62-1 ]
[ 479234-64-5 ]
[ 500013-43-4 ]

Yield	Reaction Conditions	Operation in experiment
81%		1,1'-Carbonyldiimidazole (25 mg, 0.15 mmol) was added to a solution of 5-(4-(aminomethyl)-3-methylbenzoyl)-1-methyl-4,10-dihydropyrazolo[5,4-b][1,5]benzodiazepine (31 mg, 0.09 mmol) and DIEA (0.1 ml, 0.57 mmol) in DMF (5 ml). The solution was stirred for 1h, tert-butyl 2-(1-piperazinyl)-ethylcarbamate (22 mg, 0.10 mmol) was added and stirring was continued at room temperature for 24 h. The mixture was concentrated in vacuo and the residue was taken up in EtOAc. The solution was washed with saturated Na-HCO3 and brine, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant 20% methanol/EtOAc) to give a white solid identified as 5-(4-(4-(2-(tert-butyloxycarbonylaminoethyl)piperazine-1-carbonylaminomethyl)-3-methylbenzoyl)-1-methyl-4,10-dihydropyrazolo[5,4-b][1,5]benzodiazepine (44 mg, 81%).

Reference： [1]Patent: EP1449844,2004,A1 .Location in patent: Page 34

11
[ 140447-78-5 ]
[ 1160938-26-0 ]
[ 1257315-77-7 ]

Yield	Reaction Conditions	Operation in experiment
38%	With potassium carbonate; In dimethyl sulfoxide; at 130℃; for 3h;Microwave irradiation; Sealed vial;	Example 3: 4-[(5-chloro-2-pyridinyl)methyl]oxy}-6'-[4-(aminoethyl)piperidin-1-yl]-2/-/-1 ,3'- bipyridin-2-oneA sealed vial containing 4-[(5-chloro-2-pyridinyl)methyl]oxy}-6'-(fluoro)-2/-/-1 ,3'-bipyridin-2- one (80 mg, 0.24 mmol), terf-butyl 2-(piperazin-1-yl)ethylcarbamate (66 mg, 0.29 mmol), K2CO3 (100 mg, 0.72 mmol) and DMSO (2 mL) was irradiated in the microwave at 1300C for 3 h. The mixture was filtered and the filtrate was purified by preparative HPLC to give 4-[(5- chloro-2-pyridinyl)methyl]oxy}-6'-{4-(fert-butyloxycarbonylaminoethyl)piperazin-1-yl}-2/-/-1 ,3'- bipyridin-2-one as a pale yellow solid (50 mg, 38%): 1H NMR (400 MHz, MeOH-Cf4) delta 8.57 (m, 1 H), 8.17 (dd, J = 1.6 Hz, 0.4 Hz, 1 H), 7.91 (dd, J = 8.4 Hz, 2.4 Hz, 1 H), 7.52-7.69 (m, 3H), 7.02-7.09 (m, 1 H), 6.32 (dd, J = 7.6 Hz, 2.4 Hz, 1 H), 6.09 (dd, J = 2.4 Hz, 1.2 Hz, 1 H), 5.24 (s, 2H), 3.89-4.02 (m, 2H), 3.29-3.50 (m, 10H), 1.44 (s, 9H); ES-LCMS m/z 541 (M+H)+.

Reference： [1]Patent: WO2010/141538,2010,A1 .Location in patent: Page/Page column 27

12
[ 4553-21-3 ]
[ 140447-78-5 ]

Reference： [1]Patent: US2011/294775,2011,A1

13
[ 5093-70-9 ]
[ 140447-78-5 ]
[ 1007869-46-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; at 130℃; for 0.833333h;	A mixture of 1.18 g (6.32 mmol) of 4-bromo-2,6-dimethylpyridine (Acta Chem. Scand. Ser. B 42, 1988, 373-377), 1.45 g (6.32 mmol) of product from 28b and 2.2 ml DIPEA is heated for 50 min to 130° C. in the microwave. The reaction mixture is combined with ethyl acetate and semisaturated potassium carbonate solution and then the phases are separated. The organic phase is dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 95:5:0.5).C18H30N4O2S (334.46)[M+H]+=335TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.37

Reference： [1]Patent: US2011/294775,2011,A1 .Location in patent: Page/Page column 168

14
[ 24424-99-5 ]
[ 140447-78-5 ]

Reference： [1]Patent: US2011/294775,2011,A1
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7345 - 7350
[3]Organic and Biomolecular Chemistry,2015,vol. 13,p. 5147 - 5157
[4]Journal of Medicinal Chemistry,2019,vol. 62,p. 8338 - 8356

15
[ 140447-78-5 ]
[ 1007869-47-7 ]

Reference： [1]Patent: US2011/294775,2011,A1

16
[ 1007869-45-5 ]
[ 140447-78-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 15h;Autoclave;	A mixture of 2.10 g (6.57 mmol) of product from 28a, 0.25 g palladium on charcoal (10%) and 30 ml of methanol is hydrogenated for 15 hours at ambient temperature in the autoclave. Then the catalyst is removed by suction filtering and the filtrate is evaporated to dryness in vacuo.C11H23N3O4 (229.32)[M+H]+=230TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.08

Reference： [1]Patent: US2011/294775,2011,A1 .Location in patent: Page/Page column 168

17
[ 140447-78-5 ]
[ 1407967-21-8 ]
[ 1407967-22-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10047 - 10063

18
[ 110-85-0 ]
[ 39684-80-5 ]
[ 140447-78-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7345 - 7350
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 8338 - 8356

19
[ 140447-78-5 ]
[ 2576-47-8 ]
[ 1415582-56-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7345 - 7350

20
[ 140447-78-5 ]
[ 1415582-58-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7345 - 7350

21
[ 140447-78-5 ]
[ 1415582-59-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7345 - 7350

22
[ 140447-78-5 ]
[ 1415582-60-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7345 - 7350

23
[ 140447-78-5 ]
[ 1415582-61-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7345 - 7350

24
[ 140447-78-5 ]
[ 1415582-62-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7345 - 7350

25
[ 140447-78-5 ]
[ 1415582-57-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7345 - 7350

26
[ 140447-78-5 ]
C₁₈H₂₅N₅O₂S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7345 - 7350

27
[ 140447-78-5 ]
[ 1431411-18-5 ]
[ 1431411-22-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 18h;	A solution of 4-chlorothieno[3,2-d]pyrimidine-6-carboxamide (14; 0.250 g, 1.17 mmol),DIEA (245 jiL, 1.40 mmol) and <strong>[140447-78-5]tert-butyl (2-(piperazin-1-yl)ethyl)carbamate</strong> (0.332 g,1.40 mmol) in CH3CN (15 mL) was heated at 60C for 18 hours. The reaction mixturewas cooled to room temperature and filtered to collect the product as a solid. The solid was washed with CH3CN (2 x 10 mL) and dried to obtain tert-butyl (2-(4-(6- carbamoylthieno [3 ,2-d]pyrimidin-4-yl)piperazin- 1 -yl)ethyl)carbamate as a white solid (Compound 15b; 0.440 g, 93%). MS (ESI) calcd for C18H26N6035: 406.18; found: 407 [M+H].

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 3666 - 3679
[2]Patent: WO2014/138562,2014,A1 .Location in patent: Page/Page column 68; 69

28
[ 65148-07-4 ]
[ 140447-78-5 ]
C₂₉H₃₃N₅O₃ [ No CAS ]

Reference： [1]ChemMedChem,2014,vol. 9,p. 953 - 961

29
[ 140447-78-5 ]
[ 1610549-03-5 ]

Reference： [1]ChemMedChem,2014,vol. 9,p. 953 - 961

30
[ 140447-78-5 ]
[ 1610549-52-4 ]

Reference： [1]ChemMedChem,2014,vol. 9,p. 953 - 961

31
[ 140447-78-5 ]
[ 13991-36-1 ]
(2E)‐4‐[4‐(2‐[(tert‐butoxy)carbonyl]amino}ethyl)piperazin‐1‐yl]but‐2‐enoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40.4%	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 20h;Inert atmosphere;	To a stirred solution of l-2-N-Boc-(aminoethyl)-Piperazine (2.00 g; 8.63 mmol; 1.00 eq.) and Triethyl-amine (2.65 g; 3.65 ml; 25.90 mmol; 3.00 eq.) in dry THF (17.80 g; 20.00 ml; 10.00 V) was added (E)-4-Bromo-but-2-enoic acid (1.74 g; 10.36 mmol; 1.20 eq.) at 0 C under nitrogen atmosphere. After the additon, the reaction mixture was stirred at the same temparature for another 2h. The reaction mxitrue was slowly allowed to RT for 18h. After the completion, the precipitated solid was filtered, the solid was washed with THF (25 mL) and the filtrate was evaportated under high vacum. The crude product was directly loaded to column (60-120 silica gel) using DCM and methanol as eluent (12-15%) to afford (E)-4-[4-(2-tert- Butoxycarbonylamino-ethyl)-piperazin-l-yl]-but-2-enoic acid (1.20 g; 3.48 mmol; 40.4 %). MS: m z = 314[M+H]+(TIC).
	With triethylamine; In tetrahydrofuran; at 20℃; for 15h;	[0621] A mixture of (E)-4-bromobut-2-enoic acid (500 mg, 3.03 mmol), <strong>[140447-78-5]tert-butyl (2-(piperazin-1-yl)ethyl)carbamate</strong> (694 mg, 3.03 mmol) and Et3N (612 mg, 6.06 mmol) in 20 mL ofTHF wasstirred at RT for 15 h. The mixture was concentrated and used in the next step without furtherpurification. MS (ESI) m/e [M+It 314.0.
	With triethylamine; In tetrahydrofuran; at 20℃; for 15h;	Mixture (E)-4-bromobut-2-enoic acid (500 mg, 3.03 mmol),Tert-butyl N-[2-pipemarin-l-yl)ethyl]carbamate (694 mg, 3.03 mmol) and Et3N (612 mg, 6.06 mmol) were stirred in THF (20 mL) at room temperature for 15 h.The mixture was concentrated and used in the next step without further purification.

With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;

1. <strong>[140447-78-5]tert-butyl (2-(piperazin-1-yl)ethyl)carbamate</strong> (1.1 eq) was dissolved in THFa. Diisopropyl ethyl amine (eq) was added2. (E)-4-bromobut-2-enoic acid (1) was dissolved in THF and added to reaction flask3. Flask was allowed to stir overnight4. Sample was concentrated via rotary evaporator and carried on to next step without furtherpurification.

Reference： [1]Patent: WO2015/17502,2015,A1 .Location in patent: Paragraph 00320
[2]Patent: WO2014/173289,2014,A1 .Location in patent: Paragraph 0618; 0620; 0621
[3]Organic and Biomolecular Chemistry,2015,vol. 13,p. 5147 - 5157
[4]Patent: TWI602818,2017,B .Location in patent: Paragraph 0606; 0619; 0620; 0621
[5]Patent: WO2019/5883,2019,A1 .Location in patent: Page/Page column 89; 92; 93
[6]Journal of Medicinal Chemistry,2019,vol. 62,p. 7923 - 7940

32
[ 140447-78-5 ]
tert‐butyl N‐(2‐{4‐[(2E)‐4‐{4‐[(7S)‐3‐carbamoyl‐2‐(4‐phenoxyphenyl)‐4H,5H,6H,7H‐pyrazolo[1,5‐a]pyrimidin‐7‐yl]piperidin‐1‐yl}‐4‐oxobut‐2‐en‐1‐yl]piperazin‐1‐yl}ethyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2014/173289,2014,A1

33
[ 140447-78-5 ]
(7S)‐7‐{1‐[(2E)‐4‐[4‐(2‐aminoethyl)piperazin‐1‐yl]but‐2‐enoyl]piperidin‐4‐yl}‐2‐(4‐phenoxyphenyl)‐4H,5H,6H,7H‐pyrazolo[1,5‐a]pyrimidine‐3‐carboxamide trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2014/173289,2014,A1
[2]Patent: TWI602818,2017,B

34
[ 140447-78-5 ]
N₁-(2-(4-((E)-4-(4-((S)-3-carbamoyl-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)-N₅-(15-oxo-19-((3aR,4R,6aS)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)glutaramide trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2014/173289,2014,A1

35
[ 140447-78-5 ]
1-(4-(2-aminoethyl)piperazin-1-yl)-2-methylpropan-2-ol [ No CAS ]

Reference： [1]Patent: WO2014/182829,2014,A1

36
[ 140447-78-5 ]
2-(4-(oxetan-3-yl)piperazin-1-yl)ethanamine [ No CAS ]

Reference： [1]Patent: WO2014/182829,2014,A1

37
[ 140447-78-5 ]
[ 558-42-9 ]
tert-butyl (2-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 70 - 80℃; for 24h;	To a solution of <strong>[140447-78-5]tert-butyl (2-(piperazin-1-yl)ethyl)carbamate</strong> (1 g, 4.4 mmol) in DMF (15 mL) was added 1-chloro-2-methylpropan-2-ol (1.89 g, 17.4 mmol), K2C03 (1.8 g, 13.1mmol) and Nal (1.31 g, 8.7 mmol). The reaction was stirred at 70-80 °C for 24 h, cooled to room temperature, and poured into water. The reaction mixture was extracted with ethyl acetate, and the organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was chromatographed (silica gel, DCM : MeOH = 40 : 1) to afford tert-butyl (2-(4-(2-hydroxy-2-methylpropyl)piperazin- 1 -yl)ethyl)carbamate as an oil (0.95 g, 73percent).

Reference： [1]Patent: WO2014/182829,2014,A1 .Location in patent: Page/Page column 108

38
[ 6704-31-0 ]
[ 140447-78-5 ]
tert-butyl (2-(4-(oxetan-3-yl)piperazin-1-yl)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of tert-butyl (2-(piperazin- 1 -yl)ethyl)carbamate (1 .15 g, 5 mmol) and oxetan-3-one (1.8 g, 25 mmol) in MeOH (30 mL) was added ZnC12 (3.4 g, 25 mmol). Themixture was stirred at room temperature for 3 h, and then NaBH3CN (950 mg, 15 mmol) was added. The mixture was stirred at room temperature overnight and then filtered and the filtrate was concentrated to afford tert-butyl (2-(4-(oxetan-3-yl)piperazin- 1 -yl)ethyl)carbamate (1.3 g, crude) as a light yellow oil which was used for next step without further purification.

Reference： [1]Patent: WO2014/182829,2014,A1 .Location in patent: Page/Page column 113

39
[ 140447-78-5 ]
tert-butyl (E)-(2-(4-(4-oxo-4-(4-(4-(4-phenoxyphenoxy)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidin-1-yl)but-2-en-1-yl)piperazin-1-yl)ethyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2015/17502,2015,A1

40
[ 140447-78-5 ]
(E)-4-(4-(2-aminoethyl)piperazin-1-yl)-1-(4-(4-(4-phenoxyphenoxy)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidin-1-yl)but-2-en-1-one [ No CAS ]

Reference： [1]Patent: WO2015/17502,2015,A1

41
[ 140447-78-5 ]
tert-butyl (E)-(15-oxo-18-(4-(4-oxo-4-(4-(4-(4-phenoxyphenoxy)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidin-1-yl)but-2-en-1-yl)piperazin-1-yl)-3,6,9,12-tetraoxa-16-azaoctadecyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2015/17502,2015,A1

42
[ 140447-78-5 ]
(E)-1-amino-N-(2-(4-(4-oxo-4-(4-(4-(4-phenoxyphenoxy)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidin-1-yl)but-2-en-1-yl)piperazin-1-yl)ethyl)-3,6,9,12-tetraoxapentadecan-15-amide [ No CAS ]

Reference： [1]Patent: WO2015/17502,2015,A1

43
[ 140447-78-5 ]
(E)-1-((4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-414,514-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)phenyl)amino)-N-(2-(4-(4-oxo-4-(4-(4-(4-phenoxyphenoxy)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)piperidin-1-yl)but-2-en-1-yl)piperazin-1-yl)ethyl)-1-thioxo-5,8,11,14-tetraoxa-2-azaheptadecan-17-amide [ No CAS ]

Reference： [1]Patent: WO2015/17502,2015,A1

44
4-(2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoic acid [ No CAS ]
[ 140447-78-5 ]
tert-butyl (2-(4-(4-(2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoyl)piperazin-1-yl)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	To a solution of 4-(2-(2-amino-4-oxo-4,7-dihydro- lH-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoic acid (171 mg, 0.80 mmol) in DMF (5.0 mL) was added HATU (228 mg, 0.60 mmol), tert-butyl (2-(piperazin-l-yl)ethyl)carbamate (138 mg, 0.60 mmol) and DIPEA (0.20 mL). The mixture was stirred at rt for overnight. Solvent was evaporated under reduced pressure to give a residue, which was purified by ISCO over silica gel to afford tert-butyl (2-(4-(4-(2-(2-amino-4-oxo-4,7-dihydro-lH-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzoyl)pipe razin-l-yl)ethyl)carbamate (284 mg, 97%) as a yellow solid. ESMS calculated for C26H35N7O4: 509.3; found: 510.4 (M + H)+.

Reference： [1]Patent: WO2015/38649,2015,A1 .Location in patent: Paragraph 001524

45
[ 140447-78-5 ]
(E)-6-(1-(4-bromobut-2-enoyl)piperidin-4-yl)-2-(4-phenoxyphenoxy)nicotinamide [ No CAS ]
(E)-tert-butyl (2-(4-(4-(4-(5-carbamoyl-6-(4-phenoxyphenoxy)pyridin-2-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 5h;	[00462] Crude 6- (4-Phenoxy-phenoxy)- 1?- [(E)-4- ([1,2,3] triazolo [4,5-b]pyridin-3-yloxy)-but- 2-enoyl] -1 ?,2?,3 ?,4?,5 ?,6?-hexahydro- [2,4?]bipyridinyl-5-carboxylic acid amide was combined with <strong>[140447-78-5]tert-butyl (2-(piperazin-1-yl)ethyl)carbamate</strong> (398.11 mg, 0.742 mmol, 1 eq) along with DIEA (0.366 ml, 2.23 mmol, into DMF (5 mL). The reaction was heated to 80oC for 5 hr. Heating was then removed on the solvent was removed under reduced pressure. The reaction was then purified via flash column chromatography on silica using a gradient of 0-20% MeOH/DCM to give (E)-tert-butyl (2-(4-(4-(4-(5-carbamoyl-6-(4-phenoxyphenoxy)pyridin-2-yl)piperidin- 1 -yl)4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)carbamate (33.2 mg, 22%) as a brown solid. MS: mlz =685.2 [M+H]+.

Reference： [1]Patent: WO2015/61247,2015,A2 .Location in patent: Paragraph 00462

46
C₂₁H₂₅N₃O₂ [ No CAS ]
[ 140447-78-5 ]