[ CAS No. 118753-66-5 ]

Name: 118753-66-5|tert-Butyl 4-aminopiperazine-1-carboxylate|95%
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Quality Control of [ 118753-66-5 ]

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Product Details of [ 118753-66-5 ]

CAS No. :	118753-66-5	MDL No. :	MFCD08274502
Formula :	C₉H₁₉N₃O₂	Boiling Point :	281°C at 760 mmHg
Linear Structure Formula :	-	InChI Key :	-
M.W :	201.27 g/mol	Pubchem ID :	22029174
Synonyms :

Calculated chemistry of of [ 118753-66-5 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.89
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	61.3
TPSA :	58.8 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.4 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.15
Log Po/w (XLOGP3) :	0.18
Log Po/w (WLOGP) :	-0.35
Log Po/w (MLOGP) :	0.54
Log Po/w (SILICOS-IT) :	-0.75
Consensus Log Po/w :	0.35

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.0
Solubility :	20.0 mg/ml ; 0.0993 mol/l
Class :	Very soluble
Log S (Ali) :	-0.97
Solubility :	21.4 mg/ml ; 0.106 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.21
Solubility :	125.0 mg/ml ; 0.619 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.57

Safety of [ 118753-66-5 ]

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

Application In Synthesis of [ 118753-66-5 ]

* 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 [ 118753-66-5 ]
Downstream synthetic route of [ 118753-66-5 ]

[ 118753-66-5 ] Synthesis Path-Upstream 1~5

1
[ 877177-42-9 ]
[ 118753-66-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: With acetic acid; zinc In methanol at 0 - 20℃; for 2 h; Stage #2: With sodium hydrogencarbonate In methanol; water	To a solution of the compound obtained in the above step (1) (730 mg) in methanol (10 mL) was added zinc powder (1.1 g) at room temperature and thereto was added dropwise acetic acid (10 mL) under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and to the filtrate was added an aqueous sodium hydrogencarbonate solution to basify. After stirring, the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain l-amino-4-tert- butoxycarbonylpiperazine (730 mg, yield: 100 percent) as a pale yellow oil.
58%	With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 25℃; for 12 h;	To a solution of 1 ,1 -dimethylethyl 4-nitroso-1 -piperazinecarboxylate (500 mg, 2.33 mmol) in THF (23 mL) at O0C was added dropwise a solution of LAH (5.8 mL, 5.8 mmol, 1 M in THF). The reaction mixture warmed to 25°C over 12h and was subsequently quenched by dropwise addition of a saturated solution of potassium sodium tartrate. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4) and concentrated at 250C yielding a yellow oil that was used without further purification (270 mg, 58percent): LCMS (ES) m/e 202 (M+H)+.

Reference： [1] Patent: WO2007/46550, 2007, A1, . Location in patent: Page/Page column 120
[2] Patent: WO2006/20561, 2006, A2, . Location in patent: Page/Page column 61
[3] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 247 - 258

2
[ 883554-88-9 ]
[ 118753-66-5 ]

Reference： [1] Patent: US2009/275594, 2009, A1, . Location in patent: Page/Page column 19

3
[ 24424-99-5 ]
[ 30651-60-6 ]
[ 118753-66-5 ]

Reference： [1] Patent: US2003/199689, 2003, A1, . Location in patent: Page/Page column 76

4
[ 118753-70-1 ]
[ 118753-66-5 ]

Reference： [1] Patent: US4839358, 1989, A,

5
[ 57260-71-6 ]
[ 118753-66-5 ]

Reference： [1] Patent: WO2015/22663, 2015, A1,
[2] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 247 - 258

[ 118753-66-5 ] Synthesis Path-Downstream 1~31

1
[ 118753-66-5 ]
[ 443956-14-7 ]
[ 877177-43-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	With benzotriazol-1-ol; 1,2-dichloro-ethane; In dichloromethane; N,N-dimethyl-formamide; for 12.0h;	To a solution of 1 ,1-dimethylethyl 4-amino-1 -piperazinecarboxylate (270 mg, 1.34 mmol) in DCM-DMF (4:1 , 15 ml_) were added 3-oxo-3,4-dihydro-2H-pyrido[3,2- i?][1 ,4]thiazine-6-carboxylic acid (283 mg, 1.34 mmol), EDC (250 mg, 1.61 mmol) and HOBT (217 mg, 1.61 mmol). After 12h, the solution was concentrated and the residue purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound as a yellow foam (412 mg, 78 %): LCMS (ES) m/e 394 (M+H)+.

Reference： [1]Patent: WO2006/20561,2006,A2 .Location in patent: Page/Page column 62

2
[ 24424-99-5 ]
[ 30651-60-6 ]
[ 118753-66-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 16.0h;	(i) 4-Amino-piperazine-1-carboxylic acid tert-butyl ester To a solution of Piperazin-1-ylamine in 20 ml THF and 1.37 ml NEt3, 2.2 g Boc2O in 5 ml THF were added dropwise at 0 C. The reaction mixture was stirred for 16 h at RT then 50 ml ethyl acetate and 20 ml water were added. The organic layer was separated, washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure the product was obtained as a white solid. Yield: 1.53 g.

Reference： [1]Patent: US2003/199689,2003,A1 .Location in patent: Page/Page column 76

3
[ 118753-70-1 ]
[ 118753-66-5 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; hydrazine hydrate;	Step B: Tertbutyl 4-amino-1-piperazine carboxylate Under an inert atmosphere at ambient temperature, 15.3 g of the product of Step A and 80 ml of hydrazine hydrate were mixed together and then 150 ml of a saturated aqueous solution of ammonium chloride were added. Extraction was done with methylene chloride and the organic phase was washed with an aqueous solution of ammonium chloride, dried, and the solvent was eliminated under reduced pressure. After chromatography on silica (eluent:methylene chloride - methanol, 100/7) 5 g of the expected product were obtained.

Reference： [1]Patent: US4839358,1989,A

4
[ 118753-66-5 ]
[ 350-46-9 ]
[ 333986-61-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; water;	(1) <strong>[118753-66-5]4-Amino-1-tert-butoxycarbonylpiperazine</strong> (3.00 g), 4-fluoronitrobenzene (2.54 g) and N,N-diisopropylethylamine (8.82 g) were dissolved in N-methyl-2-pyrrolidone (30 mL), and the mixture was stirred at 80C for 18 hr. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-tert-.butoxycarbonyl-4-(4-nitrophenyl)aminopiperidine (2.55 g) as a white solid.

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

5
[ 118753-66-5 ]
[ 935259-85-1 ]
3-[N-(4-tert-butoxycarbonylpiperazin-1-yl)-carbamoyl]-1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With benzotriazol-1-ol; triethylamine; In dichloromethane; at 20℃;	To a solution of 3-carboxyl-l-(2-chlorophenyl)-5-(4-chlorophenyl)-4- EPO <DP n="52"/>methoxy-lH-pyrazole (1.96 g, compound obtained in Reference Example 1(6)) in methylene chloride (20 mL) was added l-amino-4-tert-butoxycarbonylpiperazine (730 mg, compound obtained in Reference Example 16(2)), water-soluble carbodiimide HCl (1.0 g), 1-hydroxybenzotriazole hydrate (827 mg) and triethylamine (753 muL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate = 60/40 to 40/60) to obtain 3-[N-(4-tert-butoxycarbonylpiperazin-l-yl)- carbamoyl] -l-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-lH-pyrazole (1.56 g; yield: 79 %) as a colorless solid. MS(APCI)m/z; 546/548 [M+H]+

Reference： [1]Patent: WO2007/46550,2007,A1 .Location in patent: Page/Page column 49-50

6
[ 877177-42-9 ]
[ 118753-66-5 ]

Yield	Reaction Conditions	Operation in experiment
100%		To a solution of the compound obtained in the above step (1) (730 mg) in methanol (10 mL) was added zinc powder (1.1 g) at room temperature and thereto was added dropwise acetic acid (10 mL) under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and to the filtrate was added an aqueous sodium hydrogencarbonate solution to basify. After stirring, the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain l-amino-4-tert- butoxycarbonylpiperazine (730 mg, yield: 100 %) as a pale yellow oil.
96%	With ammonium chloride; zinc; In tetrahydrofuran; water; at 20℃;	To a stirred solution of tert-butyl 4-nitrosopiperazine--carboxylate (0 500 g, 2 32 mmol, 1 equiv) in THF: H20 (10: 10 mL) was added NLLCl (1.98 g, 37. 17 mmol, 16.0 equiv) and then Zn dust (1.21 g, 18.58 mmol, 8.0 equiv) was added portion wise. After completion of addition the reaction mixture was stirred at RT for overnight. Progress of the reaction was monitored by LCMS Reaction mixture was diluted with water (100 mL) and filtered off over celite bed and filtrate was extracted with DCM (100 mL c 2) Organic layer was separated and dried over anhydrous NarSCrt and concentrated under reduced pressure to obtain tert-butyl 4- aminopiperazine-l-carboxylate (0.420 g, 96 % Yield) as a yellow semi solid. LCMS 202.3 i M l l f : T-I NMR (400MHz, Chloroform-d) d 3.47 (br s , 4 H), 3.14 (br. s? 2 H), 2 56 (br. s., 4 H), 1.45 (s, 9 H).
86%	With acetic acid; zinc; In methanol; at 0 - 20℃; for 2.0h;Inert atmosphere;	1-Boc-4-nitrosopiperazine (1.46 g, 6.8 mmol) was dissolved in 10 mL of methanol at room temperature,Zinc powder (2.20 g, 33.8 mmol) was added, cooled to 0 C, acetic acid (20 mL) was slowly added dropwise, and then heated to room temperature under nitrogen protection and stirred for 2 hours.After the reaction was completed, the solution was filtered, and the pH was adjusted to 9-10 with a saturated sodium bicarbonate aqueous solution, and 40 mL of water was added.Extract three times with 180 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter,Spin-drying and purification to obtain compound 1-Boc-4-aminopiperazine (1.18 g, yield 86%)

58%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 25℃; for 12.0h;	To a solution of 1 ,1 -dimethylethyl 4-nitroso-1 -piperazinecarboxylate (500 mg, 2.33 mmol) in THF (23 mL) at O0C was added dropwise a solution of LAH (5.8 mL, 5.8 mmol, 1 M in THF). The reaction mixture warmed to 25C over 12h and was subsequently quenched by dropwise addition of a saturated solution of potassium sodium tartrate. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4) and concentrated at 250C yielding a yellow oil that was used without further purification (270 mg, 58%): LCMS (ES) m/e 202 (M+H)+.
	With acetic acid; zinc; In water; at 0℃; for 5.0h;	General procedure: To a well-stirred solution of an appropriate intermediate (7a-e) (0.10mol) in a mixed solution of AcOH (100mL) and H2O (100mL) was added zinc powder (26.2g,0.40mol) at 0C, followed by stirring for 6-8hat the same temperature. After completion of the reaction as indicated by TLC, the resulted mixture was filtered and the filtrate was concentrated under reduced pressure. Then ethyl acetate (100mL) was added and the misture was stirred for 0.5hat the room temperature. The mixture was filtered, and the filtrate was concentrated under reduced presusre to yield the corresponding intermediates 8a-e.
	With hydrogenchloride; zinc; In methanol; water; at 0℃; for 0.5h;	(0680) In a 100 ml round-bottomed flask was added Compound 232A (0.15 g) and zinc (1 g) in water/methanol (1:1, 10 ml) to give a suspension. The mixture was cooled to 0 C. 12N Aqueous HCl (2 ml) was added slowly, and the mixture was stirred at 0 C. for 30 minutes. 2N Aqueous NaOH solution was used to adjust the mixture to basic pH. The mixture was filtered, and extracted with ether (3×30 ml). After drying over Na2SO4, filtration, and concentration, the crude product was added to a silica gel column (Analogix, SF15-12 g,) and purified by eluting with 0-25% ethyl acetate in hexane.

Reference： [1]Patent: WO2007/46550,2007,A1 .Location in patent: Page/Page column 120
[2]Patent: WO2019/236710,2019,A1 .Location in patent: Paragraph 0286
[3]Patent: CN110483514,2019,A .Location in patent: Paragraph 0395; 0399; 0402; 0403
[4]Patent: WO2006/20561,2006,A2 .Location in patent: Page/Page column 61
[5]European Journal of Medicinal Chemistry,2018,vol. 158,p. 247 - 258
[6]Patent: US10213433,2019,B2 .Location in patent: Page/Page column 162
[7]European Journal of Medicinal Chemistry,2020,vol. 185

7
[ 118753-66-5 ]
[ 534595-43-2 ]
4-({1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-amino)-piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(ii) 4-({1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carbonyl}-amino)-piperazine-1-carboxylic acid tert-butyl ester To a solution of 1 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid and 1.3 ml NEM in 8 ml DCM, 914 mg TOTU were added and the mixture was stirred for 30 min at RT. Then 673 mg <strong>[118753-66-5]4-Amino-piperazine-1-carboxylic acid tert-butyl ester</strong> were added and the reaction was stirred over night. After removal of the solvent under reduced pressure the residue was directly purified by chromatography on silica gel eluding with an ethyl acetate/heptane gradient. Yield: 1.1 g.

Reference： [1]Patent: US2003/199689,2003,A1 .Location in patent: Page/Page column 76

8
[ 118753-66-5 ]
[ 541-41-3 ]
C₁₂H₂₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To Compound 33 prepared as in Intermediate Example 1 (8.29 g, 41.2 mmol) and pyridine (6.0 mL, 74.2 mmol) in MeCN (120 mL) was added dropwise ethyl chloroformate (5.9 mL, 61.9 mmol). The resulting mixture was stirred at room temperature for 3 h, then partitioned between EtOAc and saturated aqueous NaHCO3, dried with Na2SO4, and concentrated in vacuo to yield a residue, which was used in the next step without further purification. MS 274 (M+1)+

Reference： [1]Patent: US2009/275594,2009,A1 .Location in patent: Page/Page column 19

9
[ 883554-88-9 ]
[ 118753-66-5 ]

Yield	Reaction Conditions	Operation in experiment
		The white solid from step A in ethanol (50 mL) was cooled to 0 C., and a pre-mixed solution of NaOCl (10-13% active chlorine, 43.4 mL) and 15% NaOH (78.0 mL) was added dropwise via an addition funnel. The ice bath was removed and the resulting mixture was stirred at room temperature for 1 h. 1N HCl was added to the resulting mixture until the pH of the solution was about pH 1, and the resulting mixture was stirred at room temperature for an additional 15 min. The pH of the solution was made basic with saturated aqueous potassium carbonate, and the resulting solution concentrated in vacuo to half the volume, then extracted three times with EtOAc, the combined organics were dried with Na2SO4, and concentrated in vacuo to yield the title compound, which was used in the next step without further purification. MS 202 (M+1)+

Reference： [1]Patent: US2009/275594,2009,A1 .Location in patent: Page/Page column 19

10
[ 118753-66-5 ]
[ 1452467-35-4 ]

Reference： [1]Patent: US2013/225554,2013,A1
[2]Patent: WO2014/91268,2014,A1

11
[ 118753-66-5 ]
[ 1452467-36-5 ]

Reference： [1]Patent: US2013/225554,2013,A1
[2]Patent: WO2014/91268,2014,A1

12
[ 118753-66-5 ]
[ 1174020-25-7 ]
[ 1452467-34-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	Step 1. tert-butyl 4-([(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate (206) To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.17 g, 0.615 mmol) in dry DCM (10 mL) were added <strong>[118753-66-5]tert-butyl 4-aminopiperazine-1-carboxylate</strong> 205 (0.19 g, 0.923 mmol), 1-hydroxybenzotriazole (0.125 g, 0.923 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.177 g, 0.923 mmol) and 4-dimethylaminopyridine (0.113 g, 0.923 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 4-([(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 206 (0.25 g, 88%) as a clear thick oil. 1H NMR (400 MHz, CDCl3): delta 1.46 (9H, s), 1.62 (1H, m), 1.95 (2H, m), 2.38 (1H, m), 2.70 (1H, d, J=12.0 Hz), 2.76 (4H, m), 2.99 (1H, d, J=12.0 Hz), 3.30 (1H, m), 3.57 (4H, m), 3.89 (1H, d, J=8.0 Hz), 4.90 (1H, d, J=11.6 Hz), 5.04 (1H, d, J=12.0 Hz), 7.21 (5H, m), 8.90 (1H, br s).
88%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.17 g, 0.615 mmol) in dry DCM (10 mL) were added te/f-butyl 4-aminopiperazine-1-carboxylate 205 (0.19 g, 0.923 mmol), 1-hydroxybenzotriazole (0.125 g, 0.923 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.177 g, 0.923 mmol) and 4- dimethylaminopyridine (0.113 g, 0.923 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give terf-butyl 4-([(2S,5R)-6-(benzyloxy)-7-oxo- 1 ,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 206 (0.25 g, 88%) as a clear thick oil. 1H NMR (400 MHz, CDCl3): delta 1.46 (9H, s), 1.62 (1 H, m), 1.95 (2H, m), 2.38 (1 H, m), 2.70 (1 H, d, J = 12.0Hz), 2.76 (4H, m), 2.99(1H, d, J = 12.0 Hz), 3.30 (1 H, m), 3.57 (4H, m), 3.89 (1 H, d, J = 8.0 Hz), 4.90 (1H, d, J = 11.6 Hz), 5.04 (1 H, d, J = 12.0 Hz), 7.21 (5H, m), 8.90 (1 H, br s).

Reference： [1]Patent: US2013/225554,2013,A1 .Location in patent: Paragraph 1239; 1240; 1241
[2]Patent: WO2014/91268,2014,A1 .Location in patent: Page/Page column 215

13
[ 118753-66-5 ]
[ 853908-81-3 ]
tert-butyl 4-((6-bromo-7-fluoro-3-nitroquinolin-4-yl)amino)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30 g	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.0h;	[00229] Step-3: Synthesis tert-butyl 4-((6-bromo-7-fluoro-3-nitroquinolin-4- yl)amino) piperazine- 1 -carboxylate, 4: [00230] DIPEA (26.72mL, 0.15712mo1) was added to a stirred solution of 6- Bromo-4-chloro-7-fluoro-3-nitroquinoline, 9 (24g, 0.07856mo1) and <strong>[118753-66-5]tert-butyl 4-aminopiperazine-1-carboxylate</strong> (18.97g, 0.09427mo1) in DMF, 200mL at 0 00. The reaction mixture was allowed to room temperature and stirred for 2h. Reaction was monitored by TLC (30%EtOAc in hexane), after completion of reaction, diluted with water (l5OmL), the precipitated yellow solid was filtered-off, washed with water and dried under vacuum. The crude material was purified by column chromatography by using5i02 (15% EtOAc in Hexane) to afford of tert-butyl4-((6-bromo-7-fluoro-3-nitroquinolin-4- yl) amino) piperazine-1-carboxylate, 4 (30g, 81%). 1H NMR (300MHz, CDCI3): O 10.42 (5, 1H), 10.22-10.19 (d, 1H), 9.36 (5, 1H), 7.67-7.64 (d, 1H), 4.35-4.25 (t, 2H), 3.46-3.08 (t, 4H), 2.84-2.65 (t, 2H), 1.50 (5, 9H); LCMS: mlz= 469.9 (M+1) and 471.9 (M+2).

Reference： [1]Patent: WO2015/22663,2015,A1 .Location in patent: Paragraph 00229; 00230

14
[ 57260-71-6 ]
[ 118753-66-5 ]

Reference： [1]Patent: WO2015/22663,2015,A1
[2]European Journal of Medicinal Chemistry,2018,vol. 158,p. 247 - 258
[3]Patent: US10213433,2019,B2
[4]European Journal of Medicinal Chemistry,2020,vol. 185
[5]Patent: CN110483514,2019,A

15
tert-butyl 4-nitropiperazine-1-carboxylate [ No CAS ]
[ 118753-66-5 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; zinc; In tetrahydrofuran; water; for 0.5h;	[00227] Step-2: Synthesis of tert-butyl 4-aminopiperazine-1-carboxylate, 3:[00228] To a stirred solution of tert-butyl 4-nitropiperazine-1-carboxylate, 2 (22g, 0.09513mo1) in THF (200mL), a saturated solution of NH4CI (81.4g, 1.521mo1 in water l5OmL) was added. Zn (49.7g, 0.760mo1) was added portion wise and the resulting suspension was stirred for 30mm. The reaction was monitored by TLC (10% MeOH in DCM). The reaction mass was filtered through celite-pad and washed withDCM. The Aqueous layer was extracted with DCM (3x 200mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2504 and concentrated to dryness to afford crude tert-butyl 4-aminopiperazine-1-carboxylate, 3 (18g, 83%). 1H NMR (DMSO-d6, 400MHz): O 3.29-3.19 (m, 4H), 2.55-2.62 (m, 2H), 2.45-2.38 (m, 2H), 1.38 (5, 9H).

Reference： [1]Patent: WO2015/22663,2015,A1 .Location in patent: Paragraph 00227; 00228

16
[ 118753-66-5 ]
tert-butyl 4-((3-amino-6-bromo-7-fluoroquinolin-4-yl)amino)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/22663,2015,A1

17
[ 118753-66-5 ]
tert-butyl 4-(8-bromo-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/22663,2015,A1

18
[ 118753-66-5 ]
tert-butyl 4-(8-(2-chloro-4-(pyrimidin-2-yloxy)phenyl)-7-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/22663,2015,A1

19
[ 118753-66-5 ]
[ 108-12-3 ]
C₁₄H₂₇N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
120 mg	With N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; for 3.0h;	(1) The compound 1 (100 mg) and diisopropylethylamine (240 mL) were dissolved in chloroform, isovaleryl chloride(217 mL) was added to the solution, and the reaction mixture was stirred for 3 hours at room temperature. Thereaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate, and extracted twice withchloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The resulting residue was suspended and washed in a mixed solution of ethyl acetate-hexane,taken by filtration, and dried to give the compound 2 (120 mg) as a colorless solid.MS (APCI) 286 [M+H]+

Reference： [1]Patent: EP3135668,2017,A1 .Location in patent: Paragraph 0346

20
[ 118753-66-5 ]
4-(4-chloro-6-(thiophen-2-yl)-1,3,5-triazin-2-yl)morpholine [ No CAS ]
tert-butyl 4-(4-morpholino-6-(thiophen-2-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16.0h;	General procedure: Chloro derivative (1 mol), amine (1 mol) and K2CO3 (2mol) were taken in DMF (10 v). The reaction mixture washeated to 100 C, stirred for 16 h. Then the reaction mixturewas cooled to room temperature, diluted with water (50 v) extracted with EtOAC (2 x 50 v). Combined organic layerswere dried over anhydrous sodium sulphate, evaporated thesolvent in vacuo. Crude products were purified by columnchromatography.

Reference： [1]Letters in drug design and discovery,2018,vol. 15,p. 181 - 192

21
[ 118753-66-5 ]
[ 843647-60-9 ]
N-{3-{2-fluoro-4'-[(4-tert-butoxycarbonylpiperazin-1-yl)iminomethyl]-biphenyl-4-yl}-2-oxo-1,3-oxazolidine-5-(S)-ylmethyl}-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		General procedure: To a well-stirred solution of intermediate 5 (2g, 5.6mmol) in C2H5OH(60mL) was added a drop of AcOH. The resulted mixture was refluxed for 0.5h. Then intermediates 8a (2.95g) was added, followed by stirring for 10hat the same temperature. After cooled to room temperature, The resulting solid was collected by filtration and dried to give the target compounds 9a as a light yellow solid in 82% yield.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 158,p. 247 - 258

22
[ 118753-66-5 ]
(S)-N-(3-(2-fluoro-3'-hydroxy-4'-formylbiphenyl-4-yl)-2-oxo-1,3-oxazolidine-5-yl)acetamide [ No CAS ]
(S)-N-(3-(2-fluoro-3'-hydroxy-4’-((4-tert-butoxycarbonylpiperazin-1-yl)iminomethyl)biphenyl-4-yl)-2-oxo-1,3-oxazolidine-5-ylmethyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With acetic acid; In ethanol; at 78℃; for 2.0h;	General procedure: To a well-stirred solution of intermediate 5a (2.0 g,5.29 mmol) in ethanol (10 mL) was added 1-amino-4-methylpiperazine 9a (0.61 g, 5.29 mmol) and a drop of acetic acid,and the mixturewas stirred at 78 C for 2 h. The mixturewas cooledto room temperature and the resulting solid was collected byfiltration and purified by column chromatography to give the targetcompounds 6a-1 as a yellow solid in 75% yield. M.p: 228-230 C;