Name: 50606-31-0|Methyl piperazine-1-carboxylate|98%
Brand: Ambeed
SKU: A679667
Price: 17.0 USD
Availability: InStock
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1
[ 110-85-0 ]
[ 50606-31-0 ]

Reference： [1]Journal of Organic Chemistry,1948,vol. 13,p. 134,138

2
[ 106-31-0 ]
[ 50606-31-0 ]
4-butyryl-piperazine-1-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1954,vol. 76,p. 6078

3
[ 50606-31-0 ]
[ 7560-85-2 ]

Reference： [1]Journal of Organic Chemistry,1948,vol. 13,p. 134,138

4
[ 50606-31-0 ]
[ 255375-04-3 ]
4-[3-(3-cyano-phenyl)-2-(2,4,6-triisopropyl-benzenesulfonylamino)-propionyl]-piperazine-1-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 3147 - 3152

5
[ 50606-31-0 ]
[ 256430-57-6 ]
C₃₃H₄₇N₅O₇S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 3147 - 3152

6
[ 110-85-0 ]
[ 17175-16-5 ]
[ 50606-31-0 ]
[ 14609-74-6 ]

Reference： [1]Journal of Organic Chemistry,2002,vol. 67,p. 8911 - 8916

7
[ 75-44-5 ]
[ 50606-31-0 ]
[ 253175-62-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3229 - 3233
[2]Patent: US6335324,2002,B1 .Location in patent: Page column 68

8
[ 219509-79-2 ]
[ 50606-31-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3229 - 3233
[2]Patent: US6335324,2002,B1 .Location in patent: Page column 68
[3]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2807 - 2810
[4]Organic and Biomolecular Chemistry,2012,vol. 10,p. 6420 - 6431

9
[ 890300-37-5 ]
[ 50606-31-0 ]
4-{6-[(3,3'-difluoro-2'-methoxycarbonyl-biphenyl-4-ylmethyl)-amino]-pyridine-3-carbonyl}-piperazine-1-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2791 - 2795

10
[ 50606-31-0 ]
sodium 1-[4-(methoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 4356 - 4366

11
[ 50606-31-0 ]
4-[(2S,3R)-2-Carboxy-3-(3-guanidino-propyl)-4-oxo-azetidine-1-carbonyl]-piperazine-1-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3229 - 3233

12
[ 50606-31-0 ]
[ 253175-63-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3229 - 3233

13
[ 50606-31-0 ]
4-[3-(3-thiocarbamoyl-phenyl)-2-(2,4,6-triisopropyl-benzenesulfonylamino)-propionyl]-piperazine-1-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 3147 - 3152

14
[ 50606-31-0 ]
4-[3-(3-carbamimidoyl-phenyl)-2-(2,4,6-triisopropyl-benzenesulfonylamino)-propionyl]-piperazine-1-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 3147 - 3152
[2]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 3147 - 3152

15
[ 50606-31-0 ]
4-[3-(3-methylsulfanylcarbonimidoyl-phenyl)-2-(2,4,6-triisopropyl-benzenesulfonylamino)-propionyl]-piperazine-1-carboxylic acid methyl ester; hydriodide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 3147 - 3152

17
[ 50606-31-0 ]
[ 3958-57-4 ]
[ 873697-63-3 ]

Yield	Reaction Conditions	Operation in experiment
66%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 5 - 30℃; for 22.3333h;Heating / reflux;	Example 4; Step 1; A 3-neck round bottom flask was purged with nitrogen for at least ten minutes. The flask was charged with 1.0 eq of 4A, CH2Cl2 (about 1.2 M 4A in DCM), and about 1. I eq of DIPEA. The flask was then cooled to 10+/-5 C. While the flask was cooling, 1.2 eq of <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> was taken up in CH2Cl2 (about 5.3 M). The material did not go into solution, so an additional 0.05 eq of DIPEA in DCM (about 0.3 M) was added. The material did not go into solution, and the suspension was then added dropwise over 50 min, maintaining an internal reaction temperature 30 C. The cooling bath was removed and the reaction mixture was warmed to reflux. The reaction mixture was maintained at reflux for 19 hours. An additional 0.05 eq <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> was added, and the reaction was refluxed for another 2.5 hours. The reaction was cooled to RT and washed with 5 volumes of water. The water layer was back-extracted with 5 volumes of CH2Cl2. The combined organic layers were washed with 5 volumes of 10% AcOH/water. The organic layer was then washed with 5 volumes of saturated sodium bicarbonate and 5 volumes of brine. The organic layer was dried over sodium sulfate, filtered and concentrated via rotavap at 30+/-5 C. to a residue. MTBE was charged to the rotavap flask at 20+/-5 C. and the flask was rotated until a solution had been achieved. Hexane was charged into the flask and the solution stirred for 2.5 hours at 20+/-5 C. The solids were filtered and rinsed with hexanes. The solids were dried at 40 C. under maximum vacuum until constant mass was achieved (22 hours) to afford 4B as a pale yellow solid (66% yield).
66%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 10 - 30℃; for 22.3333h;Heating / reflux;	A 3-neck round bottom flask was purged with nitrogen for at least ten minutes. The flask was charged with 1.0 eq of 4A, CH2Cl2 (about 1.2 M 4A in DCM), and about 1.1 eq of DIPEA. The flask was then cooled to 10+/-5C. While the flask was cooling, 1.2 eq of <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> was taken up in CH2CI2 (about 5.3 M) .The material did not go into solution, so an additional 0.05 eq of DBPEA in DCM (about 0.3 M) was added. The material did not go into solution, and the suspension was then added dropwise over 50 min, maintaining an internal reaction temperature < 300C. The cooling bath was removed and the reaction mixture was warmed to reflux. The reaction mixture was maintained at reflux for 19 hours. An additional 0.05 eq <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> was added, and the reaction was refluxed for <n="63"/>another 2.5 hours. The reaction was cooled to RT and washed with 5 volumes ofwater. The water layer was back-extracted with 5 volumes Of CH2Cl2. The combined organic layers were washed with 5 volumes of 10% AcOH/water. The organic layer was then washed with 5 volumes of saturated sodium bicarbonate and 5 volumes of brine. The organic layer was dried over sodium sulfate, filtered and concentrated via rotavap at 30+/-5C to a residue. MTBE was charged to the rotavap flask at 20+/-5C and the flask was rotated until a solution had been achieved. Hexane was charged into the flask and the solution stirred for 2.5 hours at 20+/-5C. The solids were filtered and rinsed with hexanes. The solids were dried at <40C under maximum vacuum until constant mass was achieved (~22 hours) to afford 4B as a pale yellow solid (66% yield).
66%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 30℃;Heating/reflux;	EXAMPLE 4; Step 1 A 3-neck round bottom flask was purged with nitrogen for at least ten minutes. The flask was charged with 1.0 eq of 4A, CH2Cl2 (about 1.2 M 4A in DCM), and about 1.1 eq of DIPEA. The flask was then cooled to 10+/-5 C. While the flask was cooling, 1.2 eq of <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> was taken up in CH2Cl2 (about 5.3 M). The material did not go into solution, so an additional 0.05 eq of DIPEA in DCM (about 0.3 M) was added. The material did not go into solution, and the suspension was then added dropwise over 50 min, maintaining an internal reaction temperature 30 C. The cooling bath was removed and the reaction mixture was warmed to reflux. The reaction mixture was maintained at reflux for 19 hours. An additional 0.05 eq <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> was added, and the reaction was refluxed for another 2.5 hours. The reaction was cooled to RT and washed with 5 volumes of water. The water layer was back-extracted with 5 volumes of CH2Cl2. The combined organic layers were washed with 5 volumes of 10% AcOH/water. The organic layer was then washed with 5 volumes of saturated sodium bicarbonate and 5 volumes of brine. The organic layer was dried over sodium sulfate, filtered and concentrated via rotavap at 30+/-5 C. to a residue. MTBE was charged to the rotavap flask at 20+/-5 C. and the flask was rotated until a solution had been achieved. Hexane was charged into the flask and the solution stirred for 2.5 hours at 20+/-5 C. The solids were filtered and rinsed with hexanes. The solids were dried at 40 C. under maximum vacuum until constant mass was achieved (22 hours) to afford 4B as a pale yellow solid (66% yield).

66%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 21.5h;Heating / reflux;	A 3-neck round bottom flask was purged with nitrogen for at least ten minutes.The flask was charged with 1.0 eq of 4A, CH2Cl2 (about 1.2 M 4A in DCM), and about 1.1 eq of <n="50"/>09367-0149DIPEA. The flask was then cooled to 10+/-5C. While the flask was cooling, 1.2 eq of <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> was taken up in CH2Cl2 (about 5.3 M) .The material did not go into . solution, so an additional 0.05 eq of DIPEA in DCM (about 0.3 M) was added. The material did not go into solution, and the suspension was then added dropwise over 50 min, maintaining an internal reaction temperature < 300C. The cooling bath was removed and the reaction mixture was warmed to reflux. The reaction mixture was maintained at reflux for 19 hours. An additional 0.05 eq <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> was added, and the reaction was refluxed for another 2.5 hours. The reaction was cooled to RT and washed with 5 volumes ofwater. The water layer was back-extracted with 5 volumes of CH2CI2. The combined organic layers were washed widi 5 volumes of 10% AcOH/water. The organic layer was then washed with 5 volumes of saturated sodium bicarbonate and 5 volumes of brine. The organic layer was dried over sodium sulfate, filtered and concentrated via rotavap at 30+/-5C to a residue. MTBE was charged to the rotavap flask at 20+/-5C and the flask was rotated until a solution had been achieved. Hexane was charged into the flask and the solution stirred for 2.5 hours at 20+/-5C. The solids were filtered and rinsed with hexanes. The solids were dried at <40C under maximum vacuum until constant mass was achieved (~22 hours) to afford 4B as a pale yellow solid (66% yield).
66%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 5 - 30℃; for 22.33h;Heating / reflux;	A 3 -neck round bottom flask was purged with nitrogen for at least ten minutes.The flask was charged with 1.0 eq of 4 A, CH2Cl2 (about 1.2 M 4A in DCM), and about Ll eq of DIPEA. The flask was then cooled to 10+/-5C. While the flask was cooling, 1.2 eq of <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> was taken up in CH2Cl2 (about 5.3 M) The material did not go into solution, so an additional 0.05 eq of DIPEA in DCM (about 0.3 M) was added. The material did not go into solution, and the suspension was then added dropwise over 50 min, maintaining an internal reaction temperature < 300C. The cooling bath was removed and the reaction mixture was warmed to reflux. The reaction mixture was maintained at reflux for 19 hours. An additional 0.05 eq methyl pipera,zine-l-carboxylate was added, and the reaction was refluxed for another 2.5 hours. The reaction was cooled to RT and washed with 5 volumes ofwater. The water layer was back-extracted with 5 volumes of CH2Cl2. The <n="93"/>combined organic layers were washed with 5 volumes of 10% AcOH/water. The organic layer was then washed with 5 volumes of saturated sodium bicarbonate and 5 volumes of brine. The organic layer was dried over sodium sulfate, filtered and concentrated via rotavap at 30+/-5C to a residue. MTBE was charged to the rotavap flask at 20+/-5C and the flask was rotated until a solution had been achieved. Hexane was charged into the flask and the solution stirred for 2.5 hours at 20+/-5C. The solids were filtered and rinsed with hexanes. The solids were dried at <40C under maximum vacuum until constant mass was achieved (-22 hours) to afford 4B as a pale yellow solid (66% yield).
66%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 10℃; for 22.33h;Heating / reflux;	Example 4 Step 1. A 3-neck round bottom flask was purged with nitrogen for at least ten minutes.The flask was charged with 1.0 eq of 4A, CH2Cl2 (about 1.2 M 4A in DCM), and about 1.1 eq of DIPEA. The flask was then cooled to 10+/-5C. While the flask was cooling, 1.2 eq of <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> was taken up in CH2CI2 (about 5.3 M) The material did not go into solution, so an additional 0.05 eq of DIPEA in DCM (about 0.3 M) was added. The material did not go into solution, and the suspension was then added dropwise over 50 min, maintaining an internal reaction temperature < 300C. The cooling bath was removed and the reaction mixture was warmed to reflux. The reaction mixture was maintained at reflux for 19 hours. An additional 0.05 eq <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> was added, and the reaction was refluxed for another 2.5 hours. The reaction was cooled to RT and washed with 5 volumes ofwater. The water layer was back-extracted with 5 volumes of CH2CI2. The combined organic layers were washed with 5 volumes of 10% AcOH/water. The organic layer was then washed with 5 volumes of saturated sodium bicarbonate and 5 volumes of brine. The organic layer was dried over sodium sulfate, filtered and concentrated via rotavap at 30+/-5C to a residue. MTBE was charged to the rotavap flask at 20+/-5C and the flask was rotated until a solution had been achieved. Hexane was charged into the flask and the solution stirred for 2.5 hours at 20+/-5C. The solids were filtered and rinsed with hexanes. The solids were dried at <40C under maximum vacuum until constant mass was achieved (-22 hours) to afford 4B as a pale yellow solid (66% yield).

Reference： [1]Patent: US2006/14761,2006,A1 .Location in patent: Page/Page column 34
[2]Patent: WO2007/75377,2007,A2 .Location in patent: Page/Page column 61-62
[3]Patent: US2009/192168,2009,A1 .Location in patent: Page/Page column 21
[4]Patent: WO2007/70626,2007,A2 .Location in patent: Page/Page column 48-49
[5]Patent: WO2007/70683,2007,A2 .Location in patent: Page/Page column 91-92
[6]Patent: WO2007/78839,2007,A2 .Location in patent: Page/Page column 49-50

18
[ 50606-31-0 ]
[ 873697-69-9 ]
[ 943732-45-4 ]
[ 942224-53-5 ]

Yield	Reaction Conditions	Operation in experiment
50%		Example 3; Step 3; Steps S3A/B; A solution 1 eq of 3C, tetrahydrofuran (about 1.4 M 3C in THF) and 1.05 eq of <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> and was allowed to stir at ambient temperature for 3 hours. To the reaction mixture was added 1.5 eq of sodium triacetoxyborohydride portionwise over 40 min, maintaining an internal reaction temperature below 45 C. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was added 5 volumes of water dropwise, over 1 hour, maintaining an internal reaction temperature below 30 C. Ethyl acetate (EtOAc, 5 volumes) was then added, and the layers were separated. The aqueous layers were back extracted with 5 volumes of EtOAc. The combined organic layers were washed with saturated sodium bicarbonate and solid sodium bicarbonate was added as needed to bring the pH to 8 (pHydrion papers). The layers were separated, and the organic layer was washed with 5 volumes of brine. The organic layer was dried over sodium sulfate and activated carbon was added in the drying step. The organics were filtered through celite and the celite pad was rinsed 4 times with EtOAc. The organics were concentrated and dried overnight on the rotavap (30 in Hg at RT) to afford an amber-brown oil.

Reference： [1]Patent: US2006/14761,2006,A1 .Location in patent: Page/Page column 33

19
[ 383865-57-4 ]
[ 50606-31-0 ]
4-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-piperazine-1-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		4-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-piperazine-1-carboxylic acid methyl ester Using <strong>[383865-57-4]4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine</strong> and piperazine-1-carboxylic acid methyl ester the title compound was obtained as white solid (90%). MS: m/e=436 (M+H+).

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

20
[ 50606-31-0 ]
[ 3312-04-7 ]
1-Carbomethoxy-4-[4,4-bis(p-fluorophenyl)butyl]piperazine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In ethanol; water; ethanol-diethyl ether;	EXAMPLE 3 1-Carbomethoxy-4-[4,4-bis(p-fluorophenyl)butyl]piperazine hydrochloride To a solution of 4.3 g (0.03 mole) 1-carbomethoxypiperazine in 10 ml of ethanol was added 10.0 g (0.036 mole) of 4-chloro-1,1-bis-(p-fluorophenyl)-butane and 5.0 g of sodium bicarbonate. The mixture was heated at reflux for 36 hours. 100 ml of water was added. The mixture was extracted twice with Et2 O. The combined extracts were dried over sodium sulphate and concentrated. The residue was dissolved in ethanol-ether and the hydrochloride was precipitated with ethanolic HCl. The solid was collected by filtration and recrystallized from propan-2-ol to give 2.2 g of 1-carbomethoxy-4-[4,4-bis(p-fluorophenyl)butyl]-piperazine hydrochloride. Melting point 192-193 C.

Reference： [1]Patent: US4624953,1986,A

21
methyl 4-benzylpiperazine-1-carboxylate [ No CAS ]
[ 50606-31-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium; In ethanol;	EXAMPLE 2 1-Carbomethoxypiperazine 34.0 g (0.15 mole) of 1-carbomethoxy-4-benzylpiperazine dissolved in 300 ml of ethanol was treated with hydrogen over a palladium catalyst at 40 psi and room-temperature for 24 hours. The catalyst was removed by filtration and the solvent removed under reduced pressure. The residue was distilled, b.p. 70-75 C. at 1.5 mmHg to give 16.0 g of 1-carbomethoxypiperazine.

Reference： [1]Patent: US4624953,1986,A

22
[ 50606-31-0 ]
[ 873697-69-9 ]
[ 873697-70-2 ]

Yield	Reaction Conditions	Operation in experiment
		A solution 1 eq of 3C, tetrahydrofuran (about 1.4 M 3C in THF) and 1.05 eq of <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> and was allowed to stir at ambient temperature for 3 hours. To the reaction mixture was added 1.5 eq of sodium triacetoxyborohydride portionwise over -40 min, maintaining an internal reaction temperature below 45C. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was added 5 volumes of water dropwise, over 1 hour, maintaining an internal reaction temperature below 30C. Ethyl acetate (EtOAc, 5 volumes) was then added, and the layers were separated. The aqueous layers were back extracted with 5 volumes of EtOAc. The combined organic layers were washed with saturated sodium bicarbonate and solid sodium bicarbonate was added as needed to bring the pH to 8 (pHydrion papers). The layers were separated, and the organic layer was washed with 5 volumes of brine. The organic layer was dried over sodium sulfate and activated carbon was added in the drying step. The organics were filtered through celite and the celite pad was rinsed 4 times with EtOAc. The organics were concentrated and dried overnight on the rotavap (-30 in Hg at RT) to afford <n="61"/>an amber-brown oil.
		A solution 1 eq of 3C, tetrahydrofuran (about 1.4 M 3C in THF) and 1.05 eq of <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> and was allowed to stir at ambient temperature for 3 hours. To the reaction mixture was added 1.5 eq of sodium triacetoxyborohydride portionwise over -40 min, maintaining an internal reaction temperature below 45C. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was added 5 volumes of water dropwise, over 1 hour, maintaining an internal reaction temperature below 3O0C. Ethyl acetate (EtOAc, 5 <n="48"/>09367-0149volumes) was then added, and the layers were separated. The aqueous layers were back extracted with 5 volumes of EtOAc. The combined organic layers were washed with saturated sodium bicarbonate and solid sodium bicarbonate was added as needed to bring the pH to 8 (pHydrion papers). The layers were separated, and the organic layer was washed with 5 volumes of brine. The organic layer was dried over sodium sulfate and activated carbon was added in the drying step. The organics were filtered through celite and the celite pad was rinsed 4 times with EtOAc. The organics were concentrated and dried overnight on the rotavap (-30 in Hg at RT) to afford an amber-brown oil.

Reference： [1]Patent: WO2007/75377,2007,A2 .Location in patent: Page/Page column 59-60
[2]Patent: WO2007/70626,2007,A2 .Location in patent: Page/Page column 46-47
[3]ACS Medicinal Chemistry Letters,2010,vol. 1,p. 472 - 477

23
[ 50606-31-0 ]
[ 1877-73-2 ]
[ 873697-81-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;	An oven-dried, round-bottom flask was charged with ferr-butyl piperazine-1 - carboxylate ( 1.1 eq), 3-nitrophenylacetic acid (7 A, 1.0 eq), EDC (1.2 eq), and HOBT (1.2 eq). The flask was flushed with nitrogen, and LambdazetaN-dimethylformamide (about 0.5 M 7A in DMF) and triethylamine (2.0 eq) were added by syringe. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with EtOAc, and washed 4 times with H2O, twice with 1 N aq. KHSO4, once with saturated NaHCO3, and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Terr-butyl 4-(2-(3- nitrophenyl)acetyl)piperazine-l -carboxylate (7B) was isolated as a solid (80%) and used without further purification.

Reference： [1]Patent: WO2007/75377,2007,A2 .Location in patent: Page/Page column 68

24
[ 50606-31-0 ]
[ 873697-68-8 ]
[ 873697-70-2 ]

Yield	Reaction Conditions	Operation in experiment
		Example 3 Step 2. A solution of 3B in dichloromethane (about 1.5 M 3B in DCM) at RT under nitrogen mixture was cooled to ~0C, and 2.0 eq of IM diisobutyllithiumaluminum hydride (DIBAlH) in DCM was added drop wise over -3.5 hours, maintaining an internal reaction temperature < 00C. Upon completion of the DiBAlH addition, the reaction mixture was added dropwise with vigorous stirring to a cooled solution (-00C) of 40 volumes of 15% Rochelle salt and 10 volumes of DCM, maintaining an internal reaction temperature below 100C. The flask was rinsed with 10 volumes of DCM and the mixture was allowed to warm to room temperature and stirred for 4 hours. The layers were separated, and the aqueous layers were back extracted with 20 volumes of DCM. The combined organic layers were washed with 20 volumes of water. The organic layer was dried over sodium sulfate and concentrated to afford a brown foam, which was dried under vacuum (-30 in Hg) at RT to afford 3C (92% yield). Example 3 Step 3A/B. A solution 1 eq of 3C, tetrahydrofuran (about 1.4 M 3C in THF) and 1.05 eq of methyl piperazine-1-carboxylate and was allowed to stir at ambient temperature for 3 hours. To the reaction mixture was added 1.5 eq of sodium triacetoxyborohydride portionwise over -40 min, maintaining an internal reaction temperature below 45C. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was added 5 volumes of water dropwise, over 1 hour, maintaining an internal reaction temperature below 300C. Ethyl acetate (EtOAc, 5 volumes) was then added, and the layers were separated. The aqueous layers were back extracted with 5 volumes of EtOAc. The combined organic layers were washed with saturated sodium bicarbonate and solid sodium bicarbonate was added as needed to bring the pH to 8 (pHydrion papers). The layers were separated, and the organic layer was washed with 5 volumes of brine. The organic layer was dried over sodium sulfate and activated carbon was added in the drying step. The organics were filtered through celite and the celite pad was rinsed 4 times with EtOAc. The organics were concentrated and dried overnight on the rotavap (~30 in Hg at RT) to afford an amber-brown oil. Step 3C. All calculations are based on the amount of 3C (R= O).[0146] To 3 volumes of methanol (based on 3C, R=O)under N2 over an an ice/brine/acetone bathwas added3 eq of acetyl chloride dropwise over 3 hours, maintaining an internal reaction temperature below 00C. The solution was then stirred for an additional 1 hour below 00C. A solution of 1.0 eq of unpurified 3D (from Steps 3 A/3B above) in MeOH (about 3.6 M based on 3C, R=O) was added dropwise over 30 min, maintaining an internal reaction temperature below 15C..The reaction was allowed to warm to room temperature overnight. The solids were filtered the next day and rinsed with 2x 0.5 volumes of MeOH, 5 volumes of 1:1 rerf-butyl methyl ether (MTBE):MeOH, and 5 volumes of MTBE.[0147] The solids were then taken up in 5 volumes of EtOAc and saturated sodium bicarbonate and solid sodium bicarbonate were added as needed to bring the pH of the aqueous layer to 8 (pHydrion papers). The layers were separated, and the aqueous layer was extracted with 5 volumes of EtOAc. The combined organic layers were washed with 5 volumes of brine, dried over sodium sulfate, and concentrated to afford a pale orange solid which was dried under vacuum (-30 in Hg) at ~40C to afford 3D (50% yield).

Reference： [1]Patent: WO2007/78839,2007,A2 .Location in patent: Page/Page column 46-48

25
[ 50606-31-0 ]
[ 33512-94-6 ]
C₁₃H₁₆N₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h;	0.13 mol of compound XIII were dissolved in dry DMF. 0.14 mol each of sodium acetate and hydroxylamine hydrochloride were added and the mixture was stirred overnight at rt. After removal of the solvent, the oxime was precipitate from MeOH/diethylether (yield 70%). This compound was dissolved in dry DMF and 1.1 eq of N-chlorosuccinimide was added portionwise over 30 min. The mixture was stirred overnight at rt, then it was poured into ice-water. The suspension was extracted with ethylacetate and the organic solution was washed with water and brine. Compound XIV was obtained after removal of the organic solvent. Compound XIV was dissolved in DCM and 1 eq of <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> (or another secondary amine) were added in the presence of 2.1 eq of DIEA. The mixture was stirred for 24 h at rt, the solvent was removed and the residue was taken into ethylacetate. The organic solution was washed with water and brine and was evaporated. The obtained oil was purified by flash chromatography with silica gel and a mixture DCM/MeOH 95:5 as eluent. The nitro compound XV was reduced by hydrogenation with palladium catalyst to produce the corresponding amino compound XVI. Compound XVI was reacted with 1 eq of compound X in DCM until complete conversion to the corresponding diarylurea. The solvent was removed and the residue was dissolved in dry DMF. To this solution, 1 eq of the corresponding amino compound and 1 eq of DIEA was added. The solution was stirred at 70 C. overnight, then the solvent was removed and compound 74 was obtained after purification by preparative HPLC.

Reference： [1]Patent: US2010/197640,2010,A1 .Location in patent: Page/Page column 12-13

26
[ 50606-31-0 ]
[ 1240186-22-4 ]
[ 1242181-06-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 4.5h;Microwave irrediation;	EXAMPLE 88f6f)-Methyl 4-(3-ri-(4-amino-[1.3.51triazin-2-ylamino')ethyll-7-fluoro-8-methylquinolin- 2-yljpiperazine- 1 -carboxylateA solution of Intermediate 27 (501 mg, 1.479 mmol), methyl piperazine-1- carboxylate (981 mg, 6.802 mmol) and DIPEA (1.288 mL, 7.394 mmol) in NMP (3 mL) was heated under microwave irradiation at 13O0C for 4.5 h. After cooling, the mixture was dissolved in a 1:1 mixture of EtOAc and Et2O (250 rnL) and washed with saturated brine (3 x 50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 10% EtOAc in DCM) gave a pale yellow oil (400 mg, 60%). LCMS (ES+) 447 (M+H)+. To the oil (400 mg, 0.896 mmol) dissolved in DCM (23 mL) was added TFA (4.1 mL). The reaction mixture was stirred at r.t. for 1.5 h. The excess solvent was removed in vacuo. The oil obtained was basified with 0.2M NaOH (40 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 95:4:1 DCM/MeOH/NH3 solution in MeOH) gave a colourless gum (278 mg, 90%). LCMS (ES+) 347 (M+H)+. The colourless gum (55.6 mg, 0.161 mmol), 2-amino-4-chloro-[l,3,5]triazine (31.4 mg, 0.241 mmol), DIPEA (0.084 mL, 0.482 mmol) and ??-BuOH (1 mL) were combined and heated under microwave irradiation at 13O0C for 1 h. Purification by preparative HPLC gave the title compound (14.4 mg, 20%) as a white solid. δH (DMSO-(Z6) 8.25 (IH, d, J 12.60 Hz), 8.02 (IH, d, J 10.06 Hz), 7.95 (IH, d, J 8.01 Hz), 7.74 (IH, dd, J 8.90, 6.24 Hz), 7.33 (IH, t, J9.13 Hz), 6.78 (2H, d, J68.59 Hz), 5.41 (IH, s), 3.83-3.59 (3H, m), 3.62-3.56 (4H, m), 3.10-3.04 (3H, m), 2.56 (4H, m), 1.41 (3H, d, J6.65 Hz). LCMS (ES+) 441 (M+H)+, 8.52 minutes (Method 8).
60%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 4.5h;Microwave irradiation; Inert atmosphere;	EXAMPLE 56Methyl 4-{7-fluoro-8-methyl-3-\|Yl»Sy 1 -(pyrazoloFl ,5-α]pyrimidin-7-ylamino')ethyl1- quinolin-2-vUpiperazine-l-carboxylateA mixture of Intermediate 15 (501 mg, 1.48 mmol), methyl piperazine-1- carboxylate (981 mg, 6.80 mmol) and DIPEA (1.29 mL, 7.39 mmol) in NMP (3 mL) was heated under microwave irradiation at 1300C for 4.5 h. After cooling, the mixture was dissolved in a 1 :1 mixture of EtOAc and Et2O (250 mL) and washed with saturated brine (3 x 50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 10% EtOAc in DCM) gave a pale yellow oil (400 mg, 60%). LCMS (ES+) 447 (M+H)+. To this oil (400 mg, 0.896 mmol) dissolved in DCM (23 mL) was added TFA (4.1 mL). The reaction mixture was stirred at r.t. for 1.5 h. The excess solvent was removed in vacuo. The oil obtained was basified with 0.2M NaOH (40 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 95:4:1 DCM/MeOH/NH3 solution in MeOH) gave a colourless gum (278 mg, 90%). LCMS (ES+) 347 (M+H)+. A portion of this material (55.6 mg, 0.161 mmol), 7-chloropyrazolo[l,5-«]pyrimidine (37 mg, 0.241 mmol), DIPEA (0.084 mL, 0.482 mmol) and n-BuOH (1 mL) were combined and heated under microwave irradiation at 1300C for 1 h. Purification by preparative HPLC gave the title compound (43.7 mg, 59%) as a yellow solid. δH (DMSO-d6) 8.64 (s, IH), 8.41 (d, J 7.84 Hz, IH), 8.11-8.14 (m, 2H), 7.74 (dd, J 8.95, 6.27 Hz, IH), 7.34 (t, J 9.12 Hz, IH), 6.44 (d, J2.27 Hz, IH), 6.27 (d, J5.30 Hz, IH), 5.16 (t, J7.20 Hz, IH), 3.75-3.83 (m, 2H), 3.70 (s, 3H), 3.65-3.70 (m, 2H), 3.30-3.35 (m, 2H), 3.22-3.30 (m, 2H), 2.11 (s, 3H), 1.88 (d, J6.71 Hz, 3H). LCMS (ES+) 464 (M+H)+, RT 3.71 minutes {Method 1).
60%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 4.5h;microwave irradiation;	A mixture of Intermediate 11 (501 mg, 1.48 mmol), methyl piperazine-1- carboxylate (981 mg, 6.80 mmol) and DIPEA (1.29 mL, 7.39 mmol) in NMP (3 mL) was heated under microwave irradiation at 130C for 4.5 h. After cooling, the mixture was dissolved in a 1 :1 mixture of EtOAc and Et20 (250 mL) and washed with saturated brine (3 x 50 mL). The organic layer was separated, dried (MgS04), filtered and concentrated in vacuo. Purification by column chromatography (Si02, 10% EtOAc in DCM) gave a pale yellow oil (400 mg, 60%). LCMS (ES+) 447 (M+H)+.

60%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 4.5h;Microwave irradiation;	A solution of Intermediate 9 (501 mg, 1.49 mmol), methyl piperazine- 1- carboxylate (981 mg, 6.80 mmol) and DIPEA (1.29 mL, 7.39 mmol) in NMP (3 mL) was heated to 130C under microwave irradiation for 4.5 h. After cooling, the reaction mixture was dissolved in a 1 :1 mixture of EtOAc and Et20 (250 mL) and washed with saturated brine (3 x 50 mL). The organic layer was dried (MgS04) and concentrated in vacuo. Purification by column chromatography on silica, eluting with 10% EtOAc in DCM, gave the title compound (400 mg, 60%) as a pale yellow oil. δΗ (CDC13) 7.94 (IH, s), 7.52 (IH, dd, J 8.8, 6.1 Hz), 7.15 (IH, t, J 8.9 Hz), 5.12 (IH, br s), 4.95 (IH, br s), 3.82-3.68 (5H, m), 3.65 (2H, m), 3.49 (2H, m), 3.14 (2H, m), 2.59 (3H, d, J2.40 Hz), 1.47-1.41 (12H, m). LCMS (ES+) 447 (M+H)+.
60%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 130℃; for 4.5h;microwave irradiation;	EXAMPLE 13quinolin-2-yl I piper azine- 1 -carboxylateA mixture of Intermediate 9 (501 mg, 1.48 mmol), methyl piperazine-1- carboxylate (981 mg, 6.80 mmol) and DIPEA (1.29 mL, 7.39 mmol) in NMP (3 mL) was heated under microwave irradiation at 130C for 4.5 h. After cooling, the mixture was dissolved in a 1 :1 mixture of EtOAc and Et20 (250 mL) and washed with saturated brine (3 x 50 mL). The organic layer was separated, dried (MgS04), filtered and concentrated in vacuo. Purification by column chromatography (Si02, 10% EtOAc in DCM) gave a pale yellow oil (400 mg, 60%). LCMS (ES+) 447 (M+H)+. To this oil (400 mg, 0.896 mmol) dissolved in DCM (23 mL) was added TFA (4.1 mL). The mixture was stirred at r.t. for 1.5 h. The excess solvent was removed in vacuo. The oil obtained was basified with 0.2M NaOH (40 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. Purification by column chromatography (Si02, 95:4: 1 DCM/MeOH/NH3 solution in MeOH) gave a colourless gum (278 mg, 90%). LCMS (ES+) 347 (M+H)+. This gum (55.6 mg, 0.161 mmol), 4- chlorothieno[2,3-c ]pyrimidine (41.1 mg, 0.241 mmol), DIPEA (0.084 mL, 0.482 mmol) and «-BuOH (1 mL) were combined and heated under microwave irradiation at 130C for 1 h. Purification by preparative HPLC gave the title compound (39.3 mg, 51%) as a brown glass. δΗ (DMSO-d6) 8.42-8.36 (2H, m), 8.33 (IH, s), 7.86 (IH, d, J 5.98 Hz), 7.78 (IH, t, J 7.56 Hz), 7.65 (IH, d, J 5.94 Hz), 7.32 (IH, t, J 9.12 Hz), 5.78 (IH, t, J 6.95 Hz), 3.74-3.62 (7H, m), 3.61-3.52 (2H, m), 3.19-3.10 (2H, m), 2.57 (3H, s), 1.58 (3H, d, J 6.64 Hz). LCMS (ES+) 481 (M+H)+, RT 4.16 minutes (Method 2).

Reference： [1]Patent: WO2010/100405,2010,A1 .Location in patent: Page/Page column 109; 110
[2]Patent: WO2010/133836,2010,A1 .Location in patent: Page/Page column 78
[3]Patent: WO2011/58111,2011,A1 .Location in patent: Page/Page column 41
[4]Patent: WO2011/58108,2011,A1 .Location in patent: Page/Page column 33
[5]Patent: WO2011/58110,2011,A1 .Location in patent: Page/Page column 39

27
[ 110-85-0 ]
[ 79-22-1 ]
[ 50606-31-0 ]

Yield	Reaction Conditions	Operation in experiment
36%	With C21H30N4O5; In dichloromethane; at 20℃; for 0.5h;	Piperazine (3 g, 34.8 mmol) was dissolved in dichloromethane (50 mL), and methyl chloroformate (658 mg,6.96 mmol) was added in portions. The reaction system was reacted at room temperature for 30 min. Then the reactionsystem was added with aqueous potassium hydroxide solution (50 mL, 1 N) to quench the reaction, and extracted withdichloromethane (50 mL 3 3). The organic phases combined, dried over anhydrous sodium sulfate, and concentratedto give a white solid (1.8 g, 36% yield). LC-MS: [M+H]+ = 145.7.

Reference： [1]Patent: EP3889154,2021,A1 .Location in patent: Paragraph 0548-0550
[2]ACS Medicinal Chemistry Letters,2010,vol. 1,p. 472 - 477

28
[ 50606-31-0 ]
[ 1289135-50-7 ]
C₁₃H₁₈FN₃O₂ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2010,vol. 1,p. 472 - 477

29
[ 50606-31-0 ]
[ 1709-44-0 ]
[ 873697-72-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2010,vol. 1,p. 472 - 477

30
[ 50606-31-0 ]
[ 1242181-07-2 ]

Reference： [1]Patent: WO2011/58108,2011,A1
[2]Patent: WO2011/58110,2011,A1

31
[ 50606-31-0 ]
[ 1307256-05-8 ]

Reference： [1]Patent: WO2011/58111,2011,A1

32
[ 50606-31-0 ]
[ 1306784-64-4 ]

Reference： [1]Patent: WO2011/58108,2011,A1

33
[ 50606-31-0 ]
[ 1307263-62-2 ]

Reference： [1]Patent: WO2011/58110,2011,A1

34
1-(bromomethyl)-3-chloro-2-fluorobenzene [ No CAS ]
[ 50606-31-0 ]
[ 873697-71-3 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 3262 - 3265

35
1-(bromomethyl)-3-chloro-2-fluorobenzene [ No CAS ]
[ 50606-31-0 ]
[ 1309439-45-9 ]

Reference： [1]Journal of the American Chemical Society,2012,vol. 134,p. 11132 - 11135
[2]Organic Letters,2011,vol. 13,p. 3262 - 3265

36
[ 50606-31-0 ]
[ 114604-68-1 ]
[ 1391636-60-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2807 - 2810

37
[ 50606-31-0 ]
[ 114604-68-1 ]
[ 1260098-49-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2807 - 2810

38
[ 50606-31-0 ]
[ 873697-71-3 ]

Reference： [1]Journal of the American Chemical Society,2012,vol. 134,p. 11132 - 11135
[2]Organic Process Research and Development,2019,vol. 23,p. 1558 - 1567
[3]Organic Process Research and Development,2019,vol. 23,p. 1558 - 1567

39
[ 50606-31-0 ]
C₂₀H₂₂FN₃O₄ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2012,vol. 134,p. 11132 - 11135

40
[ 50606-31-0 ]
[ 530-62-1 ]
[ 1392831-31-0 ]

Reference： [1]Organic and Biomolecular Chemistry,2012,vol. 10,p. 6420 - 6431

41
[ 50606-31-0 ]
[ 1446251-06-4 ]
[ 1446250-93-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4210 - 4215

42
[ 50606-31-0 ]
[ 1445720-38-6 ]
[ 1445901-18-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3891 - 3897

43
[ 50606-31-0 ]
[ 946125-65-1 ]
methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a mechanically stirred toluene solution (9 volumes) of FN-Bromide (prepared from previous step) in a 60 L reactor at 22 C under an atmosphere of nitrogen, diisopropylethylamine was charged (1.90 kg, 14.69 mol, 1.14 equiv.). To this mixture a solution of piperazine carboxylate methylester (Piperazine Carboxylate) (2.03 kg, 14.05 mol, 1.09 equiv.) in toluene (1.0 L, 0.5 volumes) was added at a rate allowing the batch temperature to stay under 30.0 C (Exothermic. During the addition, jacket temperature was adjusted to 5 C in order to maintain batch temperature below 30 C. The mixture was agitated at 22 C for 3 hours and analysis of an aliquot confirmed completion of the alkylation reaction (<1.0 LCAP FN-Bromide, HPLC254 nm). The reaction mixture was treated with aqueous NH4Cl (20 wt%, 10.0 L, 5 volumes; prepared from 2.0 kg of NH4Cl and 10.0 L of DI water), the biphasic mixture was agitated (30 min), and the layers were separated. The organic layer was sequentially washed with aqueous NaHCo3 (9 wt%, 10.0 L, 5 volumes; prepared from 0.90 kg of NaHC03 and 10.0 L of DI water). The organic layer was filtered through a 5 muiotaeta Teflon cartridge line and transferred in a drum, washed the filter line with another 1.0 L toluene and the combined toluene solution (10.0 volumes) weighed, and assayed (HPLC) to quantify Piperazine Nitro free base. The assay yield for the Piperazine Nitro-freebase is 89.0%, FN-Toluene 2.5% and FN-Bromide 0.2% with FN-Bromide undetected. The total loss of product to the aqueous washes is Piperazine Nitro-HCl seed (130.0 g, 0.39 mol, 0.03 equiv.) was charged as slurry in IPA (400 mL, 0.2 volume). The mixture was agitated for 30 min and the remaining cone. HCl (80% of the charge, 1.10 L, 12.82 mol) was added over a period of 4 hours. The mixture was stirred at 55 C for 1 h, cooled to 20 C in a linear manner over 1.5 hours, and agitated at this temperature for 12 hours. The supernatant concentration of Piperazine Nitro-HCl was measured (2.8 mg/g). The mixture was filtered through an aurora filter equipped with a 5 muiotaeta Teflon cloth. The mother liquor were transferred to a clean drum and assayed. The filter cake was washed twice with IPA (11.2 L, 5.6 volumes) and dried to constant weight (defined as 99.5 wt% and 99.0% LCAP purity. Methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-l-carboxylate hydrochloride (Piperazine Nitro-HCl): 1H NMR (300 MHz, DMSO-J) delta ppm 3.25 (br. s, 3 H), 3.52-3.66 (m, 8 H), 4.47 (s, 2 H), 7.44-7.63 (t, 1 H, J = 8 Hz), 7.98-8.15 (m, 1 H), 8.17-8.34 (m, 1 H). 13C NMR (75 MHz, DMSO-J) 5 ppm 50.3, 51.4, 52.8, 119.6 (d, J = 14 Hz), 125.1 (d, J = 5 Hz), 127.9, 137.4 (d, J = 8 Hz), 139.8 (d, J = 3 Hz), 152.2, 154.7, 155.7. DSC: melt onset at 248.4 C. Exact Mass [C13H16FN304+ H]+: calculated = 298.1203, measured = 298.1198.

Reference： [1]Patent: WO2014/152198,2014,A1 .Location in patent: Paragraph 0112; 0113; 0114

44
[ 50606-31-0 ]
[ 946125-65-1 ]
methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-ethyl-N,N-diisopropylamine; In toluene; at 22 - 30℃; for 3h;Inert atmosphere;	Piperazine Nitro-HCl: [0089] To a mechanically stirred toluene solution (9 volumes) of FN-Bromide (prepared from previous step) in a 60 L reactor at 22 C under an atmosphere of nitrogen, diisopropylethylamine was charged (1.90 kg, 14.69 mol, 1.14 equiv.). To this mixture a solution of piperazine carboxylate methylester (Piperazine Carboxylate) (2.03 kg, 14.05 mol, 1.09 equiv.) in toluene (1.0 L, 0.5 volumes) was added at a rate allowing the batch temperature to stay under 30.0 C (Exothermic. During the addition, jacket temperature was adjusted to 5 C in order to maintain batch temperature below 30 C. The mixture was agitated at 22 C for 3 hours and analysis of an aliquot confirmed completion of the alkylation reaction (<1.0 LCAP FN-Bromide, HPLC254 nm)- The reaction mixture was treated with aqueous NH4C1 (20 wt%, 10.0 L, 5 volumes; prepared from 2.0 kg of NH4C1 and 10.0 L of DI water), the biphasic mixture was agitated (30 min), and the layers were separated. The organic layer was sequentially washed with aqueous NaHC03 (9 wt%, 10.0 L, 5 volumes; prepared from 0.90 kg of NaHC03 and 10.0 L of DI water). The organic layer was filtered through a 5 muiotaeta Teflon cartridge line and transferred in a drum, washed the filter line with another 1.0 L toluene and the combined toluene solution (10.0 volumes) weighed, and assayed (HPLC) to quantify Piperazine Nitro free base. The assay yield for the Piperazine Nitro-freebase is 89.0%, FN-Toluene 2.5% and FN-Bromide 0.2% with FN-Bromide undetected. The total loss of product to the aqueous washes is < 1.0 %. This solution under nitrogen atmosphere is stable for more than 12h. [0090] To a mechanically stirred toluene solution of Piperazine Nitro free base, prepared as described above, at 22 C in a 60 L reactor under an atmosphere of nitrogen, IPA (19.4 L, 9.7 volumes) and DI water (1.0 L, 0.5 volume) were charged. The mixture was heated to 55 C and 20% of the 1.4 equiv. of cone. HCl (Titrated prior to use and charge based on titer value; 276.0 mL, 3.21 mol) was charged. The contents were agitated for 15 min and Piperazine Nitro-HCl seed (130.0 g, 0.39 mol, 0.03 equiv.) was charged as slurry in IPA (400 mL, 0.2 volume). The mixture was agitated for 30 min and the remaining cone. HCl (80% of the charge, 1.10 L, 12.82 mol) was added over a period of 4 hours. The mixture was stirred at 55 C for 1 h, cooled to 20 C in a linear manner over 1.5 hours, and agitated at this temperature for 12 hours. The supernatant concentration of Piperazine Nitro-HCl was measured (2.8 mg/g). The mixture was filtered through an aurora filter equipped with a 5 muiotaeta Teflon cloth. The mother liquor were transferred to a clean drum and assayed. The filter cake was washed twice with IPA (11.2 L, 5.6 volumes) and dried to constant weight (defined as < 1.0% weight loss for 2 consecutive TGA measurements over a period of 2 hours) on filter with vacuum and a nitrogen sweep (14 h). The combined losses of Piperazine Nitro- HCl in the mother liquors and the washes were 2.5 %. Piperazine Nitro-HCl was isolated 3.59 kg in 87.6% corrected yield with >99.5 wt% and 99.0% LCAP purity. [0091] Methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-l-carboxylate hydrochloride (Piperazine Nitro-HCl): 1H NMR (300 MHz, DMSO-J) delta ppm 3.25 (br. s, 3 H), 3.52-3.66 (m, 8 H), 4.47 (s, 2 H), 7.44-7.63 (t, 1 H, J = 8 Hz), 7.98-8.15 (m, 1 H), 8.17-8.34 (m, 1 H). 13C NMR (75 MHz, DMSO-J) 5 ppm 50.3, 51.4, 52.8, 119.6 (d, J = 14 Hz), 125.1 (d, J = 5 Hz), 127.9, 137.4 (d, J = 8 Hz), 139.8 (d, J = 3 Hz), 152.2, 154.7, 155.7. DSC: melt onset at 248.4 C. Exact Mass [C13H16FN304+ H]+: calculated = 298.1203, measured = 298.1198.

Reference： [1]Patent: WO2014/152236,2014,A1 .Location in patent: Paragraph 0089-0091

45
[ 50606-31-0 ]
6-(4-chlorophenoxy)-2-[4-(3-chloropropoxy)phenyl]benzoxazole [ No CAS ]
4-(3-{4-[6-(4-chlorophenoxy)benzoxazol-2-yl]phenoxy}propyl)piperazine-1-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With sodium carbonate; potassium iodide; In butan-1-ol; at 105℃;	General procedure: A mixture of compounds 24a (for compounds 26-30; 1.0 equiv)or 25a-25e (for compounds 31-75; 1.0 equiv), secondary amine(1.5 equiv), KI (2.0 equiv), and Na2CO3 (6.0 equiv) in n-BuOH washeated to 105 C for 24 h. The mixtures was cooled to room temperatureand evaporated under reduced pressure. The residuewas dissolved in EtOAc and then washed with water, and brine.The organic layer was dried over sodium sulfate and concentratedin vacuum. The resulting residue was purified by silica gel chromatographyto afford the corresponding products (18-99%).

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 4919 - 4935

46
[ 50606-31-0 ]
(S)-2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-1,3-oxazole-4-carboxylic acid [ No CAS ]
(S)-methyl 4-(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-1,3-oxazole-4-carbonyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%		A mixture of (S) -2- (3- (benzyloxy) -4- (difluoromethoxy) phenyl) -5- (1- ( (tert-butoxycarbonyl) amino) ethyl) oxazole-4-carboxylic acid (500 mg, 0.99 mmol) , <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> (171 mg, 1.19 mmol) , EDCI (285 mg, 1.49 mmol) and HOAT (202 mg, 1.49 mmol) in DCM (20 mL) was stirred at rt fro 30 min, and DIPEA (0.52 mL, 2.97 mmol) was added dropwise at 0 . After the addition, the mixture was stirred at rt for 10 h and washed with water (25 mL × 3) . The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 2/1 to give the title compound as a white solid (567 mg, 91) .1H NMR (400 MHz, CDCl3) : δ ppm 7.66 (d, J 2.0 Hz, 1H) , 7.62 (dd, J1 8.0 Hz, J2 2.0 Hz, 1H) , 7.49 (d, J 7.4 Hz, 2H) , 7.43 (t, J 7.5 Hz, 2H) , 7.36-7.39 (m, 1H) , 7.28 (d, J 8.0 Hz, 1H) , 6.66 (t, JF-H 74.8 Hz, 1H) , 5.23-5.32 (m, 1H) , 3.25 (s, 2H) , 3.94 (br. s, 3H) , 3.77 (s, 3H) , 3.60 (br. s, 5H) , 1.56 (d, J 7.2 Hz, 3H) , 1.44 (s, 9H) and MS-ESI: m/z 631.20 [M+H] +.

Reference： [1]Patent: WO2016/34134,2016,A1 .Location in patent: Paragraph 00755

47
[ 50606-31-0 ]
(S)-5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1,3-oxazole-4-carboxylic acid [ No CAS ]
(S)-methyl 4-(5-(1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1,3-oxazole-4-carbonyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 5h;Inert atmosphere;	A mixture of (S) -5- (1- ( (tert-butoxycarbonyl)amino) ethyl) -2- (3- (cyclopropylmethoxy) -4- (difluoromethoxy) phenyl) oxazole-4-carboxylicacid (300 mg, 0.64 mmol) , <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> (138mg, 0.96 mmol) , EDCI (250 mg, 1.3 mmol) and HOAT (130 mg, 0.96 mmol) in DCM(25 mL) was stirred at 0 , and DIPEA (0.44 mL, 2.56 mmol) was added dropwise.After the addition, the mixture was stirred at rt for 5 h and washed with water(10 mL × 3) . The organic layer was dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel chromatography elutedwith Petroleum ether/EtOAc (v/v) 1/1 to give the title compound as a whitesolid (160 mg, 44) . 1H NMR (600 MHz, CDCl3): δ ppm 7.58-7.60 (m, 1H) , 7.56 (s, 1H) , 7.26 (d, J 8.3 Hz, 1H) , 6.73 (t,JF-H 75.0 Hz, 1H) , 5.22-5.27 (m, 1H) , 3.99 (d, J 6.9 Hz, 2H) ,3.90-3.99 (m, 2H) , 3.76 (s, 3H) , 3.73-3.81 (m, 2H) , 3.55-3.67 (m, 4H) , 1.56(d, J 7.0 Hz, 3H) , 1.43 (s, 9H) , 1.34-1.37 (m, 1H) , 0.69-0.72 (m, 2H) ,0.41-0.44 (m, 2H) and MS-ESI: m/z 595.30 [M+H] + .
44%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 5h;	The compound (S) -5- (1 - ((tert-butoxycarbonyl) amino) ethyl) -2- (3- (cyclopropylmethoxy) -4-(difluoromethoxy) phenyl ) -oxazole-4-carboxylic Acid (300mg, 0.64mmol), the compound 1- methylpiperazine (138mg, 0.96mmol), 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide Amine hydrochloride(250mg, 1.3mmol) and N- hydroxy-7-aza-benzotriazole (130mg, 0.96mmol) was dissolved in dichloromethane(25mL) The lower, 0 C conditions, to this solution was added dropwise N, N- diisopropylethylamine(0.44mL, 2.56mmol), stirred at room temperature 5H, water (10 mL × 3), dried over anhydrous Na 2 SO 4organic phase was dried, the solvent was removed concentrate was subjected to column chromatography (eluent:Petroleum ether / EtOAc (v / v) = 1/1), to give 160mg white solid, yield: 44%.

Reference： [1]Patent: WO2016/34134,2016,A1 .Location in patent: Paragraph 00400
[2]Patent: CN105399698,2016,A .Location in patent: Paragraph 1040-1043

48
[ 50606-31-0 ]
[ 37566-39-5 ]
methyl 4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.8 g	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;	1.00 g (5.39 mmol, 1.0 equiv.) of 5-bromo-1,3,4-thiadiazol-2-amine was provided in 12 mL of DMF,0.78 mL (7.00 mmol, 1.3 equiv.) of <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> and 1.49 g (10.8 mmol, 2.0equiv.) of potassium carbonate were added, and the mixture was stirred at 80 C over night. Afterfiltration, the remaining solution was concentrated, 0.80 g (55% of theory) of the title compoundwere obtained, which were used without further purification.‘H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 2.729 (1.16), 2.889 (1.44), 3.207 (2.68), 3.219 (3.67), 3.224 (2.62), 3.233 (3.30), 3.349 (0.49), 3.444 (2.94), 3.452 (2.45), 3.458 (3.45), 3.470 (2.37), 3.580 (0.46), 3.604 (0.74), 3.615 (16.00), 6.523 (3.89).LC-MS (Method 3): R = 0.58 mm; MS (ESIpos): m/z = 244 [M+H].

Reference： [1]Patent: WO2016/131808,2016,A1 .Location in patent: Page/Page column 67

49
[ 50606-31-0 ]
methyl 4-(5-[3-[(4-methylpiperazin-1-yl)acetyl]amino}-4-(trifluoromethoxy)benzoyl]amino}-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/131808,2016,A1

50
[ 50606-31-0 ]
[ 13206-46-7 ]
methyl 4-(2-methyl-1-oxopropan-2-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63.9%	With triethylamine; In diethyl ether; at 20℃; for 72h;Inert atmosphere;	Into a lOO-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl piperazine- l-carboxylate (2.00 g, 13.87 mmol, 1 eq.), Et20 (25 mL), TEA (4.22 g, 41.70 mmol, 3.01 eq.), and 2-bromo-2-methylpropanal (3.15 g, 20.86 mmol, 1.50 eq.). The resulting mixture was stirred for 3 days at rt. The resulting mixture was washed with 10% aq. sodium chloride solution (30 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash silica gel column to afford 1.90 g (63.9 %) of methyl 4-(2-methyl-l-oxopropan-2- yl)piperazine- l-carboxylate as a colorless oil.
1.5 g	In diethyl ether; at 25℃;	Into a 100-mL round-bottom flask, was placed methyl piperazine-l-carboxylate (1.9 g, 12.5 mmol, 2.00 equiv), diethyl ether (100 mL), and 2-bromo-2-methylpropanal (1 g, 6.29 mmol, 1.00 equiv). The resulting solution was stirred for overnight at 25 C. The resulting mixture was concentrated under vacuum affording 1.5 g of methyl 4-(2-methyl-l-oxopropan- 2-yl)piperazine-l -carboxylate as a light yellow oil which was used without further purification.

Reference： [1]Patent: WO2019/99582,2019,A1 .Location in patent: Paragraph 0585; 0586
[2]Patent: WO2016/210165,2016,A1 .Location in patent: Page/Page column 86
[3]Journal of Medicinal Chemistry,2022,vol. 65,p. 5300 - 5316

51
[ 50606-31-0 ]
(3R,4S)-4-(4-bromophenyl)-1-(2-fluoro-6-methylbenzyl)-N,N-dimethylpyrrolidin-3-amine [ No CAS ]
C₂₆H₃₅FN₄O₂ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 461 - 465

52
[ 50606-31-0 ]
2-[(1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]acetic acid [ No CAS ]
methyl 4-{2-[(1H-1,3-benzodiazol-2-yl)amino]-2-[3-(trifluoromethyl)phenyl]acetyl}piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15 mg		. (0939) (0940) To a solution of 2-[(lH-l ,3-benzodiazol-2-yl)amino]-2-[3-(trifiuoromethyl)phenyl]acetic acid (from Step 1), (200 mg, 0.6 mmol), in dichloromethane (2 mL) was added triethylamine (91 mg, 0.9 mmol) and the reaction mixture was cooled to 0 C. Then EDC.HC1 (126 mg, 0.66 mmol) and HBTU (249 mg, 0.66 mmol) were added and the reaction mixture was stirred for 10 minutes. Methyl piperazine-l-carboxylate (86 mg, 0.6 mmol) was added at 0 C and the reaction mixture was stirred at ambient temperature for 12 h. The crude was filtered through a pad of celite, purified by preparative HPLC to afford the title product (15 mg) as an off- white solid. (0941) FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-de) δ 10.50 (s, 1H), 8.15 (s, 1H), 7.88 (d, 3H, J = 10.68 Hz), 7.82 (d, 1H, J = 7.48), 7.67 (t, 1H, J = 6.56) 7.17 (bs, 1H), 6.89 (bs, 2H), 6.14 (d, 1H, J = 8.80), 3.61 (m, 2H), 3.58 (m, 5H), 3.43 (m, 2H), 3.05 (m, 2H); LCMS: m z 462.2 (M+l).

Reference： [1]Patent: WO2017/144183,2017,A1 .Location in patent: Page/Page column 123; 124

53
[ 50606-31-0 ]
6-chloro-2-ethoxynicotinic acid [ No CAS ]
2-ethoxy-6-(4-methoxycarbonylpiperazin-1-yl)pyridine-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33 mg	With triethylamine; In dimethyl sulfoxide; at 80℃; for 72h;	A solution of 6-chloro-2-ethoxynicotinic acid 18 (45 mg, 0.22 mmol), Et3N (67 mg, 0.66 mmol)and <strong>[50606-31-0]methyl piperazine-1-carboxylate</strong> 114 (40 mg, 0.28 mmol) in DMSO (2 mL) was heated at80 C for 72 hours. Water (10 mL) was added and the resulting mixture was acidified with a1 M aqueous HCI solution to pH 6-7. The aqueous fraction was extracted with DCM (3 x 10 mL) and the combined organic fractions were washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue obtained was purified by preparative reverse phase-HPLC to give the title product (33 mg, 49%) as yellow oil. LCMS: RT 2.36 mm; m/z 310.1 [M+H].

Reference： [1]Patent: WO2017/153520,2017,A1 .Location in patent: Paragraph 52

54
[ 50606-31-0 ]
methyl 4-((1r,4r)-4-aminocyclohexyl)piperazine-1-carboxylate [ No CAS ]