[ CAS No. 53292-90-3 ] {[proInfo.proName]}

Name: 53292-90-3|cis-4-((tert-Butoxycarbonyl)amino)cyclohexanecarboxylic acid|97%
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Quality Control of [ 53292-90-3 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 53292-90-3 ]

CAS No. :	53292-90-3	MDL No. :	MFCD01862294
Formula :	C₁₂H₂₁NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KXMRDHPZQHAXML-UHFFFAOYSA-N
M.W :	243.30	Pubchem ID :	2755996
Synonyms :

Safety of [ 53292-90-3 ]

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

Application In Synthesis of [ 53292-90-3 ]

* 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 [ 53292-90-3 ]
Downstream synthetic route of [ 53292-90-3 ]

[ 53292-90-3 ] Synthesis Path-Upstream 1~6

1
[ 53292-90-3 ]
[ 62456-15-9 ]

Reference： [1] ACS Combinatorial Science, 2017, vol. 19, # 5, p. 286 - 298

2
[ 53292-90-3 ]
[ 223131-01-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 16, p. 2177 - 2180
[2] Patent: US2016/333021, 2016, A1, . Location in patent: Page/Page column 0432

3
[ 53292-90-3 ]
[ 247570-24-7 ]

Reference： [1] Patent: WO2008/57468, 2008, A1,

4
[ 67-56-1 ]
[ 53292-90-3 ]
[ 146307-51-9 ]

Reference： [1] Chimia, 2005, vol. 59, # 3, p. 72 - 76
[2] ACS Combinatorial Science, 2017, vol. 19, # 5, p. 286 - 298

5
[ 53292-90-3 ]
[ 239074-29-4 ]

Yield	Reaction Conditions	Operation in experiment
96.6%	With dimethylsulfide borane complex In tetrahydrofuran at -10 - 15℃; for 4 h; Inert atmosphere	Step A: tert-butyl N- [(ir, 4r)-4-(Hydroxymethyl)cyclohexyl] carbamate. To a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen wasplaced (ir, 4r)-4-[[(tert-butoxy)carbonyl]amino]cyclohexane- 1 -carboxylic acid (1066 g, 4.38 mol, 1.00 equiv) and THF (10 L). This was followed by the dropwise addition of BH3-Me25 (10M, 660 mL) at -10 °C over 1 h. The resulting solution was stirred for 3 h at 15 °C. This reaction was performed three times in parallel and the reaction mixtures were combined. The reaction was then quenched by the addition of methanol (2 L). The resulting mixture was concentrated under vacuum. This resulted in of tert-butyl N-[(lr, 4r)-4-(hydroxymethyl)cyclohexyl]carbamate(3000 g, 99.6percent) as a white solid. MS (ESI): mass calcd. for C12H23N03, 229.32; m/z found,215.2 [M-tBu+MeCN+H] ‘H NMR: (300 IVIFIz, CDC13): 4.40 (s, 1H), 3.45 (d, J 6.3 Hz,2H), 3.38 (s, 1H), 2.05-2.02 (m, 2H), 1.84-1.81 (m, 2H), 1.44 (s, 11H), 1.17-1.01 (m, 4H)
3.5 kg	With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 30℃; for 6 h; Large scale	In the 50 L reaction kettle, adding 5 kg of trans - 4 - Boc - amino-cyclohexane carboxylic acid, 20 kg of tetrahydrofuran, 10 kilograms of sodium borohydride. Control temperature, stirring in batches under the adding 15 liter 1 M boron trifluoride ether solution. Control temperature at 0 - 10 degrees, reaction 1 hours, after up to 30 degrees, the reaction 5 hours. Concentrated off solvent, adding water, stirring, precipitated solid, filtering, to obtain 3.5 kg trans - 4 - Boc - amino-cyclohexane methanol

Reference： [1] Patent: WO2018/112382, 2018, A1, . Location in patent: Page/Page column 109; 110
[2] Patent: EP1961744, 2008, A1, . Location in patent: Page/Page column 100
[3] Patent: WO2010/45987, 2010, A1, . Location in patent: Page/Page column 44
[4] Patent: US2016/333021, 2016, A1, . Location in patent: Paragraph 1158
[5] Patent: CN107011216, 2017, A, . Location in patent: Paragraph 0024; 0025
[6] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 2, p. 89 - 93

6
[ 53292-90-3 ]
[ 1313279-48-9 ]

Reference： [1] Patent: WO2018/112382, 2018, A1,

[ 53292-90-3 ] Synthesis Path-Downstream 1~88

1
[ 53292-90-3 ]
[ 400898-94-4 ]

Reference： [1]Chimia,2005,vol. 59,p. 72 - 76
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 4990 - 5002

2
[ 53292-90-3 ]
[ 400899-08-3 ]

Reference： [1]Chimia,2005,vol. 59,p. 72 - 76

3
[ 53292-90-3 ]
[ 400899-07-2 ]

Reference： [1]Chimia,2005,vol. 59,p. 72 - 76

4
[ 53292-90-3 ]
[ 400899-12-9 ]

Reference： [1]Chimia,2005,vol. 59,p. 72 - 76

5
[ 53292-90-3 ]
[ 400899-11-8 ]

Reference： [1]Chimia,2005,vol. 59,p. 72 - 76

6
[ 53292-90-3 ]
3-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-acrylic acid ethyl ester [ No CAS ]

Reference： [1]Chimia,2005,vol. 59,p. 72 - 76

7
[ 53292-90-3 ]
[ 400899-10-7 ]

Reference： [1]Chimia,2005,vol. 59,p. 72 - 76

8
[ 53292-90-3 ]
[ 400899-16-3 ]

Reference： [1]Chimia,2005,vol. 59,p. 72 - 76

9
[ 53292-90-3 ]
5-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-pent-2-enoic acid ethyl ester [ No CAS ]

Reference： [1]Chimia,2005,vol. 59,p. 72 - 76

10
[ 53292-90-3 ]
5-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-pentanoic acid ethyl ester [ No CAS ]

Reference： [1]Chimia,2005,vol. 59,p. 72 - 76

11
[ 53292-90-3 ]
[ 400899-17-4 ]

Reference： [1]Chimia,2005,vol. 59,p. 72 - 76

12
[ 53292-90-3 ]
methanesulfonic acid 5-(4-methylamino-cyclohexyl)-pentyl ester; compound with trifluoro-acetic acid [ No CAS ]

Reference： [1]Chimia,2005,vol. 59,p. 72 - 76

13
[ 53292-90-3 ]
[ 878395-72-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 2509 - 2522

14
[ 53292-90-3 ]
4-[(naphthalen-2-ylmethyl)-amino]-cyclohexanecarboxylic acid [2-(cyclopentanecarbonyl-amino)-benzothiazol-6-yl]-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 2509 - 2522

15
[ 53292-90-3 ]
trans-N-[(2,6-dimethyl)phenyl]-4-aminocyclohexanecarboxamide hydrochloride [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2001,vol. 36,p. 265 - 286

16
[ 150-13-0 ]
4-benzylidene-2-phenyl-5-imidazolone-acetic acid (pseudo)halide [ No CAS ]
[ 53292-90-3 ]

Reference： [1]European Journal of Medicinal Chemistry,2001,vol. 36,p. 265 - 286

17
[ 207798-93-4 ]
[ 53292-90-3 ]
1-(trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl)-4-(5-chlorobenzofuran-2-sulfonyl)piperazine [ No CAS ]

Reference： [1]Patent: US6359134,2002,B1 .Location in patent: Example 251

18
[ 53292-90-3 ]
[ 203521-17-9 ]
[ 216957-26-5 ]

Reference： [1]Patent: US6359134,2002,B1 .Location in patent: Example 104

19
[ 53292-90-3 ]
[ 179051-48-0 ]
[ 216957-35-6 ]

Reference： [1]Patent: US6359134,2002,B1 .Location in patent: Example 113

20
1-(4-vinylbenzenesulfonyl)piperazine [ No CAS ]
[ 53292-90-3 ]
1-(trans-4-tert-butoxycarbonylaminocyclohexane-1-ylcarbonyl)-4-(4-styrenesulfonyl)piperazine [ No CAS ]

Reference： [1]Patent: US6359134,2002,B1 .Location in patent: Example 244

21
1-(5-chloro-2H-benzopyran-3-sulfonyl)piperazine [ No CAS ]
[ 53292-90-3 ]
[ 757171-98-5 ]

Reference： [1]Patent: US6359134,2002,B1 .Location in patent: Example 238

22
[ 53292-90-3 ]
[ 26177-43-5 ]
[ 771544-02-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; HATU; In DCM;	Step A: Synthesis of cis-[4-(3-nitrobenzylcarbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester. cis-4-(tert-Butoxycarbonylamino)-cyclohexanecarboxylic acid (2.0 g, 8.2 mmol) and 3-nitrobenzyl amine hydrochloride (1.54 g, 8.2 mmol) in DCM (30 mL) was reacted in the presence of HATU (3.5 g, 9.02 mmol) and Et3N (4 mL). The reaction was diluted with DCM, washed with 1N-HCl and water, dried over MgSO4, and concentrated. From column chromatography (silica gel, DCM/MeOH = 100:0 to 95 to 5), 2.7 g (90 %) of cis-[4-(3-nitrobenzylcarbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester was isolated. ESI MS m/e 378 M + H+; 1H NMR (400 MHz, CDCl3) delta 8.11 (brs, 1H), 8.09 (s, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 6.17 (brs, 1 H), 4.72 (brs, 1 H), 4.53 (d, J = 6.0 Hz, 2 H), 3.74 (brs, 1 H), 2.27 (m, 1 H), 1.80-1.71 (m, 6 H), 1.65-1.59 (m, 2 H), 1.45 (s, 9 H).

Reference： [1]Patent: EP1464335,2004,A2 .Location in patent: Page/Page column 303

23
[ 53292-90-3 ]
[ 6638-79-5 ]
tert-butyl (4-(methoxy(methyl)carbamoyl) cyclohexyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; In dichloromethane;	1.1 A solution of 20 g (82.2 mmol) trans-4-tert-Butoxycarbonylamino-cyclohexanecarboxylic acid in 1.2 l CH2Cl2 was treated with 12.83 g (131.5 mmol) N,O-dimethyl-hydroxylamine hydrochloride, 10.85 ml (98.6 mmol) N-methylmorpholine and at 0° C. with 18.91 g (98.64 mmol) EDCI and 12.62 g (82.2 mmol) HOBT. The reaction mixture was stirred 2 h at room temperature and extracted with aqueous 10percent KHSO4/Et2O (3*). The organic phases were washed with aqueous saturated NaHCO3, 10percent NaCl and dried over Na2SO4 to yield 24.25 g (quantitative) of trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester, mp: 130-140° C., slowly dec.; MS: 287 (MH+).
	With 4-methyl-morpholine; benzotriazol-1-ol; In dichloromethane;	Example 26 Example 26.1 A solution of 20 g (82.2 mmol) trans-4-tert-Butoxycarbonylamino-cyclohexanecarboxylic acid in 1.2 l CH2Cl2 was treated with 12.83 g (131.5 mmol) N,O-dimethyl-hydroxylamine hydrochloride, 10.85 ml (98.6 mmol) N-methylmorpholine and at 0° C. with 18.91 g (98.64 mmol) EDCI and 12.62 g (82.2 mmol) HOBT. The reaction mixture was stirred 2 h at room temperature and extracted with aqueous 10percent KHSO4/Et2O (3*). The organic phases were washed with aqueous saturated NaHCO3, 10percent NaCl and dried over Na2SO4 to yield 24.25 g (quantitative) trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester, mp: 130-140° C., slowly dec.; MS: 287 (MH+).

Reference： [1]Patent: US2003/186984,2003,A1
[2]Patent: US2002/45777,2002,A1

24
[ 53292-90-3 ]
[ 100-51-6 ]
C₁₉H₂₇NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;	A mixture of 2 g (8.2 mmol) trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (commercially available), 0.978 g (9.0 mmol) phenyl-methanol (commercially available), 3.16 g (9.8 mmol) O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 1.24 g (12.3 mmol) NEt3 in 10 mL DMF was stirred at room temperature for 1 h. The mixture was evaporated to dryness and extracted with DCM and Na2CO3 aq. The combined organic phases were dried with MgSO4 and evaporated. The residue was treated with 100 mL 4N HCl in dioxane at room temperature for 4 h. The mixture was evaporated to dryness to yield trans-4-amino-cyclohexanecarboxylic acid benzyl ester (MS(m/e): 360.4 (MH+)) which was used without further purification. 150 mL DCM was added, 2.95 g (14 mmol) 4-cyano-benzenesulfonyl chloride (commercially available) and 6.17 g (61 mmol) NEt3 and the mixture was stirred at room temperature for 16 h. The mixture was extracted with DCM and 1N HCl aq. and the combined organic phases were evaporated. The residue was recrystallized from methanol to yield 1.9 g (58percent) of the title compound. MS(m/e): 397.0 (MH-).

Reference： [1]Patent: US2007/173511,2007,A1 .Location in patent: Page/Page column 34

25
[ 4318-42-7 ]
[ 53292-90-3 ]
[ 944404-27-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;	Step 1: [trans-4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyl]-carbamic acid tert-butyl ester A mixture of 3 g (12 mmol) 4-tert-butoxycarbonylamino-trans-cyclohexane carboxylic acid (commercially available), 1.74 g (14 mmol) 1-(2-propyl)-piperazine (commercially available), 4.75 g (15 mmol) TBTU and 3.64 g (36 mmol) NEt3 in 10 ml DMF was stirred for 3 h at room temperature. After evaporation the residue was washed with 1N NaHCO3 solution, extracted with DCM and the combined organic layers dried with MgSO4 and evaporated to dryness to yield 4.56 g (94 percent) of the title compound. MS(m/e): 354.3 (MH+).

Reference： [1]Patent: US2007/173511,2007,A1 .Location in patent: Page/Page column 16

26
[ 53292-90-3 ]
[ 124-40-3 ]
[ 1032451-72-1 ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of 4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (2.43 g, 10 mmol), EDCI (6.52 g, 34 mmol) and HOBt (4.59 g, 34 mmol) in NMP (20 mL) was stirred at RT for 3 h. A solution of dimethylamine (2.0 M in THF, 15 mL, 30 mmol) was added, and the resulting mixture was stirred at RT for 64 h. Water and EtOAc were then added, and the organic layer was separated and washed twice with a saturated aqueous solution of K2CO3, aqueous HCl (1 M), a saturated aqueous solution of K2CO3, and brine. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give (4-dimethylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (1.6 g, 59percent yield) as a white solid.

Reference： [1]Patent: US2008/146565,2008,A1 .Location in patent: Page/Page column 96

27
[ 53292-90-3 ]
[ 239074-29-4 ]

Yield	Reaction Conditions	Operation in experiment
96.6%	With dimethylsulfide borane complex; In tetrahydrofuran; at -10 - 15℃; for 4h;Inert atmosphere;	Step A: tert-butyl N- [(ir, 4r)-4-(Hydroxymethyl)cyclohexyl] carbamate. To a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen wasplaced (ir, 4r)-4-[[(tert-butoxy)carbonyl]amino]cyclohexane- 1 -carboxylic acid (1066 g, 4.38 mol, 1.00 equiv) and THF (10 L). This was followed by the dropwise addition of BH3-Me25 (10M, 660 mL) at -10 °C over 1 h. The resulting solution was stirred for 3 h at 15 °C. This reaction was performed three times in parallel and the reaction mixtures were combined. The reaction was then quenched by the addition of methanol (2 L). The resulting mixture was concentrated under vacuum. This resulted in of tert-butyl N-[(lr, 4r)-4-(hydroxymethyl)cyclohexyl]carbamate(3000 g, 99.6percent) as a white solid. MS (ESI): mass calcd. for C12H23N03, 229.32; m/z found,215.2 [M-tBu+MeCN+H] ?H NMR: (300 IVIFIz, CDC13): 4.40 (s, 1H), 3.45 (d, J 6.3 Hz,2H), 3.38 (s, 1H), 2.05-2.02 (m, 2H), 1.84-1.81 (m, 2H), 1.44 (s, 11H), 1.17-1.01 (m, 4H)
		Example 22 tert-butyl [trans-4-(hydroxymethyl)cyclohexyl]carbamate To anhydrous tetrahydrofuran (30 mL) solution of trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecalboxylic acid (2.17 g), 1 N-boran-tetrahydrofuran complex/tetrahydrofuran solution (17.8 mL) was slowly added at 0°C. The reaction solution was stirred at 0°C for 2 hours. To the reaction solution, an aqueous saturated sodium hydrogen carbonate solution (100 mL) was added, and then aqueous layer was extracted twice with 100 mL of ethyl acetate. The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. Without purifying the residue, the title compound (1.6 g) having the following physical properties was obtained. TLC: Rf 0.60(ethyl acetate); NMR(CDCl3):delta 0.97-1.16 (m, 4H), 1.44 (s, 9H), 1.80-1.84 (m, 2H), 2.03-2.06 (m, 2H), 3.31 (m, 1H), 3.45 (d, J=6.6Hz, 2H), 4.37 (m, 1H).
	With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 20℃;Product distribution / selectivity;	A solution of trans -4-([(\\,\\- dimethylethyl)oxy]carbonyl}amino)cyclohexanecarboxylic acid (1.45 g, 5.96 mmol) in THF (40 mL) was added to BH3-DMS (5.2 mL, 17.28 mmol) in THF (40 mL) at 0°C. The contents were allowed to stir at room temperature for 3 hrs. To the reaction mixture MeOH (10 mL) was added and evaporated to dryness under reduced pressure. The residue was co distilled with MeOH 3 times. The resulting residue was dissolved in DCM and washed with brine solution. Evaporation of the solvent under reduced pressure afforded a white solid (1.3 g, 94percent). This crude product was carried over to the next step without further purification.

	With diborane; In tetrahydrofuran; at 0 - 20℃; for 6h;	Step A: tert-butyl (1r,4r)-4-(hydroxymethyl)cyclohexylcarbamate (1158) To a stirred solution of (1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid (2.00 g, 8.22 mmol) in THF (20 mL), borane (8.22 mL, 16.44 mmol) was added dropwise at 0° C. After the resulting mixture was stirred for 6 hr at ambient temperature, it was quenched with water (20 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed brine (2×30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound: 1H NMR (400 MHz, CDCl3): delta 4.62 (s, 1H), 3.48 (d, J=6.4 Hz, 2H), 3.01-2.98 (m, 2H), 1.89-1.71 (m, 4H), 1.70-1.61 (m, 1H), 1.49 (s, 9H), 1.05-0.90 (m, 4H).
3.5 kg	With sodium tetrahydroborate; boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 30℃; for 6h;Large scale;	In the 50 L reaction kettle, adding 5 kg of trans - 4 - Boc - amino-cyclohexane carboxylic acid, 20 kg of tetrahydrofuran, 10 kilograms of sodium borohydride. Control temperature, stirring in batches under the adding 15 liter 1 M boron trifluoride ether solution. Control temperature at 0 - 10 degrees, reaction 1 hours, after up to 30 degrees, the reaction 5 hours. Concentrated off solvent, adding water, stirring, precipitated solid, filtering, to obtain 3.5 kg trans - 4 - Boc - amino-cyclohexane methanol

Reference： [1]Patent: WO2018/112382,2018,A1 .Location in patent: Page/Page column 109; 110
[2]Patent: EP1961744,2008,A1 .Location in patent: Page/Page column 100
[3]Patent: WO2010/45987,2010,A1 .Location in patent: Page/Page column 44
[4]Patent: US2016/333021,2016,A1 .Location in patent: Paragraph 1158
[5]Patent: CN107011216,2017,A .Location in patent: Paragraph 0024; 0025
[6]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 89 - 93

28
[ 53292-90-3 ]
[ 543-27-1 ]
C₁₇H₂₉NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0℃; for 0.5h;	Intermediate 17.4 To a solution of commercially available cis-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (200 mg, 0.82 mmol) in THF (3 mL) under N2, Et3N (0.17 mL, 1.23 mmol) and isobutyl chlorofomate (0.106 mL, 0.82 mmol) are added at 0 C. After stirred at that temperature for 30 min, filtration and concentration under the reduced pressure give anhydride. To a solution of the crude in MeOH (5 mL) under N2, NaBH4 (170 mg, 4.49 mmol) is added at 0 C. After stirred at that temperature for 40 min, sat. KHSO4aq. is added to the solution. Organic phase is extracted with CH2Cl2, dried over Na2SO4. Filtration and concentration under the reduced pressure give the crude. Purification by silica gel chromatography affords intermediate 17.4 (185.3 mg, 0.808 mmol) in 99percent yield. ES-MS: M+H=230, ctret=1.62 min. 1H NMR (400 MHz, CDCl3) ? 4.38 (br, 1H), 3.45 (br, 2H), 3.38 (br, 1H), 2.04 (d, J=9.12 Hz, 2H), 1.83 (d, J=10.8 Hz, 2H), 1.47 (s, 9H), 1.26 (dd, J=7.32, 7.08 Hz, 1H), 1.15-0.99 (m, 4H).

Reference： [1]Patent: US2008/319018,2008,A1 .Location in patent: Page/Page column 38-39

29
[ 53292-90-3 ]
[ 530-62-1 ]
C₁₅H₂₃N₃O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 718 - 723

30
[ 249889-69-8 ]
[ 53292-90-3 ]
[ 615568-05-3 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 2685 - 2689

31
C₂₇H₃₈N₅O₄Pol [ No CAS ]
[ 53292-90-3 ]
C₃₉H₅₇N₆O₇Pol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 7425 - 7434

32
[ 53292-90-3 ]
[ 643067-91-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With ammonium chloride; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 1h;	(1r,4r)-4-(tert-Butoxycarbonyl-amino)cyclohexanecarboxylic acid (1.7 g, 6.99 mmol), ammonium chloride (560 mg, 10.5 mmol), O-(benzotriazol-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate (2.66 g, 6.99 mmol), triethylamine (2.92 ml, 20.96 mmol), and acetonitrile (20 ml) were stirred at room temperature for 1 h. The reaction was filtered and rinsed with fresh acetonitrile. The solid was vacuum dried to give the product (1.57 g, 93percent yield) as white solid.
93.5%		A solution of trans-4-(Boc-amino)cyclohexane carboxylic acid (Al-1) (62g,0.256mol,1.0eq) in THF (1500mL) was treated with NMM (64.6g, 0.64mol, 2.5eq) in nitrogen atmosphere. The mixture was cooled to -78°C, and isobutyl chloroformate (33.6g, 0.33mol, 1.3eq) was added dropwise. After stirring at -78°C for Ihr, H3(gas) was bubbled through the mixture for about 20mins. After that the reaction temperature rose to -30°C, then stirring at - 30°C for Ihr. The resulting slurry was filtered, washed by water (3*200mL), and oven dried to give compound Al-2 as white powder (58g, yield 93.5percent). MS-ESI:[M+1]+: 243.1 MR(300MHz, de-DMSO): 7.192(s, lH),6.688-6.728(m,2H),3.122-3.147(m, lH), 1.92- 1.959(m, 1H), 1.696-1.787(m,4H), 1.382(s,9H), 1.086-1.358(m,4H).
50%		tert-Butyl((1R,4R)-4-carbamoylcyclohexyl)carbamate. To a solution of (1R, 4R)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (2.5 g, 10 mmol) in dry THF (10 mL) was added ethyl chloroformate (1.6 g, 15 mmol) and triethyl amine (3.1 g, 30 mmol) at 0° C. and the reaction was stirred at ambient temperature for 3 h. Completion of the reaction was confirmed by TLC. The reaction was quenched with ammonia in THF (10 M solution). The product was isolated via standard methods to afford tert-butyl((1R,4R)-4-carbamoylcyclohexyl)carbamate (1.4 g, 50percent) as white solid. GCMS m/z 242 [M]+.

With ammonium chloride; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 25℃; for 3h;

To a mixture of 551 trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (65.0 g, 267.2 mmol, 1.0 eq.), 157 NH4Cl (21.4 g, 400.7 mmol, 1.5 eq.) and 156 TEA (801.5 mmol, 111.6 mL, 3 eq.) in 23 MeCN (1.3 L) was added 155 HBTU (111.5 g, 293.9 mmol, 1.1 eq.) and the mixture was stirred at 25° C. for 3 hrs. The mixture was filtered and then the filter cake was washed with petroleum ether (200 mL) and dried to give 552 trans-tert-butyl N-(4-carbamoylcyclohexyl)carbamate (140 g, crude, 2 batches) as a white solid. 1H NMR (METHANOL-d4, 400 MHz) delta=3.25-3.34 (m, 1H), 2.14 (tt, J=12.3, 3.5 Hz, 1H), 1.83-1.99 (m, 4H), 1.52 (qd, J=13.1, 2.9 Hz, 2H), 1.42 (s, 9H), 1.21 (qd, J=12.7, 3.5 Hz, 2H)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6793 - 6799
[2]Patent: WO2018/67422,2018,A1 .Location in patent: Page/Page column 37; 38
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 6866 - 6880
[4]Patent: US2017/348315,2017,A1 .Location in patent: Paragraph 0401
[5]Journal of Medicinal Chemistry,2015,vol. 58,p. 3548 - 3571
[6]Patent: US2019/77799,2019,A1 .Location in patent: Paragraph 0642-0643

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[ 791775-31-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6793 - 6799

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[ 1021920-37-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6793 - 6799

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[ 53292-90-3 ]
[ 1021919-78-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6793 - 6799

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[ 53292-90-3 ]
[ 1021917-34-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6793 - 6799

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[ 53292-90-3 ]
[ 1357278-98-8 ]

Reference： [1]Patent: US2012/28969,2012,A1

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[ 53292-90-3 ]
[ 1357278-99-9 ]

Reference： [1]Patent: US2012/28969,2012,A1

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[ 42826-42-6 ]
[ 53292-90-3 ]
[ 1357278-97-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; at 20℃;	Example 9 and 10Preparation of N-((1r,4r)-4-(5-tert-butyl-1,3,4-oxadiazol-2-yl)cyclohexyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)-1H-benzo[d]imidazole-5-sulfonamide andN-((1r,4r)-4-(5-tert-butyl-1,3,4-oxadiazol-2-yl)cyclohexyl)-2-(4-(4-methylpiperazin-1-yl)phenyl)-1H-benzo[d]imidazole-5-sulfonamide Step 1. Preparation of tert-butyl (1r,4r)-4-(2-pivaloylhydrazinecarbonyl)cyclohexylcarbamate; Pivaloyl hydrazide (4.98 g, 42.91 mmol) was added to a solution of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (8.70 g, 35.76 mmol), HATU (13.57 g, 35.67 mol), and NMM (9.04 g, 89.4 mmol) in 350 mL of DMF. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, water and brine. The organic phase was dried (Na2 SO4) and concentrated to give approximately 11.44 g crude (MS: (M+H)+=342.20). This material was used as is in the next step.

Reference： [1]Patent: US2012/28969,2012,A1 .Location in patent: Page/Page column 62-63

40
[ 53292-90-3 ]
tert-butyl N-(trans-4-ethynylcyclohexyl)-N-methylcarbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4990 - 5002
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 4990 - 5002

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[ 53292-90-3 ]
[ 400898-95-5 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4990 - 5002

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[ 53292-90-3 ]
[ 400898-93-3 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4990 - 5002

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[ 53292-90-3 ]
[ 6638-79-5 ]
[ 400898-92-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In tetrahydrofuran; methanol; at 20℃; for 2h;	To a solution of <strong>[53292-90-3](1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexane-1-carboxylic acid</strong> (1.22 g, 5.00 mmol) in THF (10 mL) and MeOH (10 mL) in a round-bottom flask were added N,O-dimethylhydroxylamine hydrochloride (540 mg, 5.50 mmol), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (1.52 g, 5.50 mmol), 4-methylmorpholine (1.00 g, 10.0 mmol). The resulting mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. Purification by flash chromatography on silica gel (0percent to 100percent AcOEt/dichloromethane linear gradient) provided the title compound (1.42 g, 4.96 mmol, 99percent yield): 1H NMR (400 MHz, CDCl3) delta 4.37 (brs, 1H), 3.88-3.67 (m, 1H), 3.70 (s, 3H), 3.51-3.36 (m, 1H), 3.17 (s, 3H), 2.67-2.52 (m, 1H), 2.15-2.02 (m, 2H), 1.88-1.78 (m, 2H), 1.69-1.54 (m, 2H), 1.45 (s, 9H), 1.21-1.08 (m, 2H).

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4990 - 5002
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 3333 - 3337

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[ 873537-32-7 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 6866 - 6880
[2]Patent: WO2018/67422,2018,A1

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[ 53292-90-3 ]
[ 1198163-55-1 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 6866 - 6880

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[ 53292-90-3 ]
[ 1198163-38-0 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 6866 - 6880

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[ 53292-90-3 ]
[ 1401728-88-8 ]
[ 1401729-07-4 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-benzoic acid hydrazide (29) (200 mg, 0.618 mmol), trans-4-(tert-butoxycarbonylamino) cyclohexanecarboxylic acid (226 mg, 0.928 mmol), EDC (119 mg, 0.618 mmol), HOBT (95 mg, 0.618 mmol) and Et3N (0.086 ml, 0.618 mmol) were dissolved in 2 ml of DMF and stirred for 16 h at rt. Then the mixture was diluted with EtOAc, washed with NaCl-solution and dried over Na2 SO4. Evaporation gave a brown oil. The crude product was purified by chromatography (silica gel, methanol/EtOAc) to yield a white solid. MS (ESI): 549 [M+H]+, 1H-NMR (DMSO-d6, 600 MHz) delta (ppm): 10.15 (s, 1H), 9.71 (s, 1H), 7.73 (d, 2H), 7.26 (d, 2H), 6.77 (s, 1H), 6.70 (br, 1H), 4.10 (s, 2H), 3.17 (m, 1H), 2.67 (q, 2H), 2.63 (s, 3H), 2.48 (s, 3H), 2.14 (m, 1H), 1.7-1.85 (m, 4H), 1.3-1.4 (m, 2H), 1.37 (s, 9H), 1.17 (m, 2H), 1.12 (t, 3H).

Reference： [1]Patent: US2012/252778,2012,A1 .Location in patent: Paragraph 0544-0545

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[ 1401728-88-8 ]
C₃₀H₃₈N₆O₃ [ No CAS ]

Reference： [1]Patent: US2012/252778,2012,A1

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[ 1456507-49-5 ]

Reference： [1]Patent: WO2013/134079,2013,A1
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 10003 - 10015

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[ 1456507-51-9 ]

Reference： [1]Patent: WO2013/134079,2013,A1

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[ 1456505-46-6 ]

Reference： [1]Patent: WO2013/134079,2013,A1

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[ 1456505-47-7 ]
[ 1456505-48-8 ]

Reference： [1]Patent: WO2013/134079,2013,A1

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[ 613-94-5 ]
[ 1456507-48-4 ]