[ CAS No. 730980-59-3 ] {[proInfo.proName]}

Name: 730980-59-3|(R)-Chroman-4-amine hydrochloride|95%
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SKU: A178396
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Quality Control of [ 730980-59-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 730980-59-3 ]

Product Details of [ 730980-59-3 ]

CAS No. :	730980-59-3	MDL No. :	MFCD08457629
Formula :	C₉H₁₂ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BVMKYKMJUZEGBU-DDWIOCJRSA-N
M.W :	185.65	Pubchem ID :	53249223
Synonyms :

Calculated chemistry of [ 730980-59-3 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.33
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	50.27
TPSA :	35.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.21 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	1.72
Log Po/w (WLOGP) :	1.95
Log Po/w (MLOGP) :	1.44
Log Po/w (SILICOS-IT) :	1.63
Consensus Log Po/w :	1.35

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.44
Solubility :	0.667 mg/ml ; 0.00359 mol/l
Class :	Soluble
Log S (Ali) :	-2.08
Solubility :	1.56 mg/ml ; 0.00839 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.36
Solubility :	0.814 mg/ml ; 0.00439 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.29

Safety of [ 730980-59-3 ]

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

Application In Synthesis of [ 730980-59-3 ]

* 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 [ 730980-59-3 ]
Downstream synthetic route of [ 730980-59-3 ]

[ 730980-59-3 ] Synthesis Path-Upstream 1~1

1
[ 730980-58-2 ]
[ 730980-59-3 ]

Reference： [1] Patent: US2004/157739, 2004, A1, . Location in patent: Page 14

[ 730980-59-3 ] Synthesis Path-Downstream 1~40

1
[ 730980-59-3 ]
[ 127099-85-8 ]
(4R)-4-(bisguanidino)chromane hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.4%	In 1,3-Dichlorobenzene; at 140 - 150℃; for 2.5h;	e. (4S)-4-(bisguanidino)chromane hydrochloride A homogeneous mixture of (4R)-3,4-dihydro-2H-4-chromanylammonium chloride (2.3 g, 0.0124 mol) and 1-cyanoguanidine (1.04 g, 0.0124 mol) in 1,3-dichlorobenzene was heated at 140-150 CC for 150 minutes.The cooled mixture was diluted with toluene and filtered to give (4S)-4-(bisguanidino)chromane hydrochloride (3.3 g, yield 89.4%) as a solid, purity 90%.

Reference： [1]Patent: US2004/157739,2004,A1 .Location in patent: Page 14

2
[ 730980-58-2 ]
[ 730980-59-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; water; In ethanol; for 12h;Heating / reflux;	d. (4R)4-aminochromane hydrochloride A solution of the above N-[(4R)4-chromanyl]-2-methoxyacetamide (2.2 g, 0.0325 mol) in ethanol (100 ml) and concentrated hydrochloric acid (30 ml) was heated at reflux for 12 hours, then evaporated.A small amount of ethyl acetate was added to the residue and the solid filtered off to give (4R)4-aminochromane hydrochloride (2.3 g), m.p. 261-263 C., chemical purity>95%.

Reference： [1]Patent: US2004/157739,2004,A1 .Location in patent: Page 14

3
[ 74124-79-1 ]
[ 913296-58-9 ]
[ 730980-59-3 ]
[ 1034770-55-2 ]

Yield	Reaction Conditions	Operation in experiment
		Di(N-succinimidyl) carbonate (538 mg, 2.1 mmol) was suspended in acetonitrile (5 mL), Example 1G (555 mg, 2.0 mmol) dissolved in acetonitrile (10 mL) and pyridine (0.17 mL, 2.1 mmol) were added, and the mixture stirred for 15 minutes at ambient temperature. <strong>[730980-59-3](R)-chroman-4-amine hydrochloride</strong> (J&W PharmLab, 371 mg, 2.0 mmol) and diisopropylethylamine (1.05 mL, 6.0 mmol) were added and the mixture stirred for 30 minutes. The mixture was filtered through a silica gel plug, rinsed with 1/1 ethyl acetate/hexane, and concentrated under reduced pressure to afford 1-(7-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl)-3-((R)-chroman-4-yl)urea.

Reference： [1]Patent: US2008/153871,2008,A1 .Location in patent: Page/Page column 19

4
[ 730980-59-3 ]
[ 1266229-00-8 ]
[ 1266230-01-6 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;	Methyl(3S,8aR)-2-[(2S)-2-[N-(tert-butoxycarbonyl)-N-methyl-L-alanyl]amino}-2-cyclohexylacetyl]octahydropyrrolo[1,2-a]pyrazine-3-carboxylate (1.80 g) was dissolved in tetrahydrofuran (40 mL), a solution prepared by dissolving lithium hydroxide monohydrate (193 mg) in water (10 mL) was added thereto, and the mixture was stirred at 50 C. for 3 hr. The mixture was allowed to cool to room temperature, 1M hydrochloric acid (4.6 mL) was added thereto, and the mixture was concentrated under reduced pressure to give a colorless amorphous powder. This amorphous powder, <strong>[730980-59-3](4R)-3,4-dihydro-2H-chromen-4-amine hydrochloride</strong> (984 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.48 g), 1-hydroxybenzotriazole (478 mg) and N,N-diisopropylethylamine (1.23 mL) were mixed in N,N-dimethylformamide (20 mL), and the mixture was stirred at room temperature for 48 hr. The mixture was diluted with ethyl acetate (30 mL), and washed with water (30 mL) and saturated brine (30 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90?100/0) and then basic silica gel column chromatography (ethyl acetate/hexane=30/70?100/0) to give tert-butyl[(1S)-2-({(1S)-1-cyclohexyl-2-[(3S,8aR)-3-[(4R)-3,4-dihydro-2H-chromen-4-ylcarbamoyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-oxoethyl}amino)-1-methyl-2-oxoethyl]methylcarbamate as a colorless oil. This colorless oil was dissolved in ethyl acetate (16 mL), 4M hydrogen chloride-ethyl acetate solution (8 mL) was added thereto, and the mixture was stirred at room temperature for 4 hr. To the mixture was added water (30 mL), and the aqueous layer was separated. The aqueous layer was neutralized with 1M aqueous sodium hydroxide solution, and extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (912 mg) as a colorless oil. LC-MS: 526.4 (MH+)1H NMR (DMSO-d6, 300 MHz): delta 0.84-1.36 (9H, m), 1.49-2.05 (12H, m), 2.18 (3H, s), 2.84-3.04 (2H, m), 3.16-3.69 (5H, m), 4.07-4.60 (3H, m), 4.66-4.80 (1H, m), 4.91-5.12 (2H, m), 6.71-6.93 (2H, m), 7.08-7.27 (2H, m), 7.85-8.05 (1H, m), 8.12-8.35 (1H, m).
1.21 g	With benzotriazol-1-ol; 1,2-dichloro-ethane; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;	A solution of 54 (1.80 g, 3.54 mmol) in THF (40 mL) was added tolithium hydroxide monohydrate (193 mg, 4.60 mmol) in water(10 mL), and the reaction mixture was stirred at 50 C for 3 h. Themixture was allowed to cool at room temperature and 1 MHCl (4.6 mL) was added to the mixture. The mixture was concentratedunder reduced pressure, and the residue was dissolved inDMF (20 mL). To the solution were added (R)-chroman-4-aminehydrochloride (984 mg, 5.30 mmol), EDC (4.48 g, 23.4 mmol), HOBt(478 mg, 3.53 mmol) and DIPEA (1.23 mL, 7.05 mmol) successively,and the mixture was stirred at room temperature for 48 h. Themixture was partitioned between EtOAc (30 mL) and water(30 mL), and the organic layer was washed with brine (30 mL),dried over MgSO4, and concentrated under reduced pressure.The residue was purified by silica gel column chromatographytwice (first column: 10-100% EtOAc in n-hexane, secondcolumn: 30-100% EtOAc in n-hexane) to give tert-butyl[(1S)-2-({(1S)-1-cyclohexyl-2-[(3S,8aR)-3-[(4R)-3,4-dihydro-2Hcromen-4-ylcarmoyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-oxoethyl}amino)-1-methyl-2-oxoethyl]methylcarbamate ascolorless oil (1.21 g). This colorless oil was dissolved in EtOAc(16 mL), and to the solution was added 4 M HCl in EtOAc (8 mL).The mixture was stirred at room temperature for 4 h. The reactionwas quenched by the addition of water (30 mL), the aqueous layerwas neutralized by 1 M NaOH (35 mL) and extracted with EtOAc(30 mL). The organic layer was dried over MgSO4 and concentratedunder reduced pressure to give a salt free form of 56 (912 mg, 42%)as colorless oil. A solution of the oil (902 mg, 1.47 mmol) in EtOAc(10 mL) was added to 4 M HCl in EtOAc (1.0 mL), and the mixturewas stirred at room temperature for 3 h. The precipitate was collectedby filtration, washed with EtOAc (10 mL), and dried under reducedpressure to give 57 (1.01 g, 48%) as a white amorphous powder

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 89
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 1228 - 1246
[3]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7938 - 7954

5
[ 730980-59-3 ]
C₁₅H₂₆N₂O₅ [ No CAS ]
[ 1266228-62-9 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 2-tert-butyl 3-methyl(3S,7R,8aR)-7-ethoxyhexahydropyrrolo[1,2-a]pyrazine-2,3(1H)-dicarboxylate (3.6 g) in tetrahydrofuran (90 mL)/water (18 mL) was added lithium hydroxide monohydrate (736 mg) at room temperature, and the reaction mixture was stirred at 50 C. for 5 hr. The reaction mixture was allowed to cool to room temperature, neutralized with 1M hydrochloric acid (17.5 mL), and concentrated under reduced pressure. The residue was subjected twice to azeotropic distillation with toluene, and the residue was dried in vacuum for 5 hr. The obtained residue was dissolved in N,N-dimethylformamide (54 mL), and 1-hydroxybenzotriazole (1.78 g) and N,N-diisopropylethylamine (5.73 mL) were added thereto. The 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.30 g) was added thereto at 0 C., and the mixture was stirred at room temperature for 30 min. (4R)-3,4-Dihydro-2H-chromen-4-amine hydrochloride (2.14 g) was added thereto, and the reaction mixture was stirred at room temperature for 3 days. The mixture was poured into ethyl acetate/water, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50?20/80). The object fractions were collected, and concentrated under reduced pressure, and the residue was dried in vacuum for 1 hr to give the title compound (4.04 g) as a white powder.LC-MS: 446.3 (MH+)1H NMR (DMSO-d6, 300 MHz): delta 1.09 (3H, t, J=7.1 Hz), 1.15-1.35 (1H, m), 1.35-1.45 (9H, m), 1.65-2.25 (6H, m), 2.87-3.08 (2H, m), 3.33 (2H, q, J=7.1 Hz), 3.30-3.45 (1H, m), 3.80-4.00 (2H, m), 4.15-4.35 (2H, m), 4.37-4.53 (1H, m), 5.02-5.14 (1H, m), 6.73-6.89 (2H, m), 7.10-7.19 (2H, m), 8.20-8.40 (1H, m).

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 82-83
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 1228 - 1246

6
[ 730980-59-3 ]
C₂₅H₄₂N₄O₇ [ No CAS ]
[ 1266230-55-0 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 40h;	To a solution of methyl(3S,7R,8aR)-2-[(2S)-2-[N-(tert-butoxycarbonyl)-N-methyl-L-alanyl]amino}-2-cyclohexylacetyl]-7-hydroxyoctahydropyrrolo[1,2-a]pyrazine-3-carboxylate (166 mg) in a mixed solvent (6.25 mL) of tetrahydrofuran/water (4/1) was added lithium hydroxide monohydrate (20 mg), and the mixture was stirred with heating at 50 C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and neutralized with 1N hydrochloric acid (0.48 mL), and the solvent was evaporated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (7 mL), <strong>[730980-59-3](4R)-3,4-dihydro-2H-chromen-4-amine hydrochloride</strong> (88 mg), 1-hydroxybenzotriazole (42.7 mg), N-ethyldiisopropylamine (0.11 mL) and N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide-hydrochloride (400 mg) were added thereto, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture were added 1-hydroxybenzotriazole (21.4 mg), N-ethyldiisopropylamine (0.11 mL) and N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (200 mg), and the mixture was stirred again at room temperature for 24 hr. The reaction mixture was diluted with ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL), and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90?100/0?ethyl acetate/methanol=80:20) to give the title compound (81 mg) as a yellow amorphous powder. LC-MS: 642.4 (MH+).1H NMR (CDCl3, 300 MHz): delta 0.63-0.80 (1H, m), 0.80-1.02 (3H, m), 1.04-1.17 (2H, m), 1.17-1.30 (2H, m), 1.34-1.56 (12H, m), 1.57-1.86 (3H, m), 1.87-2.00 (1H, m), 2.08-2.45 (7H, m), 2.49-2.60 (1H, m), 2.65-2.79 (3H, m), 2.97-3.14 (2H, m), 3.68-3.91 (1H, m), 3.98-4.09 (1H, m), 4.15-4.39 (3H, m), 4.57 (1H, br s), 4.63-4.82 (1H, m), 5.03-5.11 (1H, m), 5.24 (1H, d, J=3.4 Hz), 6.34-7.90 (5H, m).

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 104

7
[ 730980-59-3 ]
C₂₆H₄₄N₄O₇ [ No CAS ]
[ 1266230-60-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of methyl(3S,7R,8aR)-2-[(2S)-2-[N-(tert-butoxycarbonyl)-N-methyl-L-alanyl]amino}-2-cyclohexylacetyl]-7-hydroxy-7-methyloctahydropyrrolo[1,2-a]pyrazine-3-carboxylate (77 mg) in a mixed solvent (3.13 mL) of tetrahydrofuran/water (4/1) was added lithium hydroxide monohydrate (9.0 mg), and the mixture was stirred with heating at 60 C. for 3 hr. The reaction mixture was allowed to cool to room temperature, and neutralized with 1N hydrochloric acid (0.2 mL), and the solvent was evaporated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1.5 mL), <strong>[730980-59-3](4R)-3,4-dihydro-2H-chromen-4-amine hydrochloride</strong> (40 mg), N-ethyldiisopropylamine (0.05 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (272 mg) were added thereto, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL), and the aqueous layer was extracted with a mixed solvent (100 mL) of ethyl acetate/tetrahydrofuran (4/1). The combined organic layers were dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80?100/0?ethyl acetate/methanol=80/20) and basic silica gel column chromatography (ethyl acetate/hexane=10/90?80/20) to give the title compound (41.4 mg) as a colorless amorphous powder. LC-MS: 656.4 (MH+).1H NMR (CDCl3, 300 MHz): delta 0.64-1.39 (11H, m), 1.40-1.51 (9H, m), 1.60-1.85 (5H, m), 1.94-2.10 (3H, m), 2.13-2.30 (3H, m), 2.41-2.65 (2H, m), 2.64-2.84 (3H, m), 2.96-3.35 (2H, m), 3.61-4.41 (5H, m), 4.56-4.84 (2H, m), 5.06-5.32 (2H, m), 6.28-7.95 (6H, m).

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 106

8
[ 730980-59-3 ]
C₂₃H₃₉N₃O₇ [ No CAS ]
[ 1266230-62-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of methyl(3S,8aR)-2-{(2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylacetyl}-7,7-dimethoxyoctahydropyrrolo[1,2-a]pyrazine-3-carboxylate (213 mg) in a mixed solvent (10 mL) of tetrahydrofuran/water (4/1) was added lithium hydroxide monohydrate (27.8 mg), and the mixture was stirred with heating at 60 C. for 1 hr. The reaction mixture was allowed to cool to room temperature, and neutralized with 1N hydrochloric acid (0.8 mL), and the solvent was evaporated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL), <strong>[730980-59-3](4R)-3,4-dihydro-2H-chromen-4-amine hydrochloride</strong> (123 mg), N-ethyldiisopropylamine (0.155 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (838 mg) were added thereto, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL), and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95?100/0) to give the title compound (231 mg) as a yellow oil. LC-MS: 601.4 (MH+).1H NMR (CDCl3, 300 MHz): delta 0.60-1.34 (9H, m), 1.36-1.88 (11H, m), 1.96-2.11 (2H, m), 2.16-2.39 (4H, m), 2.49-2.63 (1H, m), 2.68-2.88 (1H, m), 3.01-3.12 (1H, m), 3.16-3.22 (5H, m), 3.23-3.37 (1H, m), 3.59-3.96 (1H, m), 3.97-4.32 (3H, m), 4.44-4.54 (1H, m), 4.66-4.76 (0.5H, m), 5.06-5.21 (1.5H, m), 5.25-5.37 (1H, m), 6.45-8.22 (5H, m).

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 107

9
[ 730980-59-3 ]
C₁₄H₂₄N₂O₅ [ No CAS ]
[ 1266230-65-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 14h;	To a solution of 2-tert-butyl 3-methyl(3S,7R,8aR)-7-hydroxy-7-methylhexahydropyrrolo[1,2-a]pyrazine-2,3(1H)-dicarboxylate (570 mg) in a mixed solvent of tetrahydrofuran/water (4/1) was added lithium hydroxide monohydrate (115 mg), and the mixture was stirred with heating at 60 C. for 3 hr. The reaction mixture was allowed to cool to room temperature, and neutralized with 1M hydrochloric acid (2 mL), and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (18 mL), <strong>[730980-59-3](4R)-3,4-dihydro-2H-chromen-4-amine hydrochloride</strong> (507 mg), N-ethyldiisopropylamine (6.50 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.46 g) were added thereto, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was diluted with ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL), and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95?100/0?ethyl acetate/methanol=80:20) to give the title compound (231 mg) as a yellow oil. LC-MS: 432.2 (MH+).1H NMR (DMSO-d6, 300 MHz): delta 1.18-1.23 (3H, m), 1.32-1.56 (10H, m), 1.74-2.24 (6H, m), 2.64-3.12 (2H, m), 3.23-3.39 (1H, m), 3.74-3.91 (1H, m), 4.14-4.28 (2H, m), 4.32-4.52 (1H, m), 4.57-4.69 (1H, m), 4.88-5.16 (1H, m), 6.66-6.93 (2H, m), 7.07-7.20 (2H, m), 8.17-8.44 (1H, m).

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 108

10
[ 730980-59-3 ]
C₂₆H₄₄N₄O₆ [ No CAS ]
[ 1266230-93-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;	To a solution of methyl(3S,8aR)-2-[(2S)-2-[N-(tert-butoxycarbonyl)-N-ethyl-L-alanyl]amino}-2-cyclohexylacetyl]octahydropyrrolo[1,2-a]pyrazine-3-carboxylate (300 mg) in THF (3 mL)/water (1 mL) was added lithium hydroxide hydrate (36 mg), and the mixture was stirred at 50 C. for 4 hr, neutralized with 1N hydrochloric acid (0.86 mL), and concentrated under reduced pressure. To the residue was added toluene, and the mixture was concentrated under reduced pressure, and dried under reduced pressure. The residue was diluted with DMF (6 mL), <strong>[730980-59-3](4R)-3,4-dihydro-2H-chromen-4-amine hydrochloride</strong> (138 mg), N-ethyldiisopropylamine (0.596 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (433 mg) were successively added thereto, and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with ethyl acetate, and washed successively with water, 5% aqueous sodium bicarbonate and water. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/methanol=100/0?70/30). The object fractions were concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=90/10?0/100) to give the title compound (111 mg). LC-MS: 640.4 (MH+).

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 115

11
[ 730980-59-3 ]
C₂₅H₄₀F₂N₄O₆ [ No CAS ]
[ 1266230-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	To a solution of methyl(3S,8aR)-2-[(2S)-2-[N-(tert-butoxycarbonyl)-N-methyl-L-alanyl]amino}-2-cyclohexylacetyl]-7,7-difluorooctahydropyrrolo[1,2-a]pyrazine-3-carboxylate (195 mg) in tetrahydrofuran (5.85 mL)/water (1.37 mL) was added lithium hydroxide monohydrate (24.0 mg), and the mixture was stirred at 50 C. for 5 hr. The mixture was allowed to cool to room temperature, 1M hydrochloric acid (0.58 mL) was added thereto, and the mixture was concentrated under reduced pressure. To the residue was added toluene, the mixture was concentrated under reduced pressure, and the residue was dried in vacuum. To the obtained residue were added successively N,N-dimethylformamide (3.9 mL), <strong>[730980-59-3](4R)-3,4-dihydro-2H-chromen-4-amine hydrochloride</strong> (100 mg), N,N-diisopropylethylamine (125 mul), 1-hydroxybenzotriazole (53 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (412 mg), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=33/67?0/100). The object fractions were collected, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40?5/95). The object fractions were collected, and concentrated under reduced pressure, and the residue was dried in vacuum for 1 hr to give the title compound (80 mg) as a white powder.LC-MS: 662.4 (MH+).1H NMR (DMSO-d6, 300 MHz): delta 0.80-1.28 (9H, m), 1.29-1.47 (9H, m); 1.49-1.79 (6H, m), 1.80-2.09 (2H, m), 2.13-2.59 (4H, m), 2.59-2.80 (4H, m), 3.22-3.67 (2H, m), 3.98-5.10 (7H, m), 6.71-6.90 (2H, m), 7.09-7.25 (2H, m), 7.60-7.90 (1H, m), 8.18-8.35 (1H, m).

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 117

12
[ 730980-59-3 ]
[ 1266229-03-1 ]
[ 1266229-69-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 15h;Product distribution / selectivity;	2-tert-Butyl 3-methyl(3S,8aR)-hexahydropyrrolo[1,2-a]pyrazine-2,3(1H)-dicarboxylate (852 mg) was dissolved in tetrahydrofuran (6 mL), a solution prepared by dissolving lithium hydroxide monohydrate (164 mg) in water (2 mL) was added thereto, and the mixture was stirred at 50 C. for 3 hr. To the mixture was added 1M hydrochloric acid (3.9 mL), and the mixture was concentrated under reduced pressure to give a colorless amorphous powder. This amorphous powder, <strong>[730980-59-3](4R)-3,4-dihydro-2H-chromen-4-amine hydrochloride</strong> (863 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.73 g), 1-hydroxybenzotriazole (486 mg) and N,N-diisopropylethylamine (1.57 mL) were mixed in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 15 hr. The mixture was diluted with ethyl acetate (50 mL), and washed with water (100 mL) and saturated brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50?100/0) to give the title compound (1.12 g) as a white solid. LC-MS: 402.2 (MH+)

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 91
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 1228 - 1246

13
[ 730980-59-3 ]
C₁₃H₂₀F₂N₂O₄ [ No CAS ]
[ 1266231-11-1 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	To 2-tert-butyl 3-methyl(3S,8aR)-7,7-difluorohexahydropyrrolo[1,2-a]pyrazine-2,3(1H)-dicarboxylate (0.70 g) were added tetrahydrofuran (21 mL)/water (4.9 mL) and lithium hydroxide monohydrate (147 mg), and the mixture was stirred at 50 C. for 5 hr. The mixture was allowed to cool to room temperature, 1M hydrochloric acid (3.5 mL) was added thereto, and the mixture was concentrated under reduced pressure. Toluene was added thereto, the mixture was concentrated again under reduced pressure, and the residue was dried in vacuum. To the obtained residue were successively added N,N-dimethylformamide (14 mL), <strong>[730980-59-3](4R)-3,4-dihydro-2H-chromen-4-amine hydrochloride</strong> (609 mg), N,N-diisopropylethylamine (761 mul), 1-hydroxybenzotriazole (354 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.51 g), and the mixture was stirred at room temperature for 18 hr. To the reaction mixture were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20?0/100). The object fractions were collected, the solvent was evaporated under reduced pressure, and the residue was dried in vacuum to give the title compound (450 mg).1H NMR (DMSO-d6, 300 MHz): delta 1.36-1.44 (9H, m), 1.76-2.09 (4H, m), 2.21-2.57 (4H, m), 2.91-3.14 (1H, m), 3.28-3.48 (1H, m), 3.84-3.98 (1H, m), 4.15-4.26 (2H, m), 4.38-4.57 (1H, m), 4.97-5.13 (1H, m), 6.73-6.88 (2H, m), 7.09-7.19 (2H, m), 8.23-8.43 (1H, m).

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 121
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 1228 - 1246

14
[ 730980-59-3 ]
C₁₄H₂₂N₂O₄ [ No CAS ]
[ 1266231-44-0 ]

Yield	Reaction Conditions	Operation in experiment
		5-tert-Butyl 4-methyl(1aR,4S,6aR,7aR)-octahydro-5H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazine-4,5-dicarboxylate (691 mg) was dissolved in tetrahydrofuran (5 mL), a solution prepared by dissolving lithium hydroxide monohydrate (202 mg) in water (1.5 mL) was added thereto, and the mixture was stirred at 50 C. for 5 hr. To the mixture were added 1M hydrochloric acid (4.81 mL) and concentrated under reduced pressure. To the residue was added toluene, and the mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (120 mL), <strong>[730980-59-3](4R)-3,4-dihydro-2H-chromen-4-amine hydrochloride</strong> (650 mg), 1-hydroxybenzotriazole (315 mg) and diisopropylethylamine (0.812 mL) were added thereto, and the mixture was stirred for 10 min. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.95 g) was added slowly thereto, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with water and ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated sodium chloride water, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=9/91?100/0) to give the title compound (172 mg) as a colorless oil.LC-MS: 414 (MH+).1H NMR (CDCl3, 300 MHz): delta 0.27-0.49 (1H, m), 0.68-0.78 (1H, m), 1.10-1.70 (2H, m), 1.44 (9H, s), 1.91-2.08 (1H, m), 2.13-2.29 (2H, m), 2.45-2.68 (2H, m), 2.76-2.88 (1H, m), 2.97-3.11 (1H, m), 3.45-4.21 (3H, m), 4.19-4.31 (1H, m), 4.49-4.74 (1H, m), 5.12-5.26 (1H, m), 6.43-6.76 (1H, m), 6.79-6.96 (2H, m), 7.13-7.25 (2H, m).
172 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	To a solution of 6 (691mg, 2.33mmol) in THF (5mL) were added lithium hydroxide monohydrate (202mg, 4.81mmol) and water (1.5mL). After stirring at 50C for 5h, the reaction mixture was neutralized with 1M HCl (4.8mL), and concentrated in vacuo. The residue was dissolved in DMF (120mL), and to the solution were added <strong>[730980-59-3](R)-chroman-4-amine hydrochloride</strong> 10 (650mg, 3.50mmol), 1-hydroxybenzotriazole (315mg, 2.33mmol), DIPEA (0.81mL, 4.66mmol) and WSC (2.95g, 15.38mmol) successively. The reaction mixture was stirred at room temperature for 18h, and partitioned between water (150mL) and EtOAc (150mL). The organic layer was washed with satd NaHCO3 (150mL), brine (100mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (n-Hexane/EtOAc=91:9?0:100) to give 11 (172mg, 18%) as colorless oil. 1H NMR (300MHz, CDCl3) delta 0.27-0.49 (1H, m), 0.68-0.78 (1H, m), 1.10-1.70 (2H, m), 1.44 (9H, s), 1.91-2.08 (1H, m), 2.13-2.29 (2H, m), 2.45-2.68 (2H, m), 2.76-2.88 (1H, m), 2.97-3.11 (1H, m), 3.45-4.21 (3H, m), 4.19-4.31 (1H, m), 4.49-4.74 (1H, m), 5.12-5.26 (1H, m), 6.43-6.76 (1H, m), 6.79-6.96 (2H, m), 7.13-7.25 (2H, m).

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 126
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5725 - 5737

15
[ 730980-59-3 ]
C₁₄H₂₁F₃N₂O₅ [ No CAS ]
[ 1266231-55-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;	2-tert-Butyl 3-methyl(3S,7R,8aR)-7-hydroxy-7-(trifluoromethyl)hexahydropyrrolo[1,2-a]pyrazine-2,3(1H)-dicarboxylate (350 mg) was dissolved in tetrahydrofuran (5 mL), a solution prepared by dissolving lithium hydroxide monohydrate (86.0 mg) in water (1.5 mL) was added thereto, and the mixture was stirred at 55 C. for 3 hr. 1M Hydrochloric acid (2.05 mL) and toluene were added thereto, the mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylformamide (10 mL). (4R)-3,4-Dihydro-2H-chromen-4-amine hydrochloride (265 mg), diisopropylethylamine (500 muL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (903 mg) were added thereto, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with water and ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/98?75/25) to give the title compound (324.3 mg) as a pale-yellow oil.LC-MS: 486 (MH+).1H NMR (CDCl3, 300 MHz): delta 1.37-1.47 (9H, m), 1.53-1.66 (1H, m), 1.70-2.08 (3H, m), 2.08-2.32 (2H, m), 2.37-2.60 (2H, m), 2.58-2.86 (1H, m), 3.11-3.22 (1H, m), 3.64-3.78 (1H, m), 4.01-4.32 (3H, m), 4.64-4.88 (1H, m), 5.19 (1H, brs), 6.50 (1H, brs), 6.80-6.87 (1H, m), 6.87-6.97 (1H, m), 7.18 (2H, t, J=7.20 Hz).

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 128

16
[ 730980-59-3 ]
[ 1266231-67-7 ]
[ 1266231-69-9 ]

Yield	Reaction Conditions	Operation in experiment
		5-tert-Butyl 4-methyl(1aS,4S,6aR,7aS)-octahydro-5H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazine-4,5-dicarboxylate (691 mg) was dissolved in tetrahydrofuran (4 mL), a solution prepared by dissolving lithium hydroxide monohydrate (60.3 mg) in water (1.0 mL) was added thereto, and the mixture was stirred at 50 C. for 4 hr. To the reaction product was added toluene, and the mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (10 mL), <strong>[730980-59-3](4R)-3,4-dihydro-2H-chromen-4-amine hydrochloride</strong> (200 mg) and diisopropylethylamine (280 mg) were added thereto, and the mixture was stirred for 5 min. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (683 mg) was added thereto, the mixture was stirred at room temperature for 18 hr, and the reaction mixture was diluted with water and ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated sodium chloride water, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrated was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/98?80/20) to give the title compound (254.4 mg) as a colorless amorphous solid.LC-MS: 414 (MH+).1H NMR (CDCl3, 300 MHz): delta 0.08 (1H, dt, J=8.1, 6.0 Hz), 0.78-0.86 (1H, m), 1.31-1.48 (10H, m), 1.49-1.63 (1H, m), 1.82-2.10 (2H, m), 2.14-2.33 (1H, m), 2.39-2.49 (1H, m), 2.50-2.84 (2H, m), 3.69-3.85 (1H, m), 3.93-4.32 (3H, m), 4.58-4.83 (1H, m), 5.14-5.26 (1H, m), 6.30-6.57 (1H, m), 6.78-6.95 (2H, m), 7.14-7.27 (3H, m).

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 130-131

17
[ 730980-59-3 ]
C₁₃H₂₂N₂O₄ [ No CAS ]
[ 1266229-51-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	To a solution of 2-tert-butyl 3-ethyl(3S,8aS)-hexahydropyrrolo[1,2-a]pyrazine-2,3(1H)-dicarboxylate (670 mg) in a mixed solvent (5 mL) of tetrahydrofuran/water (4/1) was added lithium hydroxide monohydrate (141 mg), and the mixture was stirred with heating at 50 C. for 3 hr. The reaction mixture was allowed to cool to room temperature, neutralized with 1M hydrochloric acid (3.1 mL), and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (10 mL), <strong>[730980-59-3](4R)-3,4-dihydro-2H-chromen-4-amine hydrochloride</strong> (500 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.98 mL), 1-hydroxybenzotriazole (363 mg) and N,N-diisopropylethylamine (0.469 mL) were added thereto, and the reaction mixture was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, and the obtained residue was diluted with ethyl acetate (300 mL) and water (100 mL). The organic layer was dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, the residue was subjected to basic silica gel column chromatography (ethyl acetate/methanol=100/0?80/20), and the collected fractions were concentrated to give the title compound (381 mg) as a colorless amorphous powder. LC-MS: 402.2 (MH+)1H NMR (DMSO-d6, 300 MHz): delta 1.26-1.47 (10H, m), 1.48-2.06 (5H, m), 2.55-2.77 (2H, m), 2.82-3.22 (4H, m), 3.48-3.62 (1H, m), 4.19 (3H, t, J=5.4 Hz), 5.02 (1H, q, J=6.9 Hz), 6.70-6.89 (2H, m), 7.06-7.26 (2H, m), 8.31 (1H, d, J=8.1 Hz).

Reference： [1]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 79-80
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 1228 - 1246

18
[ 730980-59-3 ]
C₁₅H₂₆N₂O₅ [ No CAS ]
[ 1421527-62-9 ]
[ 1421527-63-0 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 1228 - 1246

19
[ 730980-59-3 ]
[ 1266230-21-0 ]
[ 1266233-07-1 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 1228 - 1246

20
[ 730980-59-3 ]
C₁₄H₂₂N₂O₄ [ No CAS ]
[ 1266231-69-9 ]

Yield	Reaction Conditions	Operation in experiment
254 mg	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;	A mixture of 7 (240mg, 0.652mmol) and lithium hydroxide monohydrate (60.3mg, 1.44mmol) in THF (4mL) and water (1.0mL) was stirred at 50C for 4h. The reaction mixture was concentrated in vacuo, and the residue was dissolved in DMF (10mL). To the solution were added <strong>[730980-59-3](R)-chroman-4-amine hydrochloride</strong> 10 (200mg, 1.34mmol), DIPEA (280mg, 2.17mmol) and HATU (683mg, 1.80mmol) successively. The reaction mixture was stirred at room temperature for 18h, and the mixture was partitioned between water (15mL) and EtOAc (15mL). The organic layer was washed with satd NaHCO3 (20mL) and brine (20mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (n-Hexane/EtOAc=98:2?20:80) to give 12 (254mg, 94%) as colorless amorphous solid. 1H NMR (300MHz, CDCl3) delta 0.08 (1H, dt, J=8.1, 6.0Hz), 0.78-0.86 (1H, m), 1.31-1.48 (10H, m), 1.49-1.63 (1H, m), 1.82-2.10 (2H, m), 2.14-2.33 (1H, m), 2.39-2.49 (1H, m), 2.50-2.84 (2H, m), 3.69-3.85 (1H, m), 3.93-4.32 (3H, m), 4.58-4.83 (1H, m), 5.14-5.26 (1H, m), 6.30-6.57 (1H, m), 6.78-6.95 (2H, m), 7.14-7.27 (3H, m)

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5725 - 5737

21
[ 730980-59-3 ]
C₁₇H₂₂N₂O₄ [ No CAS ]
tert-butyl (3S,10aR)-3-[(4R)-3,4-dihydro-2H-chromene-4-ylcarbamoyl]-3,4,10,10a-tetrahydropyrazino[1,2-a]indole-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
280 mg	With benzotriazol-1-ol; 1,2-dichloro-ethane; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 17h;	A mixture of 24A (256 mg, 0.77 mmol) and lithium hydroxidemonohydrate (97 mg, 2.31 mmol) in THF/water (5:1, 6.0 mL) wasstirred at 50 C for 20 h. The mixture was neutralized with 1 MHCl, concentrated under reduced pressure, and the concentratewas coevaporated with toluene in vacuo. To the mixture of the residue,(4R)-3,4-dihydro-2H-chromene-4-amine hydrochloride(172 mg, 0.92 mmol) and HOBt (156 mg, 1.16 mmol) in DMF(3.0 mL) were successively added DIPEA (0.402 mL, 2.31 mmol)and EDC (179 mg, 1.16 mmol) at 0 C. The mixture was stirred atroom temperature for 17 h, and then partitioned between EtOAcand water. The organic layer was washed with brine, dried overMgSO4, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (5-30% EtOAcin n-hexane) to give 30 (280 mg, 72%) as white solid; 1H NMR(300 MHz, DMSO-d6): d 1.33-1.50 (9H, m), 1.73-2.08 (2H, m),2.52-2.58 (1H, m), 2.90-3.31 (4H, m), 3.78-4.36 (4H, m), 4.40-4.68 (1H, m), 4.86-5.11 (1H, m), 6.35-6.51 (1H, m), 6.60 (1H, t,J = 7.4 Hz), 6.70-6.86 (2H, m), 6.89-7.24 (4H, m), 8.22-8.68 (1H,m); MS (ESI): m/z 450.3 (M+H)+.