[ CAS No. 2525-16-8 ] {[proInfo.proName]}

Name: 2525-16-8|7-Methoxy-3,4,5,6-tetrahydro-2H-azepine|96%
Brand: Ambeed
SKU: A171190
Price: 7.0 USD
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Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 2525-16-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 2525-16-8 ]

CAS No. :	2525-16-8	MDL No. :	MFCD00006938
Formula :	C₇H₁₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DNXIQMQGKSQHPC-UHFFFAOYSA-N
M.W :	127.18	Pubchem ID :	75657
Synonyms :

Calculated chemistry of [ 2525-16-8 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.86
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	41.74
TPSA :	21.59 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.51 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.24
Log Po/w (XLOGP3) :	0.8
Log Po/w (WLOGP) :	1.22
Log Po/w (MLOGP) :	1.23
Log Po/w (SILICOS-IT) :	2.42
Consensus Log Po/w :	1.58

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.07
Solubility :	10.9 mg/ml ; 0.0858 mol/l
Class :	Very soluble
Log S (Ali) :	-0.83
Solubility :	18.6 mg/ml ; 0.146 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.67
Solubility :	2.74 mg/ml ; 0.0215 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.71

Safety of [ 2525-16-8 ]

Signal Word:	Danger	Class:	3
Precautionary Statements:	P210-P403+P235	UN#:	1993
Hazard Statements:	H225	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 2525-16-8 ]

* 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 [ 2525-16-8 ]
Downstream synthetic route of [ 2525-16-8 ]

[ 2525-16-8 ] Synthesis Path-Upstream 1~12

1
[ 105-60-2 ]
[ 420-37-1 ]
[ 2525-16-8 ]

Reference： [1] Organic Preparations and Procedures International, 1992, vol. 24, # 2, p. 147 - 158
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 19, p. 2651 - 2653
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 19, p. 4359 - 4362
[4] Patent: US6046211, 2000, A,
[5] Patent: US5854234, 1998, A,
[6] Journal of the American Chemical Society, 2009, vol. 131, p. 8714 - 8718
[7] Patent: WO2010/68520, 2010, A2, . Location in patent: Page/Page column 29

2
[ 105-60-2 ]
[ 77-78-1 ]
[ 2525-16-8 ]

Reference： [1] Arkivoc, 2016, vol. 2016, # 5, p. 118 - 141
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 25, p. 6307 - 6315
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 21, p. 7647 - 7663
[4] Journal of the Indian Chemical Society, 1988, vol. 65, p. 800 - 802
[5] Journal of Medicinal Chemistry, 1987, vol. 30, # 8, p. 1433 - 1454
[6] European Journal of Medicinal Chemistry, 2002, vol. 37, # 5, p. 419 - 425
[7] Journal of Medicinal Chemistry, 2016, vol. 59, # 7, p. 3018 - 3033

3
[ 111238-46-1 ]
[ 2525-16-8 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 1, p. 22 - 27

4
[ 67-56-1 ]
[ 100-64-1 ]
[ 105-60-2 ]
[ 2525-16-8 ]

Reference： [1] Patent: US6344557, 2002, B1, . Location in patent: Page column 7
[2] Patent: US6344557, 2002, B1, . Location in patent: Page column 7-8

5
[ 105-60-2 ]
[ 77-78-1 ]
[ 2525-16-8 ]
[ 2556-73-2 ]

Reference： [1] Journal of the American Chemical Society, 1948, vol. 70, p. 2115,2116[2] Org.Synth.Coll.Vol., 1963, vol. IV, p. 588

6
[ 100-64-1 ]
[ 2525-16-8 ]

Reference： [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 18, p. 3050

7
[ 105-60-2 ]
[ 2525-16-8 ]

Reference： [1] Patent: WO2004/60376, 2004, A1, . Location in patent: Page/Page column 95

8
[ 105-60-2 ]
[ 77-78-1 ]
[ 71-43-2 ]
[ 2525-16-8 ]

Reference： [1] Journal of the American Chemical Society, 1948, vol. 70, p. 2115,2116[2] Org.Synth.Coll.Vol., 1963, vol. IV, p. 588

9
[ 100-64-1 ]
[ 98-09-9 ]
[ 2525-16-8 ]

Reference： [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 18, p. 3050

10
[ 2525-16-8 ]
[ 5424-01-1 ]
[ 16298-03-6 ]
[ 36120-38-4 ]

Reference： [1] Zeitschrift fur Chemie, 1986, vol. 26, # 8, p. 290 - 292

11
[ 2525-16-8 ]
[ 54-95-5 ]

Reference： [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 2603
[2] Chemische Berichte, 1930, vol. 63, p. 1032,1033

12
[ 2525-16-8 ]
[ 4771-47-5 ]
[ 6388-47-2 ]

Reference： [1] Patent: US5486512, 1996, A,

[ 2525-16-8 ] Synthesis Path-Downstream 1~88

1
[ 2525-16-8 ]
[ 69-93-2 ]
[ 2309-49-1 ]

Reference： [1]Patent: DE944312,1953,

2
[ 2525-16-8 ]
[ 140-87-4 ]
[ 116598-69-7 ]

Reference： [1]Russian Chemical Bulletin,2006,vol. 55,p. 1636 - 1641
[2]Chemische Berichte,1957,vol. 90,p. 909,818

3
[ 2525-16-8 ]
[ 13222-85-0 ]
[ 100718-16-9 ]

Reference： [1]Journal of the American Chemical Society,1958,vol. 80,p. 5880,5884

4
[ 2525-16-8 ]
[ 20605-41-8 ]
3-methoxymethyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine [ No CAS ]

Reference： [1]Chemische Berichte,1957,vol. 90,p. 909,818

5
[ 2525-16-8 ]
[ 95-51-2 ]
[ 28669-82-1 ]

Reference： [1]Journal of the American Chemical Society,1948,vol. 70,p. 2115,2116
Org.Synth.Coll.Vol.,1963,vol. IV,p. 588

6
[ 2525-16-8 ]
[ 111-49-9 ]

Reference： [1]ChemCatChem,2018,vol. 10,p. 170 - 172
[2]Journal of the American Chemical Society,1948,vol. 70,p. 2115,2116
Org.Synth.Coll.Vol.,1963,vol. IV,p. 588
[3]Collection of Czechoslovak Chemical Communications,1959,vol. 24,p. 1146,1148
Chemicke Listy,1958,vol. 52,p. 1145

7
[ 2525-16-8 ]
[ 68-94-0 ]
[ 33155-83-8 ]

Reference： [1]Patent: DE944312,1953,

8
[ 2525-16-8 ]
[ 69-89-6 ]
[ 58-08-2 ]

Reference： [1]Patent: DE944312,1953,

9
[ 5765-44-6 ]
[ 2525-16-8 ]
[ 96600-81-6 ]

Reference： [1]Tetrahedron Letters,1985,vol. 26,p. 259 - 262

10
[ 105-60-2 ]
[ 77-78-1 ]
[ 2525-16-8 ]

Reference： [1]Arkivoc,2016,vol. 2016,p. 118 - 141
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 6307 - 6315
[3]Journal of Medicinal Chemistry,2010,vol. 53,p. 7647 - 7663
[4]Journal of the Indian Chemical Society,1988,vol. 65,p. 800 - 802
[5]Journal of Medicinal Chemistry,1987,vol. 30,p. 1433 - 1454
[6]European Journal of Medicinal Chemistry,2002,vol. 37,p. 419 - 425
[7]Journal of Medicinal Chemistry,2016,vol. 59,p. 3018 - 3033

11
[ 2525-16-8 ]
[ 4815-29-6 ]
[ 57394-70-4 ]

Reference： [1]Monatshefte fur Chemie,1986,vol. 117,p. 1295 - 1303

12
[ 2525-16-8 ]
[ 4506-71-2 ]
[ 56929-67-0 ]

Reference： [1]Monatshefte fur Chemie,1986,vol. 117,p. 1295 - 1303

13
[ 2525-16-8 ]
[ 40106-13-6 ]
[ 102254-58-0 ]

Reference： [1]Monatshefte fur Chemie,1986,vol. 117,p. 1295 - 1303

14
[ 2525-16-8 ]
[ 63-91-2 ]
[ 109717-32-0 ]
[ 13839-48-0 ]
[ 132509-73-0 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1973 - 1977
[2]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1973 - 1977
[3]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1973 - 1977

15
[ 2525-16-8 ]
[ 38487-85-3 ]
[ 151303-25-2 ]

Reference： [1]Pharmazie,1993,vol. 48,p. 410 - 414

16
[ 2525-16-8 ]
[ 33890-03-8 ]
[ 108561-92-8 ]

Reference： [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 1543 - 1549

17
[ 2525-16-8 ]
[ 10312-55-7 ]
[ 108561-87-1 ]

Reference： [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 1543 - 1549

18
[ 2525-16-8 ]
[ 60868-41-9 ]
[ 129602-02-4 ]

Reference： [1]Pharmaceutical Chemistry Journal,1990,vol. 24,p. 460 - 465
Khimiko-Farmatsevticheskii Zhurnal,1990,vol. 24,p. 24 - 27

19
[ 2525-16-8 ]
[ 7579-20-6 ]
[ 107805-65-2 ]

Reference： [1]Zeitschrift fur Chemie,1986,vol. 26,p. 290 - 292

20
[ 2525-16-8 ]
[ 6945-92-2 ]
Hexahydro-2H-azepin-2-on-2-ethoxycarbonylmethylhydrazon-hydrochlorid [ No CAS ]

Reference： [1]Pharmazie,1993,vol. 48,p. 410 - 414

21
[ 2525-16-8 ]
[ 33906-30-8 ]
2-[N'-Azepan-(2Z)-ylidene-hydrazino]-benzoic acid; hydrochloride [ No CAS ]

Reference： [1]Pharmazie,1993,vol. 48,p. 410 - 414

22
[ 2525-16-8 ]
[ 56-40-6 ]
[ 132509-60-5 ]
[ 90152-88-8 ]
[ 132509-59-2 ]

23
[ 2525-16-8 ]
hexahydro-2H-azepin-2-one oxime [ No CAS ]

Reference： [1]Journal of the Indian Chemical Society,1988,vol. 65,p. 800 - 802

24
[ 111238-46-1 ]
[ 2525-16-8 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 22 - 27

25
[ 2525-16-8 ]
[ 107-35-7 ]
[ 160427-72-5 ]

Reference： [1]Il Farmaco,1994,vol. 49,p. 653 - 658

26
[ 2525-16-8 ]
[ 3687-18-1 ]
[ 160427-75-8 ]

Reference： [1]Il Farmaco,1994,vol. 49,p. 653 - 658

27
[ 2525-16-8 ]
[ 1623-19-4 ]
[ 201230-82-2 ]
N-(1-propenylcarbonyl)azepinone [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 1256 - 1259

28
[ 2525-16-8 ]
[ 5856-63-3 ]
5-((R)-4-Ethyl-4,5-dihydro-oxazol-2-yl)-pentylamine [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,1996,vol. 338,p. 397 - 402

29
[ 2525-16-8 ]
[ 492-41-1 ]
5-((4S,5R)-4-Methyl-5-phenyl-4,5-dihydro-oxazol-2-yl)-pentylamine [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,1996,vol. 338,p. 397 - 402

30
[ 2525-16-8 ]
[ 5467-71-0 ]
[ 181226-61-9 ]

Reference： [1]Tetrahedron,1996,vol. 52,p. 9835 - 9840
[2]Chemistry of Heterocyclic Compounds,1996,vol. 32,p. 923 - 927

31
[ 105-60-2 ]
[ 420-37-1 ]
[ 2525-16-8 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 257 2-(2-butynyl)-3,4,5,6-tetrahydro-7-methoxy-2H-azepine STR263 The product of EXAMPLE 256 is reacted with trimethyloxonium tetrafluoroborate by the method of
		EXAMPLE 257 2-(2-butynyl)-3,4,5,6-tetrahydro-7-methoxy-2H-azepine STR263 The product of EXAMPLE 256 is reacted with trimethyloxonium tetrafluoroborate by the method of EXAMPLE 26 to produce the title material.
	In dichloromethane;	Step 1: Preparation of (E)-7-methoxy-3,4,5,6-tetrahydro-2H-azepine: To a solution of azepan-2-one (1.13 g, 10.0 mmol) in DCM (10 mL) in a 40 mL screw cap vial was added freshly prepared trimethyloxonium tetrafluoroborate (1.57 g, 10.59 mmol). The resulting suspension was shaken overnight. The reaction was quenched by the addition of saturated aqueous NaHCtheta3 (5 ml) (caution: vigorous CO2 evolution). More aqueous sodium hydrogen carbonate was added until the aqueous layer reached pH 8. The organic layer was removed and the aqueous layer extracted with DCM (5mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield (E)-7-methoxy-3,4,5,6-tetrahydro-2H- azepine (1.2 g, 95 %) as a clear oil. LCMS (+ESI) m/z 128.2 [M+H]+. 1H-NMR (CDCl3) delta 3.60 (s, 3H), 3.45 (m, 2H), 2.40 (m, 2H), 1.80 (m, 2H), 1.60-1.50 (m, 4H). [00145]

Reference： [1]Organic Preparations and Procedures International,1992,vol. 24,p. 147 - 158
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 2651 - 2653
[3]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4359 - 4362
[4]Patent: US6046211,2000,A
[5]Patent: US5854234,1998,A
[6]Journal of the American Chemical Society,2009,vol. 131,p. 8714 - 8718
[7]Patent: WO2010/68520,2010,A2 .Location in patent: Page/Page column 29

32
[ 2525-16-8 ]
[ 124-63-0 ]
1-Methanesulfonyl-2H-hexahydroazepin-2-one [ No CAS ]

Reference： [1]Organic Preparations and Procedures International,1992,vol. 24,p. 147 - 158

33
[ 2525-16-8 ]
[ 98-09-9 ]
[ 91641-75-7 ]

Reference： [1]Organic Preparations and Procedures International,1992,vol. 24,p. 147 - 158

34
[ 2525-16-8 ]
[ 98-59-9 ]
[ 23438-55-3 ]

Reference： [1]Organic Preparations and Procedures International,1992,vol. 24,p. 147 - 158

35
[ 2525-16-8 ]
[ 70-11-1 ]
[ 43003-19-6 ]

Reference： [1]Medicinal Chemistry Research,1998,vol. 8,p. 499 - 509

36
[ 2525-16-8 ]
[ 445-28-3 ]
[ 67829-54-3 ]

Reference： [1]Synthetic Communications,2003,vol. 33,p. 303 - 310

37
[ 2525-16-8 ]
[ 201230-82-2 ]
[ 1888-91-1 ]

Reference： [1]Organic Letters,2003,vol. 5,p. 3955 - 3957

38
[ 10200-59-6 ]
[ 2525-16-8 ]
[ 81374-64-3 ]
3-(2-thiazol-2-yl-vinyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 1877 - 1880

39
[ 2525-16-8 ]
[ 100-39-0 ]
[ 253138-70-4 ]

Reference： [1]Synlett,2006,p. 1347 - 1350

40
[ 2525-16-8 ]
[ 106-95-6 ]
[ 165385-44-4 ]

Reference： [1]Synlett,2006,p. 1347 - 1350

41
[ 2525-16-8 ]
[ 763917-01-7 ]
ethyl N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-methyl-4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidin-4-yloxy]phenyl]sulfamoylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; at 20℃; for 60h;	To a solution of ethyl N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-methyl-4-(piperidin-4-yloxy)phenyl]sulfamoylacetate (640 mg) obtained in example 65(a) in ethanol (12 ml) were added successively 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (348 mg) and triethylamine (0.26 ml) at room temperature and the resulting mixture was stirred at room temperature for 2.5 days and then evaporated in vacuo.. The residue obtained was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: 20 % acetonitrile/water).. Subsequently, to a solution of the amorphous solid obtained in ethanol (5 ml) was added a 4N solution of hydrogen chloride in dioxane (0.42 ml), and the resulting mixture was evaporated to dryness in vacuo.. The residue obtained was dissolved in water and then lyophilized to afford the title compound (336 mg, yield: 40 %) as a colorless amorphous solid. 1H NMR (400MHz, DMSO-d6) delta ppm: 1.23 (3H, t, J=7.0), 1.52-1.64 (4H, m), 1.68-1.82 (4H, m), 1.98-2.09 (2H, m), 2.17 (3H, s), 2.87 (2H, m), 3.48 (2H, m), 3.65-3.75 (2H, m), 3.77-3.88 (2H, m), 4.19 (2H, q, J=7.0), 4.33 (2H, s), 4.44 (2H, d, J=6.0), 4.74 (1H, m), 6.44 (1H, dt, J=16.0, 6.0), 6.57 (1H, d, J=16.0), 7.06 (1H, d, J=8.5), 7.25 (1H, dd, J=8.5, 2.5), 7.28 (1H, d, J=2.5), 7.55 (1H, t, J=8.0), 7.69 (1H, d, J=8.0), 7.72 (1H, d, J=8.0), 7.89 (1H, s); IR (KBr, cm-1): 1738, 1675, 1628, 1351, 1157.

Reference： [1]Patent: EP1375482,2004,A1 .Location in patent: Page 113

42
[ 2525-16-8 ]
[ 749839-29-0 ]
ethyl N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-carbamoyl-4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidin-4-yloxy]phenyl]sulfamoylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; at 20 - 40℃;	To a solution of ethyl N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-carbamoyl-4-(piperidin-4-yloxy)phenyl]sulfamoylacetate (400 mg) obtained in example 71(a) in ethanol (10 ml) were added successively 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (280 mg) and triethylamine (0.31 ml) at room temperature and the resulting mixture was stirred at room temperature overnight.. Because of the slow progress of the reaction, 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (280 mg) and triethylamine (0.31 ml) were furthermore added successively, and the resulting mixture was stirred at 40C for 12 hours and allowed to stand at room temperature overnight.. The reaction mixture was then evaporated in vacuo.. The residue obtained was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: 20 % acetonitrile/water).. Subsequently, to a solution of the amorphous solid obtained in ethanol (5 ml) was added a 4N solution of hydrogen chloride in dioxane (0.20 ml), and the resulting mixture was evaporated to dryness in vacuo to afford the title compound (140 mg, yield: 26 %) as a colorless amorphous solid. 1H NMR (500MHz, DMSO-d6) delta ppm: 1.24 (3H, t, J=7.0), 1.50-1.65 (4H, m), 1.70-1.75 (2H, m), 1.80-1.90 (2H, m), 2.05-2.15 (2H, m), 2.85-2.90 (2H, m), 3.45-3.50 (2H, m), 3.55-3.65 (1H, m), 3.65-3.75 (1H, m), 3.75-3.85 (1H, m), 3.85-3.95 (1H, m), 4.20 (2H, q, J=7.0), 4.37 (2H, s), 4.47 (2H, d, J=6.0), 4.86 (1H, m), 6.44 (1H, dt, J=16.0, 6.0), 6.58 (1H, d, J=16.0), 7.28 (1H, d, J=9.0), 7.51 (1H, dd, J=9.0, 2.5), 7.55 (1H, t, J=8.0), 7.67 (1H, d, J=8.0), 7.72 (1H, d, J=8.0), 7.78 (1H, d, J=2.5), 7.86 (1H, s); IR (KBr, cm-1): 1737, 1672.

Reference： [1]Patent: EP1375482,2004,A1 .Location in patent: Page 115-116

43
[ 2525-16-8 ]
ethyl N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-chloro-4-(piperidin-4-yloxy)phenyl]sulfamoylacetate dihydrochloride [ No CAS ]
ethyl N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-chloro-4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidin-4-yloxy]phenyl]sulfamoylacetate dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%		To a solution of ethyl N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-chloro-4-(piperidin-4-yloxy)phenyl]sulfamoylacetate dihydrochloride (0.75 g) obtained in example 47(a) in ethanol (25 ml) were added successively 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (0.39 g) and triethylamine (0.85 ml) at room temperature, and the resulting mixture was stirred at room temperature for 7 hours and then allowed to stand at room temperature for 15 hours.. Because of the slow progress of the reaction, 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (0.22 g) and triethylamine (0.51 ml) were furthermore added successively, and the resulting mixture was stirred at 45C for 12 hours, allowed to stand at room temperature for 11 hours and then furthermore stirred at 45C for 10 hours.. After stirring, to the reaction mixture was added a 4N solution of hydrogen chloride in dioxane (5 ml) and the resulting mixture was evaporated in vacuo.. The residue obtained was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: 25 % acetonitrile/water).. Subsequently, to a solution of the amorphous solid obtained in ethanol (5 ml) was added a 4N solution of hydrogen chloride in dioxane (2 ml), and the resulting mixture was evaporated to dryness in vacuo.. The residue obtained was dissolved in water and then lyophilized to afford the title compound (0.30 g, yield: 35 %) as a colorless amorphous solid. 1H NMR (400MHz, DMSO-d6) delta ppm: 1.21 (3H, t, J=7.0), 1.52-1.63 (4H, m), 1.68-1.81 (4H, m), 2.04-2.10 (2H, m), 2.84-2.88 (2H, m), 3.36-3.42 (2H, m), 3.62-3.91 (4H, m), 4.18 (2H, q, J=7.0), 4.41 (2H, s), 4.46 (2H, d, J=6.0), 4.81-4.87 (1H, m), 6.44 (1H, dt, J=16.0, 6.0), 6.57 (1H, d, J=16.0), 7.32 (1H, d, J=9.0), 7.40 (1H, dd, J=9.0, 2.5), 7.52- 7.59 (2H, m), 7.66-7.74 (2H, m), 7.88 (1H, s); IR (KBr, cm-1): 1738, 1674, 1628, 1353, 1156.

Reference： [1]Patent: EP1375482,2004,A1 .Location in patent: Page 107

44
[ 2525-16-8 ]
ethyl {N-[(E)-3-(3-amidinophenyl)-2-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]sulfamoyl}acetate dihydrochloride [ No CAS ]
ethyl N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidin-4-yloxy]phenyl]sulfamoylacetate dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With triethylamine; In ethanol; at 20℃; for 18h;	To a solution of ethyl N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]sulfamoylacetate dihydrochloride (0.51 g) obtained in example 59(a) in ethanol (5 ml) were added successively 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (0.34 g) and triethylamine (0.60 ml) at room temperature, and the resulting mixture was stirred at room temperature for 18 hours and then evaporated in vacuo.. The residue obtained was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: 25 % acetonitrile/water).. Subsequently, to a solution of the amorphous solid obtained in ethanol (5 ml) was added a 4N solution of hydrogen chloride in dioxane (1 ml), and the resulting mixture was evaporated to dryness in vacuo.. The residue obtained was dissolved in water and then lyophilized to afford the title compound (0.14 g, yield: 24 %) as a colorless amorphous solid. 1H NMR (400MHz, DMSO-d6) delta ppm: 1.23 (3H, t, J=7.0), 1.46-1.76 (8H, m), 2.01-2.10 (2H, m), 2.86-2.89 (2H, m), 3.45-3.50 (2H, m), 3.57-3.70 (2H, m), 3.85-3.97 (2H, m), 4.20 (2H, q, J=7.0), 4.34 (2H, s), 4.45 (2H, d, J=6.0), 4.70-4.76 (1H, m), 6.45 (1H, dt, J=16.0, 6.0), 6.55 (1H, d, J=16.0), 7.39 (2H, d, J=9.0), 7.54 (2H, d, J=9.0), 7.54 (1H, t, J=8.0Hz), 7.69-7.73 (2H, m), 7.90 (1H, s); IR (KBr, cm-1): 1737, 1674, 1629, 1351, 1158.

Reference： [1]Patent: EP1375482,2004,A1 .Location in patent: Page 110

45
[ 2525-16-8 ]
ethyl N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)-3-trifluoromethylphenyl]sulfamoylacetate dihydrochloride [ No CAS ]
ethyl N-[3-(3-amidinophenyl)-2-(E)-prophenyl]-N-[4-[1-(3,4,5,6-tetrahydro-2H-azepin-7-yl)piperidin-4-yloxy]-3-trifluoromethylphenyl]sulfamoylacetate dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%		To a solution of ethyl N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)-3-trifluoromethylphenyl]sulfamoylacetate dihydrochloride (900 mg) obtained in example 77(a) in ethanol (20 ml) were added successively 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (540 mg) and triethylamine (0.98 ml) at room temperature and the resulting mixture was stirred at room temperature overnight.. Because of the slow progress of the reaction, 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (540 mg) and triethylamine (0.98 ml) were furthermore added successively and the resulting mixture was stirred at room temperature for 5 hours and then at 40C for one day.. After stirring, to the reaction mixture was added a 4N solution of hydrogen chloride in dioxane and the resulting mixture was evaporated in vacuo.. The residue obtained was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: 30 % acetonitrile/water).. The amorphous solid obtained was dissolved in 1N hydrochloric acid, and the resulting mixture was evaporated to dryness in vacuo.. The residue obtained was dissolved in water and then lyophilized to afford the title compound (340 mg, yield: 33 %) as a colorless amorphous solid. 1H NMR (500MHz, DMSO-d6) delta ppm: 1.22 (3H, t, J=7.0), 1.52-1.67 (4H, m), 1.67-1.85 (4H, m), 2.06 (2H, m), 2.87 (2H, m), 3.48 (2H, m), 3.67-3.83 (4H, m), 4.19 (2H, q, J=7.0), 4.46 (2H, s), 4.50 (2H, d, J=6.0), 4.97 (1H, m), 6.46 (1H, dt, J=16.0, 6.0), 6.58 (1H, d, J=16.0), 7.44 (1H, d, J=9.5), 7.55 (1H, t, J=8.0), 7.67-7.75 (4H, m), 7.90 (1H, s); IR (KBr, cm-1): 1739, 1675, 1354, 1142.

Reference： [1]Patent: EP1375482,2004,A1 .Location in patent: Page 118-119

46
[ 2525-16-8 ]
[ 67973-80-2 ]
[ 726191-28-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	at 140℃; for 1h;	A mixture of <strong>[67973-80-2]methyl 3-hydroxy-5-aminobenzoate</strong>, prepared from the corresponding acid and ethanol and hydrochloric acid (2 g, 11.96 MMOL) and 1- aza-2-methoxy-1-cycloheptene (2 g, 15.7 MMOL) was heated neat in an oil bath at 140 C for a period of 1 hour. The resulting solid mass was cooled to room temperature and triturated with ethyl acetate. The solid was filtered and dried and used in the next step without further purification. The yield was 2.7 g (86 %) of the title compound. ESI MS (MH+) FOR C14H18N203 CALCULATED 263 found 263

Reference： [1]Patent: WO2004/60376,2004,A1 .Location in patent: Page/Page column 244-245

47
[ 2525-16-8 ]
[ 703-59-3 ]
[ 79115-74-5 ]

Yield	Reaction Conditions	Operation in experiment
42%	In methanol; chloroform; toluene;	(a) 8,9,10,11-Tetrahydro-7H-azepino[1,2-b]isoquinolin-5-one Homophthalic anhydride (4.86 g, 30 mmol) was added portionwise over 10 minutes to a refluxing solution of 1-aza-2-methoxycycloheptene (4.20 g, 33 mmol) in toluene. After addition was complete, the reaction mixture was heated an additional 1 h before cooling to ambient temperature. The reaction mixture was diluted with chloroform, the resulting solution was washed twice with sodium hydroxide, and the dried (magnesium sulfate) organic layer was concentrated in vacuo. The residue was chromatographed on silica gel using chloroform, followed by 4% methanol in chloroform, as eluent to give the desired compound. This was triturated with 20% ether in hexanes (40 ml) to yield the title compound as an off-white solid (2.21 g, 42%), m.p. 99-101 C.

Reference： [1]Patent: US5929085,1999,A

48
[ 2525-16-8 ]
[ 2797-51-5 ]
[ 7732-18-5 ]
N-[2-(hexahydro-7-imino-1H-azepin-2-yl)ethyl]-3,4,5,6-tetrahydro-2H-azepin-7-amine, bis(trifluoroacetate)salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	In methanol;	EXAMPLE 236 N-[2-(hexahydro-7-imino-1H-azepin-2-yl)ethyl)]-3,4,5,6-tetrahydro-2H-azepin-7-amine, bis(trifluoroacetate)salt STR241 The product of Example 235 E (383 mg; 1 mmol) was reacted with 1-aza-2-methoxy-1-cycloheptene (254 mg; 1 mmol) in 5 mL of MeOH for 16 hours at room temperature. The MeOH was evaporated and the residue was purified on preparative HPLC using AcN/H2 O gradient (0-30% AcN in 30 minutes), affording 470 mg (98% yield) of the title product as an oil. Mass spectral analysis for C14 H26 N4: M+ H=251.

Reference： [1]Patent: US6011028,2000,A

49
[ 2525-16-8 ]
[ 54661-57-3 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; In methanol;	EXAMPLE 258 7-(2-butynyl)hexahydro-1H-azepin-2-imine, monohydrochloride STR264 The product of EXAMPLE 257 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.

Reference： [1]Patent: US5854234,1998,A

50
[ 2525-16-8 ]
[ 4771-47-5 ]
[ 6388-47-2 ]

Yield	Reaction Conditions	Operation in experiment
	Ra-Ni; In tetrahydrofuran;	I. 4-Chloro-7,8,9,10-tetrahydroazepino[2,1,b]quinazolin-12(6H)-one 3-Chloro-2-aminobenzoic acid, obtained by catalytic hydrogenation of 3-chloro-2-nitrobenzoic acid over Ra-Ni in tetrahydrofuran was treated with 1-aza-2-methoxy-1-cycloheptene as outlined in Example 1. The crude mixture was composed mainly of the methylester of 3-chloro-2-aminobenzoic acid and a small amount of the desired compound.

Reference： [1]Patent: US5486512,1996,A

51
[ 2525-16-8 ]
[ 2305-36-4 ]
[ 7697-27-0 ]
[ 97511-55-2 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; ammonia; copper(II) sulfate; In water; toluene;	I. 3-Methyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one 25 g 2-bromo-4-methylbenzoic acid was treated with 150 mL of 28% aqueous ammonia, 50 g gaseous ammonia, 1 g CuSO4 at 140 C. for 12 hours in an autoclave, then concentrated in vacuo, dissolved in a minimal amount of water, pH adjusted to 6 with 4N HCl. The precipitate was filtered, washed with ice cold water, and dried at 60 C. The residue was extracted with THF and concentrated in vacuo, giving a light brown crystalline solid. Yield of combined material: 14 g 4-methylanthranilic acid. 6.4 g of this acid was suspended with stirring in 100 mL toluene. 11 mL 1-Aza-2-methoxy-1-cycloheptene (1) (Aldrich) were added and the mixture was refluxed under a Dean-Stark trap for 12 hours. Then the toluene was removed by distillation in vacuo, followed by removal of excess (1) in vacuo (11 mm Hg) at 140 C. The dark brown residue crystallized. It was purified by column chromatography (6:1 chloroformethyl acetate) followed by recrystallization from hexane-ethyl acetate to give 7.1 g of pure 3-methyl-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one as white, shiny crystals.

Reference： [1]Patent: US5486512,1996,A

52
[ 2525-16-8 ]
[ 865-40-7 ]
[ 62018-65-9 ]
[ 89-77-0 ]
[ 60811-50-9 ]

Yield	Reaction Conditions	Operation in experiment
76.7%	In benzene;	I. 3-Chloro-7,8,9,10-tetrahydroazpino[2,1-b]quinazolin-12(6H)-one To a stirred slurry of 17.16 g of 4-chloroanthranilic acid (Aldrich) in 120 mL benzene was added 14 mL 1-aza-2-methoxy-1-cycloheptene (1) (Aldrich) and refluxed under nitrogen using an azeotropic Dean-Stark trap to remove the water/methanol formed by the reaction. After 2 hours of reflux, 5 mL of the methoxyimine (1) was added and 2 mL more after 18 hours. The mixture was then refluxed for 4 more hours. The solvent was distilled out and the excess of (1) was removed by distillation at 140 C. (bath) at 11 mm Hg. A dark brown oil formed which soon crystallized. There was a single mobile spot on TLC (4:1 chloroform-ethyl acetate, Rf=0.6, silica gel). The mixture was chromatographed using the above solvent system, the corresponding fractions concentrated in vacuo and the residue was recrystallized from hexane-ethyl acetate, giving 19.08 g of the 3-chloro-6,7,8,9-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one (76.7% yield), m.p. 106-108 C.

Reference： [1]Patent: US5486512,1996,A

53
[ 2525-16-8 ]
[ 15151-51-6 ]
3-(1-aza-2-amino-1-cycloheptene)benzoic acid [ No CAS ]
3-(1-Aza-2-amino-1-cycloheptyl)benzoic acid hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;	EXAMPLE B 3-(1-Aza-2-amino-1-cycloheptyl)benzoic acid hydrochloride STR65 To 1-aza-2-methoxy-1-cycloheptene (3.67 g, 0.0288 mole)(Aldrich) in absolute ethanol (20 ml) was added 3-aminobenzoic acid hydrochloride (5 g, 0.0288 mole). A solution quickly formed. The reaction mixture was stirred overnight at room temperature. The resulting precipitate was filtered, washed with ether and dried under vacuum to yield 3-(1-aza-2-amino-1-cycloheptene)benzoic acid (4.9 g).
	In ethanol;	Example B 3-(1-Aza-2-amino-1-cycloheptyl)benzoic acid hydrochloride To 1-aza-2-methoxy-1-cycloheptene (3.67 g, 0.0288 mole)(Aldrich) in absolute ethanol (20 ml) was added 3-aminobenzoic acid hydrochloride (5 g, 0.0288 mole). A solution quickly formed. The reaction mixture was stirred overnight at room temperature. The resulting precipitate was filtered, washed with ether and dried under vacuum to yield 3-(1-aza-2-amino-1-cycloheptene)benzoic acid (4.9 g).

Reference： [1]Patent: US5773646,1998,A
[2]Patent: EP889877,2001,B1

54
[ 2525-16-8 ]
4-Amino-7,8,9,10-tetrahydro-6H-pyrido[1,2-a]azepin-2-one Monohydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With n-butyllithium; diisopropylamine; lithium diisopropyl amide; In tetrahydrofuran; methanol; dichloromethane;	EXAMPLE IV 4-Amino-7,8,9,10-tetrahydro-6H-pyrido[1,2-a]azepin-2-one Monohydrate To a solution of lithium diisopropylamide (LDA), prepared from n-BuLi (125 ml, 0.2M) and diisopropylamine (20.2 g, 28.1 ml, 0.2M) in dry THF (100 ml) was added under N2 at -30 to -10 C., 5-methylisoxazole (8.3 g, 0.1M). The resultant yellow suspension was mechanically stirred at -10 C. for 1 hr before 1-aza-2-methoxy-1-cycloheptene (12.7 g, 0.1M) was added dropwise. After the addition was complete, a yellow solid separated and the mixture was allowed to warm to ambient over a period of 19 hr. Then dry MeOH (50 ml) was slowly added and the resultant reddish solution was vigorously stirred at ambient for 2 hr and filtered through a silica gel pad. The filtrate was evaporated in vacuo, and the residual oil was flash column chromatographed on silica gel (EM-60) with 30% MeOH in CH2 Cl2 as the eluent to give the desired amine, which was further recrystallized from MeOH/Et2 O to give the title compound (5.75 g, 30%), mp>230 C. TLC (30% MeOH in CH2 Cl2): Rf=0.40. IR (KBr) cm-1, 3400-3200 (broad), 1660, 1635. Anal. Calcd for C10 H14 N2 O.H2 O: C, 61.19; H, 8.22; N, 14.28. Found: C, 60.70; H, 8.28; N, 14.07.

Reference： [1]Patent: US4602013,1986,A

55
[ 2525-16-8 ]
[ 31030-25-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate; In ethanol;	EXAMPLE 12 7-Hydrazino-3,4,5,6-tetrahydro-2H-azepine A 22.5 g portion 7-methoxy-3,4,5,6-tetrahydro-2H-azepine was reacted with 11.3 g of hydrazine hydrate in 200 ml of ethanol by the procedure of Example 9, giving the desired intermediate.

Reference： [1]Patent: US4550169,1985,A

56
[ 2525-16-8 ]
[ 51516-96-2 ]
[ 52176-78-0 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol;	EXAMPLE 4 SPC16 210 G (1.65 moles) of caprolactim-methyl-ether were run into a suspension of 285 g (1.5 moles) of <strong>[51516-96-2]3-nitrophenylhydrazine hydrochloride</strong> in 3,500 ml of methanol at 20C while stirring well and cooling, whereupon solution first occurred and thereafter a precipitate was again formed gradually. The mixture was then warmed to the reflux temperature and kept at 65C for a further 2 hours. After cooling, the product was filtered off and the crystals were washed with a large amount of water and recrystallized from 15 parts of methanol. The yield of caprolactam-(3-nitrophenylhydrazone) hydrochloride was 374 g (87.5% of theory) as yellow crystals of melting point 280C (with decomposition).

Reference： [1]Patent: US3936444,1976,A

57
[ 2525-16-8 ]
[ 2231-57-4 ]
4-amino-5-(5-aminopentyl)-4H-1,2,4-triazole-3-thiol hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol;	EXAMPLE 9 4-Amino-5-(5-aminopentyl)-4H-1,2,4-triazole-3-thiol hydrochloride To 200 ml of methanol is added 3.6 g (0.1 mole) of gaseous HCl followed by 12.7 g (0.1 mole) of O-methylcaprolactam and then 10.6 g (0.1 mole) of thiocarbohydrazide. After heating at reflux for 2 hours, the mixture is allowed to cool to room temperature and is refrigerated. The solid product is recrystallized twice from methanol/ethyl acetate, affording 13.4 g of 4-amino-5-(5-aminopentyl)-4H-1,2,4-triazole-3-thiol hydrochloride. m.p. 192-194 C.

Reference： [1]Patent: US4230715,1980,A

58
[ 2525-16-8 ]
[ 880165-72-0 ]
3-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; toluene; at 100℃; for 72h;	7-Methoxy-3,4,5,6-tetrahydro-2H-azepine (0.5 ml) was added to a dioxane (20 ml) and toluene (15 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentane-carbohydrazide (800 mg), followed by stirring at 100C for 3 days. The reaction solution was subjected to evaporation under reduced pressure and the resulting crude product was purified by column chromatography (chloroform:methanol=40:1). The resulting solid was washed with hexane to obtain 770 mg of 3-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-6,7,8,9-tetrahydro-SH-[1,2,4]triazolo[4,3-a]azepine (colorless solid).

Reference： [1]Patent: EP1790641,2007,A1 .Location in patent: Page/Page column 19

59
[ 2525-16-8 ]
[ 3943-56-4 ]
[ 648441-43-4 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 6307 - 6315

60
[ 2525-16-8 ]
[ 5468-37-1 ]
3-phenyl-2,5,6,7,8,9-hexahydro-3H-imidazo[1,2-a]azepin-3-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	In ethanol; at 20℃; for 48h;	3-Phenyl-2,5,6,7,8,9-hexahydro-3H-imidazori,2-a1azepin-3-ol[00188] A solution of alphaaminoacetophenone hydrochloride (3.43 g, 20 mmol) in abs EtOH (20 mL) was treated with 7-methoxy-3,4,5,6-tetrahydro-2H- azepine (2.90 mL, 20 mmol). The reaction mixture was shaken on a shake board at r.t.for 2 days. 7.55 g of crude product was obtained. 1.20 g of the crude product was recrystallized two times from acetone/MeOH to give 0.098 g of white crystals and the second crop gave 0.27 g (0.37 g, 30% in total yield). 0.95 g of the crude product was washed with acetone to give 0.59 g of the title compound as white crystals (62%). 1H NMR (CD3OD) delta: 7.60-7.54 (m, 2H); 7.50-7.40 (m, 3H); 4.08-3.99 (m, 2H); 3.35 (s, 2H); 2.92-2.86 (m, 2H); 1.96-1.77 (m, 4H); 1.65-1.58 (m, 2H). 13C NMR (CD3OD) delta: 173.4; 141.4; 131.4; 130.8; 128.0; 97.7; 60.7; 44.6; 30.7; 29.2; 28.6; 24.3. Purity by LC/MS (UV/MS): 95/90.

Reference： [1]Patent: WO2008/64136,2008,A2 .Location in patent: Page/Page column 43-44

61
[ 2525-16-8 ]
[ 354-33-6 ]
[ 1105579-10-9 ]

Reference： [1]Journal of Fluorine Chemistry,2008,vol. 129,p. 390 - 396

62
[ 2525-16-8 ]
[ 4149-06-8 ]
[ 1118915-58-4 ]

Reference： [1]Synthesis,2008,p. 3497 - 3503

63
[ 2525-16-8 ]
[ 1138448-18-6 ]
[ 1138447-82-1 ]

Yield	Reaction Conditions	Operation in experiment
43%	In ethanol; toluene; at 85℃; for 12h;	Compound 24B (23 mg, 0.079 mmol) and l-aza-2-methoxy-l-cycloheptene were placed in a 2-dram vial. Toluene (1 mL) and ethanol (0.5 mL) were added, the vial was <n="55"/>capped, and the reaction was heated to 85 C and allowed to stir at this temperature for 12 hours. The reaction mixture was cooled to RT, then concentrated in vacuo and the oily residue obtained was purified using preparative TLC (CH2Cl2 - 7N NH3 in MeOH = 20:1, 10:1, v/v) to provide compound 19 (43%, MH+ = 392.17) as an viscous oil.

Reference： [1]Patent: WO2009/45313,2009,A2 .Location in patent: Page/Page column 53-54

64
[ 2525-16-8 ]
[ 24006-09-5 ]
C₁₅H₂₃N₃*ClH [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2009,vol. 131,p. 8714 - 8718

65
[ 2525-16-8 ]
[ 1199-01-5 ]
[ 109650-67-1 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: Preparation of 3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[l,5-a]azepine- 1-carboxylic acid: (E)-7-methoxy-3,4,5,6-tetrahydro-2H-azepine (0.395 g, 3.10 mmol) and 2-phenyloxazol-5(4H)-one (0.5 g, 3.10 mmol) were dissolved together in THF (2 mL) and DCE (2 mL) in a 5mL microwave vial to give a orange solution. The vial was sealed and the solution was heated to 1500C for 5 minutes. LCMS showed two peaks of the same mass (tautomers of the condensation product, Rf 0.78 and 0.83 minutes, respectively). The reaction was concentrated and the residue diluted with MeOH (ImL) and a solution of lithium hydroxide monohydrate (0.391 g, 9.31 mmol) in water (0.5 mL). The reaction was subjected to microwave irradiation and heated at 1200C for 5 minutes. LCMS showed a single, new peak (Rf 0.53 same molecular weight) corresponding to the desired product. The reaction was concentrated to remove MeOH and then diluted with water (ImL). The solution was acidified to pH 2 with 5M HCl and extracted with of DCM (3 x 2 mL). The combined organic layers were filter, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide 3-phenyl- 6,7,8,9-tetrahydro-5H-imidazo[l,5-a]azepine-l-carboxylic acid (421mg, 59%) as a brown oil that was used without further purification. LCMS (+ESI) m/z 257.1 [M+H]+.

Reference： [1]Patent: WO2010/68520,2010,A2 .Location in patent: Page/Page column 29-30

66
[ 2525-16-8 ]
[ 1254099-85-8 ]

Reference： [1]Synthesis,2010,p. 2588 - 2598

67
[ 2525-16-8 ]
[ 68076-36-8 ]
[ 1253528-26-5 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 7647 - 7663

68
[ 2525-16-8 ]
[ 114459-62-0 ]
[ 1253528-33-4 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 7647 - 7663

69
[ 2525-16-8 ]
[ 123-54-6 ]
[ 108140-18-7 ]

Yield	Reaction Conditions	Operation in experiment
35%	With bis(acetylacetonate)nickel(II); at 100℃; for 24h;	General procedure: The title compounds were synthesized according to the literature [25]. A mixture of diketone 1a or 1b (234 mmol), corresponding lactim-methylethers (258 mmol) and a catalytic amount of nickel(II) acetylacetonate (0.59 g, 2.3 mmol)was heated at 100 C for 24 h. Then the reaction mixture was cooled. The solid products were filtered and crystallized. (In the case of 3e and 4b, water (170 mL) was added and the reaction mixture was extracted with dichloromethane (3 x 90 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. The crude product was purified chromatographically on silica gel.) The compounds prepared according to the procedure are summarised in Supplementary material.

Reference： [1]Arkivoc,2016,vol. 2016,p. 118 - 141
[2]Journal of Organometallic Chemistry,2012,vol. 699,p. 75 - 81
[3]Organometallics,2014,vol. 33,p. 4931 - 4939

70
[ 2525-16-8 ]
[ 93-91-4 ]
[ 1286205-70-6 ]

Yield	Reaction Conditions	Operation in experiment
53%	With bis(acetylacetonate)nickel(II); at 100℃; for 24h;	General procedure: The title compounds were synthesized according to the literature [25]. A mixture of diketone 1a or 1b (234 mmol), corresponding lactim-methylethers (258 mmol) and a catalytic amount of nickel(II) acetylacetonate (0.59 g, 2.3 mmol)was heated at 100 C for 24 h. Then the reaction mixture was cooled. The solid products were filtered and crystallized. (In the case of 3e and 4b, water (170 mL) was added and the reaction mixture was extracted with dichloromethane (3 x 90 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. The crude product was purified chromatographically on silica gel.) The compounds prepared according to the procedure are summarised in Supplementary material.

Reference： [1]Journal of Organometallic Chemistry,2012,vol. 699,p. 75 - 81

71
[ 2525-16-8 ]
[ 6642-31-5 ]
[ 929975-78-0 ]

Yield	Reaction Conditions	Operation in experiment
51%	In N,N-dimethyl-formamide; at 150℃;	General procedure: 6-Aminouracil (0.1 mol), iminoether (0.3 mol), and DMF (1 mL) was heated until homogenous solution appeared and after that was refluxed for additional 4 h. Then the mixture was concentrated and treated with Et2O (100 mL). The precipitate was filtered and purified by crystallization from the specified solvent.

Reference： [1]Tetrahedron,2012,vol. 68,p. 8564 - 8571

72
[ 2525-16-8 ]
[ 56075-75-3 ]
[ 1399854-23-9 ]

Yield	Reaction Conditions	Operation in experiment
54%	In N,N-dimethyl-formamide; at 150℃;	General procedure: 6-Aminouracil (0.1 mol), iminoether (0.3 mol), and DMF (1 mL) was heated until homogenous solution appeared and after that was refluxed for additional 4 h. Then the mixture was concentrated and treated with Et2O (100 mL). The precipitate was filtered and purified by crystallization from the specified solvent.

Reference： [1]Tetrahedron,2012,vol. 68,p. 8564 - 8571

73
[ 2525-16-8 ]
[ 58481-39-3 ]
[ 1399854-24-0 ]

Yield	Reaction Conditions	Operation in experiment
50%	In N,N-dimethyl-formamide; at 150℃;	General procedure: 6-Aminouracil (0.1 mol), iminoether (0.3 mol), and DMF (1 mL) was heated until homogenous solution appeared and after that was refluxed for additional 4 h. Then the mixture was concentrated and treated with Et2O (100 mL). The precipitate was filtered and purified by crystallization from the specified solvent.

Reference： [1]Tetrahedron,2012,vol. 68,p. 8564 - 8571

74
[ 2525-16-8 ]
[ 90-04-0 ]
N-(2-methoxyphenyl)-3,4,5,6-tetrahydro-2H-azepin-7-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	at 85℃; for 144h;Inert atmosphere;	A mixture of o-anisidine (1.57 mL, 13.9 mmol, 1.00 equiv) and 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (2.00 mL, 13.9 mmol, 1 equiv) was heated to 85 C and stirred under a nitrogen atmosphere for 6 days. The resulting tan precipitate was collected by vacuum filtration and washed with 3 x 3 mL Et20 to yield N-(2-methoxyphenyl)-3,4,5,6-tetrahydro-2H-azepin-7-amine as a pale tan solid (608 mg, 20%).

Reference： [1]Patent: WO2013/192301,2013,A1 .Location in patent: Paragraph 0052; 0053
[2]ChemMedChem,2020,vol. 15,p. 1044 - 1049

75
[ 2525-16-8 ]
[ 50561-16-5 ]
[ 1537193-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 120℃; for 1h;Microwave irradiation; Inert atmosphere;	A suspension containing the hydrazide (1.0 equiv.) and 7-methoxy-3,4,5,6-tetrahydro-2Hazepine(1.2 equiv.) in MeOH (0.50 M) was heated in the microwave reactor at 120 C for 1.0 h.17The reaction mixture was allowed to cool to room temperature and was then concentrated underdiminished pressure. The resulting mixture was applied to a silica gel column (50 g); elutingwith 95:5 ? 75:25 DCM-MeOH (containing 10% NH4OH) afforded the corresponding triazole.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 630 - 635

76
[ 2525-16-8 ]
pyrazole-4-carbohydrazide [ No CAS ]
[ 1537193-44-4 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 120℃; for 1h;Microwave irradiation; Inert atmosphere;	A suspension containing the hydrazide (1.0 equiv.) and 7-methoxy-3,4,5,6-tetrahydro-2Hazepine(1.2 equiv.) in MeOH (0.50 M) was heated in the microwave reactor at 120 C for 1.0 h.17The reaction mixture was allowed to cool to room temperature and was then concentrated underdiminished pressure. The resulting mixture was applied to a silica gel column (50 g); elutingwith 95:5 ? 75:25 DCM-MeOH (containing 10% NH4OH) afforded the corresponding triazole.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 630 - 635

77
[ 2525-16-8 ]
[ 15317-58-5 ]
[ 327079-48-1 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 120℃; for 1h;Microwave irradiation; Inert atmosphere;	A suspension containing the hydrazide (1.0 equiv.) and 7-methoxy-3,4,5,6-tetrahydro-2Hazepine(1.2 equiv.) in MeOH (0.50 M) was heated in the microwave reactor at 120 C for 1.0 h.17The reaction mixture was allowed to cool to room temperature and was then concentrated underdiminished pressure. The resulting mixture was applied to a silica gel column (50 g); elutingwith 95:5 ? 75:25 DCM-MeOH (containing 10% NH4OH) afforded the corresponding triazole.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 630 - 635

78
[ 2525-16-8 ]
[ 1314964-38-9 ]
[ 1537192-06-5 ]

Yield	Reaction Conditions	Operation in experiment
	In chlorobenzene; at 180℃; for 0.75h;Microwave irradiation; Inert atmosphere;	A suspension containing 2,5-dimethyl-1H-pyrrole-3-carbohydrazide (2.00 g, 13.1 mmol) and 7-methoxy-3,4,5,6-tetrahydro-2H-azepine (2.80 ml, 19.6 mmol) in chlorobenzene (15 mL) washeated in a capped reaction vial in the microwave oven at 180 C for 45 min. The reactionmixture was allowed to cool down to room temperature and was then concentrated underdiminished pressure. The residue was applied to a silica gel column (100 g); eluting with 95:5? 75:25 DCM-MeOH (methanol containing 10% NH4OH) afforded 3-(2,5-dimethyl-1H-pyrrol-3-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine (3) as a white solid; yield 2.14 g (71%);LC-MS rt (min): 2.58 min; 1H NMR (400 MHz, CDCl3) delta 9.02 (s, 1H), 5.77 (d, J = 2.6 Hz, 1H),4.03 - 3.96 (m, 2H), 3.05 - 2.95 (m, 2H), 2.23 (d, J = 1.5 Hz, 6H), 1.88 (q, J = 6.0 Hz, 2H), 1.75(dt, J = 10.0, 5.1 Hz, 4H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 630 - 635

79
[ 2525-16-8 ]
ethyl 2-(bis(4-methoxyphenyl)methyleneamino)acetate [ No CAS ]
2-(bis(4-methoxyphenyl)methylene)-6,7,8,9-tetrahydro-2H-imidazo[1,2-a]azepin-3(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With acetic acid; In toluene; at 20℃; for 24h;	General procedure: A mixture of imidate or thioimidate 9 (0.10-1.0 mmol, 1.0 equiv), N-(diarylmethylene)glycinate 10 (3.0-5.0 equiv), and acetic acid (2.0-4.0 equiv) in toluene (ca. 0.2 M concentration of the imidate) was stirred under gentle reflux (or at room temperature in some cases) for several hours to days, as shown in Tables 2 and 3. After being cooled to room temperature, the mixture was diluted with ethyl acetate and was washed with a saturated solution of NaHCO3, water, and 10% aqueous HCl. In the case of polar products (e.g., 2, 4, 5a, 5b, 7), the acidic aqueous layer was re-extracted with ethyl acetate after neutralization with a saturated solution of NaHCO3. The (combined) organic layers were washed with a saturated solution of NaHCO3 and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give DAIN as a coloured solid. The product was recrystallised from dichloromethane/hexane prior to evaluation of its properties.