[ CAS No. 25475-67-6 ] {[proInfo.proName]}

Name: 25475-67-6|Isoquinolin-3-amine|97%
Brand: Ambeed
SKU: A210781
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Quality Control of [ 25475-67-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 25475-67-6 ]

Product Details of [ 25475-67-6 ]

CAS No. :	25475-67-6	MDL No. :	MFCD00102190
Formula :	C₉H₈N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VYCKDIRCVDCQAE-UHFFFAOYSA-N
M.W :	144.17	Pubchem ID :	311869
Synonyms :

Calculated chemistry of [ 25475-67-6 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	46.15
TPSA :	38.91 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.94 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.47
Log Po/w (XLOGP3) :	1.75
Log Po/w (WLOGP) :	1.82
Log Po/w (MLOGP) :	1.32
Log Po/w (SILICOS-IT) :	1.77
Consensus Log Po/w :	1.63

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.51
Solubility :	0.446 mg/ml ; 0.0031 mol/l
Class :	Soluble
Log S (Ali) :	-2.18
Solubility :	0.943 mg/ml ; 0.00654 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.32
Solubility :	0.0693 mg/ml ; 0.000481 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.26

Safety of [ 25475-67-6 ]

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 [ 25475-67-6 ]

* 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 [ 25475-67-6 ]
Downstream synthetic route of [ 25475-67-6 ]

[ 25475-67-6 ] Synthesis Path-Upstream 1~14

1
[ 25475-67-6 ]
[ 19493-45-9 ]

Yield	Reaction Conditions	Operation in experiment
51%	With hydrogenchloride; sodium nitrite In water at 0 - 20℃; for 3.08333 h;	Synthesis 4-1 -A 3-Chloroisoquinoline 3-Aminoisoquinoline (1.44 g, 10 mmol) was suspended in 10M HCI (5 mL) and cooled to 0°C. Sodium nitrite (689 mg, 10 mmol) was added in portions over 5 minutes. The reaction mixture was stirred at 0°C for 2 hours and allowed to warm to room temperature over 1 hour. The reaction mixture was added carefully to saturated NaHCO₃ solution (200 mL) and extracted into ethyl acetate. The insoluble byproduct was removed by filtration and the aqueous layer was re-extracted into ethyl acetate. The combined organics were washed with water and brine, dried (Na₂SO₄) and concentrated to a brown oil which solidified on standing. Flash chromatography on silica, eluting with dichloromethane, gave the title compound as a white solid (827 mg, 5.05 mmol, 51percent). ¹H <n="96"/>NMR (Cl₆-DMSO, 400 MHz) δ 9.12 (s, 1 H), 8.41 (s, 1 H), 8.12 (dd, 1 H, J = 7.5, 1.0 Hz), 7.93-7.90 (m, 1 H), 7.84-7.80 (m, 1 H), 7.74-7.70 (m, 1 H). LCMS (1) Rt = 1.79min; m/z (ESI+) 164 (MH⁺).

Reference： [1] Patent: WO2009/103966, 2009, A1, . Location in patent: Page/Page column 93-94

2
[ 25475-67-6 ]
[ 7651-81-2 ]

Reference： [1] Journal of Organic Chemistry, 1956, vol. 21, p. 1297

3
[ 135737-14-3 ]
[ 25475-67-6 ]

Reference： [1] Tetrahedron, 1995, vol. 51, # 45, p. 12439 - 12444

4
[ 50458-77-0 ]
[ 25475-67-6 ]

Reference： [1] Journal of the American Chemical Society, 1951, vol. 73, p. 688
[2] Journal of Organic Chemistry, 2009, vol. 74, # 3, p. 1171 - 1178

5
[ 6624-49-3 ]
[ 25475-67-6 ]

Reference： [1] Journal of the American Chemical Society, 1951, vol. 73, p. 688

6
[ 66729-00-8 ]
[ 25475-67-6 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1959, vol. 7, p. 501,504

7
[ 19493-45-9 ]
[ 25475-67-6 ]

Reference： [1] Journal of the Chemical Society, 1956, p. 4191,4205

8
[ 34784-02-6 ]
[ 25475-67-6 ]

Reference： [1] Journal of the Chemical Society, 1956, p. 4191,4205

9
[ 3336-49-0 ]
[ 25475-67-6 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1959, vol. 7, p. 501,504

10
[ 101860-70-2 ]
[ 25475-67-6 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1959, vol. 7, p. 501,504

11
[ 36718-46-4 ]
[ 25475-67-6 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1959, vol. 7, p. 501,504

12
[ 86-94-2 ]
[ 25475-67-6 ]

Reference： [1] Journal of the Chemical Society, 1956, p. 4191,4205

13
[ 53987-60-3 ]
[ 25475-67-6 ]

Reference： [1] Journal of the Chemical Society, 1956, p. 4191,4205

14
[ 13130-79-5 ]
[ 25475-67-6 ]

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 41, p. 5264 - 5266

[ 25475-67-6 ] Synthesis Path-Downstream 1~88

1
[ 50458-77-0 ]
[ 25475-67-6 ]

Reference： [1]Journal of the American Chemical Society,1951,vol. 73,p. 688
[2]Journal of Organic Chemistry,2009,vol. 74,p. 1171 - 1178

2
[ 25475-67-6 ]
[ 123-06-8 ]
[ 102781-28-2 ]

Reference： [1]Journal of Organic Chemistry,1986,vol. 51,p. 2988 - 2994

3
[ 25475-67-6 ]
[ 673-40-5 ]
[ 109000-42-2 ]

Reference： [1]Tetrahedron,1986,vol. 42,p. 5415 - 5426

4
[ 25475-67-6 ]
[ 83548-91-8 ]
[ 87637-14-7 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1983,vol. 325,p. 353 - 358

5
[ 25475-67-6 ]
[ 83939-28-0 ]

Reference： [1]Journal of Heterocyclic Chemistry,1983,vol. 20,p. 239 - 240

6
[ 25475-67-6 ]
[ 75949-14-3 ]

Reference： [1]Journal of Organic Chemistry,1981,vol. 46,p. 843 - 846

7
[ 25475-67-6 ]
[ 108-24-7 ]
[ 6187-27-5 ]

Yield	Reaction Conditions	Operation in experiment
	at 60℃; for 16h;	EXAMPLE 181A N-3-isoquinolinylacetamide 3-Aminoisoquinoline (495 mg, 3.44 mmol) was stirred in Ac2O (9 mL) at 60° for 16 hours. The mixture was cooled to room temperature and concentrated in vacuo to provide the title compound which was used in the next step without further purification.
	With triethylamine; In dichloromethane; at 20℃; for 3.5h;	Acetic anhydride (5.92 mL, 62.6 mmol) was added to a suspension of isoquinolin-3- amine (3.01 g, 20.9 mmol) and triethylamine (3.18 mL, 23.0 mmol) in CH2Cl2 (80 mL) at ambient temperature. The mixture was stirred 3.5 hours, then the volatiles were evaporated in vacuo. The residue was chased with toluene and concentrated in vacuo (3 x 25 mL) to provide the title compound (3.89 g) as a yellow solid. This material, which was found to also contain small quantities of acetic acid, was used without further purification. 1H NMR (300 MHz, DMSO-J6) delta 10.58 (s, IH), 9.13 (s, IH), 8.45 (s, IH), 8.04 (d, J= 7.8 Hz, IH), 7.88 (d, J= 8.2 Hz, IH), 7.69 (ddd, J= 8.2, 6.8, 1.2 Hz, IH), 7.52 (ddd, J= 7.9, 6.9, 1.0 Hz, IH), 2.13 (s, 3H).
	With triethylamine; In dichloromethane; at 20℃; for 3.5h;	Acetic anhydride (5.92 mL, 62.6 mmol) was added to a suspension of isoquinolin-3- amine (3.01 g, 20.9 mmol) and triethylamine (3.18 mL, 23.0 mmol) in CH2Cl2 (80 mL) at ambient temperature. The mixture was stirred 3.5 hours, then the volatiles were evaporated in vacuo. The residue was chased with toluene and concentrated in vacuo (3 x 25 mL) to provide the title compound (3.89 g) as a yellow solid. This material, which was found to also contain small quantities of acetic acid, was used without further purification. 1H NMR (300 MHz, DMSO-J6) delta 10.58 (s, IH), 9.13 (s, IH), 8.45 (s, IH), 8.04 (d, J= 7.8 Hz, IH), 7.88 (d, J= 8.2 Hz, IH), 7.69 (ddd, J= 8.2, 6.8, 1.2 Hz, IH), 7.52 (ddd, J= 7.9, 6.9, 1.0 Hz, IH), 2.13 (s, 3H).

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660
[2]Patent: US2005/113576,2005,A1 .Location in patent: Page/Page column 50
[3]Patent: WO2010/45401,2010,A1 .Location in patent: Page/Page column 95-96
[4]Patent: WO2010/45402,2010,A1 .Location in patent: Page/Page column 94

8
[ 25475-67-6 ]
C₂₇H₂₈F₃N₅O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

9
[ 25475-67-6 ]
1-(4-(8-azabicyclo[3.2.1]octan-8-yl)-3-(trifluoromethyl)benzyl)-3-(3-aminoisoquinolin-5-yl)urea [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

10
[ 25475-67-6 ]
[ 946388-36-9 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

11
[ 25475-67-6 ]
[ 946388-37-0 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

12
[ 25475-67-6 ]
N-(3-amino-5-isoquinolinyl)-N'-[4-(1-azepanyl)benzyl]urea [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

13
[ 25475-67-6 ]
[ 946388-35-8 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

14
[ 25475-67-6 ]
[ 581813-12-9 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3651 - 3660

15
[ 25475-67-6 ]
4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid isoquinolin-3-ylamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 1857 - 1872

16
[ 25475-67-6 ]
benzo[f][1,7]naphthyridine-1-carbaldehyde [ No CAS ]

Reference： [1]Australian Journal of Chemistry,1994,vol. 47,p. 2129 - 2133

17
[ 25475-67-6 ]
benzo[f][1,7]naphthyridine-3-carbaldehyde [ No CAS ]

Reference： [1]Australian Journal of Chemistry,1994,vol. 47,p. 2129 - 2133

18
[ 25475-67-6 ]
[ 87637-19-2 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1983,vol. 325,p. 353 - 358

19
[ 25475-67-6 ]
[ 33459-64-2 ]

Reference： [1]Journal of Organic Chemistry,1981,vol. 46,p. 843 - 846

20
[ 25475-67-6 ]
[ 75961-48-7 ]

Reference： [1]Journal of Organic Chemistry,1981,vol. 46,p. 843 - 846

21
[ 25475-67-6 ]
[ 103856-57-1 ]

Reference： [1]Journal of Organic Chemistry,1956,vol. 21,p. 1297

22
[ 6624-49-3 ]
[ 25475-67-6 ]

Reference： [1]Journal of the American Chemical Society,1951,vol. 73,p. 688

23
[ 101860-70-2 ]
[ 25475-67-6 ]

Reference： [1]Chemical and pharmaceutical bulletin,1959,vol. 7,p. 501,504

24
[ 36718-46-4 ]
[ 25475-67-6 ]

Reference： [1]Chemical and pharmaceutical bulletin,1959,vol. 7,p. 501,504

25
[ 86-94-2 ]
[ 25475-67-6 ]

Reference： [1]Journal of the Chemical Society,1956,p. 4191,4205

26
[ 53987-60-3 ]
[ 25475-67-6 ]

Reference： [1]Journal of the Chemical Society,1956,p. 4191,4205

27
[ 25475-67-6 ]
[ 302963-42-4 ]
C₂₈H₂₃ClN₄O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[0553] Compound 516A was prepared from 473A by an analogous method as that of 473B, except using <strong>[25475-67-6]3-aminoisoquinoline</strong> in place of 2-bromo-6-aminopyridine.

Reference： [1]Patent: US2004/54186,2004,A1 .Location in patent: Page 132

28
[ 25475-67-6 ]
2-({2-[(morpholine-4-carbonyl)-amino]-pyridin-4-ylmethyl}-amino)-benzoic acid methyl ester [ No CAS ]
morpholine-4-carboxylic acid (4-[2-(isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With trimethylaluminum; In 1,2-dichloro-ethane; toluene; at 120℃; for 3h;	To a stirred solution of <strong>[25475-67-6]3-aminoisoquinoline</strong> (75 mg, 0.52 mmol) and 2-({2-[(morpholine-4-carbonyl)-amino]-pyridin-4-ylmethyl}-amino)-benzoic acid methyl ester (149 mg, 0.40 mmol) in DCE (6 mL) at 0°C, under argon, was added trimethylaluminium (2M in toluene, 0.4 mL, 0.8 mmol). The reaction was heated at 120 °C (bath temperature) for 3 hours. On cooling the reaction was diluted with aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phase was washed with water, dried and concentrated in vacuo. The residue was purified by chromatography on Isolute.(R). flash NH2 (Separtis) (Eluant: EtOAc) to give morpholine-4-carboxylic acid (4-[2-(isoquinolin-3-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (60 mg, 32percent) as a resin; 1H-NMR (300 MHz, d6-DMSO) 10.69 (1H, s), 9.21 (1H, s), 9.18 (1H, s), 8.60 (1H, s), 8.16-8.20 (2H, m), 8.10 (1H, d), 7.96 (1H, d), 7.90 (1H, d), 7.82 (1H, d), 7.75 (1H, t), 7.57 (1H, t), 7.28 (1H, t), 6.98 (1H, d), 6.63 (1H, t), 6.58 (1H, d), 4.48 (2H, d), 3.55-3.59 (4H, m), 3.41-3.45 (4H, m) m/z (ES+) 483 [M+H]+, 242.

Reference： [1]Patent: EP1657241,2006,A1 .Location in patent: Page/Page column 20-21

29
[ 25475-67-6 ]
[ 69958-52-7 ]

Yield	Reaction Conditions	Operation in experiment
57%	With platinum(IV) oxide; hydrogen; trifluoroacetic acid; for 3h;	A mixture of <strong>[25475-67-6]isoquinolin-3-amine</strong> (239 mg, 1.66mmol), platinum(IV)oxide (28mg, 0.123 mmol), and TFA (6mL) was hydrogenated in the Parr apparatus for 3 hrs. Thereaction mixture was filtered with the aid ofethyl acetate. Thefiltrate was evaporated in vacuo and the residue was partitionedbetween 10percent aqueous sodium carbonate and ethylacetate. The layers were separated, the aqueous phase waswashed again with ethyl acetate, and the combined organiclayers were washed with brine and dried over magnesiumsulfate. The drying agent was filtered off and the solventevaporated. The material was purified by colunm chromatographyin ethyl acetate to give 139.8 mg (57percent) 5,6,7,8-tetrahydro<strong>[25475-67-6]isoquinolin-3-amine</strong> as a yellow-white solid.
34%	With hydrogen; In ethyl acetate; trifluoroacetic acid;	EXAMPLE 64 STR66 3-Amino-5,6,7,8-tetrahydroisoquinoline Using the method of Example 63, Step A, 75 mg of <strong>[25475-67-6]3-aminoisoquinoline</strong> (7.73 mmoles) and 8.7 mg platinum oxide in 2 mL of trifluoroacetic acid was shaken under 40 psi of hydrogen for 3 h. The mixture was filtered and catalyst was washed with ethyl acetate. After concentrating the filtrate, the residue was dissolved in 10 mL of ethyl acetate and washed with 5 mL of saturated aquous sodium bicarbonate. The organic solution was dried (sodium sulfate), decanted, and concentrated to give a yellow syrup. Flash coumn chromatography on 19 g of silica gel, eluding with 600 mL of 50percent ethyl acetate/hexane gave 26.5 mg (34percent yield) of 3-amino-5,6,7,8-tetrahydroisoquinoline as a pale yellow solid. 1 H NMR (400 MHz, CDCl3): delta 7.78 (s, 1H), 6.22 (s, 1H), 4.12 (bs, 2H), 2.65-2.56 (m, 4H), 1.78-1.68 (m, 4H). Mass spectrum (FAB): m/e=149 (M+1)

Reference： [1]Patent: JP5714745,2015,B2 .Location in patent: Paragraph 0698; 0699
[2]Patent: US5972975,1999,A

30
[ 25475-67-6 ]
[ 689-98-5 ]
[ 82117-35-9 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2(B) 3-(Piperazin-1-yl)-isoquinoline is prepared from <strong>[25475-67-6]3-aminoisoquinoline</strong> and bis-2-chloroethylamine.

Reference： [1]Patent: US4590273,1986,A

31
[ 25475-67-6 ]
bis-N,N-(2-chloroethyl)-2-hydroxyethylamine [ No CAS ]
3-(4-(2-Hydroxyethyl)-piperazin-1-yl)-isoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 3(B) 3-(4-(2-Hydroxyethyl)-piperazin-1-yl)-isoquinoline is prepared from <strong>[25475-67-6]3-aminoisoquinoline</strong> and bis-N,N-(2-chloroethyl)-2-hydroxyethylamine.

Reference： [1]Patent: US4590273,1986,A

32
[ 25475-67-6 ]
bis-N,N-(2-chloroethyl)-2-pyridylamine [ No CAS ]
3-(4-(2-Pyridyl)-piperazin-1-yl)-isoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 4(B) 3-(4-(2-Pyridyl)-piperazin-1-yl)-isoquinoline is prepared from <strong>[25475-67-6]3-aminoisoquinoline</strong> and bis-N,N-(2-chloroethyl)-2-pyridylamine.

Reference： [1]Patent: US4590273,1986,A

33
[ 25475-67-6 ]
bis-N,N-(2-chloroethyl)-2-pyrimidinylamine [ No CAS ]
3-(4-(2-Pyrimidinyl)-piperazin-1-yl)-isoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 10(B) 3-(4-(2-Pyrimidinyl)-piperazin-1-yl)-isoquinoline is prepared from <strong>[25475-67-6]3-aminoisoquinoline</strong> and bis-N,N-(2-chloroethyl)-2-pyrimidinylamine.

Reference： [1]Patent: US4590273,1986,A

34
[ 25475-67-6 ]
bis-N,N-(2-chloroethyl)-methylamine [ No CAS ]
3-(4-methylpiperazin-1-yl)-isoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 1(B) 3-(4-Methylpiperazin-1-yl)-isoquinoline is prepared from <strong>[25475-67-6]3-aminoisoquinoline</strong> and bis-N,N-(2-chloroethyl)-methylamine.

Reference： [1]Patent: US4590273,1986,A

35
[ 25475-67-6 ]
[ 42453-19-0 ]
3-(1,4-Diazacycloheptan-1-yl)-isoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 12(B) 3-(1,4-Diazacycloheptan-1-yl)-isoquinoline is prepared from <strong>[25475-67-6]3-aminoisoquinoline</strong> and 2-chloroethyl-3-chloropropylamine.

Reference： [1]Patent: US4590273,1986,A

36
[ 25475-67-6 ]
[ 919278-09-4 ]
[ 7693-46-1 ]
N-{2-chloro-4-[(5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)oxy]phenyl}-N'-isoquinolin-3-ylurea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	With pyridine; In ISOPROPYLAMIDE; at 90℃; for 18h;	To a solution of <strong>[25475-67-6]3-aminoisoquinoline</strong> (210 mg, 1.5 mmol), EPO <DP n="223"/>pyridine (236 muL, 2.9 mmol) and 4-nitrophenyl chlorocarbonate (294 mg, 1.5 mmol) in N,N-dimethylacetamide (6 mL) was added 2-chloro-4- [ (5-methyl-5H-pyrrolo [3, 2-d] pyrimidin-4- yl) oxy]"aniline (200 mg, 0.73 mmol), and the mixture was stirred at 900C for 18 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate (chil) . The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate) and recrystallized from ethyl acetate-hexane to give the title compound (53 mg, 16percent) as a colorless solid.1H-NMR (DMSO-de, 300 MHz) delta 4.11 (3H, s) , 6.61 (IH, d, J = 3.0 Hz), 7.30 - 8.40 (1OH, m) , 9.19 (IH, -s) , 10.08 (IH, s) .

Reference： [1]Patent: WO2007/4749,2007,A1 .Location in patent: Page/Page column 221-222

37
[ 25475-67-6 ]
[ 6160-65-2 ]
[ 769960-94-3 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; N,N-dimethyl-formamide; at 65 - 70℃; for 1h;	General Procedure A: Preparation of isothiocyanate 1,1 '-thiocarbonylimidazole (1.1 mmol) was added to a solution of amine (1 mmol) inTHF/DMF (2 mL, 1:1) and the reaction mixture was stirred at 65-70 0C for 1 h. The product thus formed, was used for further transformation without isolation.; Example 1; Synthesis of 2-(Isoquinolin-3-ylamino)-lH-benzimidazole-5-carboxylic acid benzothiazol-6- ylamide3-Isothiocyanatoisoquinoline was prepared from <strong>[25475-67-6]3-aminoisoquinoline</strong> (5 mmol) as described in general procedure A.The isothiocyanate from above was reacted with methyl 3,4-diaminobenzoate (5mmol) followed by cyclization using EDC as described in general procedure B to obtain 2- (Isoquinolin-3-ylamino)-lH-benzimidazole-5-carboxylic acid methyl ester. The ester was hydrolyzed to yield the corresponding carboxylic acid employing general procedure C. Benzothiazol-6-ylamine (0.25 mmol) was coupled with aforementioned carboxylic acid using HBTU employing general procedure D to provide 2-(Isoquinolm-3-ylammo)-lH- benzimidazole-5-carboxylic acid benzothiazol-6-ylamide. MS: m/z 437 (M+H)+.

Reference： [1]Patent: WO2007/95124,2007,A2 .Location in patent: Page/Page column 49; 51

38
[ 25475-67-6 ]
[ 6187-27-5 ]

Yield	Reaction Conditions	Operation in experiment
	In Ac2O;	EXAMPLE 181A N-3-isoquinolinylacetamide 3-Aminoisoquinoline (495 mg, 3.44 mmol) was stirred in Ac2O (9 mL) at 60° for 16 hours. The mixture was cooled to room temperature and concentrated in vacuo to provide the title compound which was used in the next step without further purification.
	In Ac2O;	Example 181A N-3-isoquinolinylacetamide 3-Aminoisoquinoline (495 mg, 3.44 mmol) was stirred in Ac2O (9 mL) at 60° for 16 hours. The mixture was cooled to room temperature and concentrated in vacuo to provide the title compound which was used in the next step without further purification.

Reference： [1]Patent: US6933311,2005,B2
[2]Patent: US2004/157849,2004,A1

39
[ 25475-67-6 ]
[ 52913-14-1 ]
[ 75949-14-3 ]

Reference： [1]Tetrahedron,2008,vol. 64,p. 1101 - 1113

40
[ 25475-67-6 ]
[ 10321-49-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-Bromosuccinimide; In ethanol; dichloromethane; at 5 - 20℃;	To a solution of <strong>[25475-67-6]3-aminoisoquinoline</strong> (4.00 g, 27.7 mmol) in ethanol (40 mL) and methylene chloride (80 mL) was added N-bromosuccinimide (5.18 g, 29.1 mmol) in divided portions at 5°C, then the mixture was stirred at 5°C for 2 hours and 20 minutes, and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained brown residue was purified by a silica gel column chromatography (hexane:ethyl acetate = 50:50, hexane:ethyl acetate = 85:15?70:30, hexane:ethyl acetate = 90:10?75:25) to give 4-bromoisoquinoline-3-amine (4.65 g, 75percent) as a pale yellow solid. APCI-MS m/z: 223/225 [M+H]+.
75%	With N-Bromosuccinimide; In ethanol; dichloromethane; at 5 - 20℃; for 2.33h;	To a solution of <strong>[25475-67-6]3-aminoisoquinoline</strong> (4.00 g, 27.7 mmol) in ethanol (40 mE) and methylene chloride (80 mE) was added N-bromosuccinimide (5.18 g, 29.1 mmol) in divided, portions at 5°C., then the mixture was stirred at 5°C. for 2 hours and 20 minutes, and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained brown residue was purified by a silica gel column chromatography (hexane:ethyl acetate=50: 50. hexane:ethyl acetate=85:1 5?70:30, hexane:ethyl acetate=90: 10?75:25) to give 4-bromoisoquinoline-3- amine (4.65 g, 75percent) as a pale yellow solid.APCI-MS mlz: 223/225 [M+H].
67%	With N-Bromosuccinimide; In methanol; at 23 - 25℃; for 1h;	3-Aminoisoquinoline (15 mmol, 1.0 equiv) was suspended in methanol (20 mL). A solution of N-bromosuccinimide (17 mmol, 1.2 equiv) in methanol (75 mL) was added dropwise through an additional funnl while keeping the internal temperature <25 °C. After stirring at 23 °C for lh, the methanol is removed under vacuum and the residue was partititionned between ethyl acetate and water. The layers were separated and the aqueous phase was back extracted with ethyl acetate (2x). The combined orgaffic layers were dried with Na2504 and concentrated onto silica gel (Sg) and purfied using flash silica gel chromatography (gradient of 0-50percent ethyl acetate/hexanes) to provide the desired compound in 67percent yield. 1HNIVIR (400 MHz, CDC13) 6 8.79 (s, 1H), 7.96 ? 7.82 (m, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.66 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.41 ?7.29 (m, 1H), 5.07 (s, 2H). ESI-MS m/z = 223.1 [M + Hj.

Reference： [1]Patent: EP2896613,2015,A1 .Location in patent: Paragraph 0339; 0340
[2]Patent: US2015/307454,2015,A1 .Location in patent: Paragraph 0540; 0541
[3]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 862 - 867
[4]Patent: WO2017/214269,2017,A1 .Location in patent: Paragraph 00657
[5]Tetrahedron,2008,vol. 64,p. 11802 - 11809

41
[ 25475-67-6 ]
[ 108-86-1 ]
N-phenylisoquinolin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With tris-(dibenzylideneacetone)dipalladium(0); johnphos; sodium t-butanolate; In toluene; for 5h;Inert atmosphere;	A round-bottomed flask was charged with Pd2(dba)3 (5 mol percent ), ligand (10 molpercent), aryl halide (1mmol), appropriate isoquinolinamine (1 mmol), base (1.5 mmol) and dry solvent (5 mL). Theflask was flushed with argon for 5 min. The mixture was heated at reflux under magnetic stirring.After cooling down to room temperature, the reaction mixture was concentrated and the residuewas purified by flash column chromatography on silica gel.
85%	With tris-(dibenzylideneacetone)dipalladium(0); johnphos; sodium t-butanolate; In toluene; at 110℃; for 5h;Inert atmosphere;	A round-bottomed flask was charged with Pd2(dba)3 (0.233 g, 0.26 mmol, 5 mol percent), JohnPhos (0.152 g, 0.51 mmol, 10 mol percent), bromobenzene (0.800 g, 5.10 mmol), isoquinoline-3-amine (0.734 g, 5.10 mmol), and sodium tert-butoxide (0.735 g, 7.65 mmol) followed by dry toluene (20 mL). The flask was flushed with argon for 5 min. The resulting mixture was heated under reflux with magnetic stirring for 5 h. After cooling down to room temperature the reaction mixture was evaporated and the residue was purified by flash column chromatography on silica gel using hexane/EtOAc (4:1) as eluent yielding the product (0.940 g, 85percent). Yellow crystal; mp 101-102 °C (lit. mp 102-103 °C30); numax (KBr, cm-1): 3239, 3054, 1631, 1453, 741; deltaH (300 MHz, CDCl3): 6.91 (1H, s, NH), 7.08 (1H, dd, J=6.6 Hz, 6.4 Hz, H-4'), 7.20 (1H, s, H-4), 7.27-7.41 (5H, m, H-7, H-2', H-3', H-5', H-6'), 7.49-7.58 (2H, m, H-5, H-6), 7.81 (1H, d, J=8.2 Hz, H-8), 8.96 (1H, s, H-1); deltaC (75 MHz, CDCl3): 99.3 (C-4), 120.2 (C-2', C-6'), 122.9 (C-4'), 123.9 (C-7), 124.8 (C-8a), 125.5 (C-5), 128.0 (C-8), 129.7(C-3', C-5'), 130.8 (C-6), 138.8 (C-4a), 141.3 (C-1'), 152.3 (C-3, C-1). Anal. Calcd for C15H12N2 (220.26): C, 81.79; H, 5.49; N, 12.72percent. Found: C, 81.41; H, 5.56; N, 13.03percent.

Reference： [1]Tetrahedron,2008,vol. 64,p. 11802 - 11809
[2]ARKIVOC,2012,vol. 2012,p. 109 - 119
[3]Tetrahedron,2012,vol. 68,p. 3560 - 3565

42
[ 25475-67-6 ]
[ 583-53-9 ]
[ 1100242-99-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 8h;Inert atmosphere;	General procedure: A round-bottomed flask was charged with Pd2(dba)3 (5 mol percent ), ligand (10 molpercent), aryl halide (1mmol), appropriate isoquinolinamine (1 mmol), base (1.5 mmol) and dry solvent (5 mL). Theflask was flushed with argon for 5 min. The mixture was heated at reflux under magnetic stirring.After cooling down to room temperature, the reaction mixture was concentrated and the residuewas purified by flash column chromatography on silica gel.

Reference： [1]Tetrahedron,2008,vol. 64,p. 11802 - 11809
[2]ARKIVOC,2012,vol. 2012,p. 109 - 119

43
[ 25475-67-6 ]
[ 36016-40-7 ]
C₉H₁₀N₃⁽¹⁺⁾*C₉H₁₁O₃S^(1-) [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 1171 - 1178

44
[ 25475-67-6 ]
[ 102368-13-8 ]
[ 769960-94-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	In dichloromethane; at 20℃; for 2h;	Isoquinolin-3-amine (3.23 g, 22.4 mmol) was added to a solution of 1,1'-thiocarbonyldipyridin-2(1H)-one (5.20 g, 22.4 mmol) in dichloromethane (50 mL) at room temperature. The reaction was stirred for 2 h, then purified by flash chromatography on silica gel (0-10percent ethyl acetate in hexanes). Product fractions were combined and concentrated in vacuo to give 3-isothiocyanatoisoquinoline(3.9 g, 93 percent) as a white solid. 1H NMR (400 MHz, CDCl3) delta ppm 9.12 (1 H, s), 8.00 (1 H, d, J=8.06 Hz), 7.69 - 7.85 (2 H, m), 7.58 - 7.68 (1 H, m), 7.50 (1 H, s). LCMS (method F) tR, 2.47 min, MH+ = 187.23
85%	In dichloromethane; at 20℃; for 18h;	Step A: 3-Isothiocyanatoisoquinoline To a solution of 1,1'-thiocarbonyldipyridin-2(1H)-one (0.805 g, 3.47 mmol) in dichloromethane at room temperature was added <strong>[25475-67-6]isoquinolin-3-amine</strong> (0.5 g, 3.47 mmol). The reaction was stirred at room temperature for 18 hours. The LC/MS showed the desired product peak a major peak. The deep orange solution was concentrated and filtered. The filtrate was purified by silica gel chromatography (0-40percent ethyl acetate-hexanes) to afford 4-isothiocyanato-6-(3-methoxyphenyl)pyrimidine (0.55 g, 2.96 mmol, 85percent yield) a white solid. LCMS R.T.=2.47; [M+H]+=187.23.
85%	In dichloromethane; at 20℃; for 18h;	EXAMPLE 4; (5S,5'R)-N-(isoquinolin~3-yl)-4^1-azaspiro[bicyclo[3.2 ]oamine; Step A: 3-Isothiocyanatoisoquinoline; To a solution of 1 , 1 '-thiocarbonyldipyridm-2(l H)-one (0.805 g, 3.47 mmol) in dichloromethane at room temperature was added <strong>[25475-67-6]isoquinolin-3-amine</strong> (0.5 g, 3.47 mmol). The reaction was stirred at room temperature for 18 hours. The LC/MS showed the desired product peak a major peak. The deep orange solution was concentrated and filtered. The filtrate was purified by silica gel cliromatography (0- 40percent ethyl acetate-hexanes) to afford 4-isothiocyanato-6-(3- methoxyphenyl)pyrimidine (0.55 g, 2.96 mmol, 85 percent yield) a white solid. LCMS R.T. - 2.47; [M+H]+ = 187.23.

85%	In dichloromethane; at 20℃; for 18h;	Step A: 3-IsothiocyanatoisoquinolineTo a solution of l, l'-thiocarbonyldipyridin-2(lH)-one (0.805 g, 3.47 mmol) in dichloromethane at room temperature was added isoquinolin-3 -amine (0.5 g, 3.47 mmol). The reaction was stirred at room temperature for 18 hours. The LC/MS showed the desired product peak a major peak. The deep orange solution was concentrated and filtered. The filtrate was purified by silica gel chromatography (0- 40percent ethyl acetate-hexanes) to afford 4-isothiocyanato-6-(3- methoxyphenyl)pyrimidine (0.55 g, 2.96 mmol, 85 percent yield) a white solid. LCMS R.T. = 2.47; [M+H]+ = 187.23.
85%	In dichloromethane; at 20℃; for 18h;	To a solution of 1,1'-thiocarbonyldipyridin-2(lH)one(0.805 g, 3.47 mmol) in dichloromethane at room temperature was added <strong>[25475-67-6]isoquinolin-3-amine</strong> (0.5 g, 3.47 mmol).The reaction was stirred at room temperature for 18 hours.The LC/MS showed the desired product peak a major peak.The deep orange solution was concentrated and filtered. Thefiltrate was purified by silica gel chromatography (0-40percentethyl acetate-hexanes) to afford 4-isothiocyanato-6-(3-methoxyphenyl)pyrimidine (0.55 g, 2.96 mmol, 85percent yield) a white solid.
	In dichloromethane; at 20℃; for 18h;	EXAMPLES 7, 7a, 7b; (3R,4R)-N-(Isoquinolin-3-yl)-4'H-l-azaspiro[bicyclo[2.2.1]heptane-3,5'-oxazol]-2' -amine; Step A: 3-Isothiocyanatoisoquinoli; To a solution of l,l'-thiocarbonyldipyridin-2(lH)-one (0.805 g, 3.47 mmol) in dichloromethane at room temperature was added isoquinolin-3 -amine (0.5 g, 3.47 mmol). The reaction was stirred at room temperature for 18 hours. The LC/MS showed the desired product peak a major peak. The deep orange solution was concentrated and filtered. The filtrate was purified by silica gel chromatography (0- 40percent ethyl acetate-hexanes) to afford 4-isothiocyanato-6-(3- methoxyphenyl)pyrimidine (0.55 g, 2.96 mmol, 85 percent yield) a white solid. LCMS R.T. = 2.47; [M+H]+ = 187.23.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1261 - 1266
[2]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 133 - 137
[3]Patent: US2009/270405,2009,A1 .Location in patent: Page/Page column 135
[4]Patent: WO2011/56573,2011,A1 .Location in patent: Page/Page column 32
[5]Patent: WO2011/53292,2011,A1 .Location in patent: Page/Page column 239
[6]Patent: JP5714745,2015,B2 .Location in patent: Paragraph 0423-0424
[7]Patent: WO2011/56503,2011,A1 .Location in patent: Page/Page column 43

45
[ 25475-67-6 ]
N-(3-(4-chlorophenyl)-2(S)-(3-cyanophenyl)-1(S)-methylpropyl)-2-bromo-2-methyl-propanamide [ No CAS ]
[ 1190900-25-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5195 - 5199

46
[ 25475-67-6 ]
[ 1204701-61-0 ]
[ 1204701-69-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃;	EXAMPLE 1;lsoquinolin-3-vH4-pyrrolidin-1-ylmethyl-pyridin-2-yl)-amine; 2-Chloro-4-pyrrolidin-1-ylmethyl-pyridine (1eq), isoquinoline-3-ylamine (1eq), 2.0 eq. of caesium carbonate, 10percent (mol) Xantphos and 10percent (mol) of Pd2(dba)3 were mixed in toluene (3 ml). The reaction mixture was degassed for three times and then warmed to 100°C overnight. The reaction mixture was cooled, concentrated and purified by column chromatography eluting 0 -10percent sat. NH3ZMeOH and DCM to afford the title compound.LCMS r.t. 2.93 305.3 (MH+, ES+)1H NMR (DMSO-d6): delta 11.17-10.94 (1 H, br s), 9.22 (1 H, s), 8.40 (1 H, d), 8.18-8.08 (2H, br m), 7.93 (1 H, br d), 7.75 (1 H, br t), 7.57-7.49 (2H, m), 7.35-7.29 (1 H, br m), 4.45 (2H, br d), 3.47-3.42 (2H, m), 3.15-3.03 (2H, m), 2.11-1.98 (2H, m), 1.97-1.85 (2H, m).

Reference： [1]Patent: WO2010/7374,2010,A1 .Location in patent: Page/Page column 48

47
[ 25475-67-6 ]
[ 1204701-57-4 ]
[ 1204701-88-1 ]

Yield	Reaction Conditions	Operation in experiment
28%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene;Reflux;	EXAMPLE 19; 4-r2-(lsoquinolin-3-ylamino)-pyridin-4-ylmethyl1-piperazine-1-carboxylic acid methylamide; 1-(2-Chloro-pyridin-4-ylmethyl)-4-(N-methylcarbamoyl)piperazine (1.0 equiv) (Preparation B-12) was mixed with <strong>[25475-67-6]3-aminoisoquinoline</strong> (1.0 equiv), Pd2(dba)3 (0.1 equiv), xantphos (0.15 equiv), and Cs2CO3 (1.4 equiv) in toluene. The mixture was refluxed overnight, and EtOAc was added in to dilute the mixture. After filtration, the filtrate was concentrated and applied onto a silica gel column. The title compound was obtained as a yellow solid (63 mg, 28percent yield): 1H NMR (CDCI3, 300 MHz) delta: 2.49 (t, J = 4.4 Hz, 4H, PyridylCH2NCH2CH2), 2.83 (s, 6H, N(CH3)2), 3.29 (t, J = 4.8 Hz, 4H, NCH2CO), 3.52 (s, 2H, pyridylCH2), 6.88-8.98 (m, 9H, isoquinolyl+pyridyl).

Reference： [1]Patent: WO2010/7374,2010,A1 .Location in patent: Page/Page column 54-55

48
[ 25475-67-6 ]
[ 1204701-56-3 ]
[ 1204701-89-2 ]

Yield	Reaction Conditions	Operation in experiment
22%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene;Reflux;	EXAMPLE 20; 4-f2-(lsoquinolin-3-ylamino)-pyridin-4-ylmethyll-piperazine-1-carboxylic acid diethylamide; 1-(2-Chloro-pyridin-4-ylmethyl)-4-(N,N-dimethylcarbamoyl)piperazine (1.0 equiv) (Preparation B-12) was mixed with <strong>[25475-67-6]3-aminoisoquinoline</strong> (1.0 equiv), Pd2(dba)3 (0.1 equiv), xantphos (0.15 equiv), and Cs2CO3 (1.4 equiv) in toluene. The mixture was refluxed overnight, and EtOAc was added in to dilute the mixture. After filtration, the filtrate was concentrated and applied onto a silica gel column. The title compound was obtained as a yellow solid (50 mg, 22percent yield): 1H NMR (CDCI3, 300 MHz) delta: 2.47 (t, J = 5.0 Hz, 4H, PyridylCH2NCH2CH2), 2.83 (d, J = 4.8 Hz1 3H, NHCH3), 3.41 (t, J = 5.0 Hz, 4H, NCH2CO), 3.51 (s, 2H, pyridylCH2), 6.86-8.99 (m, 9H, isoquinolyl+pyridyl).

Reference： [1]Patent: WO2010/7374,2010,A1 .Location in patent: Page/Page column 55

49
[ 25475-67-6 ]
[ 1065103-42-5 ]
[ 1204701-91-6 ]

Yield	Reaction Conditions	Operation in experiment
61%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene;Reflux;	EXAMPLE 21; 4-[2-(lsoquinolin-3-ylamino)-pyridin-4-ylmethyll-piperazine-1 -carboxylic acid amide; A. 2-(lsoquinolin-3-ylamino)-4-(4-tert-butoxycarbonylpiperazin-1-ylmethyl)-pyridine 1-Boc-4-(2-chloropyridin-4-ylmethyl)piperazine (500 mg, 1.63 mmol) (Preparation B-14) was mixed with <strong>[25475-67-6]3-aminoisoquinoline</strong> (234 mg, 1.0 equiv), Pd2(dba)3 (148 mg, 0.1 equiv), xantphos (140 mg, 0.15 equiv), and Cs2CO3 (735 mg, 1.4 equiv) in toluene. The mixture was refluxed overnight, and EtOAc was added in to dilute the mixture. After filtration, the filtrate was concentrated and applied onto a silica gel column. The title compound (250 mg, yield 61percent) was obtained as yellow solid.

Reference： [1]Patent: WO2010/7374,2010,A1 .Location in patent: Page/Page column 55-56

50
[ 25475-67-6 ]
[ 1204701-51-8 ]
[ 1204701-94-9 ]

Yield	Reaction Conditions	Operation in experiment
48%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene;Reflux;	EXAMPLE 22; 1-f4-[2-(lsoquinolin-3-ylamino)-pyridin-4-ylmethvn-piperazin-1-yll-ethanone; 1-(2-Chloropyridin-4-ylmethyl)-4-acetylpiperazine (1.0 equiv) (Preparation B-15) was mixed with <strong>[25475-67-6]3-aminoisoquinoline</strong> (1.0 equiv), Pd2(dba)3 (0.1 equiv), xantphos (0.15 equiv), and Cs2CO3 (1.4 equiv) in toluene. The mixture was refluxed overnight, and EtOAc was added in to dilute the mixture. After filtration, the filtrate was concentrated and applied onto a silica gel column. The title compound was obtained as a yellow solid (50 mg, yield 48percent). 1H NMR (CDCI3, 300 MHz) delta: 2.10 (s, 3H, Ac), 2.47 (t, J = 4.1 Hz, 4H, PyCH2NCH2CH2), 3.58 (dt, J = 4.8 Hz, 50.7 Hz, 4H, NCH2CO), 3.60 (s, 2H, pyridylCH2), 6.86-8.99 (m, 9H, isoquinolyl+pyridyl).

Reference： [1]Patent: WO2010/7374,2010,A1 .Location in patent: Page/Page column 56-57

51
[ 25475-67-6 ]
[ 1204701-62-1 ]
[ 1204701-96-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene;Reflux;	EXAMPLE 23; 2-Hvdroxy-1-{4-[2-(isoquinolin-3-ylamino)-pyridin-4-ylmethyll-piperazin-1-yl)- ethanone; A. 2-(lsoquinolin-3-ylamino)-4-(4-benzyloxyacetylpiperazin-1-ylmethyl)pyridine; 1-(2-Chloropyridin-4-ylmethyl)-4-benzyloxyacetylpiperazine (1.0 equiv) (Preparation B-16) was mixed with <strong>[25475-67-6]3-aminoisoquinoline</strong> (1.0 equiv), Pd2(dba)3 (0.1 equiv), xantphos (0.15 equiv), and Cs2CO3 (1.4 equiv) in toluene. The mixture was refluxed overnight, and EtOAc was added in to dilute the mixture. After filtration, the filtrate was concentrated and applied onto a silica gel column. The title compound was obtained as a yellow solid.

Reference： [1]Patent: WO2010/7374,2010,A1 .Location in patent: Page/Page column 57-58

52
[ 25475-67-6 ]
[ 6160-65-2 ]
[ 927902-45-2 ]

Yield	Reaction Conditions	Operation in experiment
76%		0.618 g (3.47 mmol) N,N'-thiocarbonyldiimidazole was dissolved in 20 mL acetonitrile, and 0.500 g (3.47 mmol) isoquinoline-3-amine in the form of a suspension in 15 mL acetonitrile was added dropwise in portions. The clear orange solution which formed was stirred for 12 hr, whereupon a reddish precipitate formed. The intermediate product was directly reacted, without workup, with 0.535 g (6.940 mmol) ammonium acetate for 25 min at 85° C. in a CEM microwave (100 watts). The solvent was removed under vacuum. The residue was stirred in water, and the resulting precipitate was suctioned off and washed with water. For further purification the solid was taken up in 5 mL acetonitrile and combined with 50 mL diisopropyl ether. The precipitate was filtered again and dried in a vacuum drying oven at 40° C., resulting in the isolation of 0.540 g (2.647 mmol, 76percent) purified N-isoquinolin-3-yl-thiourea.ESI-MS [M+H+]=204.15 Calculated for C10H9N3S=203.27

Reference： [1]Patent: US2010/184787,2010,A1 .Location in patent: Page/Page column 51

53
[ 109-04-6 ]
[ 25475-67-6 ]
[ 1238944-84-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium tert-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 90℃; for 17h;Inert atmosphere;	2-Amino-isoquinoline (301 mg, 2.09 mmol), 2-bromopyridine (181muL, 1.90 mmol), tBuOK (320 mg, 2.55 mmol), (+/-)-BINAP (47 mg, 0.08 mmol) and Pd2(dba)3 (43 mg, 0.05 mmol) were stirred in toluene (3 mL) at 9O0C under Ar(g) for 17h. The reaction mixture was then diluted with CH2CI2 (5mL) and silica was added followed by the removal of the solvent under reduced pressure. The resulting dry loaded material was purified by silica gel column chromatography eluting with hexane/EtOAc (80:20 then 70:30) to furnish I as a white solid (252 mg, 60percent).1H NMR (400MHz, CDCI3) deltaH: 8.99 (s, 1H), 8.34 (d, J=4.0Hz, 1H), 8.28 (s, 1H), 7.87 (d, J=8.5Hz, 1 H), 7.78 (d, J=8.5Hz, 1 H), 7.67-7.55 (m, 2H), 7.39 (t, J=7.5Hz, 1H), 7.19 (d, J=7.5Hz, 1H), 6.91-6.84 (m, 1H). MW: 221.26. LCMS (ES): found 222.1 [MH]+.

Reference： [1]Patent: WO2010/86646,2010,A1 .Location in patent: Page/Page column 43

54
[ 25475-67-6 ]
2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide [ No CAS ]
2-(3-isoquinolin-3-yl-ureido)-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		To a solution of 48.4 mg (0.2 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (lH-imidazol-2-yl)-amide (Intermediate B) in dry DMF (1.0 niL) was added 49 mg (0.3 mmol) of di-imidazol-1-yl-methanone in one portion. The mixture was heated at 50 0C for 30 min, after cooling to room temperature, 23 mg (0.16 mmol) of <strong>[25475-67-6]isoquinolin-3-ylamine</strong> was added to the reaction mixtures. The reaction mixture was stirred at 45 0C for 45 min. After cooling to r.t, the organic solvent was removed under reduced pressure. The residue was purified by column chromatography eluting with DCM/methanol (v/v= 10:1 to 8:1) to give 17 mg (20percent) of 2-(3-isoquinolin-3-yl-ureido)-lH-benzoimidazole-4-carboxylic acid (IH- imidazol-2-yl)-amide. LCMS: 413 (M+l)+

Reference： [1]Patent: WO2006/99379,2006,A2 .Location in patent: Page/Page column 164

55
[ 25475-67-6 ]
[ 910122-55-3 ]
1H-benzoimidazole-2,4-dicarboxylic acid 4-[(1H-imidazol-2-yl)-amide] 2-isoquinolin-3-ylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13.6%		To a stirring solution of 100 mg (0.36 mmol) of above acid in 2.0 mL of DMF was added 140 mg (0.72 mmol) of EDCI. The reaction mixture was stirred for 10 min then 53 mg (0.36 mmol) of Isoquinolin-3-ylamine was added. The reaction mixture stirred for another 20 h and cooled to room temperature 5.0 mL of water and 5.0 mL of saturated NaHCO3 was EPO <DP n="168"/>added. The resulting solid was filtered washed with water, ether and dried to provide 20 mg (13.6percent) of lH-benzoimidazole-2,4-dicarboxylic acid 4-[(lH-imidazol-2-yl)-amide] 2- isoquinolin-3-ylamide. LCMS: 398 (M + I)+.

Reference： [1]Patent: WO2006/99379,2006,A2 .Location in patent: Page/Page column 166-167

56
[ 25475-67-6 ]
[ 1266676-71-4 ]