7651-82-3|Isoquinolin-6-ol| Ambeed

Structure of 7651-82-3

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 7651-82-3 ] Purity: 98% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 7651-82-3 ]

CAS No. :	7651-82-3
Formula :	C₉H₇NO
M.W :	145.16
SMILES Code :	OC1=CC2=C(C=NC=C2)C=C1
MDL No. :	MFCD04114860
InChI Key :	GPVPDRHTRGTSIH-UHFFFAOYSA-N
Pubchem ID :	135483582

Safety of [ 7651-82-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 7651-82-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	10
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	43.77
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	33.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.31
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.89
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.94
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.92
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.01
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.61

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.6
Solubility	0.362 mg/ml ; 0.00249 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.21
Solubility	0.899 mg/ml ; 0.00619 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.1
Solubility	0.115 mg/ml ; 0.000791 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.84 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.0

Application In Synthesis of [ 7651-82-3 ]

* 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.

Downstream synthetic route of [ 7651-82-3 ]

[ 7651-82-3 ] Synthesis Path-Downstream 1~41

1
[ 7651-82-3 ]
[ 23687-26-5 ]

References: [1]Journal of the American Chemical Society,1950,vol. 72,p. 4997.

2
[ 52986-70-6 ]
[ 7651-82-3 ]

Yield	Reaction Conditions	Operation in experiment
82%	With aqueous HBr; In water;	(c) 6-Methoxyisoquinoline (16 g, 0.1M) and 48% aqueous HBr (600 ml) were refluxed together for 6 hours and the mixture was then evaporated to dryness in vacuo. The residue was dissolved in H2 O and basified with solid Na2 CO3. The resulting precipitated solid was filtered off and recrystallized from isopropanol to give 6-hydroxyisoquinoline (12 g, 82%), m.p. 218-20 C. (lit.* 220 C.).
27%	With pyridine hydrochloride; at 160℃;	Heat a mixture of 6-methoxy-isoquinoline (2.1 g, 13.2 mmol) and pyridine hydrochloride (30 g) in a heavy walled screw cap sealed tube at 160C overnight. Cool to room temperature, add water and concentrated ammonium hydroxide to bring the pH of the mixture to 10-11, extract with ethyl acetate (4 times), wash the combined organic extracts with water (4 times), and concentrate under reduced pressure. Purification by medium pressure liquid chromatography eluting with 0-3% of 2N NH3/MeOH in dichloromethane afford the title compound (520 mg, 27%) : No.H (DMSO-d6,400 MHz) : 7.09 (s, 1H), 7.19 (dd, 1H, J = 9, 2H2), 7.56 (d, 1H, J = 6 Hz), 7.94 (d, 1H, J = 9 HZ), 8.29 (d, 1H, J = 6 Hz), 9.05 (s, 1H), 10.36 (s, 1H)
27%		b) ISOQUINOLIN-6-OL Heat a mixture of 6-methoxy-isoquinoline (2.1 g, 13.2 mmol) and pyridine hydrochloride (30 g) in a heavy walled screw cap sealed tube at 160C overnight. Cool to room temperature, add water and concentrated ammonium hydroxide to bring the pH of the mixture to 10-11, extract with ethyl acetate (4 times), wash the combined organic extracts with water (4 times), and concentrate under reduced pressure. Purification by medium pressure liquid chromatography eluting with 0-3% of 2N NH3/MeOH in dichloromethane afford the title compound (520 mg, 27%) : 8H (DMSO-d6,400 MHz): 7.09 (s, 1H), 7.19 (dd, 1H, J=9,2 Hz), 7.56 (d, 1H, J = 6 Hz), 7.94 (d, 1H, J = 9 HZ), 8.29 (d, 1H, J = 6 Hz), 9.05 (s, 1H), 10.36 (s, 1H).

With pyridine hydrochloride; ammonium hydroxide; In water; at 20 - 160℃;pH 10 - 11;

Isoquinolin-6-ol Heat a mixture of 6-methoxy-isoquinoline (2.1 g, 13.2 mmol) and pyridine hydrochloride (30 g) in a heavy walled screw cap sealed tube at 160C overnight. Cool to room temperature, add water and concentrated ammonium hydroxide to bring the pH of the mixture to 10-11, extract with ethyl acetate (4 times), wash the combined organic extracts with water (4 times), and concentrate under reduced pressure. Purification by medium pressure liquid chromatography eluting with 0-3% of 2N NH3/MeOH in dichloromethane afford the title compound (520 mg, 27%): 8H (DMSO-d6,400 MHz) : 7.09 (s, 1H), 7.19 (dd, 1H, J = 9, 2 HZ), 7.56 (d, 1H, J = 6 HZ), 7.94 (d, 1H, J = 9 Hz), 8.29 (d, 1H, J = 6 Hz), 9.05 (s, 1H), 10.36 (s, 1H).

References: [1]Patent: US4812573,1989,A .
[2]Patent: WO2004/43931,2004,A1 .Location in patent: Page 36-37.
[3]Patent: WO2004/43904,2004,A1 .Location in patent: Page 59.
[4]Journal of the American Chemical Society,1947,vol. 69,p. 1944.
[5]European Journal of Organic Chemistry,2003,p. 1681 - 1686.
[6]Patent: WO2004/43903,2004,A1 .Location in patent: Page 63.
[7]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1084 - 1088.

3
[ 110-91-8 ]
[ 7651-82-3 ]
[ 63485-77-8 ]

References: [1]Chemistry of Heterocyclic Compounds,1977,vol. 13,p. 403 - 407.
Khimiya Geterotsiklicheskikh Soedinenii,1977,vol. 13,p. 500 - 505.

4
[ 7651-82-3 ]
3-phenylcinnamaldehyde [ No CAS ]
[ 160452-18-6 ]

References: [1]Helvetica Chimica Acta,1997,vol. 80,p. 725 - 738.

6
[ 7651-82-3 ]
[ 37595-74-7 ]
[ 149353-93-5 ]

References: [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 6700 - 6704.

7
4-fluoro-6-(4-(trifluoromethyl)phenyl)pyrimidine [ No CAS ]
[ 7651-82-3 ]
6-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)isoquinoline [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3515 - 3527.

8
[ 7651-82-3 ]
1-isopropoxycarbonylmethyl-6-trifluoromethanesulfonyloxy-1H-isoquinoline-2-carboxylic acid 2,2,2-trichloro-ethyl ester [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 6700 - 6704.

9
[ 7651-82-3 ]
1-isopropoxycarbonylmethyl-6-trifluoromethanesulfonyloxy-1H-isoquinoline-2-carboxylic acid 2,2,2-trichloro-ethyl ester [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 6700 - 6704.

10
[ 7651-82-3 ]
1-isopropoxycarbonylmethyl-6-trifluoromethanesulfonyloxy-1H-isoquinoline-2-carboxylic acid 2,2,2-trichloro-ethyl ester [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 6700 - 6704.

11
[ 7651-82-3 ]
[ 206122-78-3 ]
[ 1972-28-7 ]
6-[2-[(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxazolyl ]ethoxy]isoquinoline hydrochloride monohydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triphenylphosphine; In tetrahydrofuran; chloroform; di-isopropyl ether; toluene;	EXAMPLE 34 6-[2-[(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxazolyl ]ethoxy]isoquinoline hydrochloride monohydrate Title compound was prepared from compound of Example 1C (19.1 mmole, 6.07 g), triphenylphosphine (21.1 mmole, 5.52 g) and <strong>[7651-82-3]6-hydroxyisoquinoline</strong> (21.lmmole, 3.07 g) in tetrahydrofuran (43 ml) at -10° C. (ice/acetone bath) was added diethylazodicarboxylate (21.1 mmole, 3.67 g) over an eleven minute period. After the addition was complete, the reaction was stirred at room temperature. At approximately 3.8 hours the reaction was concentrated in vacuo to an oil. The oil was taken up into chloroform then chromatographed. Material was eluted with 70-85percent ethyl acetate/hexane gradient over a thirty minute period. Fractions containing desired product were combined, reduced in volume and chromatographed. Material was eluted with 0-15percent methanol/toluene gradient over a thirty minute period. Fractions containing desired product were combined and concentrated in vacuo to a solid. The solid was treated with chloroform (100 ml), hydrogen chloride gas was passed through the solution which was then concentrated in vacuo to a yellow foam. The foam was triturated in diisopropyl ether (100 ml) then filtered. Insolubles were treated with toluene (100 ml), heated until boiling, filtered hot, and washed with toluene (50 ml). These insolubles were crystallized from methylene chloride. Crystals were treated with chloroform (60 ml), and then with hydrogen chloride gas and concentrated in vacuo to a foam. Material was triturated in toluene (100 ml) and filtered and the insolubles were collected by filtration to afford 1.38 g of product. Mass Spectrum (ion spray):m/z 444 (M-HCl). 1H NMR (DMSOd6): delta9.71 (s, 1 H), 8.56 (d, 1 H), 8.44 (d, 1 H), 8.28 (d, 1 H), 7.99 (s, 1 H), 7.84 (d, 1 H), 7.73 (s, 2 H), 7.64 (dd, 1 H), 7.56 (bs, 1 H), 4.56 (t, 2 H), 3.13 (t, 2 H), 1.41 (s, 18 H).
	With hydrogenchloride; triphenylphosphine; In tetrahydrofuran; chloroform; di-isopropyl ether; toluene;	Example 34 6-[2-[(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxazolyl]ethoxy]isoquinoline hydrochloride monohydrate Title compound was prepared from compound of Example 1C (19.1 mmole, 6.07 g), triphenylphosphine (21.1 mmole, 5.52 g) and <strong>[7651-82-3]6-hydroxyisoquinoline</strong> (21.1 mmole, 3.07 g) in tetrahydrofuran (43 ml) at -10° C. (ice/acetone bath) was added diethylazodicarboxylate (21.1 mmole, 3.67 g) over an eleven minute period. After the addition was complete, the reaction was stirred at room temperature. At approximately 3.8 hours the reaction was concentrated in vacuo to an oil. The oil was taken up into chloroform then chromatographed. Material was eluted with 70-85percent ethyl acetate/hexane gradient over a thirty minute period. Fractions containing desired product were combined, reduced in volume and chromatographed. Material was eluted with 0-15percent methanol/toluene gradient over a thirty minute period. Fractions containing desired product were combined and concentrated in vacuo to a solid. The solid was treated with chloroform (100 ml), hydrogen chloride gas was passed through the solution which was then concentrated in vacuo to a yellow foam. The foam was triturated in diisopropyl ether (100 ml) then filtered. Insolubles were treated with toluene (100 ml), heated until boiling, filtered hot, and washed with toluene (50 ml). These insolubles were crystallized from methylene chloride. Crystals were treated with chloroform (60 ml), and then with hydrogen chloride gas and concentrated in vacuo to a foam. Material was triturated in toluene (100 ml) and filtered and the insolubles were collected by filtration to afford 1.38 g of product. Mass Spectrum (ion spray): m/z 444 (M-HCl). 1 H NMR (DMSOd6): delta9.71 (s, 1H), 8.56 (d, 1H), 8.44 (d, 1H), 8.28 (d, 1H), 7.99 (s, 1H), 7.84 (d, 1H), 7.73 (s, 2H), 7.64 (dd, 1H), 7.56 (bs, 1H), 4.56 (t, 2H), 3.13 (t, 2H), 1.41 (s, 18H). Elemental analysis for C28 H33 ClN2 O3.1.0 H2 O: Calculated: C, 67.38; H, 7.07; N, 5.61. Found: C, 67.60; H, 6.87; N, 5.35.

References: [1]Patent: US2001/27194,2001,A1 .
[2]Patent: US6156748,2000,A .

12
[ 7651-82-3 ]
6-Trifluoroethylsulphonyloxy-isoquinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine; tert-butyl methyl ether; ethyl acetate;	Example XII 6-Trifluoroethylsulphonyloxy-isoquinoline 10 g of <strong>[7651-82-3]6-hydroxyisoquinoline</strong> are dissolved in 150 ml of dry pyridine at 50° C. and cooled to -20° C. Then 11.6 ml of trifluoromethanesulphonic acid anhydride are added dropwise within 15 minutes with vigorous stirring. The mixture is stirred for a further 30 minutes at -20° C. and then for 16 hours at 0° C. The reaction mixture is evaporated down and the residue is evaporated several times with toluene. The residue is taken up in 250 ml of tert.butyl-methylether and extracted five times with 20 ml of water. The organic phase is separated off, dried and evaporated down and the residue is purified by chromatography over a silica gel column using ethyl acetate. Yield: 15.9 g (84percent of theory), Rf value: 0.76 (silica gel; ethyl acetate/cyclohexane=9:1) Calculated: C 43.33; H 2.18; N 5.05; S 11.56; Found: 43.29; 2.35; 5.15; 11.62.

References: [1]Patent: US5455348,1995,A .

13
[ 7651-82-3 ]
[ 1336-21-6 ]
[ 23687-26-5 ]

Yield	Reaction Conditions	Operation in experiment
67%	In water;	(d) <strong>[7651-82-3]6-Hydroxyisoquinoline</strong> (12 g, 0.083M) was suspended in 180 ml H2 O and SO2 gas was passed through until 12 g had been absorbed. 0.880 NH4 OH (240 ml) was then added and the mixture was heated in a Berghof pressure vessel for 15 hours at 150° C. (pressure approximately 730 kilopascals). After cooling the product which crystallized out was filtered off and recrystallized from benzene/60-80 pet. ether to give 6-aminoisoquinoline (7.98 g, 67percent), m.p. 217°-8° C. (lit.* 217°-8° C.).

References: [1]Patent: US4812573,1989,A .

14
[ 7651-82-3 ]
6-methoxy-2-methylisoquinolin-2-ium iodide [ No CAS ]
[ 74-88-4 ]
[ 52986-97-7 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; hydrogen bromide; acetone;	EXAMPLE 8 6-Hydroxy-2-methylisoquinolinium bromide Method (a) 6-Methoxy-2-methylisoquinolinium iodide (7.3 g., Example 1) in 48percent hydrobromic acid (70 ml) was heated under reflux for 24 hours. The solvent was removed in vacuo to give a solid that we recrystallized from ethanol/ethyl acetate and had m.p. 216°-219°. Method (b) Methyl iodide (4 ml) and <strong>[7651-82-3]6-hydroxyisoquinoline</strong> (1 g.) in acetone (50 ml) and methanol (20 ml) were heated under reflux for 2 hours. The solution was cooled and diluted with ether to give the quaternary iodide as colourless crystals, m.p. 202°-204°. The iodide was converted into the bromide, m.p. 216°-219°, by heating under reflux with 48percent hydrobromic acid for 24 hours, evaporating the mixture and crystallising the residue from a mixture of ethanol and ethyl acetate.

References: [1]Patent: US4042697,1977,A .

15
[ 7651-82-3 ]
[ 109384-19-2 ]
[ 918490-55-8 ]

Yield	Reaction Conditions	Operation in experiment
	With polystyrene-bound triphenylphosphine; triethylamine; In dichloromethane; at 20℃;Product distribution / selectivity;	AAV1 :To 500 mg (1.5 mmol) of triphenylphosphine (bound to polystyrene, 3mmol/g) and 10 ml of dichloromethane 0.195 mL (1.2 mmol) of diethylazodicarboxylate (or alternatively diisopropylazodicarboxylate) were added. The reaction mixture was allowed to shake for 10 min. and then 0.14 mL of triethylamine, 145 mg of <strong>[7651-82-3]6-hydroxyisoquinoline</strong> (7) (or an equivalent amount of a different suitable isoquinol) (reagent 1) and 1 mmol of the desired, boc-protected aminoalcohol (reagent 2) was added. The reaction was shaken at room temperature until no further conversion could be observed by LCMS. For workup, the solution was filtered, the residue was washed with dichloromethane and EPO <DP n="90"/>the organic layer was washed twice with 1 N sodium hydroxide, twice with water and once with brine, dried over magnesium sulfate and evaporated. The crude product was purified by preparative HPLC to yield the boc protected coupled product.

References: [1]Patent: WO2007/240,2007,A1 .Location in patent: Page/Page column 88-89; 90.

16
[ 7651-82-3 ]
[ 918488-41-2 ]

Yield	Reaction Conditions	Operation in experiment
89%		5-Chloroisoquinoline-6-ol (8)0.61 ml_ (1.02 g, 7.6 mmol) of sulfuryl chloride were added to a solution of 1.0 g (6,9 mmol) of compound 7 in 30 ml_ of dichloromethane. Three drops diethyl ether were EPO <DP n="37"/>added and the reaction was stirred at room temperature for 5 h. The solvents were removed by distillation and the remainder was treated with aqueous NaHCpsi3 solution.The precipitate was filtered, washed with water and dried to give 1.1 g (89percent) of compound 8 as a green-yellow solid.1H-NMR (de-DMSO): delta = 11.37 (1 H, s), 9.18 (1H, s), 8.50 (1H, d, J = 6 Hz)1 8.00 (1H, d, J= 8.8 Hz), 7.83 (1 H, J = 6 Hz), 7.44 (1 H, d, J = 8.7 Hz).MS: m/z = 180 (MH+).
89%		5-Chloroisoquinoline-6-ol (1); 0.61 mL (1.02 g, 7.6 mmol) of sulfuryl chloride were added to a solution of 1.0 g (6,9 mmol) of <strong>[7651-82-3]6-hydroxy-isoquinoline</strong> in 30 mL of dichloromethane. Three drops diethyl ether were added and the reaction was stirred at room temperature for 5 h. The solvents were removed by distillation and the remainder was treated with aqueous NaHCO3 solution. The precipitate was filtered, washed with water and dried to give 1.1 g (89percent) of 1 as a green-yellow solid.1H-NMR (d6-DMSO): delta = 11.37 (1 H, s), 9.18 (1 H, s), 8.50 (1 H, d, J = 6 Hz), 8.00 (1 H, d, J= 8.8 Hz), 7.83 (1 H1 J = 6 Hz), 7.44 (1 H, d, J = 8.7 Hz). MS: m/z = 180 (MH+).
11.4 mg	With Escherichia coli BL21-CodonPlus (DE3)-RIL/pJZ54;Enzymatic reaction;	General procedure: Thirty milligrams of 1 was fed into the IPTG induced fermentation broth of E. coli BL21-CodonPlus (DE3)-RIL/pJZ54 that expresses Rdc2. The culture was maintained at 28 °C with shaking at 250 rpm for 36 h. The ethyl acetate extract of the broth was fractionated on a Sephadex LH-20 (20 g) column eluted with methanol to give 14 fractions, 5 mL each. Fractions 3?6 were combined and further separated by reverse-phase HPLC (Eclipse XDB-C18 column, 5 mum, 4.6 × 150 mm) with isocratic elution of 25percent acetonitrile in H2O (each containing 0.1percent TFA) for 20 min at a flow rate of 1 mL/min to yield 8.5 mg of 1a. Similarly, 30 mg of 2 was also incubated with E. coli BL21-CodonPlus (DE3)-RIL/pJZ54 under the same conditions. The ethyl acetate extract was fractionated on a Diaion HP-20 (30 g) column eluted with a stepwise gradient of isopropanol?water (0:100, 20:80, 40:60, 60:40, 80:20, 100:0, each 250 mL) to give 6 fractions. Further separation of fraction 3 by reverse-phase HPLC with isocratic elution of 10percent acetonitrile in H2O (each containing 0.1percent TFA) over 20 min at a flow rate of 1 mL/min afforded 11.4 mg of 2a in pure form.

References: [1]Patent: WO2007/240,2007,A1 .Location in patent: Page/Page column 35-36.
[2]Patent: WO2008/77554,2008,A1 .Location in patent: Page/Page column 44.
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1001 - 1003.
[4]Angewandte Chemie - International Edition,2017,vol. 56,p. 11841 - 11845.
Angew. Chem.,2017,vol. 129,p. 12003 - 12007,5.

17
[ 7651-82-3 ]
[ 918488-42-3 ]

Yield	Reaction Conditions	Operation in experiment
88%		5-Bromoisoquinoline-6-ol (9)7.9 ml_ (19.18 g, 120 mmol) of bromine were added dropwise to a suspension of 17.42 g (120 mmol) of compound 7 in 250 mL of chloroform at room temperature. After stirring for 2 h ethyl acetate was added. The precipitate was filtered, washed with ethyl acetate and dried. Aqueous NaHCO3 solution was added carefully. The precipitate was filtered and washed with NaHCO3 solution until the filtrate had a pH of 8. Drying gave 23.78 g (88percent) of compound 9 as an off-white solid.1H-NMR (d6-DMSO): delta = 11.30 (1 H, s), 9.13 (1 H, s), 8.48 (1 H, d, J = 5.9 Hz), 8.02 (1 H, d, J= 8.8 Hz), 7.78 (1H, J = 5.9 Hz), 7.40 (1H, d, J = 8.8 Hz). MS: m/z = 224 (MH+).
88%		5-Bromoisoquinoline-6-ol (2); 7.9 mL (19.18 g, 120 mmol) of bromine were added dropwise to a suspension of 17.42 g (120 mmol) of <strong>[7651-82-3]6-hydroxy isoquinoline</strong> in 250 mL of chloroform at room temperature. After stirring for 2 h, ethyl acetate was added. The precipitate was filtered, washed with ethyl acetate and dried. Aqueous NaHCO3 solution was added carefully. The precipitate was filtered and washed with NaHCO3 solution until the filtrate had a pH of 8. Drying gave 23.78 g (88percent) of 2 as an off-white solid.1H-NMR (de-DMSO): delta = 11.30 (1 H, s), 9.13 (1 H, s), 8.48 (1 H, d, J = 5.9 Hz), 8.02 (1 H, d, J= 8.8 Hz), 7.78 (1 H, J = 5.9 Hz), 7.40 (1 H, d, J = 8.8 Hz). MS: m/z = 224 (MH+).

References: [1]Angewandte Chemie - International Edition,2017,vol. 56,p. 11841 - 11845.
Angew. Chem.,2017,vol. 129,p. 12003 - 12007,5.
[2]Patent: WO2007/240,2007,A1 .Location in patent: Page/Page column 36.
[3]Patent: WO2008/77554,2008,A1 .Location in patent: Page/Page column 44.

18
[ 7651-82-3 ]
[ 918488-43-4 ]

Yield	Reaction Conditions	Operation in experiment
97%		5-lodoisoquinoline-6-ol (10)Under argon atmosphere 1.77 g (12.2 mmol) of compound 7 were added to a solution of 5.0 g (13.5 mmol) bis(pyridin)iodonium tetrafluoroborate in 100 mL of dry dichloromethane. A solution of 2.4 mL (4 g, 26.8 mmol) trifluoromethane sulfonic acid in 20 mL dry dichloromethane was added dropwise at 00C and the mixture was stirred for 3 hours at room temperature. The solvents were removed by distillation and the EPO <DP n="38"/>remainder was treated with aqueous NaHCO3 solution. The precipitate was filtered, washed with water and dried to yield 3.2 g (97percent) of compound 10 as a beige solid. 1H-NMR (d6-DMSO): delta = 9.09 (1 H1 s), 8.47 (1 H, d, J = 6.1 Hz), 8.04 (1 H, d, J= 8.8 Hz)1 7.76 (1 H, J = 6.1 Hz), 7.37 (1 H, d, J = 8.8 Hz). MS: m/z = 272 (MH+).

References: [1]Patent: WO2007/240,2007,A1 .Location in patent: Page/Page column 36-37.

19
[ 7651-82-3 ]
[ 105562-75-2 ]
[ 915714-67-9 ]

Yield	Reaction Conditions	Operation in experiment
47%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 4.5h;	Example 35; Synthesis of (S)-4-methyInaphthalene-1 -sulfonic acid [4-amino-1- (soquinolin-6-yIoxymethylbutyl)]-amide (compound 69}; Step I; [0157] Boc-L-OrnithinoI(Z) (1.13 g, 352.43 g/mol, 3.19 mmoS, 1.0 eq.) was dissolved in THF (8 ml) together with 7-hydroxyisoquinoline (601 mg, 145.16 g/mol, 4.15 mmol) and triphenylphosphine (1.1 g, 262.29 g/mol, 4.15 mmol, 1.3 eq) before DEAD (644 mul, 174.16 g/mol, 1.12 g/cm3, 0.59 mmol, 1.5 eq) was added in a dropwise fashion. After reacting for 4.5 hours at room temperature, the reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography to provide 722 mg (47 percent yield) of (S)-5-isoquinoIin-6-yloxy-4-/V-Boc-1 -A/'-Z-pentane-1 ,4-diamine.

References: [1]Patent: WO2006/123020,2006,A1 .Location in patent: Page/Page column 59; 88.

20
[ 7651-82-3 ]
[ 23426-63-3 ]
[ 945860-77-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;	Intermediate 2: Methyl 2-(l,2,3,4-tetrahydroisoquinolin-6-yloxy)-2- methylpropanoate.' .[0060] Step A: <strong>[7651-82-3]6-Hydroxyisoquinoline</strong> (1.0 g, 6.9 mmol) and methyl 2- bromoisobutyrate (3.4 mL, 27.5 mmol) are dissolved in dry DMF (20 mL). Powdered potassium carbonate (3.8 g, 27.5 mmol) is added and the mixture is heated at 100 °C for 16 h. The mixture is cooled, diluted- with ethyl acetate (40 mL), washed with water (3 x 50 mL) and brine (50 mL). The organic layer is dried (MgSO4), filtered, evaporated and purified by silica gel chromatography (0-100percent gradient, ethyl acetate in hexanes) to provide methyl 2-(isoquinolin-6-yloxy)-2-methylpropanoate 1 (1.25 g, 74percent) as a colorless oil. MS calcd. for Ci4Hi6NO3 (TVB-H+) 246.1, found 246.1.

References: [1]Patent: WO2007/89557,2007,A2 .Location in patent: Page/Page column 20.

21
[ 22428-87-1 ]
[ 7651-82-3 ]
[ 1041423-19-1 ]

Yield	Reaction Conditions	Operation in experiment
		4-(lsoquinolin-6-yloxy)-cyc.ohexanone (27); A suspension of 9 g triphenylphosphine (bound to polystyrene, Argonaut, 1.6 mmol/g, 14.4 mmol) and 1.57 ml_ (1.74 g, 10 mmol) diethyl azocarboxylate in 100 mL dichloromethane was stirred for 10 min under argon atmosphere. Then 1.45 g (10 mmol) <strong>[7651-82-3]6-hydroxy-isoquinoline</strong> and 1.58 g (10 mmol) 1 ,4-dioxa-spiro[4.5]decan-8-ol were added. After 40 min 1.39 mL (1 g, 10 mmol) triethyl amine was added and the reaction was allowed to shake for 16 h at room temperature. After filtration the organic layer was extracted with 1 N NaOH, dried over Na2SO4, filtered and concentrated in vacuo.The crude material (2.2 g) was dissolved in 200 mL acetone and 10 mL water. 1.5 g (7.9 mmol) of para-toluene sulfonic acid were added and the reaction was heated to reflux temperature for 6 h. Then the solvents were distilled off. The remainder was dissolved in dichloromethane and was extracted with aqueous Na2CO3 solution. After drying over Na2SO4, filtration and removal of the solvents the crude product was purified by flash chromatography to yield 1.19 g of 27 as a white solid. 1H-NMR (de-DMSO): delta = 9.16 (1 H, s), 8.41 (1 H, d, J = 5.8 Hz), 8.05 (1 H, d, J = 8.9 Hz), 7.70 (1 H, d, J = 5.8 Hz), 7.51 (1 H, d, J = 2.5 Hz), 7.36 (1 H, dd, J = 8.9 und 2.5 Hz), 5.04 (1 H, m), 2.44 (4H, m), 2.22 (2H, m), 2.11 (2H, m). MS: m/z = 242 (MH+).

References: [1]Patent: WO2008/77554,2008,A1 .Location in patent: Page/Page column 56.

22
[ 7651-82-3 ]
tert-butyl N-(trans-4-hydroxycyclohexyl)carbamate [ No CAS ]
C₂₀H₂₆N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine on polystyrene; In dichloromethane; at 20℃;Product distribution / selectivity;	General procedure for the reaction of N-boc-protected aminoalcohols with <strong>[7651-82-3]6-hydroxy isoquinoline</strong>s (Mitsunobu-reaction):To 500 mg (1.5 mmol) of triphenylphosphine (bound to polystyrene, 3mmol/g) and 10 ml of dichloromethane were added 0.195 ml_ (1.2 mmol) of diethylazodicarboxylate (or alternatively diisopropylazodicarboxylate). The reaction mixture was allowed to shake for 10 min. and then 0.14 ml_ of triethylamine, 145 mg of the <strong>[7651-82-3]6-hydroxyisoquinoline</strong> derivative (reagent 1) and 1 mmol of the desired, boc-protected aminoalcohol (reagent 2) was added. The reaction was shaken at room temperature until no further conversion could be observed by LCMS. For workup, the solution was filtered, the residue was washed with dichloromethane and the organic layer was washed twice with 1 N sodium hydroxide, twice with water and once with brine, dried over magnesium sulfate and evaporated. The crude product was purified by preparative HPLC to yield the boc protected coupled product.

References: [1]Patent: WO2008/77554,2008,A1 .Location in patent: Page/Page column 50-51.

23
[ 7651-82-3 ]
tert-butyl ((1s,4s)-4-hydroxycyclohexyl)carbamate [ No CAS ]
C₂₀H₂₆N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine on polystyrene; In dichloromethane; at 20℃;Product distribution / selectivity;	General procedure for the reaction of N-boc-protected aminoalcohols with <strong>[7651-82-3]6-hydroxy isoquinoline</strong>s (Mitsunobu-reaction):To 500 mg (1.5 mmol) of triphenylphosphine (bound to polystyrene, 3mmol/g) and 10 ml of dichloromethane were added 0.195 ml_ (1.2 mmol) of diethylazodicarboxylate (or alternatively diisopropylazodicarboxylate). The reaction mixture was allowed to shake for 10 min. and then 0.14 ml_ of triethylamine, 145 mg of the <strong>[7651-82-3]6-hydroxyisoquinoline</strong> derivative (reagent 1) and 1 mmol of the desired, boc-protected aminoalcohol (reagent 2) was added. The reaction was shaken at room temperature until no further conversion could be observed by LCMS. For workup, the solution was filtered, the residue was washed with dichloromethane and the organic layer was washed twice with 1 N sodium hydroxide, twice with water and once with brine, dried over magnesium sulfate and evaporated. The crude product was purified by preparative HPLC to yield the boc protected coupled product.

References: [1]Patent: WO2008/77554,2008,A1 .Location in patent: Page/Page column 50-51.

24
[ 7651-82-3 ]
[ 120-29-6 ]
6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-isoquinoline hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		625 mg of triphenyl phosphine were dissolved in 20 mL of dry dichloromethane, 0.095 mL of diethyl azodicarboxylate were added and the solution was shaken for 20 minutes. 69 muL of triethyl amine, 72.6 mg of <strong>[7651-82-3]6-hydroxy isoquinoline</strong> and 67.1 mg of tropine were added and the mixture was shaken overnight. The reaction mixture was filtered, the remainders washed thoroughly with dichloromethane and the combined organic layer was extracted twice with 1N sodium hydroxide and water, respectively. The organic layer was dried, evaporated to dryness and the crude material was purified by HPLC. The product was dissolved in 2N HCl and lyophilized to give 23 mg of 6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-isoquinoline (52) as the hydrochloride. Rt=0.52 min (Method A). Detected mass: 269.2 (M+H+).

References: [1]Patent: US2010/56566,2010,A1 .Location in patent: Page/Page column 22.

25
[ 7651-82-3 ]
[ 321744-26-7 ]
[ 1036378-73-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;	145 mg of 6-Hydroxisoquinoline and 311 mg of (2R,4S)-4-Hydroxy-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester and 341 mg of triphenylphosphine were suspended in 3.5 ml of THF and 171 mul DIPEA were added. At 0° C. 261 mg DEAD were added slowly and the mixture was allowed to come to room temperature and stirred until no further increase in product could be monitored. After Evaporation the mixture was subjected to chromatography on silica gel (50 to 80percent ethylacetate in Heptane) to give (2R,4R)-4-(Isoquinolin-6-yloxy)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as an colorless oil.

References: [1]Patent: US2010/56566,2010,A1 .Location in patent: Page/Page column 15.

26
[ 7651-82-3 ]
[ 1235034-85-1 ]
[ 1235032-86-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of methyl 2-(8-(benzo[d]thiazol-2- ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-5-(3-(tosyloxy)propyl)thiazole-4-carboxylate (8F) (133 mg, 0.2 mmol) and 5-hydroxyisoquinoline (45 mg, 0.3 mmol) in DMA (3 mL) was added Cs2CO3 (50 mg, 0.3 mmol). The mixture was stirred at rt overnight and was diluted with 2N NaOH (4 mL) and stirred at 500C for 4 hours. The reaction mixture was neutralized with 5percentHC1 and the precipitate was filtered and dried. The residue was then dissolved in DMSO/MeOH (1:1) and purified by column chromatography on silica gel to provide the desired product 2-(8-(benzo[(d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-5-(3- (isoquinolin-6-yloxy)propyl)thiazole-4-carboxylic acid (8): 1H NMR (300 MHz, DMSO-D6) delta ppm 9.16 (IH, s), 8.34 (IH, d), 7.94 (IH, d), 7.85 (IH, d), 7.71 (4H, m), 7.38 (8H, m), 4.88 (2H, s), 4.14 (2H, t), 3.71 (2H, t), 3.00 (2H, t), 2.27 (IH, m), 2.09 (2H, m). LC/MS (APCI): m/z 622.2 (M+H).

References: [1]Patent: WO2010/80503,2010,A1 .Location in patent: Page/Page column 99-100.

27
[ 7651-82-3 ]
[ 916451-11-1 ]
[ 1268517-00-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5286 - 5289.

28
[ 7651-82-3 ]
C₁₄H₁₆N₂O [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1084 - 1088.

29
[ 7651-82-3 ]
[ 1269630-47-8 ]
[ 1269630-46-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1084 - 1088.

30
[ 7651-82-3 ]
[ 85275-45-2 ]
[ 1269630-45-6 ]