[ CAS No. 164148-92-9 ] {[proInfo.proName]}

Name: 164148-92-9|tert-Butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate|98%
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SKU: A116941
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Quality Control of [ 164148-92-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 164148-92-9 ]

Product Details of [ 164148-92-9 ]

CAS No. :	164148-92-9	MDL No. :	MFCD03426351
Formula :	C₁₄H₂₀N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OLOIFCYZWOTWRO-UHFFFAOYSA-N
M.W :	248.32	Pubchem ID :	2756371
Synonyms :

Calculated chemistry of [ 164148-92-9 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.5
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	76.03
TPSA :	55.56 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.42 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.66
Log Po/w (XLOGP3) :	1.96
Log Po/w (WLOGP) :	2.04
Log Po/w (MLOGP) :	1.94
Log Po/w (SILICOS-IT) :	1.71
Consensus Log Po/w :	2.06

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.66
Solubility :	0.539 mg/ml ; 0.00217 mol/l
Class :	Soluble
Log S (Ali) :	-2.75
Solubility :	0.44 mg/ml ; 0.00177 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.11
Solubility :	0.193 mg/ml ; 0.000776 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.18

Safety of [ 164148-92-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 164148-92-9 ]

* 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 [ 164148-92-9 ]
Downstream synthetic route of [ 164148-92-9 ]

[ 164148-92-9 ] Synthesis Path-Upstream 1~7

1
[ 1154424-63-1 ]
[ 164148-92-9 ]

Yield	Reaction Conditions	Operation in experiment
91%	With ammonium formate In ethanol for 6 h; Reflux	To a stirred solution of 2 (2.2 g, 5.75 mmol) in EtOH (25 mL) was added ammonium formate (3.68 g, 57.5 mmol) and the reaction mixture was refluxed for 6 h. It was cooled, filtered though a celite^.(R). bed and filtrate was concentrated under reduced pressure gave 3 (1.3 g, 91percent) as a dark brown oil which was used without further purification.

Reference： [1] Patent: WO2009/158571, 2009, A1, . Location in patent: Page/Page column 165; 167; 168

2
[ 24424-99-5 ]
[ 72299-67-3 ]
[ 164148-92-9 ]

Yield	Reaction Conditions	Operation in experiment
73%	at 20℃; for 3 h;	EXAMPLE 3. Synthesis of N-[2-(4-chloroρhenyl)ethyl]-7-[(methylsulfonyl)amino]-3,4- dihydroisoquinoline-2(lH)-carbothioamide (Res-10-73) and N-[2-(4-chlorophenyl)ethyl]- 6- [(methylsulfonyl)amino] -3 ,4-dihydroisoquinoline-2(l H)-carbothioamide (Res-12-31).; The title compounds were synthesized according to Scheme 2. Scheme 2. Synthesis ofN-[2-(4-chlorophenyl)ethyl]-7-[(methylsulfonyl)amino]-3,4- dihydroisoquinoline-2(lH)-carbothioamide (Res-10-73) and N-[2-(4-chlorophenyl)ethyl] - 6-[(methylsulfonyl)amino] -3 , 4-dihydroisoquinoline-2(lH)-carbothioamide (Res-12-31).1,2,3,4-Tetrahydroisoquinoline (1) (1 eq.) was cooled on ice and acetic anhydride (1.5 eq.) was added dropwise. The mixture was stirred for 2 hours and then diluted with EtOAc. The organic phase was washed with NaHCO₃ (sat.), dried (MgSO₄) and concentrated to give 2-acetyl-l,2,3,4-tetrahydroisoquinoline (2) (58percent).2-Acetyl-l₅2,3,4-tetrahydroisoquinoline (2) was cooled on ice and a 1:1 mixture of concentrated nitric and concentrated sulfuric acid was added dropwise. The mixture was stirred on ice for 4 hours and then poured into a mixture of ice and water. The water phase was extracted with EtOAc. The combined organic phases were washed with NaHCO₃ (sat.), dried (MgSO₄) and concentrated to give a crude mixture of regioisomers (84percent). Pure isomers were obtained by HPLC (Microsorb, silica 5μm, 250x21.4 mm, 20ml/min of 100percent EtOAc, detection at 300 nm): 2-acetyl-7-nitro-l,2,3,4-tetrahydroisoquinoline (3a) (21percent) and 2-acetyl-6-nitro-l,2,3,4-tetrahydroisoquinoline (3b) (13percent).The corresponding 2-acetyl-mononitro-l,2,3,4-tetrahydroisoquinoline was dissolved in MeOH and some HCl (10percent in water) and palladium on carbon (5percent) was added. The mixture was stirred under hydrogen atmosphere for 1 hour, filtered through celite and concentrated to give the hydrochloride salts of 2-acetyl-l,2,3,4-tetrahydroisoquinolin-7- amine (4a) (89percent) and 2-acetyl-l,2,3,4-tetrahydroisoquinolin-6-amine (4b) (quant.).The hydrochloride salt of the corresponding 2-acetyl- 1,2,3 ,4-tetrahydroisoquinoline- monoamine was dissolved in HBr (48percent in H₂O) and heated to reflux for 4 hours. The mixture was then concentrated to give the dihydrobromide salts of 1,2,3,4- tetrahydroisoquinolin-7-amine (5a) (91percent) and l,2,3,4-tetrahydroisoquinolin-6-amine (5b) (80percent). These salts were suspended in a 6M solution of NaOH and extracted with CH₂Cl₂. The organic phases were dried (MgSO₄) and concentrated to give the free amines (quant.). EPO <DP n="16"/>The corresponding 1,2,3,4-tetrahydroisoquinoline-monoamine (1 eq.) was dissolved in THF, di-tert-butyldicarbonate (1.2 eq.) was added. The solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated, dissolved in H₂O and extracted with EtOAc. The organic phase was dried (MgSO₄), filtered and concentrated. The residue was chromatographed on silicagel (Pet. Ether :EtO Ac 1:1) yielding tert-butyl 7-amino-3,4-dihydroisoquinoline-2(lH)-carboxylate (6a) (47percent) and tert-butyl 6-amino- 3,4-dihydroisoquinoline-2(lH)-carboxylate (6b) (73percent)The corresponding tert-butyl amino-3,4-dihydroisoquinoline-2(l//)-carboxylate was dissolved in CH₂Cl₂ and cooled on ice, MsCl (1.05 eq.) and triethylamine (1.15 eq.) were added. The solution was stirred for 2 hours, then diluted with H₂O and extracted with CH₂Cl₂. The organic phase was dried (MgSO₄) and concentrated. The residue was chromatographed on silicagel (Pet. Ether: EtOAc 3:2) yielding tert-butyl 7- [(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)-carboxylate (7a) (43percent) and tert- butyl 6-[(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(l/)-carboxylate (7b) (75percent).The corresponding tert-butyl [(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)- carboxylate was dissolved in a solution consisting in 80percentTFA, 19percentCHiCl₂ and 1percent anisol. This solution was stirred at 0°C for for 30 minutes and concentrated. The residue was dissolved in CH₂Cl₂ and the mixture concentrated again. The residue was the dissolved in dry DMF and triethylamine (3 eq.) was added. This mixture was stirred for 30 minutes and then 2-(4-chlorophenyl)ethyl isothiocianate (1.1 eq.) was added. This mixture was stirred for 1 hour and then concentrated. The residue was dissolved in EtOAc and washed with 10percent HCl solution. The organic phase was dried (MgSO₄) and concentrated. The crude was chromatographed on silicagel (heptane:EtOAc:AcOH (40:60:1) yielding N- [2-(4-chlorophenyl)ethyl]-7-[(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)- carbothioamide (Res-10-73) (66percent) andN-[2-(4-chlorophenyl)ethyl]-6- [(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)-carbothioamide (Res-12-31) (56percent).

Reference： [1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 5, p. 2513 - 2528
[2] Patent: WO2007/11290, 2007, A1, . Location in patent: Page/Page column 13-15

3
[ 170097-67-3 ]
[ 164148-92-9 ]

Reference： [1] Patent: WO2009/158571, 2009, A1,

4
[ 24424-99-5 ]
[ 164148-92-9 ]

Reference： [1] Patent: WO2015/197028, 2015, A1,
[2] Patent: WO2016/73889, 2016, A1,

5
[ 186390-77-2 ]
[ 164148-92-9 ]

Reference： [1] Patent: WO2015/197028, 2015, A1,

6
[ 14026-45-0 ]
[ 164148-92-9 ]

Reference： [1] Patent: WO2016/73889, 2016, A1,

7
[ 164148-92-9 ]
[ 893566-74-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	With amyl nitrate; copper(ll) bromide In acetonitrile at 80℃; for 2 h;	2a (1.42 g, 5.7 mmol) was added to a mixture of amyl nitrate (1.42 g, 12.1 mmol) and Cu13r2 (2.16 g, 9.67 mmol) in CH3CN (20 mE). The mixture was heated at 80° C. for 2 hours, then cooled and evaporated under reduced pressure. The residue was purified by silica gel colunm chromatography (PE:EA=10: 1, v:v) to provide 2b (1.96 g, 78percent yield) as a yellow oil. LC-MS: 312 [M+1].
59%	With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 60 - 80℃; for 2 h;	To a solution of tert-butyl nitrite (0.70 mL, 6.04 mmol) and copper(II) bromide (1.10 g, 4.83 mmol) in anhydrous acetonitrile (10 mL) at 60 0C was added 6-amino-2-7V- boc-l,2,3,4-tetrahydroisoquinoline (1.00 g, 4.03 mmol) portionwise. The reaction mixture was then heated at 80 0C for 2 hours. The reaction mixture was diluted with DCM (100 mL) and washed with 0.5N HC 1 (50 mL). The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were washed with brine (50 mL) and dried (MgSO4) to give a dark crude oil. The crude material was purified by flash column chromatography (isohexane to 10percent DCM) to give an orange oil (737 mg, 59percent). 1R NMR (400.132 MHz, CDCl3) d 1.49 (s, 9H), 2.80 (m, 2H), 3.63 (m, 2H), 4.50 (m, 2H), 6.95 (m, IH), 7.27 (m, 2H)

Reference： [1] Patent: US2017/275301, 2017, A1, . Location in patent: Paragraph 0210; 0211
[2] Patent: WO2009/1128, 2008, A1, . Location in patent: Page/Page column 51

[ 164148-92-9 ] Synthesis Path-Downstream 1~88

1
2-isopropoxy-4-methylbenzoic acid [ No CAS ]
[ 164148-92-9 ]
[ 689166-50-5 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 14h;	To a solution of tert-butyl 6-amino-3,4-dihydro-2 (1H)- isoquinolinecarboxylate (261.6 mg), 2-isopropoxy-4- methylbenzoic acid (225 mg) and 1-hydroxybenzotriazole (178 mg) in N, N-dimethylformamide (2 ml) was added 1- [3- (dimethylamino) PROPYL]-3-ETHYLCARBODIIMIDE hydrochloride (WSCHCL) (222 mg), followed by N, N-dimethylaminopyridine (6.44 mg) at ambient temperature. The reaction mixture was stirred for 14 hours at ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane: ethyl acetate (6: 1) to give tert-butyl 6- [ (2-ISOPROPOXY-4- methylbenzoyl) AMINO-3, 4-dihydro-2 (1H)-ISOQUINOLINECARBOXYLATE (0.267 g) as yellow oil. 1H-NMR (CDCL3) : 8 1.47-1. 52 (15H, m), 2.40 (3H, s), 2.85 (2H, t, J=5.7 Hz), 3.64 (2H, t, J=5.7 Hz), 4.55 (2H, s), 4.82 (1H, sept, J=5.9 Hz), 6.82 (1H, s), 6.92 (1H, d, J=7.8 Hz), 7.08 (1H, d, J=8.1 Hz), 7.15-7. 85 (1H, M), 8.17 (1H, d, J=7.8 Hz), 10.16 (1H, s) ESI-MS (m/z): 447 (M+Na) +

Reference： [1]Patent: WO2004/39795,2004,A2 .Location in patent: Page 213-214

2
[ 164148-92-9 ]
[ 30529-70-5 ]
[ 689165-95-5 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h;	To a solution of tert-butyl 6-nitro-3,4-dihydro-2 (1H)- isoquinolinecarboxylate (495 mg), 2-chloro-6-methylnicotinic acid (359 mg) and 1-hydroxybenzotriazole (320 mg) in N, N- dimethylformamide (5 ml) was added 1- [3- (dimethylamino) PROPYL]-3-ETHYLCARBODIIMIDE hydrochloride (WSC"HCL) (401 mg), followed by N, N-dimethylaminopyridine (4.86 mg) at ambient temperature. The reaction mixture was stirred for 12 hours at ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane: ethyl acetate (6: 1 No. 2: 1) to give tert-butyl 6- { [ (2-CHLORO-6- methyl-3-pyridinyl) carbonyl] AMINO)-3, 4-dihydro-2 (1H)- isoquinolinecarboxylate (0.768 g) as a pale yellow foam. 1H-NMR (CDC13) : 8 1.49 (9H, s), 2.54 (3H, s), 2.83 (2H, t, J=5.9 Hz), 3.63 (2H, t, J=5.9 Hz), 4.53 (2H, s), 7.08 (1H, d, J=8.4 Hz), 7.16 (1H, d, J=7.8 Hz), 7.41-7. 70 (2H, m), 8.03 (1H, d, J=7.6 Hz), 8.63 (1H, br s) ESI-MS (m/z): 402 (M+H) +

Reference： [1]Patent: WO2004/39795,2004,A2 .Location in patent: Page 208-209

3
[ 164148-92-9 ]
[ 898252-84-1 ]
tert-butyl 6-[(2-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With triethylamine; In acetonitrile; at 120 - 160℃; for 1.66667h;Microwave irradiation;	Example 24; fert-Butyl 6-[(2-butyl-l,l-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]-3,4- dihydroisoquinoline-2(lH)-carboxylate; A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.00Og, 3.336mmol), tert-butyl 6-amino-3,4-dihydroisoquinoline-2(lH)-carboxylate (0.828g, 3.336mmol) and TEA (0.460ml, 3.33gmmol) in dry MeCN (5ml) was heated in a microwave reactor at 120C for 35mins, 140C for 20mins and 1600C for 45mins. The reaction mixture was evaporated and the residue was purified by silica gel column10 chromatography (Horizons Biotage) using 10-25% EtOAc in petroleum ether 40-60C as eluent, to give the title compound (0.76Og, 45%).

Reference： [1]Patent: WO2006/73363,2006,A1 .Location in patent: Page/Page column 152

4
[ 164148-92-9 ]
[ 133-59-5 ]
[ 185057-39-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; ethyl acetate;	A. 6-(Toluene-4-sulfonylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert butyl ester To a mixture of 275 mg (1.10 mmol) of <strong>[164148-92-9]6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester</strong>, 134 mg (1.33 mmol) of triethylamine in 6 mL of methylene chloride at 00C was added 233 mg (1.2 mmol) of toluenesulfonyl chloride in one portion. The mixture was allowed to warm to room temperature and was stirred overnight. An additional 62 mg (0.61 mmol) of triethylamine and 105 mg (0.55 mmol) of toluenesulfonylchloride was added and stirring was continued for an additional 4 h. The mixture was concentrated and the residue dissolved in ethyl acetate. The organic portion was washed twice each with 1 N NaOH and brine, dried over Na2 SO4 and the product was purified by silica gel chromatography (1:3 v/v ethyl acetate:hexane) to give 274 mg of 20A as a foam.

Reference： [1]Patent: US5936089,1999,A

5
7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester [ No CAS ]
[ 164148-92-9 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium acetate;palladium; In acetic acid;	6Amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 59 g (0.16 mol) of 7-bromo-6-nitro-3,4-dihydro-1H-isoquinolin-2-carboxylic acid tert-butyl ester, 10 g of 5% palladium on calcium carbonate and 49 g of ammonium acetate in 1 liter of acetic acid was hydrogenated on a Parr shaker for 5 hrs. The reaction was filtered through CELITEconcentrated, basified to pH 12 with 4N sodium hydroxide and extracted with methylene chloride. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to yield 40 g of an oil. 1 H NMR (300 MHz, DMSO) delta 4.87 (s, 2H); 4.27 (s, 2H); 3.44 (t, 2H); 2.57 (t, 2H); 1.39 (s, 9H).
	With ammonium acetate;palladium; In acetic acid;	6-Amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (6) A total of 59 g (0.16 mol) of 7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 10 g of 5% palladium on calcium carbonate and 49 g of ammonium acetate in 1 liter of acetic acid was hydrogenated on a Parr shaker for 5 hrs. The reaction was filtered, concentrated, basified to pH 12 with 4N sodium hydroxide and extracted with methylene chloride. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to yield 40 g of the title compound in the form of an oil. 1 H NMR (300 MHz, DMSO) delta4.87 (s, 2H); 4.27 (s, 2H); 3.44 (t, 2H); 2.57 (t, 2H); 1.39 (s, 9H).
	With ammonium acetate;palladium; In acetic acid;	6-Amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 59 g (0.16 mol) of 7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 10 g of 5% palladium on calcium carbonate and 49 g of ammonium acetate in 1 liter of acetic acid was hydrogenated on a Parr shaker for 5 hrs. The reaction was filtered through Celite, concentrated, basified to pH 12 with 4N sodium hydroxide and extracted with methylene chloride. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to yield 40 g of an oil. 1H NMR (300 MHz, DMSO) delta 4.87 (s, 2H); 4.27 (s, 2H); 3.44 (t, 2H); 2.57 (t, 2H); 1.39 (s, 9H).

Reference： [1]Patent: US5919795,1999,A
[2]Patent: US6121283,2000,A
[3]Patent: EP1181954,2002,A2

6
[ 23687-26-5 ]
[ 164148-92-9 ]
3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone [ No CAS ]
[ 72299-67-3 ]

Yield	Reaction Conditions	Operation in experiment
		Prepared from 3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone and 1.1 equivalents of an oily mixture of 2-Boc-6-amino-1,2,3,4-tetrahydro-isoquinoline [prepared from 6-amino-isoquinoline, melting point 218-220° C., by catalytic hydrogenation to obtain 6-amino-1,2,3,4-tetrahydro-isoquinoline (melting point: 69-71° C.) and subsequent reaction with 0.9 equivalents of di-tert.butyl pyrocarbonate (=(Boc)2 O)] in DMF by heating to 100° C. for 3.5 hours, pouring into water, filtering and washing the precipitate with water and EtOH.

Reference： [1]Patent: US6043254,2000,A

7
[ 164148-92-9 ]
[ 75-36-5 ]
acetic acid 2-{6-[(4'-trifluoromethylbiphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In dichloromethane; ethyl acetate; toluene;	Acetic acid 2-{6-[(4'-trifluoromethylbiphenyl-2carbonyl)-amino]-3,4-dihydro-1H -isoquinolin-2-yl}-ethyl ester Acetyl chloride (100 mg, 1.25 mmole) and 4-dimethylaminopyridine (700 mg, 5.7 mmole) were combined in 5 mL of toluene and the mixture was cooled to 0 C. in an ice bath. To this mixture was added a solution of Compound 67 from Example 6 (500 mg, 1.14 mmole) in 3 mL of methylene chloride. The reaction was allowed to warm to ambient temperature and was stirred under a nitrogen atmosphere for 2 hrs. The reaction was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine and then dried over magnesium sulfate. Purification of the residue obtained on evaporation was accomplished with silica gel chromatography using 3% methanol in ethyl acetate as the eluent. MS (Cl): 483 (M+H+) 1 H NMR (400 MHz, DMSO) delta4.25 (dd, 2H); 3.62 (s, 2H); 2.78 (m, 6H); 2.06 (s, 3H).

Reference： [1]Patent: US6121283,2000,A

8
6-Nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester [ No CAS ]
[ 164148-92-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	With iron; acetic acid; In ethanol; at 80℃; for 5h;	Step 2) tert-butyl 6-amino-3, 4-dihydroisoquinoline-2 (1H) -carboxylate A mixture of tert-butyl 6-nitro-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (278 mg, 1 mmol) and iron powder (224 mg, 4 mmol) in a mixture of EtOH (4 mL) and AcOH (4 mL) was heated at 80 for 5 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc (20 mL) . The resulting mixture was washed with water (10 mL × 2) and saturated aqueous NaCl, dried over anhydrous Na2SO4and concentrated in vacuo to give tert-butyl 6-amino-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (228 mg, 92) as puce oil.[1070]MS (ESI, pos. ion) m/z: 149.1 [M+H-Boc]+.
42 mg (57%)	Pt-C; In tetrahydrofuran;	6-Amino-3,4dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (6) The 6-nitro-3,4-dihydro-1H-isoquinoline2-carboxylic acid tert-butyl ester (82 mg, 0.29 mmol) in THF (2 mL) was hydrogenated with 5% Pt-C (50% water wet, 10 mg) at 50 psi for 5 hrs. The catalyst was filtered off, the solvent was removed under vacuum and the residue chromatographed on silica with ethyl acetate/hexanes to give 42 mg (57%) of the title product. IR(KBr) 3005, 2975, 2928, 1685, 1627, 1509, 1423, 1365, 1166 cm-1. 1 H NMR (CDCl3) delta6.90 (d, J=6 Hz, 1H), 6.56 (d, J=6 Hz, 1H), 6.48 (s, 1H), 4.47 (s, 2H), 3.60 (m, J=6 Hz, 4H), 2.73 (t, J=6 Hz, 2H), 1.49 (s, 9H).
42mg (57%)	Pt-C; In tetrahydrofuran; water;	f. 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (7) The 6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (82mg, 0.29mmol) in THF (2mL) was hydrogenated with 5%Pt-C (50% water wet, 10mg) at 50psi for 5 hrs. The catalyst was filter off, solvent removed under vacuum and chromatographed on silica with ethyl acetate / hexanes to give 42mg (57%) of the product. IR(KBr) 3005, 2975, 2928, 1685, 1627, 1509, 1423, 1365, 1166 cm-1. 1H NMR (CDCl3) delta 6.90 (d, J = 6Hz, 1H), 6.56 (d, J = 6Hz, 1H), 6.48 (s, 1H), 4.47 (s, 2H), 3.60 (m, J = 6Hz, 4H), 2.73 (t, J = 6Hz, 2H), 1.49 (s, 9H).

150 mg

With iron; ammonium chloride; In ethanol; water; at 70℃; for 2h;

To the suspension of tert-butyl 6-nitro-1,2,3,4-tetrahydroquinoline-2-carboxylate (220 mg, 0.772 mmol) and NH4Cl (330 mg, 6.176 mmol) in 6 mL of EtOH and 4 mL of H2O was added Fe powder (173 mg, 3.088 mmol) in portions. The reaction mixture was stirred at 70 C for 2 h, cooled down to room temperature and then filtered through Celite. The filter cake was washed with ethanol. The orange solution was concentrated, and the residue was purified by prep-HPLC (MeCN/10 mM NH4HCO3) to give tert-butyl 6-amino-1,2,3,4- tetrahydroquinoline-2-carboxylate as oil (150 mg, 78% 2 steps).1H NMR (400 MHz, CDCl3) delta 6.89 (d, J = 8.0 Hz, 1H), 6.54 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.47 (s, 1H), 6.45 (s, 2H), 3.60-3.58 (m, 4H), 2.73 (t, J = 5.6 Hz, 2H), 1.48 (s, 9H).

Reference： [1]Patent: WO2015/197028,2015,A1 .Location in patent: Paragraph 00131
[2]Patent: US6121283,2000,A
[3]Patent: EP1181954,2002,A2
[4]Patent: WO2016/73889,2016,A1 .Location in patent: Paragraph 00225

9
[ 164148-92-9 ]
[ 186390-66-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In dichloromethane;	6-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (7) A 7.6 g (29 mmol) sample of 4'-trifluoromethyl-biphenyl-2-carboxylic acid, 7.1 g (29 mmol) of <strong>[164148-92-9]6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester</strong>, 100 mg of DMAP and 6.1 g (32 mmol) of EDCl were reacted in 130 mL of methylene chloride for 12 hrs. The reaction mixture was extracted with 2150 mL 1N HCl, 2150 mL 1N NaOH, 150 mL water, brine and then concentrated to yield 14 g of a beige foam. MS (Cl): 519 (M+Na+) 1 H NMR (250 MHz, CDCl3) delta4.49 (s, 2H); 3.60 (t, 2H); 2.77 (t, 2H).

Reference： [1]Patent: US6121283,2000,A

10
[ 164148-92-9 ]
[ 851265-83-3 ]
1,1-dimethylethyl 6-([1-({5-chloro-2-[(2-methylpropyl)oxy]phenyl}methyl)-5-methyl-1H-pyrazol-3-yl]carbonyl}amino)-3,4-dihydro-2(1H)-isoquinolinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 5h;	To a solution of i-^S-chloro^-^-methylpropyOoxylphenylJmethyO-S-methyl-IH-pyrazole- 3-carboxylic acid (140 mg, 0.43 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1-hydroxybenzotriazole hydrate (88 mg, 0.65 mmol) and triethylamine (65 mg, 0.65 mmol) in DCM (5 mL) was added 1 ,1-dimethylethyl 6- amino-3,4-dihydro-2(1/-/)-isoquinolinecarboxylate (108 mg, 0.43 mmol) and the mixture was stirred at room temperature for 5 hours. The organic phase was then washed with HCI (1N), NaOH (1N) and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting withCH2CI2/Me0H: 99/1 to give the title compound as a white solid (40 mg). LC/MS: m/z 553 (M+H)+, Rt: 4.28 min.

Reference： [1]Patent: WO2006/114313,2006,A1 .Location in patent: Page/Page column 135

11
[ 164148-92-9 ]
[ 124-63-0 ]
[ 166398-32-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With pyridine; In dichloromethane; at 0℃; for 2h;	Step 3) tert-butyl 6- (methylsulfonamido) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate To a mixture of tert-butyl 6-amino-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (248 mg, 1 mol) and pyridine (176 mg, 2.2 mol) in DCM (10 mL) at 0 was added methylsulfonyl chloride (138 mg, 1.2 mol) . After the addition, the mixture was stirred at a low temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and diluted with EtOAc (20 mL) , then seperated. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4and concentrated in vacuo to give tert-butyl 6- (methylsulfonamido) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate as a yellow solid (326 mg, 100)[1073]MS (ESI, pos. ion) m/z: 227.1 [M+H-Boc]+.
75%	With triethylamine; In dichloromethane; for 2h;	EXAMPLE 3. Synthesis of N-[2-(4-chlororhohenyl)ethyl]-7-[(methylsulfonyl)amino]-3,4- dihydroisoquinoline-2(lH)-carbothioamide (Res-10-73) and N-[2-(4-chlorophenyl)ethyl]- 6- [(methylsulfonyl)amino] -3 ,4-dihydroisoquinoline-2(l H)-carbothioamide (Res-12-31).; The title compounds were synthesized according to Scheme 2. Scheme 2. Synthesis ofN-[2-(4-chlorophenyl)ethyl]-7-[(methylsulfonyl)amino]-3,4- dihydroisoquinoline-2(lH)-carbothioamide (Res-10-73) and N-[2-(4-chlorophenyl)ethyl] - 6-[(methylsulfonyl)amino] -3 , 4-dihydroisoquinoline-2(lH)-carbothioamide (Res-12-31).1,2,3,4-Tetrahydroisoquinoline (1) (1 eq.) was cooled on ice and acetic anhydride (1.5 eq.) was added dropwise. The mixture was stirred for 2 hours and then diluted with EtOAc. The organic phase was washed with NaHCO3 (sat.), dried (MgSO4) and concentrated to give 2-acetyl-l,2,3,4-tetrahydroisoquinoline (2) (58%).2-Acetyl-l52,3,4-tetrahydroisoquinoline (2) was cooled on ice and a 1:1 mixture of concentrated nitric and concentrated sulfuric acid was added dropwise. The mixture was stirred on ice for 4 hours and then poured into a mixture of ice and water. The water phase was extracted with EtOAc. The combined organic phases were washed with NaHCO3 (sat.), dried (MgSO4) and concentrated to give a crude mixture of regioisomers (84%). Pure isomers were obtained by HPLC (Microsorb, silica 5mum, 250x21.4 mm, 20ml/min of 100% EtOAc, detection at 300 nm): 2-acetyl-7-nitro-l,2,3,4-tetrahydroisoquinoline (3a) (21%) and 2-acetyl-6-nitro-l,2,3,4-tetrahydroisoquinoline (3b) (13%).The corresponding 2-acetyl-mononitro-l,2,3,4-tetrahydroisoquinoline was dissolved in MeOH and some HCl (10% in water) and palladium on carbon (5%) was added. The mixture was stirred under hydrogen atmosphere for 1 hour, filtered through celite and concentrated to give the hydrochloride salts of 2-acetyl-l,2,3,4-tetrahydroisoquinolin-7- amine (4a) (89%) and 2-acetyl-l,2,3,4-tetrahydroisoquinolin-6-amine (4b) (quant.).The hydrochloride salt of the corresponding 2-acetyl- 1,2,3 ,4-tetrahydroisoquinoline- monoamine was dissolved in HBr (48% in H2O) and heated to reflux for 4 hours. The mixture was then concentrated to give the dihydrobromide salts of 1,2,3,4- tetrahydroisoquinolin-7-amine (5a) (91%) and l,2,3,4-tetrahydroisoquinolin-6-amine (5b) (80%). These salts were suspended in a 6M solution of NaOH and extracted with CH2Cl2. The organic phases were dried (MgSO4) and concentrated to give the free amines (quant.). EPO <DP n="16"/>The corresponding 1,2,3,4-tetrahydroisoquinoline-monoamine (1 eq.) was dissolved in THF, di-tert-butyldicarbonate (1.2 eq.) was added. The solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated, dissolved in H2O and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated. The residue was chromatographed on silicagel (Pet. Ether :EtO Ac 1:1) yielding tert-butyl 7-amino-3,4-dihydroisoquinoline-2(lH)-carboxylate (6a) (47%) and tert-butyl 6-amino- 3,4-dihydroisoquinoline-2(lH)-carboxylate (6b) (73%)The corresponding tert-butyl amino-3,4-dihydroisoquinoline-2(l//)-carboxylate was dissolved in CH2Cl2 and cooled on ice, MsCl (1.05 eq.) and triethylamine (1.15 eq.) were added. The solution was stirred for 2 hours, then diluted with H2O and extracted with CH2Cl2. The organic phase was dried (MgSO4) and concentrated. The residue was chromatographed on silicagel (Pet. Ether: EtOAc 3:2) yielding tert-butyl 7- [(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)-carboxylate (7a) (43%) and tert- butyl 6-[(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(l/)-carboxylate (7b) (75%).The corresponding tert-butyl [(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)- carboxylate was dissolved in a solution consisting in 80%TFA, 19%CHiCl2 and 1% anisol. This solution was stirred at 0C for for 30 minutes and concentrated. The residue was dissolved in CH2Cl2 and the mixture concentrated again. The residue was the dissolved in dry DMF and triethylamine (3 eq.) was added. This mixture was stirred for 30 minutes and then 2-(4-chlorophenyl)ethyl isothiocianate (1.1 eq.) was added. This mixture was stirred for 1 hour and then concentrated. The residue was dissolved in EtOAc and washed with 10% HCl solution. The organic phase was dried (MgSO4) and concentrated. The crude was chromatographed on silicagel (heptane:EtOAc:AcOH (40:60:1) yielding N- [2-(4-chlorophenyl)ethyl]-7-[(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)- carbothioamide (Res-10-73) (66%) andN-[2-(4-chlorophenyl)ethyl]-6- [(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)-carbothioamide (Res-12-31) (56%).
26.1%	With triethylamine; In dichloromethane; at 20℃; for 16h;	To a solution of 6-amino-2-7V-boc- 1,2,3, 4-tetrahydroisoquino line (0.20 g, 0.81 mmol) and triethylamine (168 ul, 1.21 mmol) in DCM (10 mL) was added methanesulfonyl chloride (69.0 uL, 0.89 mmol) allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with DCM (50 mL), washed with water (50 mL), saturated sodium bicarbonate solution (50 mL) and dried (MgSO4) to give a crude solid. The crude was purified by flash column chromatography (silica isohexane / ethyl acetate 4:1) to give a white solid (69.0 mg, 26.1%).1H NMR (400.132 MHz, CDCl3.)d 1.49 (s, 9H), 2.82 (t, 2H), 3.00 (s, 3H), 3.64 (t, 2H), 4.54 (s, 2H), 6.32 (s, IH), 7.03 (s, 2H), 7.09 (d, IH)

120 g

With triethylamine; In dichloromethane; at 0 - 20℃;

Add methanesulfonyl chloride (62.16 g, 42.00 mL, 542.63 mmol) to a solution of tert-butyl 6-amino-3 ,4-dihydro- 1H-isoquinoline-2-carboxylate (90.00 g, 362.43 mmol) and triethylamine (73.35 g, 101.03 mL, 724.86 mmol) in dichioromethane (900 mL), which is cooled to 0 C. Stir the mixture at room temperature overnight.Treat the mixture with aqueous sodium hydroxide solution (2 M, 400 mL) andheat the reaction mixture to reflux for 48 hours. Cool to room temperature, add water(200 mL) and separate the phases. Extract the aqueous layer with ethyl acetate (500 mL), combine the organic layers and wash with saturated aqueous sodium chloride (250 mL) and concentrate under reduced pressure to a red-orange oil. Dissolve the red-orange oil in dichloromethane (300 mL) and heptanes (500 mL) and concentrate to dryness, and thenkeep the material in vacuum oven at 45 C overnight to afford the title compound (120 g,367.63 mmol). MS (mlz): 271 (M+1-tBu) as a light orange solid.

Reference： [1]Patent: WO2015/197028,2015,A1 .Location in patent: Paragraph 00132
[2]Patent: WO2007/11290,2007,A1 .Location in patent: Page/Page column 13-15
[3]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 2513 - 2528
[4]Patent: WO2009/1128,2008,A1 .Location in patent: Page/Page column 49-50
[5]Patent: WO2015/54060,2015,A1 .Location in patent: Page/Page column 11; 12

12
[ 164148-92-9 ]
[ 913541-42-1 ]
C₂₉H₂₉F₃N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine; In tetrahydrofuran; at 20℃; for 18h;	Compound 3 was dissolved in THF (2.0 mL) and a solution of N-Boc- tetrahydroisoquinoline in 2.OmL of THF was added dropwise (some precipitate formed) followed by the addition OfNEt3. The mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the crude was purified through silica gel column chromatography (EtOAc/Hexanes 0-30%). The product was not clean at this point. The product was washed with Et2O to give (0.36g) of compound 4 (purity 99%).

Reference： [1]Patent: WO2006/113910,2006,A2 .Location in patent: Page/Page column 21; 26

13
[ 24424-99-5 ]
[ 72299-67-3 ]
[ 164148-92-9 ]

Yield	Reaction Conditions	Operation in experiment
73%	In tetrahydrofuran; at 20℃; for 3h;	EXAMPLE 3. Synthesis of N-[2-(4-chlororhohenyl)ethyl]-7-[(methylsulfonyl)amino]-3,4- dihydroisoquinoline-2(lH)-carbothioamide (Res-10-73) and N-[2-(4-chlorophenyl)ethyl]- 6- [(methylsulfonyl)amino] -3 ,4-dihydroisoquinoline-2(l H)-carbothioamide (Res-12-31).; The title compounds were synthesized according to Scheme 2. Scheme 2. Synthesis ofN-[2-(4-chlorophenyl)ethyl]-7-[(methylsulfonyl)amino]-3,4- dihydroisoquinoline-2(lH)-carbothioamide (Res-10-73) and N-[2-(4-chlorophenyl)ethyl] - 6-[(methylsulfonyl)amino] -3 , 4-dihydroisoquinoline-2(lH)-carbothioamide (Res-12-31).1,2,3,4-Tetrahydroisoquinoline (1) (1 eq.) was cooled on ice and acetic anhydride (1.5 eq.) was added dropwise. The mixture was stirred for 2 hours and then diluted with EtOAc. The organic phase was washed with NaHCO3 (sat.), dried (MgSO4) and concentrated to give 2-acetyl-l,2,3,4-tetrahydroisoquinoline (2) (58%).2-Acetyl-l52,3,4-tetrahydroisoquinoline (2) was cooled on ice and a 1:1 mixture of concentrated nitric and concentrated sulfuric acid was added dropwise. The mixture was stirred on ice for 4 hours and then poured into a mixture of ice and water. The water phase was extracted with EtOAc. The combined organic phases were washed with NaHCO3 (sat.), dried (MgSO4) and concentrated to give a crude mixture of regioisomers (84%). Pure isomers were obtained by HPLC (Microsorb, silica 5mum, 250x21.4 mm, 20ml/min of 100% EtOAc, detection at 300 nm): 2-acetyl-7-nitro-l,2,3,4-tetrahydroisoquinoline (3a) (21%) and 2-acetyl-6-nitro-l,2,3,4-tetrahydroisoquinoline (3b) (13%).The corresponding 2-acetyl-mononitro-l,2,3,4-tetrahydroisoquinoline was dissolved in MeOH and some HCl (10% in water) and palladium on carbon (5%) was added. The mixture was stirred under hydrogen atmosphere for 1 hour, filtered through celite and concentrated to give the hydrochloride salts of 2-acetyl-l,2,3,4-tetrahydroisoquinolin-7- amine (4a) (89%) and 2-acetyl-l,2,3,4-tetrahydroisoquinolin-6-amine (4b) (quant.).The hydrochloride salt of the corresponding 2-acetyl- 1,2,3 ,4-tetrahydroisoquinoline- monoamine was dissolved in HBr (48% in H2O) and heated to reflux for 4 hours. The mixture was then concentrated to give the dihydrobromide salts of 1,2,3,4- tetrahydroisoquinolin-7-amine (5a) (91%) and l,2,3,4-tetrahydroisoquinolin-6-amine (5b) (80%). These salts were suspended in a 6M solution of NaOH and extracted with CH2Cl2. The organic phases were dried (MgSO4) and concentrated to give the free amines (quant.). EPO <DP n="16"/>The corresponding 1,2,3,4-tetrahydroisoquinoline-monoamine (1 eq.) was dissolved in THF, di-tert-butyldicarbonate (1.2 eq.) was added. The solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated, dissolved in H2O and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated. The residue was chromatographed on silicagel (Pet. Ether :EtO Ac 1:1) yielding tert-butyl 7-amino-3,4-dihydroisoquinoline-2(lH)-carboxylate (6a) (47%) and tert-butyl 6-amino- 3,4-dihydroisoquinoline-2(lH)-carboxylate (6b) (73%)The corresponding tert-butyl amino-3,4-dihydroisoquinoline-2(l//)-carboxylate was dissolved in CH2Cl2 and cooled on ice, MsCl (1.05 eq.) and triethylamine (1.15 eq.) were added. The solution was stirred for 2 hours, then diluted with H2O and extracted with CH2Cl2. The organic phase was dried (MgSO4) and concentrated. The residue was chromatographed on silicagel (Pet. Ether: EtOAc 3:2) yielding tert-butyl 7- [(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)-carboxylate (7a) (43%) and tert- butyl 6-[(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(l/)-carboxylate (7b) (75%).The corresponding tert-butyl [(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)- carboxylate was dissolved in a solution consisting in 80%TFA, 19%CHiCl2 and 1% anisol. This solution was stirred at 0C for for 30 minutes and concentrated. The residue was dissolved in CH2Cl2 and the mixture concentrated again. The residue was the dissolved in dry DMF and triethylamine (3 eq.) was added. This mixture was stirred for 30 minutes and then 2-(4-chlorophenyl)ethyl isothiocianate (1.1 eq.) was added. This mixture was stirred for 1 hour and then concentrated. The residue was dissolved in EtOAc and washed with 10% HCl solution. The organic phase was dried (MgSO4) and concentrated. The crude was chromatographed on silicagel (heptane:EtOAc:AcOH (40:60:1) yielding N- [2-(4-chlorophenyl)ethyl]-7-[(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)- carbothioamide (Res-10-73) (66%) andN-[2-(4-chlorophenyl)ethyl]-6- [(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)-carbothioamide (Res-12-31) (56%).

Reference： [1]European Journal of Organic Chemistry,2019,vol. 2019,p. 1341 - 1349
[2]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 2513 - 2528
[3]Patent: WO2007/11290,2007,A1 .Location in patent: Page/Page column 13-15

14
[ 164148-92-9 ]
[ 59741-04-7 ]
6-[3-(2-methoxy-5-methylphenyl)ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	In tetrahydrofuran; at 20℃; for 15h;	A solution of <strong>[164148-92-9]6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester</strong> (0.0451 g) and 2-methoxy-5-methylphenyl isocyanate (0.0392 g) in anhydrous tetrahydrofuran (10 mL) was stirred at room temperature for 15 hours. Methanol was added to the reaction mixture which was then concentrated. The residue was purified by column chromatography (dichloromethane/ethyl acetate 10:1). The obtained solid was vigorously stirred in hexane/isopropyl ether and was collected by filtration and dried under reduced pressure, and 548 mg (73%) of the title compound was obtained as a white solid. 1H-NMR spectrum (400MHz,DMSO-d6):delta(ppm)=9.24(1H, s), 8.14(1H, s), 7.99(1H, s), 7.35(1H, s), 7.19(1 H, d, J=7.1 Hz), 7.07(1H, d, J=8.2Hz), 6.89(1H, d, J=8.2Hz), 6.74(1H, d, J=8.2Hz), 4.43(2H, brs), 3.84(3H, s), 3.54(2H, t, J=5.5Hz), 2.75(2H, t, J=5.7Hz), 2.23(3H, s), 1.43(9H, s). MS(FAB) m/z:412 (M + H)+. Melting point: 183-185C.

Reference： [1]Patent: EP1764360,2007,A1 .Location in patent: Page/Page column 152

15
[ 164148-92-9 ]
[ 85-46-1 ]
6-(4-methyl-naphthalene-1-sulfonylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With pyridine; dmap; In dichloromethane; at 20℃;	Preparation of example compound 15: 6-(4-Methyl-naphthalene-1-sulfonylamino)-3,4-dihydro-1H-isoquinoline-2 -carboxylic acid tert-butyl ester; [Show Image] 4-Methyl-naphthalene-1-sulfonyl chloride (310 mg, 1.288 mmol) was added to a solution of tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1 H)-carboxylate (318 mg, 1.28 mmol), pyridine (102 mg, 1.28 mmol) and dimethylaminopyridine (15 mg) in dichloromethane (50 mL). After stirring overnight at room temperature the mixture was washed with water, dried over sodium sulfate and filtered. The organic extracts were diluted with ethanol and partial evaporation afforded the title compound (435 mg, 74 %).

Reference： [1]Patent: EP1837332,2007,A1 .Location in patent: Page/Page column 49-50

16
[ 37718-11-9 ]
[ 164148-92-9 ]
[ 1035225-07-0 ]

Yield	Reaction Conditions	Operation in experiment
24%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 216h;	Intermediate 34: 1 ,1-Dimethylethyl 6-r(1 H-pyrazol-4-ylcarbonyl)aminol-3,4-dihvdro- 2(1 HVisoalphauinolinecarboxylate; To a solution of 1 H-pyrazole-4-carboxylic acid (800 mg, 7.1 mmol), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.48 g, 7.74 mmol), 1- hydroxybenzotriazole hydrate (1.04 g, 7.74 mmol) and triethylamine (1.8 ml_, 12.9 mmol) in DCM was added 1 , 1 -dimethylethyl 6-amino-3,4-dihydro-2(1 /-/)- isoquinolinecarboxylate (1.6 g, 6.45 mmol) and the reaction mixture was stirred at room temperature for 9 days. The organic phase was washed with 1 N sodium hydroxide, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM/MeOH: 90/10 to give the title compound as a solid (580 mg, 24percent). LC/MS: m/z 341 (M-H)+, Rt: 2.70 min.

Reference： [1]Patent: WO2008/74824,2008,A2 .Location in patent: Page/Page column 44

17
[ 164148-92-9 ]
[ 1006494-87-6 ]
[ 1035224-95-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 48h;	Intermediate 28: 1.1-Dimethylethyl 6-ralphai-r(3.4-dichlorophenvnmethyll-1 H-pyrazol-4- yl}carbonyl)amino1-3,4-dihvdro-2(1 /-/)-isoquinolinecarboxylate; To a solution of 1-[(3,4-dichlorophenyl)methyl]-1 H-pyrazole-4-carboxylic acid (Intermediate 8) (105 mg, 0.39 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (75 mg, 0.39 mmol), 1-hydroxybenzotriazole hydrate (52 mg, 0.39 mmol) and triethylamine (90 mul_, 0.64 mmol) in DCM (5 ml.) was added 1 ,1-dimethylethyl 6-amino-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (80 mg, 0.32 mmol) and the reaction mixture was stirred at room temperature for 48 hours. The organic phase was then washed with a 1 N sodium hydroxide solution, with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM/MeOH: 95/5 to give the title compound as a yellow oil (120 mg, 75%). LC/MS: m/z 501 (M+H)+, Rt: 3.75 min.

Reference： [1]Patent: WO2008/74824,2008,A2 .Location in patent: Page/Page column 42

18
[ 164148-92-9 ]
[ 1038550-35-4 ]
[ 1038550-40-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;	3-[(3,4-Dimethoxy-benzoylamino)-methyl]-benzoic acid methyl ester (100 mg, 0.32 mmol), was dissolved in 5 mL DMF. Iodomethane (20 mL, 0.32 mmol) and NaH (15 mg, 0.62 mmol) were added. The mixture was stirred at room temperature for 2 hours, then <n="94"/>diluted with 15 niL water and extracted with 3 x10 mL ethyl acetate. The combined organic solvent was dried with Na2SO4 and evaporated to give 80 mg of crude product which was used without purification. The intermediate, 3-[(3,4-dimethoxy-benzoyl)- methyl-amino]-methyl} -benzoic acid methyl ester, was dissolved in methanol (20 mL) . NaOH (2 mL, 4M, 8 mmol) was added and the mixture was stirred at room temperature overnight, then diluted with 20 mL water. The resulting solution was neutralized with IN HCl and extracted with dichloromethane (3x15 mL). Evaporation of the solvent afforded 80 mg of crude product as yellow oil which was used without further purification. The intermediate, 3-[(3,4-dimethoxy-benzoyl)-methyl-amino]-methyl}-benzoic acid (80 mg, 0.24 mmol) was combined with 6-amino-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester (70 mg, 0.28 mmol), EDC (80 mg, 0.51 mmol) and EtaOBt (80 mg, 0.59 mmol) in a reaction vial. DMF (2 mL) was added followed by Etaunig's base (0.1 mL, 0.57 mmol). The mixture was stirred at room temperature for 16 h. The product was purified by preparative EtaPLC using an acetonitrile/water/formic acid gradient providing the intermediate, 6-(3 - { [(3 ,4-dimethoxy-benzoyl)-methyl-amino] -methyl} -benzoylamino)-3 ,4- dihydro-lH-isoquinoline-2-carboxylic acid tert-butyi ester, as a yellow oil. This intermediate was dissolved in dichloromethane (4 mL), and trifluoroacetic (1 mL) was added thereafter. The mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the title product as a TFA salt (119 mg, 65% yield, 4 steps); MS, electrospray, 460 (M+Eta).

Reference： [1]Patent: WO2008/86047,2008,A1 .Location in patent: Page/Page column 92-93

19
[ 164148-92-9 ]
[ 79-04-9 ]
[ 1052695-99-4 ]

Yield	Reaction Conditions	Operation in experiment
100%		To a solution of 1 ,1-dimethylethyl 6-amino-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (9.5 g, 38.3 mmol.) in THF (350 ml_) under nitrogen and cooled to 00C were added sodium hydrogenocarbonate (8 g, 95.6 mmol.) and after 2 to 3 minutes of stirring, drop-wise, a solution of chloroacetyl chloride (6.1 ml, 76.5 mmol.) in THF (10 ml_). The mixture was stirred at O0C for 10 minutes then heated up to room temperature and stirred for 2.5 hours. The mixture was poured into an aqueous saturated solution of sodium hydrogenocarbonate and ethyl acetate (500ml) was added. The organic layer was washed three times with aqueous saturated solution of sodium hydrogenocarbonate then dried on sodium sulphate, filtered and evaporated to dryness to give the title compound as yellow oil which crystallised slowly (14.09 g, quantitative yield).1H NMR (400 MHz, DMSO, ppm) delta: 10.2 (bs, 1 H), 7.44 (bs, 1 H), 7.36 (bd, 1 H), 7.12 (d, 1 H), 4.45 (m, 2H), 4.23 (s, 2H), 3.54 (t, 2H), 2.75 (t, 2H), 1.43 (s, 9H).

Reference： [1]Patent: WO2008/104524,2008,A1 .Location in patent: Page/Page column 87

20
[ 164148-92-9 ]
[ 919360-47-7 ]
[ 1046813-15-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetonitrile; at 90℃;	tert-Butyl 6-amino-3,4-dihydroisoquinoline-2(lH)-carboxylate (99.3 mg,0.4 mmol) and mesylate 27c (123 mg, 0.4 mmol) were dissolved in MeCN (1 mL). Cs2CO3 (261 mg, 0.8 mmol) was added and the mixture was stirred at 9O0C overnight. The mixture was then diluted with MeCN and filtered. The filtrate was purified by reverse-phase HPLC to yield the title compound (Example 29). 1H-NMR (400 MHz, CD3CN) delta = 7.04 (d, J = 8.4 Hz, IH), 6.81 (dd, J = 8.4, 2.4 Hz, IH), 6.76 (s, IH), 4.83 <n="62"/>(septet, J = 6.4 Hz, IH), 4.47 (s, 2H), 4.04 (br. d, J = 13.2 Hz, 2H), 3.58 (t, / = 6.0 Hz, 2H), 3.15 (t, J = 7.6 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.76-2.68 (m, 2H), 1.69-1.61 (m, 4H), 1.47 (s, 9H), 1.47-1.40 (m, IH), 1.34-1.28 (m, 2H), 1.21 (d, J = 6.4 Hz, 6H), 1.02 (ddd, J = 12.8, 12.4, 4.0 Hz, 2H); MS calcd. for [M+2H-Boc]+ C21H34N3O2: 360.2; found: 360.1.

Reference： [1]Patent: WO2008/97428,2008,A2 .Location in patent: Page/Page column 60-61; 176

21
[ 164148-92-9 ]
[ 1072084-73-1 ]
[ 1072084-78-6 ]

Yield	Reaction Conditions	Operation in experiment
36%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 20℃; for 96h;	Reference Example 28 6-(4-ChIoro-6-morpholin-4-yl-pyrimidin-2-ylamino)-3,4- dihvdro-lH-isoquinoline-2-carboxylic acid tert-butyl ester; <n="43"/>A mixture of 4-(6-chloro-2-iodo-pyrimidin-4-yl)-mophiholine (1.12 g; 3.4 mmol), 6- amino-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester (1.88 g; 7.6 mmol), NaOBu' (0.46 g; 4.8 mmol), Pd2dba3 (47 mg; 0.051 mmol) and Xantphos (98 mg; 0.17 mmol) in dioxane (40 ml) was stirred under argon at r.t. for 4 days. The reaction mixture was diluted with water (50 ml) and brine (150 ml) then extracted into EtOAc (2 x 100 ml). The combined organic layers were dried (Na2SO4), concentrated and purified by ISCO chromatography to obtain the title compound as a white solid (543 mg; 36 %). deltaeta (400 MHz, CDCl3) 1.51 (s, 9H), 2.81-2.84 (m, 2H), 3.60-3.67 (m, 6H), 3.78-3.81 (m, 4H), 4.55 (s, 2H), 6.04 (s, IH), 6.85 (s, IH), 7.07 (d, J = 8.0, IH), 7.32 (s, IH), 7.37 (d, J = 8.0, IH).

Reference： [1]Patent: WO2008/125839,2008,A2 .Location in patent: Page/Page column 40-41

22
[ 164148-92-9 ]
[ 79-22-1 ]
C₁₆H₂₂N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; at 0 - 20℃; for 24h;	tert-Butyl 6-amino-3,4-dihydroisoquinoline-2(lH)-carboxylate (0.58 g, 2.336 mmol) in DCM (10 mL) and pyridine (2 mL) cooled to 00C was added methyl chloroformate (0.217 mL, 2.80 mmol). The reaction was warmed to rt and stirred for 24 h, quenched with water (10 mL) and extracted with ethyl acetate (3 x 3OmL). The combined organic layers were washed with 0. IN HCl (10 mL), sat'd NaHCO3, brine (10 mL) and dried (MgSO4). Purification with silica gel chromatography using hexanes and ethyl acetate as eluents afforded 0.65g of a yellow solid which was re-dissolved in DCM (10 mL). To this solution was added TFA (3 mL) and stirred for 24 h. The reaction mixture was concentrated and quenched with sat'd NaHCO3 (15 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried (MgSO4) to afford 127A as yellow solid (0.38 g, 79%). MS m/z 207.2 (M + H)+.

Reference： [1]Patent: WO2008/157162,2008,A1 .Location in patent: Page/Page column 197

23
[ 164148-92-9 ]
[ 1161-13-3 ]
[ 1094106-93-0 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 2h;	To tert-butyl 6-amino- 3,4-dihydroisoquinoline-2(leta)-carboxylate (0.2 g, 0.805 mmol), CBz-phenylalanine (0.24 Ig, 0.805 mmol), PyBOP (0.419 g, 0.805 mmol) and THF (8 mL) was added Hunig'sBase (0.141 mL, 0.805 mmol). After 2 h, the reaction mixture was concentrated. The reaction was quenched with water (10 mL). The reaction product was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and dried (MgSO4). Purification by silica gel chromatography using DCM/0-10% MeOH as eluents afforded 0.6 g of 53A. LCMS m/z 530.4 (M+H).+

Reference： [1]Patent: WO2008/157162,2008,A1 .Location in patent: Page/Page column 143

24
[ 164148-92-9 ]
[ 893566-74-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	With amyl nitrate; copper(ll) bromide; In acetonitrile; at 80℃; for 2h;	2a (1.42 g, 5.7 mmol) was added to a mixture of amyl nitrate (1.42 g, 12.1 mmol) and Cu13r2 (2.16 g, 9.67 mmol) in CH3CN (20 mE). The mixture was heated at 80 C. for 2 hours, then cooled and evaporated under reduced pressure. The residue was purified by silica gel colunm chromatography (PE:EA=10: 1, v:v) to provide 2b (1.96 g, 78% yield) as a yellow oil. LC-MS: 312 [M+1].
59%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 60 - 80℃; for 2h;	To a solution of tert-butyl nitrite (0.70 mL, 6.04 mmol) and copper(II) bromide (1.10 g, 4.83 mmol) in anhydrous acetonitrile (10 mL) at 60 0C was added 6-amino-2-7V- boc-l,2,3,4-tetrahydroisoquinoline (1.00 g, 4.03 mmol) portionwise. The reaction mixture was then heated at 80 0C for 2 hours. The reaction mixture was diluted with DCM (100 mL) and washed with 0.5N HC 1 (50 mL). The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were washed with brine (50 mL) and dried (MgSO4) to give a dark crude oil. The crude material was purified by flash column chromatography (isohexane to 10% DCM) to give an orange oil (737 mg, 59%). 1R NMR (400.132 MHz, CDCl3) d 1.49 (s, 9H), 2.80 (m, 2H), 3.63 (m, 2H), 4.50 (m, 2H), 6.95 (m, IH), 7.27 (m, 2H)

Reference： [1]Patent: US2017/275301,2017,A1 .Location in patent: Paragraph 0210; 0211
[2]Patent: WO2009/1128,2008,A1 .Location in patent: Page/Page column 51

25
[ 164148-92-9 ]
[ 1174020-25-7 ]
[ 1174021-16-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 2-chloro-1-methyl-pyridinium iodide; triethylamine; In dichloromethane; at 20 - 50℃; for 0.75h;	To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-l,6-diazabicyclo[3.2.1]octane- 2-carboxylic acid (53.3 mg, 0.193 ramol) in dry dichloromethane (2 mL) was added triethylamine (0.067 mL, 0.482 mmol), 2-chloro-l-methylpyridinium iodide (58.7 mg, 0.230 mmol), and 6-amino-2-N-BOC-ls23>4-tetrahydro-isoqumoline (54.8 mg, 0.221 mmol) <n="95"/>sequentially at room temperature under nitrogen. The reaction mixture was then heated to 500C for 45 minutes then the reaction product was concentrated in vacuo. Attempts to dissolve the reaction product in eluant (2:1:1 CH3CN/DMSO/water) for HPLC were unsuccessful, so it was partitioned between aqueous layer and dichloromethane. The organic layer was collected, dried over sodium sulfate, concentrated in vacuo and set aside for separate purfcation. The aqueous layer was also collected and purified by HPLC (30X100 mm Waters Sunfire column; 5 micron; 35 mL/min.; 210 nM; 15% to 100% CH3CN + 0.05% TFA / water + 0.05% TFA over 15 minutes; the title compound eluted at 80% CH3CN + 0.05% TFA / water + 0.05% TFA).Fractions containing the title compound were lyophilized overnight to afford the title compound as a white sticky solid. The organic layer from partitioning the crude product was purified by preparative TLC (1000 micron silica gel plate eluted with 50% ethyl acetate/hexane) to afford the title compound. Both batches of the title compound were combined and used without further purification in the next step.

Reference： [1]Patent: WO2009/91856,2009,A2 .Location in patent: Page/Page column 92-93

26
[ 164148-92-9 ]
[ 1195070-12-2 ]
[ 1195069-97-6 ]

Yield	Reaction Conditions	Operation in experiment
81%		6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (74.5mg, 0.3 mmol), sodium hydrogen carbonate (84 mg, 1 mmol) were dissolved in 5 mL acetonitrile. The mixture is stirred 15 minutes, followed by the addition of a 6-bromo-2,3-dihydroimidazo[2,1-b]thiazole-5-sulfonyl chloride (95.6 mg, 0.32 mmol). The reaction mixture was stirred at room temperature (18-22 C) for 16 h., until complete conversion (TLC) CHCl3/MeOH 95:5. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (10 mL) and washed with water (2x10 mL), dried and concentrated under reduced pressure to afforded, (150 mg) of 6-(6-bromo-2,3-dihydroimidazo[2,1-b]thiazole-5-sulfonylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example 20) , the crude material were dissolved in ethyl acetate (5 mL) and hydrogen chloride 2M in diethyl ether (3 mL) was added and the mixture was stirred for 2 h. The precipitate insoluble was filtered and washed with ethyl acetate and vacuum dried at 50C, yielding 109 mg (81 %) white solid. [MH]+= 415 IR (KBr) 2933, 2801, 1508, 1458, 1429, 1211, 1161, 1125, 956, 905 cm-1

Reference： [1]Patent: EP2116546,2009,A1 .Location in patent: Page/Page column 18

27
[ 164148-92-9 ]
[ 1035223-71-2 ]
[ 1035223-83-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 48h;	Intermediate 26: 1,1-dimethylethyl 6-([5-methyl-1-(1-naphthalenylmethyl)-1H-pyrazol-3-yl]carbonyl}amino)-3,4-dihydro-2(1H)-isoquinolinecarboxylate; To a solution of 5-methyl-1-(1-naphthalenylmethyl)-1H-pyrazole-3-carboxylic acid (Intermediate 14) (200 mg, 0.75 mmol), N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (0.57 g, 1.5 mmol), diisopropylethylamine (0.28 mL, 1.5 mmol) in DMF (10 mL) was added 1,1-dimethylethyl 6-amino-3,4-dihydro-2(1H)-isoquinolinecarboxylate (186 mg, 0.75 mmol) and the mixture was stirred at room temperature for 48 hours. The DMF was evaporated under reduced pressure and the residue was dissolved in DCM, washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM/MeOH: 99/1 to give the title compound as an oil (390 mg, 100%).LC/MS: m/z 497 (M+H)+, Rt: 3.92 min.

Reference： [1]Patent: US2010/22486,2010,A1 .Location in patent: Page/Page column 18

28
[ 164148-92-9 ]
[ 1780-31-0 ]
[ 1202759-68-9 ]

Yield	Reaction Conditions	Operation in experiment
52%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 0.75h;Microwave irradiation;	A solution of 3 (1.4 g, 5.56 mmol), 4 (0.912 g, 5.56 mmol) and DIPEA (1.077 g, 8.3 mmol) in n-BuOH (15 mL) was subjected to microwave irradiation at 120 0C for 45 min. The reaction mixture was cooled and concentrated under reduced pressure. The residue was taken in ethyl acetate (20 mL) and washed with water (5 mL) and brine (5 mL). Drying over Na2SO4 followed by concentration under reduced pressure offered a residue which was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) gave 5 (1.1 g, 52%) as a cream colored solid

Reference： [1]Patent: WO2009/158571,2009,A1 .Location in patent: Page/Page column 165; 167; 168

29
[ 1154424-63-1 ]
[ 164148-92-9 ]

Yield	Reaction Conditions	Operation in experiment
91%	With ammonium formate;palladium(II) hydroxide; In ethanol; for 6h;Reflux;	To a stirred solution of 2 (2.2 g, 5.75 mmol) in EtOH (25 mL) was added ammonium formate (3.68 g, 57.5 mmol) and the reaction mixture was refluxed for 6 h. It was cooled, filtered though a celite bed and filtrate was concentrated under reduced pressure gave 3 (1.3 g, 91%) as a dark brown oil which was used without further purification.

Reference： [1]Patent: WO2009/158571,2009,A1 .Location in patent: Page/Page column 165; 167; 168

30
[ 164148-92-9 ]
[ 1111881-57-2 ]
[ 1111881-90-3 ]

Yield	Reaction Conditions	Operation in experiment
96%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 48h;	Intermediate 70: 1.1-Dimethylethyl 6-alphari-(2-biDhenylylmethvn-5-methyl-1 H-1.2.3-triazol-4- yllcarbonyl}amino)-3,4-dihvdro-2(1 H)-isoquinolinecarboxvlate; To a solution of 1-(2-biphenylylmethyl)-5-methyl-1 H-1 ,2,3-triazole-4-carboxylic acid(Intermediate 46) (0.3g, 1 mmol), HATU (0.78g, 2mmol) and DIPEA (0.38mL, 2 mmol) in DMF <n="40"/>(1OmL) the commercially available 1 ,1-dimethylethyl 6-amino-3,4-dihydro-2(1 H)- isoquinolinecarboxylate (0.25g, 1 mmol) was added. The reaction mixture was stirred at room temperature for 48 hours. The DMF was evaporated under reduced pressure and the residue was dissolved in DCM. The organic phase was then washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM/MeOH: 99/1 to give the title compound as a compact oil (0.51 g, 96%). LC/MS: m/z 524 (M+H)+, Rt: 4.01 min.

Reference： [1]Patent: WO2009/16216,2009,A1 .Location in patent: Page/Page column 38-39

31
[ 164148-92-9 ]
[ 1111881-85-6 ]
[ 1111882-11-1 ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Intermediate 91 : 1 ,1-Dimethylethyl 6-ralphai-r(3.4-dichlorophenyl)methyll-1 H-1 ,2,3-triazol-4- yl}carbonyl)amino1-3,4-dihvdro-2(1 /-/)-isoquinolinecarboxylate; A mixture of 1-[(3,4-dichlorophenyl)methyl]-1 H-1,2,3-triazole-4-carboxylic acid (Intermediate 65) (0.1g, 0.37mmol), 1 ,1-dimethylethyl 6-amino-3,4-dihydro-2(1 H)-isoquinolinecarboxylate (91 mg, 0.37mmol), HATU (0.182g, 0.48mmol) and DIPEA (83muL, 0.48mmol) in DMF (5mL) <n="45"/>was stirred at room temperature overnight. The mixture was evaporated and the residue was washed with water (2OmL) and extracted with DCM (2OmL). The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound as a brown oil (1 18mg, 64%).LC/MS: m/z 500 (M-H)+, Rt: 3.80 min.

Reference： [1]Patent: WO2009/16216,2009,A1 .Location in patent: Page/Page column 43-44

32
[ 164148-92-9 ]
[ 501-53-1 ]
[ 1154424-63-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 4h;	tert.butyl 6-benzyloxycarbonylannino-3,4-dihvdro-1 H-isoquinoline-2- carboxylate 5.O g (20.1 mmol) tert. butyl 6-amino-3,4-dihydro-1 H-isoquinoline-2-carboxylate are dissolved in 90 ml dichloromethane and at 00C combined with 4.3 ml (25.1 mmol) DIPEA. Then 3.7 ml (25.1 mmol) benzyl chloroformate are added dropwise within one hour. Then the mixture is heated to RT, stirred for 3 hours and then washed twice with water. The organic phase is dried on sodium sulphate and evaporated down i. vac.Rf value: 0.46 (silica gel; dichloromethane/ethanol = 95:5)C22H26N2O6 (382.45)Mass spectrum: (M+NH4)+ = 400

Reference： [1]Patent: WO2009/63028,2009,A2 .Location in patent: Page/Page column 34

33
[ 164148-92-9 ]
C₁₈H₁₇N₅O₄ [ No CAS ]
[ 1158269-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 20℃;	5.46 6-{3-[2-(2,6-Dioxo-piperidin-3-yl)-l-oxo-2,3-dihydro-lH-isoindol-5- ylmethyll -ureido^^-dihvdro-lH-isoquinoline^-carboxylic acid tert- butyl ester; 3-(5-aminomethyl- 1 -oxo- 1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (1.11 g, 3.0 mmol) and 1 , 1 '-Carbonyldiimidazole (535 mg, 3.3 mmol) were suspended in dry DMF (20 mL) and the mixture was stirred at rt for 24 h. While stirring, a portion of the reaction mixture (6.7 mL, ~1 mmol) was transferred to a vial containing tert-butyl 6-amino-3,4- dihydroisoquinoline-2(lH)-carboxylate (273 mg, 1.1 mmol). The resulting mixture was stirred at rt overnight and the reaction progress was monitored by LCMS. After 48 h, additional tert-butyl 6- amino-3,4-dihydroisoquinoline-2(lH)-carboxylate (50 mg, 0.2 mmol) was transferred to the reaction mixture and stirring continued for another 24 h. The reaction mixture was acidified with acidic acid and water. The volatiles were removed in vacuo and the residue was dissolved in DMF and purified using C- 18 preparatory HPLC to give 6-{3-[2-(2,6-dioxo-piperidin-3-yl)-l-oxo-2,3-dihydro-lH- isoindol-5-ylmethyl]-ureido}-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester as a white solid (290 mg, 53% yield): HPLC:Waters Symmetry Ci8, 5 mum, 3.9 x 150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 5.02 min (96.5%); mp: 230-232 0C; 1H NMR (DMSOd6) delta 1.42 (s, 9H, (CHB)3), 1.90 - 2.11 (m, IH, CHH), 2.23 - 2.47 (m, IH, CHH), 2.60 (d, J = 17.9 Hz, IH, CHH), 2.70 (t, J= 5.6 Hz, 2H, CH2), 2.81 - 3.06 (m, IH, CHH), 3.51 (t, J= 5.7 Hz, 2H, CH2), 4.18 - 4.58 (m, 6H, CH2, CH2, CH2), 5.11 (dd, J= 4.9, 13.2 Hz, IH, CH), 6.72 (t, J= 5.9 Hz, IH, NH), 7.00 (d, J = 8.3 Hz, IH, Ar), 7.17 (d, J= 8.1 Hz, IH, Ar), 7.27 (br. s., IH, Ar), 7.44 (d, J= 7.9 Hz, IH, Ar), 7.51 (s, IH, Ar), 7.69 (d, J= 7.9 Hz, IH, Ar), 8.56 (s, IH, NH), 10.98 (s, IH, NH); 13C NMR (DMSOd6) delta 22.46, 28.07, 28.44, 31.16, 41.51, 42.75, 45.04, 47.08, 51.55, 78.81, 116.01, 117.49, 121.87, 122.90, 126.20, 126.36, 126.88, 130.25, 134.70, 138.56, 142.35, 144.86, 153.97, 155.21, 167.93, 170.96, 172.83; LCMS: MH = 548; Anal Calcd for C29H33N5O6+ 1.1 H2O: C, 61.39; H, 6.25; N, 12.34. Found: C, 61.38; H, 6.11; N, 12.29.

Reference： [1]Patent: WO2010/53732,2010,A1 .Location in patent: Page/Page column 86

34
[ 164148-92-9 ]
[ 1038549-74-4 ]
C₃₁H₃₅N₃O₆ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 759 - 777

35
[ 164148-92-9 ]
[ 615-20-3 ]
[ 1190076-09-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 120℃; for 1h;Microwave irradiation;	A toluene solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (248 mg), 2-chlorobenzothiazole (186 mg), palladium acetate (22 mg), cesium carbonate (651 mg), and Xanphos (58 mg) was stirred at 120C for 1 hour under microwave irradiation. The reaction solution was purified by column chromatography to obtain the title compound (381 mg, quantitative yield). 1H NMR (400 MHz, CDCl3) : delta (ppm) = 7.77 (1H, d, J = 8.2 Hz), 7.69 (1H, d, J = 7.8 Hz), 7.40-7.29 (3H, m), 7.25-7.19 (2H, m), 4.69 (2H, s), 3.70 (2H, t, J = 5.3 Hz), 2.90 (2H, t, J = 5.7 Hz), 1.50 (9H, s).

Reference： [1]Patent: EP2256105,2010,A1 .Location in patent: Page/Page column 97

36
[ 164148-92-9 ]
[ 32315-10-9 ]
[ 643-28-7 ]
[ 1190074-19-1 ]

Yield	Reaction Conditions	Operation in experiment
81%		To a dichloromethane (10 mL) solution of triphosgene (474 mg), a dichloromethane (10 mL) solution of 2-isopropylaniline (540 mg) and triethylamine (1.2 mL) was gradually added at room temperature. After 2 hours, a dichloromethane (10 mL) solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (993 mg) and triethylamine (1.2 mL) was added thereto. The reaction mixture was stirred for 30 minutes and concentrated. The residue was purified by chromatography (dichloromethane/ethyl acetate) to obtain the title compound (1.32 g, 81%) as an off-white solid. 1H NMR (400 MHz, CDCl3): delta (ppm) = 7.43-7.38 (2H, m), 7.33-7.27 (3H, m), 7.16 (1H, brs), 7.02 (1H, d, J = 7.8 Hz), 6.35 (1H, s), 6.18 (1H, s), 4.51 (2H, s), 3.61 (2H, t, J = 5.5 Hz), 3.25-3.18 (1H, m), 2.79 (2H, t, J = 5.9 Hz), 1.49 (9H, s), 1.22 (6H, d, J = 6.7 Hz).

Reference： [1]Patent: EP2256105,2010,A1 .Location in patent: Page/Page column 43

37
[ 5395-71-1 ]
[ 164148-92-9 ]
[ 1190074-13-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	In tetrahydrofuran; at 20℃; for 4h;	A tetrahydrofuran (10 mL) solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (981 mg) and 2-ethoxyphenyl isocyanate (0.9 mL) was stirred at room temperature for 4 hours and then concentrated. The residue was purified by chromatography (hexane:ethyl acetate=5:1?1:1 and then methylene chloride:ethyl acetate=1:0?1:1) to obtain the title compound (1.62 g, quantitative yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): delta (ppm) = 8.14 (1H, dd, J = 7.7 and 2.2 Hz), 7.32-7.29 (2H, m), 7.22-7.17 (1H, m), 7.06 (1H, d, J = 7.0 Hz), 7.01-6.94 (2H, m), 6.85 (1H, dd, J = 7.4 and 2.0 Hz), 6.78 (1H, s), 4.54 (2H, s), 4.04 (2H, q, J = 7.0 Hz), 3.63 (2H, brs), 2.80 (2H, t, J = 5.9 Hz), 1.50 (9H, s), 1.35 (3H, t, J = 7.1 Hz).

Reference： [1]Patent: EP2256105,2010,A1 .Location in patent: Page/Page column 41

38
[ 164148-92-9 ]
[ 100-52-7 ]
[ 1257583-28-0 ]

Yield	Reaction Conditions	Operation in experiment
67%	With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 16h;	To a stirred solution of 6-amino-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert- butyl ester (350 mg, 1.41 mmol) in dichloromethane (15 ml) was added benzaldehyde(143 mul, 1.41 mmol), acetic acid (81 mul, 1.41 mmol) followed by sodium triacetoxyborohydride (418 mg, 1.97 mmol) and the reaction was stirred at room temperature for 16 hrs. The reaction mixture was quenched by cooling in ice batch and neutralising with aqueous sodium hydroxide 2M. The aqueous mixture was extracted using dichloromethane (3 x 50 ml) and the organics were combined, dried over sodium sulfate and then concentrated in vacuo. The crude residue was purified by column chromatography (1% methanol in dichloromethane) to afford the title compound as cream solid (320 mg, 67% yield). HPLC retention time 4.98min. Mass spectrum (ES+) m/z 339 (M+H).

Reference： [1]Patent: WO2010/139967,2010,A1 .Location in patent: Page/Page column 28

39
[ 164148-92-9 ]
[ 615-18-9 ]
[ 1190074-11-3 ]

Yield	Reaction Conditions	Operation in experiment
65%	In butan-1-ol; for 11h;Reflux;	A 1-butanol (10 mL) solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (1.00 g) and 2-chlorobenzoxazole (0.50 mL) was heated to reflux for 11 hours, then cooled to room temperature, and then diluted with ethyl acetate. The precipitate was collected by filtration, then washed with ethyl acetate, and dried under reduced pressure to obtain the title compound (791 mg, 65%) as a beige solid. MS (ESI) m/z: 266 (M + H)+.

Reference： [1]Patent: EP2256105,2010,A1 .Location in patent: Page/Page column 41

40
[ 164148-92-9 ]
[ 394-04-7 ]
[ 1190074-01-1 ]

Yield	Reaction Conditions	Operation in experiment
90%		A tetrahydrofuran (20 mL) solution of 5-fluoro-2-methoxybenzoic acid (1.00 g), DPPA (1.25 mL), and triethylamine (1.6 mL) was heated to reflux for 1 hour. A tetrahydrofuran (10 mL) solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (1.00 g) was added to the reaction solution. The reaction mixture was further heated to reflux for 5.5 hours, then cooled to room temperature, and then concentrated. The residue was purified by chromatography (dichloromethane/ethyl acetate=20:1?4:1) to obtain the title compound (1.51 g, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6): delta (ppm) = 9.33 (1H, s), 8.38 (1H, s), 8.05-7.97 (1H, m), 7.38-7.28 (1H, m), 7.24-7.16 (1H, m), 7.10-7.05 (1H, m), 7.02-6.97 (1H, m), 6.77-6.69 (1H, m), 4.41 (2H, s), 3.84 (3H, s), 3.51 (2H, t, J = 6.1 Hz), 2.73 (2H, t, J = 7.0 Hz), 1.41 (9H, s); MS (FAB) m/z: 416 (M + H)+.

Reference： [1]Patent: EP2256105,2010,A1 .Location in patent: Page/Page column 38

41
[ 164148-92-9 ]
[ 7693-46-1 ]
[ 1190074-07-7 ]