[ CAS No. 170097-67-3 ] {[proInfo.proName]}

Name: 170097-67-3|2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid|97%
Brand: Ambeed
SKU: A141712
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Quality Control of [ 170097-67-3 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 170097-67-3 ]

CAS No. :	170097-67-3	MDL No. :	MFCD05861548
Formula :	C₁₅H₁₉NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UHOIFEOHBGCPHE-UHFFFAOYSA-N
M.W :	277.32	Pubchem ID :	11357887
Synonyms :

Safety of [ 170097-67-3 ]

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

Application In Synthesis of [ 170097-67-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 170097-67-3 ]
Downstream synthetic route of [ 170097-67-3 ]

[ 170097-67-3 ] Synthesis Path-Upstream 1~13

1
[ 170097-66-2 ]
[ 170097-67-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: With methanol; sodium hydroxide; water In tetrahydrofuran at 70℃; for 1 h;	Step 2: 2-[(1 , 1 -dimethylethyl)oxylcarbonyl}-1 ,2,3,4-tetrahvdro-6-isoquinolinecarboxylic acid; To a solution of the crude carbamate from Step 1 in MeOH/THF (1 :1 , 6 ml.) was added 1 N NaOH (1.97 ml_, 1.97 mmol). The reaction was heated to 7O⁰C for 1 hour. The reaction was cooled and the MeOH evacuated. The remaining aqueous solution was acidified to pH 4 with 1 N HCI. The resulting precipitate was vacuum filtered and dried to afford the desired product (0.34 g, 93percent) which was used without further purification. MS (ES+) m/e 222.0 [M-fBu]⁺
88%	With methanol; lithium hydroxide In tetrahydrofuran at 10 - 35℃; for 2 h;	3N Aqueous lithium hydroxide solution (17.78 mL, 53.34 mmol) was added to a mixture of 2-tert-butyl 6-methyl 3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate (2.59 g, 8.89 mmol) in MeOH (21 mL) and THF (21 mL) at room temperature, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was adjusted to pH 3 with 6N hydrochloric acid. The mixture was extracted 3 times with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The precipitate was collected by filtration with IPE/hexane to give 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (2.18 g, 7.86 mmol, 88percent) as a white powder. ¹H NMR (300 MHz, CDCl₃):δ 1.50(9H,s), 2.90(2H,t,J=5.7 Hz), 3.68(2H,t,J=5.9 Hz), 4.64(2H,s), 7.21(1H,d,J=7.6 Hz), 7.89-7.94(2H,m).

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 21, p. 5167 - 5182
[2] Patent: WO2009/49154, 2009, A1, . Location in patent: Page/Page column 40
[3] Patent: EP3192791, 2017, A1, . Location in patent: Paragraph 0596
[4] European Journal of Medicinal Chemistry, 2019, p. 317 - 333
[5] Patent: WO2006/114313, 2006, A1, . Location in patent: Page/Page column 159

2
[ 63905-73-7 ]
[ 170097-67-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 21, p. 5167 - 5182

3
[ 158984-83-9 ]
[ 170097-67-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 21, p. 5167 - 5182

4
[ 158984-84-0 ]
[ 170097-67-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 21, p. 5167 - 5182

5
[ 34784-05-9 ]
[ 170097-67-3 ]

Reference： [1] Patent: EP3192791, 2017, A1,
[2] European Journal of Medicinal Chemistry, 2019, p. 317 - 333

6
[ 226942-29-6 ]
[ 170097-67-3 ]

Reference： [1] Patent: EP3192791, 2017, A1,

7
[ 893566-74-0 ]
[ 170097-67-3 ]

Reference： [1] Patent: EP3192791, 2017, A1,

8
[ 185057-00-5 ]
[ 170097-67-3 ]

Reference： [1] European Journal of Medicinal Chemistry, 2019, p. 317 - 333

9
[ 106778-42-1 ]
[ 170097-67-3 ]

Reference： [1] European Journal of Medicinal Chemistry, 2019, p. 317 - 333

10
[ 173089-82-2 ]
[ 170097-67-3 ]

Reference： [1] European Journal of Medicinal Chemistry, 2019, p. 317 - 333

11
[ 877861-62-6 ]
[ 24424-99-5 ]
[ 170097-67-3 ]

Reference： [1] Patent: WO2006/114313, 2006, A1,

12
[ 170097-67-3 ]
[ 164148-92-9 ]

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

13
[ 170097-67-3 ]
[ 622867-52-1 ]

Yield	Reaction Conditions	Operation in experiment
99.3%	Stage #1: With borane-THF In tetrahydrofuran at 25℃; for 16 h; Inert atmosphere Stage #2: With sodium carbonate In tetrahydrofuran; water for 0.25 h;	Example 16 Preparation of intermediate 6-bromomethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (D-1) To a solution of 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester (12.50 g, 45.08 mmol) in dry THF (125.0 mL), under nitrogen at 25° C., is added via syringe borane THF complex (99.17 mL, 99.17 mmol) The mixture is stirred at 25° C. for 16 h then water (10.0 mL) is slowly added followed by 2.0 M Na₂CO₃ (15.0 mL). This mixture is stirred for 15 min and then is diluted with EtOAc and the organic layers are collected. The organics are rinsed with 1M HCl, dried over MgSO₄, and concentrated under reduced pressure to afford an oil. The oil is purified by silica gel chromatography to yield D-1-1 (11.8 g, 99.3percent yield), as a white solid. To a solution of alcohol, D-1-1, (9.50 g, 36.1 mmol) and N,N-diisopropylethylamine (9.43 mL, 54.1 mmol) in dichloromethane (200.0 mL) is added triphenylphosphine dibromide (23.79 g, 54.11 mmol) at 0° C. The reaction is stirred for 1 h then concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography to yield D-1 (8.74 g, 74percent yield), as a white solid.
11.78 g	Stage #1: With borane-THF In tetrahydrofuran at 25℃; for 16 h; Inert atmosphere Stage #2: With water; sodium carbonate In tetrahydrofuran for 0.25 h;	Preparation of intermediate 6-bromomethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4-19) Compound 4-17 (12.50 g, 45.08 mmol) is dissolved in dry THF (125.0 mL) under nitrogen at 25° C. Borane THF complex (99.17 mL, 99.17 mmol) is added via syringe and the mixture is stirred at 25° C. for 16 h. Water (10.0 mL) is slowly added and then 2.0 M Na₂CO₃(15.0 mL). This mixture is stirred for 15 min and then is diluted with EtOAc and the organic layers are collected. The organics are rinsed with 1.0 M HCl, dried over MgSO₄, and concentrated in vacuo to afford an oil. The oil is purified by silica gel chromatography using a gradient of 10-80percent EtOAc in heptane to yield the desired product, 4-18 (11.78 g), as a white solid.
2 g	With borane-THF In tetrahydrofuran at 20℃; for 3 h; Sealed tube; Inert atmosphere	Borane-tetrahydrofuran complex in tetrahydrofuran (1.0 M, 15.87 mL, 15.87 mmol) was added dropwise to a stirred solution of 2-(tert-butoxycarbonyl)-1,2,3,4- tetrahydroisoquinoline-6-carboxylic acid (2.0 g, 7.21 mmol) in tetrahydrofuran (50 mL) at ambient temperature under argon in a sealed flask. After stirring for 3 hours, the mixture was carefully quenched with water and sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate (x2) and the combined extracts were washed with brine, dried (anhydrous Na₂SO₄) and evaporated to give tert-butyl 6- (hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.0 g). LCMS m/z = 207.9 [M+H–isobutylene]⁺.

Reference： [1] Patent: US2016/24059, 2016, A1, . Location in patent: Paragraph 0308-0309
[2] Patent: WO2012/122340, 2012, A1, . Location in patent: Page/Page column 77
[3] Patent: US2014/73629, 2014, A1, . Location in patent: Paragraph 0100; 0101
[4] Patent: WO2017/160632, 2017, A1, . Location in patent: Page/Page column 78; 79
[5] Patent: WO2017/216726, 2017, A1, . Location in patent: Page/Page column 643-644

[ 170097-67-3 ] Synthesis Path-Downstream 1~88

1
[ 1117-97-1 ]
[ 170097-67-3 ]
[ 371222-34-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In methanol; at 20℃;	29a 6-(Methoxy-methyl-carbamoyl)-3,4-dihydro-1/-/-isoquinoline-2-carboxylic acid te/f-butyl esterTo 2.00 g (7.21 mmol) 3,4-dihydro-1 /-/-isoquinoline-2,6-dicarboxylic acid 2-te/f-butyl ester in 70 mL MeOH is added at RT 844 mg (8.65 mmol) O,lambda/-dimethyl-hydroxylamine and 1.59 mL (14.4 mmol) 4-methyl-morpholine. The mixture is stirred at RT and then 2.10 g (7.57 mmol) 4- (4,6-dimethoxy-1 ,3,5-triazin-2-yl)-4-methyl-morpholin-4-ium chloride hydrate is added and the mixture is stirred overnight at RT. The residue is directly purified via reverse HPLC chromatography (Waters XBridge, C18; water (0.3 % NH4OH)/acetonitrile (0.3 % NH4OH) 90:10 to 10:90). Yield: 2.30 g (100% of theory) ESI Mass spectrum: [M+H]+ = 321Retention time HPLC: 1.7 min (method K).

Reference： [1]Patent: WO2008/22979,2008,A1 .Location in patent: Page/Page column 103

2
[ 24424-99-5 ]
1.) NaH; 2.) SOCl₂ [ No CAS ]
[ 170097-67-3 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 5167 - 5182

3
[ 63905-73-7 ]
[ 170097-67-3 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 5167 - 5182

4
[ 158984-83-9 ]
[ 170097-67-3 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 5167 - 5182

5
[ 158984-84-0 ]
[ 170097-67-3 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 5167 - 5182

6
[ 170097-67-3 ]
1-[(6-Chloronaphthalen-2-yl)sulfonyl]-4-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]piperazine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 5167 - 5182

7
[ 170097-67-3 ]
4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]piperazine hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 5167 - 5182

Yield	Reaction Conditions	Operation in experiment
		A. 3,4-Dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester To 1.20 g (4.1 mmol) of 5C in 36 mL of methanol was added 0.62 g (4.5 mmol) of potassium carbonate and the mixture was heated at reflux for 7 h. The product was purified by silica gel chromatography (9:1 v/v chloroform:methanol) to give 1.49 g of 88A.
		d) Saponification of 387 mg of the preceding step product with 213 mg of NaOH in 9 ml of methanol and 1 ml of water is effected at room temperature for 6 h. The reaction solution is concentrated and diluted with water. The aqueous phase is extracted with ether, adjusted to pH 5 with 1N HCl and the precipitate is filtered off under suction. After washing the crystals with water and drying there are obtained 274 mg of 1,2,3,4-tetrahydro-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester, MS (EI): 220 (M-57).

9
[ 512810-08-1 ]
[ 170097-67-3 ]
[ 1035224-65-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	Intermediate 13: 1 ,1-Dimethylethyl 6-({ri-(1-naphthalenylmethyl)-1 /-/-pyrazol-4- vHamino)carbonyl)-3,4-dihvdro-2(1 H)-isoquinolinecarboxylate; To a solution of 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6-isoquinoline carboxylic acid (138 mg, 0.5 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (114 mg, 0.6 mmol), 1-hydroxybenzotriazole hydrate (81 mg, 0.6 mmol) and triethylamine (60 mg, 0.6 mmol) in DCM (10 ml.) was added 1-(1- naphthalenylmethyl)-1 H-pyrazol-4-amine (11 1 mg, 0.5 mmol) and the reaction mixture was stirred at room temperature overnight. The organic phase was diluted with an additional volume of DCM then washed with a saturated sodium hydrogeno carbonate solution, with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM/MeOH: 97/3 to give the title compound as an orange oil (180 mg, 81%). LC/MS: m/z 483 (M+H)+, Rt: 3.53 min.

Reference： [1]Patent: WO2008/74824,2008,A2 .Location in patent: Page/Page column 38

10
[ 895929-62-1 ]
[ 170097-67-3 ]
[ 1035224-22-6 ]

Yield	Reaction Conditions	Operation in experiment
77%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	Example 24: 1 ,1-Dimethylethyl 6-r({1-r(3,4-dichlorophenyl)methvH-1 /-/-pyrazol-4- yl}amino)carbonyll-3,4-dihvdro-2(1 H)-isoquinolinecarboxylate;To a solution of 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6-isoquinoline carboxylic acid (138 mg, 0.5 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (114 mg, 0.6 mmol), 1-hydroxybenzotriazole hydrate (81 mg, 0.6 mmol) and triethylamine (60 mg, 0.6 mmol) in DCM (10 ml.) was added 1-[(3,4- dichlorophenyl)methyl]-1 H-pyrazol-4-amine (Intermediate 7) (120 mg, 0.5 mmol) and the reaction mixture was stirred at room temperature overnight. 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 white solid (190 mg, 77%) after recrystallization from CH3CN. LC/MS: m/z 501 (M+H)+, Rt: 3.65 min.

Reference： [1]Patent: WO2008/74824,2008,A2 .Location in patent: Page/Page column 52

11
[ 1035189-23-1 ]
[ 170097-67-3 ]
[ 1035189-29-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 48h;	Intermediate 8: 1 ,1-dimethylethyl 6-{r(5-methyl-1-{r2-(methyloxy)phenyllmethyl}-1 H-pyrazol- 3-yl)amino1carbonyl}-3,4-dihvdro-2(1 H)-isoquinolinecarboxylate; To a solution of 5-methyl-1-[2-(methyloxy)phenyl]methyl}-1 /-/-pyrazol-3-amine (Intermediate 5) (0.1 g, 0.46 mmol) in DCM (5m L) was added 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4- tetrahydro-6-isoquinolinecarboxylic acid (0.15 g, 0.55 mmol), HOBt (0.075 g, 0.55 mmol) and EDCI (0.105 g, 0.55 mmol), Et3N (130 muL, 0.92 mmol) and the mixture was stirred at room temperature for 48 hours. The organic phase was then washed with HCI (0.5N) and a saturated solution of NaHCO3, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM to DCM/EtOAc: 80/20 to give the title compound as an oil (115 mg, 52%). LC/MS: m/z 477 (M+H)+, Rt: 3.52 min.

Reference： [1]Patent: WO2008/74833,2008,A2 .Location in patent: Page/Page column 24

12
[ 1035201-94-5 ]
[ 170097-67-3 ]
[ 1035202-00-6 ]

Yield	Reaction Conditions	Operation in experiment
13%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 24h;	Intermediate 9: 1 ,1-dimethylethyl 6-({ri-({5-chloro-2-r(2-methylpropyl)oxylphenyl}methyl)-5- ethyl-I H-pyrazol-S-yliaminolcarbonvD-S^-dihydro^d l-D-isoquinolinecarboxylate; <n="28"/>To a solution of 1-({5-chloro-2-[(2-methylpropyl)oxy]phenyl}methyl)-5-ethyl-1 H-pyrazol-3- amine (Intermediate 7) (0.5 g, 1.62 mmol) in DMF (1 OmL) was added 2-[(1 ,1- dimethylethyOoxylcarbonylJ-I ^.S^-tetrahydro-theta-isoquinolinecarboxylic acid (0.41 g, 0.9 eq.), HATU (0.74 g, 1.2 eq.) and DIEA (0.34 ml_,1.2 eq.) and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was diluted with DCM. The organic phase was then washed with water and dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM/EtOAc: 95/5 to give the title compound as an oil (120 mg, 13%). LC/MS: m/z 567 (M+H)+ Rt: 4.23 min.

Reference： [1]Patent: WO2008/74834,2008,A2 .Location in patent: Page/Page column 26-27

13
[ 1038551-28-8 ]
[ 170097-67-3 ]
[ 1038551-30-2 ]

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;	3,4-Dimethoxybenzoic acid (100 mg, 0.55 mmol) was dissolved in DMF (1 mL). EDC (124.6 mg, 0.65 mmol) and HOBt (81 mg, 0.6 mmol) were added, followed by N- methylmorpholine (0.71 mL, 0.65 mmol). The resulting solution was agitated for 1 h. 3- Aminomethylphenyl-carbamic acid tert-butyl ester (111 mg, 0.5 mmol) was then added and the resulting mixture was agitated overnight. The reaction mixture was diluted with 4 mL dichloromethane, and the resulting mixture was washed with 1 N HCl (2 x 5 mL), NaHCO3 (saturated aqueous, 2 x 5 mL), and brine (1 x 5 mL), dried, and the solvents were evaporated to provide 190 mg (quantitative yield) of (3-[(3,4-dimethoxy-benzoylamino)- methyl]-phenyl}-carbamic acid tert-butyi ester, which was dissolved in dichloromethane (2 mL). SCX (1.14 g, 1.0 mmol) was added and the resulting mixture was agitated for 48 h. The reaction mixture was filtered and the solids were washed with dichloromethane (2 x 2 mL) and methanol (2 x 2 mL). The product was eluted with NH3 in methanol (7 N, 2 x 2 mL). The solvents were evaporated to provide 112 mg (78% yield) of 7V-(3-amino- benzyl)-3,4-dimethoxy-benzamide as a white solid, which was used directly. 3,4-Dihydro- lH-isoquinoline-2,6-dicarboxylic acid 2-tert-buty{ ester (19.1 mg, 0.069 mmol), EDC <n="106"/>(19.2 mg, 0.1 mmol), and HOBt (12.2 mg, 0.09 mmol) were combined in a reaction tube, and DMF (1 mL) was added. To the resulting solution was added N-methylmorpholine (0.013 mL, 0.12 mmol), and the mixture was agitated for 1 h. The intermediate prepared above, Lambda/-(3-amino-benzyl)-3,4-dimethoxy-benzamide (17 mg, 0.059 mmol), was then added as a solution in DMF (0.3 mL), and the reaction mixture was agitated overnight. The reaction mixture was diluted with 6 mL dichloromethane, and the resulting mixture was washed with 1 N HCl (2 x 2 mL), NaHCO3 (saturated aqueous, 2 x 2 mL), and brine (1 x 2 mL), dried, and concentrated to 32 mg of 6-{3-[(3,4-dimethoxy-benzoylamino)- methyl]-phenylcarbamoyl}-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester as an oil, which was redissolved in dichloromethane (1 mL) and treated with SCX (284 mg, 0.25 mmol). The resulting mixture was agitated overnight. The reaction mixture was filtered and the solids were washed with dichloromethane (2 x 2 mL) and methanol (2 x 2 mL). The product was eluted with NH3 in methanol (7 N, 2 x 2 mL), and the eluant was evaporated. The resulting residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound as a formate salt (20 mg, 77% yield - 2 steps), MS analysis electrospray, 446 (M+H).

Reference： [1]Patent: WO2008/86047,2008,A1 .Location in patent: Page/Page column 103-105

14
[ 1038549-47-1 ]
[ 170097-67-3 ]
[ 1038549-62-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 49h;	3,4-Dihydro-lH-isoquinoline-2,6-dicarboxylic acid 2-tert-buty ester (50 mg, 0.18 mmol), EDC (38.3 mg, 0.2 mmol) and EtaOBt (24.3 mg, 0.18 mmol) were combined in a reaction vial, and DMF (1 mL) was added. To the solution thus formed, N-methylmorpholine (0.22 mL, 0.2 mmol) was added and the reaction mixture was agitated for 1 hour. The urea, 1- (3-amino-benzyl)-3-(4-cyano-phenyl)-urea (40 mg, 0.15 mmol), prepared as described above, was then added as a solution in DMF (0.3 mL), and the reaction mixture was agitated for 48 h. The reaction mixture was diluted to 6 mL with dichloromethane, washed with IN HCl (3x2 mL), NaHCO3 (satd. aq., 3x2 mL, and brine (1 x 2 mL), dried and evaporated to 59 mg of an oil (95% yield). This intermediate (6-{3-[3-(4-cyano- phenyl)-ureidomethyl]-phenylcarbamoyl}-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester) was dissolved in dichloromethane (1 mL) and TFA (0.4 mL) was added. The reaction mixture was stirred for 2 h, then the solvents were evaporated and the resulting residue was purified directly by preparative EtaPLC using an acetonitrile/water/formic acid gradient providing the title compound (20 mg, 48% yield), MS analysis electrospray, 426 (M+Eta).

Reference： [1]Patent: WO2008/86047,2008,A1 .Location in patent: Page/Page column 84-85

15
[ 84138-74-9 ]
[ 170097-67-3 ]
[ 1052695-03-0 ]

Yield	Reaction Conditions	Operation in experiment
62%		A solution of 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (14.3 g, 52 mmol), HATU (29.5 g, 77.6 mmol), DIPEA (14.6 ml_, 62 mmol) in DMF was stirred at room temperature for 1 hour. 5-[(2- chlorophenyl)oxy]methyl}-1 ,3,4-thiadiazol-2-amine, (Intermediate 95) (15 g, 62 mmol) was added and the mixture was stirred at room temperature overnight. The DMF was evaporated under reduced pressure and the residue was dissolved in EtOAc. The organic phase was then washed with water and filtered to eliminate an insoluble. The aqueous phase was re-extracted with EtOAc, and the organic phase was dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was then diluted with DCM and the insoluble was filtered. All the organic phases were combined, dried over sodium sulphate, filtered and evaporated under reduced pressure to give the title compound (14 g, 62%).1H NMR (300 MHz, DMSO, ppm) delta: 7.96 (s, 1 H), 7.93 (d, 1 H), 7.48 (d, 1 H), 7.36 (m, 3H), 7.04 (m, 1 H), 5.64 (s, 2H), 4.59 (s, 2H), 3.60 (t, 2H), 2.86 (t, 2H), 1.44 (s, 9H).

Reference： [1]Patent: WO2008/104524,2008,A1 .Location in patent: Page/Page column 65

16
[ 1052696-06-6 ]
[ 170097-67-3 ]
[ 1052696-07-7 ]

Yield	Reaction Conditions	Operation in experiment
29%	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	A solution of 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (555 mg, 2 mmol), HATU (989 mg, 2.6 mmol), triethylamine (0.26 ml_, 2.6mmol) in DMF (15 ml.) and 5-[(2-chlorophenyl)(methyl)amino]methyl}- 1 ,3,4-thiadiazol-2-amine (Intermediate 240) (509 mg, 2 mmol) was stirred at room temperature overnight. The DMF was evaporated under reduced pressure and the residue was dissolved in DCM. The organic phase was dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with a gradient DCM 100% to DCM/MeOH: 98/2. After evaporation of the right fractions, the material was triturated in hot methyl alcohol, to give after filtration and drying the title compound as a white solid (300 mg, 29%). HRMS calculated for C25H28CIN5O3S (M+H)+ 514.1680, found: 514.1651, Rt: 3.47 min.

Reference： [1]Patent: WO2008/104524,2008,A1 .Location in patent: Page/Page column 92

17
[ 913568-01-1 ]
[ 170097-67-3 ]
[ 1103261-03-5 ]

Yield	Reaction Conditions	Operation in experiment
84%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 96h;	Intermediate 6: 1 ,1-Dimethylethyl 6-({ri-({5-chloro-2-r(cvclopropylmethyl)oxyl phenyllmethyl)- 5-methyl-1 /-/-pyrazol-3-yl1amino}carbonyl)-3,4-dihvdro-2(1 H)-isoquinolinecarboxylateTo a solution of 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (200 mg, 0.72 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (158 mg, 0.82 mmol), 1-hydroxybenzotriazole hydrate (1 11 mg, 0.82 mmol) and diisopropylethylamine (1 15 mg, 0.89 mmol) in DCM (15 ml.) was added Intermediate 4 (200 mg, 0.69 mmol) and the mixture was stirred at room temperature for 4 days. The organic phase was then washed with HCI (1 N), NaOH (1 N) and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM/EtOAc: 90/10 to give the title compound as yellow oil (316 mg, 84%). LC/MS: m/z 551 (M+H)+, Rt: 4.15 min.

Reference： [1]Patent: WO2009/10560,2009,A1 .Location in patent: Page/Page column 17

18
[ 913568-03-3 ]
[ 170097-67-3 ]
1,1-dimethylethyl 6-([1-({5-chloro-2-[(2-methylpropyl)oxy]phenyl}methyl)-5-methyl-1H-pyrazol-3-yl]amino}carbonyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4027 - 4032

19
2-(trifluoromethoxy)benzylamine [ No CAS ]
[ 170097-67-3 ]
C₂₃H₂₅F₃N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide;	Step 3: lambda/-({2-r(trifluoromethvnoxylphenyl}methylV1 ,2.3.4-tetrahvdro-6- isoquinolinecarboxamide; To a solution of aforementioned carboxylic acid (0.20 g, 0.72 mmol) in DMF (5 ml.) was added DMAP (24.0 mg, 0.22 mmol) followed by 2-(trifluoromethoxy)benzylamine (108 DL, 0.79 mmol) and EDCI (138 mg, 0.72 mmol). After stirring overnight, the reaction was poured into H2O (10 ml.) and extracted with EtOAc (2x10 ml_). The organics were dried (Na2SO4) and evacuated. The crude material was redissolved in CH2CI2 (2 ml.) and treated with TFA (2 ml_). After stirring for 30 minutes, the reaction was diluted with CH2CI2 (15 ml.) and poured into ice cold 1 N NaOH (20 ml_). The organics were extracted, dried (Na2SO4), and evacuated to afford the title compound (0.15 g, 59%), which was used without further purification. MS (ES+) m/e 335.0 [M+1]+

Reference： [1]Patent: WO2009/49154,2009,A1 .Location in patent: Page/Page column 40

20
[ 7210-76-6 ]
[ 170097-67-3 ]
[ 1200399-63-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 50℃; for 6h;	A solution of 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (296 mg, 1.07 mmol), HATU (406 mg, 1.07 mmol), DIPEA (0.41 ml_, 2.36 mmol ) and ethyl 2-amino-4-methyl-1 ,3-thiazole-5-carboxylate (199 mg, 1.07 mmol) in DMF (5 ml.) was stirred at 500C for 6 hours. The volatiles were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic phase was then washed with dilute HCI, with a solution of sodium bicarbonate, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was dissolved in a mixture of ethanol (1.5 ml.) and water (2 ml.) and sodium hydroxide was added (86 mg, 2.15 mmol) and the reaction mixture was heated at 500C for 4 hours. The reaction was then cooled, acidified with dilute HCI and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue obtained was used directly in the next step without further purification.

Reference： [1]Patent: WO2009/150196,2009,A1 .Location in patent: Page/Page column 56

21
[ 170097-67-3 ]
[ 290835-51-7 ]
[ 1200399-18-3 ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 168h;	A solution of 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (0.68 g, 2.45 mmol), HATU (1 g, 2.64 mmol), DIPEA (0.76 ml_, 4.4 mmol ) and 5-[(4-chlorophenyl)methyl]-1 ,3-thiazol-2-amine (0.5 g, 2.2 mmol) in DMF (5 ml.) was stirred at room temperature for one week. The volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane. The organic phase was then washed with water, with a 1 N NaOH solution, dried over Na2SO4, filtered and evaporated under reduced pressure. The solid was triturated with acetonitrile and recrystallised from methanol/dichloromethane to give the title compound as a white solid (0.67 g, 63%). LC/MS: m/z 484 (M+H)+, Rt : 3.86 min.

Reference： [1]Patent: WO2009/150196,2009,A1 .Location in patent: Page/Page column 44

22
2-[(4-chlorophenyl)methyl]-4-methyl-1,3-thiazol-5-amine hydrochloride [ No CAS ]
[ 170097-67-3 ]
[ 1200399-48-9 ]

Yield	Reaction Conditions	Operation in experiment
15%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 120h;	To a solution of 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (0.1 1 g, 0.4 mmol), HOBt (55 mg, 0.4 mmol), EDCI (77 mg, 0.4 mmol) and triethylamine (140 mul, 1 mmol) in DCM (5 ml.) was added 2-[(4- chlorophenyl)methyl]-4-methyl-1 ,3-thiazol-5-amine hydrochloride (80 mg, 0.33 mmol) and the resulting mixture was stirred at room temperature for 5 days. The organic phase was washed successively with a 1 N solution of hydrochloric acid, with a 1 N solution of sodium hydroxide, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM / EtOAc: 8 / 2 to give the title compound as a yellow oil (25 mg, 15%). LC/MS: m/z 498 (M+H)+, Rt : 3.83 min.

Reference： [1]Patent: WO2009/150196,2009,A1 .Location in patent: Page/Page column 51

23
[ 306321-23-3 ]
[ 170097-67-3 ]
[ 1200399-54-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 48h;	To a solution of 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (33 mg, 0.12 mmol), HOBt (19 mg, 0.14 mmol), EDCI (26 mg, 0.14 mmol) and triethylamine (14 mg, 14 mmol) in DCM (3 ml.) was added 4-[(3- nitrophenyl)methyl]-1 ,3-thiazol-2-amine (30 mg, 0.12 mmol) and the resulting mixture was stirred at room temperature for 2 days. The organic phase was washed successively with water, with a 1 N solution of sodium hydroxide, with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM / MeOH: 98 / 2 to give the title compound as a pale yellow oil (30 mg, 52%). LC/MS: m/z 495 (M+H)+, Rt : 3.68 min.

Reference： [1]Patent: WO2009/150196,2009,A1 .Location in patent: Page/Page column 52-53

24
[ 1200399-61-6 ]
[ 170097-67-3 ]
[ 1200399-62-7 ]

Yield	Reaction Conditions	Operation in experiment
17%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 168h;	To a solution of 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (100 mg, 0.36 mmol), HOBt (50 mg, 0.37 mmol), EDCI (70 mg, 0.37 mmol) and triethylamine (80 mul_, 0.58 mmol) in DCM (5 ml.) was added Intermediate 66 (75 mg, 0.29 mmol) and the resulting mixture was stirred at room <n="57"/>temperature for 1 week. The organic phase was washed successively with a 1 N solution of hydrochloric acid, with a 1 N solution of sodium hydroxide, 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 (25 mg, 17%). LC/MS: m/z 518 (M+H)+, Rt : 4.05 min.

Reference： [1]Patent: WO2009/150196,2009,A1 .Location in patent: Page/Page column 55-56

25
[ 1035223-65-4 ]
[ 170097-67-3 ]
[ 1035223-73-4 ]

Yield	Reaction Conditions	Operation in experiment
49%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 96h;	Intermediate 16: 1,1-dimethylethyl 6-([1-(2-biphenylylmethyl)-5-methyl-1H-pyrazol-3-yl]amino}carbonyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate; To a solution of 1-(2-biphenylylmethyl)-5-methyl-1H-pyrazol-3-amine (Intermediate 6) (76 mg, 0.29 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (66 mg, 0.34 mmol), 1-hydroxybenzotriazole hydrate (46 mg, 0.34 mmol) and diisopropylethylamine (48 mg, 0.37 mmol) in DCM (10 mL) was added 2-[(1,1-dimethylethyl)oxy]carbonyl}-1,2,3,4-tetrahydro-6-isoquinolinecarboxylic acid (84 mg, 0.3 mmol) and the mixture was stirred at room temperature for 4 days. The organic phase was then washed with NaOH (1N) and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with DCM to DCM/MeOH: 96/4 to give the title compound as a colorless oil (73 mg, 49%).LC/MS: m/z 523 (M+H)+, Rt: 4.03 min.

Reference： [1]Patent: US2010/22486,2010,A1 .Location in patent: Page/Page column 16

26
[ 100-51-6 ]
[ 170097-67-3 ]
[ 1154424-63-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	With diphenyl phosphoryl azide; triethylamine; In toluene; for 12h;Reflux; Inert atmosphere;	To a stirred solution of 1 (1.5 g, 5.4 mmol) in toluene (15 mL) was added DPPA (2.17 g, 8.11 mmol), Et3N (1.05 mL, 8.11 mmol) and benzyl alcohol (0.876 g, 8.11 mmol) under N2. The reaction mixture was allowed to reflux for 12 h, cooled and diluted with ethyl acetate (100 mL). It was washed with water (5 mL), brine solution (5 mL) and dried over Na2SO4. It was filtered and concentrated under reduced pressure and the residue was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) gave 2 (2.0 g, 97%) as a white solid.

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

27
[ 1111881-89-0 ]
[ 170097-67-3 ]
[ 1111882-14-4 ]

Yield	Reaction Conditions	Operation in experiment
43%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Intermediate 94: 1.1-dimethylethyl 6-r({1-r(3.4-dichlorophenyl)methyll-5-methyl-1 H-1.2.3- triazol-4-yl}amino)carbonyl1-3,4-dihvdro-2(1 H)-isoquinolinecarboxylate; <n="46"/>A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1 H-1 ,2,3-triazol-4-amine (Intermediate 69) (0.1g, 0.39mmol), 2-[(1 ,1-dimethylethyl)oxy]carbonyl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxylic acid (0.1 1g, 0.37mmol), HATU (0.19g, O.deltammol) and DIPEA (88mul_, O.deltammol) in DMF (5mL) was stirred at room temperature overnight. The mixture was evaporated. The residue was washed with water and extracted with DCM. The organic phase was dried over Na2SO4, filtered and concentrated. The title compound was obtained as a white solid after purification by flash column chromatography eluting with DCM/MeOH: 98//2 and crystallisation from isopropyl ether (86mg, 43 %). HRMS calculated for C25H27CI2N5O3 (M+H)+ 516.1569, found: 516.1591 , Rt: 3.13 min.

Reference： [1]Patent: WO2009/16216,2009,A1 .Location in patent: Page/Page column 44-45

28
[ 18107-18-1 ]
[ 170097-67-3 ]
[ 170097-66-2 ]

Yield	Reaction Conditions	Operation in experiment
		Example 10; Preparation of intermediate (2-methyl-l,2,3,4-tetrahydroisoquinolin-6- yl)methanol (10-34) 10-33 10-34A solution of TMSCHN2 (2 M in hexanes, 36.0 mL, 72.0 mmol) is added to a stirred room temperature solution of acid 10-33 (9.99 g, 36.02 mmol) in a 1: 1 mixture of PhMe/MeOH (134 mL). After 1.5 h, the mixture is quenched with glacial AcOH (10 mL) and stirred for an additional 5 min. The solvents are removed in vacuo to provide the crude ester as a solid upon standing. The intermediate ester (15.2 g, 52.1 mmol) is dissolved in THF (200 mL) and treated with LAH powder (4.95 g, 130 mmol). The resulting slurry is heated to 65 C for 3 h, then cooled to room temperature and slowly quenched with water (3.6 mL). The mixture is then treated with 2 N NaOH (3.6 mL), followed by additional water (10.8 mL). The resulting slurry is stirred for 1 h, then filtered to remove solids. The filtrate is dried over Na2S04, filtered again, and concentrated in vacuo to provide the desired product. The solids initially collected by filtration are resuspended in acetone and vigorously stirred overnight at room temperature. The slurry is refiltered, and the remaining acetone is combined with the initially collected product. Concentration of the combined organic filtrates provides the desired intermediate 10-34 (7.50 g).

Reference： [1]Patent: WO2012/122340,2012,A1 .Location in patent: Page/Page column 59-60

29
[ 170097-67-3 ]
[ 622867-53-2 ]

Reference： [1]Patent: WO2012/122340,2012,A1
[2]Patent: US2014/73629,2014,A1
[3]Patent: US2016/24059,2016,A1
[4]Patent: WO2017/216726,2017,A1

30
[ 170097-67-3 ]
[ 1398413-88-1 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 1h;Inert atmosphere;	2-(tert-Butoxycarbonyl)- 1,2,3 ,4-tetrahydroisoquinoline-6-carboxylic acid mg, 1.80 mmol) was dissolved in THF (18 mL). A 1M solution of LAH in THF (5.4 tl, 5.4 mmol) was added at 0 C, and the reaction mixture was stirred at rt under argon for lh. The reaction was quenched sequentially with 0.33 mL of water at 0 C, 0.66 mL of1M NaOH and 1.2 mL of water. Magnesium sulfate was added, and the mixture was filtered. The filtrate was concentrated to provide crude 159A containing some of the desmethyl by-product. MS(ESI) m/z 178.1 (M+H)t Used without further purification.

Reference： [1]Patent: WO2012/122340,2012,A1
[2]Patent: WO2017/40449,2017,A1 .Location in patent: Paragraph 00409

31
[ 170097-67-3 ]
[ 1398414-91-9 ]