[ CAS No. 17880-61-4 ]

Name: 17880-61-4|Methyl 5-ethynylpicolinate|97%
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Quality Control of [ 17880-61-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 17880-61-4 ]

CAS No. :	17880-61-4	MDL No. :	MFCD13189756
Formula :	C₉H₇NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PGYCVRHIHIYNBF-UHFFFAOYSA-N
M.W :	161.16	Pubchem ID :	568567
Synonyms :

Calculated chemistry of [ 17880-61-4 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.11
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	43.45
TPSA :	39.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.05 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.98
Log Po/w (XLOGP3) :	1.74
Log Po/w (WLOGP) :	0.93
Log Po/w (MLOGP) :	0.89
Log Po/w (SILICOS-IT) :	1.81
Consensus Log Po/w :	1.47

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.17
Solubility :	1.08 mg/ml ; 0.00671 mol/l
Class :	Soluble
Log S (Ali) :	-2.18
Solubility :	1.07 mg/ml ; 0.00661 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.17
Solubility :	1.08 mg/ml ; 0.00671 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.94

Safety of [ 17880-61-4 ]

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

Application In Synthesis of [ 17880-61-4 ]

* 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 [ 17880-61-4 ]
Downstream synthetic route of [ 17880-61-4 ]

[ 17880-61-4 ] Synthesis Path-Upstream 1~2

1
[ 29682-15-3 ]
[ 17880-61-4 ]

Reference： [1] Journal of Organometallic Chemistry, 2011, vol. 696, # 25, p. 4039 - 4045
[2] Patent: WO2012/31298, 2012, A2,
[3] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 2, p. 94 - 102

2
[ 30766-11-1 ]
[ 17880-61-4 ]

Reference： [1] Patent: WO2012/31298, 2012, A2,

[ 17880-61-4 ] Synthesis Path-Downstream 1~44

1
methyl 5-((trimethylsilyl)ethynyl)picolinate [ No CAS ]
[ 17880-61-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium fluoride; In methanol; dichloromethane; at 20.0℃; for 2.0h;	To a stirred solution of 2 (1.08 g, 4.63 mmol) in CH3OH/CH2Cl2 (30 mL, 1:1, v/v) was added KF (1.31 g, 13.9 mmol) as a solid. After complete consumption of the starting material (2 h), the crude reaction mixture was filtered and concentrated under reduced pressure. The residual brown solid was purified by flash column chromatography on SiO2 (hexanes:EtOAc = 4:1, v/v) to afford 3 as a yellow solid (0.67 g, 90%). 1H NMR (300 MHz, CDCl3, 298 K): delta 8.79 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.90 (dd, J = 8.0, 2.0 Hz, 1H), 4.00 (s, 3H), 3.37 (s, 1H); 13C NMR (75 MHz, CDCl3, 298 K): delta 165.2, 152.7, 146.9, 140.2, 124.5, 122.8, 83.6, 79.8, 53.2. FT-IR (thin film on NaCl, cm-1): 3444, 3254, 3097, 3066, 3015, 1726, 1581, 1555, 1455, 1362, 1311, 1275, 1241, 1206, 1120, 1018, 878, 793, 701, 679. HRMS (CI) calcd for C9H8NO2 [M + H]+ 162.0550, found 162.0543.
84%	With methanol; potassium carbonate; at 20.0℃; for 0.666667h;Inert atmosphere;	Methyl 5-ethynylpyridine-2-carboxylate (142): 141 (2.00 g, 8.58 mmol) is dissolved in anhydrous MeOH (20 mL) at room temperature, and potassium carbonate (0.024 g, 0.17 mmol, 0.02 equiv) is added. The mixture is stirred for 40 min under argon at room temperature. Then the mixture reaction is evaporated in vacuum to afford the crude product, which is purified by flash chromatography (eluting with 0- 10% MeOH in DCM) to afford 142 (1 .61 g, 84% yield) as white solid. 1 H NMR (300 MHz, CDCI3) 53.30 (s, 1 H), 3.92 (s, 3H), 7.52 (d, J=9.3 Hz, 1 H), 8.23 (d, J=10.5 Hz, 1 H), 9.13 (s, 1 H); 13C NMR (75 MHz, CDCI3) 5 52.79, 80.23, 82.43, 125.49, 127.20, 137.47, 146.07, 151 .24, 165.31 ; MS (ESI, positive): m/z 162 [M+H+].
77%	With potassium fluoride; In methanol; dichloromethane; at 20.0℃; for 12.0h;	To a solution of methyl 5-((trimethylsilyl)ethynyl)picolinate 51(1 g, 4.23 mmol) in a mixture of CH2Cl2/MeOH (26 mL, 50:50, v/v)was added KF (0.74 g, 12.7 mmol). The reaction mixture was stirred at room temperature overnight, and then filtered and concentrated in vacuo. The residue was purified by silica gel chromatography(petroleum ether/EtOAc, 80/20) to afford 53 (528 mg) as a brown solid in 77% yield. 1H NMR (300 MHz, CDCl3) delta 9.15 (d, J 2.0 Hz,1H), 8.86 (d, J 2.1 Hz, 1H), 8.37 (t, J 2.1 Hz, 1H), 3.97 (s, 3H), 3.27(s, 1H). 13C NMR (75 MHz, CDCl3) delta 165.1, 156.1, 150.1, 140.1, 125.7,119.4, 81.9, 79.4, 52.7. MS (ESI): m/z (%): 162 (100) [MH].

		(b) Methyl 5-ethynyl-2-pyridinecarboxylate In a manner similar to that of Example 6(b), starting with 2.25 g (9.6 mmol) of methyl 5-trimethylsilylethynyl-2-pyridinecarboxylate, 380 mg (24%) of the expected compound are obtained in the form of a yellow powder. m.p.=40-5 C. 1H NMR (CDCl3) delta3.40 (s, 1H), 4.02 (s, 3H), 7.93 (dd, 1H, J=8.1/2.0 Hz), 8.12 (d, 1H, J=8.1 Hz), 8.83 (d, 1H, J=1.9 Hz).
		(b) Methyl 5-ethynyl-2-pyridinecarboxylate In a manner similar to that of Example 6(b), starting with 2.25 g (9.6 mmol) of methyl 5-trimethylsilylethynyl-2-pyridinecarboxylate, 380 mg (24%) of the expected compound are obtained in the form of a yellow powder. m.p.=40-5 C. 1H NMR (CDCl3) delta3.40 (s, 1H), 4.02 (s, 3H), 7.93 (dd, 1H, J=8.1/2.0 Hz), 8.12 (d, 1H, J=8.1 Hz), 8.83 (d, 1H, J=1.9 Hz).
		(b) Methyl 5-ethynyl-2-pyridinecarboxylate In a manner similar to that of Example 6(b), starting with 2.25 g (9.6 mmol) of methyl 5-trimethylsilylethynyl-2-pyridinecarboxylate, 380 mg (24%) of the expected compound are obtained in the form of a yellow powder. m.p.=40-5 C. 1H NMR (CDCl3) delta 3.40 (s, 1H), 4.02 (s, 3H), 7.93 (dd, 1H, J=8.1/2.0 Hz), 8.12 (d, 1H, J=8.1 Hz), 8.83 (d, 1H, J=1.9 Hz).
	With potassium carbonate; at 20.0℃; for 1.0h;Inert atmosphere;	General procedure: To a solution of V-13 (739 mg, 3.185 mmol) in anhydrous THF (10 mL), K2CO3 (660 mg, 4.778 mmol) was added under argon. The solution was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The resulting mixture was extracted with ethyl acetate and the organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and then the filtrate was concentrated in vacuo to give 380 mg (74.6%) of V-25 as a white solid, used for the next step without further purification.

Reference： [1]Journal of Organometallic Chemistry,2011,vol. 696,p. 4039 - 4045
[2]Patent: WO2012/31298,2012,A2 .Location in patent: Page/Page column 124
[3]European Journal of Medicinal Chemistry,2019,vol. 168,p. 58 - 77
[4]Patent: US2003/100583,2003,A1
[5]Patent: US6201019,2001,B1
[6]Patent: US6818666,2004,B2
[7]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 94 - 102

2
5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalene diselenide [ No CAS ]
[ 17880-61-4 ]
[ 7681-65-4 ]
methyl 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; In tetrahydrofuran; n-heptane; N,N-dimethyl-formamide;	Example 22 Methyl 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate In a manner similar to that of Example 4(b), after reaction of 945 mg (1.68 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalene diselenide, in 5 ml THF, with bromine (0.092 ml, 1.78 mmol), copper iodide (1.32 g; 6.95 mmol) and <strong>[17880-61-4]methyl 5-ethynyl-2-pyridinecarboxylate</strong> (500 mg; 3.1 mmol) in 10 ml of DMF are added, and after trituration from heptane, 1 g (73%) of the expected derivative is obtained in the form of a yellow solid. m.p.=52 C. 1H NMR (CDCl3) 1.27 to 1.29(m,12H); 1.68(s,4H); 2.37(s,3H); 4.02(s,3H) 7.14(s,1H); 7.71(s,1H); 7.85(dd,1H) 8.02(s,1H) 8.11(d,1H). 13C NMR (CDCl3): 20.7; CH3/31.5; 2CH3/31.6; 2CH3/33.7; Cq/34.0; Cq/34.6; 2CH2/52.7; CH3/78; Cq/98.1; Cq/123.7; Cq/124.2;CH/124.5; Cq/128.4; CH/128.5; CH/134.3;Cq/138.3; CH/144.0; Cq/144.9; Cq/145.5;Cq/151.2; CH/162.2; Cq.
	With bromine; In tetrahydrofuran; n-heptane; N,N-dimethyl-formamide;	Example 22 Methyl 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate In a manner similar to that of Example 4(b), after reaction of 945 mg (1.68 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalene diselenide, in 5 ml of THF, with bromine (0.092 ml, 1.78 mmol), copper iodide (1.32 g; 6.95 mmol) and <strong>[17880-61-4]methyl 5-ethynyl-2-pyridinecarboxylate</strong> (500 mg; 3.1 mmol) in 10 ml of DMF are added, and after trituration from heptane, 1 g (73%) of the expected derivative is obtained in the form of a yellow solid. m.p.=52 C. 1H NMR (CDCl3): 1.27 to 1.29(m,12H); 1.68(s,4H); 2.37(s,3H); 4.02(s,3H); 7.14(s,1H); 7.71(s,1H); 7.85(dd,1H); 8.02(s,1H); 8.11(d,1H). 13C NMR (CDCl3): 20.7; CH3/31.5; 2CH3/31.6; 2CH3/33.7; Cq/34.0; Cq/34.6; 2*CH2/52.7; CH3/78.9; Cq/98.1; Cq/123.7; Cq/124.2; CH/124.5; Cq/128.4; CH/128.5; CH/134.3; Cq/138.3; CH/144.0; Cq/144.9; Cq/145.5; Cq/151.2; CH/162.2; Cq.
	With bromine; In tetrahydrofuran; n-heptane; N,N-dimethyl-formamide;	Example 22 Methyl 5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)-2-pyridinecarboxylate In a manner similar to that of Example 4(b), after reaction of 945 mg (1.68 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalene diselenide, in 5 ml THF, with bromine (0.092 ml, 1.78 mmol), copper iodide (1.32 g; 6.95 mmol) and <strong>[17880-61-4]methyl 5-ethynyl-2-pyridinecarboxylate</strong> (500 mg; 3.1 mmol) in 10 ml of DMF are added, and after trituration from heptane, 1 g (73%) of the expected derivative is obtained in the form of a yellow solid. m.p.=52 C. 1H NMR (CDCl3) 1.27 to 1.29(m, 12H); 1.68(s, 4H); 2.37(s, 3H); 4.02(s, 3H) 7.14(s, 1H); 7.71(s, 1H); 7.85(dd, 1H) 8.02(s, 1H) 8.11(d, 1H). -C NMR (CDCl3): 20.7; CH3/31.5; 2CH3/31.6; 2CH3/33.7; Cq/34.0; Cq/34.6; 2*CH2/52.7; CH3/78; Cq/98.1; Cq/123.7; Cq/124.2;CH/124.5; Cq/128.4; CH/128.5; CH/134.3;Cq/138.3; CH/144.0; Cq/144.9; Cq/145.5;Cq/151.2; CH/162.2; Cq.

Reference： [1]Patent: US2003/100583,2003,A1
[2]Patent: US6201019,2001,B1
[3]Patent: US6818666,2004,B2

3
[ 217966-72-8 ]
[ 17880-61-4 ]
[ 1350553-45-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triethylamine; In tetrahydrofuran; at 20.0℃; for 18.0h;Inert atmosphere;	A mixture of 4 (1.70 g, 4.16 mmol), 3 (0.670 g, 4.16 mmol), PdCl2(PPh3)2 (60 mg, 0.083 mmol), and CuI (24 mg, 0.012 mmol) in NEt3/THF (20 mL, 1:1, v/v) was stirred at room temperature under nitrogen atmosphere for 18 h. The crude reaction mixture was filtered through a pack of Celite, and the filtrate concentrated under reduced pressure. The residual brown solid was purified by flash column chromatography on SiO2 (hexanes:EtOAc = 4:1, v/v) to afford 5 as a yellow solid (1.57 g, 86%). 1H NMR (400 MHz, CDCl3, 298 K): delta 8.91 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.02 (dd, J = 8.0, 2.0 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.48 (dd, J = 8.8, 2.4 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 4.03 (s, 3H), 1.35 (s, 9H); 13C NMR (100 MHz, CDCl3, 298 K): delta 165.3, 152.2, 152.0, 147.8, 146.8, 139.7, 131.0, 128.4, 124.7, 123.2, 121.4, 116.6, 91.5, 89.2, 53.2, 35.0, 31.2. FT-IR (thin film on NaCl, cm-1): 2962, 1746, 1725, 1584, 1552, 1493, 1425, 1368, 1310, 1278, 1213, 1140, 1119, 1077, 1023, 927, 875, 638, 617. HRMS (CI) calcd for C20H19F3NO5S [M + H]+ 442.0931, found 442.0938.

Reference： [1]Journal of Organometallic Chemistry,2011,vol. 696,p. 4039 - 4045

4
[ 17880-61-4 ]
[ 1350553-48-8 ]

Reference： [1]Journal of Organometallic Chemistry,2011,vol. 696,p. 4039 - 4045

5
[ 17880-61-4 ]
[ 1350553-51-3 ]

Reference： [1]Journal of Organometallic Chemistry,2011,vol. 696,p. 4039 - 4045

6
[ 17880-61-4 ]
[ 1350553-54-6 ]

Reference： [1]Journal of Organometallic Chemistry,2011,vol. 696,p. 4039 - 4045

7
[ 17880-61-4 ]
[ 1350553-57-9 ]

Reference： [1]Journal of Organometallic Chemistry,2011,vol. 696,p. 4039 - 4045

8
[ 29682-15-3 ]
[ 17880-61-4 ]

Reference： [1]Journal of Organometallic Chemistry,2011,vol. 696,p. 4039 - 4045
[2]Patent: WO2012/31298,2012,A2
[3]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 94 - 102
[4]European Journal of Medicinal Chemistry,2019,vol. 168,p. 58 - 77

9
[ 30766-11-1 ]
[ 17880-61-4 ]

Reference： [1]Patent: WO2012/31298,2012,A2

10
[ 17880-61-4 ]
sodium 5-[4'-(4'-aminophenyl)buta-1',3'-diyn-1'-yl]pyridine-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2012/31298,2012,A2

11
[ 14235-81-5 ]
[ 17880-61-4 ]
[ 1363374-48-4 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine;copper diacetate; In methanol; at 20.0℃; for 20.0h;Inert atmosphere;	Sodium 5-[4'-(4'-aminophenyl)buta-1 ',3'-diyn-1 -yl]pyridine-2-carboxylate (144): Copper (II) acetate (1 .36 g, 7.46 mmol, 2.0 equiv) is added at room temperature under stream of argon to a stirred solution of 142 (0.60 g, 3.73 mmol) and 4- ethylnylbenzenamine (2.18 g 18.63 mmol, 5.0 equiv) dissolved in anhydrous pyridine (10 mL) and MeOH (10 mL). The reaction mixture is stirred at room temperature for 20 h. The resulting suspension is filtered, and the solid is washed with EtOAc (3^50 mL). The solid is dried under high vacuum for 12 h to afford as an orange powder, and then used for next step directly. 4N NaOH (10 mL) is added to a stirred solution of the crude methyl ester (600 mg) in MeOH (50 mL) at room temperature. Then reaction solution is heated to reflux for 40 min under argon. The reaction mixture turned clear. After all the starting material has been consumed monitored by TLC,the reaction mixture is cooled to room temperature, and the solvents are removed by evaporation under reduced pressure. The yellow solid is washed by water (3^50 mL), EtOAc (3x50 mL) to give a yellow solid (320 mg, 31 % yield, for two steps ), which is used for next step without future purification. 1 H NMR (300 MHz, CD3OD) 56.62 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.59 (d, J=9.0 Hz, 1 H), 8.27 (d, J=10.2 Hz, 1 H), 9.01 (s, 1 H); 13C NMR (75 MHz, CD3OD) 570.50, 75.996, 78.48, 85.59, 107.59, 1 14.17, 127.44, 133.09, 134.06, 137.62, 142.94, 150.69, 170.58; MS (ESI, positive): m/z 263 [M+H+].

Reference： [1]Patent: WO2012/31298,2012,A2 .Location in patent: Page/Page column 125

12
[ 17880-61-4 ]
[ 29682-15-3 ]
dimethyl 5,5’-(ethyne-1,2-diyl)dipicolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With tetrakis(triphenylphosphine) palladium(0); triethylamine; In tetrahydrofuran; at 75.0℃; for 41.0h;Schlenk technique;	methyl5-ethynylpicolinate (173.5 mg, 1.08 mmol) and methyl 5-bromopicolinate (233 mg,1.08 mmol) were introduced in a Schlenk flask containing 8 mL of dry degassed THF. Pd(PPh3)4 (38 mg, 0.033 mmol) and NEt3 (0.4 mL, 2.87 mmol) were then added and the reaction mixture was stirred for 41h. The yellow suspension was concentrated to dryness and the crude product was purified by flash column chromatography (7% MeOH in CH2Cl2)to afford 10a as a white solid (254mg, 80%).Data for 10a: Anal. Calcd for C16H12N2O4:C, 64.86; H, 4.08; N, 9.46. Found: C, 64.67; H, 4.09; N, 9.52. 1HNMR (CDCl3): delta = 8.86 (dd,4J=2.08 Hz, 5J=0.82 Hz, 2H), 8.13 (dd, 3J=8.14 Hz, 5J=0.85 Hz, 2H), 7.97 (dd, 3J=8.14 Hz, 4J=2.09 Hz, 2H), 3.99 (s, 6H) ppm. 13CNMR (CDCl3): delta = 165.48,152.65, 147.52, 140.26, 124.99, 123.25, 91.60, 53.83 ppm. ESI-TOF MS: m/z318.9 [M + Na]+. Selected IR (KBr, cm-1): 3411.3, 1716.4,1441.0, 1370.6, 1330.4, 1321.6, 1305.6, 1239.6, 1197.8, 1137.8, 1018.2, 958.8, 866.0,794.4, 698.1.

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 6120 - 6122

13
[ 17880-61-4 ]
5-(pyridin-4-ylethynyl)picolinic acid [ No CAS ]

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 6120 - 6122

14
[ 19524-06-2 ]
[ 17880-61-4 ]
methyl 5-(pyridin-4-ylethynyl)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With tetrakis(triphenylphosphine) palladium(0); triethylamine; In tetrahydrofuran; at 75.0℃; for 24.0h;Schlenk technique;	methyl5-ethynylpicolinate (173.5 mg, 1.08 mmol) and 4-bromopyridine hydrochloride (210 mg, 1.08 mmol) were introduced in a Schlenk flaskcontaining 8 mL of dry degassed THF. Pd(PPh3)4 (38 mg, 0.033 mmol) and NEt3 (0.4 mL, 2.87 mmol) were then added and the reaction mixture was stirred for 24 h. The yellow suspension was concentrated to dryness and the crude product was purified by flash column chromatography (ethyl acetate) to afford 9a as crystalline yellowish solid (254 mg, 98%). Data for 9a: Anal. Calcd for C14H10N2O2·0.45C4H8O2:C, 68.29; H, 4.93; N, 10.08. Found: C, 67.87; H, 4.44; N, 9,80. 1HNMR (CDCl3): delta = 8.86 (dd,4J=2.06 Hz, 5J=0.78 Hz, 1H), 8.64 (dd, 3J=4.45 Hz, 4J=1.61 Hz, 2H), 8.14 (dd, 3J=8.11 Hz, 5J=0.85 Hz, 1H), 7.96 (dd, 3J=8.12 Hz, 4J=2.08 Hz, 1H), 7.40 (dd, 3J=4.43 Hz, 4J=1.64 Hz, 2H), 4.01(s, 3H) ppm. 13CNMR (CDCl3): delta = 165.62, 152.77,150.68, 147.57, 140.29, 130.71, 126.12, 125.14, 123.36, 92.92, 90.02, 53.74 ppm.ESI-TOF MS: m/z 238.9 [M + H]+, 260.8 [M + Na]+. SelectedIR (KBr, cm-1): 3448.1, 1738.4, 1724.0, 1593.5, 1304.8, 1276.1,1236.2, 1218.7, 1191.9, 1154.5, 1114.1, 1020.2, 820.6, 698.3.

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 6120 - 6122

15
[ 17880-61-4 ]
C₁₃H₉NO₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 94 - 102

16
[ 17880-61-4 ]
C₁₈H₁₈N₂O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 94 - 102

17
[ 17880-61-4 ]
C₁₇H₁₇N₃O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 94 - 102

18
[ 6746-94-7 ]
[ 17880-61-4 ]
C₁₄H₁₁NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; copper diacetate; In methanol; at 20.0℃; for 48.0h;	General procedure: To a mixture of solution (16 mL, MeOH/pyridine=1/1), compound V-25 (380 mg, 2.375 mmol), ethynylcyclopropane (784 mg, 11.88 mmol), Cu(OAc)2 (712 mg, 4.750 mmol) were added. The solution was stirred at room temperature for 48 h. The solvent was removed under reduced pressure. The residue was partitioned between ethyl ether and water. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and then the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography with PE/EA (50/1-10/1) to give 162 mg (30.4%) of V-37 as a colorless oil.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 94 - 102

19
[ 17880-61-4 ]
5-ethynylpicolinohydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrazine hydrate; In methanol; at 20.0℃; for 0.75h;	General procedure: To a stirred solution of methyl ester (1.0 equiv) in MeOH (0.3 Ml) was added hydrazine monohydrate (7.0 equiv). After 45 min, the mixture was concentrated under reduced pressure without further purification.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 168,p. 58 - 77

20
[ 17880-61-4 ]
5-ethynylpicolinoyl azide [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 168,p. 58 - 77

21
[ 17880-61-4 ]
(±)-1-(5-ethynylpyridin-2-yl)-3-(6-oxo-1,2,3,4,6,10bhexahydropyrido[2,1-a]isoindol-10-yl)urea [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 168,p. 58 - 77

22
[ 17880-61-4 ]
(±)-1-(6-oxo-1,2,3,4,6,10b-hexahydropyrido[2,1-a]isoindol-10-yl)-3-(5-(1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-2-yl)urea [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 168,p. 58 - 77

23
[ 17880-61-4 ]
5-[2-[4-ethoxy-2-(quinoline-8-sulfonamido)phenyl]ethynyl]pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / tetrahydrofuran / 20 °C / Inert atmosphere 2: iron; ammonium chloride / water; methanol / 70 °C 3: pyridine; dmap / 20 °C 4: sodium hydroxide / tetrahydrofuran; water / 3 h / 20 °C
	Multi-step reaction with 4 steps 1: triethylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / tetrahydrofuran / 20 °C / Inert atmosphere 2: ammonium chloride; iron / water; methanol / 70 °C 3: pyridine; dmap / 20 °C 4: sodium hydroxide; water / tetrahydrofuran / 3 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

24
[ 17880-61-4 ]
5-[2-[5-ethoxy-2-(quinoline-8-sulfonamido)phenyl]ethynyl]pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: triethylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / tetrahydrofuran / 20 °C 2: iron; ammonium chloride / water; methanol / 5 h / 70 °C 3: dmap / 20 °C 4: sodium hydroxide / tetrahydrofuran; water / 2 h / 20 °C
	Multi-step reaction with 4 steps 1: triethylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / tetrahydrofuran / 20 °C 2: ammonium chloride; iron / water; methanol / 5 h / 70 °C 3: pyridine; dmap / 20 °C 4: sodium hydroxide; water / tetrahydrofuran / 2 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

25
[ 17880-61-4 ]
5-(2-{2-[(4-methoxy-2,3-dimethylphenyl)sulfamoyl]phenyl}ethynyl)pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; diisopropylamine / acetonitrile / 1 h / 80 °C / Inert atmosphere; Microwave irradiation 2: sodium hydroxide / methanol / 16 h / 20 °C 3: hydrogenchloride / 1,4-dioxane / 16 h / 20 °C
	Multi-step reaction with 3 steps 1: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine / acetonitrile / 1 h / 80 °C / Inert atmosphere; Microwave irradiation 2: sodium hydroxide / methanol / 16 h / 20 °C 3: hydrogenchloride / 1,4-dioxane / 16 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

26
[ 17880-61-4 ]
5-(2-{2-[methyl(phenyl)sulfamoyl]phenyl}ethynyl)pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: copper(l) iodide; ruphos; palladium diacetate / tetrahydrofuran / 16 h / 20 °C / Microwave irradiation; Inert atmosphere 2: potassium carbonate / N,N-dimethyl-formamide / 6 h / 120 °C 3: sodium hydroxide / 1,4-dioxane / 16 h / 20 °C
	Multi-step reaction with 3 steps 1: triethylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran / 16 h / 20 °C / Inert atmosphere 2: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C 3: sodium hydroxide / 1,4-dioxane / 16 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

27
[ 17880-61-4 ]
methyl 5-[2-(2-amino-4-ethoxyphenyl)ethynyl]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / tetrahydrofuran / 20 °C / Inert atmosphere 2: iron; ammonium chloride / water; methanol / 70 °C
	Multi-step reaction with 2 steps 1: triethylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / tetrahydrofuran / 20 °C / Inert atmosphere 2: ammonium chloride; iron / water; methanol / 70 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

28
[ 17880-61-4 ]
methyl 5-[2-[4-ethoxy-2-(quinoline-8-sulfonamido)phenyl]ethynyl]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / tetrahydrofuran / 20 °C / Inert atmosphere 2: iron; ammonium chloride / water; methanol / 70 °C 3: pyridine; dmap / 20 °C
	Multi-step reaction with 3 steps 1: triethylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / tetrahydrofuran / 20 °C / Inert atmosphere 2: ammonium chloride; iron / water; methanol / 70 °C 3: pyridine; dmap / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

29
[ 17880-61-4 ]
methyl 5-[2-(2-amino-5-ethoxyphenyl)ethynyl]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / tetrahydrofuran / 20 °C 2: iron; ammonium chloride / water; methanol / 5 h / 70 °C
	Multi-step reaction with 2 steps 1: triethylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / tetrahydrofuran / 20 °C 2: ammonium chloride; iron / water; methanol / 5 h / 70 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

30
[ 17880-61-4 ]
methyl 5-[2-[5-ethoxy-2-(quinoline-8-sulfonamido)phenyl]ethynyl]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine; bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / tetrahydrofuran / 20 °C 2: iron; ammonium chloride / water; methanol / 5 h / 70 °C 3: dmap / 20 °C
	Multi-step reaction with 3 steps 1: triethylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / tetrahydrofuran / 20 °C 2: ammonium chloride; iron / water; methanol / 5 h / 70 °C 3: pyridine; dmap / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

31
[ 17880-61-4 ]
5-{2-[2-([(tert-butoxy)carbonyl](4-methoxy-2,3-dimethylphenyl)amino}sulfonyl)phenyl]ethynyl}pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; diisopropylamine / acetonitrile / 1 h / 80 °C / Inert atmosphere; Microwave irradiation 2: sodium hydroxide / methanol / 16 h / 20 °C
	Multi-step reaction with 2 steps 1: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine / acetonitrile / 1 h / 80 °C / Inert atmosphere; Microwave irradiation 2: sodium hydroxide / methanol / 16 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

32
[ 17880-61-4 ]
methyl 5-(2-{2-[methyl(phenyl)sulfamoyl]phenyl}ethynyl)-pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: copper(l) iodide; ruphos; palladium diacetate / tetrahydrofuran / 16 h / 20 °C / Microwave irradiation; Inert atmosphere 2: potassium carbonate / N,N-dimethyl-formamide / 6 h / 120 °C
	Multi-step reaction with 2 steps 1: triethylamine; copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran / 16 h / 20 °C / Inert atmosphere 2: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

33
[ 139085-95-3 ]
[ 17880-61-4 ]
methyl 5-[2-(4-ethoxy-2-nitrophenyl)ethynyl]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; Inert atmosphere;	5 Into a 25-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 1 -bromo-4-ethoxy-2-nitrobenzene (500 mg, 1 .93 mmol, 1 eq, 95%), THF (8 ml_), TEA (618 mg, 5.8 mmol, 3 eq, 95%), Cul (39 mg, 0.19 mmol, 0.1 eq, 95%), Pd(PPh3)2Cl2 (143 mg, 0.18 mmol, 0.1 eq, 90%) and methyl 5-ethynylpyridine-2-carboxylate (394 mg, 2.4 mmol, 1 .24 eq, 98%). The reaction mixture was stirred overnight at room temperature and then diluted with 50 ml of F^O. The solids were filtered out and the resulting solution was extracted with 3x50 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum after filtration. The residue was applied onto a silica gel column with petrolethen/ethylacetate (3:1 ). The collected fractions were combined and concentrated under vacuum. This resulted in 80 mg (13%) of methyl 5-[2-(4-ethoxy-2-nitrophenyl)ethynyl]pyridine-2-carboxylate as a yellow solid.
13%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; Inert atmosphere;	5 Into a 25-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 1-bromo-4-ethoxy-2-nitrobenzene (500 mg, 1 .93 mmol, 1 eq, 95%), THF (8 mL), TEA (618 mg, 5.8 mmol, 3 eq, 95%), Cul (39 mg, 0.19 mmol, 0.1 eq, 95%), Pd(PPh3)2CI2 (143 mg, 0.18 mmol, 0.1 eq, 90%) and methyl 5-ethynylpyridine-2-carboxylate (394 mg, 2.4 mmol, 1 .24 eq, 98%). The reaction mixture was stirred overnight at room temperature and then diluted with 50 ml of H2O. The solids were filtered out and the resulting solution was extracted with 3x50 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum after filtration. The residue was applied onto a silica gel column with petrolether:/ethylacetate (3:1 ). The collected fractions were combined and concentrated under vacuum. This resulted in 80 mg (13%) of methyl 5-[2-(4-ethoxy-2-nitrophenyl)ethynyl]pyridine-2-carboxylate as a yellow solid.
13%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃; Inert atmosphere;	5 Into a 25-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 1-bromo-4-ethoxy-2-nitrobenzene (500 mg, 1 .93 mmol, 1 eq, 95%), THF (8 mL), TEA (618 mg, 5.8 mmol, 3 eq, 95%), Cul (39 mg, 0.19 mmol, 0.1 eq, 95%), Pd(PPh3)2CI2 (143 mg, 0.18 mmol, 0.1 eq, 90%) and methyl 5-ethynylpyridine-2-carboxylate (394 mg, 2.4 mmol, 1 .24 eq, 98%). The reaction mixture was stirred overnight at room temperature and then diluted with 50 ml of H2O. The solids were filtered out and the resulting solution was extracted with 3x50 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum after filtration. The residue was applied onto a silica gel column with petrolether:/ethylacetate (3:1 ). The collected fractions were combined and concentrated under vacuum. This resulted in 80 mg (13%) of methyl 5-[2-(4-ethoxy-2-nitrophenyl)ethynyl]pyridine-2-carboxylate as a yellow solid.

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1 Location in patent: Page/Page column 121; 123
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 129
[3]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 129

34
[ 57279-69-3 ]
[ 17880-61-4 ]
methyl 5-[2-(5-ethoxy-2-nitrophenyl)ethynyl]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃;	13a Into a 25-mL round-bottom flask, was placed 2-bromo-4-ethoxy-1 - nitrobenzene (566.6 mg, 2.24 mmol), methyl 5-ethynylpyridine-2-carboxylate (445 mg, 2.71 mmol), Pd(PPh3)2Cl2 (161 .5 mg, 0.22 mmol), Cul (43.8 mg, 0.22 mmol), TEA (6.55 mmol) and tetrahydrofuran (10 ml_). The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with 50 ml_ of H20, extracted with 3x50 ml_ of ethyl acetate and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column giving 140 mg (18%) of methyl 5-[2-(5-ethoxy-2- nitrophenyl)ethynyl]pyridine-2-carboxylate as a red solid.
18%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃;	13a Into a 25-mL round-bottom flask, was placed 2-bromo-4-ethoxy-1-nitrobenzene (566.6 mg, 2.24 mmol), methyl 5-ethynylpyridine-2-carboxylate (445 mg, 2.71 mmol), Pd(PPh3)2CI2 (161.5 mg, 0.22 mmol), Cul (43.8 mg, 0.22 mmol), TEA (6.55 mmol) and tetrahydrofuran (10 mL). The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with 50 mL of H2O, extracted with 3x50 mL of ethyl acetate and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column giving 140 mg (18%) of methyl 5-[2-(5-ethoxy-2-nitrophenyl)ethynyl]pyridine-2-carboxylate as a red solid.
18%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃;	13a Into a 25-mL round-bottom flask, was placed 2-bromo-4-ethoxy-1-nitrobenzene (566.6 mg, 2.24 mmol), methyl 5-ethynylpyridine-2-carboxylate (445 mg, 2.71 mmol), Pd(PPh3)2CI2 (161.5 mg, 0.22 mmol), Cul (43.8 mg, 0.22 mmol), TEA (6.55 mmol) and tetrahydrofuran (10 mL). The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with 50 mL of H2O, extracted with 3x50 mL of ethyl acetate and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column giving 140 mg (18%) of methyl 5-[2-(5-ethoxy-2-nitrophenyl)ethynyl]pyridine-2-carboxylate as a red solid.

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1 Location in patent: Page/Page column 141-142
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 147-148
[3]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 147-148

35
N-(2-iodophenyl)-N-(6-phenylpyridin-3-ylmethyl)formamide [ No CAS ]
[ 17880-61-4 ]
5-[2-(2-{N-[(6-phenylpyridin-3-yl)methyl]formamido}phenyl)ethynyl]pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: triethylamine / N,N-dimethyl-formamide / 0.17 h / Inert atmosphere 1.2: 85 °C / Inert atmosphere 2.1: lithium hydroxide monohydrate; water / tetrahydrofuran / 20 °C
	Multi-step reaction with 2 steps 1: triethylamine; copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / N,N-dimethyl-formamide / 85 °C / Inert atmosphere 2: lithium hydroxide monohydrate / tetrahydrofuran; water / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

36
N-(2-iodophenyl)-N-(6-phenylpyridin-3-ylmethyl)formamide [ No CAS ]
[ 17880-61-4 ]
5-{2-[formyl-(6-phenylpyridin-3-ylmethyl)-amino]-phenylethynyl}-pyridine-2-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.2%	Stage #1: N-(2-iodophenyl)-N-(6-phenylpyridin-3-ylmethyl)formamide; 5-ethynylpyridine-2-carboxylic acid methyl ester With triethylamine In N,N-dimethyl-formamide for 0.166667h; Inert atmosphere; Stage #2: With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide In N,N-dimethyl-formamide at 85℃; Inert atmosphere;	26.A Step A: A pressure vessel was charged with N-(2-iodo-phenyl)-N-(6-phenyl-pyridin-3- ylmethyl)-formamide (190.00 mg; 0.46 mmol), 5-ethynyl-pyridine-2-carboxylic acid methyl ester (147.84 mg; 0.92 mmol), triethylamine (anhydrous) (0.26 ml; 1.83 mmol) and N,N-dimethylformamide anhydrous, 99.8% (4.00 ml). The resulting mixture was purged with argon for 10 min. Then Copper(l) iodide, 98% (13.98 mg; 0.07 mmol) and Bis(triphenylphosphine)palladium(ll) dichloride (12.88 mg; 0.02 mmol) were added. The reaction mixture was heated with stirring at 85°C overnight. Conversion of starting matarial was confirmed by UPLC. The reaction mixture was cooled down, quenched with saturated aqueous solution of NH4CI and extracted to ethyl acetate. The organic layer were washed with brine and dried over Na2S04. The solvent were removed under reduced pressure and crude product was purified by FCC (SiHP column, 0-80% ethyl acetate gradient in hexane) providing 5-{2- [formyl-(6-phenyl-pyridin-3-ylmethyl)-amino]-phenylethynyl}-pyridine-2- carboxylic acid methyl ester (183.00 mg; 0.41 mmol; 89.2 %; yellow solid).
89.2%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 85℃; Inert atmosphere;	26.A Step A: A pressure vessel was charged with N-(2-iodophenyl)-N-(6-phenylpyridin-3-ylmethyl)formamide (190.00 mg; 0.46 mmol), 5-ethynylpyridine-2-carboxylic acid methyl ester (147.84 mg; 0.92 mmol), triethylamine (anhydrous) (0.26 ml; 1.83 mmol) and N,N-dimethylformamide anhydrous, 99.8% (4.00 ml). The resulting mixture was purged with argon for 10 min. Then Copper(l) iodide, 98% (13.98 mg; 0.07 mmol) and Bis(triphenylphosphine)palladium(ll) dichloride (12.88 mg; 0.02 mmol) were added. The reaction mixture was heated with stirring at 85°C overnight. Conversion of starting matarial was confirmed by UPLC. The reaction mixture was cooled down, quenched with saturated aqueous solution of NH4CI and extracted to ethyl acetate. The organic layer were washed with brine and dried over Na2SO4. The solvent were removed under reduced pressure and crude product was purified by FCC (SiHP column, 0-80% ethyl acetate gradient in hexane) providing 5-{2-[formyl-(6-phenyl-pyridin-3-ylmethyl)-amino]-phenylethynyl}-pyridine-2-carboxylic acid methyl ester (183.00 mg; 0.41 mmol; 89.2 %; yellow solid).
89.2%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 85℃; Inert atmosphere;	26.A Step A: A pressure vessel was charged with N-(2-iodophenyl)-N-(6-phenylpyridin-3-ylmethyl)formamide (190.00 mg; 0.46 mmol), 5-ethynylpyridine-2-carboxylic acid methyl ester (147.84 mg; 0.92 mmol), triethylamine (anhydrous) (0.26 ml; 1.83 mmol) and N,N-dimethylformamide anhydrous, 99.8% (4.00 ml). The resulting mixture was purged with argon for 10 min. Then Copper(l) iodide, 98% (13.98 mg; 0.07 mmol) and Bis(triphenylphosphine)palladium(ll) dichloride (12.88 mg; 0.02 mmol) were added. The reaction mixture was heated with stirring at 85°C overnight. Conversion of starting matarial was confirmed by UPLC. The reaction mixture was cooled down, quenched with saturated aqueous solution of NH4CI and extracted to ethyl acetate. The organic layer were washed with brine and dried over Na2SO4. The solvent were removed under reduced pressure and crude product was purified by FCC (SiHP column, 0-80% ethyl acetate gradient in hexane) providing 5-{2-[formyl-(6-phenyl-pyridin-3-ylmethyl)-amino]-phenylethynyl}-pyridine-2-carboxylic acid methyl ester (183.00 mg; 0.41 mmol; 89.2 %; yellow solid).

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1 Location in patent: Page/Page column 165; 167
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 173
[3]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 173

37
tert-butyl N-(2-iodobenzenesulfonyl)-N-(4-methoxy-2,3-dimethylphenyl)carbamate [ No CAS ]
[ 17880-61-4 ]
methyl 5-{2-[2-([(tert-butoxy)carbonyl](4-methoxy-2,3-dimethylphenyl)amino}sulfonyl)phenyl]ethyn-yl}pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; diisopropylamine In acetonitrile at 80℃; for 1h; Inert atmosphere; Microwave irradiation;	51 To a solution of tert-butyl N-(2-iodobenzenesulfonyl)-N-(4-methoxy-2,3-di- methylphenyl)carbamate (709 mg; 1 ,1 1 mmol) in Acetonitrile (10 ml) was added under argon in a microwave-vial Methyl 5-ethynylpyridine-2- carboxylate (281 ,8 mg; 1 ,66 mmol; 1 ,50 eq.), Diisopropylamine (0,2 ml; 1 ,66 mmol) Copper(l) iodide (21 mg; 0,1 1 mmol and Tetrakis(triphenylphosphine)- palladium(O) (128 mg; 0,1 1 mmol). The reaction was stirred for 1 hr at 80°C in the microwave. HPLC-MS showed the complete formation of the required product. The reactions were diluted with ethyl acetate and extracted 3x with water, dried with Na2S04 and evaporated to dryness. The residue was purified by flash chromatography giving the product methyl 5-{2-[2-([(tert- butoxy)carbonyl](4-methoxy-2,3-dimethylphenyl)amino}sulfonyl)phenyl]ethyn- yl}pyridine-2-carboxylate as yellow solid in 71% yield (451 mg).
71%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 1h; Inert atmosphere; Microwave irradiation;	51 To a solution of tert-butyl N-(2-iodobenzenesulfonyl)-N-(4-methoxy-2,3-di-methylphenyl)carbamate (709 mg; 1,11 mmol) in Acetonitrile (10 ml) was added under argon in a microwave-vial methyl 5-ethynylpyridine-2-carboxylate (281,8 mg; 1 ,66 mmol; 1 ,50 eq.), Diisopropylamine (0,2 ml; 1 ,66 mmol) Copper(l) iodide (21 mg; 0,11 mmol and Tetrakis(triphenylphosphine)-palladium(O) (128 mg; 0,11 mmol). The reaction was stirred for 1Hr at 80°C in the microwave. HPLC-MS showed the complete formation of the required product. The reactions were diluted with ethyl acetate and extracted 3x with water, dried with Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography giving the product methyl 5-{2-[2-([(tert-butoxy)carbonyl](4-methoxy-2,3-dimethylphenyl)amino}sulfonyl)phenyl]ethyn-yl}pyridine-2-carboxylate as yellow solid in 71% yield (451 mg).
71%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 1h; Inert atmosphere; Microwave irradiation;	51 To a solution of tert-butyl N-(2-iodobenzenesulfonyl)-N-(4-methoxy-2,3-di-methylphenyl)carbamate (709 mg; 1,11 mmol) in Acetonitrile (10 ml) was added under argon in a microwave-vial methyl 5-ethynylpyridine-2-carboxylate (281,8 mg; 1 ,66 mmol; 1 ,50 eq.), Diisopropylamine (0,2 ml; 1 ,66 mmol) Copper(l) iodide (21 mg; 0,11 mmol and Tetrakis(triphenylphosphine)-palladium(O) (128 mg; 0,11 mmol). The reaction was stirred for 1Hr at 80°C in the microwave. HPLC-MS showed the complete formation of the required product. The reactions were diluted with ethyl acetate and extracted 3x with water, dried with Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography giving the product methyl 5-{2-[2-([(tert-butoxy)carbonyl](4-methoxy-2,3-dimethylphenyl)amino}sulfonyl)phenyl]ethyn-yl}pyridine-2-carboxylate as yellow solid in 71% yield (451 mg).

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1 Location in patent: Page/Page column 208-210
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 215
[3]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 215

38
tert-butyl N-(2-iodobenzenesulfonyl)-N-(quinolin-8-yl)-carbamate [ No CAS ]
[ 17880-61-4 ]
5-(2-{2-[(quinolin-8-yl)sulfamoyl]phenyl}ethynyl)pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; diisopropylamine / 16 h / 80 °C / Inert atmosphere; Microwave irradiation 2: sodium hydroxide / methanol / 72 h / 20 °C
	Multi-step reaction with 2 steps 1: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine / 16 h / 80 °C / Inert atmosphere 2: sodium hydroxide / methanol / 72 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

39
tert-butyl N-(2-iodobenzenesulfonyl)-N-(quinolin-8-yl)-carbamate [ No CAS ]
[ 17880-61-4 ]
methyl 5-{2-[2-([(tert-butoxy)carbonyl](quinolin-8-yl)amino}sulfonyl)phenyl]ethynyl}pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; diisopropylamine at 80℃; for 16h; Inert atmosphere; Microwave irradiation;	52 To a solution of tert-butyl N-(2-iodobenzenesulfonyl)-N-(quinolin-8-yl)- carbamate (275,0 mg; 0,52 mmol) was added unter argon in a microwave- vial Methyl 5-ethynylpyridine-2-carboxylate (132,7 mg; 0,78 mmol), Copper(l) iodide for synthesis (10 mg; 0,05 mmol), Diisopropylamine (0,1 ml; 0,78 mmol) and Tetrakis(triphenylphosphine)-palladium(0) (60,3 mg; 0,05 mmol). The reaction was stirred for 16 hrs at 80°C. HPLC-MS showed a complete formation of the required product. The reactions were diluted with ethyl acetate and extracted 3x with water, dried over Na2SC>4 and evaporated to dryness. The residue was purified by flash chromatography giving as yellow solid in 55% yield (170 mg).
55%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine at 80℃; for 16h; Inert atmosphere;	52 To a solution of tert-butyl N-(2-iodobenzenesulfonyl)-N-(quinolin-8-yl)-carbamate (275,0 mg; 0,52 mmol) was added unter argon in a microwave-vial methyl 5-ethynylpyridine-2-carboxylate (132,7 mg; 0,78 mmol), Copper(l) iodide for synthesis (10 mg; 0,05 mmol), Diisopropylamine (0,1 ml; 0,78 mmol) and Tetrakis(triphenylphosphine)-palladium(0) (60,3 mg; 0,05 mmol). The reaction was stirred for 16 hrs at 80°C. HPLC-MS showed a complete formation of the required product. The reactions were diluted with ethyl acetate and extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography giving as yellow solid in 55% yield (170 mg).
55%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine at 80℃; for 16h; Inert atmosphere;	52 To a solution of tert-butyl N-(2-iodobenzenesulfonyl)-N-(quinolin-8-yl)-carbamate (275,0 mg; 0,52 mmol) was added unter argon in a microwave-vial methyl 5-ethynylpyridine-2-carboxylate (132,7 mg; 0,78 mmol), Copper(l) iodide for synthesis (10 mg; 0,05 mmol), Diisopropylamine (0,1 ml; 0,78 mmol) and Tetrakis(triphenylphosphine)-palladium(0) (60,3 mg; 0,05 mmol). The reaction was stirred for 16 hrs at 80°C. HPLC-MS showed a complete formation of the required product. The reactions were diluted with ethyl acetate and extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography giving as yellow solid in 55% yield (170 mg).

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1 Location in patent: Page/Page column 211-212
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 217
[3]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 217

40
[ 271796-62-4 ]
[ 17880-61-4 ]
methyl 5-{2-[2-(phenylsulfamoyl)phenyl]ethynyl}pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With copper(l) iodide; palladium diacetate; ruphos In tetrahydrofuran at 20℃; for 16h; Microwave irradiation; Inert atmosphere;	60 Synthesis of 5-(2-{2-[methyl(phenyl)sulfamoyl]phenyl}ethynyl)pyridine- 2-carboxylic acid To a solution of 2-iodo-N-phenylbenzene-1 -sulfonamide (1 ,5 g; 2 mmol; 2 eq.) in Tetrahydrofuran (10 ml) was added under argon in a microwave-vial Methyl 5-ethynylpyridine-2-carboxylate (528,7 mg; 3,12 mmol), Triethylamine (0,4 ml; 3,12 mmol), Copper(l) iodide (40 mg; 0,21 mmol) and Tetrakis- (triphenylphosphine)-palladium(O) (240,1 mg; 0,21 mmol). The reaction was stirred for 16 hrs at RT. HPLC-MS showed one peak with product mass. The reactions were diluted with ethyl acetate and extracted 3x with water, dried over Na2SC>4 and evaporated to dryness. The residue was purified by flash chromatography giving the product as yellow solid in 36% yield (306 mg).
36%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine In tetrahydrofuran at 20℃; for 16h; Inert atmosphere;	60 To a solution of 2-iodo-N-phenylbenzene-1-sulfonamide (1 ,5 g; 2 mmol; 2 eq.) in Tetrahydrofuran (10 ml) was added under argon in a microwave-vial methyl 5-ethynylpyridine-2-carboxylate (528,7 mg; 3,12 mmol), Triethylamine (0,4 ml; 3,12 mmol), Copper(l) iodide (40 mg; 0,21 mmol) and Tetrakis(triphenyl-phosphine)-palladium(O) (240,1 mg; 0,21 mmol). The reaction was stirred for 16 hrs at RT. HPLC-MS showed one peak with product mass. The reactions were diluted with ethyl acetate and extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography giving the product as yellow solid in 36% yield (306 mg).
36%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; triethylamine In tetrahydrofuran at 20℃; for 16h; Inert atmosphere;	60 To a solution of 2-iodo-N-phenylbenzene-1-sulfonamide (1 ,5 g; 2 mmol; 2 eq.) in Tetrahydrofuran (10 ml) was added under argon in a microwave-vial methyl 5-ethynylpyridine-2-carboxylate (528,7 mg; 3,12 mmol), Triethylamine (0,4 ml; 3,12 mmol), Copper(l) iodide (40 mg; 0,21 mmol) and Tetrakis(triphenyl-phosphine)-palladium(O) (240,1 mg; 0,21 mmol). The reaction was stirred for 16 hrs at RT. HPLC-MS showed one peak with product mass. The reactions were diluted with ethyl acetate and extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography giving the product as yellow solid in 36% yield (306 mg).

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1 Location in patent: Page/Page column 222
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 228
[3]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 228

41
tert-butyl N-(2-iodobenzenesulfonyl)-N-phenylcarbamate [ No CAS ]
[ 17880-61-4 ]
5-{2-[2-(phenylsulfamoyl)phenyl]ethynyl}pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; diisopropylamine / 16 h / 80 °C / Microwave irradiation; Inert atmosphere 2: sodium hydroxide / methanol / 16 h / 20 °C
	Multi-step reaction with 2 steps 1: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine / 16 h / 80 °C / Inert atmosphere 2: sodium hydroxide / methanol / 16 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

42
tert-butyl N-(2-iodobenzenesulfonyl)-N-phenylcarbamate [ No CAS ]
[ 17880-61-4 ]
methyl 5-{2-[2-([(tert-butoxy)carbonyl](phenyl)amino}sulfonyl)phenyl]ethynyl}pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; diisopropylamine at 80℃; for 16h; Microwave irradiation; Inert atmosphere;	59 To a solution of tert-butyl N-(2-iodobenzenesulfonyl)-N-phenylcarbamate (961 mg; 1 ,75 mmol) was added under argon in a microwave-vial Methyl 5- ethynylpyridine-2-carboxylate (445,6 mg; 2,63 mmol), Copper(l) iodide for synthesis (33 mg; 0,18 mmol; 0,10 eq.), Diisopropylamine (0,4 ml; 2,63 mmol) and Tetrakis(triphenylphosphine)-palladium(0) (202,4 mg; 0,18 mmol). The reaction was stirred for 16 hrs at 80°C. HPLC-MS showed complete formation of the required product. The reactions were diluted with ethyl acetate and extracted 3x with water, dried over Na2S04 and evaporated to dryness. The residue was purified by flash chromatography giving the product a yellow solid in 22% yield (200 mg).
22%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine at 80℃; for 16h; Inert atmosphere;	59 To a solution of tert-butyl N-(2-iodobenzenesulfonyl)-N-phenylcarbamate (961 mg; 1 ,75 mmol) was added under argon in a microwave-vial methyl 5-ethynylpyridine-2-carboxylate (445,6 mg; 2,63 mmol), Copper(l) iodide for synthesis (33 mg; 0,18 mmol; 0,10 eq.), Diisopropylamine (0,4 ml; 2,63 mmol) and Tetra-kis(triphenylphosphine)-palladium(0) (202,4 mg; 0, 18 mmol). The reaction was stirred for 16 hrs at 80°C. HPLC-MS showed complete formation of the required product. The reactions were diluted with ethyl acetate and extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography giving the product a yellow solid in 22% yield (200 mg).
22%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine at 80℃; for 16h; Inert atmosphere;	59 To a solution of tert-butyl N-(2-iodobenzenesulfonyl)-N-phenylcarbamate (961 mg; 1 ,75 mmol) was added under argon in a microwave-vial methyl 5-ethynylpyridine-2-carboxylate (445,6 mg; 2,63 mmol), Copper(l) iodide for synthesis (33 mg; 0,18 mmol; 0,10 eq.), Diisopropylamine (0,4 ml; 2,63 mmol) and Tetra-kis(triphenylphosphine)-palladium(0) (202,4 mg; 0, 18 mmol). The reaction was stirred for 16 hrs at 80°C. HPLC-MS showed complete formation of the required product. The reactions were diluted with ethyl acetate and extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography giving the product a yellow solid in 22% yield (200 mg).

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1 Location in patent: Page/Page column 220-221
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 227
[3]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 227

43
tert-butyl N-(2-iodobenzenesulfonyl)-N-(naphthalen-1-yl)carbamate [ No CAS ]
[ 17880-61-4 ]
5-(2-{2-[(naphthalen-1-yl)sulfamoyl]phenyl}ethynyl)pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; diisopropylamine / 32 h / 80 °C / Microwave irradiation; Inert atmosphere 2: hydrogenchloride / 1,4-dioxane / 32 h / 20 °C
	Multi-step reaction with 2 steps 1: copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine / 32 h / 80 °C / Inert atmosphere 2: hydrogenchloride / 1,4-dioxane / 16 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1

44
tert-butyl N-(2-iodobenzenesulfonyl)-N-(naphthalen-1-yl)carbamate [ No CAS ]
[ 17880-61-4 ]
5-{2-[2-([(tert-butoxy)carbonyl](naphthalen-1-yl)amino}sulfonyl)phenyl]ethynyl}pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine at 80℃; for 32h; Inert atmosphere;	63 To a solution of tert-butyl N-(2-iodobenzenesulfonyl)-N-(naphthalen-1-yl)carbamate (710, mg; 0,82 mmol) was added under argon in a microwave-vial methyl 5-ethynylpyridine-2-carboxylate (208,6 mg; 1,23 mmol), Copper(l) iodide for synthesis (15,6 mg; 0,08 mmol), Diisopropylamine (0,2 ml; 1,23 mmol) and Tetrakis(triphenylphosphine)-palladium(0) for synthesis (94,7 mg; 0,08 mmol). The reaction was stirred for 16 hrs at 80°C. HPLC-MS showed a not complete formation of the required product. More methyl 5-ethynylpyridine-2-carboxylate (208,6 mg; 1,23 mmol), Copper(l) iodide for synthesis (15,6 mg; 0,08 mmol), Diisopropylamine (0,2 ml; 1,23 mmol) and Tetrakis(triphenyl-phosphine)-palladium(O) for synthesis (94,7 mg; 0,08 mmol) was added and stirred for 16 hrs at 80°C. HPLC-MS showed as mainproduct, the required product without the boc-group and some product. The reaction was diluted with ethyl acetate and extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography giving the product as yellow oil in 15% yield (70 mg).
15%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine at 80℃; for 32h; Inert atmosphere;	63 To a solution of tert-butyl N-(2-iodobenzenesulfonyl)-N-(naphthalen-1-yl)carbamate (710, mg; 0,82 mmol) was added under argon in a microwave-vial methyl 5-ethynylpyridine-2-carboxylate (208,6 mg; 1,23 mmol), Copper(l) iodide for synthesis (15,6 mg; 0,08 mmol), Diisopropylamine (0,2 ml; 1,23 mmol) and Tetrakis(triphenylphosphine)-palladium(0) for synthesis (94,7 mg; 0,08 mmol). The reaction was stirred for 16 hrs at 80°C. HPLC-MS showed a not complete formation of the required product. More methyl 5-ethynylpyridine-2-carboxylate (208,6 mg; 1,23 mmol), Copper(l) iodide for synthesis (15,6 mg; 0,08 mmol), Diisopropylamine (0,2 ml; 1,23 mmol) and Tetrakis(triphenyl-phosphine)-palladium(O) for synthesis (94,7 mg; 0,08 mmol) was added and stirred for 16 hrs at 80°C. HPLC-MS showed as mainproduct, the required product without the boc-group and some product. The reaction was diluted with ethyl acetate and extracted 3x with water, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography giving the product as yellow oil in 15% yield (70 mg).
70 mg	With copper(l) iodide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; diisopropylamine at 80℃; for 32h; Microwave irradiation; Inert atmosphere;	63 To a solution of tert-butyl N-(2-iodobenzenesulfonyl)-N-(naphthalen-1 - yl)carbamate (710, mg; 0,82 mmol) was added under argon in a microwave- vial Methyl 5-ethynylpyridine-2-carboxylate (208,6 mg; 1 ,23 mmol), Copper(l) iodide for synthesis (15,6 mg; 0,08 mmol), Diisopropylamine (0,2 ml; 1 ,23 mmol) and Tetrakis(triphenylphosphine)-palladium(0) for synthesis (94,7 mg; 0,08 mmol). The reaction was stirred for 16 hrs at 80°C. HPLC-MS showed a not complete formation of the required product. More Methyl 5- ethynylpyridine-2-carboxylate (208,6 mg; 1 ,23 mmol), Copper(l) iodide for synthesis (15,6 mg; 0,08 mmol), Diisopropylamine (0,2 ml; 1 ,23 mmol) and Tetrakis(triphenylphosphine)-palladium(0) for synthesis (94,7 mg; 0,08 mmol) was added and stirred for 16 hrs at 80°C. HPLC-MS showed as mainproduct, the required product without the boc-group and some product. The reaction was diluted with ethyl acetate and extracted 3x with water, dried over Na2S04 and evaporated to dryness. The residue was purified by flash chromatography giving the product as yellow oil in 15% yield (70 mg).

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 233
[2]Current Patent Assignee: MERCK KGAA - WO2021/249969, 2021, A1 Location in patent: Page/Page column 233
[3]Current Patent Assignee: RYVU THERAPEUTICS SA; MERCK KGAA - WO2020/127960, 2020, A1 Location in patent: Page/Page column 226-227

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P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 17880-61-4 ]

Quality Control of [ 17880-61-4 ]

Related Doc. of [ 17880-61-4 ]

Product Details of [ 17880-61-4 ]

Calculated chemistry of [ 17880-61-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 17880-61-4 ]

Application In Synthesis of [ 17880-61-4 ]

[ 17880-61-4 ] Synthesis Path-Upstream 1~2

[ 17880-61-4 ] Synthesis Path-Downstream 1~44

Related Functional Groups of [ 17880-61-4 ]

Alkynyls

Esters

Related Parent Nucleus of [ 17880-61-4 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 17880-61-4 ]

Related Parent Nucleus of
[ 17880-61-4 ]