Name: 1532-24-7|Methyl 3,6-dichloropicolinate|97%
Brand: Ambeed
SKU: A708751
Price: 15.0 USD
Availability: InStock
Rating: 94 (28 reviews)

1
[ 3111-52-2 ]
[ 1532-24-7 ]
[ 85330-73-0 ]

Reference： [1]Journal of Heterocyclic Chemistry,1984,vol. 21,p. 97 - 101

2
[ 26385-24-0 ]
[ 1532-24-7 ]
[ 85330-61-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	In N,N-dimethyl-formamide at 100℃; for 2h;

Reference： [1]Woods, S. G.; Matyas, B. T.; Vinogradoff, A. P.; Tong, Y. C. [Journal of Heterocyclic Chemistry, 1984, vol. 21, # 1, p. 97 - 101]

3
[ 61671-44-1 ]
[ 1532-24-7 ]
[ 85330-76-3 ]

Yield	Reaction Conditions	Operation in experiment
44%	In N,N-dimethyl-formamide at 100℃; for 2h;

Reference： [1]Woods, S. G.; Matyas, B. T.; Vinogradoff, A. P.; Tong, Y. C. [Journal of Heterocyclic Chemistry, 1984, vol. 21, # 1, p. 97 - 101]

4
[ 1532-24-7 ]
[ 85330-63-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 82 percent / dimethylformamide / 2 h / 100 °C 2: 66 percent / decahydronaphthalene / 155 - 175 °C 3: 75 percent / 30percent hydrogen peroxide / acetic acid / 4 h / 75 °C

Reference： [1]Woods, S. G.; Matyas, B. T.; Vinogradoff, A. P.; Tong, Y. C. [Journal of Heterocyclic Chemistry, 1984, vol. 21, # 1, p. 97 - 101]

5
[ 1532-24-7 ]
[ 85330-75-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 72 percent / dimethylformamide / 2 h / 100 °C 2: decahydronaphthalene / 155 - 175 °C 3: 30percent hydrogen peroxide / acetic acid / 4 h / 75 °C

Reference： [1]Woods, S. G.; Matyas, B. T.; Vinogradoff, A. P.; Tong, Y. C. [Journal of Heterocyclic Chemistry, 1984, vol. 21, # 1, p. 97 - 101]

6
[ 1532-24-7 ]
[ 85330-78-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 44 percent / dimethylformamide / 2 h / 100 °C 2: 98 percent / decahydronaphthalene / 155 - 175 °C 3: 87 percent / 30percent hydrogen peroxide / trifluoroacetic acid / 2 h / 54 °C

Reference： [1]Woods, S. G.; Matyas, B. T.; Vinogradoff, A. P.; Tong, Y. C. [Journal of Heterocyclic Chemistry, 1984, vol. 21, # 1, p. 97 - 101]

7
[ 1702-17-6 ]
[ 1532-24-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In methanol; diethyl ether;	A. Methyl 3,6-Dichloropyridine-2-carboxylate To a 3-neck round bottom flask equipped with a reflux condenser was added <strong>[1702-17-6]3,6-dichloropyridine-2-carboxylic acid</strong> (50.0 g, 260.42 mmol) in methanol (200 mL). HCl(g) was bubbled in until solution became saturated and stirred at room temperature for 2 hr. The solution was concentrated to dryness in vacuo. Diethyl ether was added to make a slurry that was subsequently added to a flask filled with a 1:1 mixture of saturated sodium bicarbonate/diethyl ether and stirred for 10 min. The aqueous phase was extracted with diethyl ether (3*300 mL). The combined extracts were dried (MgSO4) and concentrated to give 46.6 g of a light yellow solid. 1H NMR(CDCl3): delta 4.00 (s, 3H); 7.41 (d, 1H); 7.80 (d, 1H).

Reference： [1]Patent: US6297197,2001,B1

8
[ 1532-24-7 ]
methyl 6-chloro-3-methoxypicolinate [ No CAS ]
3-chloro-6-methoxy-pyridine-2-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate In methanol; hexane; dichloromethane; ethyl acetate; acetonitrile	60 60. 60. Preparation of Methyl 6-Chloro-3-methoxypicolinate and Methyl 3-Chloro-6-methoxypicolinate Sodium methoxide in methanol (100 mL of 25 percent, 22.8 g, 0.42 mol) was added to a solution of methyl 3,6-dichloropicolinate (44.0 g, 0.21 mol) in acetonitrile (400 mL) and the resulting solution was stirred at room temperature for 3.5 hours. The reaction mixture was acidified with acetic acid and the solvent was removed by evaporation. The residue obtained was mixed with dichloromethane and washed sequentially with water, dilute aqueous sodium hydroxide, and dilute aqueous hydrochloric acid. The organic solvent was removed by evaporation and the residue obtained was purified by column chromatography on silica gel, eluding with 20 percent ethyl acetate in hexane until the methyl 3-chloro-6-methoxypicolinate desorbed and then with 25 percent ethyl acetate in hexane until the methyl 6-chloro-3-methoxypicolinate desorbed. Methyl 3-chloro-6-methoxypicolinate (23.4 g) was recovered as a white powder melting at 38°-39° C. and the methyl 6-chloro-3-methoxypicolinate (8.5 g) was recovered as a white powder melting at 81°-82° C.

Reference： [1]Current Patent Assignee: CORTEVA INC - US5571775, 1996, A

9
[ 1532-24-7 ]
[ 100-53-8 ]
[ 85330-76-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium <i>tert</i>-butylate In water; N,N-dimethyl-formamide	11 3,6-bis((phenylmethyl)thio)-2-pyridinecarboxylic acid EXAMPLE 11 3,6-bis((phenylmethyl)thio)-2-pyridinecarboxylic acid In 400 ml of DMF was dissolved 198 g of t-BuOK. While the temperature was kept at 70°-90° C. with cooling, 218.6 g of benzylmercaptan was added. To this mixture was added 100 g of methyl 3,6-dichloro-2-pyridinecarboxylate in 100 ml of DMF without cooling. The temperature rose to 105° C. and the temperature was maintained at 105° C. for 1 hr. The solvent was removed under reduced pressure and the residual solid obtained washed with diethyl ether. The solid was dissolved in water and allowed to stand overnight. Two layers were observed. The upper layer was acidified with concentrated HCl to a pH of about 1-2 resulting in the formation of a solid which was collected by filtration. NMR spectroscopy indicated a mono-substituted compound. The lower layer was acidified, which gave 86 g (48% yield) of a solid. The solid obtained from the lower layer was recrystallized from 2-propanol to give the product, 3,6-bis((phenylmethyl)thio)-2-pyridinecarboxylic acid, m.p. 129° C.
	With potassium <i>tert</i>-butylate In water; N,N-dimethyl-formamide	16 3,6-bis((phenylmethyl)thio)-2-pyridinecarboxylic acid EXAMPLE 16 3,6-bis((phenylmethyl)thio)-2-pyridinecarboxylic acid In 400 ml of DMF was dissolved 198 g of t-BuOK. While the temperature was kept at 70°-90° C. with cooling, 218.6 g of benzylmercaptan was added. To this mixture was added 100 g of methyl 3,6-dichloro-pyridine-2-carboxylate in 100 ml of DMF without cooling. The temperature rose to 105° C. and the temperature was maintained at 105° C. for 1 hr. The solvent was removed under reduced pressure and the residual solid obtained washed with diethyl ether. The solid was dissolved in water and allowed to stand overnight. Two layers were observed. The upper layer was acidified with concentrated HCl to a pH of about 1-2 resulting in the formation of a solid which was collected by filtration. NMR spectroscopy indicated a mno-substituted compound. The lower layer was acidified, which gave 86 g (48% yield) of a solid. The solid obtained from the lower layer was recrystallized from 2-propanol to give the product, 3,6-bis((phenylmethyl)thio)-2-pyridinecarboxylic acid, m.p. 129° C.

Reference： [1]Current Patent Assignee: DOW INC - US4616087, 1986, A
[2]Current Patent Assignee: DOW INC - US4371537, 1983, A

10
[ 1532-24-7 ]
[ 75-33-2 ]
[ 85330-65-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium <i>tert</i>-butylate In water; N,N-dimethyl-formamide	5 2,5-bis((1-methylethyl)thio)pyridine EXAMPLE 5 2,5-bis((1-methylethyl)thio)pyridine To 198 g of t-BuOK dissolved in 300 ml of DMF was added 2-propanethiol (163.47 ml) dropwise with an ice bath employed to keep the temperature below 50° C. As salt began to precipitate out an additional 50 ml of DMF was added. After addition was complete, the ice bath was removed and the mixture heated to 50° C. A solution of 100 g of methyl 3,6-dichloro-2-pyridinecarboxylate dissolved in DMF was added and the temperature during addition rose to 115° C. The temperature was then maintained at approximately 105°-110° C. until addition was completed and then the resulting mixture was heated at 100°-110° C. for 11/2 hrs. The reaction mixture was allowed to cool and the solvent removed in a rotary evaporator. The brown residue which remained was washed with ether and then dissolved in water. The solution was acidified with HCl, and the product, which oiled out, extracted with CH2 Cl2. The CH2 Cl2 was then removed using a rotary evaporator. Infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR) indicated that 3,6-bis((1-methylethyl)thio)-2-pyridinecarboxylic acid had formed. The 3,6-bis((1-methylethyl)thio)-2-pyridinecarboxylic acid was decarboxylated employing a Kugelrohr distillation apparatus, and 2,5-bis((1-methylethyl)thio)pyridine obtained, b.p. 310° C. (760 mm Hg).
	With potassium <i>tert</i>-butylate In water; N,N-dimethyl-formamide	5 2,5-bis((1-methylethyl)thio)pyridine EXAMPLE 5 2,5-bis((1-methylethyl)thio)pyridine To 198 g of t-BuOK dissolved in 300 ml of DMF was added 2-propanethiol (163.47 ml) dropwise with an ice bath employed to keep the temperature below 50° C. As salt began to precipitate out an additional 50 ml of DMF was added. After addition was complete, the ice bath was removed and the mixture heated to 50° C. A solution of 100 g of methyl 3,6-dichloro-pyridine-2-carboxylate dissolved in DMF was added and the temperature during addition rose to 115° C. The temperature was then maintained at approximately 105°-110° C. until addition was completed and then the resulting mixture was heated at 100°-110° C. for 11/2 hrs. The reaction mixture was allowed to cool and the solvent removed in a rotary evaporator. The brown residue which remained was washed with ether and then dissolved in water. The solution was acidified with HCl, and the product, which oiled out, extracted with CH2 Cl2. The CH2 Cl2 was then removed using a rotary evaporator. Infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR) indicated that 3,6-bis((1-methylethyl)thio)-2-pyridinecarboxylic acid had formed. The 3,6-bis((1-methylethyl)thio)-2-pyridinecarboxylic acid was decarboxylated employing a Kugelrohr distillation apparatus, and 2,5-bis((1-methylethyl)thio)pyridine obtained, b.p. 310° C. (760 mm Hg).

Reference： [1]Current Patent Assignee: DOW INC - US4616087, 1986, A
[2]Current Patent Assignee: DOW INC - US4371537, 1983, A

11
[ 1532-24-7 ]
[ 108-98-5 ]
[ 85330-73-0 ]

Yield	Reaction Conditions	Operation in experiment
	In potassium <i>tert</i>-butylate; water; N,N-dimethyl-formamide	10 3,6-bis(phenylthio)-2-pyridinecarboxylic acid EXAMPLE 10 3,6-bis(phenylthio)-2-pyridinecarboxylic acid In a reaction flask 50 g of methyl 3,6-dichloro-2-pyridinecarboxylate and 100 ml of DMF were placed. In a beaker were placed 90 g of t-BuOK and 200 ml of DMF, followed by 88.3 g of thiophenol. The slurry which formed was added portionwise to the reaction flask resulting in a temperature rise. The resulting reaction mixture was heated at 110° C. for 3 hrs. The solvent was removed from the reaction mixture under reduced pressure and the residual solid was dissolved in water and washed with diethyl ether. The aqueous layer was acidified and 58 g of crude product obtained. A portion of the crude product was recrystallized from methanol and the recrystallized 3,6-bis(phenylthio)-2-pyridinecarboxylic acid found to have a melting point of 131°-132° C.

Reference： [1]Current Patent Assignee: DOW INC - US4616087, 1986, A

12
Methanethiol (CH₃ SH) [ No CAS ]
[ 1532-24-7 ]
[ 85330-61-6 ]

Yield	Reaction Conditions	Operation in experiment
	In carbon dioxide; water; N,N-dimethyl-formamide	1 3,6-bis(methylthio)-2-pyridinecarboxylic acid EXAMPLE 1 3,6-bis(methylthio)-2-pyridinecarboxylic acid Methanethiol (CH3 SH), (30.26 g) was dissolved in 200 milliliters (ml) of DMF that had been chilled in Dry Ice to below 0° C. To this solution was added 70.6 grams (g) of potassium t-butoxide (t-BuOK) while the temperature was maintained below 10° C. The resulting white slurry was added to a mixture of 39.35 g of methyl 3,6-dichloro-2-pyridinecarboxylate in 100 ml of DMF. The reaction was heated to 80° C. during the addition and after the addition was complete the temperature was raised to 100° C. and maintained there for 2 hours (hrs). Upon cooling the resulting paste was diluted with ether and filtered. The salts which were obtained were taken up in water, washed with CH2 Cl2, and the aqueous phase made acidic with concentrated HCl to pH 3. The resulting solid was filtered and dried on a porous plate which gave 37 g (82% yield) of the crude product as a bright yellow solid. A portion of the crude product was recrystallized from ethanol, which gave purified 3,6-bis(methylthio)-2-pyridinecarboxylic acid as bright yellow plates, which was found to have a melting point (m.p.) of 142°-144° C.

Reference： [1]Current Patent Assignee: DOW INC - US4616087, 1986, A

13
[ 74-93-1 ]
[ 1532-24-7 ]
[ 85330-61-6 ]

Yield	Reaction Conditions	Operation in experiment
	In carbon dioxide; water; N,N-dimethyl-formamide	1 3,6-bis(methylthio)-2-pyridinecarboxylic acid EXAMPLE 1 3,6-bis(methylthio)-2-pyridinecarboxylic acid Methanethiol, (30.26 g) was dissolved in 200 milliliters (ml) of DMF that had been chilled in Dry Ice to below 0° C. To this solution was added 70.6 grams (g) of potassium t-butoxide (t-BuOK) while the temperature was maintained below 10° C. The resulting white slurry was added to a mixture of 39.35 g of methyl 3,6-dichloro-2-pyridinecarboxylate in 100 ml of DMF. The reaction was heated to 80° C. during the addition and after the addition was complete the temperature was raised to 100° C. and maintained there for 2 hours (hrs). Upon cooling the resulting paste was diluted with ether and filtered. The salts which were obtained were taken up in water, washed with CH2 Cl2, and the aqueous phase made acidic with concentrated HCl to pH 3. The resulting solid was filtered and dried on a porous plate which gave 37 g (82% yield) of the crude product as a bright yellow solid. A portion of the crude product was recrystallized from ethanol, which gave purified 3,6-bis(methylthio)-2-pyridinecarboxylic acid as bright yellow plates, which was found to have a melting point (m.p.) of 142°-144° C.

Reference： [1]Current Patent Assignee: DOW INC - US4371537, 1983, A

14
[ 1532-24-7 ]
[ 1245735-42-5 ]

Yield	Reaction Conditions	Operation in experiment
35%	With acetyl chloride; sodium iodide In acetonitrile for 8h; Heating; Reflux;
	With chloro-trimethyl-silane; sodium iodide In acetonitrile at 80℃; for 2h; Inert atmosphere;	Step 2: Into a 10-L 4-necked round-bottom flask, purged and maintained with an inert10 atmosphere of nitrogen, was placed acetonitrile (6000 mL), chlorotrimethylsilane (227.5 g, 2.09mol), sodium iodide (790 g, 5.26 mol) and methyl 3,6-dichloropyridine-2-carboxylate (360 g,1.75 mol). After stirring for 2 hat 80 °C, the reaction mixture was poured into water. Theresulting solution was extracted with ethyl acetate and the organic layers were combined, driedover anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in methyl15 3-chloro-6-iodopyridine-2-carboxylate as a white solid.

Reference： [1]Current Patent Assignee: OREXO AB - WO2010/103278, 2010, A1 Location in patent: Page/Page column 116
[2]Current Patent Assignee: MERCK & CO INC - WO2014/99836, 2014, A1 Location in patent: Page/Page column 32; 33

15
[ 1532-24-7 ]
[ 58804-10-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methyl 3,6-dichloro-2-pyridinecarboxylate With sodium tetrahydroborate In methanol at 0℃; for 1h; Inert atmosphere; Stage #2: With water In methanol	12.A.1 To a solution of the commercially available ester (2.1 g, 10 mmol) in MeOH (50 mL) at 0° C. was added NaBH4 (570 mg, 0.15 mmol) portionwise over 30 minutes. The reaction was stirred an additional 30 minutes and quenched by the addition of water. The reaction was diluted with EtOAc (100 mL), and the organics were washed with NaHCO3 and Brine. The organic layer was dried over MgSO4, filtered and concentrated to provide the alcohol as a yellow oil.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2011/21521, 2011, A1 Location in patent: Page/Page column 51

16
[ 1532-24-7 ]
[ 350602-02-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: trifluoroacetic acid; dihydrogen peroxide / water / 20 h / 60 °C 2: trichlorophosphate / 4 h / 100 °C

Reference： [1]Current Patent Assignee: EISAI CO LTD; EPIZYME, INC. - WO2012/142513, 2012, A1

17
[ 1532-24-7 ]
3,6-dichloro-2-(methoxycarbonyl)pyridin-1-ium-1-olate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dihydrogen peroxide; trifluoroacetic acid In water at 60℃; for 20h;	44.1 [01454] Step 1 : Synthesis of methyl 3,4,6-trichloropyridine-2-carboxylate [01455] To a stirred solution of methyl 3,6-dichloropyridine-2-carboxylate (0.96 g, 4.66 mmol) in TFA (5ml) was added hydrogen peroxide (30% w/w aqueous solution, 435μ1, 2.5 mmol) and the reaction mixture was heated at 60°C for 20h. The reaction mixture was then cooled and slowly poured onto saturated K2C03 solution (100ml), followed by extraction of the aqueous layer with EtOAc (2x200ml), washing of the combined organic phases with brine (2x50ml), drying (Na2S04) and evaporation. The desired 3,6-dichloro-2- (methoxycarbonyl)pyridin- l -ium- l -olate was used crude in the next stage of the synthesis without any further purification. To the crude 3,6-dichloro-2-(methoxycarbonyl)pyridin- l -ium- 1 -olate (-70% purity, 2.40 g, 7.7 mmol) was added POCl3 (3.5 ml, 38 mmol) and the solution was heated to 1 00°C for 4h. After cooling the POCI3 was removed in vacuo to give a white solid which was chromatographed over silica gel eluting with 0% to 10% of EtOAc in heptane to afford the title compound as colourless needles (340 mg, 30% over two steps). LC-MS 100%, 2.20 min (3.5 minute LC-MS method), m/z= 239.8/241 .7, NMR (500 MHz, Chloroform-d) δ 7.51 ( 1 H, s), 3.92(3H, s).

Reference： [1]Current Patent Assignee: EISAI CO LTD; EPIZYME, INC. - WO2012/142513, 2012, A1 Location in patent: Page/Page column 364-365

18
[ 1532-24-7 ]
[ 1403591-03-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: trifluoroacetic acid; dihydrogen peroxide / water / 20 h / 60 °C 2.1: trichlorophosphate / 4 h / 100 °C 3.1: triethylamine / N,N-dimethyl-formamide / 4 h / 100 °C 4.1: sodium hydroxide; water / tetrahydrofuran / 16 h / 20 °C 4.2: pH 5 - 6 5.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 20 °C 6.1: hydrogenchloride / 1,4-dioxane / 16 h / 20 °C

Reference： [1]Current Patent Assignee: EISAI CO LTD; EPIZYME, INC. - WO2012/142513, 2012, A1

19
[ 1532-24-7 ]
[ 1403596-06-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trifluoroacetic acid; dihydrogen peroxide / water / 20 h / 60 °C 2: trichlorophosphate / 4 h / 100 °C 3: triethylamine / N,N-dimethyl-formamide / 4 h / 100 °C

Reference： [1]Current Patent Assignee: EISAI CO LTD; EPIZYME, INC. - WO2012/142513, 2012, A1

20
[ 1532-24-7 ]
[ 1403596-07-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: trifluoroacetic acid; dihydrogen peroxide / water / 20 h / 60 °C 2.1: trichlorophosphate / 4 h / 100 °C 3.1: triethylamine / N,N-dimethyl-formamide / 4 h / 100 °C 4.1: sodium hydroxide; water / tetrahydrofuran / 16 h / 20 °C 4.2: pH 5 - 6

Reference： [1]Current Patent Assignee: EISAI CO LTD; EPIZYME, INC. - WO2012/142513, 2012, A1

21
[ 1532-24-7 ]
[ 1403596-08-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: trifluoroacetic acid; dihydrogen peroxide / water / 20 h / 60 °C 2.1: trichlorophosphate / 4 h / 100 °C 3.1: triethylamine / N,N-dimethyl-formamide / 4 h / 100 °C 4.1: sodium hydroxide; water / tetrahydrofuran / 16 h / 20 °C 4.2: pH 5 - 6 5.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 20 °C

Reference： [1]Current Patent Assignee: EISAI CO LTD; EPIZYME, INC. - WO2012/142513, 2012, A1

22
[ 1532-24-7 ]
[ 1403591-04-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: trifluoroacetic acid; dihydrogen peroxide / water / 20 h / 60 °C 2.1: trichlorophosphate / 4 h / 100 °C 3.1: triethylamine / N,N-dimethyl-formamide / 20 h / 100 °C 4.1: sodium hydroxide; water / tetrahydrofuran / 20 h / 20 °C 4.2: pH 5 - 6 5.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0.08 h / 20 °C 5.2: 16 h / 20 °C

Reference： [1]Current Patent Assignee: EISAI CO LTD; EPIZYME, INC. - WO2012/142513, 2012, A1

23
[ 1532-24-7 ]
[ 1403596-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trifluoroacetic acid; dihydrogen peroxide / water / 20 h / 60 °C 2: trichlorophosphate / 4 h / 100 °C 3: triethylamine / N,N-dimethyl-formamide / 20 h / 100 °C

Reference： [1]Current Patent Assignee: EISAI CO LTD; EPIZYME, INC. - WO2012/142513, 2012, A1

24
[ 1532-24-7 ]
[ 1403596-10-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: trifluoroacetic acid; dihydrogen peroxide / water / 20 h / 60 °C 2.1: trichlorophosphate / 4 h / 100 °C 3.1: triethylamine / N,N-dimethyl-formamide / 20 h / 100 °C 4.1: sodium hydroxide; water / tetrahydrofuran / 20 h / 20 °C 4.2: pH 5 - 6

Reference： [1]Current Patent Assignee: EISAI CO LTD; EPIZYME, INC. - WO2012/142513, 2012, A1

25
[ 67-56-1 ]
[ 1702-17-6 ]
[ 1532-24-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at 80℃; for 4h;	Step 1: Into a 20-L 4-necked round-bottom flask was placed <strong>[1702-17-6]3,6-dichloropyridine-2-carboxylic acid</strong> (1 000 g, 5.21 mol) and methanol (1 0000 mL). This was followed by thedropwise addition of sulfuric acid (1 00 mL) with stirring. The resulting solution was stirred for 4h at 80 C. The reaction mixture was cooled with a water/ice bath to room temperature and was5 then concentrated under reduced pressure. The residue was quenched by the addition of water(3000 mL). The resulting solution was extracted with ethyl acetate (2 x 4000 mL) and the organiclayers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum.This resulted in methyl 3,6-dichloropyridine-2-carboxylate as a white solid.
	With thionyl chloride; at 20℃; for 3h;	To a solution of <strong>[1702-17-6]3,6-dichloropyridine-2-carboxylic acid</strong> (76.8 g, 0.4 mol) in methanol (500 mL) was added 50C12 (150 ml) dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After this time, the reaction mixture was poured into water and extracted withethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound.-84-1HNMR (400 MHz, DMSO-d6): oeppm 3.90 (s, 3 H), 7.80 (d, J=8.8 Hz,1 H), 8.20 (d, J=8.8 Hz,1 H); ESI-MS(+): 228 (M + Na)+
	With sulfuric acid; at 65℃;	Step A: methyl 3 , 6-d ich loropyrid ine-2-carboxylate To a suspension of <strong>[1702-17-6]3,6-dichloropyridine-2-carboxylic acid</strong> (22.3 g, 1 16 mmol) (commercial product) in methanol (223 mL) was added sulfuric acid (12.0 g, 6.55 mL, 1 16 mmol) at ambient temperature. The resulting mixture was stirred four hours at 65C. The reaction mixture was concentrated under reduce pressure. The crude was dissolved in dichloromethane and with a saturated solution of sodium hydrogen carbonate solution. Then washed with sodium chloride and the organic layer were dried over magnesium sulfate and concentrated under vacuum. Methyl 3,6-dichloropyridine-2-carboxylate was obtained as a white crystal was obtained. H NMR (400 MHz, CDCI3) delta ppm 4.00 (s, 3 H), 7.42 (d, 1 H), 7.76 (d, 1 H).

With thionyl chloride; at 20℃; for 3h;

To a solution of <strong>[1702-17-6]3,6-dichloropyridine-2-carboxylic acid</strong> (76.8 g, 0.4 mol) in methanol (500 mL) was added SOCI2 (150 ml) dropwise at ambient temperature. The reaction mixture was stirred at ambient temperature for 3 hours. After this time, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound. ESI-MS(+): 228 (M + Na)+. 1H NMR (400 MHz, DMSO-d6): 5ppm 3.90 (s, 3 H), 7.80 (d, J=8.8 Hz,1 H), 8.20 (d, J=8.8 Hz,1 H).

Reference： [1]Patent: WO2014/99836,2014,A1 .Location in patent: Page/Page column 32; 33
[2]Patent: WO2016/116338,2016,A1 .Location in patent: Page/Page column 83
[3]Patent: WO2017/84879,2017,A1 .Location in patent: Page/Page column 80
[4]Patent: WO2018/95795,2018,A1 .Location in patent: Page/Page column 48-49

26
[ 1532-24-7 ]
[ 1214324-33-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: chloro-trimethyl-silane; sodium iodide / acetonitrile / 2 h / 80 °C / Inert atmosphere 2: potassium fluoride; copper(l) iodide / 1-methyl-pyrrolidin-2-one / 16 h / 50 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/99836, 2014, A1

27
[ 1532-24-7 ]
[ 1227584-33-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: chloro-trimethyl-silane; sodium iodide / acetonitrile / 2 h / 80 °C / Inert atmosphere 2: potassium fluoride; copper(l) iodide / 1-methyl-pyrrolidin-2-one / 16 h / 50 °C / Inert atmosphere 3: diisobutylaluminium hydride / dichloromethane; toluene / 1 h / -30 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/99836, 2014, A1

28
1,3-propanediyl 4-chloro-2-fluoro-3-methoxyphenylboronate [ No CAS ]
[ 1532-24-7 ]
methyl 3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With palladium diacetate; cesium fluoride; 1,4-di(diphenylphosphino)-butane In acetonitrile for 2h; Reflux;	16 Methyl 3-chloro-6-(4-chloro-2-fluoro-3-methoxy-phenyl)picolinate (33) Compound 32 (1.0 g, 4.85 mmol, see US20120100990 for preparation), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (1.424 g, 5.82 mmol), cesium fluoride (0.737 g, 4.85 mmol), 1,4-bis(diphenylphosphino) butane (0.207 g, 0.485 mmol), and palladium(II) acetate (0.109 g, 0.485 mmol) were combined in acetonitrile (48.5 mL) and heated at reflux for 2 h. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried, filtered, and concentrated. The product was purified by flash chromatography (ethyl acetate/hexanes gradient) to provide compound 33 (400 mg, 25% yield) as a white solid: mp 112-114°C; 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 8.6 Hz, 1H), 8.00 (dd, J = 8.6, 2.1 Hz, 1H), 7.63 (m, 1H), 7.49 (dd, J = 8.7, 1.6 Hz, 1H), 3.95 (s, 6H);19F NMR (376 MHz, DMSO) δ -131.51; ESIMS m/z 330 [(M+H)+].

Reference： [1]Epp, Jeffrey B.; Alexander, Anita L.; Balko, Terry W.; Buysse, Ann M.; Brewster, William K.; Bryan, Kristy; Daeuble, John F.; Fields, Stephen C.; Gast, Roger E.; Green, Renard A.; Irvine, Nicholas M.; Lo, William C.; Lowe, Christian T.; Renga, James M.; Richburg, John S.; Ruiz, James M.; Satchivi, Norbert M.; Schmitzer, Paul R.; Siddall, Thomas L.; Webster, Jeffery D.; Weimer, Monte R.; Whiteker, Gregory T.; Yerkes, Carla N. [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 3, p. 362 - 371]

29
[ 1532-24-7 ]
[ 811-51-8 ]
methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14.5 g	With 18-crown-6 ether In tetrahydrofuran at 20℃; for 1h;	P6.1 Step 1: Preparation of methyl 6-chloro-3-ethylsu Ifanyl-pyrid i ne-2-carboxylate 3,6-Dichloro-2-pyridinecarboxylic acid methyl ester (commercially available, 20.0 g, 97.073 mmol) wasdissolved in tetrahydrofuran (200 ml) and 18-crown-6-ether (some crystals) was added. Sodium ethanethiolate (9.073 g, 97.073 mmol) was then added in 3 portions at room temperature and the reaction was stirred for 1 hour at room temperature. The reaction mixture was poured on an aqueous saturated ammonium chloride solution (100 ml) and extracted twice with ethyl acetate (2xlOOml). The combined organic layers were washed with an aqueous saturated ammonium chloride solution (2x 50ml) and water (3x 100 ml), dried over sodium sulfate, filtered and evaporated under vacuum. The crude was purified by combi flash chromatography (220 g column; gradient cyclohexane + 0-10% ethyl acetate) to give the title compound (14.5 g) as a solid, mp 122-124°C. LCMS (method 1): 232/234 (M+H), retention time 0.94 mi 1H NMR (400 MHz, CDCI3) ö ppm: 1.42 (t, 3H), 2.96 (q, 2H), 4.02 (s, 3H), 7.45 (d, 1H), 7.70 (d, 1H).
14.5 g	With 18-crown-6 ether In tetrahydrofuran at 20℃; for 1h;	P7.1 Step 1: Preparation of methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate Step 1: Preparation of methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate 3,6-Dichloro-2-pyridinecarboxylic acid methyl ester (commercially available, 20.0 g, 97.073 mmol) was dissolved in tetrahydrofuran (200 ml) and 18-crown-6-ether (some crystals) was added. Sodium ethanethiolate (9.073 g, 97.073 mmol) was then added in 3 portions at room temperature and the reaction was stirred for 1 hour at room temperature. The reaction mixture was poured on an aqueous saturated ammonium chloride solution (100 ml) and extracted twice with ethyl acetate (2x100ml). The combined organic layers were washed with an aqueous saturated ammonium chloride solution (2x 50 ml) and water (3x 100 ml), dried over sodium sulfate, filtered and evaporated under vacuum. The crude was purified by combi flash chromatography (220 g column; gradient cyclohexane + 0-10% ethyl acetate) to give the title compound (14.5 g) as a solid, mp 122-124°C. LCMS (method 1): 232/234 (M+H)+ , retention time 0.94 min.1H NMR (400 MHz, CDCl3) ^ ppm: 1.42 (t, 3H), 2.96 (q, 2H), 4.02 (s, 3H), 7.45 (d, 1H), 7.70 (d, 1H).
	In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h;	2.D Step D: Methyl 6-chloro-3-ethylsu Ifanyl-pyrid j ne-2-carboxylate To a solution of methyl 3,6-dichloropyridine-2-carboxylate (16 g, 77.6 mmcl) in DMF (150 mL) wasadded sodium ethanethiolate (7.2 g, 85.8 mmol) at 0 °C. After the addition, the reaction mixture wasstirred at room temperature for 30 mi LCMS analysis after this time showed reaction completion. Thereaction mixture was poured into water, and precipitate formed filtered and dried under an infraredoven to afford the title compound as white solid.1HNMR (400 MHz, CDCI3): öppm 1.38 (t, 3 H), 2.92 (q, 2 H), 3.98 (s, 3H), 7.40 (d, J=8.8 Hz,1 H),7.66 (d, J=8.8 Hz,1 H); ESl-MS(+): 254 (M + Na)+.

14.5 g	With 18-crown-6 ether In tetrahydrofuran at 20℃; for 1h;	A Step A: methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate: Step A: methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate: 3,6-Dichloro-2-pyridinecarboxylic acid methyl ester (commercially available, 20 g, 97.073 mmol) was solved in tetrahydrofuran (200 imL) and 18-CROWN-6-ETHER (some crystals) was added. Sodium ethanethiolate (9.073 g, 97.073 mmol) was added in 3 portions at room temperature and reaction was stirred for 1 h at room temperature. The reaction mixture was poured on 100 ml saturated ammonium chloride aqueous solution, extracted with 2x 100ml ethyl acetate. The combined organic layers was washed with 2x 50 ml saturated ammonium chloride aqueous solution, 3x 100 ml water, dried over NaS04, filtered and evaporated under vacuum. The crude was purified by combi flash chromatography with a column of 220 g and a gradient cyclohexane + 0-10% ethyl acetate to give the title compound (14.5g). Other products were obtained are substitution of the two chlorines and the mono substitution of the in position 6. H NMR (400 MHz, CDCI3) δ ppm 1 .42 (t, 3H), 2.96 (q, 2H), 4.02 (s,3H), 7.45 (d, 1 H), 7.70 (d, 1 H)
14.5 g	With 18-crown-6 ether In tetrahydrofuran at 20℃; for 1h;	P9.A-1 Step A-1 : Preparation of methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate 3,6-Dichloro-2-pyridinecarboxylic acid methyl ester (commercially available, 20.0 g, 97.073 mmol) was dissolved in tetrahydrofuran (200 ml) and 18-crown-6-ether (some crystals) was added. Sodium ethanethiolate (9.073 g, 97.073 mmol) was then added in 3 portions at room temperature and the reaction was stirred for 1 hour at room temperature. The reaction mixture was poured on an aqueous saturated ammonium chloride solution (100 ml) and extracted twice with ethyl acetate (2x100ml). The combined organic layers were washed with an aqueous saturated ammonium chloride solution (2x 50 ml) and water (3x 100 ml), dried over sodium sulfate, filtered and evaporated under vacuum. The crude was purified by combi flash chromatography (220 g column; gradient cyclohexane + 0-10% ethyl acetate) to give the title compound (14.5g) as a solid, mp 122-124°C. LCMS (method 1 ): 232/234 (M+H)+, retention time 0.94 min. H NMR (400 MHz, CDCI3) δ ppm: 1.42 (t, 3H), 2.96 (q, 2H), 4.02 (s, 3H), 7.45 (d, 1 H), 7.70 (d, 1 H).
	In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h;	H4.2 Step 2: Preparation of methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate To a solution of methyl 3,6-dichloropyridine-2-carboxylate (16 g, 77.6 mmol) in DMF (150 mL) was added sodium ethanethiolate (7.2 g, 85.8 mmol) at 0 °C. After the addition, the reaction mixture was stirred at ambient temperature for 30 min. LCMS analysis after this time showed reaction completion. The reaction mixture was poured into water, and precipitate formed filtered and dried under an infrared oven to afford the title compound as white solid.ESI-MS(+): 254 (M + Na)+.1H NMR (400 MHz, CDCI3): 5ppm 1.38 (t, 3 H), 2.92 (q, 2 H), 3.98 (s, 3H), 7.40 (d, J=8.8 Hz, 1 H), 7.66 (d, J=8.8 Hz,1 H)-

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2016/87265, 2016, A1 Location in patent: Page/Page column 69
[2]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/87257, 2016, A1 Location in patent: Page/Page column 76
[3]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1 Location in patent: Page/Page column 84
[4]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2017/1314, 2017, A1 Location in patent: Page/Page column 65
[5]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2017/16910, 2017, A1 Location in patent: Page/Page column 88-89
[6]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2018/95795, 2018, A1 Location in patent: Page/Page column 49

30
[ 1532-24-7 ]
methyl 3-ethylsulfanyl-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 95 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / 1,4-dioxane / 95 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / 1,4-dioxane / 95 °C / Inert atmosphere

	Multi-step reaction with 2 steps 1.1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2.1: potassium carbonate / 1,4-dioxane / 0.17 h / Inert atmosphere 2.2: 95 °C
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 95 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2016/87265, 2016, A1
[2]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/87257, 2016, A1
[3]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2017/1314, 2017, A1
[4]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2017/16910, 2017, A1
[5]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2018/95795, 2018, A1

31
[ 1532-24-7 ]
methyl 3-ethylsulfonyl-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 95 °C / Inert atmosphere 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 5 °C
	Multi-step reaction with 3 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / 1,4-dioxane / 95 °C / Inert atmosphere 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 5 °C
	Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 95 °C / Inert atmosphere 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2016/87265, 2016, A1
[2]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/87257, 2016, A1
[3]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2018/95795, 2018, A1

32
[ 1532-24-7 ]
3-ethylsulfonyl-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 95 °C / Inert atmosphere 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 5 °C 4: water; lithium hydroxide / 1,4-dioxane / 20 °C
	Multi-step reaction with 4 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / 1,4-dioxane / 95 °C / Inert atmosphere 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 5 °C 4: water; lithium hydroxide / 1,4-dioxane / 20 °C
	Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 95 °C / Inert atmosphere 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h / 0 - 20 °C / Inert atmosphere 4: lithium hydroxide monohydrate / tetrahydrofuran; water / 20 °C

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2016/87265, 2016, A1
[2]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/87257, 2016, A1
[3]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2018/95795, 2018, A1

33
[ 1532-24-7 ]
6-cyclopropyl-3-ethylsulfanyl-pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 24 h / 120 °C / Reflux; Inert atmosphere 3: sodium hydroxide / tetrahydrofuran; water / 4 h / 20 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1

34
[ 1532-24-7 ]
6-bromo-2-(6-cyclopropyl-3-ethylsu lfanyl-2-pyridyl)-3-methyl-imidazo[4,5-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 24 h / 120 °C / Reflux; Inert atmosphere 3: sodium hydroxide / tetrahydrofuran; water / 4 h / 20 °C 4: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1

35
[ 1532-24-7 ]
6-bromo-2-(6-cyclopropyl-3-ethylsulfonyl-2-pyridyl)-3-methyl-imidazo[4,5-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 24 h / 120 °C / Reflux; Inert atmosphere 3: sodium hydroxide / tetrahydrofuran; water / 4 h / 20 °C 4: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 5: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1

36
[ 1532-24-7 ]
2-(6-cyclopropyl-3-ethylsulfonyl-2-pyridyl)-3-methyl-6-(trifluoromethylsulfanyl)imidazo[4,5-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 24 h / 120 °C / Reflux; Inert atmosphere 3: sodium hydroxide / tetrahydrofuran; water / 4 h / 20 °C 4: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 5: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C 6: (2,2'-bipyride-kN₁,kN₁')(1,1,1-trifluoromethanethiolato-kS)-copper / acetonitrile / 48 h / Reflux; Inert atmosphere

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1

37
[ 1532-24-7 ]
6-cyclopropyl-3-ethylsulfanyl-pyridine-2-carbonyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 24 h / 120 °C / Reflux; Inert atmosphere 3: sodium hydroxide / tetrahydrofuran; water / 4 h / 20 °C 4: oxalyl dichloride / dichloromethane / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1

38
[ 1532-24-7 ]
6-(6-cyclopropyl-3-ethylsulfanyl-2-pyridyl)-7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 24 h / 120 °C / Reflux; Inert atmosphere 3: sodium hydroxide / tetrahydrofuran; water / 4 h / 20 °C 4: oxalyl dichloride / dichloromethane / 0.5 h / 20 °C 5: tetrahydrofuran / 48 h / Reflux

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1

39
[ 1532-24-7 ]
6-(6-cyclopropyl-3-ethylsulfonyl-2-pyridyl)-7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 24 h / 120 °C / Reflux; Inert atmosphere 3: sodium hydroxide / tetrahydrofuran; water / 4 h / 20 °C 4: oxalyl dichloride / dichloromethane / 0.5 h / 20 °C 5: tetrahydrofuran / 48 h / Reflux 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1

40
[ 1532-24-7 ]
methyl 3-ethylsulfonyl-6-[3-(trifluoromethyl)pyrazol-1-yl]pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C 3: potassium carbonate; copper(l) iodide; N,N-dimethylethylenediamine / 1,4-dioxane / 4 h / 120 °C / Reflux; Inert atmosphere
	Multi-step reaction with 3 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 1 h / 50 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1
[2]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2017/1314, 2017, A1

41
[ 1532-24-7 ]
3-ethylsulfonyl-6-[3-(trifluoromethyl)pyrazol-1-yl]pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C 3: potassium carbonate; copper(l) iodide; N,N-dimethylethylenediamine / 1,4-dioxane / 4 h / 120 °C / Reflux; Inert atmosphere 4: sodium hydroxide / tetrahydrofuran; water / 2 h / 20 °C
	Multi-step reaction with 4 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 0 - 20 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 1 h / 50 °C 4: lithium hydroxide monohydrate; water / tetrahydrofuran / 5 h / 20 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1
[2]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2017/1314, 2017, A1

42
[ 1532-24-7 ]
2-[3-ethylsulfonyl-6-[3-(trifluoromethyl)pyrazol-1-yl]-2-pyridyl]-3-methyl-6-(trifluoromethylsulfanyl)imidazo[4,5-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C 3: potassium carbonate; copper(l) iodide; N,N-dimethylethylenediamine / 1,4-dioxane / 4 h / 120 °C / Reflux; Inert atmosphere 4: sodium hydroxide / tetrahydrofuran; water / 2 h / 20 °C 5: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1

43
[ 1532-24-7 ]
methyl 6-chloro-3-ethylsulfonyl-pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 15 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1
[2]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2017/1314, 2017, A1
[3]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2017/55147, 2017, A1

44
[ 1532-24-7 ]
methyl 3-ethylsulfonyl-6-pyrimidin-2-yl-pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C 3: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / 1,4-dioxane / 4 h / 120 °C / Reflux; Inert atmosphere

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1

45
[ 1532-24-7 ]
3-ethylsulfonyl-6-pyrimidin-2-yl-pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C 3: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / 1,4-dioxane / 4 h / 120 °C / Reflux; Inert atmosphere 4: sodium hydroxide / tetrahydrofuran; water / 2 h / 20 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1

46
[ 1532-24-7 ]
2-(3-ethylsulfonyl-6-pyrimidin-2-yl-2-pyridyl)-3-methyl-6-(trifluoromethylsulfanyl)imidazo[4,5-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 2 h / 20 °C 3: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide / 1,4-dioxane / 4 h / 120 °C / Reflux; Inert atmosphere 4: sodium hydroxide / tetrahydrofuran; water / 2 h / 20 °C 5: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1

47
[ 1532-24-7 ]
methyl 6-cyclopropyl-3-ethylsulfanyl-pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 24 h / 120 °C / Reflux; Inert atmosphere

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2016/116338, 2016, A1

48
[ 1532-24-7 ]
5-ethyl-2-[6-(2-ethyl-3-oxo-pyrazolidin-1-yl)-3-ethylsulfonyl-2-pyridyl]-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2.1: water; sodium hydroxide / methanol / 2 h / 20 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1 h / 20 °C / Reflux; Inert atmosphere 3.2: 3 h / Reflux; Inert atmosphere 3.3: 24 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 20 °C 5.1: potassium carbonate / N,N-dimethyl acetamide / 3 h / 110 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2017/1314, 2017, A1

49
[ 1532-24-7 ]
3-ethylsulfanyl-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate / 1,4-dioxane / 95 °C / Inert atmosphere 3: lithium hydroxide monohydrate; water / tetrahydrofuran / 20 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2017/1314, 2017, A1

50
[ 1532-24-7 ]
6-chloro-3-ethylsulfanyl-pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: water; sodium hydroxide / methanol / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: sodium hydroxide; water / methanol / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: sodium hydroxide; water / tetrahydrofuran / 4 h / 20 °C

	Multi-step reaction with 2 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / Cooling with ice 1.2: 2 h / 20 °C / Cooling with ice 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 70 °C
	Multi-step reaction with 2 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 2 h / 0 - 20 °C 2.1: sodium hydroxide / tetrahydrofuran / 3 h / Reflux
	Multi-step reaction with 2 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 0.05 h / 0 °C 1.2: 20 °C 2.1: sodium hydroxide / tetrahydrofuran; water / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 0.5 h / -5 - 20 °C / Cooling with ice 2: sodium hydroxide; water / tetrahydrofuran / 2 h / Reflux

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2017/1314, 2017, A1
[2]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2017/84879, 2017, A1
[3]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2018/95795, 2018, A1
[4]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN112062759, 2020, A
[5]Yang, Sen; Ren, Chao-Li; Ma, Tian-Yang; Zou, Wen-Qian; Dai, Li; Tian, Xiao-Yu; Liu, Xing-Hai; Tan, Cheng-Xia [International Journal of Molecular Sciences, 2021, vol. 22, # 5, p. 1 - 14]
[6]Zhong, Liangkun; Yuan, Jing; Pei, Dan; Liu, Xinghai; Xu, Tianming; Tan, Chengxia [Letters in drug design and discovery, 2021, vol. 18, # 2, p. 183 - 190]
[7]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD - CN112824402, 2021, A

51
[ 1532-24-7 ]
6-chloro-N-[1-ethyl-3-(methylamino)-2-oxo-6-(trifluoromethyl)-4-pyridyl]-3-ethylsulfanyl-pyridine-2-carboxamide [ No CAS ]
N-[4-amino-1-ethyl-2-oxo-6-(trifluoromethyl)-3-pyridyl]-6-chloro-3-ethylsulfanyl-N-methyl-pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2.1: water; sodium hydroxide / methanol / 2 h / 20 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1 h / 20 °C / Reflux; Inert atmosphere 3.2: 3 h / Reflux; Inert atmosphere
	Multi-step reaction with 4 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: sodium hydroxide; water / methanol / 2 h / 20 °C 3: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h / Reflux 4: pyridine / tetrahydrofuran / 0.05 h / Reflux

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2017/1314, 2017, A1
[2]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2017/84879, 2017, A1

52
[ 1532-24-7 ]
2-(6-chloro-3-ethylsulfanyl-2-pyridyl)-5-ethyl-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2.1: water; sodium hydroxide / methanol / 2 h / 20 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1 h / 20 °C / Reflux; Inert atmosphere 3.2: 3 h / Reflux; Inert atmosphere 3.3: 24 h / Reflux
	Multi-step reaction with 4 steps 1.1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2.1: sodium hydroxide; water / methanol / 2 h / 20 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h / Reflux 4.1: pyridine / tetrahydrofuran / 0.05 h / Reflux 4.2: 24 h / Reflux

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2017/1314, 2017, A1
[2]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2017/84879, 2017, A1

53
[ 1532-24-7 ]
2-(6-chloro-3-ethylsulfonyl-2-pyridyl)-5-ethyl-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2.1: water; sodium hydroxide / methanol / 2 h / 20 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1 h / 20 °C / Reflux; Inert atmosphere 3.2: 3 h / Reflux; Inert atmosphere 3.3: 24 h / Reflux 4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 20 °C
	Multi-step reaction with 5 steps 1.1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2.1: sodium hydroxide; water / methanol / 2 h / 20 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h / Reflux 4.1: pyridine / tetrahydrofuran / 0.05 h / Reflux 4.2: 24 h / Reflux 5.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2017/1314, 2017, A1
[2]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2017/84879, 2017, A1

54
[ 1532-24-7 ]
methyl 3-ethylsulfonyl-6-(1,2,4-triazol-1-yl)pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 0 - 20 °C / Inert atmosphere 3.1: sodium hydride / 1-methyl-pyrrolidin-2-one; paraffin oil / 0.5 h / Inert atmosphere 3.2: 0.17 h / 20 °C
	Multi-step reaction with 3 steps 1: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 20 °C / Cooling with ice 2: 3-chloro-benzenecarboperoxoic acid / chloroform / 8 h / 20 °C / Cooling with ice 3: potassium carbonate / N,N-dimethyl-formamide / 5 h / 20 °C

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2017/1314, 2017, A1
[2]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - US2019/150447, 2019, A1

55
[ 1532-24-7 ]
[ 811-51-8 ]
methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate [ No CAS ]
methyl 3,6-bis(ethylsulfanyl)pyridine-2-carboxylate [ No CAS ]
methyl 3-chloro-6-ethylsulfanyl-pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 18-crown-6 ether In tetrahydrofuran at 20℃; for 1h;	P4.A Preparation of methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate A solution of methyl 3,6-dichloropyridine-2-carboxylate (20 g, 97.073 mmol, commercial compound) intetrahydrofuran (200 mL) was treated with catalytic quantities of 18-crown-6-ether (ca. 300mg)followed by sodium ethoxide (9.073 g, 97.073 mmol) in 3 portions. The reaction was then allowed to stir at ambient temperature for 1 hour. LCMS analysis after this time showed consumption of starting materials and the formation of three new products. The reaction mixture was poured on 100 ml saturated ammonium chloride aqueous solution, extracted with 2x lOOmI EtOAc, and the combinedorganic layers washed with 2x 50 ml saturated aqueous ammonium chloride aqueous solution, 3x 100 ml water, dried over Na2504, filtered and concentrated in vacuo. The crude product was purified by combi flash chromatography with a column of 220 g and a gradient cyclohexane + 0-10% EtOAc. This gave as the first eluting product methyl 3,6-bis(ethylsulfanyl)pyridine-2-carboxylate (method 1, retention time 1.04 mins, (MH+) =258). The second product to elute was methyl 3-chloro-6-ethylsulfanyl-pyridine-2-carboxylate (method 1, retention time 0.99 mi (MH+) 232). The final product to elute was the major product and desired title product, as white crystals.1H NMR (400 MHz, CDCI3) ö ppm 1.40 (t, 3 H) 2.95 (q, 2 H) 4.00 (s, 3 H) 7.41 (d, 1 H) 7.66 (d, 1 H).
	With 18-crown-6 ether In tetrahydrofuran at 20℃; for 1h;	I5.B Step B: Preparation of methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate: Step B: Preparation of methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate: A solution of methyl 3,6-dichloropyridine-2-carboxylate (20 g, 97.073 mmol, commercial compound) in tetrahydrofuran (200 mL) was treated with catalytic quantities of 18-crown-6-ether (ca. 300mg) followed by sodium ethoxide (9.073 g, 97.073 mmol) in 3 portions. The reaction was the allowed to stir at ambient temperature for 1 hour. LCMS analysis after this time showed consumption of starting materials and the formation of three new products. The reaction mixture was poured on 100 ml saturated ammonium chloride aqueous solution, extracted with 2x 100ml Ethyl acetate, and the combined organic layers washed with 2x 50 ml saturated aqueous ammonium chloride aqueous solution, 3x 100 ml water, dried over Sodium sulfate, filtered and concentrated in vacuum. The crude product was purified by combi flash chromatography with a column of 220 g and a gradient cyclohexane + 0-10% Ethyl acetate. This gave as the first eluting product methyl 3,6- bis(ethylsulfanyl)pyridine-2-carboxylate (Method A, retention time 1.04 mins, (MH+) =258). The second product to elute was methyl 3-chloro-6-ethylsulfanyl-pyridine-2-carboxylate (Method A, retention time 0.99 min, (MH+) = 232). The final product to elute was the major product and desired title product, as white crystals. LC-MS (method A): RT 0.88mins, 232 (MH+). H NMR (400 MHz, chloroform-d) δ ppm 1.40 (t, 3 H) 2.95 (q, 2 H) 4.00 (s, 3 H) 7.41 (d, 1 H) 7.66 (d, 1 H).

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2017/55147, 2017, A1 Location in patent: Page/Page column 82; 83
[2]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2017/84879, 2017, A1 Location in patent: Page/Page column 80; 81

56
[ 1532-24-7 ]
6-chloro-3-ethylsulfanyl-pyridine-2-carbonyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 18-crown-6 ether / tetrahydrofuran / 1 h / 20 °C 2: sodium hydroxide; water / methanol / 2 h / 20 °C 3: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h / Reflux
	Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 2: sodium hydroxide; water / tetrahydrofuran / 4 h / 20 °C 3: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 24 h / 20 °C
	Multi-step reaction with 3 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / Cooling with ice 1.2: 2 h / 20 °C / Cooling with ice 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 70 °C 3.1: thionyl chloride / 4 h / 120 °C

	Multi-step reaction with 3 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 2 h / 0 - 20 °C 2.1: sodium hydroxide / tetrahydrofuran / 3 h / Reflux 3.1: thionyl chloride / 6 h / Reflux
	Multi-step reaction with 3 steps 1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 0.5 h / -5 - 20 °C / Cooling with ice 2: sodium hydroxide; water / tetrahydrofuran / 2 h / Reflux 3: thionyl chloride; N,N-dimethyl-formamide / 4 h / Reflux

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2017/84879, 2017, A1
[2]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2018/95795, 2018, A1
[3]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN112062759, 2020, A
[4]Yang, Sen; Ren, Chao-Li; Ma, Tian-Yang; Zou, Wen-Qian; Dai, Li; Tian, Xiao-Yu; Liu, Xing-Hai; Tan, Cheng-Xia [International Journal of Molecular Sciences, 2021, vol. 22, # 5, p. 1 - 14]
[5]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD - CN112824402, 2021, A

57
[ 872041-86-6 ]
[ 1532-24-7 ]
methyl 3-chloro-6-(5-fluoro-3-pyridyl)pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-methylamino-1,1'-biphenyl-2-yl)palladium(ll); potassium carbonate; In ethanol; water; at 85℃; for 2h;Inert atmosphere;	A solution of methyl 3,6-dichloropyridine-2-carboxylate (1.00 g, 4.85 mmol) and <strong>[872041-86-6](5-fluoro-3-pyridyl)boronic acid</strong> (0.752 g, 5.34 mmol) in ethanol (2.7 mL) 10.0 mL) and water (4.6 mL) were sparged with N2 for 30 minutes at room temperature.Then K2CO3 (1.342 g, 9.71 mmol) and Xantphos cyclopalladium G4 (0.117 g, 0.121 mmol) were added, and the yellow solution was heated to 85 C under N2 atmosphere for 2 h.The reaction was cooled to room temperature and diluted with EtOAc EtOAcIt was washed with water (50 mL).The aqueous phase was further extracted with EtOAc (2×50 mL). The combined organic extracts were dried with MgSO 4 The crude material was flash chromatographed on silica gel using EtOAc / isohexane gradient as eluentPurify to give the desired product (0.94 g, 73%).

Reference： [1]Patent: CN108779107,2018,A .Location in patent: Paragraph 0328-0330

58
[ 1532-24-7 ]
[ 75-08-1 ]
methyl 3,6-bis(ethylsulfanyl)pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.8 g	With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1h; Cooling with ice;	1-1 Preparation Example 1-1 To a mixture of methyl 3,6-dichloropyridine-2-carboxylate 3.0 g, ethanethiol 2.27 mL, and THF 29 mL was added sodium hydride (60%, oily) 1.28 g under ice-cooling. The mixtures were stirred at room temperature for 1 hour, and to the mixtures was added saturated aqueous ammonium chloride solution, and the resulting mixtures were extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concentrated. The residues were subjected to a silica gel column chromatography to give an intermediate compound A represented by the following formula 2.80 g.1H-NMR (CDCl3) δ: 7.53 (1H, d), 7.22 (1H, d), 3.97 (3H, s), 3.19 (2H, q), 2.90 (2H, q), 1.38 (3H, t), 1.34 (3H, t).

Reference： [1]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - US2019/150447, 2019, A1 Location in patent: Paragraph 0215-0217

59
(2-chloro-4-(difluoromethoxy)phenyl)trimethylstannane [ No CAS ]
[ 1532-24-7 ]
methyl 3-chloro-6-(2-chloro-4-(difluoromethoxy)phenyl)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide In N,N-dimethyl-formamide at 130℃; for 0.5h; Microwave irradiation;	68 Example 68: Preparation of methyl 3-chloro-6-(2-chloro-4- (difluoromethoxy)phenyl)picolinate (F157) Methyl 3,6-dichloropicolinate (0.290 g, 1.408 mmol), (2-chloro-4- (difluoromethoxy)phenyl)trimethylstannane (C93; 0.481 g, 1.408 mmol), Pd(PPh3)2Cl2 (0.296 g, 0.422 mmol), and copper(I) iodide (0.080 g, 0.422 mmol) were combined with DMF (5.63 mL) in a microwave vessel and heated at 130 °C in a Biotage microwave reactor for 30 min. The reaction mixture was filtered and concentrated. Purification of the resulting product by reverse phase HPLC provided the title compound as an off-white solid (125 mg, 24%).

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2019/84353, 2019, A1 Location in patent: Paragraph 00203

60
[ 1532-24-7 ]
[2-chloro-4-(trifluoromethyl)phenyl]boronic acid [ No CAS ]
methyl 3-chloro-6-(2-chloro-4-(trifluoromethyl)phenyl)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With bis-triphenylphosphine-palladium(II) chloride; potassium fluoride In water; acetonitrile at 85℃; for 4h;	32 Example 32: Preparation of methyl 3-chloro-6-(2-chloro-4- (trifluoromethyl)phenyl)picolinate (F66) A mixture of (2-chloro-4-(trifluoromethyl)phenyl)boronic acid (2.40 g, 10.7 mmol), methyl 3,6-dichloropicolinate (2 g, 9.71 mmol), Pd(PPh3)2Cl2 (0.681 g, 0.971 mmol) and potassium fluoride (1.69 g, 29.1 mmol) in CCN (29 mL) and water (9.7 mL) was stirred at reflux (-85 °C) for 4 h. The reaction mixture was poured into a satd aq NaHCCh solution and extracted with EtOAc (2x). The combined organic layers were dried over MgSC, filtered and concentrated. Purification by flash chromatography with a hexane-EtOAc gradient provided a solid, which was triturated with Et20-hexane (1:9). The solid was filtered, washed with hexane and dried in vacuo. The filtrate was concentrated and the resulting solid was triturated with hexane, filtered and washed with hexane. The two solid batches were combined and dried in vacuo to afford the title compound as a white solid (1.97 g, 58%).

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2019/84353, 2019, A1 Location in patent: Paragraph 00150

61
[ 661-69-8 ]
[ 1532-24-7 ]
methyl 3-chloro-6-(trimethylstannyl)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With bis-triphenylphosphine-palladium(II) chloride In 1,4-dioxane at 80℃; for 2h; Inert atmosphere;	46 Example 46: Preparation of methyl 3-chloro-6-(trimethylstannyl)picolinate (C16) A degassed (nitrogen) mixture of methyl 3,6-dichloropicolinate (0.577 g, 2.80 mmol), Pd(PPh3)2Ch (0.197 g, 0.28 mmol), and 1,1,1,2,2,2-hexamethyldistannane (0.917 g, 2.80 mmol) in dry dioxane (10 mL) was stirred at 80 °C for 2 h and then cooled to 20 °C. The brown solution was adsorbed onto neutral alumina. Purification by column chromatography with 0-20% ethyl acetate-hexane afforded the title compound as a clear liquid (870 mg, 79%): NMR (400 MHz, CDCl3) δ 7.60 (d, / = 8.0 Hz, 1H), 7.48 (d, / = 8.0 Hz, 1H), 4.00 (s, 3H), 0.36 (s, 9H); EIMS m/z 334.

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2019/84353, 2019, A1 Location in patent: Paragraph 00173

62
[ 951677-39-7 ]
[ 1532-24-7 ]
methyl 2',3',5-trichloro-[2,4'-bipyridine]-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With bis-triphenylphosphine-palladium(II) chloride; cesium fluoride In water; acetonitrile at 60 - 65℃; for 2h; Inert atmosphere;	51 Example 51: Preparation of methyl 2',3',5-trichloro-[2,4'-bipyridine]-6-carboxylate (F86) A solution of (2,3-dichloropyridin-4-yl)boronic acid (200 mg, 1.04 mmol), cesium fluoride (475 mg, 3.13 mmol), and methyl 3,6-dichloropicolinate (215 mg, 1.04 mmol) in acetonitrile (3910 μ) and water (1303 μΙ_,) was degassed (nitrogen) for 20 min before adding Pd(PPh3)2Cl2 (73 mg, 0.104 mmol) and heating to 60-65 °C. After heating for 2 h, the reaction mixture was cooled and loaded directly onto silica gel. Purification via reverse phase chromatography afforded the title compound as a white solid (62 mg, 18%).

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2019/84353, 2019, A1 Location in patent: Paragraph 00184

63
[ 1702-17-6 ]
[ 77-78-1 ]
[ 1532-24-7 ]

Yield	Reaction Conditions	Operation in experiment
90.1%	With potassium carbonate In acetone at 40℃; for 8h;
89.2%	With potassium carbonate In acetone at 20℃; for 4h;	1 Example 1: Synthesis of methyl 3,6-dichloropyridine-2-carboxylate Dissolve 3,6-dichloropyridine-2-carboxylic acid (5.0g, 26.0mmol) in 50mL acetone,Potassium carbonate (4.3g, 31.2mmol) was added, dimethyl sulfate (3.3g, 26.0mmol) was slowly added dropwise, stirred at room temperature for 4h, followed by TLC detection. After the reaction is complete, filter to remove inorganic salts,The organic phase was dried over anhydrous magnesium sulfate and filtered, and the filtrate was desolvated to obtain 4.5 g of white solid with a yield of 89.2%.
	With potassium carbonate In acetone at 40℃; for 8h;	2 Preparation of 3-chloro-6-ethylthiopicolinic acid represented by formula (3): In a 100mL three-necked flask, Add 1.92g (0.01mol) 3,6-dichloropicolinic acid, 20mL acetone, 1.66g K2CO3, 1.26g (0.01mol) dimethyl sulfate was added dropwise, After the dripping is completed, the temperature is controlled at 40°C to start the reaction. TLC tracked and monitored the experiment, and the reaction was completed in about 8 hours. After the reaction solution is cooled to room temperature, the filtrate is filtered out, and the solution is removed by rotary evaporation. Dry to obtain methyl 3,6-dichloropicolinate;

Reference： [1]Yang, Sen; Ren, Chao-Li; Ma, Tian-Yang; Zou, Wen-Qian; Dai, Li; Tian, Xiao-Yu; Liu, Xing-Hai; Tan, Cheng-Xia [International Journal of Molecular Sciences, 2021, vol. 22, # 5, p. 1 - 14]
[2]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD - CN112824402, 2021, A Location in patent: Paragraph 0076; 0086-0089
[3]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN112062759, 2020, A Location in patent: Paragraph 0027-0028

64
[ 1532-24-7 ]
methyl 2-chloro-5-(5-(6-chloro-3-(ethylthio)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / Cooling with ice 1.2: 2 h / 20 °C / Cooling with ice 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 70 °C 3.1: thionyl chloride / 4 h / 120 °C 4.1: triethylamine / toluene / 2 h / 0 °C 4.2: 3 h / 0 °C
	Multi-step reaction with 4 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 2 h / 0 - 20 °C 2.1: sodium hydroxide / tetrahydrofuran / 3 h / Reflux 3.1: thionyl chloride / 6 h / Reflux 4.1: triethylamine / toluene / 3 h / 0 °C / Reflux

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN112062759, 2020, A
[2]Yang, Sen; Ren, Chao-Li; Ma, Tian-Yang; Zou, Wen-Qian; Dai, Li; Tian, Xiao-Yu; Liu, Xing-Hai; Tan, Cheng-Xia [International Journal of Molecular Sciences, 2021, vol. 22, # 5, p. 1 - 14]

65
[ 1532-24-7 ]
2-chloro-5-(5-(6-chloro-3-(ethylthio)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)-N-phenylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / Cooling with ice 1.2: 2 h / 20 °C / Cooling with ice 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 70 °C 3.1: thionyl chloride / 4 h / 120 °C 4.1: triethylamine / toluene / 2 h / 0 °C 4.2: 3 h / 0 °C 5.1: sodium hydroxide / tetrahydrofuran; water / 2 h 6.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 7 h / 20 °C
	Multi-step reaction with 6 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 2 h / 0 - 20 °C 2.1: sodium hydroxide / tetrahydrofuran / 3 h / Reflux 3.1: thionyl chloride / 6 h / Reflux 4.1: triethylamine / toluene / 3 h / 0 °C / Reflux 5.1: sodium hydroxide / tetrahydrofuran / 2 h / Reflux 6.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 8 h / 0 °C

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN112062759, 2020, A
[2]Yang, Sen; Ren, Chao-Li; Ma, Tian-Yang; Zou, Wen-Qian; Dai, Li; Tian, Xiao-Yu; Liu, Xing-Hai; Tan, Cheng-Xia [International Journal of Molecular Sciences, 2021, vol. 22, # 5, p. 1 - 14]

66
[ 1532-24-7 ]
2-chloro-5-(5-(6-chloro-3-(ethylthio)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)-N-(2-fluorophenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / Cooling with ice 1.2: 2 h / 20 °C / Cooling with ice 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 70 °C 3.1: thionyl chloride / 4 h / 120 °C 4.1: triethylamine / toluene / 2 h / 0 °C 4.2: 3 h / 0 °C 5.1: sodium hydroxide / tetrahydrofuran; water / 2 h 6.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 8 h / 20 °C
	Multi-step reaction with 6 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 2 h / 0 - 20 °C 2.1: sodium hydroxide / tetrahydrofuran / 3 h / Reflux 3.1: thionyl chloride / 6 h / Reflux 4.1: triethylamine / toluene / 3 h / 0 °C / Reflux 5.1: sodium hydroxide / tetrahydrofuran / 2 h / Reflux 6.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 8 h / 0 °C

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN112062759, 2020, A
[2]Yang, Sen; Ren, Chao-Li; Ma, Tian-Yang; Zou, Wen-Qian; Dai, Li; Tian, Xiao-Yu; Liu, Xing-Hai; Tan, Cheng-Xia [International Journal of Molecular Sciences, 2021, vol. 22, # 5, p. 1 - 14]

67
[ 1532-24-7 ]
N-(4-bromophenyl)-2-chloro-5-(5-(6-chloro-3-(ethylthio)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / Cooling with ice 1.2: 2 h / 20 °C / Cooling with ice 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 70 °C 3.1: thionyl chloride / 4 h / 120 °C 4.1: triethylamine / toluene / 2 h / 0 °C 4.2: 3 h / 0 °C 5.1: sodium hydroxide / tetrahydrofuran; water / 2 h 6.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 9 h / 20 °C
	Multi-step reaction with 6 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 2 h / 0 - 20 °C 2.1: sodium hydroxide / tetrahydrofuran / 3 h / Reflux 3.1: thionyl chloride / 6 h / Reflux 4.1: triethylamine / toluene / 3 h / 0 °C / Reflux 5.1: sodium hydroxide / tetrahydrofuran / 2 h / Reflux 6.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 8 h / 0 °C

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN112062759, 2020, A
[2]Yang, Sen; Ren, Chao-Li; Ma, Tian-Yang; Zou, Wen-Qian; Dai, Li; Tian, Xiao-Yu; Liu, Xing-Hai; Tan, Cheng-Xia [International Journal of Molecular Sciences, 2021, vol. 22, # 5, p. 1 - 14]

68
[ 1532-24-7 ]
2-chloro-5-(5-(6-chloro-3-(ethylsulfonyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)-N-phenylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / Cooling with ice 1.2: 2 h / 20 °C / Cooling with ice 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 70 °C 3.1: thionyl chloride / 4 h / 120 °C 4.1: triethylamine / toluene / 2 h / 0 °C 4.2: 3 h / 0 °C 5.1: sodium hydroxide / tetrahydrofuran; water / 2 h 6.1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 7 h / 20 °C 7.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 20 °C
	Multi-step reaction with 7 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 2 h / 0 - 20 °C 2.1: sodium hydroxide / tetrahydrofuran / 3 h / Reflux 3.1: thionyl chloride / 6 h / Reflux 4.1: triethylamine / toluene / 3 h / 0 °C / Reflux 5.1: sodium hydroxide / tetrahydrofuran / 2 h / Reflux 6.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 8 h / 0 °C 7.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h / 20 °C

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN112062759, 2020, A
[2]Yang, Sen; Ren, Chao-Li; Ma, Tian-Yang; Zou, Wen-Qian; Dai, Li; Tian, Xiao-Yu; Liu, Xing-Hai; Tan, Cheng-Xia [International Journal of Molecular Sciences, 2021, vol. 22, # 5, p. 1 - 14]

69
[ 1532-24-7 ]
2-chloro-5-(5-(6-chloro-3-(ethylthio)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / Cooling with ice 1.2: 2 h / 20 °C / Cooling with ice 2.1: sodium hydroxide; water / tetrahydrofuran / 1 h / 70 °C 3.1: thionyl chloride / 4 h / 120 °C 4.1: triethylamine / toluene / 2 h / 0 °C 4.2: 3 h / 0 °C 5.1: sodium hydroxide / tetrahydrofuran; water / 2 h
	Multi-step reaction with 5 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 2 h / 0 - 20 °C 2.1: sodium hydroxide / tetrahydrofuran / 3 h / Reflux 3.1: thionyl chloride / 6 h / Reflux 4.1: triethylamine / toluene / 3 h / 0 °C / Reflux 5.1: sodium hydroxide / tetrahydrofuran / 2 h / Reflux

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN112062759, 2020, A
[2]Yang, Sen; Ren, Chao-Li; Ma, Tian-Yang; Zou, Wen-Qian; Dai, Li; Tian, Xiao-Yu; Liu, Xing-Hai; Tan, Cheng-Xia [International Journal of Molecular Sciences, 2021, vol. 22, # 5, p. 1 - 14]

70
[ 1532-24-7 ]
[ 75-08-1 ]
methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.1%	Stage #1: ethanethiol With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0℃; for 0.05h; Stage #2: methyl 3,6-dichloro-2-pyridinecarboxylate In N,N-dimethyl-formamide at 20℃;	Synthetic procedure for 2 To a solution of t-BuOK (6.6 g, 59.1 mmol) in DMF (15mL), EtSH (3.3 g, 53.7 mmol) was added dropwise under 0 oC for 3 min. Then, the solution was added dropwise to methyl3,6-dichloropicolinate (1) (10.0 g, 48.5 mmol) in DMF (35mL) at room temperature. After the reaction was completed,the mixture was poured into ice water (100 ml) and extractedtwice with dichloromethane, then evaporated under reducedpressure and residue was purified by chromatography using PE/EtOAc [V(PE):V(EtOAc)=5:1] to afford methyl 6-chloro-3-(ethylthio)picolinate (2) with yield 79.1%, m.p.124-125 oC; 1H NMR (CDCl3, 600 MHz) δ: 7.66 (d, 1H, J =8.4 Hz, Pyridine-H), 7.41 (d, 1H, J = 8.4 Hz, Pyridine-H),3.99 (s, 3H, OCH3), 2.94 (q, 2H, J = 7.2 Hz, CH2), 1.39 (t,3H, J = 7.2 Hz, CH3). 13C NMR (CDCl3, 150 MHz) δ: 164.9,146.2, 138.3, 136.8, 127.0, 53.1, 26.2, 14.2, 13.1. MS (ESI):232.0 [M + H]+.
74.5%	Stage #1: ethanethiol With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: methyl 3,6-dichloro-2-pyridinecarboxylate In N,N-dimethyl-formamide at 0 - 20℃; for 2h;
	Stage #1: ethanethiol With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide Cooling with ice; Stage #2: methyl 3,6-dichloro-2-pyridinecarboxylate In N,N-dimethyl-formamide at 20℃; for 2h; Cooling with ice;	2 In a 100mL three-necked flask, add 2.46g ethanethiol, Dissolve with 30ml DMF, add 1.36g potassium tert-butoxide dropwise under ice bath conditions, Start the reaction to obtain potassium ethanethiolate; In a 100mL three-necked flask, Add 3.72g prepared methyl 3,6-dichloropicolinate, Dissolve with 20ml DMF, Add potassium ethanethiolate dropwise under ice bath conditions, After the addition is complete, move to room temperature to start the reaction, TLC tracked and monitored the experiment, and the reaction ended in about 2 hours. Then add water and ethyl acetate for extraction, Take the organic phase, add anhydrous Mg2SO4 for drying, filter to take the filtrate, and spin-evaporate to remove the solvent. To obtain methyl 3-chloro-6-ethylthiopicolinate;

Reference： [1]Zhong, Liangkun; Yuan, Jing; Pei, Dan; Liu, Xinghai; Xu, Tianming; Tan, Chengxia [Letters in drug design and discovery, 2021, vol. 18, # 2, p. 183 - 190]
[2]Yang, Sen; Ren, Chao-Li; Ma, Tian-Yang; Zou, Wen-Qian; Dai, Li; Tian, Xiao-Yu; Liu, Xing-Hai; Tan, Cheng-Xia [International Journal of Molecular Sciences, 2021, vol. 22, # 5, p. 1 - 14]
[3]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN112062759, 2020, A Location in patent: Paragraph 0027; 0030-0029

71
[ 1532-24-7 ]
2-chloro-5-(5-(6-chloro-3-(ethylsulfonyl)pyridin-2-yl)-1,2,4-oxadiazol-3-yl)-N-(2,6-difluorophenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide / 1 h / 0 °C 1.2: 2 h / 0 - 20 °C 2.1: sodium hydroxide / tetrahydrofuran / 3 h / Reflux 3.1: thionyl chloride / 6 h / Reflux 4.1: triethylamine / toluene / 3 h / 0 °C / Reflux 5.1: sodium hydroxide / tetrahydrofuran / 2 h / Reflux 6.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 8 h / 0 °C 7.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h / 20 °C