Name: 944129-07-1|(4-Chloro-2-fluoro-3-methoxyphenyl)boronic acid|98%
Brand: Ambeed
SKU: A558630
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1
[ 944129-07-1 ]
[ 504-63-2 ]
1,3-propanediyl 4-chloro-2-fluoro-3-methoxyphenylboronate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 1,2-dimethoxyethane; hexane	1 The solution was cooled to -70° C., before adding 74.4 grams (g) of trimethyl borate, dropwise. The addition took about 15 min and the temperature was held below -45° C. The colorless solution was warmed to 0° C. with a warm water bath before 140 g of 37% aq. HCl was added nearly at once. The near colorless solution gave off a gas and reached 27° C. and was stirred for 20 min before transferring the two phase mixture to a separatory funnel. The lower viscous water layer (285 mL) was separated and reserved. The organic phase was placed in a 2 L roto-vap flask and 62 g of 1,3-propanediol was added to the cloudy colorless solution. The reserved water layer was extracted once with 300 mL of ether and the phases were separated into 195 mL of the aqueous fraction and about 390 mL of organic phase. The organic phase was added into the 2 L roto-vap flask. This cloudy solution was concentrated and warmed to 60-70° C. to give an near colorless oil with some water present. The mixture was taken into 700 mL of methylene chloride, dried with MgSO4, filtered and concentrated to 156 g of a colorless oil. 1H NMR and GC indicated about 5% by weight of excess propanediol.The oil was heated on the Kugelrohr at 10-12 mm Hg vacuum to 160° C. for ten minutes. Some light material came over and the sample weighed 152 g. GC showed a 2% improvement in purity to 94.2%. 1H NMR (CDCl3, 300 MHz): δ 7.15 (dd, 1H, J=6.0, 8.3 Hz,), 6.95 (dd, 1H, J=1.3, 8.3 Hz), 4.05 (t, 4H, J=5.7), 3.8 (s, 3H), 1.95 (m, 2H, J=5.7 Hz).
	In toluene for 2h; Heating / reflux;	11 11. Preparation of 2-f4-chloro-2-fluoro-3-methoxyphenyI)-ri. 3. 21- dioxaborinane; To a solution of l-bromo-4-chloro-2-fluoro-3-methoxybenzene (10.4 g, 0.043 mol) in diethyl ether (150 mL) at -78° C was slowly added n-butyl lithium (2.5M, 19.0 mL, 0.0475 mol), and the solution was stirred for thirty minutes. A solution of triisopropyl borate (12.0 g, 0.064 mL) in THF (25 mL) was slowly added and the solution warmed to 0° C. Acetyl chloride (10.0 g, 0.13 mol) was added. After stirring for one hour the solution was concentrated and the solid residue was partitioned between ethyl acetate (150 mL) and IN sodium hydroxide (50 mL). Ice was added to the aqueous phase that was subsequently acidified with sufficient concentrated hydrochloric acid to obtain a pH of 2. The heterogeneous mixture was extracted with ethyl acetate (2 x 150 mL) and the combined organic phases were dried and concentrated. The resulting solid was slurried in toluene, propane- 1, 3 -diol (6.6 g, 0.09 mol) was added, and the resulting mixture was heated under reflux to remove water via a Dean-Stark trap. After two hours, the mixture was allowed to cool and was concentrated under vacuum. The resulting oil was dissolved in methylene chloride (50 mL), washed with water (25 mL), dried, and concentrated to give 2-(4-chloro-2-fluoro-3-methoxyphenyl)-[l, 3, 2]-dioxaborinane (6.4 g, 0.062 mol): 1HNMR (CDCl3): δ 7.15 (m, IH), 6.95 (dd, IH), 4.05 (t, 4H), 3.8 (s, 3H), 1.95 (t, 2H).

Reference： [1]Current Patent Assignee: CORTEVA INC - US2009/182168, 2009, A1 Location in patent: Page/Page column 2
[2]Current Patent Assignee: CORTEVA INC - WO2007/82076, 2007, A1 Location in patent: Page/Page column 30

2
[ 944129-00-4 ]
[ 944129-07-1 ]
[ 944129-05-9 ]

Yield	Reaction Conditions	Operation in experiment
53.3%	bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 80℃; for 2.0h;	32. Preparation of 6-amino-2-(4-chloro-2-fluoro-3-melhoxy-phenyl)- pyrimidine-4-carboxylic acid methyl ester.; -Amino^-chloro-pyrimidine^-carboxylic acid methyl ester (2.25 g, 12 rnrnol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16 mmol), and bis(triphenylphosphine)palladiurn(II) dichoride (842 mg, 1.2 mmol) were combined in 12 mL of dimethoxyethane and 12 mL of water. The reaction mixture was heated at 80 C for 2 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated under vacuum. The product was purified by column chromatography to yield 6-amino-2-(4-chloro-2-fluoro-3-methoxy- phenyl)pyrimidine-4-carboxylic acid methyl ester (2.0 g, 53.5 percent yield): mp 188-190 C: 1HNMR (CDCl3): delta 7.66 (dd, IH), 7.22 (dd, IH), 7.14 (s, IH), 5.25 (br s, 2H), 4.0 (s, 3H), 3.99 (s, 3H).
53.5%	bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 80℃; for 2.0h;	6-Amino-2-chloropyrimidine-4-carboxylic acid methyl ester (2.25 g, 12 mmol, 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16 mmol), and bis(triphenylphosphine)palladium(II) dichloride (842 mg, 1.2 mmol) were combined in 12 mL of 1,2-dimethoxyethane and 12 mL of water. The reaction mixture was heated at 80 C. for 2 h and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated under vacuum. The product was purified by flash chromatography on silica gel to yield the title compound (2.0 g, 53.5% yield): mp 188-190 C.: 1H NMR (CDCl3) delta 7.66 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 5.25 (br s, 2H), 4.0 (s, 3H), 3.99 (s, 3H).

Reference： [1]Patent: WO2007/82076,2007,A1 .Location in patent: Page/Page column 41
[2]Patent: US2009/88322,2009,A1 .Location in patent: Page/Page column 11

3
[ 944129-07-1 ]
[ 1126320-49-7 ]
[ 1126318-85-1 ]

Yield	Reaction Conditions	Operation in experiment
75.6%	With palladium diacetate; potassium hydrogencarbonate; triphenylphosphine In methanol; water; acetonitrile at 50℃; for 22h; Inert atmosphere;	1 Example 1. Direct Suzuki Coupling In a round bottom flask methyl 6-amino-2-chloro-5-methoxypyrimidine-4-carboxylate (AP) (0.98g, 4.7 mmol), (4-chloro-2-fluoro-3 -methoxyphenyl)boronic acid (ABA) (1 .Og, 4.8 mmol), methanol (1.3g, 40.6 mmol), 4-methyl-2-pentanone (1.lg, 11.0 mmol) and acetonitrile (2.6g, 63.3 mmol) were combined. In a separate vial water (9.7g) and potassium bicarbonate (1.lg, 11.0 mmol) were combined to make a 10.2 wt% base solution. Both the reaction mixture and base solutions were sparged with nitrogen for 30 minutes. To the reaction mixture was added base solution (5.2g, 5.3 mmol), triphenylphosphine (0.05g, 0.19 mmol), and palladium acetate (0.02g, 0.09 mmol). The reaction was heated to 50°C. After 22 hr, the reaction was heated to 65°C and then phase separated. The organic phase was analyzed to afford 75.6% yield of methyl 6-amino-2-(4-chloro-2-fluoro-3 -methoxyphenyl)-5-methoxypyrimidine-4-carboxylate.
51.1%	With cesium fluoride In 1,2-dimethoxyethane; water at 100℃; for 0.25h; Microwave irradiation;	12 12. Preparation of 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methoxypyrimidine-4-carboxylic acid methyl ester (Compound 1) 6-Amino-2-chloro-5-methoxypyrimidine-4-carboxylic acid methyl ester (0.2 g, 0.9 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (0.29 g, 1.4 mmol), bis(triphenylphosphine)palladium(II) dichloride (65 mg, 0.1 mmol), and cesium fluoride (0.28 g, 1.9 mmol) were combined in 1 mL of 1,2-dimethoxyethane and 1 mL of water. The reaction mixture was heated in a CEM microwave at 100° C. for 15 min (other temperature/time pairs used in the subsequent examples were 110° C. for 15 min and 150° C. for 5 min). The cooled reaction mixture was diluted with ethyl acetate, washed with water, washed with brine, dried and concentrated. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to yield the title compound (162 mg, 51.1% yield): mp 155-158° C.; 1H NMR (CDCl3): δ 7.58 (dd, 1H), 7.20 (dd, 1H), 5.56 (br s, 2H) 4.00 (s, 3H), 3.99 (d, 3H), 3.94 (s, 3H).

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2017/201377, 2017, A1 Location in patent: Page/Page column 23; 24
[2]Current Patent Assignee: CORTEVA INC - US2009/62125, 2009, A1 Location in patent: Page/Page column 11

4
[ 121-43-7 ]
6-chloro-2-fluoro-3-lithioanisole [ No CAS ]
[ 944129-07-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Trimethyl borate; 6-chloro-2-fluoro-3-lithioanisole In 1,2-dimethoxyethane; hexane at -70 - -45℃; for 0.25h; Cooling with dry ice bath; Stage #2: With hydrogenchloride; water In 1,2-dimethoxyethane; hexane	1 The solution was cooled to -70° C., before adding 74.4 grams (g) of trimethyl borate, dropwise. The addition took about 15 min and the temperature was held below -45° C. The colorless solution was warmed to 0° C. with a warm water bath before 140 g of 37% aq. HCl was added nearly at once. The near colorless solution gave off a gas and reached 27° C. and was stirred for 20 min before transferring the two phase mixture to a separatory funnel. The lower viscous water layer (285 mL) was separated and reserved. The organic phase was placed in a 2 L roto-vap flask and 62 g of 1,3-propanediol was added to the cloudy colorless solution. The reserved water layer was extracted once with 300 mL of ether and the phases were separated into 195 mL of the aqueous fraction and about 390 mL of organic phase. The organic phase was added into the 2 L roto-vap flask. This cloudy solution was concentrated and warmed to 60-70° C. to give an near colorless oil with some water present. The mixture was taken into 700 mL of methylene chloride, dried with MgSO4, filtered and concentrated to 156 g of a colorless oil. 1H NMR and GC indicated about 5% by weight of excess propanediol.The oil was heated on the Kugelrohr at 10-12 mm Hg vacuum to 160° C. for ten minutes. Some light material came over and the sample weighed 152 g. GC showed a 2% improvement in purity to 94.2%. 1H NMR (CDCl3, 300 MHz): δ 7.15 (dd, 1H, J=6.0, 8.3 Hz,), 6.95 (dd, 1H, J=1.3, 8.3 Hz), 4.05 (t, 4H, J=5.7), 3.8 (s, 3H), 1.95 (m, 2H, J=5.7 Hz).
	Stage #1: Trimethyl borate; 6-chloro-2-fluoro-3-lithioanisole In hexanes; 1,2-dimethoxyethane at -65 - 20℃; Stage #2: With potassium hydroxide; water In hexanes; 1,2-dimethoxyethane at 23.1℃; for 1.11667h; Stage #3: With hydrogenchloride In water; acetonitrile	3 2. Preparation of 4-chloro-2-fluoro-3-methoxyphenylboronic acid A solution of 2-chloro-6-fluoroanisole (40.2 g) in anhydrous 1,2-dimethoxyethane (313 mL) was prepared in a 1-liter three-necked flask equipped with a magnetic stirrer, thermowell with thermocouple temperature probe, a rubber septum, and a condenser with a nitrogen pad. The solution was stirred and cooled to -69.6° C. using a dry ice/acetone bath. A solution of butyllithium (115 mL of 2.5 M butyllithium in hexanes) was added slowly over 4.15 hours using a syringe pump, maintaining the reaction temperature below -65° C. The reaction mixture was stirred for 20 minutes at -70.3° C. to -72.6° C., then trimethyl borate (43 mL) was added slowly over 1.6 hours using a syringe pump, maintaining temperature below -65° C. Upon completion of the trimethyl borate addition, the reaction mixture was allowed to slowly warm to ambient temperature overnight. A solution of potassium hydroxide in water (69.2 g of 45% KOH solution diluted with 485 mL of deionized water) was added to the reaction mixture (at ambient temperature=23.3° C.) over 26 minutes using an addition funnel. The mixture was stirred for 60 minutes, and then it was transferred to a separatory funnel where the phases were allowed to separate. The aqueous layer was washed with tert-butyl methyl ether (2305 mL) to remove unreacted 2-chloro-6-fluoroanisole. The aqueous layer was then transferred to a 1-liter Erlenmeyer flask and acidified by the dropwise addition of 6 M aqueous hydrochloric acid (161 mL). The mixture first turns milky, then the bulk of the product separates as a yellow oil. The product was extracted from the acidified mixture using ethyl acetate (2304 mL). The ethyl acetate layers were combined, washed with saturated aqueous sodium chloride (304 mL), dried with anhydrous magnesium sulfate, filtered, and concentrated on a rotary evaporator to obtain a white solid. The solid product was dried in vacuo overnight at ambient temperature to obtain 45.1 g of 4-chloro-2-fluoro-3-methoxyphenylboronic acid (88.3% yield); MP. 233-234° C.; 1H NMR (CD3CN, 300 MHz) δ 3.92 (d, 3H, JHF=1.2 Hz), 6.25 (br s, 2H), 7.23 (dd, 1H, J=8.1, 1.5 Hz), 7.35 (dd, 1H, J=8.1, 6.2 Hz) ppm.
	Stage #1: Trimethyl borate; 6-chloro-2-fluoro-3-lithioanisole In hexanes; 1,2-dimethoxyethane at -65 - 20℃; Stage #2: With potassium hydroxide; water In hexanes; 1,2-dimethoxyethane at 23.3℃; for 1.43333h; Stage #3: With hydrogenchloride In water	2 2. Preparation of 4-chloro-2-fluoro-3-methoxyphenylboronic acid A solution of 2-chloro-6-fluoroanisole (40.2 g) in anhydrous 1,2-dimethoxyethane (313 mL) was prepared in a 1-liter three-necked flask equipped with a magnetic stirrer, thermowell with thermocouple temperature probe, a rubber septum, and a condenser with a nitrogen pad. The solution was stirred and cooled to -69.6° C. using a dry ice/acetone bath. A solution of butyllithium (115 mL of 2.5 M butyllithium in hexanes) was added slowly over 4.15 hours using a syringe pump, maintaining the reaction temperature below -65° C. The reaction mixture was stirred for 20 minutes at -70.3° C. to -72.6° C., then trimethyl borate (43 mL) was added slowly over 1.6 hours using a syringe pump, maintaining temperature below -65° C. Upon completion of the trimethyl borate addition, the reaction mixture was allowed to slowly warm to ambient temperature overnight. A solution of potassium hydroxide in water (69.2 g of 45% KOH solution diluted with 485 mL of deionized water) was added to the reaction mixture (at ambient temperature=23.3° C.) over 26 minutes using an addition funnel. The mixture was stirred for 60 minutes, and then it was transferred to a separatory funnel where the phases were allowed to separate. The aqueous layer was washed with tert-butyl methyl ether (2305 mL) to remove unreacted 2-chloro-6-fluoroanisole. The aqueous layer was then transferred to a 1-liter Erlenmeyer flask and acidified by the dropwise addition of 6 M aqueous hydrochloric acid (161 mL). The mixture first turns milky, then the bulk of the product separates as a yellow oil. The product was extracted from the acidified mixture using ethyl acetate (2304 mL). The ethyl acetate layers were combined, washed with saturated aqueous sodium chloride (304 mL), dried with anhydrous magnesium sulfate, filtered, and concentrated on a rotary evaporator to obtain a white solid. The solid product was dried in vacuo overnight at ambient temperature to obtain 45.1 g of 4-chloro-2-fluoro-3-methoxyphenylboronic acid (88.3% yield); MP. 233-234° C.; 1H NMR (CD3CN, 300 MHz) δ 3.92 (d, 3H, JHF=1.2 Hz), 6.25 (br s, 2H), 7.23 (dd, 1H, J=8.1, 1.5 Hz), 7.35 (dd, 1H, J=8.1, 6.2 Hz) ppm.

Reference： [1]Current Patent Assignee: CORTEVA INC - US2009/182168, 2009, A1 Location in patent: Page/Page column 2
[2]Current Patent Assignee: CORTEVA INC - US2009/182168, 2009, A1 Location in patent: Page/Page column 3
[3]Current Patent Assignee: CORTEVA INC - US2009/182168, 2009, A1 Location in patent: Page/Page column 2-3

5
[ 944129-07-1 ]
[ 1240313-17-0 ]
[ 1240312-70-2 ]

Yield	Reaction Conditions	Operation in experiment
11%	With cesium fluoride In 1,2-dimethoxyethane; water at 140℃; for 0.333333h; Inert atmosphere; microwave irradiation;	16 4-Chloro-2-fluoro-3-methoxyphenyl boronic acid (232 mg, 1.13 mmol), 4-amino-2-chloro- 6-methoxycarbonyl-5-prop-1-ynyl-pyrimidine (prepared as described in example 15) (170 mg, 0.76 mmol), caesium fluoride (228 mg, 1.5 mmol) and [1,1'- bis(diphenylphosphino)-ferrocene] dichloropalladium (.I) complex with dichloromethane (1 :1) (62 mg, 0.075 mmol) were placed in a vial. The vial was evacuated and backfilled with nitrogen before adding dimethoxyethane (5 ml) and water (5 ml). The reaction mixture was heated in a microwave reactor at 140 0C for 20 minutes, then allowed to cool. Dichloromethane was added and the solution washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica using a gradient of hexane/ethyl acetate (9:1 to 3:2) as eluent to provide 4-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)- 6-methoxycarbonyl-5-prop-1-ynyl-pyrimidine as a white solid (30 mg, 11 %). 1H nmr (400 MHz, CDCI3) δH 7.70 (1H, t), 7.20 (1H, dd), 5.80 (2H, br s), 4.00 (6H, s), 2.20 (3H, s) ppm.

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2010/92339, 2010, A1 Location in patent: Page/Page column 109-110

6
[ 851442-71-2 ]
[ 944129-07-1 ]
[ 1417332-47-8 ]

Yield	Reaction Conditions	Operation in experiment
	With cesium fluoride In 1,2-dimethoxyethane; water at 100℃; for 0.25h; microwave irradiation;	11 Example 11; Preparation of methyl 4-acetamido-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-hydroxypicolinate; Methyl 4-acetamido-3-(benzyloxy)-6-bromopicolinate (prepared as in Kong, L. C. C. et al. U.S. Patent Application Publication 2005/0176767; 1.5 g, 4.0 mmol), (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (1.2 g, 5.9 mmol), bis(triphenylphosphine)-palladium(II) dichloride (PdCl2(PPh3)2; 278 mg, 0.4 mmol), cesium fluoride (CsF; 1.2 g, 7.9 mmol), 1,2-dimethoxyethane (DME; 7 mL), and H2O (7 mL) were combined and heated in a Biotage microwave at 100° C. for 15 min. H2O was added to the reaction mixture, and the product was extracted with EtOAc. The combined organic extracts were washed with satd aq NaCl, dried with sodium sulfate (Na2SO4), filtered and concentrated. Flash chromatography (SiO2; 0-45% EtOAc/cyclohexane gradient) afforded methyl 4-acetamido-3-(benzyloxy)-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate as a yellow solid: mp 115-120° C.; 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J=1.6 Hz, 1H), 7.66 (s, 1H), 7.59 (dd, J=8.5, 7.7 Hz, 1H), 7.45 (s, 5H), 7.24 (dd, J=8.6, 1.7 Hz, 1H), 5.13 (s, 2H), 4.03 (s, 3H), 3.99 (d, J=1.0 Hz, 3H), 1.88 (s, 3H); ESIMS m/z 459 ([M+H]+).

Reference： [1]Current Patent Assignee: CORTEVA INC - US2013/5574, 2013, A1 Location in patent: Page/Page column 16-17

7
[ 944129-07-1 ]
[ 1417332-44-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: cesium fluoride / bis-triphenylphosphine-palladium(II) chloride / 1,2-dimethoxyethane; water / 0.25 h / 100 °C / microwave irradiation 2: hydrogen / 10 wt% Pd(OH)2 on carbon / ethanol / 24 h

Reference： [1]Current Patent Assignee: CORTEVA INC - US2013/5574, 2013, A1

8
[ 944129-07-1 ]
[ 1417331-18-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: cesium fluoride / bis-triphenylphosphine-palladium(II) chloride / 1,2-dimethoxyethane; water / 0.25 h / 100 °C / microwave irradiation 2: hydrogen / 10 wt% Pd(OH)2 on carbon / ethanol / 24 h 3: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 24 h

Reference： [1]Current Patent Assignee: CORTEVA INC - US2013/5574, 2013, A1

9
[ 944129-07-1 ]
[ 1417331-20-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: cesium fluoride / bis-triphenylphosphine-palladium(II) chloride / 1,2-dimethoxyethane; water / 0.25 h / 100 °C / microwave irradiation 2: hydrogen / 10 wt% Pd(OH)2 on carbon / ethanol / 24 h 3: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 24 h 4: methanol / 25 °C

Reference： [1]Current Patent Assignee: CORTEVA INC - US2013/5574, 2013, A1

10
[ 53145-38-3 ]
[ 944129-07-1 ]

Yield	Reaction Conditions	Operation in experiment
93%		Example 2Alternate Isolation of PBA from MeCN<strong>[53145-38-3]2,6-CFA</strong> (10.0 g, 62.28 mmol) was weighed in a separate flask and transferred to a 3-neck, 500-ml round bottom flask equipped with a thermocouple temperature probe, stir bar, and a N2 inlet. The flask was rinsed with anhydrous DME. Additional DME (total volume of 106 ml) was added to the reaction. The reaction was cooled to - 78 C with a dry ice/acetone bath. Once the reaction reached approximately -77 C, n- BuLi (29 ml, 71.62 mmol, 2.5 M in hexanes) was slowly added dropwise using a syringe pump over a 45 minute period. The highest temperature reached during addition was -70.1 C. After complete addition of «-BuLi, the reaction was left to stir for 1 hour at -72.1 C. After 1 hour, B(OMe)3 (10.5 ml, 93.42 mmol) was added dropwise using a syringe pump over a period of 22 minutes. The highest temperature reached during the addition was -67.0 C. After complete addition of B(OMe)3, the diy ice/ acetone bath was removed and the reaction mixture was warmed to room temperature overnight. The next morning, the reaction mixture temperature was at22.7 C. Using an addition funnel, IN NaOH (aq) (78 ml, 77.85 mmol) was added dropwise to the reaction mixture. After complete addition, the reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was then transferred to a 500-ml separatory funnel and the organic and aqueous layers separated. The aqueous layer was washed with TBME (2 x 75 ml) to remove unwanted impurities and/or unreacted <strong>[53145-38-3]2,6-CFA</strong>. The aqueous layer was acidified with 6N aqueous HC1 (42 ml, 249.1 mmol) and then MeCN (3 x 75 ml) added. Since water and MeCN are miscible, the two distinct layers were not distinguishable. Solid NaCl was then added to saturate the aqueous layer, which resulted in the formation of two distinct layers: the MeCN layer and the aqueous layer, which were separated. The organic layers were combined, dried with MgS04, and filtered into a 500-ml round bottom flask. To determine the yield of the reaction, the PBA solution in MeCN was concentrated to dryness under reduced pressure. The white solid was further dried in a vacuum oven at 55 C to give1 1.8 g (93% yield) of PBA.

Reference： [1]Patent: WO2013/16557,2013,A2 .Location in patent: Page/Page column 12
[2]Patent: WO2013/101665,2013,A1

11
[ 1426539-30-1 ]
[ 944129-07-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-chloro-2-fluoro-3-methoxyphenyl dimethylboronate With water; potassium hydroxide at 16 - 20℃; for 0.25h; Stage #2: With hydrogenchloride In water for 0.25h;	2 Formation of PBA in a Continuous Stirred-Tank Apparatus The PBA-diMe in the intermediate solution was converted to PBA product by treatment with aqueous potassium hydroxide (KOH) followed by acidification. The intermediate solution was transferred to a 500 ml flask and placed in a cool water bath on a stir plate. A KOH solution was prepared using 22 g of 45% aqueous KOH diluted with 87 ml of deionized water to make 109 g of 9% KOH solution (2 equivalents). With the intermediate solution temperature at about 16° C., the aqueous KOH solution was added dropwise to the intermediate solution with an addition funnel over about 10 minutes. The solution was subsequently mixed for 50 minutes at 20° C. to form a reaction mixture. The reaction mixture was filtered to remove a small amount (less than about 0.2 g) of white solids using a Buchner funnel and a water aspirator. The reaction mixture was then transferred to a separatory funnel and allowed to separate. After 50 minutes the bottom (aqueous) layer was transferred to a 500 ml flask. Sodium chloride (about 3 g) was added and the reaction mixture was extracted with tert-butyl methyl ether (105 ml, 78 g) for about 30 minutes. The reaction mixture was transferred to a separatory funnel. After about 30 minutes the bottom (aqueous) layer was transferred to a flask and 36% hydrochloric acid (HCl) (4 equivalents, 35 g (30 ml) of 36% solution) was added dropwise with an addition funnel. The solution was stirred for about 15 minutes. An amorphous mass of «white» solid was observed. Acetonitrile (64 g, 81 ml) was added and the solution was stirred for about 20 minutes at about 20° C. The solution was transfered to a separatory funnel and allow to separate for 50 minutes. An upper (organic) product layer was transferred to a sample jar. Analysis of the acetonitrile solution of PBA product showed 13% PBA by weight for a 67% recovery of PBA.
	With water; potassium hydroxide In 1,2-dimethoxyethane at 30℃; for 2h; Cooling;	1 Example 1 : Synthesis and Isolation of PBA 2,6-CFA (10.0 g, 62. 28 mmol) was weighed in a separate flask and transferred to a 3-neck, 500-ml round bottom flask equipped with a thermocouple temperature probe, stir bar, and a N2 inlet. The flask was rinsed with anhydrous DME. Additional DME was added to the reaction flask to give a total DME volume of 106 ml. The reaction was cooled to -78°C with a dry ice/acetone bath. Once the reaction reached -77°C, ft-BuLi (29 ml, 71.62 mmol, 2.5 M in hexanes) was added slowly, dropwise, using a syringe pump over a 45 minute period. The highest temperature reached during addition was -70.1 °C. After complete addition of w-BuLi, the reaction was left to stir for 1 hour at -74.1°C. After 1 hour, B(OMe)3 (10.5 ml, 93.42 mmol) was added dropwise using a syringe pump over a period of 22 minutes. The highest temperature reached during the B(OMe)3 addition was -67.0°C. After the complete addition of B(OMe)3, the dry ice/acetone bath was removed and the reaction mixture warmed to room temperature (about 23.1 °C). Once the reaction mixture reached room temperature, the reaction was left to stir an additional 1 hour at that temperature. This procedure was repeated several times to generate a large amount of PBA-diMe in DME. 244.0 g of PBA-diMe in DME (10.3% PBA basis), 27.82 g of 45% KOH, and 108.70 g of deionized water were added to a one liter flask containing a magnetic stirrer. The one liter flask was cooled with a cold water bath to maintain a temperature of 25°C to 30°C during the additions. The mixture was stirred for about 2 h and was then vacuum filtered to remove lithium salts. Aqueous and organic phases of the mixture were then separated. Concentrated HC1 (40.48 g) was added to the aqueous phase. The aqueous phase was cooled with a cold water bath during the addition of the HC1 to maintain a temperature of 25°C to 30°C. The aqueous phase was stirred for about 15 minutes to achieve complete dissolution. MIBK (35.91 g) was added to the aqueous phase and the aqueous phase was stirred for about 15 minutes. An organic phase separated from an aqueous phase to give 127.6 g of the organic phase. Analysis of the organic phase gave 17.57% by weight (89.1% yield) of PBA. The organic phase was concentrated to dryness and then placed in a vacuum oven at 50°C to give a white solid.

Reference： [1]Current Patent Assignee: CORTEVA INC - US2013/66115, 2013, A1 Location in patent: Paragraph 0045
[2]Current Patent Assignee: CORTEVA INC - WO2013/101665, 2013, A1 Location in patent: Page/Page column 10-11

12
methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate [ No CAS ]
[ 944129-07-1 ]
[ 943831-44-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate; (4-chloro-2-fluoro-3-methoxyphenyl)-boronic acid With palladium diacetate; triphenylphosphine In 1,2-dimethoxyethane; acetonitrile Inert atmosphere; Stage #2: With potassium carbonate In 1,2-dimethoxyethane; water; acetonitrile at 50℃; for 2.5h;	5 Example 5 Synthesis of methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2- fluoro-3- methoxyphenyl)pyridine- 2-carboxylate (Compound 4) Example 5 Synthesis of methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2- carboxylate (Compound 4) To a 1-L jacketed reactor equipped with a condenser, mechanical stirrer, thermocouple temperature probe, and nitrogen inlet was added 40.0 g of methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate (AcAP-Me), 0.4 g of triphenylphosphine, and 0.17 g of palladium(II) acetate under a nitrogen atmosphere. A 25 ml rinse with acetonitrile (previously degassed by sparging with nitrogen for 45 minutes) was employed to ensure all solids were transferred to the reactor. A total of 157.1 g of a 22% solution of PBA (prepared as described in Example 1 or Example 2 and previously degassed by sparging with nitrogen for 45 minutes ) in 1,2-dimethoxyethane (DME) and methyl isobutyl ketone (MIBK) was added under nitrogen via a pump. The ratio of MIBK to DME in the PBA solution varies from 2: 1 to 0.7:1 (MIBK:DME) depending on the equivalents of the solvents used to prepare the PBA solution, or more commonly from 1.6: 1 to 1.2: 1. Stirring at 300 RPM was initiated. An additional 100 ml of acetonitrile (previously degassed by sparging with nitrogen for 45 minutes) was added and complete dissolution was achieved. A total of 275.3 g of a 22.9% aqueous solution of potassium carbonate (previously degassed by sparging with nitrogen for 45 minutes) was added via a pump. The solution was heated to about 50°C for 2.5 hours. Towards the end of the reaction, the product tended to precipitate and a small product rind formed on the reactor wall. The organic phase of the mixture was sampled and analyzed by GC to determine reaction completion. The mixture was heated to about 65°C to ensure complete product dissolution. The mixture was filtered (polish filtration) at 65°C to remove reduced palladium and inorganic salts. The organic and aqueous phases were separated at 65°C and the organic (top) phase was transferred to a 1 -L reactor equipped with a mechanical stirrer, condenser, thermocouple temperature probe, and nitrogen inlet. A total of 71.7 g of MIBK was added as a rinse to facilitate the transfer. A total of 380 ml of a 40% sodium bisulfite solution was added and the mixture was heated to about 80°C for about 6 hours. The mixture was filtered at 80°C to remove reduced palladium and inorganic salts and the phases were separated. The phase separation can be conducted at a temperature as low as 65°C. The organic phase (top) was transferred to a 1-L reactor equipped with a mechanical stirrer, distillation head, temperature probe, and vacuum capability. The mixture was concentrated under vacuum in order to remove water from the mixture, resulting in a slurry of methyl 4-(acetylamino)-3-chloro-6- (4-chloro-2-fluoro-3 -methoxyphenyl)pyridine-2-carboxylate.

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2013/102078, 2013, A1 Location in patent: Page/Page column 19; 20

13
[ 121-43-7 ]
[ 53145-38-3 ]
[ 944129-07-1 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1 Synthesis and Isolation of PBA (Compound 2) A solution of <strong>[53145-38-3]2,6-CFA</strong> (10 g, 62. 28 mmol) was lithiated using n-BuLi at a temperature below about -65 C in anhydrous DME under a nitrogen atmosphere. B(OMe)3 was added and the reaction mixture slowly warmed to room temperature. A solution of KOH in water was added to the reaction mixture at room temperature. After the addition, the temperature of the reaction mixture increased to 30C. The reaction mixture was cooled with a cold-water bath to maintain a temperature of from approximately 25C to approximately 30C. However, the reaction may be conducted without the cold-water bath, with no change in yield observed. The reaction mixture is stirred for 90 minutes and the contents transferred to a separatory funnel where the organic and aqueous phases were allowed to separate. The bottom aqueous layer, which contained the PBA-K, was drained to a flask and acidified by the dropwise addition of 6 M aqueous HC1. Alternatively, solid KC1 was added to the flask before acidification to minimize the amount of water extracted into the organic phase. The method for converting the PBA-K to PBA produced no difference in yield. After the addition, the temperature of the reaction mixture increased to 30C. The flask was cooled with a cold-water bath to maintain a temperature of from approximately 25 C to approximately 30C. However, the reaction can be carried out without the cold-water bath, with no change in yield observed. The mixture was stirred for 15 minutes to achieve complete dissolution. MIBK was added, and the reaction mixture stirred for 15 minutes. The organic and aqueous phases were separated to give a solution of PBA in MIBK. Analysis of the solution gave recovery of PBA in a 90% yield.

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 1211 - 1220
[2]Patent: WO2013/102078,2013,A1 .Location in patent: Page/Page column 15

14
[ 76-09-5 ]
[ 944129-07-1 ]
[ 1126321-06-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	In ethyl acetate at 23.1℃; for 2h; Inert atmosphere;	Example 2: Formation of PBE-pinacol from PBA Example 2: Formation of PBE-pinacol from PBA PBA solid (3.0 g, 14.68 mmol) was added to a 100 mL round bottom flask equipped with a magnetic stirrer and N2 inlet. The PBA solid was dissolved in EtOAc (35 mL) and pinacol (1.7 g, 14.7 mmol) was added. The mixture was stirred for 2 hours at room temperature (approximately 23.1°C). After 2 hours the reaction was complete. The reaction mixture was concentrated under reduced pressure to give an oil that, when placed on high vacuum, gave a crystalline solid of PBE-pinacol in >99% yield. A portion of the crystalline solid was purified using column cliromatography using a 8: 1 Hexane/EtOAc ratio (v/v) to give a PBE-pinacol solid that had a melting point of 61°C to 62°C.

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2013/101665, 2013, A1 Location in patent: Page/Page column 11

15
[ 944129-07-1 ]
[ 496849-77-5 ]
[ 1546765-39-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4,5,6-trichloropicolinic acid With bis-triphenylphosphine-palladium(II) chloride; triethylamine In water; acetonitrile at 50℃; for 0.25h; Inert atmosphere; Stage #2: (4-chloro-2-fluoro-3-methoxyphenyl)-boronic acid In 1,2-dimethoxyethane; water; acetonitrile at 50℃; for 5h; Inert atmosphere;	14 Example 14. 4,5 -Dichloro-6-(4-chloro-2-fluoro-3 -methoxyphenyl)picolinic acid [00108] To a 50 mL three-necked flask equipped with a stirring bar and a condenser were placed 4,5,6-trichloropicolinic acid (0.503 g, 90 % purity, 2 mmol), triethylamine (0.607, 6 mmol), acetonitrile (5 g) and water (5 g). The mixture became a homogeneous solution which was sparged with nitrogen for 15 minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.042 g, 0.06 mmol) was added and the mixture was heated to 50 °C. In a one-necked flask were placed (4-chloro-2-fluoro-3-methoxyphenyl)-boronic acid (1.951 g, 22 wt % in methyl isobutyl ketone/dimethoxyethane, 2.1 mmol) and acetonitrile (2.5 g). The solution was sparged with nitrogen for 15 minutes, and then slowly added to trichloropicolinic acid solution by a syringe pump at 50 °C. The total addition time was about two hours. The reaction mixture was stirred at 50 °C for three more hours. A sample was taken and analyzed by HPLC. The LC results indicated that the reaction was completed. The reaction mixture was allowed to cool to room temperature. To acidify the reaction mixture, hydrochloric acid (6 g, 1 N HC1 in water) was added to the flask dropwise. The resulting slurry was stirred overnight. The mixture was filtered and a light brown solid was obtained. This crude product was stirred in acetonitrile at room temperature for 2 hours. After filtration and vacuum drying, the white product (0.44 g, 92 % LC purity, 58 % yield) was obtained. ‘H NMR (400 MHz, THF-d8) ö 8.35 (s, 1H), 7.40 (dd, J = 8.5, 1.7 Hz, 1H), 7.23 (dd, J = 8.5, 6.9 Hz, 1H), 4.00 (d, J = 1.3 Hz, 3H); ‘3C NMR (101 MHz, THF-d8) ö 163.62 (s), 154.81 (s), 153.03 (s), 152.31 (s), 147.36 (s), 144.64 (d,J= 13.4 Hz), 143.70 (s), 133.21 (s), 129.55 (d, J= 3.5 Hz), 126.34 (d, J= 14.4 Hz), 125.71 (s), 125.41 -125.01 (m), 60.91 (d, J= 4.8 Hz); ‘9F NMR (376 MHz, THF-d8) ö -128.96. ESI/LC/MS/PI (M+H) = 349.9559 (100 %), 351.9531 (99.66 %), 353.95 (33.59 %).

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2014/18502, 2014, A1 Location in patent: Paragraph 00108

16
[ 944129-07-1 ]
[ 1546765-42-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: triethylamine; bis-triphenylphosphine-palladium(II) chloride / water; acetonitrile / 0.25 h / 50 °C / Inert atmosphere 1.2: 5 h / 50 °C / Inert atmosphere 2.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 75 °C

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2014/18502, 2014, A1

17
[ 944129-07-1 ]
[ 1546765-44-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: triethylamine; bis-triphenylphosphine-palladium(II) chloride / water; acetonitrile / 0.25 h / 50 °C / Inert atmosphere 1.2: 5 h / 50 °C / Inert atmosphere 2.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 75 °C 3.1: potassium fluoride / sulfolane / 20 - 130 °C

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2014/18502, 2014, A1

18
[ 944129-07-1 ]
[ 108087-83-8 ]
C₁₅H₁₄ClFO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With manganese(IV) oxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 25℃; Flow reactor;

Reference： [1]Tran, Duc N.; Battilocchio, Claudio; Lou, Shing-Bong; Hawkins, Joel M.; Ley, Steven V. [Chemical Science, 2015, vol. 6, # 2, p. 1120 - 1125]

19
[ 944129-07-1 ]
[ 496849-77-5 ]
[ 1546765-39-2 ]
5-chloro-4,6-bis(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 74% 2: 6%	Stage #1: 4,5,6-trichloropicolinic acid With palladium diacetate; triethylamine In water; acetonitrile for 0.5h; Inert atmosphere; Stage #2: (4-chloro-2-fluoro-3-methoxyphenyl)-boronic acid With triethylamine In water; acetonitrile at 65℃; for 24.5h; Inert atmosphere;	7 Catalyst Recycling with No Additional Ligand A 250 ml-round bottom flask equipped with overhead stirring, nitrogen sparge, and temperature control was charged with 4,5,6-TCPA (7.99 g, 0.033 mol). The organic- rich layer from a neutralized mother liquor solution (1.5 mol % Pd, 98 g of a 1100 ppm Pd solution) was added to the flask. A solution of ACN (94 mE), water (36 mE), and TEA (14.5 mE) was prepared and added to the 250 mE-round bottom flask. The mixture was purged with nitrogen for 30 minutes (mm) 4-Chloro-2-fluoro-3-methoxyphenyl)boronic acid (7.33 g, 0.036 mol) was added, and the mixture was sparged with nitrogen for 30 mm, then padded with nitrogen and heated for 18 hours (h) at 65° C. The reaction progress was monitored by liquid chromatography (LC). 4,5-DCPA was produced in 57% in-pot yield. The remaining balance of material was 4,5,6-TCPA.

Reference： [1]Current Patent Assignee: CORTEVA INC - US2016/340311, 2016, A1 Location in patent: Paragraph 0064

20
[ 944129-07-1 ]
[ 88912-24-7 ]
C₁₃H₈Cl₂FNO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a 100 ml round bottom flask equipped with a magnetic stirrer, reflux condenser and a nitrogen inlet were added 5,6-dichioropicolinic acid (5.00 g, 23.1 mmol), TEA (8.3 g, 81.0 mmol), ACN (39.9 g) and water (15.3 g). The solution was sparged for 30 mm with nitrogen (1 mE/mm) After sparging, 1,1 ?-bis(diphenylphosphino)ferrocene (dppf; 0.19 g, 0.343 mmol) and palladium(II) acetate (0.08 g, 0.356 mmol) were added to the solution. (4-Chioro-2-fluoro-3- methoxyphenyl)boronic acid 5.4 g, 26.9 mmol) was added in one portion, and heating was initiated. The reaction mixture was heated to 550 C., and was sampled and analyzed periodically by liquid chromatography. No boronic acid was remaining after 22 hours, and heating was stopped. The reaction mixture was allowed to cool to 45 C. Once at temperature, 50% sulfuric acid (7.2 g) was added. No precipitation was observed, so the mixture was cooled. A precipitate formed, which was isolated by filtration. The flask was rinsed with cold mother liquor to isolate all of the product. The wetcake was then rinsed with cold ACN- water solution (8.75 g and 11.25 g, respectively). The palladium content was analyzed in the wetcake, wash and mother liquors, with 96% of the palladium in the mother liquor and wash, and 4% in the wet cake. 98% of the total palladium added was recovered.

Reference： [1]Patent: US2016/340311,2016,A1 .Location in patent: Paragraph 0070-0071

21
[ 502142-81-6 ]
[ 944129-07-1 ]
methyl 6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.1%	With palladium diacetate; potassium hydrogencarbonate; triphenylphosphine In methanol; water; acetonitrile at 50℃; for 22h; Inert atmosphere;	1 Example 1. Direct Suzuki Coupling In a round bottom flask methyl 6-amino-2,5-dichloropyrimidine-4-carboxylate (AP)(3 .Og, 13.5 mmol), (4-chloro-2-fluoro-3 -methoxyphenyl)boronic acid (ABA) (3 .4g, 16.2 mmol),methanol (3.Og, 94.3 mmol), 4-methyl-2-pentanone (3.5g, 35.2 mmol) and acetonitrile (7.8g,191.0 mmol) were combined. In a separate vial water (29.Og) and potassium bicarbonate (3.4g,34.0 mmol) were combined to make a 10.5 wt% base solution. Both the reaction mixture andbase solution were sparged with nitrogen for 30 minutes. To the reaction mixture was addedbase solution (13.8g, 14.5 mmol), triphenylphosphine (0.14 g, 0.54 mmol), and palladium acetate(0.06g, 0.27 mmol). The reaction was heated to 50°C. After 22 hr, the reaction was heated to65°C and then phase separated. The organic phase was analyzed to afford 68.1% yield of methyl6-amino-5-chloro-2-(4-chloro-2-fluoro-3 -methoxyphenyl)pyrimidine-4-carboxylate.

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2017/201377, 2017, A1 Location in patent: Page/Page column 23

22
[ 944129-07-1 ]
benzyl 4-amino-3,6-dichloro-5-fluoropicolinate [ No CAS ]
[ 1390661-72-9 ]

Yield	Reaction Conditions	Operation in experiment
67.9%	With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; water; acetonitrile at 60℃; for 4h;	1 Example 1. Direct Suzuki Coupling In a round bottom flask benzyl 4-amino-3,6-dichloro-5-fluoropicolinate (AP) (1.5g, 4.8 mmol), (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (ABA) (1. ig, 5.3 mmol), methanol (1.Og, 31.0 mmol), 4-methyl-2-pentanone (1.2g, 11.6 mmol), acetonitrile (2.8g, 68.2 mmol) and water (4.2g) were combined. The mixture was sparged with nitrogen for 30 minutes before adding 47 wt% potassium carbonate (0.45g, 1.5 mmol), triphenylphosphine (0.05g, 0.19 mmol), and palladium acetate (0.02g, 0.10 mmol). The reaction was heated to 60°C and stirred for 30 minutes at which time 47 wt% K2C03 solution was added (0.47g, 1.6 mmol). The reaction was stirred for another 30 minutes at which time additional 47 wt% K2C03 solution was added (0. lOg, 0.3 mmol). The reaction was stirred for another 30 minutes at which time additional 47 wt% K2C03 solution was added (0. lOg, 0.3 mmol). After 2.5 hr, the reaction was heated to 65°C and then phase separated. The organic phase was analyzed to afford 67.9% yield of benzyl 4- amino-3 -chloro-6-(4-chloro-2-fluoro-3 -methoxyphenyl)-5-fluoropicolinate.
	With palladium diacetate; potassium hydrogencarbonate; triphenylphosphine In tetrahydrofuran at 60℃; for 16h; Inert atmosphere;	33.B B. Benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (Formula I-A) from 14 (a 6-chloropyridine compound) A 50-mL three-neck flask equipped with a stir bar, a condenser, a thermocouple, and a nitrogen pad, was charged with benzyl 4-amino-3,6-dichloro-5-fluoropicolinate (Formula Al; 1.56 g, 5.0 mmol), (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (Formula Bl; 1.12 g, 5.5 mmol), solid KHCO3 (1.00 g, 10 mmol), THF (15 mL), and water (5 mL). The mixture was stirred and sparged with nitrogen gas for 30 minutes. Triphenylphosphine (PI13P; 26.2 mg, 0.1 mmol), and palladium acetate (Pd(OAc)2; 11.2 mg, 0.050 mmol) were added under nitrogen. The mixture was heated and stirred at 60 °C for 16 hours. HPLC analysis of the reaction mixture showed the reaction gave 73.0 area% of the title compound, with only 22.9 area% of unreacted Formula Al, and no boronic acid (which means that the reaction stalled).

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2017/201377, 2017, A1 Location in patent: Page/Page column 24
[2]Current Patent Assignee: CORTEVA INC - WO2021/188654, 2021, A1 Location in patent: Page/Page column 37-38

23
[ 350601-39-7 ]
[ 944129-07-1 ]
halauxifen methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.4%	With palladium diacetate; potassium carbonate; triphenylphosphine; In water; acetonitrile; at 50.0℃; for 22.0h;Inert atmosphere;	Methyl 4-amino-3,6-dichloropyridine-2-carboxylate (AP-Me) (8.OOg, 36.19 mmol), a 25.55 wt% solution of 4-chloro-2-fluoro-3-methoxy-phenylboronic acid (ABA) (33.30g, 41.60 mmol), acetonitrile (23.9 mL) and water (28.0 mL) were added to a round bottom flask. The flask contents were sparged with nitrogen for 30 minutes as well as a 47 wt% aqueous solution of K2C03 (26.6g, 90.50 mmol, sparged separately). After loading the K2C03 solution, triphenylphosphine (0. 190g, 0.724 mmol) and palladium acetate (0.08 ig, 0.3 62 mmol) were added to the flask. The reaction was heated at 50C for 22 hours. After 22 h, the reaction was heated to 65 C and the phase separated. The organic phase was analyzed to afford 81.4% yield of methyl 4-amino-3 -chloro-6-(4-chloro-2-fluoro-3 -methoxyphenyl)pyridine-2-carboxylate.
	With bis-triphenylphosphine-palladium(II) chloride; potassium fluoride; In water; acetonitrile; for 4.0h;Reflux;	Intermediate b (22.7 mmol), substituted boronic acid (34.1 mmol),Potassium fluoride (60 mmol), dichlorobis(triphenylphosphine)palladium (2.27 mmol) dissolved in acetonitrile/water 40 mL (V/V = 3:1).Heated to reflux for 4 h,After the reaction, the celite was suction filtered, and the filtrate was extracted with ethyl acetate and dried.Dichloromethane/ethyl acetate = 100:1 (V/V) was passed through a silica gel column to afford intermediate c.

Reference： [1]Patent: WO2017/201377,2017,A1 .Location in patent: Page/Page column 22; 25; 26; 27; 28; 29; 30; 31; 32
[2]Patent: CN109485600,2019,A .Location in patent: Paragraph 0063-0065

24
[ 496850-09-0 ]
[ 944129-07-1 ]
methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.1%	With palladium diacetate; potassium carbonate; triphenylphosphine In methanol; lithium hydroxide monohydrate; acetonitrile at 60℃; for 7h;	1 Example 1. Direct Suzuki Coupling In a round bottom flask methyl 4-amino-3,6-dichloro-5-fluoropicolinate (AP) (3. ig, 13.0 mmol), (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (ABA) (3.Og, 14.5 mmol), methanol (2.7g, 84.3 mmol), 4-methyl-2-pentanone (3.lg, 31.0 mmol), acetonitrile (7.6g, 185.1 mmol) and water (11.3g) were combined. The mixture was sparged with nitrogen for 30 minutes before adding 47 wt% potassium carbonate (1.2g, 4.1 mmol), triphenylphosphine (0.07 g, 0.27 mmol) and palladium acetate (0.03g, 0.13 mmol) in one portion. The reaction was heated to 60°C and stirred for 30 minutes at which time 47 wt% K2C03 solution was added (1.2g, 4.1 mmol). The reaction was stirred for another 30 minutes at which time additional 47 wt% K2C03 solution was added (0.8g, 2.7 mmol). The reaction was stirred for another 30 minutes at which time additional 47 wt% K2C03 solution was added (0.6g, 2.0 mmol). After 5.5 hours, the reaction was heated to65°C and then phase separated. The organic phase was analyzed to afford 88.1% yield of methyl4-amino-3 -chloro-6-(4-chloro-2-fluoro-3 -methoxyphenyl)-5-fluoropicolinate.
65.8%	With potassium fluoride; bistriphenylphosphorus palladium(II) dichloride In 1,4-dioxane; lithium hydroxide monohydrate at 100℃; for 16h; Inert atmosphere;	1.1 Step 1: Synthesis of compound 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate methyl ester Methyl 4-amino-3,6-dichloro-5-fluoropicolinate (5.00 g, 20.9 mmol) was added to a mixed solution of dioxane (40 mL) and water (10 mL), and fluorine was separated at room temperature. Potassium chloride (3.65g, 62.8mmol) and (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (5.13g, 25.1mmol) were added to the system, and then bistriphenyl was added under nitrogen protection. Phosphorus dichloride (0.73g, 1.05mmol) was added to the system, the temperature was raised to 100°C, and the reaction was performed at 100°C for 16 h. After the reaction was completed, the temperature was lowered to room temperature, water (50 mL) was added, and ethyl acetate (50 mL) was used to extract 2 For the second time, the organic phases were combined, the solvent was removed under reduced pressure, and purified by column chromatography (eluent: PE/EtOAc (v/v)=5/1) to obtain 5.00 g of a white solid product, yield: 65.8%.

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2017/201377, 2017, A1 Location in patent: Page/Page column 24; 25
[2]Current Patent Assignee: DONGGUAN HEC PESTICIDE RES AND DEVELOPMENT CO LTD - CN114507226, 2022, A Location in patent: Paragraph 0181-0186

25
[ 944129-07-1 ]
C₁₁H₇Cl₃N₄O₂ [ No CAS ]
C₁₈H₁₂Cl₃FN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; cesium fluoride In 1,4-dioxane; water at 120℃; for 12h; Inert atmosphere;	6 6. Synthesis of Compound 126 Compound II-5 (1 g, 3.0 mmol, 1 eq), (674 mg, 3.30 mmol, 1.1 eq) was added sequentially to a 50 ml single-necked flask at room temperature.CsF (911 mg, 6 mmol, 2 eq), 1,4-dioxane and water (V/V = 4/1).After replacing N2 three times, Pd(dppf)Cl2.CH2Cl2 (122 mg, 0.15 mmol, 0.05 eq) was added, followed by heating to 120 ° C and stirring for 12 hours.The TLC detects that the starting material is completely reactive. The reaction solution was poured into 20 ml of water, extracted with ethyl acetate three times, and the organic phase was dried and then dried.After separation and purification by column chromatography, compound 126 (0.7 g, 51% yield) (yellow solid).

Reference： [1]Current Patent Assignee: QINGDAO KING AGROOT PLANT PROTECTION SERVICE CO LTD - CN108774179, 2018, A Location in patent: Paragraph 0141; 0142; 0143

26
[ 132308-19-1 ]
[ 944129-07-1 ]
5-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid [ No CAS ]