301 302 a. Preparation of compound 301. To a dry, argon purged three-neck round bottom flask (1000 mL) were added anhydrous dichloromethane (100 mL) and Et₂Zn (28 mL, 273 mmol) at 0 °C. (CAUTION: Source of argon can not be from needle. Use appropriate glass adapter only. A second bubbler can also be attached to the flask to prevent excessive pressure build up.) Cyclopenten-3-ol (10.0 mL, 119 mmol) was then added dropwise (large quantity of ethane gas was produced) to the flask and the reaction mixture was allowed to stir until the evolution of gas had ceased. Diiodomethane (22 mL, 242 mmol) was then added dropwise over a period of 30 minutes. The reaction was allowed to warm to room temperature and continued to stir overnight under a positive flow of argon, at which point TLC analysis had indicated complete disappearance of the starting alcohol. The reaction was then diluted with CH₂CI₂ and quenched with 2M HCI (white precipitate should be completely dissolved). The biphasic mixture was poured into a separatory funnel and the organic layer was collected. The solvent was removed under reduced pressure until 100 mL of material containing compound 301 remained. b. Preparation of compound 302. Anhydrous dichloromethane (525 mL) was added to the flask followed by the dropwise addition of triethylamine (34 mL, 245 mmol). The reaction continued to stir at room temperature under a positive flow of nitrogen at which point, disuccinimidylcarbonate (40.7 g, 159 mmol) was added to the flask portion wise. The reaction was allowed to stir until TLC analysis indicated complete disappearance of the starting material (2-3 days). Upon completion, the reaction mixture was quenched with 1 M HCI (200 mL x 2) and washed with H₂0 (200 mL x 2). The desired material was extracted using CH₂CI₂and the combined organic layers were dried using anhydrous MgS0 and passed through a silica plug. The solvent was removed under reduced pressure and the crude material was purified using flash chromatography (R_f = 0.33, 1 :1 Hex/EtOAc) to provide compound 302 (22 g, 75%): ¹H NMR (300 MHz, CDCI₃): δ 5. 24 (t, 1 H), 3.82 (s, 4H), 2.24 (m, 2H), 2.03 (d, 2H), 1.38 (m, 2H), 0.48 (m, 1 H), 0.40 (m, 1 H).

c. Preparation of compound 304. N-i-Boc-cis-4-Hydroxy-L-Proline methyl ester 303 (100.0 g, 407.7 mmol) and DABCO (1.5eq, 68.6g, 61 1.6 mmol) were dissolved in anhydrous toluene (200 mL) in a 2 L three necked round bottom flask with a mechanical stirrer and an addition funnel. After cooling the solution to 0 °C under N₂, A solution of 4-Bromo-benzenesulfonyl chloride (1.3eq, 135.6g, 530.0 mmol) in 300 mL of toluene was added through addition funnel over 60 minutes. The reaction mixture was stirred and warmed to room temperature overnight (16 hours). The mixture was slowly poured into 2L 1 M Na₂C0₃ (aq.), and the product was extracted with EtOAc (2L). After the organic phase was washed by 0.5 N HCI (2L), H₂0 (1 L), and brine (1 L), it was dried (MgS0₄), concentrated to give 195.45 g of a yellow oily brosylate product. To a solution of the above brosylate (407.7 mmol) in dichloromethane (300 mL) was slowly added 4.0 M HCI in dioxane (500 mL, 5eq) and the resulting solution was allowed to stir at room temperature for 2 hours. After ether (500mL) was added to the reaction mixture, the mixture was stirred for 15 minutes and the white precipitate was collected by filtration. The solid was washed with ether and hexane and then dried under vacuum overnight to obtain 153.0 g of the HCI amine salt of compound 304, 381.8 mmol, in 94% yield for two steps. d. Preparation of compound 305. To a solution of Boc-fert-butyl-glycine (97.0g, 420.0 mmol) in DMF (200mL) and DCM (200mL) were added HATU (217.76g, 572.7 mmol) and Hunig’s base (126 mL, 1 145.4 mmol) at room temperature. After the mixture was stirred for 20 minutes at room temperature, a solution of the previous HCI salt (153.0 g, 381.8 mmol) and Hunig’s base (126 mL, 1 145.4 mmol) in DMF (200mL) and dichloromethane (200mL) was added to the above acid mixture in one portion. The reaction mixture was stirred at room temperature for 3h, with monitoring by LCMS. The reaction mixture was concentrated to remove dichloromethane under reduced pressure and the white solid that formed was filtered off. The remaining DMF solution was diluted with ethyl acetate (1 L), washed successively with 3% LiCI (aq) (3x650mL), sat’d NH₄CI (2x500mL), 0.5N HCI (aq) (2x600ml_), brine (500ml_), sat’d NaHC0₃ (3x500mL), and brine (500mL). The resulting organic fraction was dried (MgS0₄) and concentrated to afford compound 305 (111g). e. Preparation of compound 306. To a solution of the methyl ester 305 (120 g, 207.8 mmol) in THF (300 ml_), MeOH (75 mL) was added a solution of LiOH (26.18 g, 623.4 mmol) in H₂0 (150 ml_). The solution was allowed to stir at room temperature for 4 hours. The mixture was cooled in an ice-bath while acidifying with 3N HCI to pH about 5.5, stirred for 10minut.es, and the resulting white solids were collected by filtration. The solids were washed with more water, ether and hexane. The solids were dried under vacuum at 40°C overnight to give 95.78g (82%) of the acid 306. f. Preparation of compound 307. To a solution of the carboxylic acid 306 (81.4 g, 144.27 mmol) in DMF (200ml_) and dichloromethane (200mL) was added HATU (82.3g, 216.4 mmol) and Hunig’s base (47.5 mL, 432.8 mmol) at room temperature. After the mixture was stirred for 20 minutes at room temperature, a solution of amine (158.7 mmol) and Hunig’s base (47.5 mL, 1145.4 mmol) in DMF (200mL) and dichloromethane (200mL) was added to the above acid mixture in one portion. The reaction mixture was stirred at room temperature for 3 hours and monitored by LCMS. After the mixture was concentrated under reduced pressure to remove dichloromethane, the white solids that formed were filtered off. The remaining DMF solution was diluted with ethyl acetate (600mL) and successively washed with 3% LiCI (aq) (2x550mL), sat’d NH₄CI (500mL), 1 N HCI (aq) (500mL), sat’d NaHC0₃(500mL), and brine (300mL). The resulting organic fraction was dried (Na₂S0₄) and concentrated to afford compound 307 (111 g). g. Preparation of compound 308. Compound 307 was dissolved in 4N HCI in dioxane (300 mL) at room temperature and stirred for 2 hours. It was then concentrated under vacuum, and co-evaporated with dichloromethane (2 x 200mL) to dryness. The residue was dissolved in EtOAc (600mL) and sat’d aq. NaHC0₃ (1 L). It was stirred vigorously. After 10 minutes, carbonic acid bicyclo[3.1.0]hex-3-yl ester 2,5-dioxo-pyrrolidin-1-yl ester 302 (41.4 g, 173.1 mmol) was added in one portion. After the resulting mixture was stirred for another 30 minutes, the organic layer was collected and washed with brine (500mL), dried (Na₂S0₄), and concentrated. The crude product was purified by flash chromatography on silica gel with ethyl acetate/hexane to afford 94.44 g (92%) of compound 308.

h. Preparation of compound 310.1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone 309 (70.7 g, 354 mmol) was stirred in 48% aq. HBr (500 mL) at 110 °C for 72 hours. After the mixture was cooled to 0 °C with stirring, the solids were filtered and washed with water. The resulting solids were triturated with a saturated NaHC0₃ solution (-350 mL), filtered, washed with water, and dried under vacuum to give – 40 g (61%) of crude 310 as a dark brown solid. LC/MS = 186 (M⁺+1). i. Preparation of compound 311. 1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone 310 (40 g, 215 mmol) was dissolved in DMF (360 ml). Cesium carbonate (140 g, 430 mmol) was added, followed by bromoacetaldehyde dimethyl acetal (54.5 g, 323 mmol). The mixture was then vigorously stirred at 65 °C for 24 hours. Upon cooling to room temperature, EtOAc (1 L) and H₂0 (1 L) were added to the mixture. The organic layer was extracted with EtOAc (1 x 400 ml). The combined organic layer was washed with aqueous 3% LiCI solution (2 x 1 L), brine, dried (Na₂S0₄) and concentrated in vacuo. The residue was purified by silica gel chromatography to give compound 311 as a white solid (39 g, 67%). j. Preparation of compound 312. To a mixture of 1-[2-Amino-3-chloro-4-(2,2-dimethoxy-ethoxy)-phenyl]-ethanone 311 ( 13 g, 47.5 mmol) and isopropylaminothiazole-4-carboxylic acid hydrobromide (12.64 g, 47.5 mmol) in pyridine (150 ml) was slowly added phosphorus oxychloride (9.47 g, 61.8 mmol) at -40 °C. The mixture was then stirred at 0 °C for 4 hours. Upon completion of the reaction, H₂0 (30 ml) was added dropwise to the mixture. The mixture was then stirred at 0 °C for another 15 minutes. The mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with a sat. NaHC0₃ aqueous solution. The organic layer was dried (Na₂S0₄) and concentrated in vacuo. The residue was dissolved in CH₂CI₂, hexanes were added slowly to the solution, and a yellow solid started to crash out. More hexanes were added until not much product was left in the mother liquid to provide compound 312 (18 g, 85%). k. Preparation of compound 313. 2-lsopropylamino-thiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)- phenyl]-amide 312 (18 g, 40.7 mmol) was suspended in toluene (400 ml). NaH (2.4 g, 61 mmol) was added to the vigorously stirred mixture while monitoring H₂evolution. The mixture became a clear solution during heating to reflux. The reaction was complete after refluxing for 3 hours. The mixture was cooled to room temperature. A solution of AcOH (69.2 mmol) in H₂0 (3 vol) was added to the mixture. After vigorous agitation for 1 hour at 0 °C, the solids were collected by filtration, rinsed forward with H₂0. The wet cake was dried under high vacuum to a constant weight to provide compound 313 ( 5 g, 86%). I. Preparation of compound 314. To a mixture of brosylate intermediate 303 (15 g, 35 mmol) and compound 313 (27.5 g, 38.5 mmol) in NMP (200 ml) was added cesium carbonate (25.1 g, 77 mmol). The mixture was stirred at 65 °C for 5 hours. The reaction was cooled to room temperature and EtOAc (600 ml) and an aqueous solution of 3% LiCI (600 ml) were added to the mixture. The organic layer was washed with aqueous 3% LiCI (1 x 600 ml), brine, dried (Na₂S0₄) and concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired methyl ester as a yellow solid (23.6 g, 75%). LC/MS = 900. 1 3(M⁺+ 1 ) . m. Preparation of compound 315. Methyl ester 314 (23.6 g, 26 mmol) was dissolved in glacial acetic acid (200 ml), 1.4 N HCI in H₂0 (75 ml) was added to the solution. The mixture was stirred at 60 °C for 1 hour. Upon completion of the reaction, the mixture was concentrated to remove the solvents, coevaporated with toluene (x 2) to remove residual acetic acid. The residue was then dissolved in EtOAc (500 ml) and sat. NaHC0₃ aqueous solution (enough to neutralize the mixture) while monitoring C0₂ evolution. The organic layer was washed with brine, dried (Na₂S0₄) and concentrated in vacuo. The residue was further dried under high vacuum for 1 h and used as is for the next step. The crude was dissolved in CH₂CI₂ (360 ml), morpholine (3.4 g, 39 mmol) and sodium triacetoxyborohydride (7.2 g, 34 mmol) were added to the mixture at 0 °C. Then glacial acetic acid (0.47 g, 7.8 mmol) was added dropwise to the mixture. The reaction was complete in 10 minutes at 0 °C. Sat. NaHC0₃ aqueous solution was added to quench the reaction. After stirring for another 20 minutes, the organic layer was washed with brine, dried (Na₂S0₄) and concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired amine product 315 as a yellow solid (12 g, 50%). LC/MS = 924.63(M⁺+ 1 )

Preparation of 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylic acid 215. To a solution of methyl 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylate 214 (36.5g, 0.145 mol) in a mixture of 1 :1 of MeOH: THF (160 mL total) was added a solution of LiOH (30.5 g, 0.725 mol) in H₂0 (80 mL). The mixture was stirred at room temperature for an hour when LCMS analysis showed complete conversion to the carboxylic acid. The reaction was worked up by removal of the volatiles and adjusting the pH of the solution to 6 using aqueous 6N HCI. The resulted gummy residue was filtered and dried on the lyophilizer for 2 days to provide 34.4 g (99.6 %) of compound 215 as a white solid. El MS (mlz) 253.9 [M+H]. j. Preparation of 2-(2-diazo-l-oxo)-8-chloro-7-methoxyquinolin-4-yl isobutyl carbonate 216. To a solution of 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylic acid 215 (10.2 g, 0.04 mol) in THF (400 mL) was added triethyl amine (12.3 mL, 0.088 mol) and /-Butylchloroformate (11.6 mL, 0.088 mol) at 0°C under an argon atmosphere. The mixture was stirred at 0°C for 1 hour when LCMS analysis demonstrated completion of the reaction to provide the desired mixed anhydride. El MS (mlz) 454.0 [M+H]. To the reaction mixture of the anhydride was added a 1 M solution of diazomethane (121 mL, 0.121 mol) in diethyl ether via a plastic funnel at 0°C. This mixture was allowed to stir while warming up to room temperature for additional 2 hours. Analysis of the mixture by LCMS demonstrated completion of the reaction. The septum was removed and the reaction was stirred for additional 20 minutes before removal of the solvent. The residue was dried further under high vacuum to provide compound 216, which was carried on to the next step. El MS (m/z) 377.9 [M+H]. k. Preparation of 8-chloro-2-(2-(isopropylamino)thiazol-4-yl)-7-methoxyquinoiin-4-ol 207. To a cooled solution of 2-(2-diazo-l-oxo)-8-chloro-7-methoxyquinolin-4-yl isobutyl carbonate 216 (15.2 g, 0.040 mol) at 0°C in THF (268 mL) was added 48% HBr (23 mL, 0.201 mol) slowly over 15 minutes. The solution was stirred at 0°C for an additional 40 minutes when LCMS analysis demonstrated complete reaction. The reaction was worked up by addition of aqueous 1 N NaOH (180 mL) at 0° C to adjust the pH of the aqueous layer to 9. The layers were separated and the aqueous layer was washed with EtOAc (2 x 200 mL). Combined organic extracts were washed with brine and dried over MgS04. The solvent was removed in vacuo to provide 17.7 g of a yellow solid. El MS (m/z) 4³¹.9 [M+H]. The solution of the bromoketone obtained from the previous reaction was suspended in i-propanol (270 mL) and isopropylisourea (9.4 g, 0.080 mol). The reaction mixture was heated at 72 °C for 32 hours. LCMS analysis of the reaction demonstrated complete conversion to the desired- product. The reaction was allowed to cool to room temperature to allow for the product to precipitate out of the solution. The reaction was further cooled to 0°C for 12 hours before filtration. The filtrate was washed with ether and dried on lyopholizer to provide 8.03 g of compound 207 as an orange solid. ¹H NMR (500 MHz, CDCI₃): δ 8.21 (d, J= 9 Hz, 1 H), 7.74 (s, 1 H), 7.44 (d, J= 10Hz), 1 H), 7.07 (s, 1 H), 4.05 (s, 3H), 3.92 (pentet, J=6 Hz, 1 H), 1.25 (d, J= 7 Hz, 6H): El MS (m/z) 350.0 [M+H].

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