Name: 58349-01-2|4-Bromo-2-chloro-6-nitrophenol|98%
Brand: Ambeed
SKU: A633712
Price: 14.0 USD
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1
[ 3964-56-5 ]
[ 619-08-9 ]
[ 58349-01-2 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; sodium nitrite

Reference： [1]Raiford; Miller [Journal of the American Chemical Society, 1933, vol. 55, p. 2125,2129]

2
[ 3964-56-5 ]
[ 58349-01-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sulfuric acid; nitric acid; sodium nitrite In water; propionic acid at 30℃; for 3.166h;	49 To a solution of 4-bromo-2-chlorophenol (25.0 g, 120 mmol) in propionic acid (160 ml) were added 70% nitric acid (0.8 ml, 12.0 mmol), sulfuric acid (1.6 ml, 30 mmol) and an aqueous sodium nitrite solution (3.3 mg, 0.048 mmol in a 5 drops of water) at 300C. Additional 70% nitric acid (64 ml, 100 mmol) was added to the mixture over 10 min. After stirring for 3 hr at 300C, the reaction mixture was diluted with H2O. The orange precipitate was collected by filtration, washed with H2O and dried in vacuo to give the title compound (26.7 g, 88%). 1H-NMR (300 MHz, DMSCHd6) δ: 8.07 (IH, , J = 2.5 Hz), 8.10 (1 H, d, J = 2.5 Hz) .
84%	With nitric acid In acetic acid at 20℃;	109 To a solution of 4-bromo-2-chlorophenol (400 g, 1.93 mol) in acetic acid (2.0 1) at room temperature was added nitric acid (70%, 231 ml, 3.86 mol) slowly and the resulting solution was stirred at room temperature overnight. The reaction mixture was poured into water and the yellow precipitate was collected by filtration to afford the title compound (412 g, 84%) . LCMS (ESI"), M-H+: 252.
72%	With nitric acid; acetic acid at 20 - 30℃; for 4.25h;	20.1 In a three neck flask with dropping funnel, thermometer and nitrogen bubbler (no nitrogen input), 4-bromo-2- chlorophenol (5.0 g, 0.024 mol) was fully dissolved in acetic acid (25 mL) at room temperature. Nitric acid (70%, 2.9 mL, 0.048 mol) was added slowly dropwise over approx 15 minutes keeping the temperature at below 30oC. The reaction turned orange with an orange precipitate. The reaction was stirred for a further 4 hours at 20oC. After this time the reaction mixture was cautiously transferred via pipette onto approximately 50 mL ice. Once the ice had melted the yellow precipitate was filtered and washed with water (50 mL). The yellow solid was air dried under vacuum for 1 hour before being dissolved in DCM and dry loaded onto 5.5g silica. The compound was purified by flash column chromatography (elution; 100% heptane, to 20% DCM in heptane, to 40% DCM in heptane, to 50%> DCM in heptanes) to give the desired compound (4.38 g, 72% yield (at) 100% UV purity) as a yellow solid. Tr = 1.97min m/z (ES+) no ionisation.

70%	With sulfuric acid; nitric acid; acetic acid; sodium nitrite at 30℃; for 3h;	1 Synthesis of 4-bromo-2-chloro-6-nitrophenol (48) [00392] Synthesis of 4-bromo-2-chloro-6-nitrophenol (48): 4-bromo-2-chlorophenol (47; 25.0 g, 121 mmol) was dissolved in acetic acid (120 mL). Nitric acid (0.8 mL, 12.0 mmol, 70%), sulfuric acid (1.6 ml, 30 mmol) and sodium nitrite (3 mg, 0.05 mmol) were added at 30 °C. Additional nitric acid (64 mL, 100 mmol, 70%) was added to the mixture over 10 min. After stirring for 3 h at 30 °C, the reaction mixture was diluted with H20. The yellow precipitate was collected by filtration, washed with H20 and dried in vacuo to give 21 g of 4-bromo-2-chloro-6-nitrophenol (48) (70% yield). LCMS: m/z 252.1 [M+H]+, tR = 1.72 min.
	With nitric acid; acetic acid
	durch Nitrierung;
24 g	With nitric acid; acetic acid In water at 20℃;	16.i 4-Bromo-2-chloro-6-nitrophenol 70% aqueous nitric acid (11.5 mL, 190 mol) was added slowly to a solution of 4-bromo-2-chlorophenol (20.0 g, 96.4 mmol) in acetic acid (100 mL) at rt. The resultant precipitate was collected by filtration to afford the subtitled compound as a yellow solid (24.0 g). Used without further purification in the next step.
24 g	With nitric acid; acetic acid In water at 20℃;	70% aqueous nitric acid (11.5 mL, 190 mol) was added slowly to a solution of 4-bromo-2-chlorophenol (20.0 g, 96.4 mmol) in acetic acid (100 mL) at rt. The resultant precipitate was collected by filtration to afford the subtitled compound as a yellow solid (24.0 g). Used without further purification in the next step.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2007/77961, 2007, A2 Location in patent: Page/Page column 309-310
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2007/77961, 2007, A2 Location in patent: Page/Page column 298
[3]Current Patent Assignee: CHDI FOUNDATION - WO2013/33085, 2013, A1 Location in patent: Paragraph 00254
[4]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2017/31204, 2017, A1 Location in patent: Paragraph 00392
[5]Ling [Journal of the Chemical Society, 1889, vol. 55, p. 585,587]
[6]Kohn; Sussmann [Monatshefte fur Chemie, 1927, vol. 48, p. 209]
[7]Current Patent Assignee: ASTRAZENECA PLC - US2015/210655, 2015, A1 Location in patent: Paragraph 0299
[8]Current Patent Assignee: ASTRAZENECA PLC - US9522894, 2016, B2 Location in patent: Page/Page column 35

3
[ 4526-56-1 ]
[ 58349-01-2 ]
[ 20294-55-7 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; sodium nitrite

Reference： [1]Raiford; Miller [Journal of the American Chemical Society, 1933, vol. 55, p. 2125,2129]

4
[ 58349-01-2 ]
[ 108-24-7 ]
2-acetoxy-5-bromo-1-chloro-3-diacetylamino-benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; zinc Erhitzen des Reaktionsprodukts mit Acetanhydrid;

Reference： [1]Kohn; Krasso [Journal of Organic Chemistry, 1948, vol. 13, p. 329]

5
[ 603-86-1 ]
[ 58349-01-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 1,2-ethanediylbis(triphenylphosphonium) ditribromide; In methanol; dichloromethane; at 20℃; for 0.0833333h;	General procedure: To a mixture of anilines or phenols (0.7 mmol) the brominatingagent (1) (0.72 g, 0.7 mmol) in dichloromethane(30 ml)-methanol (15 ml) was added. The reactionmixture was stirred at room temperature until decolorizationof the orange solution took place. The progress of thereaction was monitored by TLC (eluent: n-hexane/ethylacetate, 7:3). After completion of the reaction, the solventwas evaporated and diethyl ether (10 ml) was added to theresidue. The supernatant was decanted and the insolubleresidue was washed by ether (3 × 10 ml). The combinedether extracts were dried on magnesium sulfate and also evaporated under vacuum to afford monobromo anilines ormonobromo phenols which was purified by flash columnchromatography over silica gel (n-hexane/ethyl acetate,7:3).

Reference： [1]Journal of the Iranian Chemical Society,2016,vol. 13,p. 2019 - 2028
[2]Journal of Chemical Research - Part S,2002,p. 272 - 275
[3]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2006,vol. 45,p. 796 - 800
[4]Tetrahedron Letters,2007,vol. 48,p. 1255 - 1259

6
[ 95-57-8 ]
[ 58349-01-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetrachloromethane; bromine 2: glacial acetic acid; NaNO₂

Reference： [1]Raiford; Miller [Journal of the American Chemical Society, 1933, vol. 55, p. 2125,2129]

7
[ 50638-47-6 ]
[ 58349-01-2 ]

Reference： [1]Monatshefte fur Chemie,1927,vol. 48,p. 209

8
[ 58349-01-2 ]
[ 96-32-2 ]
[ 943994-32-9 ]

Yield	Reaction Conditions	Operation in experiment
43%	With potassium carbonate In N,N-dimethyl-formamide at 70℃;	109 A mixture of 4-bromo-2-chloro-6-nitrophenol (412 g, 1.63 mol), methyl 2-bromoacetate (185 ml, 1.96 mol) and K2CO3 (1.13 kg, 8.16 mol) in DMF (800 ml) was heated at 70°C overnight. The reaction mixture was poured into water, and the precipitate was collected by filtration to give the title compound as yellow solid (230 g, 43%) . LCMS (ESI"), M-H+: 323.
	With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 12h;

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2007/77961, 2007, A2 Location in patent: Page/Page column 298
[2]Location in patent: experimental part Hasui, Tomoaki; Matsunaga, Nobuyuki; Ora, Taiichi; Ohyabu, Norio; Nishigaki, Nobuhiro; Imura, Yoshimi; Igata, Yumiko; Matsui, Hideki; Motoyaji, Takashi; Tanaka, Toshimasa; Habuka, Noriyuki; Sogabe, Satoshi; Ono, Midori; Siedem, Christopher S.; Tang, Tony P.; Gauthier, Cassandra; De Meese, Lisa A.; Boyd, Steven A.; Fukumoto, Shoji [Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8616 - 8631]

9
[ 58349-01-2 ]
2-amino-4-bromo-6-chlorophenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With iron; calcium chloride In ethanol; water at 80℃; for 2h;	1 Synthesis of 2-amino-4-bromo-6-chlorophenol (49) [00393] Synthesis of 2-amino-4-bromo-6-chlorophenol (49): A suspension of 4-bromo- 2-chloro-6-nitrophenol (48; 17 g, 67.75 mmol), Fe (18.9 g, 338.6 mmol) and CaCl2 (74 mg, 67 mmol) in 80 mL EtOH and 20 mL H20 was stirred at 80 °C for 2 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was treated with EtOAc and H20. The organic layer was separated, washed with H20 and brine, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-20% EtO Ac/petroleum ether) to give 11 g of 2-amino-4-bromo-6- chlorophenol (49) (73% yield). LCMS: m/z 222.0 [M+H]+, tR = 1.56 min.
72%	With iron; ammonium chloride In ethanol; water at 50℃; for 1h;	20.2 4-Bromo-6-chloro-2- nitrophenol (4.38 g, 17.35 mmol) was dissolved in ethanol (120 mL). Water (28 mL) and saturated aqueous ammonium chloride (28 mL) were added followed by iron powder (7.75 g, 139 mmol). The reaction was heated to 50oC and stirred for 1 hour, after which time the reaction was cooled to room temperature and filtered through a pad of celite (approx. 5cm in a Jones tube), washing with 50 mL EtOH followed by excess EtOAc until the liquid ran clear. The organic layer was washed with water (50 mL). The water was re-extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with brine (20 mL), dried (MgS04), filtered and concentrated. The resulting residue was dry loaded onto 5g silica and purified by flash column chromatography (elution; 0-30%> EtOAc in heptanes) to give the desired compound (2.76g, 72% yield (at) 100% UV purity) as a pale brown solid. Tr = 1.65min m/z (ES+) (M+H+) 222/224/226.
66%	With ammonium chloride	5.1 Example 5 Step 1: 4-bromo-2-chloro-6-nitrophenol 5a (2.50 g, 10.0 mmol) was dissolved in 50 ml EtOH and 20 ml water, iron powder (5.60 g, 100.0 mmol) and ammonium chloride (5.60 g, 100.0 mmol) were added in sequence, the reaction solution was stirred and reacted for 1.5 hours at 80° C., filtered, concentrated under reduced pressure, extracted, dried and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=33%) to obtain compound 2-amino-4-bromo-6-chlorophenol 5b (1.5 g, light yellow solid) with a yield of 66%. MS m/z (ESI): 224.1 [M+1].

66%	With iron; ammonium chloride In ethanol; water at 80℃; for 1.5h;	5.1 Example 5 Step 1: 4-bromo-2-chloro-6-nitrophenol 5a (2.50 g, 10.0 mmol) was dissolved in 50 ml EtOH and 20 ml water, iron powder (5.60 g, 100.0 mmol) and ammonium chloride (5.60 g, 100.0 mmol) were added in sequence, the reaction solution was stirred and reacted for 1.5 hours at 80° C., filtered, concentrated under reduced pressure, extracted, dried and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=33%) to obtain compound 2-amino-4-bromo-6-chlorophenol 5b (1.5 g, light yellow solid) with a yield of 66%. MS m/z (ESI): 224.1 [M+1].
66%	With iron; ammonium chloride In ethanol; water at 80℃; for 1.5h;	5.1 Example 5 Step 1: 4-bromo-2-chloro-6-nitrophenol 5a (2.50 g, 10.0 mmol) was dissolved in 50 ml EtOH and 20 ml water, iron powder (5.60 g, 100.0 mmol) and ammonium chloride (5.60 g, 100.0 mmol) were added in sequence, the reaction solution was stirred and reacted for 1.5 hours at 80° C., filtered, concentrated under reduced pressure, extracted, dried and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate=33%) to obtain compound 2-amino-4-bromo-6-chlorophenol 5b (1.5 g, light yellow solid) with a yield of 66%. MS m/z (ESI): 224.1 [M+1].
45%	With iron; calcium chloride In ethanol; water at 80℃; for 2h;	16.ii 2-Amino-4-bromo-6-chlorophenol Calcium chloride (443 mg, 4 mmol) and iron (11.16 g, 0.2 mol) were added to a solution of 4-bromo-2-chloro-6-nitrophenol (10.0 g) in ethanol (400 mL) and water (100 mL). The suspension was heated at 80° C. for 2 h. The reaction was cooled, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with saturated sodium chloride solution (500 mL) and extracted with EtOAc (2*500 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure to afford the subtitled compound as a black solid (4 g, 45%). 1H NMR (400 MHz, CDCl3): δ 6.85 (d, 1H), 6.75 (d, 1H), 5.38 (s, 1H), 3.92 (bs, 2H).
45%	With iron; calcium chloride In ethanol; water at 80℃; for 2h;	ii Calcium chloride (443 mg, 4 mmol) and iron (11.16 g, 0.2 mol) were added to a solution of 4-bromo-2-chloro-6-nitrophenol (10.0 g) in ethanol (400 mL) and water (100 mL). The suspension was heated at 80° C. for 2 h. The reaction was cooled, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with saturated sodium chloride solution (500 mL) and extracted with EtOAc (2*500 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure to afford the subtitled compound as a black solid (4 g, 45%). 1H NMR (400 MHz, CDCl3): δ 6.85 (d, 1H), 6.75 (d, 1H), 5.38 (s, 1H), 3.92 (bs, 2H).
39%	With calcium chloride In ethanol; water at 80℃; for 2h;	50 A suspension of 4-bromo-2-chloro-6-nitrophenol (2.15 g, 8.51 mmol), Fe (2.38 g, 42.6 iranol) and CaCl2 (94 mg, 0.85 itimol) in 80% aqueous EtOH (100 ml) was stirred for 2 hr at 80°C. After filtration of the reaction mixture, the filtrate was concentrated in vacuo. The residue was treated with EtOAc and H2O. The organic layer was separated, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (730 mg, 39%). 1H-NMR (300 MHz, DMSO-d6) δ: 5.23 (2H, brs) , 6.66 (1 H, d, J = 2.5 Hz), 6.71 (1 H, d, J = 2.5 Hz), 9.05 (IH, brs).
	With water; ammonium chloride; zinc In methanol at 50℃; for 1h;	1 Synthesis of 2-amino-4-bromo-6-chlorophenol (10): Synthesis of 2-amino-4-bromo-6-chlorophenol (10): 4-Bromo-2-chloro-6- nitrophenol (9) (10 g, 39.61 mmol) was dissolved in methanol (100 mL) at room temperature. Zinc dust (13 g, 198 mmol) was added to the reaction mixture followed by dropwise addition of saturated NH4C1 (100 mL) at room temperature (CAUTION: Exothermic reaction was observed). After completion of addition, the reaction mixture was heated at 50 °C for 1 h. The reaction mixture was allowed to cool to room temperature, filtered and washed with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to give crude 2-amino-4- bromo-6-chlorophenol (10), which was used in the next step without further purification. NMR (400 MHz, DMSO-i/6) δ 8.97-8.85 (bs, 1 H), 6.71 (s, 1 H), 6.68 (s, 1 H), 5.57-5.10 (bs, 2H).

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2017/31204, 2017, A1 Location in patent: Paragraph 00393
[2]Current Patent Assignee: CHDI FOUNDATION - WO2013/33085, 2013, A1 Location in patent: Paragraph 00255
[3]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - US2021/386721, 2021, A1
[4]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - US2021/386721, 2021, A1 Location in patent: Paragraph 0261-0262
[5]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - US2021/386721, 2021, A1 Location in patent: Paragraph 0261-0262
[6]Current Patent Assignee: ASTRAZENECA PLC - US2015/210655, 2015, A1 Location in patent: Paragraph 0300
[7]Current Patent Assignee: ASTRAZENECA PLC - US9522894, 2016, B2 Location in patent: Page/Page column 35
[8]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2007/77961, 2007, A2 Location in patent: Page/Page column 310
[9]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2015/3166, 2015, A1 Location in patent: Paragraph 00370

10
[ 58349-01-2 ]
6-acetyl-8-chloro-2H-1,4-benzoxazin-3(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 65 °C 2: acetic acid; zinc / 12 h / 100 °C 3: dichlorobis(tri-O-tolylphosphine)palladium; potassium carbonate / water; N,N-dimethyl-formamide / 12 h / 80 °C / Inert atmosphere

Reference： [1]Hasui, Tomoaki; Matsunaga, Nobuyuki; Ora, Taiichi; Ohyabu, Norio; Nishigaki, Nobuhiro; Imura, Yoshimi; Igata, Yumiko; Matsui, Hideki; Motoyaji, Takashi; Tanaka, Toshimasa; Habuka, Noriyuki; Sogabe, Satoshi; Ono, Midori; Siedem, Christopher S.; Tang, Tony P.; Gauthier, Cassandra; De Meese, Lisa A.; Boyd, Steven A.; Fukumoto, Shoji [Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8616 - 8631]

11
[ 58349-01-2 ]
1-(8-chloro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4,4,4-trifluorobutane-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 65 °C 2: acetic acid; zinc / 12 h / 100 °C 3: dichlorobis(tri-O-tolylphosphine)palladium; potassium carbonate / water; N,N-dimethyl-formamide / 12 h / 80 °C / Inert atmosphere 4: 6,7,9,10,12,13,20,21-octahydrodibenzo[b,h][1,4,7,10,13,16]hexaoxacyclooctadecine; sodium hydride / tetrahydrofuran; ethanol / 12 h / 60 °C

Reference： [1]Hasui, Tomoaki; Matsunaga, Nobuyuki; Ora, Taiichi; Ohyabu, Norio; Nishigaki, Nobuhiro; Imura, Yoshimi; Igata, Yumiko; Matsui, Hideki; Motoyaji, Takashi; Tanaka, Toshimasa; Habuka, Noriyuki; Sogabe, Satoshi; Ono, Midori; Siedem, Christopher S.; Tang, Tony P.; Gauthier, Cassandra; De Meese, Lisa A.; Boyd, Steven A.; Fukumoto, Shoji [Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8616 - 8631]

12
[ 58349-01-2 ]
8-chloro-6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2H-1,4-benzoxazin-3(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 65 °C 2: acetic acid; zinc / 12 h / 100 °C 3: dichlorobis(tri-O-tolylphosphine)palladium; potassium carbonate / water; N,N-dimethyl-formamide / 12 h / 80 °C / Inert atmosphere 4: 6,7,9,10,12,13,20,21-octahydrodibenzo[b,h][1,4,7,10,13,16]hexaoxacyclooctadecine; sodium hydride / tetrahydrofuran; ethanol / 12 h / 60 °C 5: triethylamine; trifluoroacetic acid / isopropyl alcohol / 3 h / 80 °C

Reference： [1]Hasui, Tomoaki; Matsunaga, Nobuyuki; Ora, Taiichi; Ohyabu, Norio; Nishigaki, Nobuhiro; Imura, Yoshimi; Igata, Yumiko; Matsui, Hideki; Motoyaji, Takashi; Tanaka, Toshimasa; Habuka, Noriyuki; Sogabe, Satoshi; Ono, Midori; Siedem, Christopher S.; Tang, Tony P.; Gauthier, Cassandra; De Meese, Lisa A.; Boyd, Steven A.; Fukumoto, Shoji [Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8616 - 8631]

13
[ 58349-01-2 ]
[ 121564-96-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 65 °C 2: acetic acid; zinc / 12 h / 100 °C

Reference： [1]Hasui, Tomoaki; Matsunaga, Nobuyuki; Ora, Taiichi; Ohyabu, Norio; Nishigaki, Nobuhiro; Imura, Yoshimi; Igata, Yumiko; Matsui, Hideki; Motoyaji, Takashi; Tanaka, Toshimasa; Habuka, Noriyuki; Sogabe, Satoshi; Ono, Midori; Siedem, Christopher S.; Tang, Tony P.; Gauthier, Cassandra; De Meese, Lisa A.; Boyd, Steven A.; Fukumoto, Shoji [Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8616 - 8631]

14
[ 58349-01-2 ]
[ 1226070-17-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: iron; ammonium chloride / ethanol; water / 1 h / 50 °C 2: toluene-4-sulfonic acid / 140 °C
	Multi-step reaction with 3 steps 1: ammonium chloride 2: triethylamine
	Multi-step reaction with 3 steps 1: ammonium chloride; iron / water; ethanol / 1.5 h / 80 °C 2: triethylamine / dichloromethane / 1.5 h / 20 °C 3: toluene-4-sulfonic acid / toluene / 12 h / 110 °C

Reference： [1]Current Patent Assignee: CHDI FOUNDATION - WO2013/33085, 2013, A1
[2]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - US2021/386721, 2021, A1
[3]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - US2021/386721, 2021, A1

15
[ 58349-01-2 ]
[ 1426321-16-5 ]
[ 1438262-45-3 ]
2-amino-4-bromo-6-chlorophenyl cyclopropanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: iron; ammonium chloride / ethanol; water / 1 h / 50 °C 2.1: triethylamine / dichloromethane / 1 h / 20 °C / Inert atmosphere 2.2: 20 °C / Cooling with ice

Reference： [1]Current Patent Assignee: CHDI FOUNDATION - WO2013/33085, 2013, A1

16
[ 58349-01-2 ]
[ 32272-98-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: calcium chloride; iron / water; ethanol / 2 h / 80 °C 2: tetrahydrofuran / 2.5 h / Reflux; Inert atmosphere
	Multi-step reaction with 2 steps 1: iron; calcium chloride / ethanol; water / 2 h / 80 °C 2: tetrahydrofuran / 2.5 h / Inert atmosphere; Reflux
	Multi-step reaction with 2 steps 1: iron; ammonium chloride / ethanol; water / 1 h / 50 °C 2: tetrahydrofuran / 2 h / 65 °C

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US2015/210655, 2015, A1
[2]Current Patent Assignee: ASTRAZENECA PLC - US9522894, 2016, B2
[3]Current Patent Assignee: CHDI FOUNDATION - WO2013/33085, 2013, A1

17
[ 58349-01-2 ]
[ 1226065-43-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: iron; ammonium chloride / ethanol; water / 1 h / 50 °C 2.1: tetrahydrofuran / 2 h / 65 °C 3.1: sodium hydride / N,N-dimethyl-formamide / 1 h / Cooling with ice 3.2: 2 h / 20 °C

Reference： [1]Current Patent Assignee: CHDI FOUNDATION - WO2013/33085, 2013, A1

18
[ 58349-01-2 ]
5-bromo-7-chloro-2-(chloromethyl)benzo[d]oxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: zinc; water; ammonium chloride / methanol / 1 h / 50 °C 2: boron trifluoride diethyl etherate / dichloromethane / 4 h / 0 - 20 °C
	Multi-step reaction with 2 steps 1: iron; calcium chloride / water; ethanol / 2 h / 80 °C 2: dichloromethane / 18 h / 20 °C

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2015/3166, 2015, A1
[2]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2017/31204, 2017, A1

19
[ 58349-01-2 ]
2-(azidomethyl)-5-bromo-7-chlorobenzo[d]oxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: zinc; water; ammonium chloride / methanol / 1 h / 50 °C 2: boron trifluoride diethyl etherate / dichloromethane / 4 h / 0 - 20 °C 3: sodium azide; 15-crown-5; sodium iodide / acetonitrile / 18 h / 90 °C
	Multi-step reaction with 3 steps 1: iron; calcium chloride / water; ethanol / 2 h / 80 °C 2: dichloromethane / 18 h / 20 °C 3: potassium iodide; sodium azide / N,N-dimethyl-formamide / 18 h / 25 - 60 °C

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2015/3166, 2015, A1
[2]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2017/31204, 2017, A1

20
[ 58349-01-2 ]
(5-bromo-7-chlorobenzo[d]oxazol-2-yl)methanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: zinc; water; ammonium chloride / methanol / 1 h / 50 °C 2: boron trifluoride diethyl etherate / dichloromethane / 4 h / 0 - 20 °C 3: sodium azide; 15-crown-5; sodium iodide / acetonitrile / 18 h / 90 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 20 °C
	Multi-step reaction with 4 steps 1.1: iron; calcium chloride / water; ethanol / 2 h / 80 °C 2.1: dichloromethane / 18 h / 20 °C 3.1: potassium iodide; sodium azide / N,N-dimethyl-formamide / 18 h / 25 - 60 °C 4.1: triphenylphosphine / tetrahydrofuran / 1 h / Inert atmosphere 4.2: 18 h / Inert atmosphere

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2015/3166, 2015, A1
[2]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2017/31204, 2017, A1

21
[ 58349-01-2 ]
(E)-3-(6-aminopyridin-3-yl)-N-((5-bromo-7-chlorobenzo[d]oxazol-2-yl)methyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: zinc; water; ammonium chloride / methanol / 1 h / 50 °C 2: boron trifluoride diethyl etherate / dichloromethane / 4 h / 0 - 20 °C 3: sodium azide; 15-crown-5; sodium iodide / acetonitrile / 18 h / 90 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 20 °C 5: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 8 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2015/3166, 2015, A1

22
[ 58349-01-2 ]
(E)-3-(6-aminopyridin-3-yl)-N-((7-chloro-5-(4-(morpholine-4-carbonyl)phenyl)benzo[d]oxazol-2-yl)methyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: zinc; water; ammonium chloride / methanol / 1 h / 50 °C 2: boron trifluoride diethyl etherate / dichloromethane / 4 h / 0 - 20 °C 3: sodium azide; 15-crown-5; sodium iodide / acetonitrile / 18 h / 90 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 20 °C 5: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / dichloromethane / 8 h / 0 - 20 °C 6: potassium fluoride; di-μ-bromobis(tri-tert-butylphosphino)dipalladium(I) / tetrahydrofuran / 0.5 h / 100 °C / Inert atmosphere; Microwave irradiation

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2015/3166, 2015, A1

23
[ 58349-01-2 ]
tert-butyl (5-bromo-7-chlorobenzo[d]oxazol-2-yl)methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: zinc; water; ammonium chloride / methanol / 1 h / 50 °C 2: boron trifluoride diethyl etherate / dichloromethane / 4 h / 0 - 20 °C 3: sodium azide; 15-crown-5; sodium iodide / acetonitrile / 18 h / 90 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 20 °C 5: triethylamine / dichloromethane / 4 h / 0 - 20 °C
	Multi-step reaction with 5 steps 1.1: iron; calcium chloride / water; ethanol / 2 h / 80 °C 2.1: dichloromethane / 18 h / 20 °C 3.1: potassium iodide; sodium azide / N,N-dimethyl-formamide / 18 h / 25 - 60 °C 4.1: triphenylphosphine / tetrahydrofuran / 1 h / Inert atmosphere 4.2: 18 h / Inert atmosphere 5.1: triethylamine / dichloromethane / 4 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2015/3166, 2015, A1
[2]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2017/31204, 2017, A1

24
[ 58349-01-2 ]
tert-butyl (7-chloro-5-(4-(3,3-difluoroazetidine-1-carbonyl)phenyl)benzo[d]oxazol-2-yl)methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: zinc; water; ammonium chloride / methanol / 1 h / 50 °C 2: boron trifluoride diethyl etherate / dichloromethane / 4 h / 0 - 20 °C 3: sodium azide; 15-crown-5; sodium iodide / acetonitrile / 18 h / 90 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 20 °C 5: triethylamine / dichloromethane / 4 h / 0 - 20 °C 6: bis-triphenylphosphine-palladium(II) chloride; potassium carbonate / 1,4-dioxane; water / 3 h / 85 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2015/3166, 2015, A1

25
[ 58349-01-2 ]
(4-(2-(aminomethyl)-7-chlorobenzo[d]oxazol-5-yl)phenyl)(3,3-difluoroazetidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: zinc; water; ammonium chloride / methanol / 1 h / 50 °C 2: boron trifluoride diethyl etherate / dichloromethane / 4 h / 0 - 20 °C 3: sodium azide; 15-crown-5; sodium iodide / acetonitrile / 18 h / 90 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 20 °C 5: triethylamine / dichloromethane / 4 h / 0 - 20 °C 6: bis-triphenylphosphine-palladium(II) chloride; potassium carbonate / 1,4-dioxane; water / 3 h / 85 °C / Inert atmosphere 7: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2015/3166, 2015, A1

26
[ 58349-01-2 ]
(E)-3-(6-aminopyridin-3-yl)-N-((7-chloro-5-(4-(3,3-difluoroazetidine-1-carbonyl)phenyl)benzo[d]oxazol-2-yl)methyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: zinc; water; ammonium chloride / methanol / 1 h / 50 °C 2: boron trifluoride diethyl etherate / dichloromethane / 4 h / 0 - 20 °C 3: sodium azide; 15-crown-5; sodium iodide / acetonitrile / 18 h / 90 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 20 °C 5: triethylamine / dichloromethane / 4 h / 0 - 20 °C 6: bis-triphenylphosphine-palladium(II) chloride; potassium carbonate / 1,4-dioxane; water / 3 h / 85 °C / Inert atmosphere 7: trifluoroacetic acid / dichloromethane / 2 h / 0 - 20 °C 8: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2015/3166, 2015, A1

27
[ 58349-01-2 ]
tert-butyl (7-chloro-5-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)benzo[d]oxazol-2-yl)methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: iron; calcium chloride / water; ethanol / 2 h / 80 °C 2.1: dichloromethane / 18 h / 20 °C 3.1: potassium iodide; sodium azide / N,N-dimethyl-formamide / 18 h / 25 - 60 °C 4.1: triphenylphosphine / tetrahydrofuran / 1 h / Inert atmosphere 4.2: 18 h / Inert atmosphere 5.1: triethylamine / dichloromethane / 4 h / 0 - 20 °C 6.1: potassium carbonate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water / 3 h / 85 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2017/31204, 2017, A1

28
[ 58349-01-2 ]
tert-butyl (5-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)-7-(4-fluorophenyl)benzo[d]oxazol-2-yl)methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: iron; calcium chloride / water; ethanol / 2 h / 80 °C 2.1: dichloromethane / 18 h / 20 °C 3.1: potassium iodide; sodium azide / N,N-dimethyl-formamide / 18 h / 25 - 60 °C 4.1: triphenylphosphine / tetrahydrofuran / 1 h / Inert atmosphere 4.2: 18 h / Inert atmosphere 5.1: triethylamine / dichloromethane / 4 h / 0 - 20 °C 6.1: potassium carbonate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water / 3 h / 85 °C / Inert atmosphere 7.1: chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); potassium phosphate / 1,4-dioxane; water / 1 h / 90 °C

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2017/31204, 2017, A1

29
[ 58349-01-2 ]
(4-(2-(aminomethyl)-7-(4-fluorophenyl)benzo[d]oxazol-5-yl)phenyl)(4,4-difluoropiperidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: iron; calcium chloride / water; ethanol / 2 h / 80 °C 2.1: dichloromethane / 18 h / 20 °C 3.1: potassium iodide; sodium azide / N,N-dimethyl-formamide / 18 h / 25 - 60 °C 4.1: triphenylphosphine / tetrahydrofuran / 1 h / Inert atmosphere 4.2: 18 h / Inert atmosphere 5.1: triethylamine / dichloromethane / 4 h / 0 - 20 °C 6.1: potassium carbonate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water / 3 h / 85 °C / Inert atmosphere 7.1: chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); potassium phosphate / 1,4-dioxane; water / 1 h / 90 °C 8.1: trifluoroacetic acid / dichloromethane / 1 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2017/31204, 2017, A1

30
[ 58349-01-2 ]
(1S,2S)-2-(6-aminopyridin-3-yl)-N-((5-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)-7-(4-fluorophenyl)benzo[d]oxazol-2-yl)methyl)cyclopropanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: iron; calcium chloride / water; ethanol / 2 h / 80 °C 2.1: dichloromethane / 18 h / 20 °C 3.1: potassium iodide; sodium azide / N,N-dimethyl-formamide / 18 h / 25 - 60 °C 4.1: triphenylphosphine / tetrahydrofuran / 1 h / Inert atmosphere 4.2: 18 h / Inert atmosphere 5.1: triethylamine / dichloromethane / 4 h / 0 - 20 °C 6.1: potassium carbonate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane; water / 3 h / 85 °C / Inert atmosphere 7.1: chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); potassium phosphate / 1,4-dioxane; water / 1 h / 90 °C 8.1: trifluoroacetic acid / dichloromethane / 1 h / 0 - 20 °C 9.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: KARYOPHARM THERAPEUTICS INC - WO2017/31204, 2017, A1

31
[ 58349-01-2 ]
methyl 4-(3'-chloro-4'-hydroxy-5'-nitro-3-biphenyl)-5-phenylisoxazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 18 h / 90 °C / Inert atmosphere 2: sodium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; N,N-dimethyl-formamide / 3 h / 90 °C / Inert atmosphere

Reference： [1]Vickers, Clare F.; Silva, Ana P. G.; Chakraborty, Ajanta; Fernandez, Paulina; Kurepina, Natalia; Saville, Charis; Naranjo, Yandi; Pons, Miquel; Schnettger, Laura S.; Gutierrez, Maximiliano G.; Park, Steven; Kreiswith, Barry N.; Perlin, David S.; Thomas, Eric J.; Cavet, Jennifer S.; Tabernero, Lydia [Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8337 - 8352]

32
[ 58349-01-2 ]
4-(3'-chloro-4'-hydroxy-5'-nitro-3-biphenyl)-5-phenylisoxazole-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 18 h / 90 °C / Inert atmosphere 2: sodium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; N,N-dimethyl-formamide / 3 h / 90 °C / Inert atmosphere 3: sodium hydroxide / methanol; water / 1 h / 20 °C / Inert atmosphere

Reference： [1]Vickers, Clare F.; Silva, Ana P. G.; Chakraborty, Ajanta; Fernandez, Paulina; Kurepina, Natalia; Saville, Charis; Naranjo, Yandi; Pons, Miquel; Schnettger, Laura S.; Gutierrez, Maximiliano G.; Park, Steven; Kreiswith, Barry N.; Perlin, David S.; Thomas, Eric J.; Cavet, Jennifer S.; Tabernero, Lydia [Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8337 - 8352]

33
[ 58349-01-2 ]
[ 73183-34-3 ]
pinacolyl 3-chloro-4-hydroxy-5-nitrophenylboronate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 90℃; for 18h; Inert atmosphere;

Reference： [1]Vickers, Clare F.; Silva, Ana P. G.; Chakraborty, Ajanta; Fernandez, Paulina; Kurepina, Natalia; Saville, Charis; Naranjo, Yandi; Pons, Miquel; Schnettger, Laura S.; Gutierrez, Maximiliano G.; Park, Steven; Kreiswith, Barry N.; Perlin, David S.; Thomas, Eric J.; Cavet, Jennifer S.; Tabernero, Lydia [Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8337 - 8352]

34
[ 58349-01-2 ]
[ 74-88-4 ]
5-bromo-1-chloro-2-methoxy-3-nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2h; Inert atmosphere;	General Procedure for the Preparation of Bromo-alkoxy-5-nitrobenzenes; 1-bromo-3-ethoxy-5-nitrobenzene (S2a), Method A. General procedure: To a solution of 3-bromo-5-nitrophenol (S1a) (100.0 mg, 0.46 mmol) and K2CO3 (126.7mg, 0.92 mmol) in anhydrous DMF (2 mL) was added iodoethane (0.07 mL, 0.92 mmol) underargon. The resulting mixture was stirred at 60 °C for 2 h. After being quenched with H2O (5 mL),the aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic extracts werewashed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue waspurified by column chromatography on silica gel (EtOAc/hexane, 2.5:97.5 to 10:90) to affordS2a (111 mg, 98%) as a pale yellow solid.
	With potassium carbonate In N,N-dimethyl-formamide at 45℃; for 4h;	1.a [0143] Step a: Iodomethane (1.5 mL, 24 mmol) was added to a suspension of 4-bromo-2- chloro-6-nitrophenol (3.2 g, 12.7 mmol) and K2CO3 (3 g, 21.7 mmol) in DMF (40 mL) in a 250 mL round bottom flask under magnetic stirring. The resulting mixture was stirred at 45 °C for 4 h, diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (2 to 25% EtOAc in hexanes) to give 5-bromo-1-chloro-2-methoxy-3-nitrobenzene. MS: (ES) m/z calculated for C7H6BrClNO3 [M + H]+ 265.9, found 265.9.
	With potassium carbonate In N,N-dimethyl-formamide at 45℃; for 4h;	c Step c: Iodomethane (1.5 mL, 24 mmol) was added to a suspension of 4-bromo-2-chloro-6-nitrophenol (3.2 g, 12.7 mmol) and K2CO3 (3 g, 21.7 mmol) in DMF (40 mL) in a 250 mL round bottom flask under magnetic stirring. The resulting mixture was stirred at 45° C. for 4 h, diluted with EtOAc, washed with brine, and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (2 to 25% EtOAc in hexanes) to give 5-bromo-1-chloro-2-methoxy-3-nitrobenzene. MS: (ES) m/z calculated for C7H6BrClNO3 [M+H]+ 265.9, found 265.9.

Reference： [1]Suebsuwong, Chalada; Dai, Bing; Pinkas, Daniel M.; Duddupudi, Anantha Lakshmi; Li, Li; Bufton, Joshua C.; Schlicher, Lisa; Gyrd-Hansen, Mads; Hu, Ming; Bullock, Alex N.; Degterev, Alexei; Cuny, Gregory D. [European Journal of Medicinal Chemistry, 2020, vol. 200]
[2]Current Patent Assignee: CHEMOCENTRYX INC - WO2018/222598, 2018, A1 Location in patent: Paragraph 0143
[3]Current Patent Assignee: CHEMOCENTRYX INC - US2019/300526, 2019, A1 Location in patent: Paragraph 0145

35
[ 58349-01-2 ]
3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 45 °C 2: tetrahydrofuran / 1.5 h / -60 - -30 °C / Inert atmosphere 3: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)CH₂Cl₂ / dimethyl sulfoxide / 2 h / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)CH₂Cl₂ / water; 1,4-dioxane / 2 h / 100 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane; dichloromethane / 2 h / 20 °C 6: N-ethyl-N,N-diisopropylamine; lithium carbonate / acetonitrile / 0.5 h / 75 °C

Reference： [1]Current Patent Assignee: CHEMOCENTRYX INC - US2019/300526, 2019, A1

36
[ 58349-01-2 ]
4-bromo-6-chloro-7-methoxy-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 45 °C 2: tetrahydrofuran / 1.5 h / -60 - -30 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: CHEMOCENTRYX INC - US2019/300526, 2019, A1

37
[ 58349-01-2 ]
6-chloro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 45 °C 2: tetrahydrofuran / 1.5 h / -60 - -30 °C / Inert atmosphere 3: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / dimethyl sulfoxide / 2 h / 120 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: CHEMOCENTRYX INC - US2019/300526, 2019, A1

38
[ 58349-01-2 ]
tert-butyl 3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 45 °C 2: tetrahydrofuran / 1.5 h / -60 - -30 °C / Inert atmosphere 3: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)CH₂Cl₂ / dimethyl sulfoxide / 2 h / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)CH₂Cl₂ / water; 1,4-dioxane / 2 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: CHEMOCENTRYX INC - US2019/300526, 2019, A1

39
[ 58349-01-2 ]
3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 45 °C 2: tetrahydrofuran / 1.5 h / -60 - -30 °C / Inert atmosphere 3: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)CH₂Cl₂ / dimethyl sulfoxide / 2 h / 120 °C / Inert atmosphere 4: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)CH₂Cl₂ / water; 1,4-dioxane / 2 h / 100 °C / Inert atmosphere 5: hydrogenchloride / 1,4-dioxane; dichloromethane / 2 h / 20 °C

Reference： [1]Current Patent Assignee: CHEMOCENTRYX INC - US2019/300526, 2019, A1

40
[ 58349-01-2 ]
5-bromo-3-chloro-2-methoxyaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C / Inert atmosphere 2: ammonium chloride; iron / ethanol; water / 1 h / 85 °C

Reference： [1]Suebsuwong, Chalada; Dai, Bing; Pinkas, Daniel M.; Duddupudi, Anantha Lakshmi; Li, Li; Bufton, Joshua C.; Schlicher, Lisa; Gyrd-Hansen, Mads; Hu, Ming; Bullock, Alex N.; Degterev, Alexei; Cuny, Gregory D. [European Journal of Medicinal Chemistry, 2020, vol. 200]

41
[ 58349-01-2 ]
N-(5-bromo-3-chloro-2-methoxyphenyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C / Inert atmosphere 2: ammonium chloride; iron / ethanol; water / 1 h / 85 °C 3: pyridine / 24 h / 20 °C / Inert atmosphere

Reference： [1]Suebsuwong, Chalada; Dai, Bing; Pinkas, Daniel M.; Duddupudi, Anantha Lakshmi; Li, Li; Bufton, Joshua C.; Schlicher, Lisa; Gyrd-Hansen, Mads; Hu, Ming; Bullock, Alex N.; Degterev, Alexei; Cuny, Gregory D. [European Journal of Medicinal Chemistry, 2020, vol. 200]

42
[ 58349-01-2 ]
C₃₀H₃₈ClN₅O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C / Inert atmosphere 2.1: ammonium chloride; iron / ethanol; water / 1 h / 85 °C 3.1: pyridine / 24 h / 20 °C / Inert atmosphere 4.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran / 16 h / Inert atmosphere; Reflux 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide; acetonitrile / 0.17 h / 20 °C / Inert atmosphere 5.2: Suzuki-Miyaura Coupling / 16 h / 90 °C / Inert atmosphere 6.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,2-dimethoxyethane / 0.17 h / 20 °C / Inert atmosphere 6.2: 16 h / Inert atmosphere; Reflux

Reference： [1]Suebsuwong, Chalada; Dai, Bing; Pinkas, Daniel M.; Duddupudi, Anantha Lakshmi; Li, Li; Bufton, Joshua C.; Schlicher, Lisa; Gyrd-Hansen, Mads; Hu, Ming; Bullock, Alex N.; Degterev, Alexei; Cuny, Gregory D. [European Journal of Medicinal Chemistry, 2020, vol. 200]

43
[ 58349-01-2 ]
N-(3-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C / Inert atmosphere 2: ammonium chloride; iron / ethanol; water / 1 h / 85 °C 3: pyridine / 24 h / 20 °C / Inert atmosphere 4: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran / 16 h / Inert atmosphere; Reflux

Reference： [1]Suebsuwong, Chalada; Dai, Bing; Pinkas, Daniel M.; Duddupudi, Anantha Lakshmi; Li, Li; Bufton, Joshua C.; Schlicher, Lisa; Gyrd-Hansen, Mads; Hu, Ming; Bullock, Alex N.; Degterev, Alexei; Cuny, Gregory D. [European Journal of Medicinal Chemistry, 2020, vol. 200]

44
[ 58349-01-2 ]
N-(5-(2-amino-5-bromopyridin-3-yl)-3-chloro-2-methoxyphenyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C / Inert atmosphere 2.1: ammonium chloride; iron / ethanol; water / 1 h / 85 °C 3.1: pyridine / 24 h / 20 °C / Inert atmosphere 4.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran / 16 h / Inert atmosphere; Reflux 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide; acetonitrile / 0.17 h / 20 °C / Inert atmosphere 5.2: Suzuki-Miyaura Coupling / 16 h / 90 °C / Inert atmosphere

Reference： [1]Suebsuwong, Chalada; Dai, Bing; Pinkas, Daniel M.; Duddupudi, Anantha Lakshmi; Li, Li; Bufton, Joshua C.; Schlicher, Lisa; Gyrd-Hansen, Mads; Hu, Ming; Bullock, Alex N.; Degterev, Alexei; Cuny, Gregory D. [European Journal of Medicinal Chemistry, 2020, vol. 200]

45
[ 58349-01-2 ]
N-(5-(2-amino-5-(4-(piperazin-1-yl)phenyl)pyridin-3-yl)-3-chloro-2-methoxyphenyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 60 °C / Inert atmosphere 2.1: ammonium chloride; iron / ethanol; water / 1 h / 85 °C 3.1: pyridine / 24 h / 20 °C / Inert atmosphere 4.1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran / 16 h / Inert atmosphere; Reflux 5.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide; acetonitrile / 0.17 h / 20 °C / Inert atmosphere 5.2: Suzuki-Miyaura Coupling / 16 h / 90 °C / Inert atmosphere 6.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,2-dimethoxyethane / 0.17 h / 20 °C / Inert atmosphere 6.2: 16 h / Inert atmosphere; Reflux 7.1: trifluoroacetic acid / dichloromethane / 16 h / 20 °C

Reference： [1]Suebsuwong, Chalada; Dai, Bing; Pinkas, Daniel M.; Duddupudi, Anantha Lakshmi; Li, Li; Bufton, Joshua C.; Schlicher, Lisa; Gyrd-Hansen, Mads; Hu, Ming; Bullock, Alex N.; Degterev, Alexei; Cuny, Gregory D. [European Journal of Medicinal Chemistry, 2020, vol. 200]

46
[ 58349-01-2 ]
N-(5-bromo-3-chloro-2-hydroxyphenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: ammonium chloride 2: triethylamine
	Multi-step reaction with 2 steps 1: ammonium chloride; iron / water; ethanol / 1.5 h / 80 °C 2: triethylamine / dichloromethane / 1.5 h / 20 °C