(3-bromophenyl)boronic acid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 50 ml round bottom flask was charged under nitrogen with 2-chloro-7-iodo-5-(toluene-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazine (6) (950 mg, 2.2 mmol), 3-bromophenyl boronic acid (440 mg, 2.2 mmol), tetrakis-triphenylphosphine palladium (50 mg, 0.04 mmol), 2M aqueous potassium carbonate (2.2 ml, 4.4 mmol) in a toluene/ethanol mixture (15/3 ml) under nitrogen. The reaction mixture was refluxed for 18 h, then allowed to cool to room temperature. The solution was diluted with ethyl acetate (˜70 ml). The organic was washed with brine, dried over magnesium sulfate and concentrated in vacuo, The residue was triturated in dichloromethane/methanol. A pale yellow solid was removed by filtration (300 mg). The residue was taken up in a tetrahydrofuran/methanol/1M NaOH mixture (4/1/1 ml) and stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated in methanol. A solid was filtered off as the title compound (10 mg, 1%). 1H NMR (DMSO-d6): 7.35-7.45 (2H, m), 8.10-8.15 (1H, d), 8.35 (1H, s), 8.4 (1H, s), 8.6 (1H, s). MS (ES+): 310, 312. The reaction mixture was refluxed for 18 h The organic was washed with brine dried over magnesium sulfate concentrated in vacuo The residue was triturated in dichloromethane/methanol A pale yellow solid was removed by filtration (300 mg) The reaction mixture was diluted with ethyl acetate washed with brine dried over magnesium sulfate concentrated in vacuo The residue was triturated in methanol A solid was filtered off as the title compound (10 mg, 1%)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of [Rh(cod)C1]2 (171.3 mg, 0.3518 mmol) in 30 mL of dioxane was added aqueous KOH (6.097 mL of 1.5 M, 9.145 mmol) followed by ethyl 2-(oxetan-3-ylidene)acetate (1 g, 7.035 mmol) and a solution of (3-bromophenyl)boronic acid (2.119 g, 10.55 mmol) in 10 mL of dioxane. The reaction was stirred for 30 minutes at room temperature then further (3-bromophenyl)boronic acid (706 mg, 0.5 eq) was added and the reaction stirred overnight. Brine was added and the aqueous layer extracted twice with ethyl acetate. The combined organics were washed with brine and then dried, filtered and concentrated under reduced pressure. The crude product was purified on silica (Companion, 80 g) eluting with 1-20% EtOAc:Petrol ether to give ethyl 2-[3-(3-bromophenyl)oxetan-3-yl]acetate as a yellow oil (1.50 g, 71%). the reaction stirred overnight the aqueous layer extracted twice with ethyl acetate The combined organics were washed with brine dried filtered concentrated under reduced pressure The crude product was purified on silica (Companion, 80 g) eluting with 1-20% EtOAc

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of [RhCl(COD)]2 (63 mg, 0.031 mmol) in dioxane (10 mL) was added aqueous KOH (1.5M, 8.29 mmol, 5.53 mL), followed by (3-bromophenyl)boronic acid (1.67 g, 8.29 mmol). Then a solution of the tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate in dioxane (7.5 mL) was added. The reaction mixture was microwaved at 100° C. for 5 min at 300 W. Brine was added and the mixture was extracted twice with ethyl acetate. The combined organics were washed with brine and then dried (MgSO4), filtered and concentrated. Purification by column chromatography (4/1 Pet ether/ethyl acetate) gave the Michael adduct (1.31 g, 79%) as a light yellow oil. The reaction mixture was microwaved at 100° C. for 5 min at 300 W the mixture was extracted twice with ethyl acetate The combined organics were washed with brine dried (MgSO4) filtered concentrated Purification by column chromatography (4/1 Pet ether/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromophenylboronic acid (2.00 g, 9.96 mmol) in CH2Cl2 (80 mls) was added Isoxazol-3-ylamine (0.84 g, 19.92 mmol), Cu(OAc)2 (0.9 g, 0.46 mmol) and triethylamine. (14 mls). The reaction mixture was stirred at room temperature for 18 h, filtered and the resulting precipitate purified by silica column chromatography (20-80% EtOAc in hexane) to afford the title compound (0.33 g). MS: [M+H]+=239, 241 filtered the resulting precipitate purified by silica column chromatography (20-80% EtOAc in hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: {4-[3-(4-Cyano-phenoxy)-5-hydroxy-benzoylamino]-cyclohexyl}-carbamic acid isopropyl ester (1.0 g, 2.2 mmol) and copper acetate (0.4 g, 2.2 mmol), dissolved in 30 ml of dichloromethane, were charged in a 100 ml capacity seal-tube. 3-bromophenyl boronic acid (0.667 g, 3.32 mmol), 4 Å molecular sieves (3.0 g) and 0.438 g (5.53 mmol) of pyridine, in 20 ml of dichloromethane, was added to the reaction mixture in a sealed-tube and reaction mixture was stirred at RT for 20 h. After reaction completion 2.0 g of silica-gel was added and the mixture was filtered. Thus obtained filterate was concentrated under reduced pressure and subjected to column chromatography to afford 0.3 g of the required product. Percentage purity (LCMS): 86.0%, (M+1)=605.1+1. were charged in a 100 ml capacity seal-tube reaction mixture After reaction completion 2.0 g of silica-gel was added the mixture was filtered Thus obtained filterate was concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 500 mg of 5-amino-2-bromobenzotrifluoride (Dakwood Products, Inc.), 6.2 mMol 3-bromophenylboronic acid (Aldrich), 70 mg of Pd(PPh3)4 and 5 ml of Na2CO3, 2 M solution in H2O, in 14 ml of toluene is stirred at reflux for 1 our. The mixture obtained is allowed to cool to rt and filtered through a pad of celite. The layers obtained are separated and the aqueous phase obtained is extracted with CH2Cl2. The organic phase obtained is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The concentration residue obtained is subjected to MPLC(CH3CN/H2O/TFA). 3′-Bromo-2-trifluoromethyl-biphenyl-4-amine is obtained. MS: 315.9 [M−1]−; HPLCDtRet=4.9; Rf=0.16 (Hexane/EtOAc, 4:1). at reflux for 1 our The mixture obtained filtered through a pad of celite The layers obtained are separated the aqueous phase obtained is extracted with CH2Cl2 The organic phase obtained is washed with brine dried (Na2SO4) filtered concentrated in vacuo The concentration residue obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from trifluoro-methanesulfonic acid 6′-methyl-6-trifluoromethyl-[3,4′]bipyridinyl-2′-yl ester (example A.5) (0.773 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.43 g, 2.1 mmol) according to the general procedure IIb. Obtained as a white solid (0.69 g, 88%). MS (ISP) 393.1 [(M+H)+] and 395.1 [(M+2+H)+].

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from trifluoro-methanesulfonic acid 6′-methyl-6-trifluoromethyl-[3,4′]bipyridinyl-2′-yl ester (example A.5) (0.773 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.43 g, 2.1 mmol) according to the general procedure IIb. Obtained as a white solid (0.69 g, 88%). MS (ISP) 393.1 [(M+H)+] and 395.1 [(M+2+H)+].

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from 2-chloro-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.4) (0.41 g, 1.5 mmol) and commercially available 3-bromo-benzene-boronic acid (0.33 g, 1.64 mmol) according to the general procedure IIb. Obtained as a light yellow solid (0.30 g, 51%). MS (ISP) 394.0 [(M+H)+]; mp 130° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from 2-chloro-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.3) (2.0 g, 6.46 mmol) and commercially available 3-bromo-benzene-boronic acid (1.43 g, 7.12 mmol) according to the general procedure IIb. Obtained as a white solid (0.89 g, 32%). MS (ISP) 430.1 [(M+H)+]; mp 148.5° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from 2-chloro-4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidine (example A.1) (1.2 g, 4.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.88 g, 4.38 mmol) according to the general procedure IIb. Obtained as a white solid (0.73 g, 43%). MS (EI) 419.9 [(M)+]; mp 124° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.2) (1.50 g, 4.38 mmol) and commercially available 3-bromo-benzene-boronic acid (1.01 g, 5.03 mmol) according to the general procedure IIb. Obtained as a white solid (1.15 g, 56%). MS (EI) 448.0, 450.0 [(M)+]; mp 160° C.