Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24]C)=[C:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:11][N:10]=[C:9]2[NH2:23])[CH:7]=1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)=[N:11][N:10]=[C:9]2[NH2:23])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-n1c(N)nnc1-c1ccc(C(F)(F)F)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1nnc(-c2ccc(C(F)(F)F)cc2)n1-c1cc(Cl)ccc1O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4-(5-Chloro-2-methoxyphenyl)-5-[4-(trifluoromethyl)-phenyl]-4H-1,2,4-triazol-3-amine (1.5 g, 4.1 mmol) was taken up in methylene chloride (forms suspension), cooled to 0° C. under N2, and from 3 to 6 eq. boron tribromide (25 ml, 1.0M in CH2Cl2) added. The reaction was stirred at 24° C. for 18 h, and 1N sodium hydroxide (80 ml) was added and the solvent was removed by rotary evaporation and the residue was taken up in ethyl acetate and enough THF added to complete dissolution. After being washed with 0.1N HCl solution and brine the solution was dried over MgSO4. Chromatography, elution 1% AcOH/5% methanol in dichloromethane gave 795 mg (55%). mp 147-155° C. H. Res. MS calcd. for C15H10ClF3N4O: 355.0574; Found: 355.0566; Dev: 2.3 ppm.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](=O)[CH2:13][S:14]([CH3:16])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([N:22]=[C:12]([C:3]1[C:2]([OH:1])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:13][S:14]([CH3:16])=[O:15])[CH2:19][CH2:20][CH3:21]
Reactant: CS(=O)CC(=O)c1cc2ccccc2cc1O
Reactant: CCCCN
Product: CCCCN=C(CS(C)=O)c1cc2ccccc2cc1O
Yield: 55 %

Procedure:
A solution of 3'-hydroxy-2-(methylsulfinyl)-2'-acetonaphthone (10 g, 0.040 mole) in n-butylamine (50 ml) was stirred at room temperature for 24 hrs. The reaction mixture was poured into petroleum ether (400 ml) and the product, which precipitated, was filtered off. Recrystallization from absolute ethanol gave light brown crystals (7.0 g, 55%), mp 162°-164°.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH:13]([F:15])[F:14])[CH:10]=[C:9]([C:16]3[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)[N:8]=2)[CH:6]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:12]=[C:11]([CH:13]([F:15])[F:14])[CH:10]=[C:9]([C:16]4[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=4)[N:8]=3)[CH:6]=2)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)cn2)c1

Procedure:
3-{1-[4-Difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonic acid tert-butylamide was prepared from 2-(4-iodo-imidazol-1-yl)-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.8) (0.47 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure III. Obtained as light yellow solid (0.06 g), which was subsequently deprotected.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CO[C:21]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(OC)OC>C(O)(=O)C>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[C:21]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Solvent: CC(=O)O
Product: COC(=O)c1cccc2nc(-c3ccccc3)n(CC(OC)OC)c12
Temperature: 25 °C
Yield: 81.6 %

Procedure:
Methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (922 mg, 3.6 mmol) from Step C of Example 13 was stirred in glacial acetic acid (2.5 mL) and (trimethoxymethyl)benzene (2.0 g, 10.9 mmol) at 70° C. for 3 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (silica gel, 80:20 hexanes/ethyl acetate) to give methyl 1-(2,2-dimethoxyethyl)-2-phenyl-1H-benzo[d]imidazole-7-carboxylate as a brown oil (1.0 g, 83%): 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.72-7.70 (m, 2H), 7.53-7.51 (m, 3H), 7.33 (t, J=8.0 Hz, 1H), 4.76 (d, J=5.0 Hz, 2H), 4.24 (t, J=5.0 Hz, 1H), 3.99 (s, 3H), 3.07 (s, 6H); MS (ESI+) m/z 341 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[H-].[Na+].CI.[C:19]([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:19][NH:6][C:5]1[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-nitro-4-trifluoromethylaniline (200 mmol, 41.2 g) in DMF (200 mL) cooled to 0° C. was added portionwise NaH (210 mmol, 8.4 g of a 60% suspension in mineral oil) (exothermic, gas evolution). The reaction was allowed to reach ambient temperature for 45 min, then cooled back to 0° C. MeI (220 mmol, 13.7 mL) was added via syringe (exothermic) and the resulting slurry was stirred for 2 h. The reaction mixture was poured into a 1:1 mixture of saturated NaHCO3 and brine (1 L) to provide the product as a bright orange precipitate, which was filtered, washed with water and dried in vacuo. 1H NMR (500 MHz, CDCl3), δ (ppm): 8.52 (d, J=1.2 Hz, 1H), 8.31 (br s, 1H), 7.70 (d, J=8.9 Hz, 1H), 6.98 (d, J=9.2 Hz, 1H), 3.13 (d, J=5.3 Hz, 3H). LC-MS (ESI, Method C): 3.34 min, m/z 221.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1.F[C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[C:25]=1[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:24]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][CH2:34][C:35]5[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=5)[C:25]=4[C:26]#[N:27])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#Cc1c(F)cccc1NCCc1ccncc1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)cn2C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(NCCc2ccncc2)cccc1Oc1ccc(-c2cn(C3CCOC3)c3ncnc(N)c23)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-[4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-phenol (0.517 g), 2-fluoro-6-(2-(4-pyridinyl)ethylamino)benzonitrile (0.42 g), potassium carbonate (0.48 g) and dimethylformamide (20 ml) were heated at 120° C. under nitrogen for 8 hours. The mixture was allowed to cool, diluted with water then extracted with ethyl acetate to give a solid which was recrystallised from ethyl acetate to give solid which was purified by flash column chromatography on silica using ethyl acetate and then ethyl acetate/methanol (9:1, 8:1, 4:1) to give 2-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]-6-(2-(4-pyridyl)ethylamino)-benzonitrile, m.p 212-213° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:20].B1([O-])OO1.O.O.O.O.[Na+]>CO>[N:1]1([CH2:7][CH2:8][S:9]([C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[O:20])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccc(SCCN2CCOCC2)cc1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)CCN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cold (0° C.) solution of 1-[[(4-morpholinyl)ethyl]thio]-4-nitrobenzene in methanol is treated slowly with excess 30% sulfuric acid and then sodium perborate tetrahydrate (10 equivalents) is added. The mixture is stirred at 0° C. for 2 hrs and then at ambient temperature for 2 hrs. The methanol is removed in vacuo and the residue basified with 50% sodium hydroxide solution and filtered. The filter cake is washed with methylene chloride and the aqueous filtrate extracted with the methylene chloride washings. The combined extract is washed with water, dried, and concentrated to obtain the product.
Reaction SMILES: [CH:1]1([C:5](=O)[CH2:6][C:7]#[N:8])[CH2:4][CH2:3][CH2:2]1.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH:1]1([C:5]2[CH:6]=[C:7]([NH2:8])[N:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:17]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NNc1ccccc1
Reactant: N#CCC(=O)C1CCC1
Solvent: CCO
Product: Nc1cc(C2CCC2)nn1-c1ccccc1
Temperature: 90 °C
Yield: 42.7 %

Procedure:
A stirred mixture of 3-cyclobutyl-3-oxopropanenitrile (24.6 g, 0.20 mol) and phenylhydrazine (23.62 g, 0.20 mol) in ethanol (200 mL) was heated at 90° C. for 15 h. The reaction mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate, concentrated under reduced pressure to give a solid which was triturated with a mixture of 10% petroleum ether in ethyl acetate, followed by trituration with diethyl ether to afford 3-cyclobutyl-1-phenyl-1H-pyrazol-5-amine (18.20 g, 43% over two steps) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 7.55-7.57 (m, 2H), 7.42-7.46 (m, 2H), 7.26 (m, 1H), 5.40 (s, 1H), 5.25 (s, 2H), 3.33 (m, 1H), 2.05-2.50 (m, 4H), 1.82-1.96 (m, 2H).
Reaction SMILES: Cl[S:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](Cl)=[O:6].Cl.[CH3:17][NH2:18].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:15][O:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:3]2[S:2][N:18]([CH3:17])[C:5](=[O:6])[C:4]=2[CH:8]=1
Reactant: COc1cc(SCl)c(C(=O)Cl)cc1OC
Reactant: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc2sn(C)c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Chlorosulfenyl-4,5-dimethoxybenzoyl chloride (5.0 g) was dissolved in pyridine (30 ml) and methylamine hydrochloride (6.0 g) was added. The mixture was stirred at room temperature for 2 days. Ethyl acetate was added and the mixture was washed with 1 N HCl and water. Ethyl acetate was dried with Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography eluting with heptane-ethyl acetate (1:9).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]=1.[CH3:17][NH:18][CH3:19].CO>>[CH2:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]=[C:2]([N:18]([CH3:19])[CH3:17])[CH:11]=1)[CH3:13]
Reactant: CCc1cc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: CNC
Solvent: CO
Product: CCc1cc(N(C)C)nc2ccc([N+](=O)[O-])cc12

Procedure:
The product was obtained from the product of Step B and a solution of 2N dimethyl-amine in methanol (5 mL, 25 mmol) according to the procedure of Example 1, Step C.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([C:31]1[CH:32]=[N:33][C:34]([O:37][CH3:38])=[N:35][CH:36]=1)[CH2:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[C:16]=2[N:29]=1)([OH:3])=[O:2].FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:38][O:37][C:34]1[N:35]=[CH:36][C:31]([C@@H:5]([CH2:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]=3[N:29]=2)[CH2:4][C:1]([OH:3])=[O:2])=[CH:32][N:33]=1
Reactant: COc1ncc([C@H](CC(=O)O)CC(=O)CCCCc2ccc3c(n2)N(C(=O)OC(C)(C)C)CCCC3)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ncc([C@H](CC(=O)O)CC(=O)CCCCc2ccc3c(n2)NCCCC3)cn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
The BOC-protected product of Example 11 (15 g) was dissolved in dichloromethane (75 ml) and the solution cooled to 5° C. Trifluoroacetic acid (48.7 g) was added dropwise maintaining the internal temperature at <10° C. The reaction mixture was then heated to 30° C. and aged for ca. 2 hours. The reaction mixture was then cooled to 0° C. and a 2M solution of sodium hydroxide was added dropwise maintaining the temperature at or below ambient. The resulting solution was allowed to settle for ca. 1 hour and the layers separated. The aqueous layer was treated with Ecosorb™ C-941 (0.75 g) at ambient temperature for 1 hour. The resulting mixture was filtered through a bed of Hyflo™. The filter-bed was washed with water (10 ml). The combined filtrates were acidified to pH 6.0 by adding concentrated hydrochloric acid (ca. 8 ml) whilst maintaining the temperature at or below ambient temperature. The aqueous solution was extracted with dichloromethane (2×150 ml) and the organics washed with water (50 ml). The solution was solvent switched to isopropanol (65 ml) at atmospheric pressure and the solution warmed to 40° C., seeded with 0.6% w/w seed, and maintained at 40° C. for 12 hours. Heating was then removed and the slurry allowed to cool to 20° C. Isolation by filtration and washing with isopropanol (3×15 ml) afforded the title compound (9.0g, 74% yield).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:29][C:30](=O)[CH2:31][C:32]1[NH:33][N:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30](=[O:29])[CH2:31][C:32]1[NH:33][N:34]=[C:35]([CH:37]([CH3:38])[CH3:39])[N:36]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: CCOC(=O)Cc1nc(C(C)C)n[nH]1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C(C)C)n[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 25 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (5-isopropyl-2H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 10 h to afford the title compound as tan solid (96 mg, 25%). LC/MS (Method B) 3.39 min, [M+1]+ 504.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].C([Li])CCC.C[O:23][B:24](OC)[O:25]C.Cl>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH3:9])=[C:2]([B:24]([OH:25])[OH:23])[CH:3]=2)=[CH:11][CH:12]=1
Reactant: COB(OC)OC
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1B(O)O
Temperature: -78 °C
Yield: 69.1 %

Procedure:
3-Bromo-4′-chloro-4-ethylbiphenyl (10 g, 0.03 mol) is dissolved in tetrahydrofuran (250 ml), and the temperature is cooled to −78° C. n-Butyllithium (1.33 molar solution in hexanes, 34.6 ml) is added dropwise over 30 minutes, maintaining the temperature at around −78° C. The reaction mixture is stirred for one and a half hours, then trimethylborate (4.9 g, 0.05 mole) is added dropwise and the reaction mixture is stirred for two hours. A solution of 2N aqueous hydrochloric acid (100 ml) is added dropwise, and once the addition is complete the mixture is stirred for two hours. The mixture is concentrated to remove most of the tetrahydrofuran, then diluted with water and extracted with diethyl ether. The organic extracts are washed with water and brine, combined, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is further purified by flash column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 4′-chloro-4-ethylbiphen-3-ylboronic acid (5.4 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc([N+](=O)[O-])c3)n2)n1

Procedure:
The 6-methyl-6′-(3-nitro-phenyl)-4-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl (example E.26) (5.0 g, 12.71 mmol) and commercially available 3-nitrophenylboronic acid (2.547 g, 15.26 mmol) according to the general procedure VI. Obtained as a white solid (3.7 g, 66%). MS (ISP) 436.2 [(M+H)+].
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:7]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN(c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitro-diphenylamine (Aldrich) is reacted with methyl bromoacetate in the presence of potassium carbonate in DMF at 70° C. to give methyl [(4-nitro-phenyl)-phenyl-amino]-acetate (brown oil). MS: 287 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C@@H:7]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[C@@H:8]([NH:10][CH:11]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH3:9])=[CH:4][CH:3]=1.[NH:34]1[CH:38]=[N:37][CH:36]=[N:35]1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.CCOCC.[Cu]I>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C@@H:7]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])[C@@H:8]([NH:10][CH:11]([C:17]2[CH:22]=[CH:21][C:20]([N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)=[CH:19][CH:18]=2)[C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: C[C@H](NC(c1ccc(Br)cc1)C(C)(C)C#N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: C[C@H](NC(c1ccc(-n2cncn2)cc1)C(C)(C)C#N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Temperature: 195 °C

Procedure:
To a solution of 22.5 mg (0.043 mmol) of 3-(1(S)-(4-chlorobenzyl)-2(S)-((1-(4-bromophenyl)-2-cyano-2-methylpropyl)amino)propyl)benzonitrile in 0.5 mL of N-methyl-pyrrolidone, 12 mg (0.173 mmol) of 1,2,4-triazole, 2.3 mg of CuI and 24 mg of K2CO3 were added. The mixture was heated in a microwave reactor at 195° C. for 4 hr. The reaction was diluted with ether, washed with water, brine, dried and concentrated. The residue was purified by prep TLC using 50% EtOAc-hexane to isolate the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:22])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COc1ccc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 49.6 g of N-t-butoxycarbonyl-5-methoxy-2-nitroaniline (prepared as described in Preparation 6) in 300 ml of dehydrated dimethylformamide was added, whilst ice-cooling, to a suspension of 12.0 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 300 ml of dehydrated dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes, after which 17.2 ml of methyl iodide were added at room temperature. The reaction mixture was stirred for 1 hour, after which it was allowed to stand overnight at room temperature. It was then concentrated to about one-fifth of its original volume by evaporation under reduced pressure. The concentrate was mixed with ice-water and the resulting aqueous mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. On distilling off the solvent, there were obtained 52.1 g of the title compound, melting at 122°-124° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([OH:35])[C:33]#[CH:34].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[F:10][C:9]([F:12])([F:11])[O:8][C:4]1[CH:3]=[C:2]([C:34]#[C:33][CH2:32][OH:35])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCO
Reactant: FC(F)(F)Oc1cccc(I)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: OCC#Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 1-iodo-3-(trifluoromethoxy)benzene (5.00 g), copper(I) iodide (66.3 mg), triphenylphosphine (228 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (360 mg), propargyl alcohol (1.13 ml), diisopropylethylamine (12.1 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 15 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to give the object product (3.28 g) as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[C:27]([Cl:39])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[Cl:39][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([Cl:31])[C:28]=1[O:32][CH2:33][CH2:34][C:35]([F:36])([F:37])[F:38]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2cc(Cl)c(OCCC(F)(F)F)c(Cl)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(Cl)c(OCCC(F)(F)F)c(Cl)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-{4-[3,5-dichloro-4-(3,3,3-trifluoropropoxy)phenyl]-1,3-thiazol-2-yl}acetamide (160 mg, 0.334 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 30 mg of the product as a white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 2.85-2.92 (m, 2H), 3.17 (s, 3H), 3.39 (s, 3H), 4.18-4.23 (m, 2H), 5.32 (s, 2H), 6.23 (s, 1H), 7.35 (s, 1H), 7.88 (s, 1H), 8.00-8.08 (m, 2H), 12.71 (br s, 1H); APCI-MS (m/z) 576.23 (M+H)+.