Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[ClH:10].[N:11]([O-])=O.[Na+]>[OH-].[Na+]>[ClH:10].[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][NH2:11]
Reactant: Nc1c(F)cccc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NNc1c(F)cccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-6-fluoroaniline (2.0 g, 10 mmol) was dissolved in hydrochloric acid (7.0 mL, 12 N aqueous, 8.0 equiv) and cooled to 0° C. An aqueous solution (10 mL) of sodium nitrite (0.80 g, 11 mmol, 1.1 equiv) was added dropwise over 30 minutes via addition funnel and the mixture was stirred for an additional 30 minutes at 0° C. A hydrochloric acid solution (10 mL, 12 N aqueous) of stannous chloride (7.1 g, 31 mmol, 3.0 equiv) was then added to the mixture over 45 minutes via addition funnel and the mixture was stirred for an additional 1 hour at 0° C. To the mixture, sodium hydroxide (30 mL, 1 N aqueous) was added slowly until basic (pH>8). The mixture was warmed to ambient temperature, poured into sodium hydroxide (50 mL, 25% aqueous) and the aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic extracts were dried with sodium sulfate, filtered and partially concentrated in vacuo. The mixture was diluted with diethyl ether (200 mL) and treated with gaseous hydrochloric acid until saturated, resulting in a white precipitate, which was filtered and washed with diethyl ether (2×50 mL), providing the titled compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH2:23]>>[CH3:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH:23][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: Cc1ccc(C)c(N)c1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Product: Cc1ccc(C)c(Nc2cc(-c3ccccn3)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 2,5-dimethylaniline (17 μl, 0.140 mmol) similar to Example 111 and isolated as a yellow oil (7 mg, 21%). 1H NMR (CDCl3): 8.88–8.86 (m, 1H), 8.71–8.68 (m, 1H), 8.64–8.58 (m, 2H), 7.92–7.82 (m, 2H), 7.50 (s, 1H), 7.43–7.32 (m, 2H), 7.23 (s, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.09 (s, 1H), 7.04 (dd, J=1.8, 7.8 Hz, 1H), 2.36 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@@:16]([OH:20])([CH3:19])[CH:17]=[O:18].[BH4-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:19])([OH:20])[CH2:17][OH:18]
Reactant: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)C=O)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
180 mg (0.643 mmole) of (S)-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-hydroxy-2-methylbutanal was dissolved in 5 ml of ethanol, and 30 mg (0.79 mmole) of sodium borohydride was added, followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution which was then extracted with methylene chloride. The organic extract was washed with a saturated aqueous solution of sodium chloride dried over sodium sulfate and freed from the solvent under reduced pressure. The residue was purified on silica gel column to obtain 156 mg (86%) of (S)-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2-methyl-1,2-butanediol.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH2:20])[CH:14]=2)[C:9](F)=[N:10][CH:11]=1)=[CH2:5])C.[F:21][C:22]1[CH:23]=[C:24]([NH2:30])[CH:25]=[N:26][C:27]=1[O:28][CH3:29].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[NH2:20][C:15]1[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]2[CH:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[N:10][C:9]=2[NH:30][C:24]2[CH:25]=[N:26][C:27]([O:28][CH3:29])=[C:22]([F:21])[CH:23]=2)[CH:14]=1
Reactant: COc1ncc(N)cc1F
Reactant: C=C(OCC)c1cnc(F)c(-c2cc(N)nc(C)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)=O)cc2-c2cc(N)nc(C)n2)cc1F
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
A mixture of 6-(5-(1-ethoxyvinyl)-2-fluoropyridin-3-yl)-2-methylpyrimidin-4-amine (208 mg, 0.76 mmol) and 5-fluoro-6-methoxypyridin-3-amine (162 mg, 1.14 mmol) in 1.5 mL of THF at 0° C. was added sodium bis(trimethylsilyl)amide (1 M in THF) (2.28 mL, 2.28 mmol) dropwise at 0° C. and the dark red solution was stirred at this temperature for 30 min. It was quenched with 4 mL of 0.5N HCl and stirred for 10 min. The mixture was basified with 1 N NaOH to pH of 8 and stirred with 10 mL of EtOAc for 5 min. The precipitated brown solid was filtered, washed with 2×2 mL of water followed by 2×2 mL of EtOAc. The brown solid was dried in a vacuum oven at 45° C. for 18 h to give 1-(5-(6-amino-2-methylpyrimidin-4-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (90 mg, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.93 (s, 1H), 8.90 (s, 1H), 8.50 (s, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 7.10 (br., 2H), 6.93 (s, 1H), 3.95 (s, 3H), 2.60 (s, 3H), 1.58 (s, 3H). m/z (ESI, positive ion) 369.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11]C(=O)C(F)(F)F)=[C:4]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:3]=1
Reactant: O=C(Nc1c(CN2CCOCC2)cc(Cl)cc1[N+](=O)[O-])C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(CN2CCOCC2)cc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 16 h
Yield: 76.7 %

Procedure:
To a solution of N-[4-chloro-2-(morpholin-4-ylmethyl)-6-nitrophenyl]-2,2,2-trifluoroacetamide (3.6 g, 9.6 mmol) in ethanol (60 mL) is added a 10% aqueous NaOH solution (60 mL, 150 mmol) and the reaction is heated to 80° C. for 3 h. The mixture is cooled to room temperature and is stirred an additional 16 h. Most of the ethanol is evaporated under reduced pressure and the resulting solid is isolated by filtration to afford the title compound (2 g, 77%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][C@H:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[N:23]([C:26]1[CH:27]=[C:28]([CH:32]([CH3:43])[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1)=[C:24]=[O:25]>O1CCCC1>[C:10]([O:9][C:7]([C@@H:6]1[CH2:14][CH2:15][C@H:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:5]1[C:3](=[O:4])[CH2:2][NH:1][C:24](=[O:25])[NH:23][C:26]1[CH:27]=[C:28]([CH:32]([CH3:43])[C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C(=O)OCc1ccccc1)c1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](c2ccccc2)N1C(=O)CN
Solvent: C1CCOC1
Product: CC(C(=O)OCc1ccccc1)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2C(=O)OC(C)(C)C)c1
Yield: 59.2 %

Procedure:
Benzyl 2-{3-{3-[2-((2S,5R)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenyl}propionate (B form) may be obtained in a fashion similar to that described in Example 2, but starting from 0.79 g of tert-butyl (2S,5R)-1-(2-aminoacetyl)-5-phenylprolinate and 0.8 g of benzyl 2-(3-isocyanato-phenyl)propionate (B form) in 40 cm3 of tetrahydrofuran. After treatment, 0.9 g of benzyl 2-{3-{3-[2-((2S,5R)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenyl}propionate, melting at 75° C., is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:11]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(CNc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(OC)cc(-c3cccc(F)c3)c2)c1F
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of 2,4-difluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenol (500 mg, 1.4 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (634 mg, 1.9 mmol, 1.4 eq). The reaction mixture was stirred for 1 h, then ethyl 2-bromoacetate (279 mg, 1.7 mmol, 1.2 eq) was added. The reaction mixture was stirred for a further 1 h, then poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (500 mg, 80%).
Reaction SMILES: FC(F)(F)S([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1)(=O)=O.[N:40]1C2C=CC=CC=2N[CH:41]=1>[C-]#N.[Zn+2].[C-]#N.CN(C)C=O>[NH:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25]([C:41]#[N:40])[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C(c1ccc2c(c1)ncn2S(=O)(=O)C(F)(F)F)N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A flask charged with a stir bar, zinc cyanide (0.32 g), trifluoromethanesulfonic acid cis-1-(1-trifluoromethanesulfonyl-1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment at N-1 or N-3 of the benzimidazole, 1.08 g), and N,N-dimethylformamide (5 mL) is sparged with argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.31 g) is then added and the resulting mixture is heated to 100° C. and stirred at this temperature for 2 h. After cooling to room temperature, 1-hydroxybenzotriazole hydrate (0.45 g) and water (1.5 mL) are added and stirring is continued at room temperature for 3 h. Ethyl acetate, little methanol, and saturated aqueous Na2CO3 solution are added and the mixture is filtered over Celite. The aqueous phase of the filtrate is separated and neutralized with 2 M aqueous citric acid and extracted with ethyl acetate. The organic phases are combined and washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 96:4→90:10) to give the title compound as a solid. Yield: 0.42 g (68% of theory).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[O:19]=[C:20]([CH3:30])[CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:27]([C:24]3[CH:23]=[C:22]([CH2:21][C:20](=[O:19])[CH3:30])[O:26][N:25]=3)=[O:28])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CC(=O)Cc1cc(C(=O)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(=O)Cc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) and 5-(2-oxopropyl)isoxazole-3-carboxylic acid (169 mg, 0.997 mmol). The product was purified with flash chromatography using a gradient of methanol in DCM affording 101 mg (32%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 1.54 (s, 3H), 3.96 (s, 2H), 4.20-4.49 (m, 2H), 4.53-4.64 (m, 1H), 6.63 (d, 1H), 6.65-6.69 (m, 1H), 7.48 (d, 1H), 7.69 (d, 1H), 7.79-7.90 (m, 2H), 8.04 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=2)[CH2:17][CH2:16]1.N([O-])=O.[Na+].[N-:29]=[N+:30]=[N-].[Na+]>C(O)(=O)C.O>[N:24]([C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH2:16][N:15]2[C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:19][CH:20]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc2ncnc(N3CCc4ccc(N)cc43)c2cc1OC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ncnc(N3CCc4ccc(N=[N+]=[N-])cc43)c2cc1OC
Temperature: 22 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To 1-(6,7-dimethoxy-quinazolin-4-yl)-2,3-dihydro-1H-indol-6-ylamine (104 mg, 0.323 mmol; from Example 30) in 80% acetic acid/H2O (8 mL) was added NaNO2 (35 mg, 0.35 mmol) in H2O(200 μL) at 5° C. After stirring 10 min. at 5° C. a solution of NaN3 (22mg, 0.34 mmol) in H2O(200 μL) was added and the mixture was allowed to warm to 22° C. and stirred for 1 hour. Following the removal of solvents by lyophilization the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 (2×), and brine, and the organic phase was dried over MgSO4(s), filtered and concentrated in vacuo. The residue was chromatographed on silica (2% MeOH/CHCl3) to afford 72 mg of the azide. (M.P. 184°-186° C. (dec); LC-MS: 349 (MH+); anal. RP18-HPLC RT: 4.70 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Br:17])=[CH:10][CH:9]=2)=[O:7])=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Yield: 62.6 %

Procedure:
A mixture of 4-(4-chlorobenzoyl)toluene (5.48 g, 23.8 mmol), dibenzoylperoxide (100 mg, 0.413 mmol), and N-bromosuccinimide (4.56 g, 25.6 mmol) in carbon tetrachloride (70 ml) was refluxed for 2 hours, cooled, filtered, and evaporated under vacuum. The residue was chromatographed on silica gel (1 kg) eluted with 97:3 (v/v) hexane-ethyl acetate using a preparative high-performance liquid chromatograph. Appropriate fractions were pooled and evaporated under vacuum to provide 4.61 g (63%) of 4-(4-chlorobenzoyl)benzyl bromide, m.p. 103°-104° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccccc1B(O)O
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccccc1-c1ccc2oc(-c3ccc(OC)c([N+](=O)[O-])c3)nc2c1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 2-methoxyphenylboronic acid (130 mg, 0.85 mmol) the subtitle compound was obtained (163 mg, 76%). 1H NMR (CDCl3) δ 8.75(d, 1H), 8.45(dd, 1H), 7.93(d, 1H), 7.61(d, 1H), 7.54(dd, 1H), 7.39–7.34(m, 2H), 7.25(d, 1H), 7.09–7.01(m, 2H), 4.07(s, 3H), 3.83(s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][CH:12]=C)[C:3]=1[OH:14].C[OH:16]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][CH2:12][OH:16])[C:3]=1[OH:14]
Reactant: CO
Reactant: C=CCc1cc([N+](=O)[O-])cc(Br)c1O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)c(O)c(CCO)c1

Procedure:
2-Bromo-6-prop-2-enyl-4-nitrophenol (5.8 g) was dissolved in dichloromethane (30 ml) and methanol (30 ml) and the resulting solution was cooled to -78° C. Ozone was bubbled through the solution until a faint blue coloration was observed and all starting material had reacted. The solution was purged with nitrogen, sodium borohydride (850 g) was added and the solution was allowed to come to room temperature. The solvent was evaporated and the residue was dispersed between ethyl acetate and HCl (1N). The ethyl acetate layer was washed with water, brine, dried (MgSO4) and concentrated. The residue was purified on silica using 2% methanol in dichloromethane as eluent to afford the title compound as a white solid (4 g). 1H NMR (360 MHz, CDCl3) δ 3.03 (2H, t, J=5.4 Hz), 4.06 (2H, t, J=5.5 Hz), 8.01 (1H, d, J=2.6 Hz), 8.35 (1H, d, J=2.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][OH:14])=[N:10][C:9]=2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[F:40][C:41]1[C:56]([F:57])=[CH:55][C:44]2[NH:45][C:46]([CH2:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][NH:50]3)=[N:47][C:43]=2[CH:42]=1>CN(C=O)C>[F:40][C:41]1[C:56]([F:57])=[CH:55][C:44]2[NH:45][C:46]([CH2:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][N:50]3[C:15]([C:9]3[N:10]=[C:11]([CH2:13][OH:14])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:17])=[N:47][C:43]=2[CH:42]=1
Reactant: O=C(O)c1nc(CO)sc1-c1ccc(F)cc1
Reactant: Fc1cc2nc(CC3CCCCN3)[nH]c2cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1nc(CO)sc1-c1ccc(F)cc1)N1CCCCC1Cc1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
A strirring solution of 5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazole-4-carboxylic acid (632 mg, 2.0 mmol, 80% pure), EDC.HCl (311 mg, 2.0 mmol) and 1-hydroxybenzotriazole (270 mg, 2.0 mmol) in DMF (20 ml) was treated with (RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D18 (500 mg, 2.0 mmol). The reaction mixture was stirred at room temperature, under argon for 16 h. The DMF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-10% methanol-ethyl acetate) afforded the title compound as a pale yellow solid (350 mg, 36%).
Reaction SMILES: [CH3:1][C:2](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25](O)=[O:26].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl>C(N(CC)CC)C>[CH3:34][O:33][C:29]1[CH:28]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[C:30]=1[O:31][CH3:32])[C:25]([N:4]([CH2:3][C:2]([CH3:1])=[CH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:26]
Reactant: CC(=Cc1ccccc1)CNCCN1CCCCC1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(CCN2CCCCC2)CC(C)=Cc2ccccc2)cc(OC)c1OC
Yield: 12 %

Procedure:
Experimental condition analogous to Example 13 were used with (2-Methyl-3-phenyl-allyl)-(2-piperidin-1-yl-ethyl)-amine, 0.5 g (1.9 mmol), 3,4,5-trimethoxy benzoic acid 0.49 g (2.3 mmol), 0.2 ml of triethylamine, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate 1.2 g (3.8 mmol). The reaction yielded 102 mg of an off-white solid as an HCl salt. Yield: 12%.