Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:40]=[CH:39][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:38])[C:21]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:30][CH2:31][CH2:32][CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OC1C=CC2NC(C3C(=O)C(CCC)(CCC)C4C(C=3O)=CC=CC=4)=NS(=O)(=O)C=2C=1)C1C=CC=CC=1>>[CH2:30]([C:21]1([CH2:34][CH2:35][CH2:36][CH3:37])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]([OH:29])=[C:19]([C:14]2[NH:13][C:12]3[CH:39]=[CH:40][C:9]([OH:8])=[CH:10][C:11]=3[S:16](=[O:18])(=[O:17])[N:15]=2)[C:20]1=[O:38])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Agent: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2ccccc21
Yield: 100 %

Procedure:
The title compound was prepared following the procedure of Example 2G, substituting the product of Example 5D for the product of Example 2F to afforded the title compound (70 mg, 100%). 1H NMR (300 MHz, DMSO-d6): δ 8.16 (d, J=8.09 Hz, 1 H), 7.74 (m, 1 H), 7.54 (m, 2 H), 7.17 (m, 2 H), 7.07 (m, 1 H), 2.16 (m, 2 H), 2.00 (m, 2 H), 1.05 (m, 4 H), 0.88 (m, 2 H), 0.67 (t, J=7.17 Hz, 6 H), 0.50 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1>>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:20]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2
Reactant: COc1cccc(C=O)c1F
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Product: COc1cccc(C=C2c3ccccc3CCc3ccccc32)c1F
Yield: 29.5 %

Procedure:
Following procedures essentially as described in Example 28 and using 2-fluoro-3-methoxybenzaldehyde (2.4 g, 15.4 mmol) and dibenzosuberane (3.0 g, 15.4 mmol), provides 1.5 g of title compound as white crystals. mp 148.9° C. HPLC shows 96% purity.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([CH3:16])[CH3:15])=[CH:10][CH:9]=1.[N:24]#[C:25]Br.CC(C)=O.C(N(CC)CC)C>O>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:25]#[N:24])=[CH:21][CH:22]=2)([CH3:16])[CH3:15])=[CH:12][CH:13]=1
Reactant: N#CBr
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(N2C(=O)C=CC2=O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(c1ccc(OC#N)cc1)c1ccc(N2C(=O)C=CC2=O)cc1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 91.4 %

Procedure:
A 21.70 gram portion of 4-(1-(4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)phenyl)1-methylethyl)phenol (0.1037 mole), 11.53 grams of cyanogen bromide (0.1089 mole) and 250 milliliters of acetone were added to a reactor and maintained under a nitrogen atmosphere with stirring. The stirred solution was cooled to -5° C. then 10.55 grams of triethylamine (0.1043 mole) was added to the reactor over a eight minute (480 s) period and so as to maintain the reaction temperature at -5° to -3° C. After completion of the triethylamine addition, the reactor was maintained at -5° to -3° C. for an additional 37 minutes (2220 s), followed by addition of the reactor contents to 1500 milliliters of deionized water. After 5 minutes (300 s), the water and product mixture was multiply extracted with three 100 milliliter volumes of methylene chloride. The combined methylene chloride extract was washed with 500 milliliters of 0.05 percent aqueous hydrochloric acid followed by washing with 500 milliliters of deionized water then drying over anhydrous sodium sulfate. The dry methylene chloride extract was filtered and solvent removed by rotary evaporation under vacuum for 30 minutes (1800 s) at 90° C. 4-(1-(4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)phenyl)-1-methylethyl)phenyl cyanate (22.2 grams) was recovered in 91.4 percent yield as a light amber colored oil. Infrared spectrophotometric analysis of a film sample of the product confirmed the product structure (disappearance of phenolic hydroxyl absorbance, appearance of cyanate absorbance at 2242 and 2271 cm-1, maintenance of maleimide carbonyl absorbance at 1722 cm-1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)CC4)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a solution of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (230.0 mg, 0.55 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (185.4 mg, 1.39 mmol) in n-BuOH (3 mL) was added DIPEA (215.7 mg, 1.67 mmol). The mixture was stirred at 150° C. overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/100 to 1/70) to give the product as a light yellow solid (87.0 mg, 33.0%).
Reaction SMILES: CC1(C)COB([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([OH:18])[CH2:17][O:16][CH2:15]3)=[C:10]([O:19][CH3:20])[CH:9]=2)OC1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[F:32])[NH:28][CH:27]=[C:26]2[CH:33]=[O:34].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:32][C:31]1[CH:30]=[C:29]2[C:25]([C:26]([CH:33]=[O:34])=[CH:27][NH:28]2)=[CH:24][C:23]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:18])[CH2:15][O:16][CH2:17]2)=[C:10]([O:19][CH3:20])[CH:9]=1
Reactant: COc1cc(B2OCC(C)(C)CO2)ccc1C1(O)COC1
Reactant: O=Cc1c[nH]c2cc(F)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc(-c2cc3c(C=O)c[nH]c3cc2F)ccc1C1(O)COC1
Temperature: 110 °C
Yield: 72.4 %

Procedure:
To a solution of 3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]oxetan-3-ol (101 mg, 0.348 mmol) and 5-bromo-6-fluoro-1H-indole-3-carbaldehyde (88.5 mg, 0.365 mmol) in toluene/ethanol (8 mL, 3:1) was added 2N potassium carbonate (145 mg, 1.051 mmol) and Pd(dppf)Cl2 (30 mg, 0.041 mol). The reaction was degassed with N2 for 2 minutes. The reaction was heated to 110° C. for 3 hours. The reaction mixture was concentrated to give a crude residue, which was purified by column chromatography on a silica gel to afford the title compound (86 mg, 73%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 8.80 (br. s, 1H), 8.32 (d, 1H), 7.79 (d, 1H), 7.32 (d, 1H), 7.15 (m, 2H), 7.07 (s, 1H), 3.88 (s, 3H), 3.62 (s, 1H), 2.50 (m, 2H), 2.34 (m, 2H), 1.98 (m, 1H), 1.64 (m, 1H)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Cl)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COc1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 106.6 %

Procedure:
According to the general procedure A described above, 4-chloroanisole (130 mg, 0.92 mmol) reacted with diphenylamine (169 mg, 1.00 mmol) at 80° C. for 12 h using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 catalyst and sodium tert-butoxide to give the title compound (270 mg, 99%) as a solid: 1H-NMR (300 MHz, CDCl3): δ 7.30 (app.t, 4H, J=7.5 and 8.1 Hz), 7.17 (app.t, 6H, J=8.4 and 9.0 Hz), 7.04 (app.t, 2H, J=7.2 and 6.9 Hz), 6.94 (d, 2H, J=9.0 Hz), 3.88 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 156.11, 148.13, 140.74, 129.04, 127.26, 122.84, 121.78, 114.71, 55.44. GC/MS(EI): m/z 275 (M+).
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3([CH3:24])[CH2:23][O:22]3)[C:15]=2[CH:25]=1.C([O-])(=O)C.[Na+].[H-].[Na+]>C(O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3([CH3:23])[O:22][C:2]4=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]4[CH2:24]3)[C:15]=2[CH:25]=1
Reactant: CC1(Cn2c(=O)oc3ccc(Br)cc32)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CC1(Cn2c(=O)oc3ccc(Br)cc32)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 75 °C
Reaction time: 17 h
Yield: 21.1 %

Procedure:
A mixture of 2-chloro-4-nitro-1H-imidazole (3.22 g, 21.8 mmol), 5-bromo-3-(2-methyloxiran-2-ylmethyl)-3H-benzoxazol-2-one (6.2 g, 21.8 mmol); sodium acetate (1.97 g, 24 mmol) and ethanol (50 ml) was stirred under reflux for 8 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, and the resulting solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in 1,4-dioxane (60 ml). To the solution, sodium hydride (528 mg, 13.21 mmol) was added followed by stirring at 70-80° C. for 17 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1) to afford 5-bromo-3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-3H-benzoxazol-2-one (1.82 g, yield 37%) as a white powder.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=1)[CH3:2].[BH4-].[Na+].CO>O1CCCC1>[CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][OH:10])[N:8]=1)[CH3:2]
Reactant: CCNc1nc(C(=O)OCC)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1nc(CO)cs1

Procedure:
The reaction described in Preparation 17 was repeated but using 10 g of ethyl 2-ethylaminothiazole-4-carboxylate, 3.8 g of sodium borohydride, 70 ml of methanol and 150 ml of tetrahydrofuran, giving the title compound as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][O:10][C:9]2[CH:8]=[C:7]3[NH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:6]3=[CH:5][C:4]=2[NH:3]1.[CH2:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[CH2:18]([CH:25]1[CH2:30][CH2:29][N:28]([C:15]([C:13]2[NH:12][C:7]3=[CH:8][C:9]4[O:10][CH2:11][C:2](=[O:1])[NH:3][C:4]=4[CH:5]=[C:6]3[CH:14]=2)=[O:17])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1COc2cc3[nH]c(C(=O)O)cc3cc2N1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C1COc2cc3[nH]c(C(=O)N4CCC(Cc5ccccc5)CC4)cc3cc2N1

Procedure:
The title compound is prepared from 6-oxo-1,5,6,7-tetrahydro-8-oxa-1,5-diaza-cyclopenta[b]naphthalene-2-carboxylic acid and 4-benzylpiperidine according to the method described in Example 1/c. Mp.: 225-231° C. (diethyl ether).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][C@@H:6]([C:18](O)=[O:19])[CH2:5]1)=[N+:2]=[N-:3].ClC(OCC(C)C)=O.CN1CCOCC1>C(COC)OC>[N:1]([C@@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:8][CH2:7][C@@H:6]([CH2:18][OH:19])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C[C@@H]1N=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)C[C@@H]1N=[N+]=[N-]
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
(1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonyl-amino)cyclohexane-1-carboxylic acid (1.86 g) was dissolved in dimethoxyethane (20 ml), and to the solution isobutyl chloroformate (1.02 ml) and N-methylmorpholine (860 mg) were added at −15° C. The mixture was stirred for 10 minutes at the same temperature. The hydrochloride of N-morpholine deposited was separated by filtration, and an aqueous solution (4 ml) of sodium borohydride (370 mg) was added to the filtrate to stir the mixture for 10 minutes. After water was added, and the solvent was distilled off under reduced pressure, the residue was extracted with dichloromethane and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane 1:1) to obtain the title compound (1.35 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([Br:12])([F:11])[F:10])[CH:5]=[C:4]([O:18][CH:19]([F:21])[F:20])[C:3]=1[NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:24].ClC1C=CC=C(C(OO)=[O:43])C=1>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:15])([F:14])[F:16])[C:9]([Br:12])([F:10])[F:11])[CH:5]=[C:4]([O:18][CH:19]([F:20])[F:21])[C:3]=1[NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N+:31]([O-:43])=[CH:30][CH:29]=[CH:28]2)=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)Br)cc1OC(F)F)c1ccc2ncccc2c1
Solvent: ClCCl
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)Br)cc1OC(F)F)c1ccc2c(ccc[n+]2[O-])c1
Yield: 108.2 %

Procedure:
N-[2-Bromo-4-(1-bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)phenyl]-quinoline-6-carboxamide (0.73 g) was dissolved in dichloromethane (50 ml), added with 3-chloroperbenzoic acid (purity 70%, 0.48 g), and sited at room temperature for S hours. The solvent was distilled off under the reduced pressure and the residue was dissolved in ethyl acetate, Sodium hydrocarbonate solution and potassium carbonate were added thereto. After extracting the mixture twice with ethyl acetate, the organic phases were combined and washed with water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was filtered off and the solvent was removed by distillation under the 1.5 reduced pressure to obtain N-[2-bromo-4-(1-bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)phenyl]quinoline-6-carboxamide-1-oxide (0.81 g, 98%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]OC(=O)C=C)=[CH:11][CH:10]=1.[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]CCCCCCBr)(=[O:30])[CH:28]=[CH2:29].C(OCCCCCCBr)(=O)C=C>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:27](=[O:30])[CH:28]=[CH2:29])=[CH:13][CH:14]=1
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: C=CC(=O)OCCCCCCCCCCCCBr
Agent: C=CC(=O)OCCCCCCBr
Product: C=CC(=O)OCCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Yield: 24.1 %

Procedure:
The same procedure as in the synthesis (b) of Example 2 was repeated except that 6.7 g of 12-bromododecyl acrylate were used instead of 5.0 g of 6-bromohexyl acrylate to give 2.1 g (Y., 24.1%) of 2,3-difluoro-4'-[12-(acryloyloxy)dodecyloxy]biphenyl. m.p.; 59.7°-60.7° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)C(O)=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1.C(O)(C)(C)C.Cl>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccc(C=C(C(=O)O)c2cccc(F)c2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ccc(CC(=O)c2cccc(F)c2)cc1
Temperature: 0 °C
Yield: 40.3 %

Procedure:
A solution of the intermediate from Step 1 (3.57 g, 12.4 mmol) and triethylamine (1.41 g, 13.9 mmol) dissolved in 35 mL of anhydrous toluene was cooled to 0° C. and treated with diphenylphosphoryl azide (3.53 g, 12.8 mmol). The solution was maintained at 0° C. for twenty minutes and warmed to room temperature for 3 hours. The reaction was poured into water, extracted with ether, dried over magnesium sulfate, and concentrated in vacuo to remove the ether. The remaining toluene solution was heated to reflux for 1 hour. tert-Butyl alcohol (4 mL, 42 mmol) was added to the reaction mixture. After an additional twenty minutes, concentrated hydrochloric acid (4 mL) was cautiously added and the reaction maintained at 80° C. overnight (14 hours). After cooling the solution to room temperature, the mixture was poured into a separatory funnel and washed with water. The toluene layer was dried with anhydrous MgSO4, filtered and concentrated in vacuo to give a yellow powder. The crude solid was crystallized from a mixture of dichloromethane and isooctane to provide 1.30 g (40%) of the desired ketone: mp 116°-120° C. 1H NMR (CDCl3) 300 MHz 7.77 (d, J=7.9 Hz, 1H), 7.68 (dt, J=9.4 Hz 2.6 Hz, 1H), 7.43 (m, 1H), 7.21-7.29 (m, 3H), 7.18 (d, J=8.3 Hz, 2H), 4.22 (s, 2H), 2.46 (s, 3H); 19F NMR (CDCl3) -111.82 (m). Mass spectrum M+H=261.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:3]=1.C([Li])CCC.CN(C)[CH:28]=[O:29]>O1CCCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:8]([C:4]2[N:3]=[C:2]([CH:28]=[O:29])[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=1
Reactant: CN(C)CCC(c1ccc(Cl)cc1)c1cccc(Br)n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)CCC(c1ccc(Cl)cc1)c1cccc(C=O)n1
Reaction time: 0.08 h

Procedure:
To a cold (-70°) solution of 2-bromo-6-(1-(4-chlorophenyl)-3-dimethylaminopropyl)pyridine (1.44 g) under nitrogen in dry tetrahydrofuran (50 mL) was added with stirring a solution of n-butyllithium (2.4 mL, 1.7M in hexane). After an additional 5 min at -70°, dry dimethylformamide (1.5 mL) was added dropwise during 2 min. The solution was allowed to warm and then quenched with water (5 mL). The solvents were removed under reduced pressure and the residue was dissolved in methylene chloride (50 mL). This solution was extracted with water (3×25 mL), dried (Na2SO4), and concentrated to give crude 6-(1-(4-chlorophenyl)-3-dimethylaminopropyl)2-pyridine carboxaldehyde (formyl proton δ 10.05, 60 MHz, CDCl3) which was chromatographed on reverse phase (C18, Waters Prep 500, 60:40/acetonitrile:water, K1 =6.3 (C18 ; 70:30/acetonitrile:water).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:19][C:20]3([C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.O>C1COCC1.CO.[OH-].[K+]>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:19][C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=4)[CH2:21][CH2:22]3)=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cccc4ccn(Cc5ccc(C(F)(F)F)cc5)c34)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(NC(=O)c3cccc4ccn(Cc5ccc(C(F)(F)F)cc5)c34)CC2)cc1
Temperature: 50 °C

Procedure:
Methyl 4-{1-[({1-[4-(trifluoromethyl)benzyl]-1H-indol-7-yl}carbonyl)amino]cyclopropyl}benzoate (27 g, 55 mmol) was dissolved in 549 ml of THF 549 ml of MeOH and 249 ml of a 2M solution of KOH. The mixture was heated at 50° C. for 2 h. After cooling to RT, 200 ml of water was added and the organic solvents removed. The solution was acidified to pH 1-1.5 with 3N HCl and the resulting solid was filtered and washed with water. 1H NMR (500 MHz, DMSO-d6): δ 12.80 (bs, 1H), 9.15 (s, 1H), 7.80 (d, 3H), 7.60 (d, 2H), 7.50 (d, 1H), 7.40 (d, 1H), 7.25-7.11 (m, 3H), 6.90 (d, 2H), 6.65 (d, 1H), 5.70 (s, 2H), 1.15 (m, 2H), 0.90 (m, 2H). MS−ESI (477.4).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Br)[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)C>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:18][CH2:17][CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:20])#[N:2]
Reactant: CCOC(=O)CCCBr
Reactant: N#Cc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: CCOC(=O)CCCn1ccc2c(C#N)cccc21
Yield: 91.4 %

Procedure:
Combined 4-cyanoindole (5 g, 35.2 mmol), ethyl-4-bromobutanoate (10.29 g, 52.8 mmol) and cesium carbonate (22.92 g, 70.3 mmol) and heated to 80° C. under argon for 1 hour. The reaction was allowed to cool and then 150 ml diethyl ether was added and the organic solution was washed with 3×150 ml H2O. Dried the organic solution over MgSO4 and evaporated the solvent. Dried on high vacuum over the weekend to afford the title compound (8.25 g) as an orange oil. δH (400 MHz, d6-DMSO). 1.13 (3H, t), 1.96-2.05 (2H, m), 2.26 (2H, t), 3.99 (2H, q), 4.29 (2H, t), 6.60 (1H, dd), 7.29 (1H, apparent t), 7.55 (1H, dd), 7.68 (1H, d), 7.90 (1H, d). MS (ES): C15H16N2O2 requires 256; found 257 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([CH3:23])[C:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[OH:21])=[CH:10][N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH3:23])[C:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:10][N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1ncc(C(=O)c2ccc(OC)cc2O)n1C
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(C(=O)c2ccc(OC)cc2OCC(=O)OC(C)(C)C)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92426 %

Procedure:
To a mixture of NaH (80% oil dispersion, 41 mg, 1.35 mmol, previously washed with hexanes) in DMF (4 ml) was added dropwise a solution of 2-n-butyl-1-methyl-5-(2-hydroxy-4-methoxybenzoyl)-1H-imidazole (361 mg, 1.25 mmol) in DMF (3 ml) at 0° under argon. The cooling bath was removed and the mixture stirred for 20 min. at ambient temperature. t-Butyl bromoacetate (222 μl, 1.35 mmol) was added neat and the reaction stirred overnight. The mixture was partitioned between water and EtOAc and the layers separated. The aqueous layer was further extracted (EtOAc, 2x) and the combined organic extract was washed with water (5x) and brine. Evaporation under reduced pressure after drying (MgO4 anhydrous) afforded the title compound as a reddish oil (465 g, 93%).