Reaction SMILES: Cl.[CH:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:4][CH2:3]1.C1(C)C=CC=CC=1.I[C:34]1[CH:42]=[C:41]2[C:37]([C:38]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:39][N:40]2[CH3:43])=[CH:36][CH:35]=1.CC(C)([O-])C.[Na+]>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.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CCCCCCC.O>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:7]1[C:6]([CH2:18][O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:34]3[CH:42]=[C:41]4[C:37]([C:38]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:39][N:40]4[CH3:43])=[CH:36][CH:35]=3)[CH2:22][CH2:21]2)=[C:5]([CH:2]2[CH2:3][CH2:4]2)[O:9][N:8]=1
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1COC1CCNCC1
Reactant: Cn1cc(C(=O)OC(C)(C)C)c2ccc(I)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)OC(C)(C)C)c2ccc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc21
Temperature: 22.5 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
Add 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-[(piperidin-4-yloxy)methyl] isoxazole hydrochloride (15.609 Kg, 38.66 mol) to toluene (229.5 Kg) under a nitrogen atmosphere. Add tert-butyl 6-iodo-1-methylindole-3-carboxylate (18.0 Kg, 50.39 mol) and sodium tert-butoxide (9.3 Kg, 96.76 mol) and heat to 55-60° C. for at least 1 hour. Add 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (304 g, 0.77 mol) and tris(dibenzylidene acetone)dipalladium, Pd2 dba3, (354 g, 0.39 mol) and heat the mixture to 55-60° C. Do not allow temperature to go above 65° C. Follow by TLC until no starting material (5-cyclopropyl-3-(2,6-dichlorophenyl)-4-[(piperidin-4-yloxy)methyl] isoxazole hydrochloride is observed). Discontinue heating, add water (31.2 Kg) and cool mixture to 15-30° C. Separate the layers and filter the aqueous layer and emulsion through diatomaceous earth. Wash the filter cake with toluene (2×5.4 Kg) and combine the washes with the aqueous filtrate. Stir for 10 minutes and separate the layers. Combine the organic layer with the original organic layer. Re-extract the aqueous layer with toluene (13.5 Kg). Combine organics and wash with brine (2×30.3 Kg) and separate the layers. Add magnesium sulfate (5.0 Kg) and charcoal (800 g) to the organic layer and stir for 20 minutes. Filter the mixture. Rinse filter cake with toluene (5.4 Kg) and combine the organics. Add silica gel (7.0 Kg), and stir for 20-30 minutes. Add thiol derivatized silica gel (6.2 Kg) and stir for at least 15 hours. Filter solids. Wash the filter cake with toluene (2×10.8 Kg) and combine washes with filtrate. Concentrate washes at 50-55° C. to lowest stirrable volume. Cool to 15-30° C. and add heptane (22.3 Kg) in a thin stream. Stir for 30-60 minutes. Add heptane (21.3 Kg) in a thin stream and stir for at least 1 hour. Cool to 0-5° C. and stir for 1-2 hours. Collect solids by filtration. Wash the filter cake with heptane (2×4.2 kg) cooled to 0-5° C. Dry the solids at 50-55° C. for 12-72 hours under vacuum. Add the dry solids to toluene (45.7 Kg) and heat until a clear solution is obtained. Cool to 15-30° C. and add heptane (36.2 Kg). Stir for 30-90 minutes at room temperature. Add heptane (18.1 Kg) and stir 30-90 minutes. Repeat the addition of heptane (18.1 Kg) and stir for 1-2 hours. Cool the suspension to 0-5° C. and stir for 30-90 minutes. Collect the solids by filtration. Wash the filter cake with heptane (2×9.0 kg) cooled to 0-5° C. Dry the solids at 50-55° C. for 12-72 hours under vacuum. Add the dry solids to methanol (118.6 Kg) and heat the suspension to reflux for 30-60 minutes. Cool the suspension to 0-5° C. and stir for 30-60 minutes. Collect the solids by filtration. Wash the filter cake with methanol (16.9 kg) cooled to 0-5° C. Dry the solids at 45-50° C. for 12-72 hours under vacuum to give 19.102 Kg (89%) of the title compound.