Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:24]=[CH:23][C:17]([C:18](OCC)=[O:19])=[CH:16][N:15]=2)=[CH:11][CH:10]=1.C([Li])CCCCC.[OH-].[Na+]>C1COCC1.CCCCCCC>[N:1]1([C:18]([C:17]2[CH:16]=[N:15][C:14]([O:13][C:12]3[CH:25]=[CH:26][C:9]([F:8])=[CH:10][CH:11]=3)=[CH:24][CH:23]=2)=[O:19])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(Oc2ccc(F)cc2)nc1
Reactant: C1CNCCNC1
Agent: [Li]CCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=C(c1ccc(Oc2ccc(F)cc2)nc1)N1CCCNCC1
Temperature: 0 °C
Yield: 55.7 %

Procedure:
A 5-L, 4-necked round-bottomed flask fitted with an external cooling bath, overhead stirrer, thermometer, addition funnel, under a nitrogen atmosphere was charged with THF (2 L), a solution of homopiperazine (234.4 g, 2.34 mol) in THF (20 mL), and ethyl 6-(4-fluorophenoxy)nicotinate (dry; 251.34 g, 0.962 mol). The mixture was stirred to dissolve the solids, leaving a slightly cloudy solution. The mixture was cooled to ca. 0° C. and treated with hexyllithium (440.41 g, 1.43 mol) via an addition funnel over a period of ca. 0.75 to 1 h. The addition rate and external cooling were adjusted such that the internal reaction temperature was maintained between 0 and 10° C. After addition of the hexyllithium is complete, the reaction was warmed to ca. 25° C. and monitored by HPLC until the ester is consumed (ca. 2 h). The mixture was cooled to ca. 15° C. and quenched with water (1 L). The phases were separated and the amount of product in the aqueous phase was checked by HPLC prior to being discarded. The aqueous phase was optionally extracted with MTBE (¼ volume). The basic aqueous phase was discarded and the combined organic phases were extracted with HCl (2 N, 600 mL) (aqueous phase pH ca. 2-3). The phases were separated and the organic phase was extracted with HCl (2 N, 200 mL). The organic phase was discarded. The aqueous extracts were combined and allowed to stand for several hours for any remaining {4-[6-(4-fluoro-phenoxy)-pyridine-3-carbonyl]-[1,4]diazepan-1-yl}-[6-(4-fluoro-phenoxy)-pyridin-3-yl]methanone (diamide by-product) to crystallize as a fine solid. The solid was removed by filtration through a glass fiber filter and the filtrate was extracted with MTBE (7×180 mL) to remove any remaining diamide. The aqueous phase was treated with NaOH (50% w/w; 175.4 g, 2.19 mol). Once the pH was greater than 9, a second liquid phase separated. The two phases were separated and the aqueous phase was extracted with EtOAc (2×150 mL). The organic phases obtained from the basified aqueous extracts are combined and washed with satd. aq. NaCl (100 mL). Once the phases are completely separated, the organic phase was placed in a distillation apparatus and treated with EtOAc (100 mL). The excess EtOAc was distilled at atmospheric pressure to azeotropically remove water. An additional charge of EtOAc (600 mL) was added in several portions and distillation was continued (repeated until Karl-Fischer analysis of the pot residue showed less than 0.8% water). The residue was filtered hot to remove NaCl and the filtrate was stirred for several hours until a large amount of solid formed. The mixture was treated slowly with heptane (500 mL) over a period of about 1 hour and allowed to stir an additional hour. The solid is isolated by filtration and dried to give the title compound (168.9 g). mp: 95.4° C. (by DSC). 1H-NMR (CDCl3): δ 8.24 (d, J=2.2 Hz, 1H), 7.80 (dd, J=2.2, 8.4 Hz, 1H), 7.12 (s, 2H), 6.95 (d, J=8.4 Hz, 1H), 3.76 (br m, 2H), 3.51 (br m, 2H), 3.60 (br m, 1H), 2.90 (br m, 3H), 1.90 (br m, 1H), 1.80 (br s, 3H).