Reaction SMILES: ClC1C=CC(C(O)=O)=CN=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.Cl[C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][N:28]=1.[OH-].[Na+].[Cl:42][C:43]1[CH:44]=[C:45]([N:50]2[C:54](=[O:55])[C@@:53]3([C@H:59]([C:60]4[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][CH:61]=4)[CH2:58][NH:57][CH2:56]3)[N:52]([CH3:68])[C:51]2=[O:69])[CH:46]=[C:47]([Cl:49])[CH:48]=1.CC1C=CC(C(O[C@H](C(O)=O)[C@H](OC(C2C=CC(C)=CC=2)=O)C(O)=O)=O)=CC=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.O1CCCC1.C(OC)(C)(C)C>[C:64]([C:63]1[CH:66]=[CH:67][C:60]([C@H:59]2[C@:53]3([N:52]([CH3:68])[C:51](=[O:69])[N:50]([C:45]4[CH:44]=[C:43]([Cl:42])[CH:48]=[C:47]([Cl:49])[CH:46]=4)[C:54]3=[O:55])[CH2:56][N:57]([C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][N:28]=3)[CH2:58]2)=[CH:61][CH:62]=1)#[N:65]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(C(=O)O[C@H](C(=O)O)[C@H](OC(=O)c2ccc(C)cc2)C(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(c1ccc(C(=O)OC(C)(C)C)cn1)C[C@H]2c1ccc(C#N)cc1
Temperature: 62.5 °C
Yield: 86 %

Procedure:
A 3-necked flask was charged with 6-chloronicotinic acid (53.0 g, 336 mmol), 4-(dimethylamino)-pyridine (3.03 g, 24.6 mmol), and tetrahydrofuran (350 mL). The contents of the flask was heated to 62.5° C. and a solution of di-tert-butyl dicarbonate (200.2 g, 917 mmol) in tetrahydrofuran (240 mL) was slowly added over a period of 4.6 h. The contents of the flask were maintained at 62.5° C. for approximately 1 h and then cooled to 21° C. A portion of the solution (219 mL), which contained tert-butyl 6-chloronicotinate (16.4 g, 76.8 mmol), was mixed with 1 N NaOH (150 mL) and methyl tert-butyl ether (150 mL) at 21° C. To this mixture was charged 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt (37.4 mmol, 61.5 mmol). After mixing for 10 minutes, a phase split was performed, the aqueous layer was discarded and the organic layer was distilled under atmospheric pressure. After 220 mL of distillate was collected, 220 mL of methyl tert-butyl ether was charged back and the distillation was resumed. After an additional 250 mL of distillate was collected, 100 mL of n-methyl-2-pyrrolidinone was charged and the distillation was continued until the pot temperature rose to 90° C. Diisopropylethyl amine (27 mL, 155 mmol) was then charged and the mixture was heated at 110° C. for approximately 17 h. A portion of the crude reaction mixture (48 mL) was transferred into a separate funnel and was extracted twice with 3.4:1 heptane:cyclohexane (31 mL). The top layers were discarded and the bottom layer was extracted three times with a mixture of methyl tert-butyl ether (36 mL) and H2O (24 mL). The bottom aqueous layers were discarded. To the top layer was added methyl tert-butyl ether (40 mL) and was filtered back to a distillation flask. After most of methyl tert-butyl ether was distilled off, the mixture was diluted to a total volume of 169 mL with 1:1 methyl tert-butyl ether:isopropyl alcohol. p-Toluenesulfonic acid (0.358 g) was then added to this solution and was dissolved upon gently heating. The solution was then cooled and stirred until crystals appeared. A second charge of p-toluenesulfonic acid (0.424 g) was added and the slurry was further stirred at 21° C. for 30 minutes before it was filtered and washed twice with 25 mL of 1:1 methyl tert-butyl ether:isopropyl alcohol. The product (3.34 g, 86% yield) was isolated as white crystals and was dried in a vacuum oven at 40° C.