Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[C:16]([O:19][CH2:20][CH2:21]Br)(=[O:18])[CH3:17].[I-].[Na+]>CC(C)=O>[C:16]([O:19][CH2:20][CH2:21][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OCCBr
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCCOc1cccc(C#N)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3-Cyanophenol (10.1 g, 84.8 mmol) and potassium carbonate (19.5 g, 141 mmol) were suspended in acetone (280 ml), 2-bromoethyl acetate (7.8 ml, 70.7 mmol) was added, and the mixture was stirred at 50° C. for 8 hours. Sodium iodide (1.06 g, 7.07 mmol) was added to the reaction mixture, and the mixture was heated under reflux for two nights and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the mixture was washed with 1N sodium hydroxide, 1N hydrochloric acid, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound without purification.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[CH:7]1[NH:12][C:11]([Cl:13])=[N:10][CH:9]=[CH:8]1>CCOC(C)=O.O=[Mn]=O>[Br:1][C:2]1[N:3]=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:8]=[CH:9][N:10]=[C:11]([Cl:13])[N:12]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(C(F)(F)F)cc2)nc(Br)c1C1C=CN=C(Cl)N1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(C(F)(F)F)cc2)nc(Br)c1-c1ccnc(Cl)n1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A solution of 4,5-dibromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1.0 g, 2.0 mmol) in dry THF (10 mL) was cooled to −78° C. under Argon. n-BuLi (1.0 mL, 2.5 M in hexane, 2.5 mmol) was added dropwise, afterwards the reaction was maintained below −70° C. for an additional 45 minutes. A solution of 2-chloropyrimidine (0.29 g, 2.5 mmol) in dry THF (2 mL) was added dropwise at −78° C. After addition, the reaction was allowed to warm to −40° C. over 25 minutes and maintained at −40° C. for 20 minutes. The reaction was then warmed to −5° C. in a brine-ice bath, quenched with water (30 mL), and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and partitioned between EtOAc and water. The organic phase was separated, dried (Na2SO4), and concentrated. The resulting residue was further purified by flash chromatography (SiO2, 0-20% EtOAc in hexanes) to afford 1.1 g (2.05 mmol, 82%) of 6-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazol-5-yl)-2-chloro-1,6-dihydropyrimidine. A solution of 6-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloro-1,6-dihydropyrimidine (410 mg, 0.8 mmol) in EtOAc (20 mL) was treated with MnO2 (920 mg, 10.6 mmol) and the resulting reaction mixture was heated to and maintained at reflux for 18 hours. The reaction was allowed to cool to room temperature and was then filtered through Celite. The filter cake was washed with EtOAc (2×20 mL) and the combined filtrates were concentrated to give 400 mg (0.75 mmol, 98%) of 4-(4-bromo-2-(4-(trifluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine: 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=5.4 Hz, 1H), 8.02 (d, J=5.4 Hz, 1H), 7.96 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 5.77 (s, 2H), 3.49 (t, J=7.5 Hz, 2H), 0.83 (t, J=7.5 Hz, 2H), 0.01 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]#[CH:8])[CH2:4][CH3:5])[CH3:2].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[CH2:1]([N:3]([CH2:6][C:7]#[C:8][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:25][CH:24]=[N:23][C:22]=1[CH3:26])/[C:14](=[O:19])[NH:15]2)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, N,N-diethyl propargylamine (38 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-4-[3-(N,N-diethylamino)-1-propynyl]-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 20 mg, 42%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.N1C=CC=CC=1.[F:20][C:21]([F:50])([F:49])[C:22]1[CH:23]=[C:24]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:25][N:26]([CH:30]1[CH2:36][CH2:35][CH2:34][NH:33][C:32]2[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:31]1=2)[C:27](=[O:29])[CH3:28]>ClCCl>[C:1]([N:33]1[CH2:34][CH2:35][CH2:36][CH:30]([N:26]([CH2:25][C:24]2[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=[C:22]([C:21]([F:20])([F:49])[F:50])[CH:23]=2)[C:27](=[O:29])[CH3:28])[C:31]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:32]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2cc(Cl)ccc21
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2ccc(Cl)cc21
Reaction time: 15 h
Yield: 71.7 %

Procedure:
Add acetyl chloride (0.3 mmol) followed by dimethylaminopyridine (cat.) and pyridine (0.3 mmol) to a solution of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.05 g, 0.11 mmol) in dichloromethane (1 ml). After stirring for 14-16 h dilute with dichloromethane (2 mL) and wash with 5% HCl (2 mL), water (2 mL) and brine (2 mL). Dry the organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the crude product over silica gel using ethyl acetate/hexane (10-30%) to elute. This afford the title compound (0.04 g, 89%) as a colorless solid: MS (ES+): 507 (M+H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].[CH3:7][C:8]([S@@:11](/[N:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)=[CH:17][CH:16]=1)=[O:12])([CH3:10])[CH3:9]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH3:10][C:8]([S@@:11]([NH:13][C@H:14]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][N:22]=2)=[CH:19][CH:20]=1)[CH2:1][CH:2]([CH3:4])[CH3:3])=[O:12])([CH3:7])[CH3:9]
Reactant: CC(C)C[Mg]Br
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)C[C@H](N[S@@](=O)C(C)(C)C)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
A three-neck three liter flask equipped with a mechanical stirred, internal thermometer, and dropping funnel was evacuated, heated with a heatgun, and backfilled with dry nitrogen three times. The apparatus was then charged with anhydrous zinc chloride (667 ml, 333 mmol, 0.5M in tetrahydrofuran) and the solution was cooled to 0° C. A solution of isobutylmagnesium bromide (511 ml, 1.02 mol, 2.0M in diethylether) was added dropwise to the well-stirred solution over approximately 1.5 hours, resulting in an exothermic reaction and the formation of a precipitate. The temperature was maintained below 15° C. through the course of the addition. At the conclusion, the dropping funnel was washed with tetrahydrofuran (3×20 ml) and the reaction was slowly warmed to ambient temperature and stirred for approximately 1.5 h. The reaction was cooled to −78° C., whereupon a solution of the (S)-2-methyl-N-[(1E)-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}methylene]propane-2-sulfinamide (78.78 g, 222.3 mmol) in tetrahydrofuran (250 ml) was added dropwise over approximately 30 minutes. At this point, the reaction was quenched carefully with saturated aqueous ammonium chloride, the cold bath was removed, water was added and the reaction allowed to warm to ambient temperature. The contents were transferred to a separatory funnel, along with methyl tert-butylether and some additional water. The layers were separated and the aqueous layer was extracted with methyl tert-butylether (3×500 ml). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified via ISCO MPLC (SiO2, 0-80% ethyl acetate in heptane) to yield the product (74.0 g, 81%) as a gum. 1H NMR (400 MHz, CDCl3, δ): 8.94 (s, 1H), 7.96-8.05 (m, 3H), 7.84 (d, J=8.2 Hz, 1H), 7.49 (d, J=8.2 Hz, 2H), 4.43-4.52 (m, 1H), 3.40-3.50 (m, 1H), 1.85-1.94 (m, 1H), 1.62-1.75 (m, 1H), 1.47-1.57 (m, 1H), 1.24 (s, 9H), 0.95 (d, J=6.4 Hz, 3H), 0.90 (d, J=6.6 Hz, 3H). MS (M-C4H10NOS): 292.1.
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[CH2:16][N:3]3[C:2]([Br:1])=[C:6]([Br:7])[C:5]([Br:8])=[N:4]3)[CH2:24][CH2:23]2)=[CH:30][CH:29]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Brc1n[nH]c(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(Br)c(Br)c1Br)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3,4,5-Tribromo-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.96-7.2 (m, 2H), 6.84-6.9 (m, 2H), 5.4 (s, 2H), 3.74-3.8 (m, 2H), 3.6-3.68 (m, 2H), 3.04-3.14 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.4, 158, 156, 144.2, 128, 118.4, 118.2, 116, 100, 52.8, 50.2, 50.0, 46.0, 42.2.
Reaction SMILES: [CH2:1]([C:3]([NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[C:13]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:12]=1)([CH2:7][CH3:8])[C:4]([OH:6])=O)[CH3:2].Cl.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH3:33])[C:4]([C:3]([NH:9][C:10]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[C:13]([O:21][CH2:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:12]=1)=[O:29])([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:6]
Reactant: CNC
Reactant: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1)C(=O)O
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CCOCC2)n1)C(=O)N(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-ethyl-2-(6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(trifluoromethyl)picolinamido)butanoic acid (Example 253 a) and dimethylamine hydrochloride as starting materials. MS (EI): m/e=463.4 [M+NH4]+.
Reaction SMILES: O=S(Cl)Cl.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=[O:16])[CH:9]=[CH:10][C:11]=1[CH3:12].[CH3:19]O>>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][C@@H:14]([OH:18])[C:15]([O:17][CH3:19])=[O:16])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(C[C@@H](O)C(=O)O)cc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](O)Cc1ccc(C)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.0 mL (27.4 mmol) SOCl2 were slowly added dropwise to a solution of 2.8 g (10.4 mmol) of (R)-3-(3-chloro-4-methyl-phenyl)-2-hydroxy-propionic acid in 100 mL MeOH while cooling with ice and the reaction solution was stirred for 1 h at 0° C. and for 1 h at RT. The reaction mixture was evaporated down i.vac., the residue was taken up in EtOAc, the organic phase was washed with saturated NaHCO3 solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was purified by chromatography (silica gel, gradient DCM to DCM/MeOH 50:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:31]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:31])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(OCc2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: NCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 81 %

Procedure:
To a solution of 4-benzyloxybenzyl alcohol (3.1 g) in toluene (40 ml) were sequentially added diphenylphosphoryl azide (4.8 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 g), and the solution was stirred for 25 hours at room temperature. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by silica gel column chromatography (hexane-ethyl acetate system), to a solution of the resulting 1-azidomethyl-4-benzyloxybenzene (3.0 g) in tetrahydrofuran (40 ml) were sequentially added water (3 ml) and triethylphosphine (2.0 ml), and the solution was stirred for 1 hour and 10 minutes at room temperature. The reaction solution was concentrated in vacuo, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.5 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].CC1(C)C(C)(C)OB([C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:28]([O:27][C:25]([C:24]1[CH:32]=[CH:33][C:21]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=2)[C:5]([OH:7])=[O:6])=[CH:22][CH:23]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)cc(-c2ccc(C(=O)OC(C)(C)C)cc2)n1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
2-Chloro-6-methoxyisonicotinic acid (15.0 g, 80.0 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (29.2 g, 96.0 mmol), 1,4-dioxane (500 mL) and sodium carbonate (25.4 g, 240 mmol) dissolved in water (160 mL) were combined in a 1 L, 3 necked flask equipped with an internal thermometer, condenser and nitrogen inlet. The solution was degassed by bubbling with nitrogen for 15 min while stirring. Tetrakis(triphenylphosphine)palladium (3.70 g, 3.20 mmol) was then added and the mixture heated to reflux for 17 h. The mixture was then cooled to room temperature and concentrated under vacuum to give a thick brown suspension, which was portioned between ethyl acetate (400 mL) and water (150 mL). The aqueous layer was separated and extracted with further ethyl acetate (2×100 mL). The organic portions were combined and washed with 1 N HCl and water, and the black solids removed by filtration through a pad of celite. The aqueous layer was discarded and the organic solution dried over anhydrous magnesium sulfate and filtered. The solution was then treated with decolorlizing charcoal and heated to 70° C. for 20 min. The solution was then filtered through celite while hot and the solvent removed under vacuum to afford a yellow powder. This material was purified by addition of methyl tert-butyl ether (55 mL) followed by the slow addition of 1.85 L heptane with stirring. The mixture was stirred for 2 days and then filtered to give 2-(4-(tert-butoxycarbonyl)phenyl)-6-methoxyisonicotinic acid (22.01 g, 84%) as a pale yellow powder. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.61 (s, 9H) 4.08 (s, 3H) 7.34 (d, J=0.98 Hz, 1H) 7.97 (d, J=1.17 Hz, 1H) 8.09 (s, 2H) 8.13 (s, 2H); m/z: 330.2+ [M+H].
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1CCC(O)=O.F>>[C:5]12([CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]1)[C:8]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2](=[O:1])[CH2:3][CH2:4]2
Reactant: O=C(O)CCC1CC(c2ccccc2)CCC1=O
Agent: F
Product: O=C1CCC2(CC1)CCC(=O)c1ccccc12

Procedure:
A 4-oxo-1-phenylcyclohexane-3-propionic acid (i) prepared in step (6) or (6') is cyclized, e.g., by allowing it to stand at room temperature for from about 15 to about 80 hours with liquid hydrogen fluoride, to yield a corresponding spiro[cyclohexane-1,1'(2'H)-naphthalene]-4,4'(3'H)-dione (o).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)Cl>[C:24]([CH2:23][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1)([O:26][CH2:27][CH3:28])=[O:25]
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Product: CCOC(=O)CSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
To 1.0 gm (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole in 50 ml methylene chloride at 0° was added a solution of 0.63 g (3.7 mmole, 0.43 ml) ethyl bromoacetate in 10 ml CH2Cl2 over a period of 10 minutes. The reaction was allowed to come to room temperature and was stirred for 30 minutes. The mixture was then diluted with methylene chloride and washed with 3N NaHCO3, saturated NaCl, treated with Na2SO4, stripped, then flash chromatographed on silica with methylene chloride containing 1% to 5% MeOH. The isolated material was recrystallized from ethyl acetate to give 0.35 g of the titled product. 27.2% yield, mp 102°-103° C. Analyzed for C21H21N3O2S, Calculated, C: 66.47, H:5.58, N: 11.07; Found, C: 66.39, H: 5.62, N: 10.97.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])[CH:5]=[N:6][CH:7]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C:27]([CH3:31])([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:19]3[CH:20]=[C:21]4[N:28]([CH3:29])[C:27]([CH3:31])([CH3:30])[CH2:26][N:22]4[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:17])[CH:5]=[N:6][CH:7]=1
Reactant: OCc1ccc(Oc2cncc(Cl)c2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3ccc(Oc4cncc(Cl)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((5-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and 7-chloro-1,2,2-trimet-hyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(=O)([O-])O.[Na+].Br[CH2:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O>[CH2:1]([N:4]([CH2:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCNc1ccc(CC(=O)OCC)cc1
Reactant: CCOC(=O)c1ccccc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCN(Cc1ccccc1C(=O)OCC)c1ccc(CC(=O)OCC)cc1
Yield: 85.8 %

Procedure:
N-n-propyl-4-ethoxycarbonylmethylaniline (11.1 g, b.p. 131°-135°C./0.5 mmHg), sodium hydrogencarbonate (6.3 g), water (10 ml), and ethyl 2-bromomethylbenzoate (14.6 g) were treated in the same manner as described in Example 1 to obtain N-n-propyl-N-(2-ethoxycarbonylbenzyl)-4-ethoxycarbonylmethylaniline (16.5 g).
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:53]=[CH:52][CH:51]=[C:50]2[C:45]=1[CH:46]=[CH:47][C:48]([S:54]([N:57]([CH2:63][C:64]1[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][C:65]=1[O:72][CH3:73])[C:58]1[S:62][N:61]=[CH:60][N:59]=1)(=[O:56])=[O:55])=[CH:49]2.[C:74]([Zn]C#N)#[N:75]>O.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]>[C:74]([C:44]1[CH:53]=[CH:52][CH:51]=[C:50]2[C:45]=1[CH:46]=[CH:47][C:48]([S:54]([N:57]([CH2:63][C:64]1[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][C:65]=1[O:72][CH3:73])[C:58]1[S:62][N:61]=[CH:60][N:59]=1)(=[O:56])=[O:55])=[CH:49]2)#[N:75]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(C#N)cccc3c2)c(OC)c1
Temperature: 120 °C

Procedure:
A microwave vial was charged with Xantphos (44.5 mg, 0.077 mmol) and Pd2(dba)3 (35.2 mg, 0.038 mmol). The vessel was flushed with Ar (g), then DMF (3843 μl) was added. The vessel was sealed and heated in a microwave reactor at 120° C. for 10 min. The mixture was cooled, then a solid mixture of 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D; 200 mg, 0.384 mmol) and dicyanozinc (226 mg, 1.922 mmol) was added. The vial was re-sealed and heated in the microwave for 3 h at 120° C. The mixture was then diluted with water and extracted with EtOAc (3×). The combined organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography on a 40-g column with 50 to 100% EtOAc/Heptane to give 5-cyano-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide as an off-white solid. This material was dissolved in DCM (1 mL) and TFA (0.5 mL). The mixture was stirred for 4 h, then diluted with 2-propanol and concentrated. The residue was purified by silica gel chromatography (12-g, with 0 to 10% MeOH/DCM) to give 5-cyano-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (12.98 mg, 0.041 mmol, 67.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.70 (br. s., 1H), 8.60 (d, J=9.0 Hz, 1H), 8.48 (br. s., 1H), 8.34 (d, J=7.1 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.88-7.77 (m, 1H); m/z (ESI) 317.2 (M+H)+.