Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]23[CH2:14][O:13][C:10]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]#C)([O:11][CH2:12]2)[O:9][CH2:8]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)CCCCC#C>>[CH:1]1([C:7]23[CH2:12][O:11][C:10]([CH2:15][CH2:16][CH2:17][C:18]#[CH:19])([O:9][CH2:8]2)[O:13][CH2:14]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C#CCCCCC12OCC(C3CCCCC3)(CO1)CO2
Agent: C#CCCCCC(=O)O
Product: C#CCCCC12OCC(C3CCCCC3)(CO1)CO2

Procedure:
In an analogous manner 4-cyclohexyl-1-(hex-5-ynyl)-2,6,7trioxabicyclo[2.2.2]octane, was prepared from hept-6-ynoic acid.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([SH:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].CS(O[CH:18]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])(=O)=O>CO>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([S:12][CH:18]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(S)cc1OC
Reactant: COC(=O)C(C)(C)C(CCCCc1ccccc1)OS(C)(=O)=O
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C)(C)C(CCCCc1ccccc1)Sc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
Sodium (0.5 g, 2.2 mmol) is added to MeOH (10 mL) cooled in ice. When the reaction is complete a solution of 3,4-dimethoxybenzenethiol (6 g, 3.5 mmol) in MeOH (5 mL) is added. After 2 minutes a solution of methyl 3-methanesulfonyloxy-2,2-dimethyl-7-phenylheptanoate (3 g, 8.8 mmol) in MeOH (5 mL) is added. The cooling bath is removed and the reaction is stirred at room temperature overnight. The solvent is removed in vacuo, CH2Cl2 (50 mL) added and the solution washed with NaHCO3 (50 mL), 1 N HCl (50 mL) and brine (50 mL). The solution is dried over MgSO4 and the solvent removed in vacuo. The product is purified by column chromatography (silica, 20% ether in petroleum ether) to yield methyl 3-(3,4-dimethoxyphenylsulfanyl)-2,2-dimethyl-7-phenylheptanoate (0.65 g, 18%): 1H NMR (300 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.19-7.11 (m, 3H), 7.02-6.91 (m, 2H), 6.77 (d, J=8.2 Hz, 1H), 3,87 (s, 3H), 3.85 (s, 3H), 3.57 (s, 3H), 3.22 (dd, J=10.0, 3.2 Hz, 1H), 2.64-2.51 (m, 3H), 1.81-1.74 (m, 1H), 1.66-1.42 (m, 4H), 1.27 (s, 3H), 1.22 (s, 3H); MS (FAB) m/e 416 (M+).
Reaction SMILES: Br[C:2]1[C:3]([Cl:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:12](N(CC)CC)[CH3:13]>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].C(Cl)Cl.C(O)C>[Cl:11][C:3]1[C:2]([CH:12]=[CH2:13])=[CH:9][CH:8]=[C:7]([F:10])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(F)ccc(Br)c1Cl
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: C=Cc1ccc(F)c(C#N)c1Cl

Procedure:
3-Bromo-2-chloro-6-fluorobenzonitrile (15.4 g, 65.6 mmol), potassium vinyl trifluoroborate (17.6 g, 131 mmol), triethylamine (18.3 mL, 131 mmol) and PdCl2(dppf)-CH2Cl2 adduct (2.68 g, 3.28 mmol) were added to ethanol (75 mL) then degassed and heated at reflux for 3 h. The reaction was diluted with ethyl acetate and washed with brine, dried and evaporated to dryness. The product was purified by chromatography through a 330 g ISCO Redi-Sep column with 10% ethyl acetate/hexane solvent system to yield 2-chloro-6-fluoro-3-vinylbenzonitrile.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[NH:9][CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:9]2[C:10]3[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=3[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1c[nH]c2c1CCCC2=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cn(C2CCN(C(=O)OC(C)(C)C)CC2)c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a mixture of methyl 7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (100 mg 0.52 mmol), tert-butyl-4-hydroxypiperidine-1-carboxylate (105 mg, 0.52 mmol), and triphenylphosphine (136 mg, 0.52 mmol), in anhydrous THF (5 mL) at room temperature, was added di tert-butyl-diazadicarboxylate (DTAD) (120 mg, 0.52 mmol). The mixture was stirred at room temperature for 8 h. HPLC/MS suggested 40% conversion and 60% SM remained. Reagents were added, triphenylphosphine (136 mg, 0.52 mmol) and DTAD (120 mg, 0.52 mmol), the mixture was stirred for 4 hours. HPLC/MS showed 80% conversion and 20% SM remained. Reagents were re-added TPP (136 mg, 0.52 mmol) and DTAD (120 mg, 0.526 mmol) and the solution was stirred for additional 4 hours. The volatiles were removed in vacuo, the crude solid was purified by flash chromatography on silica gel (hexane/EtOAc 7/3) to afford 140 mg (70% yield) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]([NH:7][C:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[C:22]([O:29][C@@H:30]3[O:56][C@H:55]([CH2:57][O:58][C:59](=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61])[C@@H:47]([O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]3[O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[N:23][NH:24][C:25]=2[CH:26]([CH3:28])[CH3:27])=[C:16]([CH3:65])[CH:15]=1)=[O:9])([CH3:6])[CH3:5])(O)=[O:2].[OH:66][CH2:67][CH2:68][N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[OH:66][CH2:67][CH2:68][N:69]1[CH2:74][CH2:73][N:72]([C:1]([C:4]([NH:7][C:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[C:22]([O:29][C@@H:30]4[O:56][C@H:55]([CH2:57][O:58][C:59](=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61])[C@@H:47]([O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:43])([CH3:44])[CH3:45])[C@H:31]4[O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:36])[CH3:37])=[N:23][NH:24][C:25]=3[CH:26]([CH3:27])[CH3:28])=[C:16]([CH3:65])[CH:15]=2)=[O:9])([CH3:5])[CH3:6])=[O:2])[CH2:71][CH2:70]1
Reactant: Cc1cc(OCCCC(=O)NC(C)(C)C(=O)O)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Reactant: OCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCCC(=O)NC(C)(C)C(=O)N2CCN(CCO)CC2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (40 mg) in N,N-dimethylformamide (2 mL) were added 1-(2-hydroxyethyl)piperazine (7 mg), 1-hydroxybenzotriazole (7 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13 mg) and triethylamine (0.018 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloro-methane/methanol=15/1) to give 4-[(4-{3-[1-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-1-(methyl)ethyl-carbamoyl]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (27 mg). This material was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.015 mL), and the mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (12 mg).
Reaction SMILES: [CH3:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[CH:8](=[O:17])[CH2:9][CH2:10]CCCCCC.C([Mg]Cl)(C)(C)C.CC(C)(C(O)CCCCCCCC)C.CC(C)(C(=O)CCCCCCCC)C.O1C=CC=C1C=O>O.O.O.O.O.[OH-].[OH-].[Cr].[Cr]>[CH3:4][C:3]([CH3:6])([CH3:5])[CH:2]([C:1]1[O:17][CH:8]=[CH:9][CH:10]=1)[OH:7]
Reactant: CCCCCCCCC=O
Reactant: CC(=O)C(C)(C)C
Agent: [Cr]
Agent: CC(C)(C)[Mg]Cl
Agent: CCCCCCCCC(=O)C(C)(C)C
Solvent: O=Cc1ccco1
Solvent: O
Product: CC(C)(C)C(O)c1ccco1

Procedure:
It should be noted that pinacolone 2a used in Examples 2 and 3 were purchased from Aldrich Chemical. Ketone 2b (2,2-dimethyl-3-undecanone) used in Example 4 was obtained by reacting 1-nonanal with tert-butyl magnesium chloride to synthesize 2,2-dimethyl-3-undecanol and oxidizing the resultant 2,2-dimethyl-3-undecanol with bichromic acid. Ketone 2c (pivalophenone(tert-butylphenyl ketone)) used in Example 5 was purchased from Aldrich Chemical. Ketone 2d (2,2-dimethyl-1-(2-furyl)-1-propanone) used in Example 6 was obtained by reacting 2-furaldehyde with tert-butyl magnesium chloride to yield 2,2-dimethyl-1-(2-furyl)-1-propanol and then oxidizing the resultant 2,2-dimethyl-1-(2-furyl)-1-propanol with N-methylmorpholine-N-oxide in the presence of a catalyst, TPAP (tetrapropylammonium perruthenate). Ketone 2e (2,2-dimethyl-1-(2-thienyl)-1-propanone) used in Example 7 was obtained by reacting thiophene with pivaloyl chloride in the presence of aluminum chloride. Ketone 2f (4,4-dimethyl-1-phenyl-3-pentenone) used in Example 8 was synthesized by a previously reported process (Org. Syn. Coll. Vol I, 81-82). Ketone 2g ((E)-2,2-dimethyl-4-undecen-3-one) used in Example 9 was obtained as a mixture with a ratio E/Z of 5:1 by reacting 1-bromo-3,3-dimethyl-2-butanone, which was obtained by bromination of pinacolone, with triphenylphosphine, treating the resultant product with sodium hydroxide to yield phosphorus ylide, and then reacting the resultant phosphorus ylide with 1-heptanal. Ketone 4a (ethyl 2,2-dimethyl-3-oxobutanoate) used in Example 10 was synthesized by a previously reported process (J. Am. Chem. Soc. 1988, vol 110, pp. 1539-1546). Ketone 4b (ethyl 2,2-dimethyl-3-oxo-3-phenyl propionate) used in Example 11 was also synthesized by a previously reported process (J. Chem. Soc., Perkin Trans. I 1986, pp. 1139-1143). Ketone 6 (adamantyl methyl ketone) used in Example 12 and ketone 7 (2,2-dimethylcyclohexanone) used in Example 13 were purchased from Aldrich Chemical. Ketone 8a (2,2-dimethyl-1-indanone) used in Example 14 and ketone 8b (2,2-dimethyl-1-tetralone) used in Example 15 were synthesized by previously reported processes (J. Am. Chem. Soc. 1975, vol. 97, pp. 4667-4672).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:8]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].N12CCCN=C1CCCCC2.[C:38](Cl)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>C(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[C:3]([CH:8]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)c1N
Solvent: O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1ncc(C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a solution of di-tert-butyl [2-(5-amino-1-methyl-1H-pyrazol-4-yl)-1,3-propanediyl]biscarbamate (1.27 g) in methylene chloride (10 ml) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.05 g) and trityl chloride (1.44 g) at room temperature. The mixture was stirred for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to give di-tert-butyl {2-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-1,3-propanediyl}biscarbamate (1.7 g).
Reaction SMILES: [C:1]([C:4]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)[CH2:6][CH2:5]1)([OH:3])=[O:2].[OH-].[Na+].[BH4-].[Na+].Cl>CC(O)C.O>[C:19]([C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([OH:22])[CH2:10][CH2:9][CH2:8][CH2:7][C:4]2([C:1]([OH:3])=[O:2])[CH2:5][CH2:6]2)[CH2:17][CH2:18]1)([OH:21])=[O:20]
Reactant: O=C(CCCCC1(C(=O)O)CC1)CCCCC1(C(=O)O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)C1(CCCCC(O)CCCCC2(C(=O)O)CC2)CC1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a suspension of 1-[9-(1-carboxycyclopropyl)-5-oxononyl]-1-cyclopropanecarboxylic acid (6.95 g, 22.4 mmol) in iPrOH (40 mL) and H2O (40 mL) was added NaOH (1.80 g, 45.0 mmol). After 30 min of stirring, NaBH4 (0.45 g, 11.8 mmol) was added to the resulting clear solution. After 3 h and 15 min, the mixture was acidified to pH˜1 with aqueous HCl (1M) and extracted with Et2O (3×100 mL). The combined organic phases were dried (Na2SO4) and evaporated in vacuo to give 1-[9-(1-carboxycyclopropyl)-5-hydroxynonyl]-1-cyclopropanecarboxylic acid (6.02 g, 86%) as a slightly yellow oil. 1H NMR (CD3OD): δ=3.49 (br s, 1H), 1.57-1.25 (m, 16H), 1.14 (dd, J=3.6, 6.3, 4H), 0.70 (dd, J=3.3, 6.3, 4H). 13C NMR (CD3OD): δ=178.9 (2×), 72.2, 38.4 (2×), 35.1 (2×), 28.9 (2×), 27.0 (2×), 24.3 (2×), 16.3 (2×), 16.2 (2×).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CN(C)C=O>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: CCCCCCCCCC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCC(=O)Nc1cc(C(=O)O)ccc1C
Yield: 73.8 %

Procedure:
A solution of 3-amino-4-methylbenzoic acid (15.1 g) and n-decanoyl chloride (19.4 g) in dry dimethylformamide (150 ml) was heated on a steam bath for 90 minutes. The solution was poured into water and the solid was collected, and recrystallised from ethanol (600 ml) to give 3-(n-decanamido)-4-methylbenzoic acid (22.5 g), in the form of a white powder, m.p. 246°-250° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N+:8]([C:11]1[CH:37]=[CH:36][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])=[CH:13][CH:12]=1)([O-:10])=[O:9]>CN(C)C1C=CN=CC=1.O1CCCC1>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:30][C:1](=[O:3])[CH3:2])(=[O:32])=[O:31])=[O:21])=[CH:36][CH:37]=1)([O-:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
In a stream of nitrogen and at 0° C. 0.07 ml (0.80 mmol) of acetic anhydride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.70 mol) of 3-(4-nitrobenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 5 and 171 mg (1.40 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 290 mg (yield: 89.8%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14](OCC)=[O:15])#[N:12]>>[C:11]([CH2:13][C:14]([NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15])#[N:12]
Reactant: CCOC(=O)CC#N
Reactant: NCCc1ccc(F)cc1
Product: N#CCC(=O)NCCc1ccc(F)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-fluorophenethylamine (10.6 g, 76.2 mmol) and ethyl cyanoacetate (8.09 mL, 76.2 mmol) was heated in an open flask at 100° C. for 18 hours. The mixture was cooled and the resulting solid was triturated with ethanol, filtered and dried. Recrystallization from ethanol provided off-white crystals (8.2 g, 52%). 1H NMR (300 MHz, CDCl3) δ7.17 (m, 2H), 7.03 (t, J=9 Hz, 2H), 6.26 (bs, 1H), 3.54 (q, J=7 Hz, 2H), 3.35 (s, 2H), 2.84 (t, J=7 Hz, 2H). Mass spec (ES−) m/z 205.2 (M−H−, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:19])[CH:11]=[C:12](C(O)=O)[N:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:19])[CH:11]=[CH:12][N:13]([CH3:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(OCc2ccccc2)c(=O)cc1C(=O)O
Solvent: CN(C)C=O
Product: Cn1ccc(=O)c(OCc2ccccc2)c1
Temperature: 135 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A suspension of 5-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (18.2 g, 70.2 mmol) in 100 mL of DMF was stirred at oil bath temperature (130-140° C.) for 1.5 h. The reaction mixture was concentrated in vacuo, and the residual oil was diluted with dichloromethane (10 mL) and ethyl acetate (80 mL). The precipitated solid was collected by suction filtration to give 3-benzyloxy-1-methyl-1H-pyridin-4-one as a yellow powder (14.2 g, 94% yield). MS-ESI (m/z): 215.7 [M+1]+, 91.2.
Reaction SMILES: [C:1]1(=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C:3](=[O:11])[CH2:2]1.C(N(CC)CC)C.C1(C)C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1>C(O)C>[N+:29](=[C:2]1[C:3](=[O:11])[CH2:4][CH:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[C:1]1=[O:12])=[N-:30]
Reactant: O=C1CC(=O)C2CCCCC2C1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1C(=O)CC2CCCCC2C1=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
A solution of 10.0 g (0.0768 mol) of decalin-1,3-dione in 50 ml of ethanol was magnetically stirred under nitrogen and cooled to -10° C. To the solution was added 7.77 g (0.0768 mol) of triethylamine followed by 15.14 g (0.0768 mol) of p-toluenesulfonylazide added all at once. The mixture was stirred for one hour at 0° C., and the solvent removed at reduced pressure at a temperature of less than 40° C. To the residue was added 200 ml of ether, and the ether removed to yield a yellow solid. This was recrystallized from ethanol to give 5.23 g of yellow crystals, mp 81°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: O=C1c2ccc(O)cc2CCc2cc(Cl)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccc(Cl)cc2CCc2cc(OCCN3CCOCC3)ccc21

Procedure:
For the synthesis of the title compound, 0.44 g (1.69 mmol) of 2-chloro-8-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.345 g (1.86 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.93 g (6.75 mmol) of K2CO3 in 15 ml of acetonitrile are reacted by method Q. C21H22ClNO3(Mr=371.87)
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>[Pd].C(O)C>[NH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:20]
Reactant: [H][H]
Reactant: O=C(NCCCn1ccnc1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)NCCCn2ccnc2)c1

Procedure:
A mixture of 2.35 g. of N-[3-(1H-imidazol-1-yl)propyl]-3-nitrobenzamide, 0.5 g. of 10% palladium on carbon catalyst and 150 ml. of ethanol was shaken under 45 lbs. of hydrogen in a Parr hydrogenator until the reaction was complete. The catalyst was removed by filtration and the mother liquor concentrated. The crystalline residue was washed onto a filter with ether, giving the desired product, m.p. 88°-90° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(COC)OC.O.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]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)c1ccc(Br)c(-c2ccncc2)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 78.1 %

Procedure:
To a solution of compound 1-bromo-2-iodo-4-(trifluoromethyl)benzene (10 g, 28.4 mmol) and pyridin-4-ylboronic acid (7 g, 34.1 mmol) in dimethoxyethane (150 mL) and water (50 mL), sodium bicarbonate (9.54 g, 113.6 mmol) was added. The reaction mixture was purged with nitrogen for 15 minutes and Pd(dppf)2Cl2 (2.3 g, 2.84 mmol) was added. The reaction was stirred at 90° C. for 5 h. Then the reaction mixture was diluted with water (500 mL) extracted with ethyl acetate (2×200 mL). Organic layer was combined, dried over sodium sulfate, filtered and concentrated under a vacuum to give the compound which was further purified by column chromatography using silica gel (100 to 200 mesh) and 0% to 30% ethyl acetate/hexane as eluent to obtain 4-(2-bromo-5-(trifluoromethyl)phenyl)pyridine (6.7 g, 77.6%) as an off white solid. MS (ESI, positive ion) [M+1]+: 301.98; 1H NMR (400 MHz, DMSO) δ 8.71 (d, J=5.9 Hz, 2H), 8.05 (d, J=8.2 Hz, 1H), 7.84-7.75 (d, J=11.3 Hz, 2H), 7.50 (d, J=5.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[N:20])=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.ClC1C(C#N)=CC(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2Cl)N=1.C(N)CC.C[Mg+].[Br-].[C:59](Cl)(=[O:62])[CH2:60][CH3:61]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH2:16][CH2:17][CH3:18])[C:59](=[O:62])[CH2:60][CH3:61])[C:12]([C:19]#[N:20])=[CH:11][C:10]=1[C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1
Reactant: CCC(=O)Cl
Reactant: CCCNc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: C[Mg+]
Agent: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: [Br-]
Solvent: CCCN
Product: CCCN(C(=O)CC)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N

Procedure:
6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-(propylamino)pyridine-3-carbonitrile (prepared by reaction of the product of Step C Example 1 with propylamine using the procedure of Step D EXAMPLE 26) was reacted with MeMgBr followed by propionyl chloride using the procedure of EXAMPLE 42 Step A to afford the title compound. HPLC/MS: 472.1 (M+1), 474.1 (M+3); Rt=4.40 min.