Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([NH:8][N:9]=[C:10]([C:12]([NH2:14])=[O:13])[NH2:11])=CC=1COCC(F)(F)C(F)(F)C(F)(F)F.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>C(O)(=O)C>[C:29]1([CH:28]2[NH:8][N:9]=[C:10]([C:12]([NH2:14])=[O:13])[NH:11]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NC(=O)C(N)=NNc1ccc(Cl)c(COCC(F)(F)C(F)(F)C(F)(F)F)c1
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)C1=NNC(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In 0.7 ml of acetic acid, 245 mg (0.6 mmol) of oxamide 4-chloro-3-[(2,2,-3,3,4,4,4-heptafluorobutoxy)methyl]phenylhydrazone was dissolved and nitrogen was saturated. The solution was added with 76 mg (0.72 mmol) of benzaldehyde under a nitrogen atmosphere and stirred at room temperature for 16 hours. Then water was added to the solution and the formed crystals were filtered out, washed with water and dried in vacuo. The resulting product was recrystallized from ethyl acetate/n-hexane with nitrogen saturated to obtain 257 mg (86.5% yield) of 1-[4-chloro-3-](2,2,3,3,4,4,4-heptafluorobutoxy)methyl]phenyl]-4,5-dihydro-5-phenyl-1H-1,2,4-triazole-3-carboxamide (m.p. 157°-159° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([NH:24][CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)[C@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.00995 mole), 1,1'-carbonyldiimidazole (1.61 g, 0.00995 mole) and dry tetrahydrofuran (60 ml) was stirred at room temperature for 1.75 hours with a stream of nitrogen bubbling through it. A solution of methylamine in tetrahydrofuran (20 ml of a 3.03M solution, 0.060 mole) was added and the reaction mixture was stirred at room temperature overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in water, collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution, and twice again with water. The solid was dissolved in hot isopropyl alcohol and filtered hot. Upon cooling to room temperature, solid precipitated which was collected by filtration and dried under high vacuum at 50° C. overnight to give 0.86 g (28%) of title compound, mp 218°-220° C.
Reaction SMILES: [C:1]([Si:5]([O:8][C@@H:9]1[C@H:18]2[C@@:13]([CH3:26])([C@@H:14]([C@H:19]([CH3:25])[CH2:20][CH:21]=[C:22](Br)Br)[CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH3:32][C:33]([CH3:35])=[O:34].[C-]#[C-]>C1COCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][C@H:9]1[CH2:10][CH2:11][CH2:12][C@@:13]2([CH3:26])[C@H:18]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@H:19]([CH3:25])[CH2:20][C:21]#[C:22][C:33]([CH3:35])([OH:34])[CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: C[C@H](CC=C(Br)Br)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: [C-]#[C-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](CC#CC(C)(C)O)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Yield: 79.1 %

Procedure:
3.05 g (6.00 mmol) of tert-butyl-[(1S,4aR,5R,8aR)-5-((R)-4,4-dibromo-1-methyl-but-3-enyl)-4a-methyl-decahydro-naphthalen-1-yloxy]-dimethyl-silane was dissolved in 35 ml of abs. THF and cooled down to -78°. 11.6 ml of nBuLi (1.55M, hexane) was slowly added and the temperature maintained for 1 h. 2.15 ml (29.3 mmol) of acetone, dissolved in 5 ml of abs. THF, was then added to the resultant acetylide-solution and allowed to react for 30 minutes. The reaction was quenched by pouring onto crushed ice/NH4Cl, extracted twice with ether, washed with water and brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=9/1) yielded 1.93 g of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([N:28]1[C:32]([CH3:34])([CH3:33])[C:31](=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[C:38]([C:45](F)(F)F)[CH:37]=2)[C:29]1=[O:49])[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([C:23](F)(F)F)[CH:15]=2)[C:7]1=[O:27].CC1(C)NC(=O)N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O>>[CH2:5]([N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([CH3:23])[CH:15]=2)[C:7]1=[O:27])[CH2:4][CH2:3][CH2:2][CH2:1][N:28]1[C:32]([CH3:34])([CH3:33])[C:31](=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[C:38]([CH3:45])[CH:37]=2)[C:29]1=[O:49]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Agent: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Product: Cc1cc(N2C(=O)N(CCCCCN3C(=O)N(c4ccc([N+](=O)[O-])c(C)c4)C(=O)C3(C)C)C(C)(C)C2=O)ccc1[N+](=O)[O-]
Yield: 67 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, intermediate 10.1 replacing 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-imidazolidine-2,4-dione. The expected compound is obtained in the form of a white solid with a yield of 67% (495 mg). Melting point: 130-131° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([CH3:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[Br:16]Br.S([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([Br:16])[C:13]([CH3:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: BrBr
Reactant: CC(=O)Cc1ccc(OC(C)C)c(Br)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C(Br)c1ccc(OC(C)C)c(Br)c1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 100 mg (0.369 mmol) of 1-(3-bromo-4-isopropoxyphenyl)acetone (from Example 228, Step C) in toluene (0.26 mL) was added bromine (0.019 mL, 0.369 mmol) dropwise via syringe. After stirring 30 min. At RT, a solution of sodium sulfite (676 mg) in water (1.5 mL)) was added and the mixture was extracted with 3×15 mL of ethyl ether. The combined organic layers were washed 20 mL of saturated sodium bicarbonate followed by 20 mL of brine. Drying over sodium sulfate and evaporation gave 119 mg of product as a red oil. Mass spectrum (NH3/CI): m/z=349 (M+1)
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1([CH3:22])[O:9][CH:8]([CH2:10][O:11][C:12]2[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:21])[CH2:7][O:6]1>CO>[CH3:4][C:5]1([CH3:22])[O:9][CH:8]([CH2:10][O:11][C:12]2[C:19]([CH3:20])=[CH:18][C:15]([C:16]([NH:2][OH:3])=[NH:17])=[CH:14][C:13]=2[CH3:21])[CH2:7][O:6]1
Reactant: NO
Reactant: Cc1cc(C#N)cc(C)c1OCC1COC(C)(C)O1
Agent: Cl
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Yield: 59.7 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy-benzonitrile (5.0 g, 34.0 mmol) in THF (40 mL), rac-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (4.49 g, 34.0 mmol) followed by triphenylphosphine (13.4 g, 50.9 mmol) is added. The mixture is cooled with an ice-bath before DEAD (8.87 g, 50.9 mmol, 23.4 mL of a 40% solution in toluene) is added dropwise. The mixture is stirred at rt for 1 h, the solvent is removed in vacuo and the residue is purified by CC on silica gel eluting with heptane:EA 99:1 to 92:8 to give rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-benzonitrile (7.20 g) as a pale yellow oil; LC-MS: tR=0.99 min, [M+1]+=not detected. b) To a solution of potassium tert.-butylate (6.18 g, 55.1 mmol) in methanol (125 mL), hydroxylamine hydrochloride (5.74 g, 82.7 mmol) is added. To this solution, a solution of rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,5-dimethyl-benzonitrile (7.20 g, 27.6 mmol) in methanol (40 mL) is added. The mixture is refluxed for 72 h before the solvent is removed in vacuo. The residue is purified by prep. HPLC (XBridge Prep C18, 30×75 mm, 5 μm, 2-95% acetonitrile in water containing 0.5% sat. aq. NH3) to give the title compound (4.85 g) as a pale yellow solid; LC-MS: tR=0.67 min, [M+1]+=295.06; 1H NMR (CDCl3): δ1.43 (s, 3H), 1.48 (s, 3H), 2.29 (s, 6H), 3.76-3.81 (m, 1H), 3.83-3.88 (m, 1H), 3.93-3.99 (m, 1H), 4.17-4.23 (m, 1H), 4.47-4.54 (m, 1H), 5.02 (s br, 1H), 7.28 (s, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.CCCCCC.C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22]>O1CCCC1.O>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCCBr
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: ClCCCCc1ccco1
Temperature: -25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
Furan (1.36 g) was dissolved in tetrahydrofuran (50 ml) and cooled to -25° C. Hexane solution (12.5 ml) of n-butyllithium of 1.68 mol/l was added to the reaction solution, which was stirred at -15° C. for 4 hours. Subsequently, 1-bromo-4-chlorobutane (3.43 g) was dissolved in tetrahydrofuran (2.5 ml) and added to the reaction solution. This solution was further stirred at -15° C. for 1 hour and stood overnight at room temperature. The reaction solution was poured into icy water and extracted with ether. The extracted solution was successively washed with water, a saturated ammonium chloride solution and a saturated sodium chloride solution. It was then dried over magnesium sulfate and filtered. The filtrate was concentrated and the resultant oil-like product was purified by distillation under reduced pressure (130° C./12 mmHg). The object compound (2.87 g) was obtained in the form of oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:26]3[C:25]4[N:24]=[C:23]([NH:27][CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[N:22]=[CH:21][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]([C:33]([NH2:35])=[O:34])=[N:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)C>C(O)(=O)C.O=[Pt]=O>[CH:28]1([NH:27][C:23]2[N:22]=[CH:21][C:20]3[CH2:19][CH2:18][C:17]4[C:16]([C:33]([NH2:35])=[O:34])=[N:15][N:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[C:26]=4[C:25]=3[N:24]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: NC(=O)c1nn(C2CCN(Cc3ccccc3)CC2)c2c1CCc1cnc(NC3CCCC3)nc1-2
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC(=O)c1nn(C2CCNCC2)c2c1CCc1cnc(NC3CCCC3)nc1-2
Yield: 80 %

Procedure:
500 mg (1.1 mmol) of 1-(1-benzylpiperidin-4-yl)-8-(cyclopentylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide were dissolved in 50 mL of acetic acid and 50 mg of PtO2 were added. The mixture was submitted to hydrogenation at 60 psi at room temperature. After 12 hors the catalyst was filtered on celite and the filtrate evaporated. The residue was redissolved with dicholoromethane and washed with aqueous NaHCO3. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure. The title compound (80% yield) was collected by filtration after trituration with diethylether.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=O)[CH2:13][O:14][CH:15]([CH3:17])[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:22]1CCOCC1.C(OC(Cl)=O)C(C)C.N>O1CCCC1>[NH2:22][C:18](=[O:20])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][O:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)OC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
N-[(benzyloxy)carbonyl]-O-isopropyl-L-serine (0.346 g, 1.23 mmol) was dissolved in tetrahydrofuran (5 ml) and the resulting solution was cooled to −10° C. N-methyl morpholine (0.189 g, 1.84 mmol) was added, followed by isobutylchloroformate (0.21 g, 1.48 mmol) over a period of 5 minutes. The reaction mixture was stirred for 10 minutes at −10° C. and aqueous ammonia (approximately 500 μl) was added in one portion and the reaction mixture was allowed to warm to room temperature. The resulting suspension was concentrated and extracted with EtOAc (2×20 ml). The combined extracts were washed with water (5 ml), 10% w/v aqueous solution of potassium hydrogensulfate, saturated aqueous sodium bicarbonate (5 ml) and water (5 ml). The organics were dried over magnesium sulfate filtered and concentrated to give benzyl [(1S)-2-amino-1-(isopropoxymethyl)-2-oxoethyl]carbamate as a white solid, (0.340 g, 100%); 1H NMR Spectrum: (CDCl3) 1.15 (m, 6H), 3.66 (m, 1H), 3.86 (m, 2H), 4.28 (m, 1H), 5.13 (s, 2H), 5.43 (br s, 1H), 5.72 (br s, 1H), 6.54 (br s, 1H), 7.35 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][O:12][C:10](=[O:11])[CH:9]2[CH2:14]OS(C)(=O)=O)=[CH:4][CH:3]=1.C(O)(=O)C.[SH-:24].[Na+]>C(O)C.C(OCC)(=O)C>[SH:24][CH2:14][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)[CH2:13][O:12][C:10]1=[O:11]
Reactant: CS(=O)(=O)OCC1C(=O)OCC1c1ccc(Cl)cc1
Reactant: [SH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1OCC(c2ccccc2)C1CS
Yield: 52 %

Procedure:
To a solution of 1.0 g of α-methanesulfonyloxymethyl-β-phenyl-γ-butyrolactone (III) in 20 ml of ethanol were added 1.5 ml of acetic acid and then 1.2 g of commercially available 70% sodium hydrosulfide and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was diluted with 150 ml of ethyl acetate, washed with water in a conventional manner, dried over magnesium sulfate and the solvent was distilled off. The crude product thus obtained was purified by a column chromatography to give 400 mg (yield 52%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13]SC3C([N+]([O-])=O)=CC=CN=3)[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.Br[CH2:66][C:67]([C:69]1[CH:70]=[C:71]2[C:75](=[CH:76][CH:77]=1)[CH2:74][CH2:73][CH2:72]2)=[O:68]>CC(C)=O.O>[CH2:74]1[C:75]2[C:71](=[CH:70][C:69]([C:67](=[O:68])[CH2:66][S:13][C@H:10]3[C:11](=[O:12])[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C@@H:9]3[C:24]3[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:37][CH:38]=3)=[CH:77][CH:76]=2)[CH2:72][CH2:73]1
Reactant: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SSc3ncccc3[N+](=O)[O-])C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(CBr)c1ccc2c(c1)CCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)CCC4)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4-{(2R,3R)-1-(4-fluorophenyl)-3-[(3-nitropyridin-2-yl)dithio]-4-oxoazetidin-2-yl}phenoxy)acetate (0.100 g, 0.179 mmol) in acetone (2 ml) and water (0.5 ml) was added triphenylphosphine (0.047 g, 0.179 mmol). After 30 minutes, the mixture was concentrated. To the residue was added dichloromethane (3 ml) followed by the addition of triethylamine (0.073 g, 0.717 mmol) and 2-bromo-1-(2,3-dihydro-1H-inden-5-yl)ethanone (0.107 g, 0.448 mmol). After 30 minutes, full conversion of the thiol had been achieved. The mixture was concentrated and to the residue was added formic acid (2 g) and trifluoroacetic acid (0.2 g). The mixture was allowed to stir at room temperature for 3 h. The crude product was purified through preparative HPLC using an eluent of 10-50% CH3CN in 0.1M NH4OAc buffer. Freeze drying of pure fractions afforded the desired compound. 1H NMR [(CD3)2SO), 400 MHz] δ1.96-2.04 (m, 2H), 2.83-2.89 (m, 4H), 4.23-4.34 (m, 5H), 5.09 (d, 1H), 6.76-7.74 (m, 11H).
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:32]=[CH:31][C:18]2[N:19]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH2:20][CH2:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.[Li+].C[Si]([N-:38][Si](C)(C)C)(C)C.Cl.[OH-].[Na+]>C1COCC1.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]>[CH3:30][N:27]1[CH2:28][CH2:29][CH:24]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:17]3[CH:16]=[C:15]([NH2:38])[CH:32]=[CH:31][C:18]2=3)[CH2:25][CH2:26]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN1CCC(N2CCCCc3cc(Br)ccc32)CC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCC(N2CCCCc3cc(N)ccc32)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A suspension of Pd2(dba)3 (70 mg, 0.077 mmol) and PtBu3 10% wt in hexanes (0.94 m/L, 0.31 mmol) in THF (5.0 mL) was treated with a solution of compound 4 (500.0 mg, 1.55 mmol) in THF (5.0 mL) followed by LiHMDS 1 M in THF (3.1 mL, 3.1 mmol) at room temperature. The resulting brown mixture was stirred at 100° C. for 2 hours then cooled to room temperature and treated with 1 N HCl (10 mL) and stirred for 15 minutes. The mixture was basified with 1 N NaOH (25 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic fractions were washed with brine (100 mL), dried (Na2SO4) and concentrated to give a dark brown residue. The crude product was purified by flash chromatography on silica gel (MeOH:CH2Cl2, 5:95 followed by 2 N NH3 in MeOH:CH2Cl2, 5:95) to give compound 5 (339.6 mg, 84.7%) as a dark viscous oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9]1.OS(O)(=O)=O.[CH3:20]O>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:12]([O:14][CH3:20])=[O:13])[CH2:9][CH2:10][CH2:11]1
Reactant: O=C(O)C1(c2ccccc2I)CCC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1(c2ccccc2I)CCC1

Procedure:
A solution of 1-(2-iodophenyl)cyclobutanecarboxylic acid A52 (425 mg, 1.41 mmol) in MeOH (25 mL) and conc. H2SO4 (1.0 mL) was stirred at 60° C. overnight. The volatiles were removed in vacuo and the resulting residue diluted in EtOAc (50 mL) and sat. soln. Na2CO3 (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL), the combined organic fractions were dried (MgSO4) and the volatiles removed in vacuo to give the title compound A53 as a clear oil (361 mg, 81%). LCMS-A: rt 7.020 min; m/z 317 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7](Cl)=[O:8].[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>>[F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1)=[O:8]
Reactant: NCC1CCCCN1
Reactant: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
In still another aspect of the invention, a method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is provided which comprises the following steps. Hydroquinone is contacted with 2,2,2-trifluoroethyl trifluoromethanesulfonate under conditions to yield 1,4-bis(2,2,2-trifluoroethoxy)benzene. Then, in the presence of a Lewis acid catalyst, the 1,4-bis(2,2,2-trifluoroethoxy)benzene is treated with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The methyl moiety of the acetophenone function of the 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is thereafter replaced using hypochlorite to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. Subsequently, the 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is treated with an inorganic chloride to provide 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride. Finally, the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride is contacted with 2-aminomethylpiperidine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)CCC.[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32](I)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.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:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32]([C:6]3[O:7][CH:8]=[CH:9][N:10]=3)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCN(CCC)[C@@H]1Cc2c(I)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCN(CCC)[C@@H]1Cc2c(-c3ncco3)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Yield: 67.5 %

Procedure:
A solution of 5.0 g (13.8 mmol) of the crude 2-tributylstannyloxazole prepared above and 6.8 g (13.9 mmol) of (+)(2aR,4S)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 100 ml of toluene was treated with 0.7 g (0.6 mmol) of tetrakis(triphenylphosphine)palladium then refluxed under nitrogen for 20 hours. After cooling the reaction mixture was washed with a saturated brine solution and then dried over Na2SO4. Concentration in vacuo provided a viscous oil which was chromatographed over a silica gel column using a solvent gradient progressing from toluene to 1:1 toluene/EtOAc. The product from the column was dissolved in 1M HCl. This solution was then washed with ether, made alkaline with 5M NaOH, and extracted with CH2Cl2. Concentration of the extract in vacuo gave about 4 g of a brown oil. When this oil was dissolved in pentane a small amount of a red/brown resin separated leaving a clear, yellow solution. The resin was separated and the pentane was evaporated to provide a residue. This residue was crystallized by dissolving it in a small amount of CH2Cl2 and slowly adding isoctane. The crystalline (-)(2aR,4S)-1-benzoyl-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole, obtained in four crops, weighed 2.63 g. mp 103°-104° C.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[In].[OH:12][C:13]1[C:14](=[O:24])[C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2>CN(C)C=O>[OH:24][C:14]1([CH2:1]/[CH:2]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([OH:23])=[CH:22][C:13]1=[O:12]
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Reactant: BrCC=Cc1ccccc1
Agent: [In]
Solvent: CN(C)C=O
Product: O=C1C=C(O)c2ccccc2C1(O)C/C=C/c1ccccc1
Yield: 9.1 %

Procedure:
Cinnamyl bromide (0.43 g, 2.2 mmol) was added to a suspension of indium metal (0.17 g, 1.5 mmol) in N,N-dimethylformamide (1 mL) at 25° C. for 0.5 h causing dissolution of the metal. 2-Hydroxy-1,4-naphthoquinone (0.25 g, 1.5 mmol) was dissolved in N,N-dimethylformamide (1 mL) and added to the mixture. After 0.5 h the mixture was partitioned between 1% HCl and ethyl acetate. The orgamic layer was separated, washed with water, brine, dried over sodium sulfate and the solvents were evaporated. The crude residue was purified using BioTage 12L column and 5% methanol/dichloromethane to give the title compound (40 mg, 10% yield).