Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[C:11]=1[NH:19][C:20]([C:22]1[S:23][CH:24]=[C:25]([CH:27]([CH3:29])[CH3:28])[N:26]=1)=O)(=[O:9])[CH3:8]>C(O)(C)(C)C.C(OCC)(=O)C>[CH:27]([C:25]1[N:26]=[C:22]([C:20]2[CH:8]=[C:7]([OH:9])[C:10]3[C:11](=[C:12]([CH3:18])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[N:19]=2)[S:23][CH:24]=1)([CH3:29])[CH3:28]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 90 °C
Reaction time: 4 h
Yield: 108.3 %

Procedure:
Sodium tert-butoxide (3.20 g, 28.6 mmol., 2.1 eq.) was added portion wise, at ambient temperature, to a solution of 1-acetyl-2-[(4-isopropyl-thiazol-2-yl)-carbonylamino]-3-methyl-4-methoxy-benzene (4.52 g, 13.6 mmol., 1.0 eq.) in dry tert-butanol (45 mL). The reaction mixture was stirred at 90° C. for 4 hours. LCMS analysis showed the reaction to be complete. The reaction mixture was left to cool to ambient temperature and then diluted with ethyl acetate (100 mL). The organic layer was washed with 1M aqueous potassium hydrogen sulphate (75 mL), water (50 mL), brine (50 mL), dried over sodium sulphate, filtered and the solvent removed under vacuum to give 4.63 g (99%) of the title compound as an off white solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.59 (br. s, 1 H), 8.26 (d, J=9.16 Hz, 1 H), 7.10 (s, 1 H), 7.03 (d, J=9.16 Hz, 1 H), 6.77 (s, 1 H), 3.98 (s, 3 H), 3.20 (spt, J=6.87 Hz, 1 H), 2.43 (s, 3 H), 1.39 (d, J=7.02 Hz, 6 H). LC-MS: 95% (UV), tR 2.24 min, m/z [M+1]+ 315.15.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]([CH3:21])([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH3:11].O.[OH-].[Na+]>C1COCC1>[CH3:21][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])[CH2:9][OH:8]
Reactant: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a suspension of lithium aluminum hydride (1.00 g, 26.3 mmol) in 50 mL of THF at 0° C. was added 2-methyl-2-(4-nitro-phenyl)-propionic acid methyl ester (2.20 g, 9.86 mmol, Hartwig, et al, J. Am. Chem. Soc, 2004, 126, 5182) in 10 mL of THF dropwise. The resulting mixture was stirred at 0° C. for 3 h and treated with 1 mL of H2O followed by 1 mL of 15% aq NaOH and 3 mL of H2O. The solid was removed by filtration on Celite and the filtrate was concentrated in vacuo to give a light yellow oil (1.56 g, 81%). The product was used in the next step without further purification. 1H-NMR (CDCl3; 400 MHz): δ 7.92 (d, 2H, J=8.6 Hz), 7.55 (d, 2H, J=8.6 Hz), 3.69 (s, 2H), 1.40 (s, 6H).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:18][O:17][C:15]([C:14]1[S:13][C:2]2[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=2[CH:4]=1)=[O:16]
Reactant: O=Cc1ccc(F)cc1F
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2ccc(F)cc2s1
Yield: 67.3 %

Procedure:
Using 2.00 g (14.07 mmol) of 2,4-difluorobenzaldehyde, 0.84 g (21.11 mmol) of sodium hydride (60% pure) and 1.64 g (15.48 mmol) of methyl mercaptoacetate, 1.99 g of the desired product are obtained. The product is obtained in a purity which permits further reaction and is reacted without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[C:5]1([CH:1]([OH:4])[CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(=O)c1ccccc1
Agent: Cl[Ru]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccc(C(C)C)cc1
Product: CCC(O)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Dichloro(p-cymene)ruthenium(II) dimer (1.2 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=i-Pr, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in i-propanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 85° C. After the mixture was cooled to room temperature, propiophenone (0.4 mmol), i-propanol (2 mL) and a solution of sodium carbonate in i-propanol (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (5 atm) at 10° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/8). Accordingly, pure 1-phenylpropanol was obtained and the ee value (ee=99.2%) was measured by GC analysis.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:5]=1.[OH-].[K+].Cl>C(Cl)Cl.O.CO.C(O)C>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:25])=[O:2])=[CH:9][CH:8]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 99 %

Procedure:
To 20 g of product from Example 1 is added 9.66 g potassium hydroxide, 160 ml methyl alcohol, 10 ml water and 70 ml ethyl alcohol. The reaction mixture is refluxed for 6.5 hours, during which time an additional 100 ml methyl alcohol and 100 ml water is added. To the cooled reaction mixture is added 1 L of methylene chloride and sufficient concentrated hydrochloric acid to make the reaction pH acidic. The white crystals are collected and dried in vacuo over phosphorus pentoxide to give 19.0 g of the desired product. MP 94°-96° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[CH:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.[Cu](I)I>[C:17]1([C:2]#[C:1][CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Ic1ccccc1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Tert-butyl 4-ethynylpiperidine-1-carboxylate (12.5 g) and iodobenzene (12.8 g) was dissolved in THF:TEA=1:1 (v/v) mixed solvent (125 ml), then at room temperature, copper iodide (455 mg) and palladium tetrakistriphenylphosphine complex (1.38 g) were added thereto in that order, followed by stirring overnight at room temperature. The solvent was evaporated, EtOAc was added to it, and washed with aqueous 1 M hydrochloric acid solution, water and saturated brine in that order. This was dried over magnesium sulfate, and the solvent was evaporated to obtain a light brown oil. This was purified by silica gel column chromatography (eluent: hexane:EtOAc=19:1 (v/v)) to obtain tert-butyl 4-(phenylethynyl)piperidine-1-carboxylate (15.5 g) as a light brown oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C.[Cu]I>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]#[C:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Ic1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccccc2)CC1
Temperature: 82 °C
Yield: 73 %

Procedure:
N-BOC4-ethynylpiperidin, 0.5 g (2.40 mmol), and iodobenzene, 0.29 mL (2.64 mmol) were dissolved in triethylamine (9 mL) and argon was passed through for a few minutes. Copper(I) iodide, 0.087 g (0.5 mmol), and bis[triphenylphosphine]palladium dichloride, 0.070 g (0.1 mmol), were added and the mixture was heated to 82° C. in a closed vessel for 17 hours. TLC analysis indicated complete reaction. Triethylamine was evaporated and the mixture was purified by silica gel chromatography (75 mL) using heptane/ethyl acetate (4+1) as eluant. Evaporation of pure fractions gave 0.497 g (73%) of N-BOC4-(phenylethynyl)piperidine. The protected piperidine, 0.497 g (1.74 mmol), was dissolved in dichloromethane and trifluoroacetic acid (1 mL) was added. The reaction was completed within 20 hours and the mixture was evaporated to give an oil. NMR analysis showed pure ammonium trifluoroacetate, contaminated with trifluoroacetic acid. The product was dissolved in dichloromethane and extracted with aqueous sodium hydrogen carbonate and water. Evaporation of solvent gave 0.284 g (88%) of the sub-titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8]C(=O)OC(C)(C)C)[N:5]2[N:16]=[CH:17][C:18]([CH:19]=[O:20])=[C:4]2[N:3]=1.O1CCOCC1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>O>[NH2:8][C:6]1[N:5]2[N:16]=[CH:17][C:18]([CH:19]=[O:20])=[C:4]2[N:3]=[C:2]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([Cl:27])[CH:29]=2)[CH:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc2c(C=O)cnn12
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(Nc2cccc(Cl)c2)nc2c(C=O)cnn12
Temperature: 95 °C
Yield: 38 %

Procedure:
Tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-ylcarbamate (1.1 g, 3.8 mmol) was added to 1,4-dioxane (15 mL) along with 3-chloroaniline (2.4 mL, 22.6 mmol) and p-toluenes sulfonic acid monohydrate (73 mg, 0.4 mmol). The reaction was heated at 95° C. for 12 hours then cooled to room temperature, diluted with water and filtered. Analysis of the recovered solid by LCMS showed product mass (M+1=288), as well as, product with chloro aniline imine mass (M+1=397). To completely convert this mixture to the desired product, the solid was dissolved in 6 mL of MeOH/conc. HCl solution (1:1) and heated at 60° C. for 1.5 hours. The reaction was quenched by slow addition to ice cold 6N NaOH. The mixture was diluted with water then the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, 7-amino-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde, was collected as orange-red solid in 38% yield. LCMS (M+1=288)
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.CN1CCOCC1.[CH3:15][O:16][C:17](Cl)=[O:18]>C1COCC1>[CH3:15][O:16][C:17]([N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7])=[O:18]
Reactant: COC(=O)Cl
Reactant: O=C1CCC(=O)N1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)N1C(=O)CCC1=O
Reaction time: 2 h

Procedure:
To a solution of 19.8 g (200 mmole) of succinimide and 22 ml (200 mmole) of N-methylmorpholine in 350 ml THF at -5° was added 15.5 ml (200 mmole) methylchloroformate over 20 minutes. After stirring for two hours at 25°, the solvent was removed under reduced pressure and the residue was taken up in EtOAc. The suspension was filtered, and washed with saturated NaCl, saturated NaHCO3, and saturated NaCl. After drying, the solution was concentrated under reduced pressure and Et2O was added, giving the product as a crystalline solid, 10.0 g. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[S-:13][C:14]#[N:15].[K+].BrBr>C(O)(=O)C>[NH2:15][C:14]1[S:13][C:12]2[CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2nc(N)sc2c1
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
Ethyl 4-aminobenzoate (23.2 g, 140.4 mmol) and potassium thiocyanate (40.9 g, 420.9 mmol) were dissolved in acetic acid (280 ml), and under an ice cooling, bromine (22.4 g, 140.4 mmol) was slowly added thereto. The mixture was stirred under an ice cooling for 10 minutes and then stirred at a room temperature overnight. To the mixture, purified water was added and then ice was added. Thereafter, the resulting mixture was neutralized with ammonia water. The precipitate was separated by filtration, washed with purified water, and then subjected to through circulation drying to give the title compound (25.2 g, 81%) as a white powder.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH:5]([OH:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>O1CCCC1.[Cl-].[Na+].O>[CH:3]#[C:4][CH:5]([OH:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC(O)C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(O)CCCCCCCC
Reaction time: 0.5 h
Yield: 112.5 %

Procedure:
To 8.65 g of the crude product from Example 6 was added 40 ml of 1M (n-C4H9)4NF in tetrahydrofuran (THF). The reaction mixture became warm and stirring was continued at room temperature for 1/2 hour. Thereafter, the reaction mixture was poured into brine and extracted 2× with diethyl ether. The combined ether extracts were washed 2× with brine and then dried (MgSO4). Removal of the solvent produced a brown oil. The oil was flash chromatographed on a silica gel column. Gradient elution from 10% diethyl ether in petroleum ether to 20% diethyl ether in petroleum ether produced 6.81g of the titled product as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)[CH3:2].ClC(Cl)C.[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>CO>[Br:23][CH:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)Cl
Solvent: CO
Product: CC(Br)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To the solution dissolved 15.0 g of 2-ethylanthraquinone (63 mmol; produced by Wako Pure Chemical Industries, Ltd.) into 100 mL of dichloroethane, 11.3 g of N-bromosuccinimide (NBS) (63.5 mmol; produced by Wako Pure Chemical Industries, Ltd.) and 1.0 g of 2,2′-azobis(isobutyronitrile) (AIBN) (6.1 mmol; produced by Wako Pure Chemical Industries, Ltd.) were added, then, the solution was reacted by stirring for 2 hours at 60° C. After completing reaction, the reaction solution was condensed, and 120 mL of methanol was poured into the condensed residue, and after the resultant crystal was filtered, the resultant crystal was dried to obtain 18.0 g of 2-(1-bromo-1-ethyl)anthraquinone (yield: 90%) as pale yellow crystal. Measurement results of 1H-NMR are shown as the follows:
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reaction time: 1 h
Yield: 987.9 %

Procedure:
tert-Butyl-dimethyl-(4-nitro-phenoxy)-silane (7.3 g, 2.9 mmol) was dissolved in MeOH (75 ml) and hydrogenated in the presence of Pd on C (10%, E 101 N/D) at room temperature and atmospheric pressure for 1 hour. The catalyst was filtered and the solvent was evaporated to provide 4-(tert-Butyl-dimethyl-silanyloxy)-phenylamine (6.4 g, 99%) as light yellow oil, MS: m/e=223 (M+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH2:3]1
Reactant: OC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCCC(O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixed solution containing 33.5 g of 3-hydroxypiperidine and 62.7 ml of triethylamine dissolved in 250 ml of methylene chloride was added dropwise a solution of 55.7 ml of benzyloxycarbonyl chloride in 150 ml of methylene chloride, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous citric acid and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 75.5 g of benzyl 3-hydroxypiperidine-1-carboxylate.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>CO>[CH3:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(C)cccc4C)c3O2)cc1
Solvent: CO
Product: CNCC1Cc2cc(F)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.298 g, 79%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (−)-[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.2 mmol) and methylamine (0.372 g, 12.0 mmol). [α]D25=−3.0 (c 10.0 in methanol); mp 171-173° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=2)[S:3]1.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=2)[S:3]1
Reactant: CCOC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 27.5 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
To a stirred solution of ethyl [4-[[2,4-dioxo-1,3-thiazolidine-5-yl]methyl]phenoxy]acetate (110 g, 0.36 mol) in methanol (0.65 L) was added as solutino of Na2CO3 (200 g, 1.88 mol) in water (0.65 L) and stirred for 5 h at 25 to 30° C. After completion of the reaction, methanol was removed under reduced pressure; water was added to the residue and was acidified with hydrochlori acid. The precipitated while solid was filtered and dired to yield the title compound (80 g, 80%). mp: 181-183° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:17]>C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][Cl:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CO)cc1OC1CCCC1
Reactant: Cl
Solvent: ClCCl
Product: COc1ccc(CCl)cc1OC1CCCC1
Yield: 98.9 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzyl alcohol (112 g, 0.50 mol) prepared as described above, in 1 liter of methylene chloride was stirred at room temperature with concentrated HCl (110 ml, 1.2 mol) for 3 hours at which time the reaction was done by TLC. The layers were separated and the methylene chloride solution was washed twice with water and evaporated under reduced pressure to give 3-cyclopentyloxy-4-methoxybenzyl chloride (119 g, 100%).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)[CH:8]=[C:9]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC(N(C)C)=O.O.C([SiH](CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([CH:8]=[C:9]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:10]=1)/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:23][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C#Cc2ccc(NS(C)(=O)=O)cc2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 70 °C
Yield: 88.1 %

Procedure:
To a vessel N-(4-((3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)ethynyl)phenyl)methanesulfonamide (6) (5.00 g; 10.69 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.375 g; 5.35 mmol) are charged and the vessel is purged with nitrogen. Nitrogen purged dimethylacetamide (20 ml) and water (0.578 g, 32.1 mmol) are charged to the vessel and the mixture was heated to 70° C. Triethylsilane (2.49 g, 21.4 mmol) was charged over 2 hours at a temperature of 70° C. The mixture was heated at 70° C. for approximately 5 hours and cooled to ambient temperature. The mixture was diluted with tetrahydrofuran (40 g) and extracted with a 1% Cysteine/2.5% NaHCO3/7% NaCl solution. The solids which formed were removed by filtration and washed with tetrahydrofuran (18 g). The aqueous layer was extracted with tetrahydrofuran (18 g). The combined tetrahydrofuran extracts were washed successively with a 1% Cysteine/2.5% NaHCO3/7% NaCl solution and a 2.5% NaHCO3/7% NaCl solution. Methanol (28 g) was charged and the solution concentrated to 28 g. Methanol (28 g) was charged and the product was allowed to crystallize. Methanol (28 g) was charged and the slurry was concentrated to 45 g. Methanol (60 g) was charged and the mixture concentrated to 75 g. The slurry was heated to 60° C. for 30 minutes and then cooled to ambient temperature. The solids were isolated by filtration, washed with methanol (2×8 gm) and vacuum dried at 50° C. to provide 4.42 g of the titled compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 (s, 9 H) 2.99 (s, 3 H) 3.76 (s, 3 H) 5.62 (d, J=7.82 Hz, 1 H) 7.12-7.29 (m, 5 H) 7.51-7.65 (m, 3 H) 7.72 (d, J=7.82 Hz, 1 H) 9.83 (s, 1 H) 11.39 (s, 1 H). MS (APCI) m/e 470.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:9]2=O)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:9]2)=[CH:27][CH:28]=1
Reactant: COCCOCCOc1cccc2c1C(=O)N(Cc1ccc(OC)cc1)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COCCOCCOc1cccc2c1CN(Cc1ccc(OC)cc1)C2
Temperature: 60 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
2-(4-Methoxy-benzyl)-4-[2-(2-methoxy-ethoxy)-ethoxy]-isoindole-1,3-dione (149 m g, 0.38 mmol) was treated with a 1M solution of lithium aluminium hydride in TEF (5 mL, 5 mmol). The mixture was maintained at r.t. for 4 hours, 60° C. for 1 hour, then r.t. for a further 18 hours. The mixture was then cooled in ice and quenched by the dropwise addition of water (0.2 mL), 2N sodium hydroxide solution (0.4 mL) and water (0.4 mL). Magnesium sulfate was added, followed by ethyl acetate and then the mixture was stirred at r.t. for 15 minutes. The solids were removed by filtration, being well washed with ethyl acetate. Concentration of the filtrate gave a residue which was absorbed onto an SCX cartridge and washed with 5% methanol/dichloromethane then eluted with 10% 1M ammonia in methanol/dichloromethane to afford the title compound (134 mg, 97%). 1H NMR (methanol-d4) 7.43-7.39 (2H, m), 7.27 (1H, t), 6.99-6.96 (2H, m), 6.90 (1H, d), 6.88 (1H, d), 4.33 (2H, s), 4.28 (2H, s), 4.23 (2H, s), 4.18-4.15 (2H, m), 3.85-3.79 (5H, m), 3.67-3.64 (2H, m), 3.54-3.51 (2H, m), 3.33 (3H, s). MS: [M+H]+ 358.