Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C@H:14]([OH:26])[CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20](CCN)=[CH:19][CH:18]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[C:8]1([C@H:14]([OH:26])[CH2:15][NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCCc1ccc(NC[C@@H](O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O[C@H](CNc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-(2-phenyl-2-(S)-hydroxyethyl)-4-(2-aminoethyl)aniline trifluoroacetate 31 (0.144 g, 0.3 mmole) in methanol (10 mL) was added aq. NaOH solution (1.0 M, 0.625 mL). The solution was concentrated to dryness and the residue was dissolved in anhydrous THF (5 mL). α,α-Dihydroxy-4-hydroxy-3-methoxycarbonylacetophenone 12 (0.067 g, 0.3 mmole) was added and the reaction mixture was stirred for 12 h at rt. BH3-Me2S (0.2 mL, 2M) was added at 0° C. and the reaction mixture was heated at 75° C. for 6 h. After cooling the reaction mixture in ice bath, MeOH (5 mL) was slowly added to it to quench the reaction, and the reaction mixture was stirred for 30 min., at rt. The organics were removed and the residue was dissolved in TFA/MeOH (1/9; 20 mL), and concentrated. The crude product was dissolved in 20% MeCN/H2O, and purified by preparative HPLC: 5 to 20% MeCN/H2O; 20 mL/min; 254 nm.) to give 1-{2-[N-2-(4-hydroxy-3-hydroxy-methylphenyl)-2-hydroxyethyl]amino]ethyl}-4-[N-(2-phenyl-2-(S)-hydroxyethyl)-amino]benzene 33.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:26][CH2:25]2)[CH:19]=1)=[O:16]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4ccccc4n3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2-quinolinecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 388.1 (M+H)+.
Reaction SMILES: O=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>C(O)C>[N:31](=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1)[OH:32]
Reactant: NO
Reactant: CCCCCCCCCCC(=O)CCCCCNc1ccc(C(=O)OCC)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)OCC)cc1)=NO

Procedure:
A mixture of 1.0 g. of ethyl 4-(6-oxohexadecylamino)benzoate, 207 mg. of hydroxylamine hydrochloride, 244 mg. of sodium acetate and 20 ml. of 95% ethanol is stirred under reflux for 3 hours and filtered. The filtrate is evaporated and a methylene chloride solution of the residue is washed with water, dried over magnesium sulfate, and evaporated to yield ethyl 4-(6-oximinohexadecylamino)benzoate as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1([CH3:29])[CH2:16][O:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=2OC)=[N:13]1.O>O1CCCC1>[CH3:26][O:25][C:19]1[C:18]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:17]([C:14]2[O:15][CH2:16][C:12]([CH3:11])([CH3:29])[N:13]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: Br[Mg]CCc1ccccc1
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(OC)c1OC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(C)(C)CO2)c(CCc2ccccc2)c1OC
Reaction time: 16 h

Procedure:
A solution of phenylethyl magnesium bromide (1M in tetrahydrofuran (40 ml) was added to a stirred solution of 4,5-dihydro 4,4-dimethyl-2-(2,3,4-trimethoxyphenyl) oxazole (5.3 g 0.02M) in dry tetrahydrofuran under a nitrogen atmosphere. The mixture was stirred at 20° for 16 hours. Water (200 ml) was added and the aqueous phase thoroughly extracted with diethyl ether (3×200 ml). The organic solution was dried over magnesium sulphate, filtered and evaporated to leave an oil which was purified by column chromatography on SiO2 eluting with ether/petroleum ether (50/50) to give a colorless oil (6.2 g); MS m/e 339.
Reaction SMILES: O[CH2:2][C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([CH2:12][CH2:13][CH3:14])[S:9]2)[C@@H:5]([OH:15])[C@@H:4]1[OH:16].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>N1C=CC=CC=1.C(Cl)Cl>[N:28]([CH2:2][C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([CH2:12][CH2:13][CH3:14])[S:9]2)[C@@H:5]([OH:15])[C@@H:4]1[OH:16])=[N+:29]=[N-:30]
Reactant: CCCC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CN=[N+]=[N-])O[C@@H]2S1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
(3aR,5R,6S,7R,7aR)-5-(hydroxymethyl)-2-propyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (200 mg, 0.81 mmol) was dissolved in pyridine (2 mL) and CH2Cl2 (2 mL) and cooled to 0° C. Tosyl chloride (230 mg, 1.2 mmol) was then added and the solution allowed to warm to room temperature over 1 h. The mixture was diluted with CH2Cl2 (10 mL) and washed with water (2×5 mL), dried (MgSO4), filtered and concentrated. The resultant colourless residue (280 mg) was taken up in DMF (3 mL) and NaN3 (158 mg, 2.4 mmol) was added. The resultant mixture was stirred at 55° C. for 2 days. Concentration of the mixture gave a residue which was taken up in CH2Cl2 (20 mL) and washed with water (2×5 mL), dried (MgSO4), filtered and concentrated. Flash chromatography of the residue on silica gel (MeOH:EtOAc, 1:9) gave 180 mg (82% yield) of (3aR,5R,6S,7R,7aR)-5-(azidomethyl)-2-propyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (50) as a colourless oil. 1H NMR (500 MHz, methanol-d4): δ 0.98 (t, 3H, J=7.3 Hz), 1.63-1.67 (m, 2H), 2.46-2.50 (m, 2H), 3.33 (m, 1H), 3.54 (dd, 1H, J=4.3, 9.5 Hz), 3.44 (dd, 1H, 2.3, 12.0 Hz), 3.55 (dd, 1H, J=6.2, 12.0 Hz), 4.06 (dd, 1H, J=4.4, 4.6 Hz), 4.29 (m, 1H, J=4.3 Hz), 6.31 (d, 1H, J=6.9 Hz).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[C:8]([O:12][C:13]([NH:15][CH:16]=[CH:17][CH:18]=[CH2:19])=[O:14])([CH3:11])([CH3:10])[CH3:9]>O1CCCC1>[C:8]([O:12][C:13]([NH:15][CH:16]1[CH:17]=[CH:18][CH2:19][CH:3]2[CH:2]1[C:1](=[O:7])[NH:5][C:4]2=[O:6])=[O:14])([CH3:10])([CH3:11])[CH3:9]
Reactant: C=CC=CNC(=O)OC(C)(C)C
Reactant: O=C1C=CC(=O)N1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C=CCC2C(=O)NC(=O)C12
Reaction time: 8 h
Yield: 42.8 %

Procedure:
48.0 g (0.5 mol) of maleimide dissolved in 200 ml of absolute tetrahydrofuran are introduced into a reaction vessel, and 120 g (0.5 mol) of approx. 70% 1-(tert.-butyloxycarbonylamino)-1,3-butadiene dissolved in 500 ml of absolute tetrahydrofuran are added dropwise, during which process the temperature is kept at 20° to 30° C. Stirring is continued overnight at room temperature. The mixture is then concentrated, and the product is recrystallised from ethyl acetate. 57 g of product of a melting point of 177° to 182° C. are obtained. A further 13 g of a melting point of 158° to 160° C. are obtained from the mother liquor.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15]N1C(=O)CCC1=O>CC#N.C(O)(C(F)(F)F)=O>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(Cl)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 5.7 %

Procedure:
3-Phenoxyphenol (1.00 g, 5.4 mmol) was dissolved in MeCN (40 mL) and TFA (0.5 mL). N-Chlorosuccinimide (717 mg, 5.4 mmol) was added and the reaction stirred at ambient temperature for 48 h. Solvents were removed in vacuo to afford the crude product as an oil (2.15 g). 300 mg of this crude material was purified by HPLC to afford in order of elution 4-chloro-3-phenoxyphenol (68 mg, 0.31 mmol, 41%) M.S. (ESI) (m/z): 219,221 [M−H]−; and 6-chloro-3-phenoxyphenol (73 mg, 0.33 mmol, 44%) M.S. (ESI) (m/z): 219,221 [M−H]−.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc(F)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(3-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 411.2 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[I:15]CI.N(OCCC(C)C)=O>C(OCC)C>[I:15][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: ICI
Reactant: CCOC(=O)CCc1cccc(N)c1
Agent: CC(C)CCON=O
Solvent: CCOCC
Product: CCOC(=O)CCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 42 %

Procedure:
To a solution of Part (2) compound (7.2 g, 32 mmol) in diiodomethane (10.3 mL, 128 mmol) under argon at RT was added isoamyl nitrite (6.5 mL, 64 mmol) over 10 min. The brownish solution was stirred at RT for 40 min and then heated to 80° C. for 2 h. Ethyl ether (300 mL) was added to the reaction and the organic layer was washed with 1N hydrochloric acid (70 mL×2), water (70 mL), saturated sodium bicarbonate (70 mL×2), 10% sodium bisulfite solution (30 mL) and dried over magnesium sulfate. Purification was performed by flash chromatography on 800 g silica gel, loaded and eluted with 7% ethyl acetate in hexane. Pure, fractions were combined and evaporated to give the title compound (4.1 g, 42%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[O:11]CC(C)(C)N=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].Cl.[OH2:26]>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[C:10]([OH:11])=[O:26])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]
Reactant: CC(C1=NC(C)(C)CO1)c1ccc(-c2ccc(F)cc2F)c(F)c1
Reactant: O
Agent: Cl
Product: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)c(F)c1

Procedure:
2-[1-(2,2',4'-Trifluoro-4-biphenylyl)ethyl]-4,4-dimethyl-2-oxazoline (0.53 g.) was stirred and refluxed with hydrochloric acid (5 ml. of 2N) for 5 hrs. The mixture was diluted with water, extracted with ether and the latter extracted with 2.5% potassium carbonate solution. The aqueous extracts were acidified with dilute hydrochloric acid and the precipitate isolated in ether, washed with water, dried and evaporated. The residue was recrystallized from light petroleum (b.p. 80°-100° C.) to give 2-(2,2',4'-trifluoro-4-biphenylyl)propionic acid, m.p. 107°-108.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.[C:10](OCC)(=[O:12])C>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([N:5]=[C:10]=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCOCC
Product: O=C=Nc1cccc(Br)c1
Yield: 87 %

Procedure:
3-Bromoaniline (2.63 g, 15.3 mmol) was dissolved in ethyl acetate (100 ml) and 1N dry hydrogen chloride in diethyl ether (15.3 ml) was added and the solvents were removed in vacuo. The residue was stripped twice with toluene and the residue was suspended in toluene (30 ml). Diphosgene (6.1 ml) was added and the mixture was refluxed for 1.5 hour. After cooling, the solution was concentrated in vacuo to afford 2.63 g (87%) 3-bromophenyliso-cyanate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][S:17]([CH3:16])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(2S,4R)-4-Fluoro-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.87 g, 13.1 mmol) was dissolved in 45 mL of CH2Cl2. The mixture was cooled down to 0° C., and methanesulfonyl chloride (2.55 mL, 32.8 mmol) and triethylamine (4.56 mL, 32.8 mmol) were added. The mixture was allowed to warm to RT and stirred for 1.5 h. The mixture was quenched with a saturated aqueous solution of NaHCO3, extracted twice with CH2Cl2, dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAC 3:7) to afford the desired material. TLC, Rf (c-hexane/EtOAc 1:1)=0.4; MS: 320.0 [M+Na]+, 198.1 [MH−Boc]+, 617.2 [2M+Na]+.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1)=[O:5])#[N:2].[CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[C:39]=[S:40])([CH3:31])[CH3:30].[H-].[Na+].Cl>CN(C=O)C>[C:1](/[C:3](=[C:39](\[NH:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH:29]([CH3:31])[CH3:30])/[SH:40])/[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1)=[O:5])#[N:2]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: N#CCC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1N/C(S)=C(\C#N)C(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
The cyanoacetanilide from Step 1 (0.30 g, 0.775 mmol) and 2-isopropylphenyl isothiocyanate (0.16 g, 0.903 mmol) were dissolved in 5 mL of DMF and stirred under N2 while NaH (60%; 62 mg, 1.55 mmol) was added in one portion. The solution was allowed to stir at ambient temperature for 1 h, then it was poured into 20 mL of 1 N HCl. The gummy solid was collected and crystallized from EtOH/water to give 0.32 g (71%) of the title compound as a light yellow solid, mp 159-162° C. 1H NMR (CDCl3) δ 12.56 (s, 1H), 8.56 (s, 1H), 8.18 (d, J=8.7 Hz, 2H), 7.85-7.77 (m, 2H), 7.68-7.60 (m, 3H), 7.45-7.36 (m, 4H), 7.32-7.27 (m, 1H), 7.20 (d, J=7.7 Hz, 1H), 4.42 (s, 1H), 3.11 (heptet, J=6.9 Hz, 1H), 1.26 (d, J=6.9 Hz, 6H); ESIMS m/z 565 ([M+H]+).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([SH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na]>>[CH:8](/[S:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCc1ccccc1
Reactant: C#Cc1ccccc1
Agent: [Na]
Product: C(=C\c1ccccc1)\SCc1ccccc1

Procedure:
A solution of phenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the Procedure 2, part A, to form (Z)-styryl benzylsulfide. The title compound was obtained in 65% yield by oxidation of the sulfide according to the Procedure 2, part B. 1HNMR (CDC13) δ4.50 (2H, s),6.65(1H, d, JH,H=11.2),7.18-7.74 (10H aromatic+1H ethylenic).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][CH2:12][C@H:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(OCC)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: COC(=O)/C=C/[C@H]1CC[C@@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@H]1CC[C@@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Yield: 90.6 %

Procedure:
Palladium-carbon (containing 50% water, 900 mg) was added to a solution of tert-butyl (E)-(2S,5R)-2-(3,4-difluorophenyl)-5-(2-methoxycarbonylvinyl)pyrrolidine-1-carboxylate (4.5 g) in ethyl acetate (100 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for 2.5 hours. Palladium-carbon in the reaction solution was removed by filtration through celite, and the filtrate was concentrated under reduced pressure to obtain 4.1 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [N:1]([C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH:20]([CH3:22])[CH3:21])[CH2:15]1)[CH2:5][O:6]CC1C=CC=CC=1)=[N+]=[N-].[ClH:23].O1CCOCC1.[H][H]>C(O)C.[C].[Pd]>[ClH:23].[NH2:1][C@H:4]([C@H:14]1[O:18][C:17](=[O:19])[C@H:16]([CH:20]([CH3:22])[CH3:21])[CH2:15]1)[CH2:5][OH:6]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 10.12 g of (3S,5S)-5-[(S)-1-azido-2-benzyloxyethyl]-3-isopropyldihydrofuran-2-one obtained in Example (1e) (33.5 mmol), 16.7 ml of a solution of 4 N hydrochloric acid in dioxane (66.8 mmol) and 3.57 g of 10% palladium-carbon (50% wet) in ethanol (170 ml) was stirred under a hydrogen atmosphere at room temperature for six hours. Hydrogen in the reaction vessel was replaced by nitrogen, and then the reaction mixture was diluted with 170 ml of ethanol. Palladium-carbon was separated by filtration and washed with ethanol. The solvent was evaporated from the filtrate under reduced pressure to obtain 8.50 g of crude (3S,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-isopropyldihydrofuran-2-one hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].CO[C:21](OC)([CH3:23])[CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:5][C:6]([N:7]1[CH:8]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[CH2:9][O:10][C:21]1([CH3:23])[CH3:22])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccc(I)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C(c2ccc(I)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a stirred solution of (RS)-[2-hydroxy-1-(4-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester (7.97 g) in dichloromethane (400 ml) were added sequentially 2,2-dimethoxypropane (36 ml) and p-toluenesulphonic acid monohydrate (0.75 g) and the mixture was stirred at room temperature for 18 hours. The mixture was then washed with 0.5 N aq NaOH, the phases were separated and the organic phase was dried over sodium sulphate, filtered and concentrated in vacuo to afford (RS)-4-(4-iodo-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (7.05 g, 89%) as a yellow solid. MS (EI): 403 (M+), 388 ([M-CH3]+), 332 ([M-CH3—C4H8]+), 288 ([M-CH3—C4H8—CO2]+), 57 ([C4H9]+).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([CH3:25])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1)[CH2:8]Br>O.C(O)C>[CH3:4][C:5]1[CH:6]=[C:7]([CH2:8][C:1]#[N:2])[CH:10]=[C:11]([CH3:25])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1
Reactant: [C-]#N
Reactant: COc1ccc(Oc2c(C)cc(CBr)cc2C)cc1C(C)C
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2c(C)cc(CC#N)cc2C)cc1C(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a stirred solution of sodium cyanide (0.23 g, 4.69 mmol) in H2O (2 mL) at room temperature was added a solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl bromide (0.85 g, 2.34 mmol) in ethanol (5 mL). The reaction mixture was heated at 80° C. for 2 h, cooled to room temperature, and poured into ice water (100 mL). The mixture was stirred for 1 h and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:4) to afford 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenylacetonitrile as a brown solid (0.64 g, 85%, m.p.: 56-58° C.): 1H NMR (300 MHz, CDCl3): δ 7.07 (s, 2 H), 6.78 (d, J=3.3 Hz, 1 H), 6.68 (d, J=9.0 Hz, 1 H), 6.35 (dd, J=3.0, 8.7 Hz, 1 H), 3.80 (s, 3 H), 3.73 (s, 2 H), 3.40-3.25 (m, 1 H), 2.16 (s, 6 H), 1.19 (d, J=7.2 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:4); Rf=0.5.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ncccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2n[nH]c3ncccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0321 g, 0.0672 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0152 g, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH2:17][NH:18][CH3:19])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C.[Cl:27][C:28]1[CH:29]=[C:30]([S:35](Cl)(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1[F:34]>C(Cl)Cl>[Br:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]([CH3:19])[S:35]([C:30]2[CH:31]=[CH:32][C:33]([F:34])=[C:28]([Cl:27])[CH:29]=2)(=[O:37])=[O:36])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: CNCc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1)S(=O)(=O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
To a solution of t-butyl 2-(2-bromo-4-((methylamino)methyl)phenoxy)acetate (2) (68.8 g, 0.21 mol, 1 eq) in DCM (500 mL) was added triethylamine (42 g, 0.42 mol, 2 eq) and 3-chloro-4-fluorobenzene-1-sulfonyl chloride (47.8 g, 0.21 mol. 1 eq, Aldrich, Milwaukee, Wis., USA). After the mixture was stirred for 2 h at room temperature, DCM was evaporate. Crude product was recrystallized from ethanol to yield tert-butyl 2-(2-bromo-4-((3-chloro-4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (10) (64 g, 59%).