Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[CH3:24])[CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])(=[O:10])=[O:9].B([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([S:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH:29]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:23][C:20]1[C:19]([CH3:24])=[C:18]([N:11]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([S:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH:29]=2)(=[O:10])=[O:9])[O:22][N:21]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 77.5 °C
Yield: 44.8 %

Procedure:
After purging a solution of 2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide (595 mg; 1.42 mmol) in 14 ml of toluene and 12 ml of EtOH with argon for 20 minutes, the title product of Step (C) (600 mg; 1.99 mmol) was added followed by 2M Na2CO3 (10 ml; previously purged with argon) and tetrakis(triphenylphosphine)palladium(0) (200 mg). The heterogeneous mixture was heated to 75-80° C. for 5 hrs. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and water (25 ml). The aqueous layer was extracted with an additional 25 ml of ethyl acetate and the combined organic layers were washed with water (25 ml) and brine (25 ml). After drying (MgSO4) and decolorizing (Darco), the green solution was concentrated to afford a dark green residue which was chromatographed on a 5×12 cm silica gel column, using 2 L EtOAc:hexanes, 1:3, 1 L EtOAc:hexanes, 3:7 and 1 L EtOAc:hexanes, 35:65 as the mobile phase. The pure fractions were concentrated to afford 379 mg (45%) of the title product of this step as a blue-green foam.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH2:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[C:22](F)[CH:23]=2)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]1)[CH3:14]>CCOCC>[CH2:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[C:22]([N:11]3[CH2:10][CH2:9][NH:8][CH:7]([CH2:6][N:1]4[CH:5]=[CH:4][CH:3]=[CH:2]4)[CH2:12]3)[CH:23]=2)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]1)[CH3:14]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: c1ccn(CC2CNCCN2)c1
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(Cn4cccc4)C3)cc21

Procedure:
A 1 g portion of 2-(1H-pyrrol-1-ylmethyl)piperazine and 0.76 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid were heated at 70°-75° C. in a sealed pressure bottle, filled with argon, for 18 hours, then ether was added and the solid collected, washed with ether and purified by chromatography, giving 595 mg of the desired product, mp 185°-188° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]([C:13]([NH2:15])=[O:14])[C:10]([NH2:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(OCC)(=O)C.C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([C:10]([NH2:12])=[O:11])[C:13]([NH2:15])=[O:14])=[CH:16][CH:17]=1
Reactant: NC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(N)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)C(Cc1ccc(N)cc1)C(N)=O
Reaction time: 56 h
Yield: 48.8 %

Procedure:
A 100-mL round bottom flask was charged with 2-(4-nitrobenzyl)malonamide (0.40 g, 1.68 mmol) and 10% palladium on carbon (0.10 g) in 1:2 ethyl acetate/ethanol (15 mL). This mixture was vigorously stirred under H2 (1 atm) for 56 h. After this time, the mixture was filtered through celite to afford the title compound (0.17 g, 49%) as a white solid. MW=207.23. 1H NMR (DMSO-d6, 500 MHz) δ 7.16 (s, 2H), 6.95 (s, 2H), 6.82 (d, J=8.5 Hz, 2H), 6.43 (d, J=8.5 Hz, 2H), 4.81 (s, 2H), 3.17 (t, J=8.0 Hz, 1H), 2.78 (d, J=7.5 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([O:13]CC)=[O:12])[C:3]=1/[CH:16]=[CH:17]/[Si:18]([CH3:21])([CH3:20])[CH3:19].CO.O.O.[OH-].[Li+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1/[CH:16]=[CH:17]/[Si:18]([CH3:19])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1nc(C2CC2)nc(N)c1/C=C/[Si](C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[Si](C)(C)/C=C/c1c(N)nc(C2CC2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.2 %

Procedure:
(E)-ethyl 6-amino-2-cyclopropyl-5-(2-(trimethylsilyl)vinyl)pyrimidine-4-carboxylate (0.666 g, 2.180 mmol) was dissolved in THF (8.7 mL), MeOH (8.7 mL), and Water (4.4 mL). Lithium hydroxide hydrate (0.274 g, 6.54 mmol) was added as a solid. The reaction mixture was stirred for 15 min at room temperature. The solvent was removed under vacuum. The resulting solid was partitioned between 1 N HCl and ethyl acetate. The aqueous phase was extracted with ethyl acetate three times. The combined organics were washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The solid was triturated with hexane (15 mL) and gently heated with heat gun. The solid from the resulting suspension was collected via filtration and dried under vaccum to provide the title compound as an off-white solid (0.104 g, 17% yield): mp 146-149° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.12 (s, 9H), 0.91-1.03 (m, 4H), 2.02 (tt, J=7.8, 5.1 Hz, 1H), 6.22 (d, J=19.3 Hz, 1H), 6.74 (d, J=19.3 Hz, 1H), 7.34 (s, 2H); ESIMS m/z 278 ([M+H]+), 276 ([M−H]−)
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[O:6])[CH:2]=[CH2:3].Cl[CH:9]([C:15]([C:17]([F:20])([F:19])[F:18])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[CH2:1]([NH:4][C:5]1[O:6][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([C:17]([F:18])([F:20])[F:19])[N:7]=1)[CH:2]=[CH2:3]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: C=CCNC(N)=O
Product: C=CCNc1nc(C(F)(F)F)c(C(=O)OCC)o1
Yield: 36.1 %

Procedure:
By the procedure of Example 4, 6 g (60 mmol) of allyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 18 hours. The product was separated and then recrystallized from methylcyclohexane to yield 4.77 g of a yellow solid product (m.p.=48°-49° C.) identified in Table I.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:24]=1[NH2:25].Cl.[OH-].[Na+]>O.C(O)C>[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:24]=1[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: FC(F)(F)c1ccc(-c2nc(Cl)cc(C(F)(F)F)n2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3ccc(C(F)(F)F)nc3)n2)c1
Yield: 4.4 %

Procedure:
A mixture of crude 4-chloro-2-[6-(trifluoromethyl)-3-pyridinyl]-6-(trifluoromethyl)pyrimidine (50 mg, 0.152 mmol), 2-chloro-5-methoxyaniline (50 mg, 0.229 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 120 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10-12. The mixture was extracted with ethyl acetate (75 ml), washed with water (2×20 ml), with aqueous saturated NaCl (1×20 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified by preparative TLC to give a white solid (3 mg, 4%). 1H NMR (CDCl3): 9.72 (s, 1H), 8.90 (dd, J=3.0, 7.8 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.75 (s, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.36 (s, 1H), 6.99 (s, 1H), 6.75 (dd, J=3.0, 8.7 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:20]=[CH:19][C:15]3[CH:16]=[N:17][S:18][C:14]=3[C:13]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[F:29])=[O:11])[CH2:4][O:3]1.Cl>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]2[CH:16]=[N:17][S:18][C:14]=2[C:13]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=1[F:29])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ccc3cnsc3c2Nc2ccc(Br)cc2F)O1
Agent: Cl
Solvent: CO
Product: O=C(NOC[C@H](O)CO)c1ccc2cnsc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
To a solution of 7-(4-bromo-2-fluoro-phenylamino)-benzo[d]isothiazole-6-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (370 mg, 0.75 mmol) in MeOH (4 mL) was added a 1.0M aqueous solution of hydrochloric acid (1.50 mL). The reaction mixture was stirred at room temperature for 2 hours before being concentrated in vacuo. The resultant residue was taken up in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate then brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 100%, MeOH in DCM) to afford the title compound as a yellow solid (242 mg, 71%). LCMS (method A): RT=8.80 min, [M+H]+=456/458. 1H NMR (CD3OD, 400 MHz) 8.87 (1 H, s), 7.76-7.70 (1 H, m), 7.61 (1 H, d, J=8.36 Hz), 7.42-7.36 (1 H, m), 7.30-7.25 (1 H, m), 6.95 (1 H, t, J=8.66 Hz), 4.06 (1 H, dd, J=10.08, 3.55 Hz), 3.96-3.83 (2 H, m), 3.64-3.54 (2 H, m).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)=O>C(O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NN1CCOCC1
Agent: O=C=O
Solvent: CCO
Product: Nc1ccccc1C(=O)NN1CCOCC1
Temperature: 70 °C

Procedure:
33 g isatoic anhydride are suspended in 200 cc ethanol heated to 70° C.; 20.5 g 4-amino-morpholine are slowly added thereto. After completion of the addition, the temperature is maintained at the same level until carbon dioxide is no longer evolved. The ethanol is partly removed (100 cc) and the reaction product is crystallized by addition of 100 cc benzene. It may be purified by recrystallization from a benzene-ethanol mixture. M.P.=172° C.
Reaction SMILES: CC[O-].[Na+].[NH2:5][C:6]([NH2:8])=[NH:7].[CH3:9][C:10]1[O:14][N:13]=[C:12]([C:15](OCC)=[O:16])[CH:11]=1>C(O)C.Cl.NC(N)=N>[CH3:9][C:10]1[O:14][N:13]=[C:12]([C:15]([NH:7][C:6]([NH2:8])=[NH:5])=[O:16])[CH:11]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cc(C)on1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)NC(=N)N)no1
Reaction time: 12 h

Procedure:
To a solution of sodium ethylate (75 parts by weight) in anhydrous ethanol (500 parts by volume), guanidine monohydrochloride (96 parts by weight) is added under stirring and ice-cooling to make an ethanolic solution of free guanidine. To this solution, a solution of ethyl 5-methylisoxazole-3-carboxylate (155 parts by weight) in anhydrous ethanol (200 parts by volume) is added within 2 hours under stirring at 40° C. The resultant mixture is allowed to stand at 20° C for 12 hours. The precipitated crude crystals are filtered off, washed with a small amount of water and recrystallized from ethanol to give 1-(5-methyl-3-isoxazolylcarbonyl)guanidine as colorless prisms melting at 192° to 192.5° C under decomposition. IR (Nujol): 1652 cm-1 (=C=O).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1)=[O:9].[Br:16][C:17]1[N:22]=[C:21]([C:23](OCC)=[O:24])[CH:20]=[CH:19][CH:18]=1.O>O1CCCC1.C(O)(=O)C>[Br:16][C:17]1[N:22]=[C:21]([C:23](=[O:24])[CH2:7][C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1cccnc1
Reactant: CCOC(=O)c1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=C(CC(=O)c1cccc(Br)n1)c1cccnc1
Temperature: 25 °C

Procedure:
3.71 g (33.0 mmol) of potassium tert-butoxide were added to a mixture of 4.00 g (33.0 mmol) of 3-acetopyridine and 7.60 g (33.0 mmol) of ethyl 6-bromo-2-pyridinecarboxylate in 100 ml of tetrahydrofuran. The solution was stirred at room temperature until a solid mixture has formed. 100 ml of water and 10 ml of acetic acid were then added, and the aqueous phase was subsequently extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, and the solvent was then removed under reduced pressure. The residue that remained was purified chromatographically (mobile phase: cyclohexane/ethyl acetate), the solid was then washed with diethyl ether. This gave 6.91 g (69% of theory) of 1-(6-bromopyridin-2-yl)-3-(pyridin-3-yl)propane-1,3-dione.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)C.[OH-].[Na+].Cl>CO.O>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:19])=[O:3])[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (5.28 g) obtained in the above (1) is dissolved in methanol (32 ml), and thereto is added 1N aqueous sodium hydroxide solution (23.4 ml), and the mixture is stirred at room temperature for three hours. The reaction mixture is diluted with water, and the pH value thereof is adjusted to pH 2 with 1N hydrochloric acid, and extracted three time with ethyl acetate. The extract is washed twice with a saturated brine, and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (5.18 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[Br:18]Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[C:11]([Br:18])[CH:12]=1)[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(O)c(Br)c1)OCC
Reaction time: 1 h
Yield: 88 %

Procedure:
To a stirred solution of (S)-2-ethoxy-3-(4-hydroxyphenyl)-propionic acid ethyl ester (Tetrahedron Letters, Vol. 35, No 19, 3139–3142, 1994) (9.5 g, 40 mmol) in dry methylene chloride (100 ml) was over 1 h dropwise added a solution of bromine in methylene chloride (40 ml) at room temperature. The reaction was stirred for 60 min, washed with saturated sodium sulfite and brine. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using heptane:ethyl acetate (9:1) as eluent to give 11.25 g (88%) of (S)-3-(3-bromo-4-hydroxy-phenyl)-2-ethoxy-propionic acid ethyl ester.
Reaction SMILES: [CH:1]([N:4]([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C:5]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:6]=1[O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[OH-].[Na+:38]>CO>[Na+:38].[CH:1]([N:4]([S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30])[C:5]1[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][C:6]=1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([O-:17])=[O:16])=[CH:18][CH:19]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(c1ccc(C(F)(F)F)cc1OCc1ccc(C=CC(=O)O)cc1)S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(c1ccc(C(F)(F)F)cc1OCc1ccc(C=CC(=O)[O-])cc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4-[2-(N-isopropyl-phenylsulfonylamino)-5-trifluoromethylphenoxymethyl]cinnamic acid (425 mg; prepared in Example 18(40).) in MeOH (5 ml), 2N NaOH (0.41 ml) was added. The mixture was stirred at room temperature. The mixture was distilled off azeotropically with benzene three times to give the title compound (430 mg) having the following physical data.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][N:11]([CH2:19][C@@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[O:21]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)S(O[C:53]1[CH:54]=[CH:55][C:56]2[C:61](=[O:62])[O:60][C:59]([CH3:64])([CH3:63])[O:58][C:57]=2[CH:65]=1)(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Si:1]([O:8][C@H:9]([CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][N:11]([CH2:19][C@@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:53]3[CH:54]=[CH:55][C:56]4[C:61](=[O:62])[O:60][C:59]([CH3:64])([CH3:63])[O:58][C:57]=4[CH:65]=3)[CH:26]=2)[O:21]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(C)OC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2O1
Reactant: CC(C)(C)OC(=O)N(C[C@@H]1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1)C[C@@H](COc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C[C@@H]1CCc2cc(-c3ccc4c(c3)OC(C)(C)OC4=O)ccc2O1)C[C@@H](COc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Yield: 75.2 %

Procedure:
To a degassed solution of tert-butyl (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3-phenoxypropyl{[(2S)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (1.0 g, 1.53 mmol, 1.0 eq.) in toluene (12 mL) were added 2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl trifluoromethanesulfonate (0.60 g, 1.84 mmol, 1.2 equiv.), dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium(II) dichloromethane adduct (0.18 g, 0.23 mmol, 0.15 eq.) and saturated sodium bicarbonate (8.0 mL) under argon atmosphere at room temperature. The reaction mixture was allowed to heat up at 80° C. under argon atmosphere for 18 hours. The mixture was then quenched with distilled water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford black oil. Purification by flash chromatography on a silica gel column (5%-15% ethyl acetate/hexanes) yielded the desired product as colorless oil (0.81 g, 76%). 1H NMR (CDCl3) δ7.86 (d, 1 H), 7.27-6.78 (m, 11H), 4.20-3.85 (m, 2H), 3.81-3.40 (m, 4H), 3.37-3.20 (m, 2H), 2.80-2.21 (m, 2H), 1.95-1.84 (m, 1H), 1.64 (s, 7H), 1.39 (s, 9H), 0.81 (s, 9H), 0.020 (s, 6H).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:68])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:66])[C:57]4[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][CH3:65])=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:67])[C:36]([O:38]C)=[O:37]>>[CH3:68][CH:34]([CH3:33])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:66])[C:57]4[CH:58]=[CH:59][C:60]([CH2:63][CH2:64][CH3:65])=[CH:61][CH:62]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:67])[C:36]([OH:38])=[O:37]
Reactant: CCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)cc1
Yield: 80 %

Procedure:
The compound of example 170 was prepared analogous to compound of example 98 by hydrolysis of compound of example 169.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])C.Cl>O>[C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1[C@@H](c2ccccc2)CC(=O)N1C
Agent: Cl
Solvent: O
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C(=O)O
Temperature: 25 °C
Yield: 66.9 %

Procedure:
(±)-(4R*,5R*)-5-(Ethoxycarbonyl)-1-methyl-4-phenylpyrrolidin-2-one (16 g, 64.8 mmol), prepared according to the method of W. Hartwig and L. Born, J. Org. Chem., 52, 4352 (1987), was heated at the reflux temperature overnight in a 3:1 mixture of 3M HCl solution and water. The resulting mixture was allowed to cool to room temperature, extracted with EtOAc, dried (Na2SO4) and concentrated under reduced pressure. The crude product was triturated (Et2O) to give (±)-(4R*,5R*)-5-carboxy-1-methyl-4-phenylpyrrolidin-2-one (9.5 g, 67%): 1H NMR (CDCl3) δ 2.60 (dd, J=8.3, 16.0 Hz, 1H), 2.82-2.91 (m, 4H), 3.90 (q, J=8.9 Hz, 1H), 3.95 (br s, 1H), 4.37 (d, J=8.6 Hz, 1H), 7.19-7.32 (m, 5H).
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][CH:14]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Product: CCOC(=O)C(CCCc1ccccc1)Cc1ccc(O)cc1
Yield: 99.4 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 2-(4-benzyloxybenzyl)-5-phenylvalerate (3.32 g) and palladium on carbon (5%, 0.40 g) and the reaction mixture was treated to afford the desired compound (2.56 g) as a syrup.
Reaction SMILES: [CH3:1][C:2]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:5]1[CH3:20])=[CH2:3].C(O)C.[H][H]>[Pd].C(OCC)(=O)C>[CH:2]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:5]1[CH3:20])([CH3:3])[CH3:1]
Reactant: [H][H]
Reactant: C=C(C)n1c(C)c(-c2ccc(F)cc2)c2cccnc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(-c2ccc(F)cc2)c2cccnc2n1C(C)C
Reaction time: 16 h

Procedure:
Into a parr vessel are placed 330 mg of the olefinic product of Step 4, above, 20 ml of 100% ethanol and 100 mg of 5% palladium on carbon. Hydrogen gas is added at 40 to 50 psi and held at R.T. for about 16 hrs. Ethyl acetate is then added, the mixture filtered through Celite® and then evaporated to dryness to give the title product of this step as a slightly yellowish gum, which solidified on standing to a light cream solid (mp 57°-68°).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[N:26][OH:27])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)(=[O:8])=[O:7].Cl.O1CCOCC1.[OH-].[Na+]>CO.O1CCCC1.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.O>[CH3:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][NH:26][OH:27])=[CH:23][CH:24]=2)=[CH:12][CH:11]=1)(=[O:8])=[O:7]
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=NO)cc2)cc1
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(CNO)cc2)cc1
Yield: 59.3 %

Procedure:
1.88 g (30 mmole) sodium cyanoborohydride was added to a solution of 2.0 g (6 mmole) 4-{2-[4-(hydroxyiminomethyl)phenoxy]ethyl}phenyl methanesulfonate in 90 ml methanol and 18 ml tetrahydrofuran. Gas evolution was observed. 5 mg methyl orange was added resulting in a yellow colour. 4 M hydrochloric acid:dioxane (2:1) was added dropwise until the color was dark red (pH 2-3). The reaction mixture was poured into water, basified with 2 M sodium hydroxide (pH 9). More water was added and the product was extracted with ethyl acetate, dried, filtered and evaporated. The yellow residue was purified by chromatography on silica gel using ethyl acetate as eluent to give 1.2 g colourless oil of 4-(2-{4-[hydroxyaminomethyl]phenoxy}ethyl)phenyl methanesulfonate.