Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[C:9](=[O:14])[N:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:7]2O.[OH2:20].[CH2:21]([O:23][CH2:24][CH3:25])[CH3:22]>COCCOC>[Cl:13][C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[Cl:3])[CH:7]([CH2:22][C:21]([O:23][CH2:24][CH3:25])=[O:20])[N:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]2=[O:14]
Reactant: CC(C)CN1C(=O)c2cc(Cl)c(Cl)cc2C1O
Reactant: CCOCC
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)CC1c2cc(Cl)c(Cl)cc2C(=O)N1CC(C)C
Temperature: 20 °C

Procedure:
Ethyl (5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate is prepared as described in Example 2, starting with 0.75 g of 60% sodium hydride in 45 cm3 of 1,2-dimethoxyethane, 3.71 cm3 of triethyl phosphonoacetate and 3.42 g of 5,6-dichloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 5.5 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 75 cm3 of water and then 100 cm3 of diethyl ether. After separation of the phases by settling, the aqueous phase is extracted twice with 100 cm3 of diethyl ether. The organic extracts are combined, washed with 100 cm3 of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under argon pressure (80 kPa) on a cartridge of silica gel (particle size 32-63 μm), eluting with successive mixtures of cyclohexane/ethyl acetate (90/10 and then 80/20 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.93 g of ethyl (5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate is thus obtained in the form of a white solid (Rf=0.74, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.C([O:34][C:35](=[O:37])[CH3:36])(=O)C.C1C=CC=CC=1.CCCCCC>N1C=CC=CC=1>[OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.[CH3:27][C:2]([CH2:3][C:4]([CH2:36][C:35]([OH:34])=[O:37])=[O:30])=[O:1]
Reactant: CC(=O)OC(C)=O
Agent: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 0 °C

Procedure:
The triol from (b) above (0.5 g) in pyridine (0.5 ml) and acetic anhydride (8 ml) was heated at reflux for 1.5 hours. The solution was cooled, poured into ice-water and stirred to decompose the anhydride. Work up by extraction with ethyl acetate as usual gave a brown oil which was chromatographed on alumina (act. III, 25 g). Elution with hexane-benzene (7:3) gave a trace of non polar material. Benzene-hexane (1:1) yielded the title compound (0.58 g) as a very soluble colourless oil which resisted all attempts at crystallization. This material was homogeneous on t.l.c. on silica gel, alumina and silica gel-silver nitrate. νmax. (film) 1730 cm-1 (CDCl3) 5.50 (1 proton, narrow multiplet, H6), δ5.2-4.6 (2 protons, one broad and one narrow multiplet, H1 and H3 with H1 as a narrow multiplet at δ5.03), 2.00, 1.98, 1.91 (singlets, acetates), 1.40, 1.05, 0.67 (singlets, C26-27, C19, C18 methyls respectively.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([N:26]([CH3:33])[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:50]([Cl:52])[Cl:51]>C(O)(=O)C>[NH3:1].[CH2:50]([Cl:52])[Cl:51].[CH2:19]([N:26]([CH3:33])[CH:27]1[CH2:32][CH2:31][N:30]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)[CH2:29][CH2:28]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(Cc1ccccc1)C1CCNCC1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)C1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Product: N
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (155 mg), benzyl-methyl-piperidin-4-yl-amine (123 mg), and acetic acid (0.11 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (190 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (155 mg). 1H NMR (400 MHz, CDCl3): 7.31-7.28 (m, 4H), 7.24-7.18 (m, 3H), 6.84 (d, J=8.8 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.56 (s, 2H), 3.42 (s, 2H), 2.94 (m, 2H), 2.47 (m, 2H), 2.40 (m, 4H), 2.19 (s, 3H), 2.01-1.88 (m, 4H), 1.77 (m, 2H), 1.67 (m, 2H), 1.59 (m, 4H), 1.44 (m, 2H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)(=O)=O.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[C:36]1(C)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>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(COC)OC>[C:27]1([C:7]2[C:16]3[C:11](=[C:12]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccccc1
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)(Oc1cccc2c(OS(=O)(=O)C(F)(F)F)cccc12)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2cccc3c(-c4ccccc4)cccc23)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
Under an argon gas atmosphere, 49.0 g (106.1 mmol) of 5-{[(trifluoromethyl) sulfonyl]oxy}naphthyl trifluoromethanesulfonate, 28.5 g (233.3 mmol) of phenylboronic acid, 4.90 g (4.24 mmol) of tetrakis(triphenylphosphine)palladium(0), 200 ml of toluene, 100 ml of dimethoxyethane and 320 ml of 2M sodium carbonate solution were mixed, and stirred for 24 hours at 90 degrees C. After the reaction in the mixture was over, the mixture experienced filtration, through which aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, the solvent was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 18.0 g of 1.5-diphenylnaphthalene was obtained with an yield of 60%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:19][C@@H:20]([CH:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:30])[C:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22].C(N[C@H](C(O)=O)[C@@H](C)OC(C)(C)C)(OC(C)(C)C)=O.N1CCOCC1>C(Cl)(Cl)Cl.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:19][C@@H:20]([CH:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:30])[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(OC(C)(C)C)[C@H](N)C(=O)N1CCOCC1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1COCCN1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(OC(C)(C)C)[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)N1CCOCC1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and 4-[(S)-2-amino-3-tert-butoxybutyryl]-morpholine (prepared from N-BOC-O-tert-butyl-L-threonine (Sigma) and morpholine (Aldrich) using General Procedure M, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.1 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 96:4 CHCl3/MeOH as the eluent.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27].CO.Cl>C[O-].[Na+].O>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][CH2:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27])=[O:4]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Yield: 82.6 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (68 mg, 0.23 mmol) and 3-amino-2,2-dimethyl-propionic acid (81 mg, 0.69 mmol) (ChemBridge) in 0.5 N NaOMe in MeOH solution (0.92 mL, 0.46 mmol) was microwaved at 120° C. for 1 h. Reaction mixture was diluted with water (50 mL) and acidified by 1 N HCl solution to pH=3-4. Precipitate was collected and rinsed with water and dried in vacuo to provide the title compound (71 mg, 0.19 mmol) as an off-white solid in 81% yield. LC-MS ESI−: 379.04 (M−1)−.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[O:10])[CH2:5][CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[C:22]([O:1][N:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[O:10])[CH2:5][CH2:4]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCc2cc(C(=O)N3CCC(=NO)CC3)ccc2N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)ON=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 Grams of 6-(4-hydroxyimino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril, 11.4 ml of acetic anhydride and 31.8 ml of triethylamine in 300 ml of methylene chloride solution were mixed together and stirred at room temperature overnight. The reaction mixture was poured into ice-water, and extracted with chloroform. The chloroform extract was dried with anhydrous sodium carbonate, then the solvent was removed by evaporation to yield 16.5 g of 6-(4-acetyloxyimino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.
Reaction SMILES: O=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:4]2[CH:13]=[N:14][NH:15][C:3]1=2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(=O)c2[nH]ncc2[nH]1
Product: CCOC(=O)c1cc(Cl)c2[nH]ncc2n1
Yield: 83 %

Procedure:
Ethyl 4,7-dihydro-7-oxo-1H-pyrazolo[4,3-b]pyridine-5-carboxylate (5.0 g, 24 mmol) was heated under reflux in phosphoryl chloride (50 ml) for 25 min. Excess reagent was removed in vacuo and the residue was treated with water to give a yellow solid. After neutralisation with 10% sodium hydroxide solution, the solid was collected and dried to give the title compound (4.48 g, 83%), m.p. 276°-279° C. after recrystallisation from ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:20][O:21][CH2:22][C@H:23](O)[CH2:24][CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[CH3:20][O:21][CH2:22][C@@H:23]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH2:24][CH3:25]
Reactant: CC[C@@H](O)COC
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: 10 °C
Reaction time: 16 h
Yield: 68.6 %

Procedure:
A stirred solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (7.5 g, 29 mmol), (R)-1-methoxy-butan-2-ol (3.76 g, 36.25 mmol) and triphenylphosphine (9.5 g, 36.25 mmol) in dry THF (75 mL) was cooled in an ice-bath and a solution of 40% DEAD in toluene (15.8 mL, 36.25 mmol) was added dropwise over 30 minutes. The reaction mixture was allowed to warm slowly to 10° C. and stirred for 16 hours. The THF was evaporated and the residue was dissolved in 30% ethyl acetate in isohexane and cooled in ice. The resultant precipitate was removed by filtration and washed with 10% ethyl acetate in isohexane. The filtrate was evaporated and purified by column chromatography, eluting with 10% ethyl acetate in isohexane, to give the title compound as a colourless oil (6.85 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[Cl:18])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(NC(=O)c2ccnc(N3CCOCC3)c2)ccc1Cl
Reactant: O=C(Cl)c1ccnc(Cl)c1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
Using an analogous procedure to that described in Example 2, except that the reaction mixture was heated to 80° C. for 5 hours, 2-chloropyridine-4-carbonyl chloride was reacted with N-(3-amino-4-chlorophenyl)-2-morpholinopyridine-4-carboxamide to give the title compound in 95% yield; NMR Spectrum: (DMSOd6) 3.53 (m, 4H), 3.75 (m, 4H), 7.11 (d, 1H), 7.27 (s, 1H), 7.56 (d, 1H), 7.73 (d, 1H), 7.88 (d, 1H), 7.98 (s, 1H), 8.06 (s, 1H), 8.26 (d, 1H), 8.64 (d, 1H), 10.53 (m, 2H); Mass Spectrum: M+H+ 472.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1>[C:17]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1)(=[O:19])[CH3:18]
Reactant: OC[C@H]1CC[C@H](O)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of trans-4-(hydroxymethyl)cyclohexanol (1.8 g, 14 mmol, Tetrahedron Lett. 1970, 11, 4281-4284.), triethylamine (2.4 mL, 17 mmol), and N,N-dimethylaminopyridine (0.34 g, 3.0 mmol) in tetrahydrofuran (70 mL) was added acetic anhydride (1.4 mL, 15 mmol) at room temperature. After being stirred at room temperature for 48 h, the mixture was concentrated in vacuo to give an oil. The residual oil was extracted with ethyl acetate (100 mL). The organic layer was washed with successively 2N hydrochloric acid, aq. sodium hydrogencarbonate, and brine. The extract was dried over magnesium sulfate and concentrated in vacuo give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 1:1 to 1:2) to give 1.2 g (50%) the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@@H:4]1[C@@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6][NH:5]1.[OH-:12].[Na+].[CH3:14][OH:15]>>[CH3:1][O:2][C:3](=[O:11])[C@@H:4]1[C@H:8]([CH2:9][CH3:10])[CH2:7][CH2:6][N:5]1[C:14]([O:15][C:8]([CH3:9])([CH3:4])[CH3:7])=[O:12]
Reactant: CO
Reactant: [OH-]
Reactant: CC[C@H]1CCN[C@@H]1C(=O)OC
Agent: [Na+]
Product: CC[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)OC
Temperature: 0 °C
Reaction time: 20 h

Procedure:
N-[(tert Butyloxy)carbonyl]-cis, trans-3-ethylproline methyl ester (29.1 g, 0.113 mol) was dissolved in CH3OH (114 mL) with cooling to 0° C., then treated with 1N NaOH (114 mL). After stirring for 20 h at 23° C., the solution was concentrated to remove the CH3OH and then extracted with EtOAc (3×). The organic layers were combined, dried (MgSO4), filtered, and concentrated to give 12.8 g of N-[(tert-Butyloxy)carbonyl]-cis-3-ethylproline methyl ester as an oil. The aqueous layer was acidified with solid citric acid and extracted with EtOAc (2×), the organic layers combined, dried (MgSO4), filtered, and concentrated to give N-[(tert Butyloxy)carbonyl]-trans 3-ethylproline as an oil. 1H NMR (CD3OD) δ3.86 and 3.78 (2 d, 1H, J=6 Hz), 3.33-3.58 (m, 2H), 2.01-2.22 (m, 2H), 1.5-1.74 (m, 2H), 1.33-1.5 (m, 1H), 1.45 and 1.42 (2 s, 9H), 0.98 (t, 3H, J=8 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C:6]2[C:8]3[C:13]([CH2:14][CH2:15][CH3:16])=CC(=O)O[C:9]=3[C:18]([C:21](=[O:24])[CH2:22][CH3:23])=[C:19]([OH:20])[C:5]=2[CH:4]=[CH:3]1.[CH2:26](OC(OCC)C)[CH3:27].F[C:35](F)(F)[C:36]([OH:38])=[O:37]>C(OCC)(=O)C>[CH3:16][CH2:15][CH2:14][C:13]1[C:8]2[C:6]3[O:7][C:2]([CH3:1])([CH3:25])[CH:3]=[CH:4][C:5]=3[C:19]3[O:20][C@H:26]([CH3:27])[C@@H:22]([CH3:23])[C:21](=[O:24])[C:18]=3[C:9]=2[O:38][C:36](=[O:37])[CH:35]=1
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(C)OCC
Solvent: CCOC(C)=O
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@H](C)[C@@H](C)C3=O
Temperature: 140 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
A solution containing chromene 4 (344 mg, 1.0 mmol), acetaldehyde diethylacetal (473 mg, 4.0 mmol), trifluoroacetic acid (1.5 mL, 19.4 mmol) and anhydrous pryidine (0.7 mL) was heated at 140° C. under N2. The reaction was monitored by TLC analysis. After 4 hours, the reaction mixture was cooled to room temperature, diluted with ehtyl acetate and washed several times with 10% aqueous NaHCO3 and brine. The organic layer was separated and dried over Na2SO4. The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography eluting with ethyl acetate/hexane (2:3). Chromanone 7 (10,11-trans-dihydro-6,6,10,11-tetramethyl-4-propyl-2H,6H,12H-benzo[1,2-b:3,4-b':5,6-b"]-tripyran-2,12-dione) (110 mg, 30% yield) was obtained m.p. 176~177° C. (Lit.5 130~132° C.). 1H-NMR5 (CDCl3) δ 1.02 (3H, t, J=7.5 Hz, CH3); 1.21 (3H, d, J=6.8 Hz, CH3); 1.51 (3H, d, J=7.0 Hz, CH3); 1.55 (6H, 2s, 2 CH3); 1.63 (2H, sextet, J=7.0 Hz, CH2); 2.55 (1H, dq, J=6.9 Hz, J=11.0 Hz, H11); 2.88 (2H, t, J=7.6 Hz, CH2); 4.28 (1H, dq, J=6.3 Hz, J=11.0 Hz, H10); 5.60 (1H, d, J=9.9 Hz, H8); 6.04 (1H, s, H3); 6.65 (1H, d, J=11.8 Hz, H7); MS (CI): 369 (100, M+1).
Reaction SMILES: [CH:1]([CH:14]1[N:18]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]([N-]C(C)C)(C)C.[Li+].[O:41]1[CH2:45][CH2:44][CH2:43]C1>>[CH:1]([CH:14]1[N:18]([CH:19]([CH:45]([OH:41])[CH:44]([CH3:33])[CH3:43])[C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16][O:15]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1CCOC1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)CN1C(c2ccccc2)COC1C(c1ccccc1)c1ccccc1
Agent: [Li+]
Product: CC(C)C(O)C(C(=O)OC(C)(C)C)N1C(c2ccccc2)COC1C(c1ccccc1)c1ccccc1

Procedure:
Scheme 4 and 5 show routes for preparation of compound of formula 2b. The protected amino acid is either commercially available material or prepared as described in known literature. For example, the CBZ protected (2S,3S)-hydroxyleucine (CBZ: benzyloxycarbonyl) is prepared according to the analogous procedure to that described in the literature (Panek, J., J. Org. Chem., 1998, 63, 2382). As shown in scheme 4, phenylglycinol is alkylated with tert-butyl bromoacetate in the presence of base such as triethylamine in a solvent such as anhydrous tetrahydrofuran, to provide tert-butyl (2-hydroxy-1-phenyl-ethylamino)-acetate. Reaction of tert-butyl (2-hydroxy-1-phenyl-ethylamino)-acetate and diphenylacetaldehyde in the presence of a drying agent such as magnesium sulfate in a solvent such as anhydrous methylene chloride provides tert-butyl (2-benzhydryl-4-phenyl-oxazolidin-3-yl)-acetate. The oxazolidine is treated with a nucleophile such as lithium diisopropylamide in an anhydrous solvent such as anhydrous tetrahydrofuran at low temperature such as −78° C., followed by addition of an electrophile such as isopropylaldehyde, to provide tert-butyl 2-(2-benzhydryl-4-phenyl-oxazolidin-3-yl)-3-hydroxy-4-methyl-pentanoate. The oxazolidine ring is cleaved by treatment with acid such as formic acid in a solvent such as a mixture of water and tetrahydrofuran to provide tert-butyl 3-hydroxy-2-(-2-hydroxy-1-phenyl-ethylamino)-4-methyl-pentanoate. The amine is freed by hydrogenolysis using catalyst such as 5-10% palladium on carbon in a solvent such as methanol or ethanol, to provide tert-butyl 2-amino-3-hydroxy-4-methyl-pentanoate. The resulting free amine is protected by treatment with an agent such as (benzyloxycarbonyloxy)succinimide or benzyloxycarbonyl chloride in a solvent such as anhydrous methylene chloride, then the ester is cleaved by treatment with an acid such as trifluoroacetic acid to provide 2-{[(benzyloxy)carbonyl]-amino}-3-hydroxy-4-methylpentanoic acid. Optically pure compound can be prepared by using an optically pure starting material. For example, optically pure (S)-phenylglycinol provides (2S,3S)-2-{[(benzyloxy)carbonyl]-amino}-3-hydroxy-4-methylpentanoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:22](=[O:25])(=[O:24])[NH2:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:5]([OH:7])=[O:6].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH2:34](O)[CH3:35]>>[CH2:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:22](=[O:24])(=[O:25])[NH2:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=1)[C:5]([O:7][CH2:34][CH3:35])=[O:6])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCO
Reactant: BrCc1ccccc1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1cc(NCc2ccccc2)c(Oc2cccc(C(F)(F)F)c2)c(S(N)(=O)=O)c1

Procedure:
A mixture of 3-amino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoic acid (1.82 g), benzyl bromide (2 g), and anhydrous ethanol (15 ml) was refluxed for 7 hours. The soluton was cooled, and the precipitated ethyl 3-benzylamino-5-sulphamyl-4-(m-trifluoromethylphenoxy)-benzoate was collected by suction. After recrystallization from ethanol, the melting pont was 166°-168°C.