Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH:31]([O:33][CH2:34][CH3:35])=[CH2:32]>C(OCC)=C.C(OCC)(=O)C>[CH2:31]([O:33][CH:34]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2)[CH3:35])[CH3:32]
Reactant: O=Cc1ccc2cc(O)ccc2c1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: CCOC(C)Oc1ccc2cc(C=O)ccc2c1
Temperature: 25 °C
Yield: 73 %

Procedure:
In a 500 mL three neck flask, equipped with a magnetic stirrer, an addition funnel, and a reflux condenser, were charged 25 g of HNAL (0.1462 mol) and 300 mL of ethyl acetate. 6-Hydroxy-2-naphthaldeyde was not completely soluble even after 3 h stirring at room temperature. To this was added 3.30 g of PPTS (0.0131 mol) and the solution mixture was heated to 70° C. At this temperature, 21 g of ethyl vinyl ether (0.2912 mol) was added dropwise and the reaction mixture became homogeneous upon addition of a few drops of ethyl vinyl ether. After completion of ethyl vinyl ether addition, the reaction temperature was lowered to room temperature and the reaction mixture was stirred overnight. The crude product was purified by column chromatography (silica gel, CH2Cl2) to yield 26 g of pure 6-(1-ethoxy ethoxy)-2-naphthaldehyde (yield: 73%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:12](=[O:26])[CH2:13][N:14]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:15])[CH3:11])=[CH:6][CH:5]=1.CO>C1COCC1>[CH2:19]([O:18][C:16](=[O:17])[N:14]([CH2:13][C:12](=[O:26])[N:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1)[CH3:11])[CH3:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(N(C)C(=O)CN(C)C(=O)OCc2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CN(CC(=O)N(C)c1ccc(CO)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
Under argon 742.7 mg (32.4 mmol, 1.5 eq) lithium borhydride in 35 ml THF were added dropwise to 8 g (21.6 mmol) 4-[[(Benzyloxycarbonyl-methyl-amino)-acetyl]-methyl-amino]-benzoic acid methyl ester in 100 ml THF at RT. The suspension was stirred at RT over night, heated to 50° C. for 3.25 h, recooled to RT and 21 ml MeOH were added slowly. The solution was added to ice water, extracted with ether (3×), the combined organic layers were washed with water, dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel with a gradient of CH2Cl2/MeOH (100:0-99.9:0.1) yielding 3.9 g (52%) {[(4-Hydroxymethyl-phenyl)-methyl-carbamoyl]-methyl}-methyl-carbamic acid benzyl ester as yellow oil (Rf 0.4 CH2Cl2:MeOH 9:1), MS: 343 (MH+).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1.[Cl:23]CCl.FC(F)(F)C(O)=O>CS(C)=O>[ClH:23].[CH:3]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][N:17]=1)=[O:2]
Reactant: COC(OC)c1ccncc1OCc1ccc(C(=O)O)cn1
Reactant: ClCCl
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=Cc1ccncc1OCc1ccc(C(=O)O)cn1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Into an 8-mL vial, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-3-carboxylic acid (100 mg, 0.33 mmol, 1.00 equiv) in a solvent mixture of dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The resulting solution was stirred for 3 h at 40° C., and then it was concentrated under vacuum. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water (0.05% HCl) and MeCN (10.0% MeCN up to 40.0% in 3 min, up to 100.0% in 2 min, down to 10.0% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 30 mg (31%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]pyridine-3-carboxylic acid hydrochloride as a white solid. The compound exhibited a melting point of 192-194° C. LC-MS-PH-GBT-ZL-HS-14-0: (ES, m/z):259 [M+1]+/277 [M+1+18]+. 1H-NMR-PH-GBT-ZL-HS-14-0: (300 MHz, DMSO, ppm): 13.42 (s, 1H), 10.48 (s, 1H), 9.03 (s, 1H), 8.74 (s, 1H), 8.40 (d, J=4.8 Hz, 1H), 8.30 (dd, J=8.1 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.57 (d, J=4.8 Hz, 1H), 5.55 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C@@H:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.O.[OH-].[Li+]>C1COCC1.O.CCOCC>[CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C@@H:14]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCC[C@@H](COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCC[C@@H](COc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
The ester (1 g), dissolved in 20 ml THF/5 ml H2O/5 ml methanol, was treated with 380 mg of lithium hydroxide hydrate. The mixture was stirred at room temperature 4 hours. The mixture was diluted with 50 ml water and acidified to pH 2 with 1N hydrochloric. The resulting suspension was taken in 100 ml ether and the phases were separated. The aqueous phase was extracted with three portions of 50 ml ether. The combined extracts were dried over MgSO4. The solvent was removed in vacuo and the crude product was purified recrystalization from acetonitrile/water, yielding 796 mg of product as shining platelets. M.p. 74-76° C., [α]D=−22.2 (c=0.500, in CHCl3).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[SH-:10].[Na+]>CO>[NH2:8][C:7]1[C:6]([SH:10])=[N:5][CH:4]=[N:3][C:2]=1[Cl:1]
Reactant: [SH-]
Reactant: Nc1c(Cl)ncnc1Cl
Agent: [Na+]
Solvent: CO
Product: Nc1c(S)ncnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4,6-dichloropyrimidine-5-amine (E-2) (16.0 g, 98.2 mmol) and sodium hydrosulphide (7.15 g, 128 mmol) in MeOH (320 mL) is stirred at reflux for 3 h. The resulting mixture is allowed to cool to RT and then concentrated in vacuo. The residue is poured into aqueous NaOH solution (200 mL, 1 M) and then neutralized with acetic acid to adjust the pH value to 5-6. The resulting mixture is stirred at RT for 30 min. The solid is collected by filtration, rinsed with water (2×50 mL) and dried in vacuo to afford the product, 5-amino-6-chloropyrimidine-4-thiol (E-3).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[O:15].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:13]/[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[O:15])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: COc1cccc(C(C)=O)c1
Reactant: CCCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.1 %

Procedure:
To a stirred solution of 4-propoxybenzaldehyde (1 g, 6.09 mmol) and 3-methoxyacetophenone (0.91 g, 6.09 mmol) in methanol (30 ml) was added 50% w/v solution of aqueous sodium hydroxide (9.7 ml, 0.122 mol). The reaction mixture was stirred at room temperature for 24 h. A precipitate was isolated by filtration, washed with cold methanol and subsequently recrystallised from methanol to afford 0.38 g (21%) of pale yellow crystals. 1H-NMR δ (CDCl3), 1.6 (t, 3H), 1.85 (m, 2H), 3.9 (s, 2H), 3.95 (t, 2H), 6.9 (d, 2H), 7.1 (1H), 7.38 (m, 2H), 7.55 (m, 4H), 7.8 (d, 1H). 13C-NMR (CDCl3) δ 190.3, 161.3, 159.9, 139.9, 127.4, 69.6, 22.5. Mass Spectrum m/e (M+1) 297. Anal. Calcd. for C19H20O3: C, 77.00; H, 6.80. Found C, 76.86; H, 6.94.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[C:12]=2[N:19]([C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH2:35].C[N+]1([O-])CC[O:40]CC1>CC(C)=O.O=[Os](=O)(=O)=O>[OH:35][CH:2]([CH2:3][OH:40])[CH2:1][C:4]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[C:12]=2[N:19]([C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH2:5][CH2:6]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=CCC1(S(=O)(=O)Nc2ccc(=O)n(C)c2N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: Cn1c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)c(NS(=O)(=O)C2(CC(O)CO)CC2)ccc1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a solution of tert-butyl (3-{[(1-allylcyclopropyl)sulfonyl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)(2-fluoro-4-iodophenyl)carbamate (180 mg, 0.298 mmol) in acetone (20 ml) was added water (3 ml). The mixture was cooled to 0° C. and 4-methylmorpholine N-Oxide (7.36 eq, 257 mg, 2.195 mmol) was added, followed by OsO4 (2.5% w.t. in t-butanole, 111 μl). The mixture was stirred a room temperature for 18 hours. Since the reaction was not complete, more 4-methylmorpholine N-Oxide (6 eq, 210 mg, 1.790 mmol) was added, followed by OsO4 (2.5% w.t. in t-butanole, 110 μl). The mixture was stirred a room temperature for another 18 hours and then concentrated in vacuo. The residue was diluted in ethyl methyl ketone and washed with water. The aqueouse phase was separated and extracted twice with ethyl methyl ketone. The combined organic layers were washed once with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound (177 mg, 93%).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O[CH:17]([O:19][C:20](=[O:23])[CH:21]=[CH2:22])[CH3:18].[CH2:24](N(CC)CC)C.[CH2:31]([OH:34])[CH2:32][OH:33]>ClCCl>[OH:33][CH2:32][CH2:31][O:34][CH2:22][C:21](=[CH2:24])[C:20]([O:19][CH2:17][CH3:18])=[O:23]
Reactant: CCN(CC)CC
Reactant: C=CC(=O)OC(C)O
Reactant: OCCO
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C=C(COCCO)C(=O)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
To a solution of 32.52 g trifluoromethanesulphonic anhydride in 100 ml dichloromethane a solution of 15 g (0.115 mol) α-hydroxyethylacrylate and 11.66 g (0.115 mol) triethylamine in 200 ml dichloromethane was added slowly, so that the temperature of the reaction mixture stays below 5° C. The solution was added drop wise at room temperature to 210 g (1.127 mol) 1,2-ethandiol. After the reaction mixture was stirred for 12 h at room temperature the solution was successively washed with 1×200 ml water, 2×250 ml of an aqueous sodium carbonate solution (25 wt %) and 1×200 ml water. The organic layer was dried over magnesium sulphate and filtered. After the evaporation of the solvent the oily raw product was stabilized with 15 mg BHT and purified by vacuum distillation (63° C./0.032 mbar). This afforded 10.12 g (yield: 50%) of a clear, colorless oil.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[N+:6]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[C:18]([CH:19]=O)=[C:17]([Cl:21])[N:16]=[C:15]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH2:28]1[CH2:32]OC[CH2:29]1>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[N+:6]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[C:18]([CH:19]=[CH:5][C:4]3[CH:32]=[CH:28][CH:29]=[CH:2][CH:3]=3)=[C:17]([Cl:21])[N:16]=[C:15]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: C1CCOC1
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc([N+](=O)[O-])cc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nc(Cl)c(C=Cc2ccccc2)n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.4 g of benzyltriphenylphosphonium chloride in 20 mL of dried THF was cooled to -30°. To the above solution was added 0.65 mL of 1.6M n-BuLi dropwise. As the BuLi was added the solution turned to deep orange color. After stirring for 10 min. at -30°, 0.32 g of 1-(4-nitrobenzyl)-2-butyl-4-chloroimidazole-5-aldehyde was added and the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 2 hours. The reaction mixture was quenched with 2 mL of saturated NH4Cl solution and diluted with ethyl acetate, and the ethyl acetate solution was washed with water and a brine solution. Evaporation gave a thick oily residue which was purified by the flash silica gel column chromatography (hexane:ethyl acetate=3:1 elution) to give a thick yellow oil, 0.39 g.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:11]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:57]#[N:58])[C:12]2[C:17]([C:18]=1[CH2:19][N:20]1[C:31](=[O:32])[C@@H:30]([NH:33][C:34](=[O:46])[C@@H:35]([N:37](C)[C:38](=O)OC(C)(C)C)[CH3:36])[C:24]3([CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[O:23][C:22]3[CH:47]=[CH:48][CH:49]=[CH:50][C:21]1=3)=[CH:16][CH:15]=[CH:14][CH:13]=2)#[N:9].C([O-])(O)=O.[Na+].O>C(Cl)Cl>[C:8]([C:10]1[N:11]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:57]#[N:58])[C:12]2[C:17]([C:18]=1[CH2:19][N:20]1[C:31](=[O:32])[C@@H:30]([NH:33][C:34](=[O:46])[C@@H:35]([NH:37][CH3:38])[CH3:36])[C:24]3([CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[O:23][C:22]3[CH:47]=[CH:48][CH:49]=[CH:50][C:21]1=3)=[CH:16][CH:15]=[CH:14][CH:13]=2)#[N:9]
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C#N)n(-c3ccccc3C#N)c3ccccc23)c2ccccc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C#N)n(-c3ccccc3C#N)c3ccccc23)c2ccccc2OC12CCOCC2
Yield: 99.4 %

Procedure:
TFA (37.0 g, 25 mL, 324 mmol, Eq: 55.9) was added dropwise over 2 h to a solution of tert-butyl (S)-1-((S)-5-((2-cyano-1-(2-cyanophenyl)-1H-indol-3-yl)methyl)-4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (4 g, 5.81 mmol) in DCM (50 mL) at 0° C. After 30 min. the mixture was added to sat. NaHCO3/H2O 1:1, the organic phase was separated, dried over Na2SO4, filtered and concentration to give the title compound (3.4 g, 97%) as a light yellow solid. MS m/z 589 (MH+)
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@H:8]1[C@H:21]([OH:22])[C@@H:20]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19][C@@H:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C@@H:9]1[N:32]=[N+:33]=[N-:34])=[O:6])[CH:2]=[CH2:3].N1C=NN=N1.C(N(CC)[P:43]1[O:49][CH2:48][C:47]2[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=2[CH2:45][O:44]1)C.C1C=C(Cl)C=C(C(OO)=[O:64])C=1>C(Cl)Cl>[CH2:1]([O:4][C:5]([O:7][C@H:8]1[C@H:21]([O:22][P:43]2(=[O:64])[O:44][CH2:45][C:46]3[CH:53]=[CH:52][CH:51]=[CH:50][C:47]=3[CH2:48][O:49]2)[C@@H:20]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19][C@@H:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])[C@@H:9]1[N:32]=[N+:33]=[N-:34])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H]1[C@H](O)[C@@H](COCc2ccccc2)O[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1N=[N+]=[N-]
Reactant: CCN(CC)P1OCc2ccccc2CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: C=CCOC(=O)O[C@@H]1[C@@H](N=[N+]=[N-])[C@H](O[Si](C)(C)C(C)(C)C)O[C@H](COCc2ccccc2)[C@H]1OP1(=O)OCc2ccccc2CO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a solution of compound 9 (1.30 g, 2.50 mmol) and 1H-tetrazole (3% wt, 10.0 mmol) in DCM (30 mL) was added N,N-diethyl-1,5-dihydro-3H-2,4,3-benzodioxaphosphepin-3-amine (1.20 g, 1.05 mmol). After the reaction mixture was stirred at room temperature for 15 min, it was cooled (−20° C.), stirred for another 10 min and then mCPBA (3.40 g, 50-55% wt, 10.0 mmol) was added. The reaction mixture was stirred at −20° C. for 20 min, and then quenched by the addition of saturated aqueous NaHCO3 (40 mL) and diluted with DCM (30 mL). The organic phase was washed with saturated aqueous NaHCO3 (2×60 mL) and brine (2×40 mL), dried (MgSO4) and filtered. Next, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, 5/1-3/1, v/v) to give 10 as a pale yellow oil (1.48 g, 89%). Rf=0.40 (hexane/ethyl acetate, 1/1, v/v). [α]25D=−10.3° (c=1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.35-7.15 (m, 9H, aromatic), 5.98-5.85 (m, 1H, OCH2CH═CH2), 5.65 (d, 1H, J=1.2 Hz, J=17.4 Hz, OCH2CH═CH2), 5.50 (d, 1H, J=1.2 Hz, J=10.5 Hz, OCH2CH═CH2), 5.18-5.01 (m, 4H, C6H4(CH2O)P), 3.81 (dd, 1H, J2,3=10.5 Hz, J3,4=9.3 Hz, H-3), 4.64-4.52 (m, 6H, H-1, H-4, OCH2CH═CH2, CH2Ph), 3.82 (d, 1H, J6a,6b=9.0 Hz, H-6a), 3.72-3.61 (m, 2H, H-5, H-6b), 3.41 (dd, 1H, J1,2=7.4 Hz, J2,3=10.5 Hz, H-2), 0.92 (s, 9H, SiC(CH3)3), 0.16 (s, 3H, Si(CH3)), 0.15 (s, 3H, Si(CH3)). 13C NMR (75 MHz, CDCl3): δ 154.38 (C═O), 138.02-127.56 (aromatic), 131.33 (OCH2CH═CH2), 118.99 (OCH2CH═CH2), 97.13 (C-1), 76.77 (C-3), 74.27 (C-4), 74.08 (C-5), 73.50 (CH2Ph), 69.06 (OCH2CH═CH2), 68.74 (C-6), 68.55 (OC6H4(CH2O)P), 68.50 (OC6H4(CH2O)P), 65.97 (C-2), 25.53 (SiC(CH3)3), 17.92 (SiC(CH3)3), −4:35 (Si(CH3)2), −5.28 (Si(CH3)2). HR MS (m/z) calculated for C31H42N3O10PSi[M+Na]+, 698.2275; found, 698.2315.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(C)C=CC=CC=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.O.C(O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(-c3ccccc3)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Yield: 87.2 %

Procedure:
A mixture of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), phenylboronic acid (100 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg), toluene (6 ml), ethanol (0.8 ml) and 2M aqueous sodium carbonate solution (0.8 ml) was heated under reflux under a nitrogen atmosphere for 6 hrs. To the reaction mixture were further added dihydroxyphenylborane (100 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg), ethanol (0.8 ml) and 2M aqueous sodium carbonate solution (0.8 ml), and the mixture was heated under reflux for 6 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (260 mg).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.O[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][C:14]=1[C:23](=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([CH:7]3[CH:24]([C:25]([O:27][CH3:28])=[O:26])[C:23](=[O:29])[C:14]4[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH:20]([CH3:22])[CH3:21])[CH:15]=4)[O:8]3)=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)CC(=O)c1cc(OC(C)C)ccc1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1C(=O)c2cc(OC(C)C)ccc2OC1c1ccc2c(c1)OCO2
Temperature: 0 °C

Procedure:
A solution of piperonal (182.4 g, 1.22 mol) in toluene (1 L) was heated to reflux in a flask equipped with a Dean Stark dehydration apparatus to which a mixture of methyl 3-(2-hydroxy-5-isopropoxy-phenyl)-3-oxo-propionate (VIII-2) (151 g, 0.61 mol) synthesized by the method described in Reference Example 4, piperidine (1.55 g, 0,018 mol), acetic acid (3.65 g, 0.061 mol) in toluene (1.3 L) was added dropwise over a period of 1 h and the solution was refluxed for another 1 h. After cooling, the reaction mixture was poured into ice water (3 L) and extracted with toluene. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was treated with Girard T reagent (143 g) in methanol (500 ml) and toluene (2 L) for 2 h. Brine (3.5 L) was added and the organic layer was separated and the aqueous layer was further extracted with toluene. The combined organic layers were washed with water, dried, and concentrated. The residue was subjected to a chromatographed on silica gel (toluene). During the elution, the products gradually cyclized to give compound (IV-2) (102 g, 44%) as an oil. The oil was clarified a keto-enol tautomeric mixture as shown by NMR. NMR(CDCl3):1.3 l(d, J=6.0), 1.32*(d, J=6.2), 3.67*(s), 3.76(s), 4.02*(d, J=12.0), 4.46(m), 4.53*(m), 5.55*(d, J=12.0), 5.91*(s), 6.00(s),6.10(s), 6.67-7.36(m) (* are signals derived from a major product)
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH:17]([CH3:19])[C:16](=O)[C:15]([CH3:23])([CH2:21][CH3:22])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:25].[Na+]>CO>[NH2:25][CH:16]1[CH:17]([CH3:19])[CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][C:15]1([CH3:23])[CH2:21][CH3:22]
Reactant: [BH3-]C#N
Reactant: CCC1(C)CN(Cc2ccccc2)CC(C)C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC1(C)CN(Cc2ccccc2)CC(C)C1N
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Ammonium acetate (2.5 g, 32.46 mmol) was added to the stirred solution of 1-benzyl-3,5-dimethyl-3-ethyl-4-piperidone (3.0 g, 12.25 mmol) in methanol (40 ml) and stirring was continued for 20 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.8 g, 12.7 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 20 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 2) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH 9) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,5-dimethyl-3-ethylpiperidine. Yield 2.2 g (73%), C16H26N2, m/z 247 (M+1).