Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(N(C(C)C)C(C)C)C>CN(C1C=CN=CC=1)C.ClCCl.O>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:38]2[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]2)=[N:11][CH:10]=1)=[O:23]
Reactant: OC1CCNCC1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(N2CCC(O)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 70 h
Yield: 79.6 %

Procedure:
A mixture of 10.0 g (20.5 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide, 3.1 g (31 mmol) 4-hydroxypiperidine, 10.6 ml (62 mmol) N-ethyldiisopropylamine and 0.13 g (1.0 mmol) 4-(N,N-dimethylamino)-pyridine was stirred at 140° C. for 70 h. After cooling to room temperature the residue was dissolved in a mixture of dichloromethane and water. The layers were separated and the aqueous layer was extracted with four portions of dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated to give 11.1 g of crude product. Flash chromatography afforded 9.0 g (80%) of the title compound as a white solid. MS m/e (%): 552 (M+H+, 100), M.p. 150-152°C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:20][C:21]1[S:25][C:24]([CH:26]=O)=[CH:23][CH:22]=1>[OH-].[K+].CCO>[Cl:20][C:21]1[S:25][C:24]([CH:26]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)s2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 77.7 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.25 g, 0.98 mmol) was reacted with 5-chlorothiophene-2-carboxaldehyde (0.215 g, 1.47 mmol) in 5 mL of 4% KOH in EtOH to afford 0.293 g (77%) of the title compound as a coarse cream solid, mp 143-144° C.: APCI-MS m/e 385.5 M++1);
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:59]([O:66][C:67]1[CH:68]=[C:69]([C:73]2[C:85]3[C:84]4[C:79](=[CH:80][CH:81]=[CH:82][CH:83]=4)[NH:78][C:77]=3[CH:76]=[CH:75][CH:74]=2)[CH:70]=[N:71][CH:72]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:59]([O:66][C:67]1[CH:68]=[C:69]([C:73]2[C:85]3[C:84]4[C:79](=[CH:80][CH:81]=[CH:82][CH:83]=4)[N:78]([C:2]4[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=4)[C:77]=3[CH:76]=[CH:75][CH:74]=2)[CH:70]=[N:71][CH:72]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: c1ccc(COc2cncc(-c3cccc4[nH]c5ccccc5c34)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: N#Cc1ccc(-n2c3ccccc3c3c(-c4cncc(OCc5ccccc5)c4)cccc32)cc1F
Temperature: 25 °C
Yield: 64.6 %

Procedure:
1.08 g of 4-bromo-2-fluorobenzonitrile, 4.48 g of caesium carbonate, 0.25 g of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and 0.08 g of palladium acetate are successively added, under argon, to a solution of 1.27 g of 4-[5-(benzyloxy)pyridin-3-yl]-9H-carbazole in 100 ml of dioxane. The reaction mixture is refluxed for 2 and a half hours, cooled to ambient temperature, filtered through celite and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (80/20 by volume), so as to give 1.1 g of 4-{4-[5-(benzyloxy)pyridin-3-yl]-9H-carbazol-9-yl}-2-fluorobenzonitrile in the form of a colourless oil, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=3[CH2:26][CH2:27][O:28]C)=[CH:16][CH:17]=2)[NH:12][N:11]=1.B(Br)(Br)Br>CCOC(C)=O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=3[CH2:26][CH2:27][OH:28])=[CH:16][CH:17]=2)[NH:12][N:11]=1
Reactant: COCCc1cc(O)ccc1-c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Product: OCCc1cc(O)ccc1-c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
3-1H-Benzoimidazol-2-yl-6-(2-(2-methoxyethyl)-4-hydroxyphenyl)-1H-indazole, from Example 24(i), (99 mg, 0.26 mmol) was dissolved in EtOAc (20 mL) and cooled to −78° C. under argon. Boron tribromide was added dropwise, and the reaction was allowed to stir while warming to r.t over 3 h. The solution was diluted with EtOAc (60 mL) and washed with sat NaHCO3 and brine (20 mL each). Organics were dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (THF) gave 56 mg (59%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.60 (s, 1H), 13.01 (s, 1H), 9.41 (s, 1H), 8.49 (d, 1H, J=8.4 Hz), 7.71 (br s, 1H), 7.51 (br s, 1H), 7.46 (s, 1H), 7.21 (app d, 3H, J=8.1 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.77 (d, 1H, J=2.1 Hz), 6.69 (dd, 1H, J=8.1, 2.1 Hz), 4.57 (br s, 1H), 3.46 (t, 2H, J=7.2 Hz), 2.68 (t, 2H, J=7.2 Hz). MS (ES) [m+H]/z calc'd 371. found 371. [m−H]/z calc'd 369. found 369.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28]([CH2:32][CH:33]=[O:34])([CH3:31])[CH:27]=1.C1(C=CC=C(O)C=1)[OH:36].Cl([O-])=O.[Na+].Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28]([CH2:32][C:33]([OH:36])=[O:34])([CH3:31])[CH:27]=1
Reactant: Oc1cccc(O)c1
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=CC(C)(CC=O)CC1)C(=O)OC2
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=CC(C)(CC(=O)O)CC1)C(=O)OC2
Reaction time: 0.03 h

Procedure:
The 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-1-methylcyclopent-2-en-1-ylacetaldehyde was dissolved in dioxane (8 mL) and pH 5 buffer (3 mL) and treated with resorcinol (0.10 g). To this mixture was then added sodium chlorite (0.080 g). After 2 minutes, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the combined organic layers were dried over magnesium sulfate. The residue, 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-1-methylcyclopent-2-en-1-ylacetic acid obtained after solvent removal was carried on without further purification.
Reaction SMILES: [CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([O:10][C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H:4]([OH:22])[C@@H:3]([OH:23])[C@H:2]1[NH:24][C@@H]1[C@H](O)[C@@H](O)[C@H](O)C(CO)=C1>[Pt]=O>[CH2:1]1[C@:6]([OH:9])([CH2:7][OH:8])[C@@H:5]([OH:10])[C@H:4]([OH:22])[C@@H:3]([OH:23])[C@H:2]1[NH2:24]
Reactant: OCC1=C[C@H](N[C@H]2C[C@](O)(CO)[C@@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=[Pt]
Product: N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 27.6 %

Procedure:
An aqueous solution (30 mL) of validamycin G (106 mg) was submitted to catalytic reduction at room temperature under atmospheric pressure in the presence of platinum oxide (10 mg). The catalyst was removed by filtration and the filtrate was adsorbed onto a column of Amberlite CG-50 (NH4+ form, 30 mL) followed by washing with water and then elution with 0.5N aqueous ammonia. The eluate was concentrated to dryness under reduced pressure, and the residue was dissolved in 1N sulfuric acid (20 mL) and hydrolyzed at 80° C. for 10 hours. The reaction mixture was neutralized with barium hydroxide and the supernatant obtained by centrifugation was concentrated under reduced pressure. The concentrate was adsorbed onto a column of Amberlite CG-50 (ammonium form, 20 mL) followed by washing with water and then elution with 0.5N aqueous ammonia. The eluate was concentrated under reduced pressure and submitted to column chromatography on Dowex 1×2 (OH- form, 100 mL) followed by elution with water. The eluate fractions were concentrated under reduced pressure and then freeze-dried, to give a white powder of valiolamine (11 mg).
Reaction SMILES: Br[C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][O:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:15][C:14]=1[F:26].[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[F:37].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl>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.O1CCOCC1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=2[CH2:11][O:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:15][C:14]=2[F:26])=[CH:30][C:29]=1[F:37]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: COC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)nsc2Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)nsc2-c2ccc(Cl)c(F)c2)c(F)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(4-[[5-bromo-3-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate (70 mg, 0.15 mmol, 1.00 equiv), (4-chloro-3-fluorophenyl)boronic acid (32 mg, 0.18 mmol, 1.20 equiv), K3PO4 (161 mg, 0.76 mmol, 5.00 equiv), Pd(PPh3)4 (17.3 mg, 0.01 mmol, 0.10 equiv), dioxane (1.5 mL). The resulting solution was stirred for 2 h at 90° C. in an oil bath. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:5). The pH value of the solution was adjusted to 6 with hydrogen chloride (2 mol/L). The resulting mixture was washed with 1×2 mL of H2O. The resulting solution was extracted with 3×2 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC-Plate with ethyl acetate/petroleum ether (1:6). This resulted in 80 mg (98%) of methyl 3-(4-[[5-(4-chloro-3-fluorophenyl)-3-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate as yellow oil.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([OH:16])=[O:15])[O:3]1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](S(O)(=O)=O)=[CH:20][CH:19]=1.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[O:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(O)cc2c1C(CC(=O)OCc1ccccc1)OB2O

Procedure:
To a solution of 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetic acid (400 mg, 1.8 mmol) in 30 mL toluene was added 4-methylbenzenesulfonic acid (68.5 mg, 0.36 mmol) and BnOH (583.8 mg, 5.4 mmol). The reaction mixture was refluxed for 5 h and concentrated to dryness. The residue was dissolved in 20 mL EtOAc and washed with H2O (15 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated to dryness. The residue was used directly in next step reaction without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[O:18])=[CH:10][CH:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]>Cl.CO.[Pt](=O)=O>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[O:18])=[CH:12][CH:13]=2)[C:6]2[CH2:30][CH2:31][CH2:32][CH2:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CCc1nc2c(n1-c1ccc(CCNC(=O)NS(=O)(=O)c3ccc(C)cc3)cc1)CCCC2
Reaction time: 8 h
Yield: 19.3 %

Procedure:
A mixture of 2-Ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl) amino]ethyl}phenyl)-1H-benzimidazole (100 mg, 0.20 mmol) and platinum (IV) oxide (22 mg, 0.096 mmol) in 2 M HCl (10 mL) and CH3OH (2 mL) was stirred for 8 h under hydrogen atmosphere (3 kgf/cm2). The mixture was filtered through a pad of Celite and the filtrate was concentrated. The crude product was purified by TLC with ethyl acetate/ethanol (10:1) to afford 18 mg (14%) of the title compound as colorless solid: MS (ESI) m/z 467 [M+H]+, 465 [M−H]−, 1H-NMR (CDCl3)δ1.15 (3H, t, J=7.6 Hz), 1.78 (2H, br), 2.26 (2H, br), 2.41 (3H, s), 2.55 (2H, q, J=7.6 Hz), 2.65 (2H, br), 2.83 (2H, br), 2.86 (2H, m), 3.49 (2H, m), 6.71 (1H, br), 7.10 (2H, d, J=8.4 Hz), 7.28 (4H, m), 7.79 (2H, d, J=8.2 Hz).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][NH:2]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].Cl>C(#N)C>[CH2:12]([N:7]1[CH2:8][CH2:9][C:10]2[C:1](=[O:11])[NH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]ccc2cnccc12
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1[nH]ccc2c1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a suspension of 2,6-naphthyridin-1(2H)-one (2.04 g, 13.96 mmol) in acetonitrile (35 mL) was added benzylbromide (1.992 mL, 16.75 mmol). The mixture was heated to reflux. After 2 h the mixture was cooled to rt. The solvent was removed under reduced pressure and the residue was dissolved in EtOH (30 mL) and cooled to 0° C. Sodium borohydride (2.64 g, 69.8 mmol) was added portionwise over 30 min and the mixture was warmed to rt as the ice bath melted. After stirring the reaction mixture overnight at rt, the mixture was carefully acidified to pH=3 with 1N HCl and was stirred for 30 minutes at rt. The solution was concentrated under reduced pressure. The residue was neutralized with sat. aq. NaHCO3 and was extracted with dichloromethane (3×150 mL). The organic solution was concentrated under reduced pressure, and the residue was purified by BIOTAGE® flash chromatography using a 0-10% MeOH in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give 6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (2.56 g, 10.65 mmol, 76% yield) as a light-yellow solid. LC/MS: m/z 241.08 (M+H)+, 1.362 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.29 (br. s., 1H) 7.31-7.37 (m, 4H) 7.24-7.30 (m, 1H) 7.12 (d, J=6.41 Hz, 1H) 5.89 (d, J=6.71 Hz, 1H) 3.63 (s, 2H) 3.32 (br. s., 2H) 2.62 (t, J=5.80 Hz, 2H) 2.40 (t, J=5.04 Hz, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=1.[OH:10][C:11]([CH3:44])([CH3:43])[CH2:12][C@@:13]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:18][C:17](=[O:19])[N:16]([C@H:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[CH3:21])[CH2:15][CH2:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:10][C:11]([CH3:43])([CH3:44])[CH2:12][C@@:13]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:18][C:17](=[O:19])[N:16]([C@H:20]([C:22]2[CH:23]=[CH:24][C:25]([C:2]3[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[CH:3]=3)=[CH:26][CH:27]=2)[CH3:21])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cn1ccc(I)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 27.7 %

Procedure:
A mixture of 4-iodo-1-methylpyridin-2(1H)-one (0.909 g, 3.76 mmol), (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (1.5 g, 3.13 mmol), 2 M aq Cs2CO3 (3 mL, 6 mmol), and PdCl2(PPh3)2 (0.201 g, 0.282 mmol) in 1,4-dioxane (15 mL) was refluxed under N2 for 2 hours. The reaction mixture was filtered, and the filtrate was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to obtain the crude compound, which was purified by preparative HPLC and chiral HPLC to obtain (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (399 mg, 28%). LC-MS and 1H NMR (CD3OD) were the same as those of product made by Method 1. The compound was recrystallized using below methods.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.ClCCl.[CH2:22]([O:29][C:30]([NH:32][CH:33]([CH2:44][CH2:45][P:46](OCl)([O:48][CH3:49])=[O:47])[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CCOC(C)=O.CCCCCC>[CH2:22]([O:29][C:30]([NH:32][CH:33]([CH2:44][CH2:45][P:46]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH:3]=1)([O:48][CH3:49])=[O:47])[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCl
Reactant: O=C(Cc1cccc(O)c1)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1cccc(CC(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
Benzyl 3-hydroxyphenylacetate 0.88 g (3.60 mmol) was added to 30 mL of a dry dichloromethane solution containing 3.60 mmol of benzyl 2-(N-benzyloxycarbonylamino)-4-[chloro(methyl)phosphono]butanoate obtained in the same manner as Example 1. After the solution was cooled to 0° C., 0.51 mL (3.60 mmol) of triethylamine was added and stirred at 0° C. for 15 minutes. Thereafter, the temperature was increased and reaction was carried out at 34° C. for 45 minutes. After the completion of the reaction was confirmed by TLC (EtOAc/hexane=1:1), the reaction mixture was vacuum-concentrated and the residue was dissolved in 30 mL of ethyl acetate and the insoluble salt was removed by filtration. The filtrate was vacuum-concentrated, and the crude product was purified by flash column chromatography on neutral silica gel 60 N using a solvent mixture of ethyl acetate and hexane at 4:3 to obtain benzyl 2-(N-benzyloxycarbonylamino)-4-{[3-(benzyloxycarbonylmethyl)phenyl] (methyl)phosphono}butanoate as a colorless oily substance (0.72 g, yield 31%).
Reaction SMILES: C.C(O[C:7]([NH:9][C@H:10]([C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1)CC(C)C)=[O:8])(C)(C)C.[C:25]([NH:35][C@H:36](C(O)=O)[CH2:37][CH:38]([CH3:40])[CH3:39])([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(N[C@H](C(N[C@H](C(O)=O)CC(C)C)=O)CC(C)C)(OCC1C=CC=CC=1)=O>>[CH2:28]([O:27][C:25]([NH:35][C@@H:36]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:7]([NH:9][CH2:10][C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1)=[O:8])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1csc([C@H](CC(C)C)NC(=O)OC(C)(C)C)n1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Product: CCOC(=O)c1csc(CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)n1

Procedure:
Following the procedure of Example 13, except substituting 1-(tert-butoxycarbonyl)amino -1-4-carboethoxythiazol-2-yl)methane for (1S)1-(tert-butoxycarbonyl)amino-1-(4carboethoxythiazol-2-yl)-3-methylbutane, and N-Cbz-L-leucine for N-Cbz-L-leucinyl-L-leucine, the title compound was prepared (0.120 g, 32%). MS (MH+): 434.2.
Reaction SMILES: CC(N(C)C)C(O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(NC1C=CC=CC=1)C.[CH:29]1([CH:35]=[C:36]([N:43]2[CH:47]=[N:46][CH:45]=[N:44]2)[C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.Cl>COC(C)(C)C.O>[CH:29]1(/[CH:35]=[C:36](/[N:43]2[CH:47]=[N:46][CH:45]=[N:44]2)\[CH:37]([OH:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)C(=O)C(=CC1CCCCC1)n1cncn1
Agent: CC(C(O)c1ccccc1)N(C)C
Agent: Cl
Agent: [Al+3]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCNc1ccccc1
Product: CC(C)(C)C(O)/C(=C\C1CCCCC1)n1cncn1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A solution of 628 g (3.5 mols) of the (-)-antipode of N-methyl-ephedrine in 7.5 liters of tert.-butyl methyl ether is added dropwise to a suspension of 133 g (3.5 mols) of lithium aluminum hydride in 1.5 liters of tert.-butyl methyl ether in the course of 45 minutes at 20° C. under an argon atmosphere. Stirring is continued for 30 minutes at 40° C., after which the mixture is cooled to 10° C., and 848 g (7 mols) of N-ethyl-aniline are added in the course of 45 minutes. The mixture is stirred for a further hour at 40° C. and then cooled to -15° C., and a solution of 522 g (2 mols) of the (E)-isomer of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one in 4.7 liters of tert.-butyl methyl ether is then added dropwise in the course of 30 minutes, the temperature of the reaction mixture being kept at -10° C. to -15° C. The mixture is stirred for a further 16 hours at -15° C., and 8 liters of water are then added slowly. 3.5 liters of 10% strength aqueous hydrochloric acid are added to the resulting reaction mixture. Thereafter, the organic phase is separated off, and the aqueous phase is extracted with three times 2.5 liters of tert.-butyl methyl ether. Tbe combined organic phases are washed with twice 2 liters of water and then evaporated down under a pressure of 20 mbar. The crystalline residue which remains is stirred with cyclohexane, and the product is filtered off under suction and dried under reduced pressure at 35° C. In this manner, 466 g (87% of theory) of the (-)-antipode of (E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene are obtained in the form of a crystalline product.