Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[N:31]1([C:23]([C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:18][CH2:17]3)=[CH:27][CH:26]=2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1Nc2cc(CN3CCN(c4ccc(C(=O)N5CCCC5)cc4)CC3)cnc2N2CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
In a 1 dram vial, (S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) then added pyrrolidine (0.024 mL, 0.295 mmol), HATU (140 mg, 0.368 mmol) and N-methylmorpholine (0.108 mL, 0.982 mmol). The r×n was stirred at RT overnight. The mixture was purified by prep HPLC-MS (acidic mode, 15-35%). The pH of the combined fractions was adjusted to pH=8-9 and extracted with EtOAc (3×30 ml), washed with brine, dried with MgSO4, filtered and concentrated to dryness. The residue was taken up with water/ACN (1:1), and concentrated in vacuo to provide the title compound as a fluffy white solid (29 mg, 26% yield). m.p.=121.3° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.73-1.87 (m, 4H) 1.87-2.01 (m, 3H) 2.14-2.21 (m, 1H) 2.43-2.49 (m, 4H) 3.15-3.23 (m, 4H) 3.35 (br. s., 2H) 3.37-3.49 (m, 5H) 3.54-3.65 (m, 1H) 3.95-4.04 (m, 1H) 6.91 (d, J=9.09 Hz, 2H) 6.99 (d, J=2.02 Hz, 1H) 7.42 (d, J=8.84 Hz, 2H) 7.62 (d, J=1.77 Hz, 1H) 10.44 (s, 1H). [M+H] calc'd for C26H32N6O2, 461; found, 461.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:19]([C:16]2[S:15][C:11]3[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[O:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][O:25][CH2:24]4)[C:10]=3[C:17]=2[CH3:18])=[O:20])[CH2:32][CH2:31]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c12
Product: Cc1c(C(=O)NC2CCN(C)CC2)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 4-{4-fluoro-2-[(R)-(tetrahydro-pyran-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 1-methyl-piperidin-4-ylamine.
Reaction SMILES: C([O:5][C:6](=[O:91])[C:7]([O:10]/[N:11]=[C:12](/[C:78]1[N:79]=[C:80]([NH:83]C(OC(C)(C)C)=O)[S:81][CH:82]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18][CH2:19][C:20]([CH2:37][N+:38]1([CH2:43][C:44]3[C:53](=[O:54])[C:52]4[C:47](=[CH:48][C:49]([O:66]CC5C=CC(OC)=CC=5)=[C:50]([O:56]CC5C=CC(OC)=CC=5)[C:51]=4[Cl:55])[N:46]([CH2:76][CH3:77])[CH:45]=3)[CH2:42][CH2:41][CH2:40][CH2:39]1)=[C:21]2[C:25]([O:27]CC1C=CC(OC)=CC=1)=[O:26])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.C(OC(C)C)(C)C>ClCCl>[NH2:83][C:80]1[S:81][CH:82]=[C:78](/[C:12](=[N:11]/[O:10][C:7]([C:6]([OH:91])=[O:5])([CH3:8])[CH3:9])/[C:13]([NH:15][C@@H:16]2[C:23](=[O:24])[N:22]3[C@@H:17]2[S:18][CH2:19][C:20]([CH2:37][N+:38]2([CH2:43][C:44]4[C:53](=[O:54])[C:52]5[C:47](=[CH:48][C:49]([OH:66])=[C:50]([OH:56])[C:51]=5[Cl:55])[N:46]([CH2:76][CH3:77])[CH:45]=4)[CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:21]3[C:25]([O-:27])=[O:26])=[O:14])[N:79]=1
Reactant: CCn1cc(C[N+]2(CC3=C(C(=O)OCc4ccc(OC)cc4)N4C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c5csc(NC(=O)OC(C)(C)C)n5)[C@H]4SC3)CCCC2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CCn1cc(C[N+]2(CC3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c5csc(N)n5)[C@H]4SC3)CCCC2)c(=O)c2c(Cl)c(O)c(O)cc21
Temperature: 25 °C
Yield: 48.6 %

Procedure:
To a solution of 1-(((6R,7R)-7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-(((4-methoxybenzyl)oxy)carbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)-1-((5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinolin-3-yl)methyl)pyrrolidin-1-ium (2.668 g, 80% purity, 1.632 mmol) in Dichloromethane (DCM) (15 mL) under N2 at 0° C. was added anisole (1.783 mL, 16.32 mmol), followed by TFA (5.0 mL, 64.9 mmol). The mixture was warmed up to rt and stirred at rt over night. LCMS indicated completion of the deprotection. The mixture was cooled to 0° C. Diisopropyl ether (50 mL) was then added. The mixture was stirred for 10 min and the solid was collected by filtration, and washed twice with diisopropyl ether (2×10 mL). The solid (˜2.0 g) was dissolved in a mixture of CH3CN (10 mL)/water (10 mL)/2M HCl (2.5 mL), HP20SS resin (12 g) was then added. The mixture was concentrated to dryness, and the resin was loaded in a pre-column containing HP20SS resin (15 g), and was then purified by reverse phase Combiflash using C18 column and eluting with 0-30% CH3CN/water to afford (6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-3-((1-((5-chloro-1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinolin-3-yl)methyl)pyrrolidin-1-ium-1-yl)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (0.66 g, 0.793 mmol, 48.6% yield) as a slightly brown solid. LCMS: (M+H)+: 790.1. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.50 (s, 3 H) 1.62 (d, J=6.57 Hz, 6 H) 2.12-2.28 (m, 4 H) 3.42-3.63 (m, 6 H) 3.95-4.05 (m, 1 H) 4.07-4.16 (m, 1 H) 4.26-4.40 (m, 3 H) 4.47-4.55 (m, 1 H) 5.30-5.37 (m, 1 H) 5.89-5.97 (m, 1 H) 6.91 (s, 1 H) 7.04-7.10 (m, 1 H) 8.17-8.24 (m, 1 H).
Reaction SMILES: [C:1]([C:3]1[N:7]([CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([F:19])=[CH:13][C:14]=3[F:18])[CH2:9]2)[C:6](=[S:20])[NH:5][CH:4]=1)#[N:2].C1(C)C=CC=CC=1.Cl.O.[F-].[K+].C([Sn]([N:45]=[N+:46]=[N-:47])(CCCC)CCCC)CCC>C(OCC)C.O.C(OCC)(=O)C>[F:18][C:14]1[CH:13]=[C:12]([F:19])[CH:11]=[C:10]2[C:15]=1[CH2:16][CH2:17][CH:8]([N:7]1[C:3]([C:1]3[NH:47][N:46]=[N:45][N:2]=3)=[CH:4][NH:5][C:6]1=[S:20])[CH2:9]2
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1c[nH]c(=S)n1C1CCc2c(F)cc(F)cc2C1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1cc(F)c2c(c1)CC(n1c(-c3nnn[nH]3)c[nH]c1=S)CC2
Temperature: 25 °C

Procedure:
A mixture of 5-cyano-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (0.554 g, 1.9 mmol), prepared as in Example 19, in 1.6 mL of tributyltin azide was heated at 130° C. under a nitrogen atmosphere for 2.5 hours and then 10 mL of toluene was added. The mixture was allowed to cool to room temperature and approximately 5 mL of diethyl ether was added. The mixture was cooled to 0° C. and then treated with 10 mL of 1N hydrogen chloride in diethyl ether for approximately 15 minutes. The mixture was poured into a solution of potassium fluoride monohydrate (15.0 g) in 15 to 20 mL of water and 75 mL of ethyl acetate. The ethyl acetate layer was extracted with 2N sodium hydroxide and the aqueous layer was washed 6 times with methylene chloride. The aqueous layer was acidified with concentrated hydrochloric acid and then extracted with ethyl acetate. Evaporation of the solvents gave 1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-5(1H)-tetrazol-5-yl-1,3-dihydroimidazole-2-thione (0.57 g, 1.7 mmol), m.p. 214°-215° C.
Reaction SMILES: [N:1]1([C:7]2[C:8]([NH2:17])=[N:9][C:10]([NH2:16])=[N:11][C:12]=2[CH2:13][CH2:14][CH3:15])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:8]([NH2:17])=[N:9][C:10]([NH2:16])=[N:11][C:12]=3[CH2:13][CH2:14][CH3:15])[CH2:2][CH2:3]2)=[CH:20][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCCc1nc(N)nc(N)c1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCc1nc(N)nc(N)c1N1CCN(c2ccc(C#N)cc2)CC1
Temperature: 140 °C
Yield: 85.2 %

Procedure:
A mixture of 9.6 g (0.0407 mole) of 5-(1-piperazinyl)-6-propyl-2,4-pyrimidinediamine, 5.4 g (0.0448 mole) of 4-fluorobenzonitrile and 6.18 g (0.0448 mole) of sodium carbonate in 200 ml of dimethyl sulfoxide was heated at 140° C. for two hours. The reaction mixture was cooled and poured into 500 ml of ice water. The solid was collected and recrystallized from N,N-dimethylformamide to give 11.7 g of the product as a white solid; mp>300° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Br-:17].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>Br.CC(O)=O>[Br:17][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccc(NC(=O)C(C)(C)C)c1
Reactant: [Br-]
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.3 %

Procedure:
To a stirred solution of N-(3acetylphenyl)pivalamide 8z (0.30 g, 1.37 mmol) in 33% HBr in HOAc (5 mL) was added pyridinium tribromide (0.48 g, 1.51 mmol) and the mixture was stirred at room temperature for 24 h then poured into ice-cold water. The organic layer was extracted with DCM, washed with sat. aq. NaHCO3 and brine, dried over anhydrous MgSO4, and filtered. Evaporation of the solvent afforded 9z (0.32 g, 78%) which was used in the next step without further purification. 1H NMR (600 MHz, CDCl3): δ 8.08 (t, J=1.8 Hz, 1H), 7.94 (br s, 1H), 7.82 (dt, J=8.4, 1.2 Hz, 1H), 7.60 (dd, J=7.2 Hz, 1.2 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 4.30 (s, 2H), 1.27 (s, 9H). 13C NMR (150 MHz, CDCl3): δ 191.2, 177.3, 139.0, 134.4, 129.3, 125.8, 124.4, 120.4, 39.7, 31.4, 27.5. MS m/z (ESI) 298.06 [M+H]+, 300.02 [(M+2)+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18])C.C([O-])([O-])=O.[K+:28].[K+]>CO>[K+:28].[F:1][C:2]([F:12])([F:11])[C:3](=[N:18][C@H:17]([C:16]([O-:23])=[O:15])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)C[C@H](N=C(c1ccccc1)C(F)(F)F)C(=O)[O-]
Temperature: 50 °C

Procedure:
2,2,2-Trifluoroacetophenone (4.24 g, 24.3 mmol) was added to a mixture of L-leucine ethyl ester (3.52 g, 22.1 mmol) and K2CO3 (2.90 g, 20.9 mmol) in MeOH (50 mL). The mixture was warmed to 50° C. for 18 h. The mixture was cooled to 20–25° C., filtered and concentrated. The residue was suspended in TBME (100 ml) and filtered to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]=[C:11]([F:17])[C:12](OCC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]=[C:11]([F:17])[CH2:12][OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(F)=CCNC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC=C(F)CO
Reaction time: 2 h

Procedure:
To a stirring, cold (−10° C.) solution of ethyl 4-(tert-butoxycarbonylamino)-2-fluorobut-2-enoate (a 10:1 mixture of EIZ isomers; 6.33 g, 25.6 mmol) in CH2Cl2 (200 mL) under Ar was added dropwise Diisobutylaluminium hydride solution (1M solution in hexanes, 70.5 mL, 70.49 mmol). After addition was complete the reaction was left to stir at this temperature for a further 2 h. The reaction was then quenched carefully by dropwise addition of cold water. The resulting slurry was poured into a flask containing a saturated aqueous solution of sodium potassium tartrate (400 mL) and the biphasic mixture was stirred vigorously for 2 h. After transferring the mixture to a separatory funnel the aqueous phase was extracted with CH2Cl2 (3×100 mL). The combined organics were washed with brine (100 mL), dried over anhydrous MgSO4 and concentrated in vacuo to give tert-butyl-3-fluoro-4-hydroxybut-2-enylcarbamate as a 10:1 mixture of E/Z isomers. Purification and separation of the desired E isomer was performed using silica gel chromatography eluting with 30% ethyl acetate in hexanes affording (E)-tert butyl-3-fluoro-4-hydroxybut-2-enylcarbamate (4.25 g, 20.7 mmol, 81%) as a colourless oil that solidified upon cooling, 1H-NMR (200 MHz, CDCl3): δppm: 1.43 (9H, s), 3.72 (2H, dd, J 7.5, 5.4 Hz), 4.25 (2H, d, J 21.5 Hz), 4.85 (1H, br s), 5.18 (1H, dt, 19.2, 8.5 Hz).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]1[CH2:52][O:51]1)[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:53][NH2:54]>CO.O1CCCC1>[CH3:53][NH:54][CH2:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:51]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C5CO5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(O)CNC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(oxiran-2-yl)-6,8-dioxabicyclo[3.2.1]octane 10a (50 mg, 0.56 mmol, obtained from the synthetic method described in step 1 of example 10) in a methanol/tetrahydrofuran mixture (v/v=2/1, 9 mL) was added methylamine solution (1 mL, 1.25 mmol). The mixture was heated to 55° C. and stirred for 16 h. The resulting mixture was extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (10 mL×2) and saturated brine (10 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 11a as a white solid (37.4 mg, 71.6%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.41 (m, 2H), 7.40 (m, 1H), 7.32 (m, 3H), 7.26 (m, 6H), 7.17 (m, 3H), 7.04 (d, 2H), 6.85 (m, 2H), 6.73 (m, 2H), 4.87 (m, 1H), 4.75 (m, 3H), 4.26 (m, 1H), 4.11 (m, 2H), 3.97 (m, 2H), 3.92 (m, 3H), 3.82 (m, 2H), 3.72 (m, 3H), 2.65 (m, 1H), 2.55 (m, 1H), 2.22 (s, 3H), 1.27 (t, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:20]\[OH:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:24](I)C.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl.O>[CH3:24][O:21]/[N:20]=[C:11]1/[C:10](=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[C:19]2[C:14]([CH2:13][CH2:12]/1)=[CH:15][CH:16]=[CH:17][CH:18]=2
Reactant: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CO/N=C1\CCc2ccccc2C1=Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one oxime (50 mg, 0.15 mmol), ethyl iodide (0.023 ml, 0.37 mmol) and potassium carbonate (0.063 g, 0.46 mmol) were added into dimethylformamide (2.0 ml). Then, the solution was stirred at 95˜100° C. overnight, and cooled to room temperature. Again, water and dichloromethane were added, and an organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to remove organic solvent. The residue was purified through silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3, v/v). As a result, 40.7 mg of the present compound (productive yield 78%) was obtained as a white solid crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].Cl[CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][C:47]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[C:48]([O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:49]=2)[CH:44]=1.C(=O)([O-])[O-].[I-].[Na+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:11]1[CH:12]=[C:13]([O:36][CH2:39][CH2:40][CH2:41][CH2:42][C:43]2[CH:44]=[C:45]3[C:50](=[CH:51][CH:52]=2)[CH:49]=[C:48]([O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:47]([O:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:46]3)[CH:14]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:16]=1
Reactant: ClCCCCc1ccc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2c1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCc2ccc3cc(OCc4ccccc4)c(OCc4ccccc4)cc3c2)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 49.3 %

Procedure:
A mixture of 1.5 g (2.88 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 1.24 g (2.88 mmol) of 2-(4-chlorobutyl)-6,7-bis(phenylmethoxy) naphthalene, 0.8 g (5.75 mmol) ofpotassium carbonate and 0.43 g (2.88 mmol) of sodium iodide in 50 ml of acetone and 10 ml of DMF was stirred at reflux under argon for 40 hours. The acetone was removed by distillation and 50 ml of DMF, 1.24 g of 2-(4-chlorobutyl)-6,7-bis(phenylmethoxy)naphthalene, 0.8 g of potassium carbonate and 0.43 g of sodium iodide were added and the mixture was stirred and heated at 85° for 4 days. The DMF was removed using an oil pump at 55°. The residue was extracted with methylene chloride,the extract was concentrated and the product was purified by HPLC using 20%ethyl acetate-hexane to give 1.3 g (49% yield) of N-(2 -methoxy-2oxoethyl)-N-[3-(octadecyloxy)-5-[4-[2,3-bis(phenylmethoxy)-6-naphthalenyl]butoxy]phenyl]glycine methyl ester as a semisolid. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Br:26])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19]>C(OCCCC)CCC>[Cl:1][C:2]1[C:11]2[N:10]([C:18]([C:17]3[CH:21]=[C:22]([Br:26])[C:23]([O:24][CH3:25])=[C:15]([Br:14])[CH:16]=3)=[O:19])[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2c1NCCO2
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: COc1c(Br)cc(C(=O)N2CCOc3ccnc(Cl)c32)cc1Br
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49.7 %

Procedure:
In a 50 ml flask equipped with a reflux apparatus, 5-chloro-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (890 mg, 5.22 mmol) was dissolved in butyl ether (20 ml), and 60% sodium hydride in mineral oil (250 mg, 6.26 mmol) was added and stirred at 1250 for 3.5 hours. The mixture was cooled to room temperature and 3,5-dibromo-4-methoxy-benzoyl chloride (2.06 g, 6.26 mmol) was added thereto and then stirred at 1250 for 24 hours. The mixture was cooled to room temperature and filtered and evaporated under reduced pressure. The residue was washed with methanol and dried under reduced pressure to obtain white solid (1.2 g, 50%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([P:10]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:16])[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:5]1.[CH2:25]([O:32][C:33]1[CH:43]=[CH:42][C:36]([O:37][CH2:38][C@@H:39]2[CH2:41][O:40]2)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([O:37][CH2:38][CH:39]([OH:40])[CH2:41][NH:1][CH2:2][CH2:3][CH:4]2[CH2:9][CH2:8][CH:7]([P@:10]([CH2:17][O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:16])[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:5]2)=[CH:42][CH:43]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCCOP(=O)(COc1ccccc1)C1CCC(CCN)CC1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Product: CCCCO[P@](=O)(COc1ccccc1)C1CCC(CCNCC(O)COc2ccc(OCc3ccccc3)cc2)CC1

Procedure:
The title compound was prepared from 4-(2-aminoethyl)phenoxy methylcyclohexylphosphinic acid, n-butyl ester and (S)-2-(4-benzyloxyphenoxymethyl)oxirane according to the method described in Procedure 13.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[F:21][C:22]([F:31])([F:30])[C:23]1[S:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.O>[CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:28][C:26]4[S:27][C:23]([C:22]([F:31])([F:30])[F:21])=[CH:24][CH:25]=4)=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2]
Reactant: OCc1ccc(C(F)(F)F)s1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (120 mg), (5-(trifluoromethyl)-2-thienyl)methanol (162 mg) and tributylphosphine (270 mg) in THF (8 ml) was added 1,1′-(azodicarbonyl)dipiperidine (337 mg), and the reaction mixture was stirred at 60° C., for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH to give the title compound (33.9 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:12]([O:14]C)=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O[Li].O>>[OH:1][C:2]1([C:12]([OH:14])=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)C1(O)CCCc2ccccc21
Agent: [Li]O
Solvent: O
Product: O=C(O)C1(O)CCCc2ccccc21

Procedure:
The sub-title compound was prepared according to the method described in Example 1(ii) above from 1-hydroxytetralin-1-yl-carboxylic acid, methyl ester (2.5 g; 12.1 mmol; from step (i) above) and LiOH.H2O (1.02 g; 24.2 mmol). Yield 400 mg (17%).