Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26]([C@@H:28]([OH:37])[C@@H:29](Cl)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([Cl:47])[CH:40]=2)[C:5](=[O:6])[NH:4][CH2:3]1.[Li+].[Cl-]>CC(C)=O>[CH3:1][CH:2]1[C:20](=[O:21])[O:19][CH:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][CH:14]([CH:26]([CH:28]2[O:37][CH:29]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][CH:7]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([Cl:47])[CH:40]=2)[C:5](=[O:6])[NH:4][CH2:3]1
Reactant: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@@H](O)[C@@H](Cl)c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: COc1ccc(CC2NC(=O)/C=C/CC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/C[C@@H]([C@H](C)[C@@H](O)[C@@H](Cl)c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: [Cl-]
Solvent: CC(C)=O
Product: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a solution of Cryptophycin 8 (20 mg) in 1.0 mL of dry acetone(distilled from K2CO3) was added 20 mg of LiCl. The mixture was stirred for 3 days at 100° C., cooled to room temperature, and evaporated. The residue was subjected to reversed-phase HPLC using 82/18 MeOH/H2O to give Cryptophycin 27 (6.8 mg) and recovered Cryptophycin 8 (10.1 mg).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:12]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:11]=2[O:10][C@@H:9]1[CH3:26])(C)(C)C.P(=O)(O)(O)O>O1CCCC1>[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([F:18])([F:20])[F:19])[C:12]2[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:11]=2[O:10][C@@H:9]1[CH3:26]
Reactant: C[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Product: C[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
To a solution of 0.50 g (1.27 mmol) [(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester in 5 ml tetrahydrofurane were added 1.89 g ortho-phosphoric acid. The mixture was stirred at room temperature for 2 days. Extraction with ethylacetate/water and chromatography on silicagel with dichloromethane/methanol 98/2 yielded 0.31 g (83%) (6R,7S)-7-amino-2-fluoro-6-methyl-9-(2,2,2-trifluoro-ethyl)-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one, MS m/e (%): 293.1 (M+H+, 100).
Reaction SMILES: CC(OC(C)=O)=O.CCN(CC)CC.[N+:15]1([O-])[C:16](=[CH:20][CH:21]=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])C(O)=O.OC1C=CC(C(O)=O)=CN=1.C(Cl)[Cl:39]>>[Cl:39][C:16]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][N:15]=1
Reactant: O=C(O)c1ccc(C(=O)O)[n+]([O-])c1
Reactant: ClCCl
Agent: O=C(O)c1ccc(O)nc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1ccc(Cl)nc1
Yield: 53.8 %

Procedure:
This example proceeded as in Example 1, but the reaction was carried out at 0° to 5° C. the bath used had 25.5 g of Ac2O, 20 g of Et3N, 350 g of CH2Cl2 and 18.3 of isocinchomeronic acid-N-oxide. The yield was 53.8 percent of 6-chloronicotinic acid (2-chloro-5-pyridine carboxylic acid), and 39.0 percent of 6-hydroxynicotinic acid (2-hydroxy-5-pyridine-carboxylic acid).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[CH3:22][CH:23]([CH3:25])[O-:24].[Na+].Cl.O>C(O)(C)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:14][OH:15])[CH2:18][OH:17])=[C:4]([O:24][CH:23]([CH3:25])[CH3:22])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: CC(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1nc(N)nc2c1ncn2CCC(CO)CO
Reaction time: 0.42 h

Procedure:
A solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.25 g, 0.8 mmol) in isopropanol (2.5 ml) containing sodium isopropoxide (0.5M) was stirred at 60° for 25 minutes. After cooling, hydrochloric acid (5M, 0.3 ml) and water (0.7 ml) were added and the solution was stirred for 15 minutes at room temperature. The solution was neutralised by addition of aqueous.sodium bicarbonate and the solvent was removed. The residue was extracted with chloroform-ethanol (2:1) and the solution purified by column chromatography on silica gel eluting with chloroform-methanol (7:1) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)-6-isopropoxypurine which was crystallised from chloroform-carbon tetrachloride (0.18 g, 76%), m.p. 111.5-113.5° C., δH [(CD3)2SO] 1.34 (6H, d, J 6.3 Hz, C(CH3)2), 1.45 (1H, m, 3′-H), 1.74 (2H, q, J 7.2 Hz, 2′-H), 3.3-3.5 (4H, AB part of ABX, 2×4′-H), 4.06 (2H, t, J 7.3 Hz, 1′-H), 4.40 (2H, br, 2×OH), 5.49 (1H, septet, J 6.3 Hz, CH(CH3)2), 6.27 (2H, s, 2-NH2), and 7.83 (1H, s, 8-H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[CH3:10][C:11]1([CH3:20])[CH2:16][CH2:15][C:14](B(O)O)=[CH:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+].CCO>CCOC(C)=O.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.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:14]2[CH2:15][CH2:16][C:11]([CH3:20])([CH3:10])[CH2:12][CH:13]=2)[CH:3]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: CC1(C)CC=C(B(O)O)CC1
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: CCOC(C)=O
Solvent: CCO
Product: CC1(C)CC=C(c2cc(Br)ccc2N)CC1
Temperature: 80 °C
Yield: 65.6 %

Procedure:
A flask is charged with 4-bromo-2-iodo-phenylamine (1.10 g, 3.70 mmol), 4,4-dimethylcyclohexen-1-ylboronic acid (0.630 g, 4.07 mmol), Pd(PPh3)4 (0.240 g, 5 mol %), 2 M Na2CO3 (16 mL), EtOH (16 mL) and toluene (32 mL) and heated at 80° C. for 6 h. The reaction was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (2×100 mL) and brine (100 mL), and the organic layer dried over Na2SO4 and evaporated. The crude product was purified by flash silica gel chromatography eluting with 10% EtOAc/hexane to give 0.68 g (66%) of the title compound as a light yellow oil: Mass spectrum (ESI, m/z) calcd. for C14H18BrN, 280.1 (M+H), found 280.1.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1([C:11]([NH:13][C@@H:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:35])[C:27]3[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[N+]=[N-].CP(C)C.O>C1COCC1>[NH2:1][CH2:4][CH2:5][C:6]1([C:11]([NH:13][C@@H:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:35])[C:27]3[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])=[CH:23][CH:24]=2)[C:15]([OH:17])=[O:16])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: [N-]=[N+]=NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of (S)-2-[[1-(2-azidoethyl)cyclopentanecarbonyl]amino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid (6.28 g, 12.11 mmol) in THF (91 mL) was added a solution of trimethylphosphine in THF (48.5 mL, 48.46 mmol, 1.0M) at 0° C. It was a clear solution in the beginning and after 30 min some precipitate was formed and this mixture was stirred for overnight at which time TLC analysis of the mixture indicated the absence of starting material. Then, 10 equiv. of water (120 mmol, 2.16 mL) was added and the mixture was stirred for 2 h at room temperature. The solvent was removed under vacuum and the residue was azeotrophed two times with toluene to give a pasty material which was purified using HPLC to obtain 4.57 g (77% yield) of (S)-2-[[1-(2-aminoethyl)cyclopentanecarbonyl]amino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid as an amorphous white solid. ES(+)-HRMS m/e calcd. for C24H27Cl2N3O4 (M+H)+ 492.1452, obsd. 492.1451.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[OH-].[Na+].O.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>COC(C)(C)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
4-Chloroaniline (52.7 kg, 413 mol) was dissolved in a mixture of t-butyl methyl ether (180 kg), 30% aqueous sodium hydroxide (61.6 kg, 463 mol) and water (24.2 kg), then cooled to 15° C. To the resulting slurry was charged trimethylacetyl chloride (52.2 kg, 448 mol) over 1 h, keeping the temperature below 40° C. After stirring 30 min at 30° C. the slurry was cooled to −10° C. and held for 2 hours. The product was collected by filtration, washed with a solution of 90/10 water/methanol (175 kg), then dried in vacuo to give 85 kg (97% yield) of the title compound as a crystalline solid: mp 152-153° C.; 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=9 Hz, 2H) 7.28 (d, J=9 Hz, 2H); 13C NMR (75 MHz, CDCl3) d 176.7, 136.6, 129.1, 128.9, 121.4, 39.6, 27.6.
Reaction SMILES: [N+:1]([C:4]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2)([O-])=O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2
Reactant: O=c1[nH]c2cc(Cl)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a stirred mixture of 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (110 mg, 0.40 mMol) in ethanol (6 mL) was added SnCl2 ·2H2O (448 mg, 2.0 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 1 h to form a clear solution and continually refluxed for another 3 h. The mixture was then cooled to room temperature and the yellow precipitate was collected by filtration and washed with cold ethanol (2×1 mL) to give 61 mg (62%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 43 mg of pure title compound as bright yellow needles, mp>350° C. (dec.), changed color from 320° C. IR (KBr, cm-1): 3468; 3389; 3057; 1695; 1636; 1596; 1397. NMR (1H, DMSO-d6): δ5.935 (s, 2H); 6.595 (s, 1H); 11.317 (s, 1H); 11.868 (s, 1H). Purity>98.95% by HPLC. HRMS: calcd for C8H5N3O2Br2 (M+) m/z: 244.9757; found 244.9740. Potency relative to DCK: 323%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH3:11]I.O>CN(C=O)C>[CH3:11][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ccc(O)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
Sodium hydride (3.6 g, 150 mmol) was added portionwise to 5-hydroxy-2-picoline (15.0 g, 137 mmol) in DMF (120 mL). After 30 min., CH3I (10.2 mL, 156 mmol) was added and the mixture stirred 2 hours at r.t. Water was added and the compound was extracted with Et2O (3×). The organic extracts were washed with brine (2×), dried over Na2SO4 and concentrated in vacuo to give 6.7 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:6]2
Reactant: C1CCNC1
Reactant: COc1ccc2c(c1)CCC(=O)C2
Solvent: CO
Product: COc1ccc2c(c1)CCC(N1CCCC1)=C2

Procedure:
A solution of 6-methoxy-3,4-dihydro-1H-naphthalen-2-one (1) (5.64 g, 32 mmol) in methanol (60 mL) was treated with pyrrolidine (3.5 mL, 41.6 mmol) and the resultant mixture was stirred at ambient temperature for 1.5 h. The product precipitated from solution within minutes of the addition of pyrrolidine. The resultant suspension was cooled in an ice bath and the enamine product (2) was collected by filtration as a white solid (5.6 g, 76%). NMR (CDCl3):δ 1.86-1.94 (m, 4 H), 2.46 (t, 2H), 2.80 (t, 2 H), 3.19-3.25 (m, 4 H), 3.77 (s, 3 H), 5.10 (s, 1 H), 6.59-6.65 (m, 2 H) and 6.78 (d, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].I[CH2:15][CH3:16]>CN(C)C=O>[CH2:15]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH3:16]
Reactant: O=Cc1ncc[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccnc1C=O
Temperature: 50 °C
Yield: 83.8 %

Procedure:
To a suspension of 1H-imidazole-2-carbaldehyde (480 mg, 5 mmol) and potassium carbonate (936 mg, 6 mmol) in N,N-dimethylformamide (7 mL) was added iodoethane (829 mg, 6 mmol) and the mixture was heated at 50° C. for 5 hrs. Solvent was removed under reduced pressure. The residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 1-ethyl-1H-imidazole-2-carbaldehyde as light yellow oil (520 mg, yield 84%). 1H NMR (400 MHz, CDCl3) δ (ppm): 1.42-1.46 (t, J=7.2 Hz, 3H), 4.42-4.47 (q, 2H), 7.19 (s, 1H), 7.29 (s, 1H), 9.82 (s, 1H). LC-MS (ESI) m/z: 125 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[CH:25]([Mg]Cl)([CH3:27])[CH3:26].C([Mg]Cl)CC>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:24])[CH:25]([CH3:27])[CH3:26])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC(C)[Mg]Cl
Agent: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (150.0 mg, 0.394 mmol) in tetrahydrofuran (3.0 mL) was added i-propylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.59 mL, 0.591 mmol). The reaction mixture was stirred at 0° C. for 2 hrs. To the mixture was added 1-propylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.59 mL, 0.591 mmol). The mixture was stirred at 0° C. for 1 hr. After cooling, the mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic is layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-60% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (78.8 mg, 0.186 mmol, 47%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.P(Br)(Br)[Br:19]>O>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]([Br:19])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrP(Br)Br
Solvent: O
Product: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To 1-(3,5-bis(trifiuoromethyl)phenyl)-1-hydroxyethane (10 g) was added phosphorous tribromide (3.7 ml) to give a clear solution. After 30 minutes the solution was added to water (300 ml) and the solution stirred for a further 30 minutes. Petroleum ether bp=60°-80° C. was added and the organic solution washed with water (×3), saturated, NaHCO3, saturated brine and dried (MgSO4). The solution was evaporated in vacuo and the residue distilled b1-4 mm =69° C. to give 1-(3,5-bis(trifluoromethyl)phenyl)-1-bromoethane- 1H NMR (250 MHz; CDCl3) δ7.88 (2H; s; 2,6-arylH), 7.80 (1H; s; 4-arylH), 5.23 (2H,; q, J =6.9 Hz; CH3CH), 2.09 (3H; d, J =6.9 Hz; CH3).
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:26]([O-:28])=[O:27])[CH2:19]C1C=CC=CC=1.C([S+]1CCCC1)C1C=CC=CC=1.Cl>C(#N)C>[O:9]([C:1]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH3:19])=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)[O-]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Agent: c1ccc(C[S+]2CCCC2)cc1
Solvent: CC#N
Product: C[C@H](NC(=O)Oc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 428 mg (2 mmol) of diphenyl carbonate and 5 mL of acetonitrile were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at room temperature. Next, 618 mg (2 mmol) of S-benzyltetrahydrothiophenium phenylalanine salt and 15 mL of acetonitrile were dropped to the solution, and then the mixture was stirred for 30 minutes. After that, a 1M aqueous HCl solution was added to the reaction solution to terminate the reaction, and then the resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. The resultant organic layer was washed with water and brine, and was then dried with sodium sulfate. After that, the dried product was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-alanine was obtained. An isolation amount and an isolation yield were 456.2 mg and 80%, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:13](=[C:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CC2
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)C(=O)C(=Cc1ccccc1)C2
Temperature: 25 °C
Yield: 15 %

Procedure:
6-Methoxy-1-indanone (10 g, 61.2 mmol), benzaldehyde (7.85 g, 74.0 mmol), piperidine (1.05 g, 12.3 mmol), and acetic acid (4.4 g, 74.0 mmol) were refluxed in toluene (150 ml) for 3 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed serially with saturated saline and water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting crystals were washed with diethyl ether to provide the title compound (yield 2.3 g, 80%).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([NH:7][C@H:8]([C:11]([OH:13])=[O:12])[CH2:9][OH:10])=[O:6])[CH3:3].[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].C(Cl)Cl>CN(C)C=O.C(O)(=O)C.CO>[CH3:3][C:2]([CH3:14])([O:4][C:5]([NH:7][C@H:8]([C:11]([OH:13])=[O:12])[CH2:9][O:10][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C

Procedure:
A solution of N-[(1,1-dimethylethoxy)carbonyl]-L-serine (24.3 g., 0.118 mole) in dry dimethylformamide (25 ml.) was added dropwise over a period of 1.0 hour to a cooled (0°, ice-salt bath) suspension of 60% sodium hydride (10.1 g., 0.25 mole) in dry dimethylformamide (200 ml.) and stirring was continued at 0° until the frothing subsided (about 2.0 hours). The reaction mixture was treated dropwise with 1-fluoro-2-nitrobenzene (14.3 ml., 0.13 mole) over a period of 20 minutes, stirred at 0° under argon for 4.0 hours then poured into ice-water (750 ml.) and extracted with ethyl acetate (2×100 ml.). The aqueous phase was brought to pH 1.0 with 6N hydrochloric acid (70 ml.), extracted with ethyl acetate (3×500 ml.) and the combined organic extracts were washed with brine (100 ml.), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuo. The crude product mixture was chromatographed on a silica gel column (Merck), eluting the column with methylene chloride:methanol:acetic acid (100:5:0.2) to give 27.22 g. of product as a thick yellow syrup; Rf =0.27 (methylene chloride:methanol:acetic acid, 100:5:0.5).
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)\[CH2:6][CH2:7][C:8]([O:10]C)=[O:9].Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:31][C:30]1[O:29][C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:27][C:26]=1[CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:3]/[N:4]=[C:5](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:39][CH:38]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere to a solution of methyl E-4-hydroxyimino-4-phenylbutyrate (661 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred at room temperature for 1.5 hours. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (907 mg, yield 60%) as colorless crystals. m.p. 126-127° C. (decomposition)