Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H](C(O)=O)CC1N=CNC=1.[OH-].[Na+].C(=O)C(C)C.Cl.[CH:20]([CH:23]1[C:28]2[N:29]=[CH:30][NH:31][C:27]=2[CH2:26][CH:25]([C:32]([OH:34])=[O:33])[NH:24]1)([CH3:22])[CH3:21]>O.CO>[CH:20]([C@H:23]1[C:28]2[N:29]=[CH:30][NH:31][C:27]=2[CH2:26][C@@H:25]([C:32]([OH:34])=[O:33])[NH:24]1)([CH3:22])[CH3:21]
Reactant: CC(C)C1NC(C(=O)O)Cc2[nH]cnc21
Agent: CC(C)C=O
Agent: Cl
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)O
Solvent: CO
Solvent: O
Product: CC(C)[C@@H]1N[C@H](C(=O)O)Cc2[nH]cnc21
Temperature: 80 °C

Procedure:
L-Histidine (10.0 g, 43.8 mmol) was dissolved in a solution of NaOH (7.73 g, 193 mmol) in water (25 mL) and MeOH (100 mL), and isobutyraldehyde (11.8 mL, 129 mmol) was added. The reaction mixture was heated under reflux at 80° C. for 24 h. The pH was adjusted to 7 with 1 M aq HCl solution and the solvents were removed in vacuo. The residue was dissolved in hot EtOH and cooled to room temperature. The precipitate was removed by filtration and the mother liquor concentrated in vacuo, washed with acetone (100 mL) and dried to give 4-isopropyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid as a pale yellow solid (18.6 g, crude, 6:1 mixture of (4S,6S):(4R,6S) diastereoisomers).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:7]([O:19][CH3:20])[CH2:6]1)=[O:4].O.[OH-].[Li+]>CO.O>[C:15]([O:14][C:12]([NH:11][C@@H:8]1[CH2:9][CH2:10][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6][C@H:7]1[O:19][CH3:20])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](OC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CO[C@@H]1C[C@H](C(=O)O)CC[C@H]1NC(=O)OC(C)(C)C
Yield: 96.3 %

Procedure:
The ester (e) (5.47 g, 19 mmol) and lithium hydroxide monohydrate (0.96 g, 23 mmol) in methanol/water (50 ml/50 ml) were stirred at room temperature for 18 hours then evaporated to dryness. The residue was partitioned between ethyl acetate and water (30 ml) containing sodium dihydrogen phosphate (7 g). The aqueous phase was further extracted with ethyl acetate and the combined extracts washed with brine, dried and evaporated to give a solid (5.0 g, 96%).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[N:16][C:15]([CH:18]2[CH2:20][CH2:19]2)=[C:14]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[N:13]=1)=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6].[OH-].[Li+].Cl>C1COCC1.O>[CH:18]1([C:15]2[N:16]=[CH:17][C:12]([C:10]([NH:9][C@@H:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]([OH:26])=[O:2])=[O:11])=[N:13][C:14]=2[O:21][CH2:22][CH:23]2[CH2:24][CH2:25]2)[CH2:20][CH2:19]1
Reactant: COC(=O)[C@@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[C@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(=O)O
Yield: 109.7 %

Procedure:
To a solution of (S)-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-amino]-3,3-dimethyl-butyric acid methyl ester (58 mg, 160 μmol) in THF (3 mL) was added lithium hydroxide (30 mg, 715 μmol) in water (1 mL) and the mixture was stirred at reflux temperature for 3 hours. After cooling the mixture was poured into water (10 mL), acidified with 1 N HCl (1 mL) and extracted with TBME. Organic phases were combined, dried with Na2SO4, filtered and concentrated in vacuo to give the title compound (61 mg, quant.) as white solid; LC-MS (UV peak area/ESI) 100%, 348.1920 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([C:15]([CH:17]2[CH2:23][CH2:22][C:21]3([C:25]4([CH3:30])OCC[O:26]4)[CH2:24][CH:18]2[C:19](=[O:31])[O:20]3)=[O:16])[CH:4]=1.Cl.[CH3:33][OH:34]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([C:15]([CH:17]2[CH2:23][CH2:22][C:21]([C:25](=[O:26])[CH3:30])([OH:20])[CH2:24][CH:18]2[C:19]([O:34][CH3:33])=[O:31])=[O:16])[CH:4]=1
Reactant: CO
Reactant: COc1cc(C(=O)C2CCC3(C4(C)OCCO4)CC2C(=O)O3)c(OC)c2ccccc12
Agent: Cl
Product: COC(=O)C1CC(O)(C(C)=O)CCC1C(=O)c1cc(OC)c2ccccc2c1OC

Procedure:
Operating as described in Example 5, the treatment of 2-(1,4-dimethoxy-3-naphthylcarbonyl)-5-(2-methyldioxolan-2-yl)-6-oxa-bicyclo[3,2,1]octan-7-one, prepared as described in Example 10, with a solution of hydrogen chloride in methanol afforded 1-(1,4-dimethoxy-3-naphthylcarbonyl)-2-methoxycarbonyl-4-acetyl-4-hydroxy-cyclohexane (X, R=H) in almost quantitative yield. m/z 414 (M+.): IR (film): 3460 cm-1 (OH), 1730 cm-1 (C=O ester), 1710 cm-1 (C=O ketone) and 1670 cm-1 (C=O, benzylic ketone). PMR (CDCl3): inter alia: δ2.3 (s, CH3CO), 2.9-3.6 (m, two H), 3.7-3.9 (s, three OCH3), 6.9 (s, aromatic H) and 7.4-8.4 (m, four aromatic H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[CH2:4][C:5]1([CH3:25])[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([O:16][Si](C(C)(C)C)(C)C)[CH2:12][CH2:11]2)[C:6]1=[O:24].ClC1C(C)=C(Cl)C=CC=1CC1(C)CCN([C@H]2CC[C@@H](O[Si](C(C)(C)C)(C)C)CC2)C1=O>C(O)C>[Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[CH2:4][C:5]1([CH3:25])[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:11][CH2:12][C@@H:13]([OH:16])[CH2:14][CH2:15]2)[C:6]1=[O:24]
Reactant: CC1(Cc2ccc(Cl)cc2Cl)CCN([C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)C1=O
Agent: Cc1c(Cl)ccc(CC2(C)CCN([C@H]3CC[C@@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)c1Cl
Solvent: CCO
Product: CC1(Cc2ccc(Cl)cc2Cl)CCN([C@H]2CC[C@@H](O)CC2)C1=O
Temperature: 70 °C

Procedure:
Dissolve 3-(2,4-dichloro-benzyl)-1-(cis-4-t-butyldimethylsilyloxy-cyclohexyl)-3-methyl-pyrrolidin-2-one and 3-(2,4-dichloro-3-methyl-benzyl)-1-(cis-4-t-butyldimethylsilyloxy-cyclohexyl)-3-methyl-pyrrolidin-2-one (0.42 g, 0.89 mmol) in ethanol-2N HCl (1:1, 9 mL) and stir at 70° C. 2 h. Cool the mixture and partition between dichloromethane and saturated aqueous sodium bicarbonate and brine, dry the organic layer over sodium sulfate and evaporate. Purify the residue by column chromatography on silica gel (eluting 0% to 100% ethyl acetate in hexane) to give the desired product (97 mg, 31%). MS(ES+) m/z=356.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:38]=[C:37](I)[CH:36]=[CH:35][C:34]=3[O:40][CH3:41])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:42][O:43][C:44]([C:46]1[O:50][C:49](B(O)O)=[CH:48][CH:47]=1)=[O:45].N#N.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:38]=[C:37]([C:49]4[O:50][C:46]([C:44]([O:43][CH3:42])=[O:45])=[CH:47][CH:48]=4)[CH:36]=[CH:35][C:34]=3[O:40][CH3:41])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(B(O)O)o1
Reactant: COc1ccc(I)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(N4CCC4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (4S,5R)-3-{[6-azetidin-1-yl-3-(5-iodo-2-methoxyphenyl)pyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (20 mg, 0.029 mmol) and [5-(methoxycarbonyl)-2-furyl]boronic acid (14.75 mg, 0.087 mmol) in THF (0.5 mL) was degassed with N2 at 25° C. 1N K2CO3 (0.5 mL) was added followed by 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1.885 mg, 2.89 μmol) and the reaction was stirred vigorously at 25° C. under N2 overnight. The reaction was diluted with water and extracted with EtOAc (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by preparative TLC (20×20, 1000 μm, hexanes/EtOAc (70/30)) to give methyl 5-{3-[6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}-2-furoate. LCMS calc.=689.2. found=690.2 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.85 (s, 1H); 7.81-7.55 (m, 4H); 7.37 (d, J=8.3 Hz, 1H); 7.24 (d, J=3.7 Hz, 1H); 7.02 (d, J=8.6 Hz, 1H); 6.66 (s, 1H); 6.31 (d, J=8.3 Hz, 1H); 5.74-5.36 (m, 1H); 4.84 (d, J=16.1 Hz, 1H); 4.25 (s, 1H); 4.18-4.01 (m, 5H); 3.90 (s, 3H); 3.87 (s, 3H); 2.48-2.39 (m, 2H); 0.75-0.59 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:5]1[C:6]([OH:11])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]([OH:1])=[C:3]([C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCc1c(O)c(Br)cc(C(C)=O)c1O
Reaction time: 0.75 h
Yield: 73.2 %

Procedure:
To a cold suspension (7°) of 5 g (0.026 mol) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone in 150 ml of chloroform was added 27 ml (0.027 mol) of 1M bromine in chloroform dropwise. The mixture was stirred at 5° for 45 minutes and solvent was removed in vacuo. The residue was extracted with hot hexane and the hexane extract was boiled down to 50 ml and allowed to crystallize. Filtration gave 5.2 g, melting point 67° (74% yield) of 1-(5-bromo-2,4-dihydroxy-3-propylphenyl)ethanone.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[C:33]3[C:28]([CH:27]=[CH:26][CH:25]=[N:24]3)=[CH:29][CH:30]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc3cccnc3c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and quinolin-7-ol: 1H-NMR (CDCl3) δ 8.96 (1H, m), 8.60 (1H, d, J=2.8 Hz), 8.24–8.14 (3H, m), 8.00–7.88 (4H, m), 7.47–7.26 (4H, m), 5.39 (1H, m), 3.89 (3H, s), 1.60 (3H, d, J=7.0 Hz).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[N:6][C:7](Cl)=[N:8][CH:9]=1>>[NH2:2][CH2:1][C:7]1[N:6]=[CH:5][C:4]([Br:3])=[CH:9][N:8]=1
Reactant: CN
Reactant: Clc1ncc(Br)cn1
Product: NCc1ncc(Br)cn1
Temperature: 115 °C
Yield: 93.5 %

Procedure:
Methylamine (2.0 M in methanol, 40 mL, 80 mmol) was added to 5-bromo-2-chloropyrimidine (5.6 g, 29.0 mmol) in a sealable reaction vessel. After allowing to vent for a few minutes, the vessel was sealed, placed behind a safety shield and heated in a 115° C. oil bath for 48 hours. Upon cooling the volatiles were removed in vacuo. The material was dissolved in CH2Cl2 (200 mL) and washed with 1M NaOH (40 mL). The aqueous layer was extracted further with CH2Cl2 (2×50 mL). The combined organics were dried over MgSO4, filtered and concentrated yielding an off white solid (5.1 g, 93%). LCMS (m/z): 188.0/190.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N1C=CC=CC=1.C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:19])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 56.3 %

Procedure:
To a solution of 4-fluoro-3-nitro aniline (1.41 g, 9.0 mmol) in THF (50 mL) was added cyclohexanecarbonyl chloride (1.46 g, 9.6 mmol) and pyridine (0.97 mL, 12 mmol), and the mixture stirred for 22 h at room temperature. Ethyl acetate (100 mL) was added, and the solution was washed in turn with 1M HCl (50 mL) and saturated sodium bicarbonate (50 mL). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate (7:3) to give cyclohexanecarboxylic acid (4-fluoro-3-nitro-phenyl)amide (1.35 g, 56%).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]([C@@H:6]1[C@H:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]32[O:17][CH2:16][CH2:15][O:14]3)[CH2:7]1)=[O:5])[CH3:2]>C[O-].[Na+]>[CH2:31]([N:3]([CH2:1][CH3:2])[C:4]([C@@H:6]1[C@@H:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10]32[O:17][CH2:16][CH2:15][O:14]3)[CH2:7]1)=[O:5])[CH3:32]
Reactant: CCN(CC)C(=O)[C@H]1CN2CC[C@H]1C1(OCCO1)C2C(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: CCN(CC)C(=O)[C@H]1CN2CC[C@@H]1C1(OCCO1)C2C(c1ccccc1)c1ccccc1
Yield: 86.4 %

Procedure:
A suspension of 21 (9.8 g, 22 mmol) in sodium methoxide (28% in MeOH; 400 g) was heated at reflux temperature for 9 hours. The resulting solution was poured on ice (300 ml) and extracted with CH2Cl2 (150 ml) three times. The combined extracts were dried over sodium sulfate (Na2SO4) and concentrated. The clude was purified by recrystallization from ethanol (EtOH) to give 22 (1:4 mixture at 6-position; 8.4 g, 19 mmol, 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].[CH3:11][CH:12]1[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][O:13]1.Cl>BrCCBr.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:16]2([OH:18])[CH2:15][CH2:14][O:13][CH:12]([CH3:11])[CH2:17]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1CC(=O)CCO1
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC1CC(O)(c2cc(F)cc(F)c2)CCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A Grignard reagent was prepared from 3,5-difluorobromobenzene (0.772 g), 1,2-dibromoethane (2 drops), magnesium (0.106 g) and THF (5 ml). The mixture was stirred at ambient temperature for 15 minutes and then heated to 50° C. for 15 minutes. The mixture was allowed to recool to ambient temperature and a solution of 2-methyltetrahydropyran-4-one (J. Amer. Chem. Soc., 1982, 104, 4666) in THF (1 ml) was added dropwise. The mixture was stirred at ambient temperature for 1 hour. The mixture was poured into dilute aqueous hydrochloric acid and extracted with diethyl ether. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 9:1 v/v mixture of methylene chloride and diethyl ether as eluent. There was thus obtained a less polar isomer, (2RS,4SR)-4-(3,5-difluorophenyl)-4-hydroxy-2-methyltetrahydropyran (0.25 g, 36%), having the 2-methyl and 4-hydroxy substituents in a trans-relationship.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.C([O:16][C:17](=[O:32])[C@@H:18]([O:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28]Br)=[CH:22][CH:21]=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:28][CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C@H:18]([O:30][CH3:31])[C:17]([OH:32])=[O:16])=[CH:25][CH:24]=2)=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of biphenyl-4-ol (0.39 mmol, 68 mg) in 10 ml of DMF in was treated with (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester obtained in Step 2 (0.33 mmol, 100 mg) and cesium carbonate (0.66 mmol, 214 mg) in a round bottom flask. The reactants were filtered and was washed with DMF several times and the solvent was evaporated under vacuo. The residue was reconstituted in a mixture of ethanol (20 ml) and NaOH (1M) (8 ml), and then stirred at room temperature until TLC indicated the disappearance of starting material. Ethanol was removed under vacuum, and the aqueous solution was diluted with 20 ml of brine and washed with diethyl ether (3×15 mL). The aqueous phase was acidified with
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:33]([O:37][C:38]([NH:40][C@@H:41]1[CH2:46][CH2:45][C@H:44]([NH2:47])[CH2:43][CH2:42]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:33]([O:37][C:38]([NH:40][C@H:41]1[CH2:42][CH2:43][C@@H:44]([NH:47][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)[CH2:45][CH2:46]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: Brc1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2cccc3cnccc23)CC1
Temperature: 70 °C
Yield: 77.1 %

Procedure:
Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (253 mg), tris(dibenzylideneacetone)palladium(0) (58 mg), 2-(di-tert-butylphosphino)biphenyl (74 mg), Intermediate 38 (311 mg) and sodium tert-butoxide (165 mg) in toluene was stirred with heating at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (320 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.CC1C([C:26](O)=[O:27])=CC=CC=1.C[O-].[Na+].C(OCC)(=O)C.C(O)(=O)C>CO>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][OH:27])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: Cc1ccccc1C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Cn1c(CO)nc2c(Cl)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 7.2 %

Procedure:
4-Chloro-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methyl benzoate (14.3 g; 0.36 mol, Example 7) was suspended in dry methanol (350 mL). The mixture was made basic (pH 10) with 25% sodium methoxide. The mixture was stirred at room temperature for 5 hr after which time only a trace of starting material was detected by silica gel TLC (ethyl acetate eluent). The mixture was made acidic with acetic acid and then concentrated to dryness. The residue was slurried in ether. The solid was filtered from the mixture and then suspended in aqueous sodium hydroxide. The product was filtered from the mixture, washed with water, and dried to yield 7.5 g (71.4%) of tan solid. The product was recrystallized from ethanol to yield 4.8 g of pure product m.p. 162-166° C. Analysis: Calculated: C, 62.2; H, 5.6; N, 14.5. Found: C, 62.2; H, 5.6; N, 14.3.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=[N+]([O-])c1nccn1C1CCCCO1
Yield: 83.7 %

Procedure:
A suspension of 0.113 g (1.0 mmol) of 2-nitroimidazole and 10 ml of 2,3-dihydropyran was stirred at 80° C. in the presence of 5 mg of p-toluenesulfonic acid for 1 hr. according to the procedure of Robins et al. [J. Am. Chem. Soc 83, 2574 (1961)]. The excess of 2,3-dihydropyran was removed under reduced pressure. The residue was chromatographed on silica gel by elution with ethyl acetate-benzene mixture (employing a gradient from 9:1 to 1:1) to provide 0.165 g (83.7%) of the title compound, which was recrystallized from petroleum ether, mp 50° C.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C@@H:3]([N:5]([CH2:9][CH2:10][C:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([OH:15])[CH2:12][CH:13]=[CH2:14])[C:6](=O)[O-:7])[CH3:4].[H-].[Na+]>C1COCC1>[CH2:12]([C:11]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:15][C:6](=[O:7])[N:5]([C@H:3]([C:2]([CH3:24])([CH3:23])[CH3:1])[CH3:4])[CH2:9][CH2:10]1)[CH:13]=[CH2:14]
Reactant: C=CCC(O)(CCN(C(=O)[O-])[C@@H](C)C(C)(C)C)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-hydroxyhex-5-enyl)carba-mate (2.2 g, 6.27 mmol) in dry THF (25 mL) was added NaH (752 mg, 18.80 mmol) at 0° C. under N2, and the mixture was stirred at rt overnight. The reaction was quenched with water, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford the crude product, which was purified by chromatography to give two isomers of 6-allyl-3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([Cl:17])=[O:15]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1C(=O)Cl

Procedure:
A solution of 5-methyl-3-phenylisoxazole-4-carboxylic acid (1 g) and PCl5 (1 g) in dichloromethane (20 mL) was refluxed for one hour. Then dichloromethane and POCl3 were removed under reduced pressure to give 5-methyl-3-phenylisoxazole-4-carbonyl chloride.
Reaction SMILES: [F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[C:8]([N+:13]([O-])=O)[C:9]([O:11][CH3:12])=[CH:10][C:4]=2[O:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[F:16][C:2]1([F:1])[O:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([NH2:13])=[CH:7][C:5]=2[O:6]1
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])OC(F)(F)O2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N)OC(F)(F)O2
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
2,2-Difluoro-5-methoxy-6-nitrobenzo[d][1,3]dioxole (1.7 g, 7.3 mmol) was dissolved in ethyl acetate (50 mL) and treated with 5% palladium on carbon (200 mg) and hydrogen at 40-50 pounds per square inch (psi) on a shaker. After 90 min, the catalyst was removed by filtration, the solvent was removed by evaporation, and the product dried under vacuum to give the title compound as a brown solid (1.5 g, qt (quantitative)): 1H NMR (400 MHz, CDCl3) δ 6.63 (s, 1H), 6.50 (s, 1H), 3.82 (s, 3H), 3.76 (d, J=23.0 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −50.32 (s); EIMS m/z 203.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].[CH:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:7][O:6][C:4]([CH:3]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:15][CH:2]=[N:1]1)=[O:5]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=Cc1ccccc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1N=COC1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
39/3 mg (0.55 mmole) of (S)-N-methyl-N-[3-(diethylamino) -propyl]-1-[(R)-1',2-bis(diphenylphosphino)ferrocenyl] -ethylamine and 14.1 mg (0.055 mmole) of silver trifluoromethane-sulfonate was stirred in methylene chloride (5.5 ml) at room temperature for 30 minutes, and then, 0.549 g (5.54 mmole) of methyl isocyano-acetate and 0.642 g (6.05 mmole) of benzaldehyde was added thereto and stirred for 20 hours at 25° C. in nitrogen After being distilled under conditions of 110° C./0.3 mmHg, 1.0 g of 4- methoxycarbonyl-5-phenyl-2-oxazoline (trans/cis =87/13) was obtained. Yield: 91%. The trans-form and the cis-form were separated from each other by column chromatography, and the optical purity of the transform was determined by means of 1H NMR spectroscopy with the same shift reagent Eu(dcm)3 as Example 1, which was 51% ee. After acid-hydrolysis with 6N HC1, L-threo-β-phenylserine, which is a known compound, was obtained.