Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](CC)[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]=[O:21])=[CH:18][N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[C:14]2=[CH:15][N:16]=1)C.[CH2:31]([Mg]Cl)[CH:32]([CH3:34])[CH3:33].[NH4+].[Cl-].[CH2:39]1COCC1>>[CH3:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:39])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([CH:20]([OH:21])[CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:18][N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:29])[CH3:30])=[CH:24][CH:23]=3)[C:14]2=[CH:15][N:16]=1
Reactant: C1CCOC1
Reactant: CCc1cccc(CC)c1-c1cc2c(C=O)cn(-c3ccc(C(C)C)cc3)c2cn1
Reactant: CC(C)C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cccc(C)c1-c1cc2c(C(O)CC(C)C)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (50 mg, 0.13 mmol, prepared by the procedure described in Example 11, Step 3) in THF (2 mL) at −78° C., iso-butylmagnesium chloride (1M solution in THF, 300 μL, 0.32 mmol) is added. The mixture is stirred at −78° C. for two hours and is subsequently allowed to warm to room temperature. A saturated aqueous NH4Cl solution (5 mL) is added, and THF is removed under reduced pressure. The product is extracted with EtOAc. The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Chromatography of the residue affords 1-[5-(2,6-dimethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3-methyl-butan-1-ol as colorless oil. 1H NMR: (CDCl3) 8.97 (s, 1H), 7.64 (s, 1H), 7.9 (s, 1H), 7.48 (d, J=120 Hz, 2H), 7.41 (d, J=10 Hz, 2H), 7.29 (t, J=10 Hz, 1H), 7.15 (d, J=12 Hz, 2H), 5.13 (m, 1H), 3.95 (m, 1H), 2.44 (m, 4H), 1.34 (d, J=14 Hz, 6H), 1.04 (t, J=10 Hz, 6H); LCMS m/z 455.34 (2.58 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:3]1[C:17](Cl)=[O:18].CC1(C)[C@@H](/C=C\C(OCC(F)(F)F)=O)[C@H]1C([O:37][C@H:38]([C:52]#N)[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45]C2C=CC=CC=2)[CH:40]=1)=O.[CH:55]1C=CC=CC=1.Cl>O.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:3]1[C:17]([O:45][CH:41]1[CH2:52][C:38](=[O:37])[C:39]([CH2:44][CH:43]=[CH2:42])=[C:40]1[CH3:55])=[O:18]
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1/C=C\C(=O)OCc1ccccc1
Reactant: c1ccccc1
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: C=CCC1=C(C)C(OC(=O)[C@@H]2[C@H](/C=C\C(=O)OCc3ccccc3)C2(C)C)CC1=O
Reaction time: 6 h

Procedure:
1 g of (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-benzyloxy-1-propenyl]-cyclopropane-carboxylic acid chloride was added to a mixture of 450 mg of (S) 3-(2-propenyl)-1-hydroxy-2-methyl-4-oxo-cyclopent-2-en-1-yl, 20 ml of benzene and 0.6 ml of pyridine and the mixture was stirred for 6 hours and was then poured into a mixture of iced water and N hydrochloric acid. The mixture was extracted with benzene and the combined benzene phases was washed with water, dried and evaporated to dryness. The 1.5 g of residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain (1S) 2-methyl-4-oxo-3-(2propenyl)-2-cyclopenten-1-yl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-benzyloxy-1-propenyl]-cyclopropane-carboxylate having a specific rotation of [α]D20 =+37°±2.5 (c=0.5% in benzene).
Reaction SMILES: OC([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([O:42]C)=O)[CH:34]=[CH:33]2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.[OH:44][C:45](C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)([C:49]1[N:50]=[CH:51][N:52](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:53]=1)[CH:46]([CH3:48])[CH3:47].[CH2:86]([NH2:89])[CH2:87][CH3:88]>>[OH:44][C:45]([C:36]1[C:37]2[C:32](=[CH:31][CH:30]=[CH:39][CH:38]=2)[CH:33]=[CH:34][C:35]=1[C:40]([NH:89][CH2:86][CH2:87][CH3:88])=[O:42])([C:49]1[N:50]=[CH:51][NH:52][CH:53]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCN
Product: CCCNC(=O)c1ccc2ccccc2c1C(O)(c1c[nH]cn1)C(C)C

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.83 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with n-propylamine (0.66 mL) in a similar manner as described in Example 24-(i) to give the titled compound (2.74 g) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[NH2:35][CH:36]1[CH2:41][C:40]([CH3:43])([CH3:42])[NH:39][C:38]([CH3:45])([CH3:44])[CH2:37]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27]([NH:35][CH:36]2[CH2:37][C:38]([CH3:45])([CH3:44])[NH:39][C:40]([CH3:43])([CH3:42])[CH2:41]2)=[O:33])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC1(C)CC(N)CC(C)(C)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NC4CC(C)(C)NC(C)(C)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) to prepare a solution. Triphosgene (110 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 4-Amino-2,2,6,6-tetramethylpiperidine (79 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (66 mg, yield 41%).
Reaction SMILES: [C:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:14](=O)([O-])O.[Na+].O.C(OCC)(=O)C>CN(C)C(=O)C>[CH3:14][O:2][C:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1OCCO2
Reaction time: 24 h

Procedure:
3.46 g (19.2 mmol) of the acid obtained in Step A are added to a mixture of 9.62 g (114.6 mmol) of sodium hydrogen carbonate and 3.57 ml (57.6 mmol) of iodomethanie in 40 ml of N,N-dimethylacetamide. After 24 hours' stirling under argon and protected from light, the solvent is removed by evaporation in vacuo. The residue obtained is then taken up in a 1/1 water/ethyl acetate mixture and the aqueous phase is subsequently extracted with ethyl acetate. After drying over magnesium sulphate and filtration, the solvent is removed by evaporation under reduced pressure. The title ester is obtained pure in the form of a white solid after chromatography over silica gel (eluant:AcOEt/PE:25/75).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][CH2:11][CH2:12][NH:13][CH3:14])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(O)C>[CH3:14][N:13]([CH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:15]=[CH:16][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=1)[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=2)[N:20]=1
Reactant: CNCCCOc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CN(CCCOc1ccc([N+](=O)[O-])cc1)Cc1ccc2cc([N+](=O)[O-])ccc2n1

Procedure:
N-[3-(4-Nitrophenoxy)propyl]methylamine hydrochloride (3.08 g, 12.49 mmol), 2-(chloromethyl)-6-nitroquinoline (2.78 g, 12.49 mmol), and potassium carbonate (3.45 g, 25.0 mmol) were stirred in 2:1 acetonitrile/ethanol (120 mL) at reflux for 18 hours. The mixture was concentrated and the residue was partitioned between 10% aqueous K2CO3 and 4:1 dichloromethane/isopropanol. The organic phase was dried, decolorized and concentrated to afford crude product which was purified by column chromatography (1:2 hexane/ethyl acetate). Yield: 2.63 g (53%) as a yellow oil.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([C:18](=[O:20])[CH3:19])[CH:17]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>C(O)(=O)C>[CH3:22][O:21][C:15]1[CH:14]=[CH:13][C:12]([N:11]2[CH:1]=[N:25][N:24]=[N:23]2)=[CH:17][C:16]=1[C:18](=[O:20])[CH3:19]
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(N)cc1C(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-n2cnnn2)cc1C(C)=O
Temperature: 75 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Triethyl orthoformate (28.79 ml, 25.65 g, 173 mmol) was added to a stirred, heated (80° C.) solution of 1-(5-amino-2-methoxyphenyl)ethanone (8.16 g, 49 mmol) in acetic acid (80 ml) and the mixture was stirred at 75° C. for 1 hour. Sodium azide (9.64 g, 148 mmol) was added in portions over 90 minutes, then the mixture was stirred at 75° C. for 4 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. Hydrochloric acid (1M, 100 ml) was added and the mixture was stirred at room temperature 1 hour. The solid was collected, flushed with toluene (100 ml) and dried in vacuo at room temperature. The residue was recrystallized from ethanol (700 ml) to give 1-[2-methoxy-5-(1H-tetrazol-1-y1)phenyl]ethanone as tan coloured needles (7.88 g, 73%), 1H NMR (d6 -DMSO) δ 10.06 (1H, s), 8.06 (2H, m), 7.46 (1H, d, J=7.8 Hz), 3.99 (3H, s), and 2.60 (3H, s). m/e (CI+) 219 (MH+)
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:11][C:5]3[C:4](=[C:9]([I:10])[CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:13])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: NCCCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cccc2CN1CCCc1cccc(F)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.150 g, 0.42 mmol), 3-(3-fluoro-phenyl)-propylamine (0.091 mL, 0.6 mmol), and K2CO3 (0.138 g, 1 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(3-fluoro-phenyl)-propyl]-7-iodo-2,3-dihydro-isoindol-1-one (0.110 g, 69%). 1H NMR (300 MHz, CDCl3): δ ppm) 2.01 (m, 2H), 2.72 (t, 2H), 3.66 (t, 2H), 4.25 (s, 2H), 6.82-7.24 (m, 5H), 7.41 (d, 1H), 7.92 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([O:1][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: ClCCCBr
Reactant: O=C([O-])c1ccc(O)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)cc1
Yield: 106.7 %

Procedure:
Ethyl, 4-hydroxybenzoate 83.1 g (0.50 mole), 107 ml (1.0 mole) of 1-bromo-3-chloropropane, and potassium carbonate (1.5 mole, 207.3 g) were mechanically stirred in 600 ml of refluxing acetone under nitrogen overnight. The potassium carbonate was removed by filtration, and the filtrate was evaporated under reduced pressure to give 122 g of a liquid. This liquid was dissolved in 250 ml of petroleum ether and with stirring and cooling in an ice/2-propanol bath. A white precipitate formed and was collected by filtration and washed with cold petroleum ether to yield 108 g of a solid. An additional 6 g of the product was obtained from the mother liquor. A small sample of the solid was dissolved in petroleum ether at room temperature. The solution was stirred and cooled in an ice bath. White crystals were collected by filtration, washed with cold petroleum ether and dried under vacuum at room temperature, m.p. 24°-25° C.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[N:87]1([CH2:92][C:93](O)=[O:94])[CH:91]=[CH:90][N:89]=[CH:88]1>>[N:87]1([CH2:92][C:93]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:94])[CH:91]=[CH:90][N:89]=[CH:88]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)Cn1ccnc1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cn3ccnc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except imidazol-1-ylacetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 638.5 (M+H)+, 2.05 min (method 6). 1H NMR (400 MHz, 1:1 CDCl3:MeOD) δ=8.88 (s, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.47 (ddd, J=1.6, 1.8, 9.7 Hz, 2H), 7.42 (s, 1H), 7.20 (d, J=8.5 Hz, 2H), 5.33-5.25 (m, 1H), 5.02 (d, J=5.0 Hz, 2H), 4.78 (d, J=1.3 Hz, 1H), 4.65 (d, J=1.8 Hz, 2H), 2.72 (dt, J=5.3, 11.0 Hz, 1H), 2.66-2.57 (m, 1H), 2.33 (dd, J=8.2, 12.7 Hz, 1H), 2.13 (dd, J=6.3, 17.1 Hz, 1H), 2.00-1.88 (m, 2H), 1.80 (d, J=14.6 Hz, 1H), 1.74 (br. s., 1H), 1.72 (s, 3H), 1.71-1.67 (m, 1H), 1.60-1.32 (m, 11H), 1.30-1.22 (m, 1H), 1.19-1.13 (m, 1H), 1.12 (s, 3H), 1.03 (s, 3H), 1.02 (s, 2H), 0.95 (s, 3H), 0.94 (br. s., 3H).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH2:31][NH2:32].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CS(C)=O>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH2:31][NH:32][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: NCCCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCCc3ccccc3Br)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 20-mL sealed tube, was placed methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (180 mg, 0.60 mmol, 1.00 equiv), toluene/DMSO (5/1 mL), 3-(2-bromophenyl)propan-1-amine (385 mg, 1.80 mmol, 2.99 equiv), and potassium carbonate (414 mg, 3.00 mmol, 4.98 equiv). The resulting solution was stirred overnight at 100° C. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50). This resulted in 240 mg (80%) of methyl 3-(3-(2-bromophenyl)propylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][CH:22]([NH2:27])[CH2:23][CH:24]([CH3:26])[CH3:25].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:21][CH:22]([NH:27][C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CC(C)CC(C)N
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NC(C)CC(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1,3-dimethyl-butylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C18H27NO5 [M−H]−: 336.
Reaction SMILES: C[O:2][C:3]1[C:4](=O)[CH:5]([C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]([CH3:10])([CH3:9])[CH2:7][CH:8]=1.[CH3:19][NH:20][NH2:21]>C(O)(=O)C.O>[CH3:19][N:20]1[C:4]2[C:3](=[O:2])[CH2:8][CH2:7][C:6]([CH3:10])([CH3:9])[C:5]=2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:21]1
Reactant: CCOC(=O)C(=O)C1C(=O)C(OC)=CCC1(C)C
Reactant: CNN
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nn(C)c2c1C(C)(C)CCC2=O
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A solution of ethyl (3-methoxy-6,6-dimethyl-2-oxocyclohex-3-en-1-yl)(oxo)acetate from the previous step (40.2 mmol theoretically) in acetic acid (65 mL) was treated dropwise with a solution of methyl hydrazine (2.14 mL, 40.2 mmol) in acetic acid (20 mL) and allowed to stand at room temperature overnight. The mixture was then diluted with water (800 mL) and extracted with ethyl acetate (500 mL×2). The organic extracts were washed with brine, dried on Na2SO4 and evaporated to dryness. The crude material was chromatographed on silica gel eluted with dichloromethane/ethyl acetate 100:5 to obtain the pure title compound (4.8 g, 47.7% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[CH3:15][O:16][C:17]1([O:28][CH3:29])[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1.Cl[C:31]([O:33][CH3:34])=[O:32]>C1COCC1>[CH3:15][O:16][C:17]1([O:28][CH3:29])[CH2:22][CH2:21][C:20]([C:31]([O:33][CH3:34])=[O:32])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)C1CCC(OC)(OC)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C(=O)OC)CCC(OC)(OC)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a −78° C. solution of iPr2NEt (3.95 mL, 27.7 mmol) in THF (50 mL) was added n-BuLi (17.3 mL of a 1.6 M solution in hexanes; 27.7 mmol) was added. After 15 min, ethyl 4,4-dimethoxycyclohexane-carboxylate (4.0 g, 18.50 mmol) was added and the reaction mixture was stirred at −78° C. for 1 h. Methyl chloroformate (2.87 mL, 37.0 mmol) was added and the reaction mixture was warmed to rt. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (100 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude oil was chromatographed (SiO2; continuous gradient from 0 to 20% EtOAc:hexanes) to afford the title compound (4.7 g, 93% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 4.21 (q, J=7.1 Hz, 2H), 3.75 (s, 3H), 3.19 (s, 6H), 2.16-2.05 (m, 4H), 1.79-1.69 (m, 4H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[C:26]([C:31]([O:33]C)=[O:32])[CH:25]=[CH:24]5)=[CH:17][CH:16]=3)=[C:11]([CH:35]([CH3:37])[CH3:36])[O:10][N:9]=2)=[C:6]([CH3:38])[CH:5]=[CH:4][N:3]=1.CO.[OH-].[Na+].Cl>C1COCC1>[CH3:1][C:2]1[C:7]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[C:26]([C:31]([OH:33])=[O:32])[CH:25]=[CH:24]5)=[CH:17][CH:16]=3)=[C:11]([CH:35]([CH3:36])[CH3:37])[O:10][N:9]=2)=[C:6]([CH3:38])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(C)ccnc5C)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccnc(C)c1-c1noc(C(C)C)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 100 °C
Yield: 86.1 %

Procedure:
A solution of methyl 6-[4-({[3-(2,4-dimethyl-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (20 mg, 0.04 mmol) in THF (0.4 mL) was placed in a microwave reaction tube followed by methanol (0.20 mL) followed by a 1 N solution of sodium hydroxide (0.08 mL, 0.08 mmol). The tube was sealed and heated to 100° C. for 10 minutes. The solution was neutralized with 1 N HCl and concentrated. The residue was diluted with water and filtered. The resulting solid was dried with P2O5 in a 45° C. vacuum oven under reduced pressure to yield 6-[4-({[3-(2,4-dimethyl-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (17 mg, 86%). 1H NMR (400 MHz, DMSO-d6): δ 13.5-13.2 (br s, 1H), 8.53 (d, J=9 Hz, 1H), 8.38 (d, J=5 Hz, 1H), 8.27 (s, 1H), 8.17-8.08 (m, 3H), 7.74 (d, J=9 Hz, 2H), 7.22 (d, J=5 Hz, 1H), 7.22 (d, J=9 Hz, 2H), 4.79 (s, 2H), 3.47 (septet, J=7 Hz, 1H), 2.24 (s, 3H), 2.08 (s, 3H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 494 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[O:21][CH2:22][O:23][CH3:24])[N:10]=1.C(O)C.[BH4-].[Na+].O>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][C:14]=2[O:21][CH2:22][O:23][CH3:24])[N:10]=1
Reactant: COCOc1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COCOc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)benzaldehyde (15.50 g) in tetrahydrofuran (100 mL)-ethanol (50 mL) was gradually added sodium borohydride (1.71 g) at 0° C. After stirring at room temperature for 2 hrs, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)phenyl)methanol as colorless crystals (14.11 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 92-93° C.