Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].[NH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(=O)CC.[Cl-].[Na+].O.[I-].[Li+].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(CBr)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 96.7 %

Procedure:
A stirred mixture of 4-bromomethyl-2-nitro-benzoic acid methyl ester (66.3 g, 241.9 mmol), di-tert-butyl iminodicarboxylate (52.72 g, 242.6 mmol), cesium carbonate (161.58 g, 495.9 mmol), and lithium iodide (1.62 g, 12 mmol) in 2-butanone (700 mL) was heated to reflux in a 100° C. oil bath for 12 hours while stirred with a mechanical stirrer. The mixture was allowed to cool to room temperature. To the mixture, was added brine (300 mL), water (300 mL), and ethyl acetate (600 mL), and the mixture was stirred for 10 minutes. The suspension was filtered through a pad of Celite. The two layers were separated, and the organic layer was evaporated to a less volume. The aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine (1×500 mL), dried over magnesium sulfate while de-colored at the same time by charcoal at room temperature with stirring for 30 minutes. The black mixture was filtered through a pad of Celite, and the filtrate was evaporated to give 4-(di-tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester as a brown oil (96.0 g, 96.7% yield). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14](Br)[CH:13]3[CH2:19][CH:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([Cu])#[N:30]>CN(C=O)C.O.ClCl.[Cu]I>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([C:29]#[N:30])=[C:13]3[CH2:19][CH:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(CCC)C1CC2CN(C(=O)c3ccccc3)C3=C2C(C1)C(Br)C=C3
Reactant: N#C[Cu]
Agent: [Cu]I
Agent: ClCl
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(C1)CN3C(=O)c1ccccc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To a solution of (±)-1-benzoyl-6-bromo-4-(di-n-propylamino) hexahydrobenz[cd]indole (5.5 g, 12.5 mmol) in DMF (100 mL) under a N2 atmosphere was added 3.4 g (37.5 mmol) of CuCN and 7.1 g (37.5 mmol) of CuI. The reaction mixture was then stirred at 140° C. for 6 hr. The reaction mixture was poured onto ice, diluted with water, CH2 Cl2 added and stirred for 30 minutes. The mixture was filtered through a Celite pad and the filtrate was extracted twice with CH2 Cl2. The organic solution was washed twice with saturated NaCl solution. The CH2Cl2 solution was dried over MgSO4 and then evaporated to provide 4 g of a solid. Chromatography of this crude product over silica gel with 1:19 MeOH/CH2Cl2 as eluent gave 3 g (62%) of product.
Reaction SMILES: [Na].[NH2:2][C:3]1[NH:22][C:6]2=[CH:7][C:8]3[C:9]([CH3:21])([CH3:20])[C:10](=[O:19])[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=3[CH:13]=[C:5]2[N:4]=1.[BH4-].[Na+].[CH3:25]O>O>[CH3:20][C:9]1([CH3:21])[C:8]2[CH:7]=[C:6]3[NH:22][C:3]([NH:2][CH3:25])=[N:4][C:5]3=[CH:13][C:12]=2[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]1=[O:19]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC)nc3cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Freshly cut sodium (300 mg) is dissolved in dry MeOH (12 ml) and D5 (700 mg) is added and the mixture stirred for 5 min. Then p-formaldehyde (102 mg; 3.4 mmol) is added and the mixture stirred for 20 h at RT. After the addition of NaBH4 (93 mg; 2.46 mmol) the solution is heated under reflux for 2 h, cooled to RT and diluted with water. The aqueous layer is extracted with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4 and concentrated in vacuo. The compound (700 mg) is obtained by flash chromatography on silica gel eluted with CH2Cl2/MeOH (95:5).
Reaction SMILES: [C:1]([O:9][C:10]1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(OC)OC.C(=O)(OC1C=CC=CC=1)OC.C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccccc1)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: COC(=O)Oc1ccccc1
Solvent: COC(=O)OC
Product: COC(=O)c1ccccc1
Yield: 40 %

Procedure:
Into an autoclave made of SUS316 having an internal volume of 100 ml were charged the above-produced phenyl benzoate 30 g (151 mmole), dimethyl carbonate 6.82 g (75.7 mmole) and titanium tetraisopropoxide 0.43 g (1.51 mmole). The pressure was elevated to 20 kg/cm2 with nitrogen, and the contents were reacted for three hours at 150° C. After completing the reaction, the reaction mixture was analyzed by gas chromatography. As a result, the yield of methyl phenyl carbonate was 19%, and the yield of diphenyl carbonate was 21%. Furthermore, at the same time, methyl benzoate was produced as a by-product with a yield of 40% (the yield was based on phenyl benzoate).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:8][CH2:9][CH:10]=[CH2:11])([CH3:7])[CH3:6])C.[BH4-].[Li+].[Cl-].[NH4+].Cl>O1CCCC1>[CH2:9]([O:8][C:5]([CH3:7])([CH3:6])[CH2:4][OH:3])[CH:10]=[CH2:11]
Reactant: C=CCOC(C)(C)C(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CCOC(C)(C)CO
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A solution of 2-allyloxy-2-methyl-propionic acid ethyl ester (1.72 g, 10 mmol) in anhydrous tetrahydrofuran (40 mL) was stirred at room temperature under nitrogen. Lithium borohydride (44 mg, 20 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was cooled to 0° C. and saturated ammonium chloride solution was cautiously added followed by hydrochloric acid (2 M) to acidify the reaction mixture to pH 2. The mixture was extracted with diethyl ether and the organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford 2-allyloxy-2-methyl-propan-1-ol (10 mmol) which was used crude in the next step. LCMS (m/z) 153.2 [M+Na], Tr=1.16 min. A suspension of 2-allyloxy-2-methyl-propan-1-ol (10 mmol) in dichloromethane (40 mL) was stirred at 0° C. Meta-chloroperbenzoic acid (70% pure containing 20% water and 10% meta-chlorobenzoic acid, 2.9 g, 12 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 24 h. The reaction mixture was cooled to 0° C. and saturated sodium hydrogen carbonate solution and sodium thiosulfate solution were added and the mixture was stirred at 0° C. for 15 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (4×). The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford 2-methyl-2-oxiranylmethoxy-propan-1-ol (10 mmol) which was used crude in the next step. LCMS (m/z) 169.2 [M+Na], Tr=0.72 min. A solution of 2-methyl-2-oxiranylmethoxy-propan-1-ol (10 mmol) in dichloromethane (50 mL) and racemic camphor-10-sulfonic acid (765 mg, 3.3 mmol) was stirred at room temperature for 18 h. Saturated sodium hydrogen carbonate solution was added and the organic layer separated. The aqueous layer was extracted with dichloromethane and the organic extracts were combined, filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 2:3 to 1:4 to afford the title compound (826 mg, 57% over 3 steps) as a yellow oil. 1H NMR (300 MHz, d6-DMSO): δ 1.02 (s, 3H), 1.20 (s, 3H), 3.23 (d, J=11.1 Hz, 1H), 3.30-3.50 (m, 6H), 4.68 (t, J=5.4 Hz, 1H). LCMS (m/z) 169.2 [M+Na], Tr=0.72 min.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH:19]=[C:20]([C:22](O)=[O:23])[N:21]=3)=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(Cl)CCl.[CH:29]1[CH:30]=CC2N(O)N=[N:35][C:33]=2[CH:34]=1.N1CCCC1>CN(C=O)C.CCOC(C)=O.O>[N:35]1([C:22]([C:20]2[N:21]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][N:1]4[C:9]5[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=5)[CH:3]=[CH:2]4)=[CH:12][CH:13]=3)[O:18][CH:19]=2)=[O:23])[CH2:30][CH2:29][CH2:34][CH2:33]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1coc(-c2ccc(Cn3ccc4ccccc43)cc2)n1
Solvent: ClCCCl
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(c1coc(-c2ccc(Cn3ccc4ccccc43)cc2)n1)N1CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
A stirred solution of 2-[4-(1H-indol-1-ylmethyl)phenyl]-1,3-oxazole-4-carboxylic acid (0.4 g, 1.26 mmol) in DMF was treated sequentially with EDC (0.29 g, 1.51 mmol), HOBt (0.186 g, 1.38 mmol) and pyrrolidine (0.098 g, 11.38 mol) was stirred at 80° C. overnight. The resultant residue was dissolved in EtOAc and water. The layers were separated and the aqueous layer was washed with EtOAC. The combined organic layers were washed successively with water, saturated sodium chloride, dried over Mg2SO4 and concentrated under reduced pressure to give a crude oil. The oil was purified by column chromatography (silica, MeOH:CH2Cl2 5%) to give the title product in 44% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 372 (MH+).
Reaction SMILES: [CH3:1][S:2][C@H:3]1[CH2:7][NH:6][C@@H:5]2[C@@H:8]([OH:11])[CH2:9][O:10][C@H:4]12.C(=O)([O-])[O-].[Na+].[Na+].[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33](Cl)=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>O1CCOCC1.O>[OH:11][C@@H:8]1[C@H:5]2[N:6]([C:33]([O:32][CH2:31][CH:29]3[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:22]4[C:30]3=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:34])[CH2:7][C@H:3]([S:2][CH3:1])[C@H:4]2[O:10][CH2:9]1
Reactant: CS[C@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CS[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of (3R,3aR,6S,6aS)-6-(methylthio)hexahydro-2H-furo[3,2-b]pyrrol-3-ol in 1,4-dioxane (5 mL) was added whilst stirring to a solution of sodium carbonate (123 mg, 1.16 mmol) in water (1.5 mL) at 0° C. A solution of 9-fluorenylmethoxycarbonyl chloride (150 mg, 0.58 mmol) in 1,4-dioxane (1.5 mL) was added dropwise over 5 minutes then the mixture allowed to warm to ambient temperature over 2 hours. Water (20 mL) was added and the product extracted into dichloromethane (3×10 mL). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with diethyl ether:pentane mixtures 2:1 gave alcohol (55) as a white solid (130 mg, 60%). TLC (Rf=0.19, Et2O:pentane 2:1); HPLC-MS 398.2 [M+H]+, 420.1 [M+Na]+, 817.3 [2M+H]+; analytical HPLC single main peak, Rt=16.096 min., [α]D17−59.4° (c=2.78, CHCl3); δH (500 MHz, CDCl3) mixture of rotamers major:minor 4:3; 1.06 (0.57H, d, J=3.63 Hz, OH major), 2.04 (1.71H, s, SCH3 major), 2.14 (1.29H, s, SCH3 minor), 2.57 (0.43H, d, J=2.83 Hz, OH minor), 3.10 (0.57H, d, J=5.40 Hz, FmocNCH2 major), 3.21-3.24 (0.43H, m, FmocNCH2 minor), 3.41 (0.57H, dd, J=12.18 and 5.57 Hz, OCH2CHOH major), 3.52-3.82 (4.43H, m, FmocNCH, CHSCH3 OCH2CHOH minor, 1×FmocNCH2 and 1×OCH2CHOH), 3.92 (0.43H, dd, J=9.85 and 4.41 Hz, OCH2CHOH minor), 4.23-4.84 (4.57H, m, Fmoc CH, OCHCHSCH3, Fmoc CH2 minor and 1×OCH2CHOH major), 7.28-7.80 (8H, Fmoc aromatic CH); δC (125 MHz, CDCl3) 14.574/14.768 (SCH3), 47.234, 47.445, 48.069 and 48.826 (Fmoc CH and CHSCH3), 50.417/50.633 (FmocNCH2), 65.752/67.282 (Fmoc CH2), 68.555/69.282 (FmocNCH), 74.361/74.600 (OCH2CHOH), 75.774/76.148 (OCH2CHOH), 85.505/86.026 (OCHCHOCH3), 119.848, 120.003, 120.029, 124.512, 124.593, 124.946, 127.030, 127.063, 127.427, 127.507, 127.755, 127.771 and 127.892 (Fmoc aromatic CH), 141.196, 141.320, 141.378, 141.428, 143.581, 143.818, 143.890 and 143.964 (Fmoc quaternary), 154.115/154.849 (Fmoc C═O).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[C:15](=O)[CH3:16].[NH2:21][C:22]1[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=1>C(O)(C)C>[C:18]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:23]2[C:24](=[O:28])[NH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:15]=1[CH3:16])(=[O:20])[CH3:19]
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Reactant: Nc1cc[nH]c(=O)c1
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12

Procedure:
4.00 g (14.79 mmol) of 3-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione and 1.63 g (14.79 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] are dissolved in 40 ml of isopropanol and heated at the reflux temperature under argon for 4 days. The mixture is then concentrated and the residue is recrystallized from methanol. 4.1 g (76% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[CH:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20].[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][C:27]([Si:24]([CH3:26])([CH3:25])[O:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([CH:18]([OH:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[CH:12]=1)([CH3:30])[CH3:29]
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C(O)C(C)(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)C(C)(C)C)c1
Reaction time: 16 h
Yield: 75.7 %

Procedure:
To a stirred solution of 66.13G (0.500 g, 2 mmol) in DCM (10.00 mL) at 23° C. was added tert-butyidimethylsilyl chloride (0.3 mL, 2 mmol), followed by TEA (0.3 mL, 2 mmol) and DMAP (0.02 g, 0.2 mmol). The reaction was then stirred for 16 hours and concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 69.16A as a colorless oil (0.655 g, 96% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[Li])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OC1C=C(OC)C=CC=1Br)C1C=CC=CC=1.[Li]CCCC>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:10]([C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [Li]c1ccc(OC)cc1OCc1ccccc1
Reactant: O=C1OC(=O)c2ncccc21
Agent: COc1ccc(Br)c(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ncccc2C(=O)O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a THF (20 ml) solution of pyridine-2,3-dicarboxylic acid anhydride (1.92 g, 12.9 mmol) was added a THF solution of 2-benzyloxy-4-methoxyphenyllithium (10 ml), which was prepared from 2-benzyloxy-4-methoxyphenyl bromide (3.77 g, 12.9 mmol) and BuLi (1.6M hexane solution, 8.85 ml, 14.2 mmol) at -78° C., at -78° C. over a period of 5 min. The temperature of the mixture was raised to room temperature and the mixture was additionally stirred at the same temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between 1N HCl and AcOEt. The organic layer was washed with 1N HCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 1N NaOH and the solution was washed with AcOEt and chloroform. The aqueous layer was acidified with conc. HCl and extracted with AcOEt. The AcOEt layer was washed with 1N HCl and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from chloroform and chloroform-ether to give 2-(2-benzyloxy-4-methoxyphenylcarbonyl)-3-pyridine carboxylic acid (2,03 g) as a colorless solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39](O)=[O:40])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:52])([CH3:51])[C:48]([NH2:50])=[O:49].[Cl-].[NH4+]>>[C:48]([C:47]([NH:46][C:39](/[CH:38]=[CH:37]/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:45])[CH3:44])=[C:32]([CH3:42])[CH:33]=1)=[O:40])([CH3:52])[CH3:51])(=[O:49])[NH2:50]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(N)=O
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(/C=C/C(=O)NC(C)(C)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 26 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and ammonium chloride, respectively.
Reaction SMILES: [C:1]([C:4]1[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=1[N+:18]([O-])=O)=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:3])[CH3:2].NN>[Ni]>[C:1]([C:4]1[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=1[NH2:18])=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c([N+](=O)[O-])c2ccccc2c2ccccc12
Agent: [Ni]
Agent: NN
Product: CC(=O)c1c(N)c2ccccc2c2ccccc12

Procedure:
The pure 9-acetyl-10-nitrophenanthrene is reduced with hydrazine and Raney nickel to give 9-acetyl-10-aminophenanthrene. This is purified by recrystallization from toluene.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[OH-].[Li+].S(OC)(O[CH3:18])(=O)=O>C1COCC1.C(OCC)C>[CH3:18][O:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccc(C#N)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C)ccc1C#N
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 2-Hydroxy-4-methylbenzonitrile (0.46 g, 3.46 mmol) in THF (17 mL) was added lithium hydroxide monohydrate (0.292 g, 6.95 mmol) followed by dimethyl sulfate (0.50 mL, 5.28 mmol). The resultant mixture was heated to reflux for 2 hours then cooled to room temperature. The mixture was diluted with diethyl ether (50 mL), washed with saturated aqueous NaHCO3 (3×15 mL), dried (MgSO4) and concentrated. Purification of the crude material by column chromatography on silica gel (4:1 hexanes-EtOAc) provided 0.456 g (90%) of 2-methoxy-4-methylbenzonitrile as a white solid. 1H NMR (CDCl3) δ 2.41 (s, 3H), 3.91 (s, 3H), 6.77 (s, 1H), 6.81 (d, 1H, J=6 Hz), 7.43 (d, 1H, J=6 Hz). ES-MS m/z 148 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH:10]=2)[CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:19][N:20]([CH3:22])[CH3:21])=[C:4]([C:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH:10]=2)[CH:3]=1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2N)CC1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1ccc(Br)cc1C1=CCC(C)(C)CC1
Yield: 73 %

Procedure:
A solution of 4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenylamine (as prepared in Example 1, step (a), 3.0 g, 10 mmol) in N,N-dimethylformamide dimethyl acetal (20 mL) was heated at reflux under Ar for 48 h. The solvent was removed under reduced pressure and the residue was purified on silica gel (5-20% EtOAc/hexane) to obtain the title compound (2.6 g, 73%). 1H-NMR (CDCl3; 400 MHz): δ 7.36 (s, 1H), 7.23-7.21 (m, 2H), 6.65 (d, 1H, J=8.0 Hz), 5.64 (m, 1H), 2.97 (s, 6H), 2.37 (m, 2H), 1.95 (m, 2H), 1.44 (m, 2H), 0.99 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]=[C:12]3[NH:16][C@@H:15]([CH:17]([CH2:19][CH3:20])[CH3:18])[CH2:14][S:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]=[C:12]3[N:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C@@H:15]([CH:17]([CH2:19][CH3:20])[CH3:18])[CH2:14][S:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(C)CBr
Reactant: CCC(C)[C@H]1CSC(=Nc2ccc3c(c2)CCC3=O)N1
Product: CCC(C)[C@H]1CSC(=Nc2ccc3c(c2)CCC3=O)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 5-Aminoindan-1-one was converted to 1-oxo-5-indanyl isothiocyanate according to Method A2a. The isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(1-oxo-5-indanylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(1-oxo-5-indanylimino)-4-(2-butyl)-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15]/[C:16](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17]\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:32]>C(O)C.ClCCl>[ClH:32].[C:24]1(/[C:16](=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOC/C(=C\c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCN(CCOC/C(=C\c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The above ester (3.15 g, 8 mmol) was dissolved in absolute ethanol (25 ml) and 4N sodium hydroxide (4.0 ml) was added. After stirring at ambient temperature for 4.5 h the mixture was diluted with dichloromethane (400 ml), cooled to 0° C. and 4N hydrochloric acid (7.5 ml) was added. The mixture was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was re-evaporated with acetone, suspended in diethylether and stirred for 21 days to give an amorphous solid which was triturated 16 h with anhydrous diethylether. This afforded 2.1 g of the title compound as an amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:36]([CH3:35])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(N(C)c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and N-methylaniline.