Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[C:11]([CH:12]=O)[C:10]([OH:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:17](C(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=3[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=Cc1cc(-c2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc2cc(-c3ccccc3)ccc2o1

Procedure:
A mixture of 0.99 g of 1A, 0.96 g of diethyl bromomalonate and 1.25 g of anhydrous potassium carbonate in 20 ml of 2-butanone, was refluxed for 10 hours. The solvent was evaporated under reduced pressure. The residue was cooled, poured into 100 ml of water and extracted with ether. The extract was washed with cold 5% sodium hydroxide solution and water and then concentrated under reduced pressure. The residue was recrystallized from ethanol to give ethyl 5-phenylbenzofuran-2-carboxylate (1B), as white crystals, mp: 109°-110° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:51]([NH:50][C:44]1[N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:47]([F:48])=[CH:46][C:45]=1[F:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)Nc1nc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To 15 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 4.20 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 3.30 g of 2-amino-6-(t-butylamino)-3,5-difluoropyridine. The solution was concentrated under reduced pressure to obtain orange-colored solid residue. To this residue were added 4.0 g of anhydrous potassium carbonate and 8 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 10 minutes and allowed to cool. The solution was separated by adding 50 ml of chloroform and 500 ml of distilled water, and the chloroform layer was washed twice with 500 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 4.67 g of the title compound as a colorless powder.
Reaction SMILES: CN(C)C=O.[C:6](=[O:26])([O:22][CH:23](Cl)[CH3:24])[O:7][CH2:8][CH2:9][CH2:10][C@@H:11]([O:18][N+:19]([O-:21])=[O:20])[C@H:12]([O:14][N+:15]([O-:17])=[O:16])[CH3:13].[CH2:27]([C:31]1[N:32]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]3[N:57]([C:58]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[N:56]=[N:55][N:54]=3)=[CH:43][CH:42]=2)[C:33]([C:37]([OH:39])=[O:38])=[C:34]([Cl:36])[N:35]=1)[CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH2:27]([C:31]1[N:32]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]3[N:57]([C:58]([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)([C:71]4[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[N:56]=[N:55][N:54]=3)=[CH:45][CH:46]=2)[C:33]([C:37]([O:39][CH:23]([O:22][C:6]([O:7][CH2:8][CH2:9][CH2:10][C@@H:11]([O:18][N+:19]([O-:21])=[O:20])[C@H:12]([O:14][N+:15]([O-:17])=[O:16])[CH3:13])=[O:26])[CH3:24])=[O:38])=[C:34]([Cl:36])[N:35]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CC(Cl)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A N,N-dimethylformamide (20 mL) solution of (4R,5R)-4,5-bis(nitrooxy)hexyl 1-chloroethyl carbonate (1.15 g, 3.48 mmol) was added to a stirred N,N-dimethylformamide (20 mL) suspension of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (2.54 g, 3.74 mmol) and cesium carbonate (1.25 g, 3.84 mmol). The solution was stirred at 70° C. for 2 hours. Water (100 mL) was added, and the solution was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 20-60% ethyl acetate/hexanes to give the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J=7.4 Hz, 1H), 7.49 (dt, J=1.4, 7.6 Hz, 1H), 7.45 (dt, J=1.1, 7.5 Hz, 1H), 7.31-7.36 (m, 4H), 7.26 (t, J=7.8 Hz, 6H), 7.10 (d, J=8.0 Hz, 6H), 6.93 (d, J=7.8 Hz, 2H), 6.86 (q, J=5.5 Hz, 1H), 6.79 (d, J=8.0 Hz, 2H), 5.54 (d, J=15.4 Hz, 1H), 5.32 (d, J=16.2 Hz, 1H), 5.14-5.24 (m, 2H), 4.10-4.20 (m, 2H), 2.50 (t, J=7.8 Hz, 2H), 1.7-1.9 (m, 4H), 1.62 (quintet, J=7.7 Hz, 2H), 1.54 (d, J=5.5 Hz, 3H), 1.37 (d, J=6.1 Hz, 3H), 1.27 (sextet, J=7.4 Hz, 2H), 0.85 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([C@H:5]1[C:32](=[O:33])[N:31]2[CH2:34][C@@H:28]([CH2:29][C@H:30]2[C:35]([O:37][CH3:38])=[O:36])[O:27][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([OH:26])=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:39][C@H:9]2[O:8][C:7](=[O:40])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][N:42]1[CH2:47][CH2:46][CH:45](O)[CH2:44][CH2:43]1>>[C:1]([C@H:5]1[C:32](=[O:33])[N:31]2[CH2:34][C@@H:28]([CH2:29][C@H:30]2[C:35]([O:37][CH3:38])=[O:36])[O:27][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([O:26][CH:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:39][C@H:9]2[O:8][C:7](=[O:40])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)CC1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCN(C)CC1)O2
Temperature: 40 °C

Procedure:
Methyl (1aR,55,8S,10R,22aR)-5-tert-butyl-17-hydroxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-8-carboxylate synthesized in example 113, step 5 was reacted with 1-methylpiperidin-4-ol using the procedure described for Example 137 (heating was required: 40° C. for 18 hours). LRMS (ES+) m/z 651.55 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:67]=[CH:68][C:69](=[O:72])[NH:70][CH:71]=1>C(Cl)Cl>[O:72]=[C:69]1[NH:70][CH:71]=[C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:30])[CH:67]=[CH:68]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(=O)[nH]c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(=O)[nH]c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.44 mmol) in methylene chloride (8 mL), HATU (Aldrich, 166 mg, 0.50 mmol) was added followed by the addition of DIPEA (200 uL) and 5-amino-2-pyridinone (Alfa, 97 mg, 0.88 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 40-80% EtOAc/hexanes) to give a solid. 168 mg.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[N:13]=[O:14]
Reactant: Oc1ccc2ccc(O)cc2c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Nc1c(O)ccc2ccc(O)cc12
Reaction time: 2 h

Procedure:
2,7-Dihydroxynaphthalene (BAYER) (250 g=1.56 mol) was dissolved in 875 ml of glacial acetic acid at 0°-90° C. and precipitated again by addition of 2.5 kg of crushed ice. A very finely disperse, light-beige, viscous suspension was formed and the temperature fell to -10° to -12° C. With good stirring and external cooling, 107.88 g (1.56 mol) of solid sodium nitrite were introduced in portions into this suspension, the mixture was stirred for another hour and a further 10.7 g (0.56 mol) of solid sodium nitrite were then added. Stirring was then continued for a further two hours at -8° to -5° C. The 2,7-dihydroxy-1-nitrosonaphthalene formed as dark-red crystals was filtered off with suction and well-pressed on the suction filter. The reaction product, still moist from the suction filter, was then stirred into 5 1 of water at 20°-25° C. for about one hour, again filtered off with suction, pressed down well and dried for 24 hours at 20°-25° C. in a circulating-air oven.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([C:34](=[O:38])[CH:35]=[N+]=[N-])[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:40].C(O)(=O)C>ClCCl>[Br:40][CH2:35][C:34](=[O:38])[CH:25]([NH:24][C:22]([CH:18]1[N:15]2[C:16](=[O:17])[CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][CH2:12][C:13](=[O:39])[N:14]2[CH2:21][CH2:20][CH2:19]1)=[O:23])[CH2:26][C:27]([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)C=[N+]=[N-]
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)CBr
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 506a (2.27 g, 4.2 mmol) in dry dichloromethane (50 ml) was treated with 30% hydrobromic acid in acetic acid (1.84 ml, 9.2 mmol, 2.2 equiv) at 0° C., under nitrogen. After 10 min stirring at 0° C. the reaction was complete and a white solid crystallised in the medium. The solid was filtered and washed with ethylacetate and diethylether to afford 2.20 g (100%) of [3S(1S,9S)] 5-bromo-3-(9-benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxamido)-4-oxopentanoic acid which was used without further purification: 1H NMR (D6-DMSO) δ 8.87 (1H, d, J=7.3), 8.63 (1H, d, J=7.6), 7.91-7.87 (2H, m), 7.60-7.44 (3H, m), 6.92 (1H, bs), 5.14-5.09 (1H, m), 4.92-4.65 (2H, m), 4.43 (2H, AB), 4.41-4.35 (1H, m), 3.33-3.22 (1H, m), 2.98-2.90 (1H, m), 2.89-2.57 (2H, m), 2.35-2.15 (3H, m), 1.99-1.91 (2H, m), 1.75-1.60 (2H, m). A solution of the bromoketone (535 mg, 1 mmol) in dry DMF (10 ml) was treated with potassium fluoride (150 mg, 2.5 mmol, 2.5 equiv), under nitrogen. After 5 min stirring at room temperature, 2-mercaptothiazole (140 mg, 1.2 mmol, 1.2 equiv) was added. After overnight reaction ethylacetate (150 ml) was added and the organic solution was washed with brine, dried over magnesium sulphate and reduced in vacuo. The residue was crystallised in diethyl ether, filtered and purified on silica gel using a gradient of MeOH (0% to 5%) in dichloromethane. Evaporation afforded 344 mg (60%) of a white solid: mp. 90-95° C. (decomp.); [α]D20 −82° (c 0.2, CH2Cl2)); IR (KBr) 3328, 2941, 1745, 1659, 1535, 1422, 1276, 1255, 1223, 1072; 1H NMR (D6-DMSO)δ 8.92 (1H, d, J=7.6), 8.68 (1H, d, J=7.6), 7.98-7.90 (2H, m), 7.75-7.67 (1H, m), 7.64-7.50 (4H, m), 5.22-5.18 (1H, m), 4.95-4.74 (2H, m), 4.58-4.38 (3H, m), 3.52-3.19 (1H, m), 3.05-2.65 (4H, m), 2.40-1.50 (6H, m). Anal. Calcd for C25H27N5O4S2.H2O: C, 50.75; H, 4.94 N, 11.84. Found: C, 51.34; H, 4.70; N, 11.58. MS (ES+) 572.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=[CH:22][C:9]=1[CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[CH2:29]([O:31][CH:32]([O:35][CH2:36][CH3:37])[CH2:33]Br)[CH3:30]>O>[CH2:29]([O:31][CH:32]([O:35][CH2:36][CH3:37])[CH2:33][N:11]([CH2:10][C:9]1[CH:22]=[CH:23][C:24]2[O:28][CH2:27][O:26][C:25]=2[C:8]=1[O:7][CH3:6])[S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH3:30]
Reactant: CCOC(CBr)OCC
Reactant: COc1c(CNS(=O)(=O)c2ccc(C)cc2)ccc2c1OCO2
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 100 °C
Reaction time: 10 h
Yield: 79.3 %

Procedure:
44 mg (1.1 mmol) of 60% oil dispersion of sodium hydride was washed twice with 2 ml of dry hexane to eliminate oil. 2 ml of dry N,N-dimethylformamide, 335 mg (1 mmol) of N-(2-methoxy-3,4-methylenedioxybenzyl)-p-toluenesulfonamide (1) and 0.18 ml (1.1 mmol) of bromoacetaldehyde diethylacetal (purity 95%) were added in order. The resulting mixture was stirred at 100° C. for 10 hours. On cooling, to this 5 ml of water was added and the reaction mixture was extracted with 8 ml and then 2 ml of methylene chloride successively. The liquid extract was washed with 5 ml of water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (eluate: ethylacetate/n-hexane=1/4) to obtain 358 mg of N-(2-methoxy-3,4-methylenedioxybenzyl)-N-(p-toluenesulfonyl)aminoacetaldehyde diethylacetal (2) as an oil. Yield 79%.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:14][C:15]2[S:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][N:19]=2)=[O:13])[N:10]=1)=[O:4].[CH3:23][NH:24][CH3:25].CO.[I-].[K+].Cl>O>[CH3:23][N:24]([CH3:25])[CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:14][C:15]2[S:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][N:19]=2)=[O:13])[N:10]=1)=[O:4]
Reactant: CNC
Reactant: CC(C)c1cnc(NC(=O)Cc2csc(NC(=O)CCl)n2)s1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)c1cnc(NC(=O)Cc2csc(NC(=O)CN(C)C)n2)s1
Yield: 20 %

Procedure:
A mixture of 2-chloro-N-(4-{2-[(5-isopropyl-1,3-thiazol-2-yl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)acetamide (0.5 g, 1.4 mmol), 2M dimethylamine in methanol (3.5 ml, 7 mmol) and potassium iodide (0.116 g, 0.7 mmol) was refluxed for about 6 hours. After cooling, the solution was diluted with water, acidified with 1N HCl and extracted with diethyl ether to eliminate the unreacted products. The aqueous solution was then basified with 1N NaOH and extracted with diethyl ether. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel, using CH2Cl2:MeOH 97:3 and then 95:5 as eluent. The title compound was obtained in 20% yield (0.1 g) as a light yellow solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:15][CH2:16][O:17][C:18](=[O:39])[C@H:19]([OH:38])[CH2:20][C@H:21]([NH2:37])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=2[F:36])=[CH:25][CH:24]=1)(=[O:14])[CH2:11][CH2:12][CH3:13].[OH:40][N:41]1[CH:45]=[C:44]([C:46](O)=[O:47])[N:43]=[N:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C>>[C:10]([O:15][CH2:16][O:17][C:18](=[O:39])[C@H:19]([OH:38])[CH2:20][C@H:21]([NH:37][C:46]([C:44]1[N:43]=[N:42][N:41]([OH:40])[CH:45]=1)=[O:47])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=2[F:36])=[CH:25][CH:24]=1)(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)c1cn(O)nn1
Reactant: CCCC(=O)OCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(=O)OCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
DIPEA (35.8 μL, 206 μmol) was added to a solution of (2R,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid butyryloxymethyl ester (30.0 mg, 68.5 μmol), 1-hydroxy-1H-1,2,3-triazole-4-carboxylic acid (13.3 mg, 103 μmol) and HATU (39.1 mg, 103 μmol) in DMF (500 μL, 6.5 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then concentrated in vacuo to yield a clear yellow liquid. The crude liquid was purified by preparative scale HPLC (C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (9.0 mg). MS m/z [M+H]+ calc'd for C25H26ClFN4O7, 549.15. found 549.1.
Reaction SMILES: Br.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:5][CH:4]=1.O.C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O1CCOCC1>[C:21]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: NCCCCc1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Yield: 110.7 %

Procedure:
4-(4-Hydroxyphenyl)butylamine hydrobromide (4) (197 g, 0.80 mole), water (1 L), 1,4-dioxane (1 L) and sodium bicarbonate (336 g, 4 mole) were combined and stirred while cooled in an ice-methanol cooling bath. Benzyl chloroformate (141 mL, 0.96 mole) was dripped in over 5 min. at −2° C. with no appreciable exotherm observed. This was stirred and allowed to warm to room temperature as the cooling bath thawed overnight. An additional quantity of benzyl chloroformate (8 mL, 0.54 mol) was dripped in and this was allowed to stir for 2 h. The product mixture was then evaporated to approximately 500 mL and transferred to a 2 L separatory funnel with ethyl acetate while decanting away from the solids. The aqueous layer was extracted with ethyl acetate (3×1 L). The extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to afford 265 g of the crude product. A portion of the crude product (130 g) was chromatographed (silica gel, 5:1 hexanes/ethyl acetate) using toluene to load the column. The remaining crude material was crystallized from 1:1 toluene/heptane. This material was suction filtered to collect the solid and washed with 1:1 toluene/heptane. This material was vacuum desiccated at 45° C. for 2 h. The combined yield of compound (29) was 150 g (62%) of a white crystalline solid. 1H NMR (300 MHz, CDCl3) δ 1.43-1.65 (m, 4H), 2.52 (t, J=7.4 Hz, 2H), 3.19 (q, J=6.4 Hz, 2H), 4.78 (br s, 1H), 5.09 (s, 2H), 5.77 (s, 1H), 6.74 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.5 Hz, 2H), 7.34 (s, 5). CI MS m/z=300 [C18H21NO3+H]+.
Reaction SMILES: [CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1.C(OO)(=[O:24])C>>[O:24]1[C:19]([CH3:21])([CH3:20])[CH:18]1[CH2:17][CH2:16][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1
Reactant: CC(=O)OO
Reactant: CC(C)=CCCC(C)=CCOc1ccc2c(c1)OCCC2
Product: CC(=CCOc1ccc2c(c1)OCCC2)CCC1OC1(C)C

Procedure:
Following the procedure of Example 17, 7-(3,7-dimethyl-2,6-octadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3,7-dimethyl-2-octenyloxy)-chromane, nD20 = 1.5341.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:29]\[OH:30])/[C@:18]5(O)[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.CC1C=CC(S(O)(=O)=[O:39])=CC=1.O.C([O-])(O)=O.[Na+]>CC(C)=O>[OH:30]/[N:29]=[C:17]1\[CH2:16][C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[C:18]\1=[CH:19][C:20](=[O:39])[CH2:21][CH2:22]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](C/C(=N\O)[C@@]4(O)CCCC[C@]34C)[C@@H]1CC13OCCOC12OCCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)C=C1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 67 %

Procedure:
A solution of 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6-(E)-hydroxyimino-androstane (Prepn. 27) (1.05 g) and pTSA H2O (4.00 g) in acetone (100 mL) was stirred at room temperature for 5 h. The solution was neutralized by addition of 5% aqueous NaHCO3 and acetone was evaporated. The aqueous suspension was extracted with CH2Cl2 (3×). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/CH2Cl2/acetone 80/10/10) to give the title compound II-bw in 67% yield. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 11.60 (1H, s), 5.90 (1H, s), 3.36 (1H, d), 2.60-1.15 (16H, m), 1.08 (3H, s), 0.82 (3H, s)
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:30])[CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1.O>C1C=CC=CC=1>[Cl:11][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][CH:13]([CH3:30])[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:28][CH:29]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 13.3 %

Procedure:
A solution of 2.5 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8) and 3.58 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione in 50 ml of benzene was heated under reflux for 1.5 hours, whilst the water being formed during the reaction was continuously removed. At the end of this time, the benzene used was removed by distillation under reduced pressure. The resulting residue was dissolved in 100 ml of absolute methanol, and then 3 g of sodium borohydride were added to the resulting solution. The reaction mixture was allowed to stand overnight at room temperature, after which it was concentrated by evaporation under reduced pressure, and the concentrate was mixed with water. The resulting aqueous mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using ethyl acetate, followed by a 10:1 by volume mixture of ethyl acetate and ethanol, as the eluent. The product was recrystallized from ethyl acetate, to give 0.74 g of the title compound as crystals, melting at 100°-125° C.