Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:40])[C:22]=1[N:23]1[CH2:29][C:28]([F:31])([F:30])[CH2:27][CH:26]([NH:32]C(=O)OC(C)(C)C)[CH2:25][CH2:24]1)=[O:16])=O)(C)(C)C.[F:41][C:42]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([F:50])[C:43]=1B(O)O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].Cl.O1CCOCC1>COC.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:8][C:9]1[S:13][C:12]([C:43]2[C:42]([F:41])=[CH:47][C:46]([O:48][CH3:49])=[CH:45][C:44]=2[F:50])=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:40])[C:22]=1[N:23]1[CH2:24][CH2:25][CH:26]([NH2:32])[CH2:27][C:28]([F:30])([F:31])[CH2:29]1)=[O:16]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: COC
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3N3CCC(N)CC(F)(F)C3)c(N)s2)c(F)c1
Temperature: 120 °C
Yield: 6.3 %

Procedure:
To a solution of tert-butyl 1-(4-(5-(tert-butoxycabonyl-amino)-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate (200 mg, 0.31 mmol) in dimethyl ether (3 mL) was added 2,6-difluoro-4-methoxyphenylboronic acid (101 mg, 0.54 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (50 mg, 0.06 mmol), sodium carbonate (67 mg, 0.63 mmol) and water (1 mL). The mixture was degassed for 5 minutes before being heated in a microwave at 120° C. for 2.5 hour. The mixture was concentrated under reduced pressure and the residue purified via silica gel column chromatography (0-100% EtOAc/isohexane) to give a brown oil. To a solution of this oil in MeOH (10 mL) was added HCl in dioxane (4 M, 10 mL, 40.0 mmol) and the mixture was heated at 40° C. for 3 hr. Purification via preparative HPLC gave 459 as a white solid (10 mg, 6% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.82 (s, 1H), 7.54 (s, 1H), 7.43 (s, 2H), 6.99-6.88 (m, 2H), 3.85 (s, 3H), 3.79-3.50 (m, 4H), 3.47-3.33 (m, 1H), 3.29-3.16 (m, 2H), 3.15-3.05 (m, 1H), 2.29-2.09 (m, 2H), 1.90-1.78 (m, 1H), 1.77-1.65 (m, 1H), 1.62 (s, 2H). LCMS (ES+) m/z 514 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:14])[C:6]2=O.[BH4-].[Na+].Cl>C1COCC1.CO>[Br:12][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[C:3]2[C:7]=1[CH:6]=[C:5]([CH3:14])[CH2:4]2
Reactant: Cc1cc(Br)c2c(c1Br)C(=O)C(C)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=Cc2c(Br)c(C)cc(Br)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 16.9 g (52.2 mmol) of 4,7-dibromo-2,6-dimethyl-1-indanone in 300 ml of THF-methanol (2:1, vol.), 3.80 g (100 mmol) of NaBH4 was added in small portions over 1.5 hours at −5° C. (Caution: temperature must be lower 0° C.). The mixture was stirred overnight at ambient temperature. The resulting mixture was acidified with 10% HCl to pH=4. The organic layer was separated; the aqueous layer was extracted with 3×100 ml of methyl-tert-butyl ether. The combined organic fractions were dried over Na2SO4 and evaporated to dryness. To the residue 500 ml of toluene were added. This toluene solution was treated with pTolSO3H (ca. 5 g) for 2 hours at reflux. Then, one more portion (ca. 5 g) of pTolSO3H was added, and the mixture was refluxed for an additional 2 hours. The resulting mixture was cooled to room temperature and passed through a short Silica Gel 60 column (40-63 μm, d 40 mm, 1 100 mm). This column was additionally eluted with 600 ml of hexanes. The combined extract was evaporated to dryness to give a white solid of the title product. Yield 13.6 g (85%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH:7](Br)[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1.C1CCN2C(=NCCC2)CC1.Cl.[OH2:52]>>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:52])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:12][C@@H:11]1[OH:37]
Reactant: O
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](CC(=O)CCCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Temperature: 0 °C

Procedure:
Under an atmosphere of nitrogen, a solution of 970 mg of (13E)-(5RS,6RS-9α,11α,15S)-5-bromo-6,9-epoxy-11,15-bis(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester (prepared as described in Reference Example 1) and 2 ml of DBU was stirred at room temperature overnight, and then cooled to 0° C. 6 ml of water was added to the reaction mixture, which was then acidified to pH 1 with 1 N hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give the crude title compound having the following physical characteristic:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:29]=[CH:28][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][C:3]=1[F:30].FC(F)(F)C(O)=O.[SH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].[OH-].[Na+]>C(Cl)Cl>[C:41]([CH2:40][CH2:39][S:38][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([F:30])[CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:43])=[O:42]
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc21
Reactant: O=C(O)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc21
Temperature: 0 °C
Yield: 52.4 %

Procedure:
While stirring under ice cooling, 1 g of 2-(7-chloro-6-fluoroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine was added to a mixed solution of 8 ml of trifluoroacetic acid and 6 ml of methylene chloride, then 0.25 g of 3-mercaptopropionic acid was added to the solution and the mixture was stirred under ice cooling for 2 hours. After completion of the reaction, 180 ml of ice water was added the mixture, the mixture was adjusted to about pH 3 with a 1N-sodium hydroxide aqueous solution and then the aqueous layer was extracted with 200 ml of methylene chloride. The organic layer was washed with water and dried over anhydrous sodium sulfate and the residue obtained by removing the solvent under reduced pressure was recrystallized from ethyl acetate to obtain 0.63 g of the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=2)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:20][N:19]=[C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:17]=1.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:43]([N:24]1[CH2:25][CH2:26][CH:21]([C:18]2[N:17]=[C:16]([NH:15][C:14]3[N:13]=[CH:12][C:11]([O:27][C:28]4[CH:29]=[CH:30][C:31]([CH:32]=[O:33])=[CH:34][CH:35]=4)=[CH:10][C:9]=3[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[S:20][N:19]=2)[CH2:22][CH2:23]1)(=[O:45])[CH3:44]
Reactant: O=Cc1ccc(Oc2cnc(Nc3nc(C4CCNCC4)ns3)c(Sc3ccccc3Cl)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Oc4ccc(C=O)cc4)cc3Sc3ccccc3Cl)n2)CC1
Reaction time: 0.33 h
Yield: 96.6 %

Procedure:
4-(5-(2-chlorophenylthio)-6-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)pyridin-3-yloxy)benzaldehyde (154 mg, 0.294 mmol) was dissolved in methylene chloride (3 mL) and triethylamine (81.9 μL, 0.588 mmol) and acetic anhydride (33.3 μL, 0.353 mmol) were added. After stirring for 20 minutes, the reaction was poured into saturated aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer was concentrated to afford 4-(6-(3-(1-acetylpiperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-chlorophenylthio)pyridin-3-yloxy)benzaldehyde (161 mg, 0.284 mmol, 96.8% yield).
Reaction SMILES: C[O:2][C:3](=[O:5])[O-:4].[CH3:6][N+:7]([CH3:10])([CH3:9])[CH3:8]>O>[C:3](=[O:2])([O-:5])[OH:4].[CH3:6][N+:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: O
Product: O=C([O-])O
Reaction time: 3 h

Procedure:
108.0 g of tetramethylammonium monomethylcarbonate and 72.0 g of water were introduced in the same reactor as used in Preparation Example 1 and heated with stirring. After the temperature in the reactor reached 100° C., the reaction was continued for 3 hours at 100° C. Tetramethylammonium hydrogencarbonate was obtained in a yield of 96.7 mol %.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([C:36]3(O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[CH:28]2)(=[O:25])=[O:26])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3(O)CCCCC3)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCCC3)c3ccccc32)cc1
Reaction time: 1.5 h
Yield: 87 %

Procedure:
Under N2, add triethylsilane (676 mg, 0.929 ml, 5.82 mmol, 2.6 eq) followed by trifluoroacetic acid (4.08 g, 2.7 ml, 35.79 mmol, 16.0 eq) to a CH2CL2 solution (20 ml) of 4-[3-(1-Hydroxy-cyclohexyl)-indole-1-sulfonyl]-benzoic acid methyl ester (925 mg, 2.24 mmol, 1 eq). Stir for 1.5 hours and then remove volatiles on rotovap. Add EtOAc to crude mix and workup with sat aqueous sodium bicarbonate. Extract product into organics, separate organics, dry over MgSO4, and concentrate on rotovap to give crude product as a pink oil. Purify by silica gel chromatography to give 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid methyl ester (775 mg, 87% yield) as a white solid. Mass Spectrum (m/e): 397.99 (MH+).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]([CH3:13])[C:9](=[O:12])[CH:10]=[CH2:11])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Br[C:31]1[CH:42]=[N:41][C:34]2[NH:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][C:33]=2[CH:32]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]([C:4]1[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]([CH3:13])[C:9](=[O:12])/[CH:10]=[CH:11]/[C:31]1[CH:42]=[N:41][C:34]2[NH:35][C:36](=[O:40])[CH2:37][NH:38][CH2:39][C:33]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: O=C1CNCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1cccc(C(C)C)c1OCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCC(=O)N3)cccc1C(C)C
Yield: 32.1 %

Procedure:
A solution of N-(3-isopropyl-2-propoxybenzyl)-N-methylacrylamide (0.385 g, 1.40 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.39 mL, 2.25 mmol) and 7-bromo-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.07 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.024 g, 0.10 mmol) and P(o-tol)3 (0.065 g, 0.21 mmol) were then added and the solution deoxygenated with Ar for 20 min. The solution was heated to reflux for 18 h, then allowed to cool. The solution was diluted with H2O (30 mL) and the mixture was washed with EtOAc (3×50 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 95:5) gave the title compound (0.15 g, 33%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.08-10.05 (m, 1H), 8.45-8.39 (m, 1H), 8.03-7.93 (m, 1H), 7.55-7.49 (m, 1H), 7.32-7.20 (m, 2H), 7.13-7.04 (m, 1H), 6.88-6.86 (m, 1H), 4.81-4.66 (m, 2H), 3.91-3.86 (m, 2H), 3.76-3.69 (m, 2H), 3.63-3.60 (m, 2H), 3.30-3.25 (m, 1H), 3.12-2.90 (m, 4H), 1.83-1.75 (m, 2H), 1.24-1.17 (m, 6H), 1.06-1.01 (m, 3H).
Reaction SMILES: BrBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:34]=[CH:33][N:32]([NH:35][C:36](=O)[CH2:37][N:38]2[CH:46]=[N:45][C:44]3[C:39]2=[N:40][CH:41]=[N:42][C:43]=3[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C:31]=1[C:56]([NH:58][C@@H:59]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH3:60])=[O:57].N>ClCCl>[Cl:29][C:30]1[CH:34]=[CH:33][N:32]2[C:31]=1[C:56](=[O:57])[N:58]([C@@H:59]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH3:60])[C:36]([CH2:37][N:38]1[CH:46]=[N:45][C:44]3[C:39]1=[N:40][CH:41]=[N:42][C:43]=3[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[N:35]2
Reactant: C[C@@H](NC(=O)c1c(Cl)ccn1NC(=O)Cn1cnc2c(NC(=O)OC(C)(C)C)ncnc21)c1ccccc1
Agent: BrBr
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)n1c(Cn2cnc3c(NC(=O)OC(C)(C)C)ncnc32)nn2ccc(Cl)c2c1=O
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of bromine (37 mg, 0.24 mmol) in dichloromethane (100 μL) was added dropwise to a solution of triphenylphosphine (63 mg, 0.24 mmol) in dichloromethane (1 ml) under nitrogen. The solution was stirred for 30 min, and triethylamine (78 μL, 0.56 mmol) and tert-butyl [9-(2-{[3-chloro-2-({[(1R)-1-phenylethyl]amino}carbonyl)-1H-pyrrol-1-yl]amino}-2-oxoethyl)-9H-purin-6-yl]carbamate (100 mg, 0.19 mmol) were added. The reaction mixture was refluxed for 1.5 h, and quenched with 10% aqueous sodium bicarbonate solution. The organic phase was separated, dried (sodium sulphate) and concentrated to obtain an oil that was treated with 6 ml of a 7M methanolic solution of ammonia at 60° C. in a sealed vessel. The solvent was then evaporated to obtain 66 mg (34% yield, 48% purity) of tert-butyl [9-({5-chloro-4-oxo-3-[(1R)-1-phenylethyl]-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl}methyl)-9H-purin-6-yl]carbamate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:22]C(OC(C)(C)C)=O)[C:11]([O:13][C@H:14]([CH3:21])[C@H:15]([O:17][C:18](=[O:20])[CH3:19])[CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[ClH:30]>O1CCOCC1>[ClH:30].[NH2:22][C@@H:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:11]([O:13][C@H:14]([CH3:21])[C@H:15]([O:17][C:18](=[O:20])[CH3:19])[CH3:16])=[O:12]
Reactant: CC(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)O[C@H](C)[C@@H](C)OC(=O)[C@@H](N)Cc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
(1R,2R)-2-Acetyloxy-1-methylpropyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate (8) (0.4 g, 0.97 mmol) was dissolved in 8 mL of 4M HCl in 1,4-dioxane. The resulting mixture was stirred at room temperature for 60 min. After removing dioxane, acetonitrile (5 mL) was added. The title compound (5) (0.16 g, 53% yield) was crystallized and collected by filtration. 1H NMR (400 MHz, CD3OD): δ 1.19 (d, J=6.4 Hz, 3H), 1.21 (d, J=6.4 Hz, 3H), 2.04 (s, 3H), 3.02 (dd, J=12.0, 6.4 Hz, 1H), 3.07 (dd, J=12.0, 6.4 Hz, 1H), 4.21 (t, J=6.4 Hz, 1H), 4.95 (m, 1H), 5.04 (m, 1H), 6.57 (dd, J=8.0, 2.0 Hz, 1H), 6.67 (d, J=2.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H). MS (ESI) m/z 312.2 (M+H)+ and 310.2 (M−H)−.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[CH:14]=[C:15]([C:25]([F:28])([F:27])[F:26])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:5]([O:4][C:2]([N:22]1[CH2:23][CH2:24][N:19]([C:16]2[C:15]([C:25]([F:28])([F:26])[F:27])=[CH:14][C:13]([Br:12])=[CH:18][N:17]=2)[CH2:20][CH2:21]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: FC(F)(F)c1cc(Br)cnc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2ncc(Br)cc2C(F)(F)F)CC1
Temperature: 0 °C

Procedure:
Benzyl chloroformate (806 μL, 5.7 mmol, Aldrich) was added dropwise to a mixture of 1-(5-bromo-3-trifluoromethyl-pyridin-2-yl)-piperazine (1.6 g, 5.2 mmol, Example 112a) and diisopropylethylamine (1.1 mL, 6.24 mmol, Aldrich) in dichloromethane (35 mL) with stirring at 0° C. The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (2%-100% EtOAc/hexane) to give the title compound as an orange oil. MS (ESI, positive ion) m/z: 444 (M+1).
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]([F:31])([F:30])[C:8]([F:29])([F:28])[C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5])[CH3:2].[H-].[Na+].[CH2:34]([O:41][C:42]([N:44]1[CH2:46][CH2:45]1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:1]([N:3]([CH2:46][CH2:45][NH:44][C:42]([O:41][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:43])[S:4]([C:7]([F:31])([F:30])[C:8]([F:28])([F:29])[C:9]([F:26])([F:27])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5])[CH3:2]
Reactant: O=C(OCc1ccccc1)N1CC1
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCNC(=O)OCc1ccccc1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C

Procedure:
5.272 g (10 mmol) of perfluorooctylsulfonic acid-N-ethylamide is dissolved in 30 ml of dimethylformamide. With exclusion of moisture, it is mixed with 330 mg (11 mmol) of sodium hydride (80% in oil). After gas generation is completed, the solution of 2.093 g (10 mmol) of N-benzyloxycarbonyl-aziridine is added dropwise to it. It is poured into 300 ml of ice water, extracted with dichloromethane, the organic solution is washed with water, it is dried on sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel with dichloromethane/methanol. The title compound is a glass-like solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[CH2:7]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na]>CO>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:24][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: COC(=O)CBr
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCOc1ccc(C(=O)OCC(=O)OC)cc1
Reaction time: 1.5 h

Procedure:
Following the addition of 11.2 g (73 mMols) of bromoacetic acid methyl ester, a suspension of 20 g (67 mMols) of p-decyloxybenzoic acid, sodium salt, in 100 ml of methanol was heated for 3 hours and, after the addition of another 2 ml of bromoacetic acid methyl ester, for another 1.5 hours to boiling temperature. After the volatile constituents had been distilled off, the residue was extracted cold with methylene chloride, the solution was washed with water, concentrated by evaporation, the oily residue was taken up in petroleum ether, the solution was treated with active carbon and then reconcentrated by evaporation. p-decyloxybenzoyloxy acetic acid methyl ester melting at 30° to 32° C. was obtained in a yield of 15.8 g (68%). Purification by column chromatography (SiO2, Merck/methylene chloride:toluene=7:3) produced pure ester melting at 32.5° to 34° C.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].OCC[C:14]#[N:15]>>[O:4]=[C:1]([CH2:2][CH3:3])[CH2:5][C:6]([O:8][CH2:9][CH2:10][C:14]#[N:15])=[O:7]
Reactant: CCOC(=O)CC(=O)CC
Reactant: N#CCCO
Product: CCC(=O)CC(=O)OCCC#N
Temperature: 192.5 °C
Yield: 55.5 %

Procedure:
A mixture of 4.86 g of ethyl propionylacetate (33.7 mmol) and 2.00 g of 3-hydroxypropionitrile (28.1 mmol) were placed in a round bottom flask (magnetically stirred) equipped with a short distillation path. The resulting mixture was gradually heated to 180-205° C. in an oil bath. The distillate was collected (1.2 mL). The mixture was then cooled to room temperature and the residue was distilled under reduced pressure to give 2.64 g of product: bp 95-98° C. (0.5 mm Hg). The product was used in the next step after spectral characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:21]O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[O:13][C:14]=1[CH3:15].S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:21][Cl:25])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[O:13][C:14]=1[CH3:15]
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cc1Cl
Reactant: O=S(Cl)Cl
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1Cl
Reaction time: 2 h
Yield: 94 %

Procedure:
(3-Chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}phenyl)methanol (4.0 g) was added to thionyl chloride (10 mL) at 0° C., and the mixture was stirred for 2 hrs. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-(2-chloro-4-chloromethylphenoxy)methyl-2-(2-furyl)-5-methyl-1,3-oxazole as colorless crystals (3.96 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 103-104° C.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CCC(Oc1ccc(F)cc1F)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(F)cc1F)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 18.9 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.24 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2,4-difluorophenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 49, above] and 24.8 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 163 mg of the title compound as white crystals, melting at between 153° and 155° C.