Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]2[CH2:29][CH2:28][C:12]3([CH2:17][C:16](=[O:18])[N:15]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:14](=[O:27])[CH2:13]3)[CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][C:12]3([CH2:13][C:14](=[O:27])[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:16](=[O:18])[CH2:17]3)[CH2:28][CH2:29]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)CC2(CCN(CCc3ccncc3)CC2)CC1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1C(=O)CC2(CCN(CCc3ccncc3)CC2)CC1=O

Procedure:
0.1 g (0.25 mmol) of the ester from Step C were stirred in 2 ml trifluoroacetic acid at room temperature for 30 minutes. The solvent was removed in vacuo, and the remaining title compound was purified by treating with ethanol and dichloromethane, successively, which was removed under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][NH:8][C:9]([C:11]2[C:12](=[O:26])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH:14]=[CH:15][CH:16]=2)=[O:10])[S:5][CH:6]=1.[C:27]1([S:33]([N:36]2[C:40]3=[N:41][CH:42]=[CH:43][CH:44]=[C:39]3[C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37]2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.ClCCl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.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]>[C:27]1([S:33]([N:36]2[C:40]3=[N:41][CH:42]=[CH:43][CH:44]=[C:39]3[C:38]([C:2]3[CH:3]=[C:4]([CH2:7][NH:8][C:9]([C:11]4[C:12](=[O:26])[N:13]([CH2:17][C:18]5[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=5)[CH:14]=[CH:15][CH:16]=4)=[O:10])[S:5][CH:6]=3)=[CH:37]2)(=[O:35])=[O:34])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(NCc1cc(Br)cs1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cs1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 100 °C

Procedure:
Into a Vial was dissolved 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (4-bromo-thiophen-2-ylmethyl)-amide (0.0953 g, 0.217 mmol;), 1-Benzenesulfonyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.3 mmol;) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (28 mg, 0.035 mmol; Strem;) in 1,4-Dioxane (3.69 mL, 47.3 mmol; Acros;). To this was added 2.0 M of Sodium carbonate in water (0.92 mL). The reaction was purged with Ar and sealed. The reaction was heated at 100° C. under an atmosphere of Argon for 2 hours. LC-MS showed the formation of product at 1.80 with the correct mass 661.13. The reaction was worked up by dissolving in methylene chloride then washing 1× with citric acid, 1× with saturated bicarbonate and 1× with brine before drying with magnesium sulfate and concentrating to give the crude product. The crude was then purified by combiflash using a 0-100 percent hex/ea gradient to give pure product. ES (+) MS m/e=661.13
Reaction SMILES: [CH2:1]([O:4][N:5]([C@@H:18]1[CH:23]=[C:22]([CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C@@H:21]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[NH:20][CH2:19]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(ON[C@@H]1C(C)=C[C@@H](CO[Si](C(C)(C)C)(C)C)NC1)C=C>CO.ClCCl>[CH2:1]([O:4][NH:5][C@@H:18]1[CH:23]=[C:22]([CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:28])[CH3:29])[C@@H:21]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[NH:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C
Solvent: CO
Solvent: ClCCl
Product: C=CCON[C@@H]1C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC1
Yield: 85.5 %

Procedure:
The title compound was prepared from N-(allyloxy)-N-((3R,6S)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,6-tetrahydropyridin-3-yl)-2-nitrobenzenesulfonamide (Intermediate 283, 6.49 g, 10.11 mmol) according to the procedure described for Intermediate 12. Silica gel chromatography (0%-5% methanol/dichloromethane) afforded the desired product (3.95 g, 86%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:4]#[N:5])[CH:2]=[CH2:3].[CH2:6]([SiH:9]([Cl:11])[Cl:10])[CH:7]=[CH2:8]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:10][Si:9]([Cl:11])([CH2:3][CH2:2][CH2:1][C:4]#[N:5])[CH2:6][CH:7]=[CH2:8]
Reactant: C=CCC#N
Reactant: C=CC[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C=CC[Si](Cl)(Cl)CCCC#N
Yield: 60081.9 %

Procedure:
Using the same apparatus and procedure described in EXAMPLE 1, 97.9 g (1.46 mol) of allyl cyanide and 350 μl of 1% chloroplatinic acid in isopropanol were added to the flask. Through the dropping funnel was added dropwise 20.6 g (0.15 mmol) of allyldichlorosilane for 30 min at 80° C. and the solution was further reacted for 17.5 hrs to complete the reaction. Vacuum distillation (76-78/0.5 torr) of the product mixture gave 18.76 g (62%) of 4,4-dichloro-7-cyano-4-sila-1-heptene.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[S:19][CH:20]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CCCCO>[C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[S:19][CH:20]=4)[CH:13]=[N:12][C:11]=23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(O)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1

Procedure:
A solution of methyl 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carboxylate (5-2, 2.0 g, 6.0 mmol, 1 equiv) in a mixture of aqueous sodium hydroxide solution (1N, 18 mL, 18 mmol, 3.0 equiv) and n-BuOH (100 mL) was heated at reflux for 1 hour. The reaction mixture was concentrated, and the residue was suspended in aqueous 1 N hydrogen chloride solution (100 mL) and filtered. The filtered solid was washed with water and dried to give 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carboxylic acid (5-3). 1H NMR (400 MHz, DMSO-d6) δ 9.68 (d, 1H, J=2.4 Hz), 9.15 (d, 1H, J=2.2 Hz), 8.79 (s, 1H), 8.48 (d, 1H, J=1.6 Hz), 8.41 (d, 1H, J=1.6 Hz), 8.16 (br d, 1H, J=7.8 Hz), 7.46 (br t, 2H, J=7.8 Hz), 7.26 (t, 1H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>O.CC(OC)(C)C>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
To a flask equipped with a nitrogen inlet, addition funnel, thermowell, and mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and dimethylacetimide (9.6 L). The mixture was cooled to −5° C. in an ice/brine bath and sodium hydride (NaH, 60 wt %, 174 g, 4.35 mol, 1.1 equiv) was added in portions as a solid. The mixture went to a dark solution during 15 minutes and trimethylsilylethoxymethyl chloride (2, 763 mL, 4.31 mol, 1.1 equiv) was added slowly via an addition funnel at a rate that the temperature did not exceed 5° C. The reaction was stirred for 30 minutes, determined to be complete by TLC and HPLC, and water (1 L) was slowly added to quench the reaction. The mixture was then diluted with water (12 L) and MTBE (8 L). The layers were separated and the aqueous was re-extracted with MTBE (8 L). The combined organic layers were washed with water (2×4 L) and brine (4 L), dried over sodium sulfate (NaSO4), and solvents removed under reduced pressure. The residue was dissolved in heptane (2 L), filtered and loaded onto a silica gel (3.5 kg) column eluting with heptane (˜6 L), 95% heptane/ethyl acetate (˜12 L), 90% heptane/ethyl acetate (10 L), and finally 80% heptane/ethyl acetate (10 L). The pure fractions were combined and concentrated under reduced pressure to give 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 987 g, 1109.8 g theoretical, 88.9% yield) as a pale yellow oil that partially solidified to an oily solid on standing at room temperature. For 3a: 1H NMR (DMSO-d6, 300 MHz) δ ppm 8.67 (s, 1H), 7.87 (d, 1H, J=3.8 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.1 Hz), 1.24 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, −1.48; C12H18ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M++H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:27]([O:31][C:32]([O:34][CH:35](I)[CH3:36])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:35]([O:34][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH3:36])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(I)OC(=O)OC(C)(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(OC(=O)OC(C)(C)C)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 42.7 %

Procedure:
In the same manner as in Example 81, 89 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 162 mg of 1-(t-butoxycarbonyloxy)ethyl iodide.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OS(C)(=O)=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc([C@H]2c3ccc(O)cc3OC[C@H]2c2ccccc2)cc1
Temperature: -78 °C

Procedure:
In dry glassware and under a nitrogen atmosphere, (+,-) cis Methanesulfonic acid 4-(7-methoxy-3-phenyl-chroman-4-yl)-phenyl ester (5.0 g, 12.2 mmol) was dissolved in dry methylene chloride (150 ml), and cooled to -78° C. A solution of 1M boron tribromide in methylene chloride was added dropwise with stirring at such a rate that the temperature did not exceed -70° C. The reaction mixture was stirred at -78° C. for 60 min, and for 60 min. after the cooling was removed. A 5% sodium bicarbonate solution (100 ml) was slowly added, and the mixture extracted with ethyl acetate (300+2×25 ml). The combined organic extracts were washed with water and brine, dried (magnesium sulphate) and evaporated.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:25]([OH:27])=[O:26])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@H:29](C(O)=O)[CH2:30]S.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>CCO>[CH2:29]([O:26][C:25](=[O:27])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:30]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CS(=O)(=O)Nc1cccc(CC(NC(=O)OCc2ccccc2)C(=O)O)c1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1cccc(NS(C)(=O)=O)c1)NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Treat the product of Step B (12.5 g) in EtOH (400 mL) with papain (2.56 g freshly ground), L-cysteine (0.156 g) and freshly made 1M citrate buffer pH 4.5 (2.8 mL). After 2 hr, add papain (1.28 g), L-cysteine (0.078 g), and 1M citrate buffer pH 4.5 (1.4 mL). Repeat the latter addition of papain, L-cystein, and citrate buffer at 4 and 6 hr intervals. Stir the resulting mixture for 4 days. Filter, wash with EtOH, and concentrate in vacuo to a residue. Partition the residue between Et2O (1400 mL)/5% NaHCO3 (6×150 mL). Concentrate the dried (MgSO4) Et2O solution in vacuo to give N-benzyloxycarbonyl-3-methanesulfonamido-L-phenylalanine ethyl ester, [α]26D =-6.7° (MeOH).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]([OH:11])=O.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][N:4]1[CH2:5][CH2:6][CH2:7][CH:3]1[CH3:2])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC1CCCN1CC(=O)O
Agent: Cl
Product: CC1CCCN1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 47 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-methylpyrrolidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 63, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-methylpyrrolidin-1-yl)acetamido)propanamide (19 mg, 47%). 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 7.93 (t, 1H), 7.60 (d, 2H), 7.29 (m, 5H), 7.19 (m, 2H), 7.00 (m, 4H), 4.73 (s, 1H), 4.52 (s, 2H), 3.69 (m, 2H), 3.05 (m, 1H), 2.82 (m, 1H), 2.46 (m, 1H), 2.23 (m, 1H), 1.91 (m, 1H), 1.67 (m, 2H), 1.33 (m, 1H), 1.03 (d, 3H). MS (EI) for C29H32FN3O4: 506.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[C:17]([O:22][CH2:23]Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>CC(C)=O>[C:17]([O:22][CH2:23][O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)OCCl
Reactant: O=Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(=O)OCOc1ccc(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a 500 mL dry round bottom flask a were added 2-fluoro-4-hydroxybenzaldehyde (5.60 g, 40 mmol), anhydrous K2CO3 (10.6 g, 76.9 mmol) and acetone (200 mL). The mixture was stirred at room temperature for 30 minutes. To another 500 mL dry round bottom flash b were added chloromethyl butyrate (9.33 g, 61.5 mmol), KI (14.2 g, 66.6 mmol) and acetone (150 mL). This mixture was also stirred at room temperature for 30 minutes. After the solid settled down on the glassware bottom, the top yellow acetone solution in flask b was decanted into the stirring solution in the round bottom flask a. The resulting mixture was refluxed for 4 hours. Most acetone was rotary evaporated, and the residual solid was triturated with methyl tert-butyl ether (MTBE) three times (100 mL, 50 mL, 50 mL). The MTBE extract was concentrated, and the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give (3-fluoro-4-formylphenoxy)methyl butyrate (6.40 g) as a colorless oil. Yield: 43%. 1H NMR (CDCl3, 300 MHz): δ=10.18 (s, 1H), 7.80 (t, J=8.7 Hz, 1H), 6.93-6.89 (m, 1H), 6.82 (dd, J=12.3, 2.1 Hz, 1H), 5.83 (s, 2H), 2.36 (t, J=7.5 Hz, 2H), 1.64 (sextet, J=7.5 Hz, 2H), 0.92 (t, J=7.5 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz): δ=185.5 (d, J=6.1 Hz), 169.7 (d, J=258.8 Hz), 162.8 (d, J=12.2 Hz), 130.2 (d, J=3.7 Hz), 119.1 (d, J=8.5 Hz), 112.4 (d, J=3.1 Hz), 103.5 (d, J=24.4 Hz), 84.1, 35.7, 18.0, 13.3.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([NH:24][NH2:25])=[O:23])[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:43](N1C=CN=C1)(N1C=CN=C1)=[O:44]>C1COCC1.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]4[O:23][C:43](=[O:44])[NH:25][N:24]=4)[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:33])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NN)nc3-c3ccccc3C(F)(F)F)cc2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(-c4n[nH]c(=O)o4)nc3-c3ccccc3C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.8 %

Procedure:
To a solution of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole-4-carbohydrazide (216 mg, 0.432 mmol), triethylamine (0.132 mL, 0.949 mmol) in 1 mL anhydrous THF was added carbonyldiimidazole (140 mg, 0.864 mmol). The reaction was stirred for 24 h at room temperature. The reaction was diluted with ethyl acetate, washed with water, brine, and dried with MgSO4. The residue was absorbed onto silica and purified by column chromatography using hexanes:ethyl acetate as eluents to afford 5-(1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1,3,4-oxadiazol-2(3H)-one (120 mgs, 52%) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 12.48 (s, 1H), 8.39 (s, 1H), 8.15-8.14 (m, 1H), 8.04-8.01 (m, 1H), 7.93-7.90 (m, 1H) 7.87-7.82 (m, 3H), 7.75-7.70 (m, 3H), 7.66-7.64 (m, 1H), 7.38 (d, J=8.61 Hz, 2H), 3.28 (s, 3H); MS (ES): 527.3 [M+H]+ and 549.3 [M+Na]+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:13]C)[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].OC[C@@H](NC(=O)OC(C)(C)C)C>>[ClH:1].[ClH:1].[NH2:3][C@@H:4]([CH3:13])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: Cl
Product: C[C@H](N)[C@H](O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate in the second step (A2).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH2:14]([NH2:18])[CH2:15][CH:16]=[CH2:17]>>[CH2:14]([NH:18][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCCN
Reactant: C=CCCCCCCCCC(=O)O
Product: C=CCCCCCCCCC(=O)NCCC=C

Procedure:
Following the aforementioned procedure, diene was prepared from undec-10-enoic acid and but-3-en-1-amine. The resulting yellow solid was purified by silica gel chromatography (5:1 hexanes: ethyl acetate) to afford the desired product as a white solid. IR (neat): 3296 (br, s), 3078 (m), 2925 (s), 2854 (s), 1640 (s), 1548 (s), 1437 (s), 1359 (m), 1271 (m), 1151 (m), 991 (s), 909 (s), 722 (m), 634 (m); 1H NMR (400 MHz, CDCl3): δ 5.85-5.71 (2H, m), 5.45 (1H, s, br), 5.12-4.91 (4H, m), 3.33 (2H, dt, J=6.8, 6.4 Hz), 2.25 (2H, ddd, J=13.6, 6.8, 0.8 Hz), 2.14 (2H, t, J=7.6 Hz), 2.06-2.00 (2H, m), 1.65-1.57 (2H, m), 1.38-1.24 (10H, m); 13C NMR (100 MHz, CDCl3): δ 173.2, 139.3, 135.5, 117.3, 114.3, 38.4, 37.0, 34.0, 33.9, 29.5, 29.4, 29.4, 29.2, 29.0, 25.9; HRMS (ESI+) [M+H]+ calcd for C15H28N1O1: 238.2171. found: 238.2167. For proof of stereochemistry, see FIG. 3.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16](/[CH:18]=[C:10]1/[C:11](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=2[CH2:7][CH2:8][CH2:9]/1)[CH3:17]
Reactant: O=C1CCCCc2ccccc21
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C1\CCCc2ccccc2C1=O
Yield: 82 %

Procedure:
A solution of 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.0 g, 6.24 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (2.5 mL) was heated at 100° C. for 24 hours. On completion of the reaction, the solvent was removed under reduced pressure. The oily residue was triturated with n-hexane (2×50 mL) to give the desired pure product, (E)-6-((dimethylamino)methylene)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.1 g, 82%) as a brown solid. 1H NMR (CDCl3, 400 MHz): δ 7.75 (s, 1H), 7.62 (d, J=6.2 Hz, 1H), 7.34-7.25 (m, 2H), 7.09 (d, J=6.4 Hz, 1H), 3.11 (s, 6H), 2.75 (t, J=6.8 Hz, 2H), 2.35 (t, J=6.4 Hz, 2H), 1.83 (quintet, J=6.8 Hz, 2H). LCMS [M+H]: 216.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[C:12]([NH:23][C:24]([C:26]3[N:27]([CH2:37][C:38]([O:40]C)=[O:39])[C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=4[CH3:36])=[O:25])[S:13][C:14]=2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:4]([O:42][CH3:43])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl>O.C(O)CCC>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[C:12]([NH:23][C:24]([C:26]3[N:27]([CH2:37][C:38]([OH:40])=[O:39])[C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=4[CH3:36])=[O:25])[S:13][C:14]=2[CH2:15][CH2:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:4]([O:42][CH3:43])[CH:3]=1
Reactant: COC(=O)Cn1c(C(=O)Nc2nc(-c3cc(OC)c(Cl)cc3OC)c(CCC3CCCCC3)s2)cc2cc(C)cc(C)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: COc1cc(-c2nc(NC(=O)c3cc4cc(C)cc(C)c4n3CC(=O)O)sc2CCC2CCCCC2)c(OC)cc1Cl
Temperature: 90 °C
Yield: 79.3 %

Procedure:
A mixture of 4 g of the compound obtained in step A of Example 5a, 2.65 g of K2CO3 in 9.2 ml of water and 16 ml of n-butanol is heated at 90° C. for 12 hours. After cooling to RT, 19.2 ml of 2N HCl are added. The white precipitate formed is washed with 3 times 200 ml of water and then 3 times 200 ml of ethyl ether. 3.1 g of the expected product are obtained: m.p.=241° C.
Reaction SMILES: C([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:31]=[C:30]([C:32]#[C:33][CH3:34])[CH:29]=[C:28]2[CH:35]=[O:36])[CH2:24][CH2:23]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)(=O)C>[C@@H:25]1([N:27]2[CH:31]=[C:30]([C:32]#[C:33][CH3:34])[CH:29]=[C:28]2[CH:35]=[O:36])[O:26][C@H:22]([CH2:21][OH:20])[CH2:23][CH2:24]1
Reactant: CC#Cc1cc(C=O)n([C@H]2CC[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c1
Solvent: CC(=O)O
Product: CC#Cc1cc(C=O)n([C@H]2CC[C@@H](CO)O2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A solution of 1-(2,3-dideoxy-5-O-trityl-β-D-ribofuranosyl)-4-(1-propynyl)pyrrole-2-carbaldehyde (82 mg, 171 μmol) dissolved in 80% acetic acid (10 ml) was stirred at room temperature for 3 hours, and then at 50° C. for 2 hours. The reaction solution was concentrated under reduced pressure and repeated co-evaporation with water. The resulting crude product was purified by column chromatography on silica gel (0-1% CH3OH in CH2Cl2) and RP-HPLC (35-80% CH3CN in water, 12 min) to give the title product (31 mg, 78%).