Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37](Br)=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:74])(=O)=O)=CC=1>C1COCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37]([F:74])=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Br)CCC3)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2F)CCC3)cc1
Reaction time: 0.33 h

Procedure:
To a solution of the intermediate 17 (1.01 g, 1.2 mmol) in anhydrous THF (12.0 mL) were added dropwise n-BuLi (2.5M in hexane, 0.77 mL, 1.92 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 20 min at the same temperature. Then a solution of N-fluorobenzenesulfonimide (0.68 g, 2.16 mmol) in THF (3.0 mL) was added dropwise, and the mixture was stirred for 1 h at the same temperature. The reaction mixture was quenched with saturated NaCl solution (10 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 19, which was used without further purification (0.95 g, 1.21 mmol, 101%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:3][C@H:4]([OH:33])[C@@H:5]([NH:20][C:21]([C@@H:23]([NH:28][C:29](=[O:32])[O:30][CH3:31])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:41][O:42][C:43]([NH:45][C@@H:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:31][O:30][C:29](=[O:32])[NH:28][C@@H:23]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:21](=[O:22])[NH:20][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[C@@H:4]([OH:33])[CH2:3][C@H:2]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[NH:1][C:47](=[O:48])[C@H:46]([C:50]([CH3:52])([CH3:51])[CH3:53])[NH:45][C:43](=[O:44])[O:42][CH3:41]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccc(C)cn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
A solution containing the product from Example 89C (0.032 g, 0.059 mmol) in THF (0.5 mL) was treated with the product from Example 1F (0.014 g, 0.076 mmol), DEPBT (0.034 g, 0.114 mmol), and N,N-diisopropylethylamine (0.066 mL, 0.38 mmol) and the mixture was stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-5% methanol in ethyl acetate, to give the title compound (0.028 g, 61% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77 (s, 9H), 0.83(s, 9H), 1.58-1.39(m, 2H), 2.32(s, 3H), 2.77-2.69(m, 3H), 3.51(s, 3H), 3.54(s, 3H), 3.67-3.60(m, 1H), 3.81-3.78(d, J=9.93 Hz, 1H), 3.95-3.92(d, J=9.93 Hz, 1H), 4.17-4.01(m, 2H), 4.86-4.84(d, J=5.52 Hz, 1H), 6.63-6.60(d, J=9.56 Hz, 1H), 6.78-6.75(d, J=9.93 Hz, 1H), 7.14-7.06(m, 5H), 7.29-7.26(d, J=8.46 Hz, 2H), 7.61-7.58(d, J=9.19 Hz, 1H), 7.68-7.65(m, 1H), 7.80-7.73(m, 2H), 7.90-7.87(d, J=8.09 Hz, 2H), 8.47(s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[OH-].[Na+].[CH2:29]([OH:32])[CH2:30][CH3:31]>>[N:21]1([NH:20][C:4]2[C:5]3[N:6]=[CH:7][N:8]([C:18]=3[N:19]=[C:2]([O:32][CH2:29][CH2:30][CH3:31])[N:3]=2)[C@@H:9]2[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCO
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1nc(NN2CCCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Yield: 37 %

Procedure:
2-Chloro-N-(1-piperidinyl)adenosine (0.50 g, 1.3 mmol) (Example 5) was dissolved in a solution of sodium hydroxide (0.51 g, 1.3 mmol) in 1-propanol (15 ml), and the solution was heated at reflux for 4.5 hours, after which time TLC investigation showed that the starting material had been consumed. The reaction mixture was evaporated and the resultant residue was dissolved in water. The solution was neutralized with 4N aqueous hydrochloric acid and extracted with dichloromethane (3×50 ml). The combined extracts were dried (MgSO4) and evaporated to an oil which was triturated with diethyl ether to afford a fawn foam. This foam was purified by column chromatography on silica gel (2×20 cm); elution with a mixture of dichloromethane/ethanol 25% aqueous ammonia solution (60/10/1) provided the title compound (0.20 g, 37%) as a semi-solid foam; 1H NMR (400 MHz, Me2SO-d6) δ 3.54, 3.65 (2H, ABX, H-5'a and H-5'b), 3.92 (1H, q, H-4'), 4.15 (1H, q, H-3'), 4.60 (1H, q, H-2'), 5.80 (1H, d, H-1'), 8.16 (1H, s, H-8).
Reaction SMILES: CS(C)=O.[C-:5]#[N:6].[Na+].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:13]([CH:19]=1)[C:14](Cl)=[N:15][O:16][CH3:17]>C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:13]([C:14](=[N:15][O:16][CH3:17])[C:5]#[N:6])[CH:19]=1
Reactant: CON=C(Cl)c1cc(Cl)ccc1OCc1ccc(Cl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CON=C(C#N)c1cc(Cl)ccc1OCc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
Dimethyl sulfoxide (3 ml) and 95% sodium cyanide (0.31 g, 6 mmol) were added to 5-chloro-2-(4-chlorobenzyloxy)-α-methoxyiminobenzyl chloride (1.03 g, 3 mmol), and the mixture was stirred at 100° C. for 4 hours. After completion of the reaction, ethyl acetate (150 ml) was added, and the mixture was washed with saturated brine (100 ml) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetatein-hexane) to give 5-chloro-2-(4-chlorobenzyloxy)-α-methoxyiminophenylacetonitrile (0.92 g, 91.5%) as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1)[CH3:2].N1C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[Cl:43])[C:37](Cl)=[O:38].Cl>C(O)C.[C].[Pd]>[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[Cl:43])[C:37]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:9]2[CH:8]=[CH:7][C:6]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5][C:4]=2[O:3][CH2:1][CH3:2])=[N:12][CH:13]=1)=[O:38]
Reactant: CCOC(=O)CCc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(OCC)c1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)c(OCC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-[3-ethoxy-4-(5-nitropyridin-2-yloxy)phenyl]propionate (0.82 g, 2.3 mmol) in ethanol (40 mL) was added 10% palladium-carbon (0.15 g) under a nitrogen atmosphere, and the resulting solution was stirred under a hydrogen atmosphere at atmospheric pressure for 1 hour at room temperature. The palladium-carbon was removed by filtration, and the filtrate was concentrated. The obtained filtrate (0.58 g) was dissolved in dichloromethane (30 mL), and to the resulting solution were added pyridine (0.17 mL, 2.1 mmol) and 3,4-dichlorobenzoyl chloride (0.39 g, 1.84 mmol) under ice cooling. The resulting solution was stirred under ice cooling for 1 hour, and then stirred for 12 hours at room temperature. The reaction solution was made acidic by adding 10% hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 0.94 g of the title compound.
Reaction SMILES: C(O[C:5]1[C:9](N=C=O)=[CH:8][S:7][C:6]=1/[C:13](=[CH:15]/[CH:16]([CH3:18])[CH3:17])/[CH3:14])(C)C.[CH:19]([O:22][C:23](NC1C=CSC=1/C(=C\C(C)C)/C)=[O:24])([CH3:21])[CH3:20].C(OC(NC1C=CSC=1C(CC(C)C)=C)=O)(C)C>[C].[Pd].CO>[CH:19]([O:22][C:23]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH:13]([CH3:14])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:24])([CH3:21])[CH3:20]
Reactant: C/C(=C\C(C)C)c1scc(N=C=O)c1OC(C)C
Reactant: C/C(=C/C(C)C)c1sccc1NC(=O)OC(C)C
Agent: [Pd]
Agent: C=C(CC(C)C)c1sccc1NC(=O)OC(C)C
Solvent: CO
Product: CC(C)CC(C)c1sccc1C(=O)OC(C)C
Reaction time: 9 h
Yield: 70 %

Procedure:
2.06 g (7.72 mmol) of the mixture of 3-isopropoxy-carbonylamino-{2-(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-isopropoxycarbonylamino-{2-(Z)-(4-methyl-2-penten-2-yl)}thiophene, and 3-isopropoxycarbonylamino-{2-(4-methyl-1-penten-2-yl)}thiophene obtained in Example 13 and 0.41 g of 5% palladium carbon (Degussa chemical catalyst E106R/W) were charged into 20 ml of methanol, and after nitrogen purge, a hydrogenation reaction was conducted at normal pressure under hydrogen atmosphere for 9 hours. After nitrogen purge, the catalyst was filtrated off, and the solvent was distilled off under reduced pressure. The resulted residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 1.61 g of the intended compound as a colorless crystal (yield: 70%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CC(C)([O-])C.[Na+].[C:19]([C:23]1[O:27]/[C:26](=[N:28]\[C:29](=[O:41])[C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=2F)/[N:25]([CH2:42][C@H:43]2[CH2:47][CH2:46][CH2:45][O:44]2)[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C1COCC1.O>[C:19]([C:23]1[O:27]/[C:26](=[N:28]\[C:29]([C:30]2[CH:35]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:33]=[CH:32][C:31]=2[O:1][CH:2]2[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2)=[O:41])/[N:25]([CH2:42][C@H:43]2[CH2:47][CH2:46][CH2:45][O:44]2)[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)o1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2C(=O)/N=c2\oc(C(C)(C)C)cn2C[C@H]2CCCO2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (167 mg, 0.965 mmol) in THF (2 mL) was added sodium tert-butoxide (93 mg, 0.965 mmol). The reaction was stirred at room temperature for 20 min. The reaction was cooled to 0° C. and a solution of Example 95A (200 mg, 0.483 mmol) in THF (1 mL) was added. The reaction was stirred at 0-5° C. for 2 hours. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The organic layer was combined and dried over MgSO4, filtered and concentrated to afford the title compound 260 mg (93%). MS (DCI/NH3) m/z 568 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.S1C=CC=C1>[Pd].CO>[C:11]1([CH2:10][N:9]([CH2:8][C@@H:7]2[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C@H:2]2[OH:1])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNCc2ccccc2)[C@H](O)C1
Reactant: O=Cc1ccccc1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](CN(Cc2ccccc2)Cc2ccccc2)[C@H](O)C1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of 1,1-dimethylethyl (trans)-3-hydroxy-4-[[(phenylmethyl)amino]methyl]-1-piperidinecarboxylate (intermediate (1-d) in WO-99/02156) (0.426 mol), benzaldehyde (0.5 mol) and palladium-on-carbon (10%) (5 g) in a thiophene solution (5 ml) and methanol (1000 ml) was stirred at 70-80° C. overnight. The solvent was evaporated. The residue was partitioned between DCM (150 ml) and 5% aqueous NaOH (150 ml). The mixture was separated into its layers. The aqueous layer was extracted with DCM. The combined organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE and a drop of ACN. The precipitate was filtered off and dried, yielding 2.35 g 1,1-dimethylethyl (trans)-4-[[bis(phenylmethyl)amino]methyl]-3-hydroxy-1-piperidinecarboxylate (intermediate 27), mp. 133° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][OH:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:30]Br>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][O:22][CH2:30][C:29]2[CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=[C:27]([C:26]([F:25])([F:39])[F:40])[CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](CO)C1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 124.3 %

Procedure:
To a solution of (3S,4R)-4-(4-fluoro-phenyl)-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.58 g, 5.11 mmol) in 30 ml DMF were added 0.29 g (6.0 mmol) sodium hydride (50% in mineral oil) at 0° C. The reaction mixture was allowed to warm to room temperature. After 20 min. 3,5-bis(trifluoromethyl)benzyl bromide (3.14 g, 10.2 mmol) was added. Stirring at room temperature for 2 h was followed by quenching with water and extraction with three portions of tert-butyl methyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, heptane/ethyl acetate) to give 3.4 g (>100%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22](O)=[O:23])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:37]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[NH2:37][C:22]([C:21]1[CH:20]=[C:19]([S:16]([N:14]2[C:13]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:12][C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15]2)(=[O:17])=[O:18])[CH:27]=[CH:26][CH:25]=1)=[O:23]
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(=O)O)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C(N)=O)c2)c1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution (5 mL) of 3-[(4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-2-phenyl-1H-pyrrol-1-yl)sulfonyl]benzoic acid (205 mg) in N,N-dimethylformamide were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (125 mg) and 1-hydroxy-1H-benzotriazole ammonium salt (100 mg) at room temperature. The mixture was stirred at the same temperature for 1 hr, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1→1:4) to give the title compound as a colorless oil (yield 193 mg, 94%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[CH:12]1[O:16]CCO1.[B:17]([O-])([O-:23])[O:18]CCCC.Cl>CCCCCC.CCOCC>[CH:12]([C:8]1[S:9][CH:10]=[CH:11][C:7]=1[B:17]([OH:23])[OH:18])=[O:16]
Reactant: Brc1ccsc1C1OCCO1
Reactant: CCCCOB([O-])[O-]
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1sccc1B(O)O
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
A 1.1 N solution of n-butyllithium in hexane (28 ml) was added dropwise (10 mins) to a solution of 2-(3-bromo-2-thienyl)-1,3-dioxalane (3) (6.6 g, 28.1 mmol) in anhydrous ether (30 ml) at −70° C. After stirring for 10 mins, butyl borate (9.1 ml, 33.7 mmol) in anhydrous ether (20 ml) was added in a single portion. The reaction mixture was stirred for 4 hrs at −70° C. and then left to return to room temperature. 1 N hydrochloric acid (20 ml) was added, and the mixture was left for 1 hr with stirring. The aqueous phase was extracted with ether and the combined ether phases were washed with a solution of sodium bicarbonate, dried (Na2SO4), and evaporated under reduced pressure to give the intermediate (4) (2.2 g, 14.1 mmol, 50% yield) as a brown solid.
Reaction SMILES: C(C1OC1)Cl.B(F)(F)F.[CH3:10][CH2:11][O:12][CH2:13][CH3:14].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].[CH3:27][N:28]1C=C[CH:31]=[CH:30][C:29]1=O>CCOCC.C(Cl)Cl>[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:11]([O:12][C:13]1[CH:14]=[CH:31][CH:30]=[CH:29][N+:28]=1[CH3:27])[CH3:10]
Reactant: CCOCC
Reactant: Cn1ccccc1=O
Agent: CC[O+](CC)CC
Agent: FB(F)F
Agent: F[B-](F)(F)F
Solvent: ClCC1CO1
Solvent: ClCCl
Product: CCOc1cccc[n+]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
Triethyloxonium fluoroborate is prepared from 3.70 g (0.040 mole) of epichlorohydrin in 14 ml of ether and 7.58 g (0.054 mole) of boron trifluoride etherate in 6 ml of ether. The resulting solid triethyloxonium tetrafluoroborate is dissolved in 20 ml of dry methylene chloride and treated under nitrogen with 4.36 g (0.040 mole) of 1-methyl-2-pyridone in 15 ml of methylene chloride. The reaction mixture is stirred under nitrogen at room temperature overnight (about 16 hours). The solvent is evaporated at room temperature, in vacuo and the quaternary salt obtained is recrystallized from methanol-ether (1:1) to give 8.0 g (71%) of 2-ethoxy-1-methylpyridinium fluoroborate, m.p. 58°-60° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([F:13])=[C:6]([CH:9]=[C:10](Cl)[CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].C(N(CC)CC)C>CO.[H][H].[Pd]>[C:1]([C:4]1[C:5]([F:13])=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)cc(C#N)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)c1cccc(C#N)c1F

Procedure:
Reduction of 3-acetyl-5-chloro-2-fluorobenzonitrile in methanol using H2 /Pd-C for 3 h under 45 p.s.i.g. of H2 in the presence of triethylamine affords 3-acetyl-2-fluorobenzonitrile, which is the starting material.
Reaction SMILES: [F:1][C:2]([F:33])([CH2:29][CH2:30][CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(C(C)C)CC)(C)C.[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(#N)C>[F:33][C:2]([F:1])([CH2:29][CH2:30][CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:26]
Reactant: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OCc2ccccc2)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.1 %

Procedure:
To the crude 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (17) (132.1 mmol) in acetonitrile (315 ml), diisopropyl ethylamine (69.0 ml, 369 mmol) and benzyl bromide (47.1 ml, 369 mmol) were added and the mixture was stirred for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate (366 ml) and water (280 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (224 ml). The organic layers were combined and washed with 1N-hydrochloric acid (336 ml), saturated sodium bicarbonate water (336 ml) and saturated aqueous sodium chloride (336 ml). After drying with anhydrous magnesium sulfate (51 g), the solution was concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2400 g; ethyl acetate:hexane =1:2) to give benzyl 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (18) (74.44 g; 130.9 mmol; yield: 99.1%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.O[C:22]1[CH:31]=[CH:30][C:25]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:27]([NH:26][C:25]1[CH:30]=[CH:31][C:22]([O:1][CH2:2][CH2:3][CH:4]2[CH2:10][CH2:9][C:8]3[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=3[CH2:6][CH2:5]2)=[CH:23][CH:24]=1)(=[O:29])[CH3:28]
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(NC(C)=O)cc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 62.4 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (101 mg), p-hydroxyacetanilide (166 mg), and triphenylphosphine (126 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (81 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 80 min and concentrated. The residue was purified successively by silica gel column chromatography (eluent:ethyl acetate/hexane=1/1) and by alumina column chromatography (eluent:ethyl acetate/hexane=1/1) and then with recrystallization from ethyl acetate-hexane to obtain the entitled compound (93 mg).