Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].N1C=CN=C1.[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)Cl)([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1>[Si:18]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](Oc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Yield: 55.1 %

Procedure:
To a solution of 8.26 g of hydroquinone and 6.3 g of imidazole in 80 mL of pyridine was added 20.6 g of t-butyldiphenylchlorosilane in 20 mL of pyridine. After 1.5 hr the mixture was partitioned between water and ethyl acetate. The organic layer was washed twice with phosphate buffer (pH 2) and once each with phosphate buffer (pH 8) and brine before being filtered through N/N/S and concentrated in vacuo. Preparative liquid chromatography [silica; hexane/ethyl acetate (85:15)] afforded 14.4 g of 4-(t-butyldiphenylsilyloxy)phenol. The structure was confirmed by its NMR spectrum.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[F:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(=O)C.[Na+]>C(O)(C)C>[C:21]1([NH:27][N:28]=[C:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2[F:18])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2F)CC1
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)N1CCC(C(=NNc2ccccc2)c2ccc(Br)cc2F)CC1
Reaction time: 16 h
Yield: 92.8 %

Procedure:
A mixture of 1-acetyl-4-(4-bromo-2-fluorobenzoyl)piperidine (16.6 g, 0.051 mol), phenylhydrazine hydrochloride (16.6 g, 0.11 mol), sodium acetate, (22.2 g) and isopropanol (250 ml) was stirred and refluxed for 4 hours. The reaction stood at ambient temperature for 16 hours, and then was filtered The filtercake was treated with water, and the insoluble hydrazone was collected and dried to yield 13.7 g. The isopropanol filtrate was concentrated in vacuo to a solid, which when triturated with ether yielded 6.1 g more of the hydrazone (total yield 19.8 g; 93%) The phenylhydrazone was a mixture of the two geometric isomers. A 3.5 g sample of the compound was recrystallized from isopropanol to yield 2.1 g of the phenylhydrazone; mp 174°-176° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]>>[Cl:10][C:11]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: COC(=O)C(OC)OC
Product: COC(OC)C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 36 h

Procedure:
Into a sealed tube were added methyl dimethoxyacetate (0.78 g, 5.8 mmol) and 2,4-dichlorobenzylamine (1.0 g, 5.8 mmol). This mixture was stirred at 50° C. for 36 h. The completed reaction mixture was transferred to a flask and re-crystallized from heptane yielding the desired product as an off-white solid. MS (ES+): m/z=278.10/280.09/282.08 [MH+]. HPLC: tR=3.03 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH:36][CH2:37][C:38]([NH:40][NH2:41])=O>CC1C=CC(C)=CC=1>[OH:36][CH2:37][C:38]1[N:26]2[C:21]3[CH:20]=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)=[N:28][C:22]=3[O:23][CH2:24][C:25]2=[N:41][N:40]=1
Reactant: NNC(=O)CO
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(CO)nnc3CO4)cc2)CCC1
Temperature: 150 °C
Yield: 14.8 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (250 mg, 0.513 mmol) and 2-hydroxyacetohydrazide (230 mg, 2.56 mmol) in p-xylene (1.5 ml) was heated to 150° C. for 30 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (40 mg, 15%). LCMS (Method D): RT=1.297 min, M+1=526. 1H NMR (500 MHz, CDCl3) δ 8.33 (1H, s), 7.37-7.32 (2H, m), 7.31-7.27 (5H, m), 7.25-7.20 (2H, m), 5.59 (2H, s), 5.06 (2H, bs), 5.02 (1H, bs), 2.53-2.43 (4H, m), 2.14-2.02 (1H, m), 1.88-1.76 (1H, m), 1.45-1.27 (9H, bs).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][C@H:16]([OH:18])[CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]2.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][C@H:16]([OH:18])[CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([N:19]([CH2:33][C:32]1[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1)[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[N:9]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)C[C@H](O)CC[C@H]2CS1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)C2=N[C@@]3(c4ccccc4F)C[C@H](O)CC[C@H]3CS2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl(±)-[(4aR*,7R*,8aS*)-8a-(2-fluorophenyl)-7-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in Preparation Example 58-(8) (500 mg) was dissolved in DMF (10 mL), and the mixture was cooled in an ice bath under a nitrogen atmosphere. p-Methoxybenzyl chloride (161 μL, specific gravity: 1.154 g/cm3) and potassium carbonate (247 mg) were added thereto, followed by stirring for one hour. Thereafter, the reaction solution was warmed to room temperature and stirred for 19 hours. Ethyl acetate and water were added to the reaction solution, followed by further stirring. Then, the aqueous layer was separated. The organic layer was sequentially washed with a saturated ammonium chloride solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (541 mg).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH2:12]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of indole-4-carbonitrile (2.0 g, 14.1 mmol, 1 eq) and benzyl bromide (2.17 mL, 18.3 mmol, 1.3 eq) in dry DMF (20 mL) was added, at rt, NaH (733 mg, 18.3 mmol, 1.3 eq) portionwise under Ar(g). The resulting reaction mixture was stirred at rt overnight, and was subsequently partitioned with H2O (30 mL), and then extracted with EtOAc (3×20 mL) and CH2Cl2 (20 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (9:1-1:3) to furnish the product, 2, as a white solid (3.30 g, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]O)[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)[CH:20]=1
Reactant: OCc1cccnc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(OCc3cccnc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 103.6 %

Procedure:
Into a solution of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (500 mg), 3-pyridinemethanol (405 mg) and triphenylphosphine (0.98 g) in THF (10 ml) was added at 0° C. diethyl azodicarboxylate (a 40% solution in toluene) (1.62 g), and the resulting mixture was stirred at room temperature for 20 hours. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate) to obtain methyl 7-(3-pyridylmethoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (694 mg) as colorless crystals.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C@H:10]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[C@@H:11]2[CH3:14])=[CH:6][CH:5]=1.O.CO.C(OCC)C.[BrH:30]>>[BrH:30].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C@H:10]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[C@@H:11]2[CH3:14])=[CH:6][CH:5]=1
Reactant: CCCN(CCC)[C@H]1CCc2ccc(OC)cc2[C@H]1C
Agent: Br
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CCCN(CCC)[C@H]1CCc2ccc(O)cc2[C@H]1C
Yield: 84 %

Procedure:
cis-7-Methoxy-1-methyl-2-(di-n-propylamino) tetralin hydrochloride (500 mg, 1.60 mmol) was heated in 48% aqueous HBr (5 ml) for 3 h at 140° C. under N2. Water (20 ml) was added and the volatiles were evaporated in vacuo. The faint orange-coloured residue was treated with abs. ethanol twice (with intervening evaporation). The dry residue was dissolved in methanol and the solution was treated with active charcoal. After filtration the solvent was evaporated, whereupon the residue was dissolved in methanol and ethyl ether was added. The obtained white crystals were recrystallized from MeOH-ethyl ether yielding the desired product (450 mg, 84% yield), m.p. 195°-196° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.C(Cl)Cl.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>>[Cl:1][C:2]1[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:4]([CH2:8][NH:9][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: NCc1cncc(Cl)c1COC1CCCCO1
Solvent: ClCCl
Product: CC(C)C(=O)NCc1cncc(Cl)c1COC1CCCCO1
Reaction time: 8 h

Procedure:
To a solution of C-[5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridin-3-yl]-methylamine (0.37 g, 1.4 mmol) in DCM (20 mL) DIPEA (0.41 mL, 2.2 mmol) and isobutyryl chloride (0.18 mL, 1.6 mmol) were added. Stirring was continued overnight at RT. The solvent was evaporated and the residue was used in the following step without further purification. MS (m/z): 326.9 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[CH:15]=[CH:14][C:13]=1[C:23]1[C:24]([S:29]([N:32]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[C:40]=2[CH3:45])COCCOC)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.[Si](Cl)(C)(C)C.[Na+].[I-].O>CC#N.CCOC(C)=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[CH:15]=[CH:14][C:13]=1[C:23]1[C:24]([S:29]([NH:32][C:39]2[O:43][N:42]=[C:41]([CH3:44])[C:40]=2[CH3:45])(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CN1Cc2ccccc2C1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN2Cc3ccccc3C2=O)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the title compound of Step (A) in 4 ml of CH3CN, Me3SiCl (174 mg, 1.6 mmol) was added and followed by NaI (240 mg, 1.6 mmol). The mixture was stirred at room temperature for 20 min. Additional Me3SiCl (74 mg, 1.6 mmol) and NaI (240 mg, 1.6 mmol) were added in four portions and the reaction was stirred for additional 1 hr and 10 min. The reaction mixture was then added to 3 ml H2O and 30 ml EtOAc. The organic layer was separated and washed with 1 ml saturated aqueous Na2S2O3, brine, dried and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 30% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 70% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (43 mg, 40% for two steps) as a white solid, m.p. 135°-142° C. (amorphous).
Reaction SMILES: Cl.[CH2:2]1[C@H:6]2[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9][C@H:5]2[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30].O>CN(C=O)C>[F:26][C:25]([F:27])([F:28])[C:22]1[CH:21]=[C:20]([C:29]([F:30])([F:31])[F:32])[CH:19]=[CH:24][C:23]=1[N:3]1[CH2:4][C@@H:5]2[CH2:9][CH:8]([CH:10]=[O:11])[CH2:7][C@@H:6]2[CH2:2]1
Reactant: OCC1C[C@H]2CNC[C@H]2C1
Reactant: Fc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CC1C[C@@H]2CN(c3ccc(C(F)(F)F)cc3C(F)(F)F)C[C@@H]2C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
To a solution of (3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-ylmethanol hydrochloride (862 mg) and potassium carbonate (1.68 g) in DMF (10 mL) was added 1-fluoro-2,4-bis(trifluoromethyl)benzene (1.24 g). The reaction mixture was stirred at 80° C. for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). To a solution of the obtained oil (1.71 g) and triethylamine (2.03 mL) in DMSO (10 mL) and ethyl acetate (10 mL) was added sulfur trioxide pyridine complex (2.32 g) under cooling to 0° C. The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (215 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1.[Li]CCCC.[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:26]([CH:27]=[O:28])=[C:25]([CH3:29])[O:24][N:23]=2)=[N:20][CH:21]=1>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:26]([CH:27]([OH:28])[CH2:1][C:2]3[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=3)=[C:25]([CH3:29])[O:24][N:23]=2)=[N:20][CH:21]=1
Reactant: Cc1onc(-c2ccc(F)cn2)c1C=O
Reactant: Cc1ncc(C(=O)O)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cn2)c1C(O)Cc1ncc(C(=O)O)s1
Temperature: 25 °C
Yield: 65.8 %

Procedure:
To a stirred solution of 2-methyl-thiazole-5-carboxylic acid (1.15 g, 8.05 mmol) in THF (67 mL) at −70° C. and under argon was added BuLi (1.6M in hexanes, 10.06 mL, 16.1 mmol) dropwise. After 2 h a solution of 3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carbaldehyde (1.66 g, 8.05 mmol) in THF (24 mL) was added dropwise. After 3 h the reaction mixture was quenched with citric acid solution (5%, 50 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were washed with brine, water, dried over sodium sulfate, filtered and concentrated. Purification by trituration (ethyl acetate) afforded the title compound (1.85 g, 66%) as a light yellow solid. MS: m/e=348.2 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:18]([O:20]C)=[O:19])([C:6]4[C:11]3=[CH:10][CH:9]=[C:8]([Cl:17])[CH:7]=4)[C:4]=2[CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:18]([OH:20])=[O:19])([C:6]4[C:11]3=[CH:10][CH:9]=[C:8]([Cl:17])[CH:7]=4)[C:4]=2[CH:3]=1
Reactant: COC(=O)C12CC(c3ccc(Cl)cc31)c1ccc(Cl)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C12CC(c3ccc(Cl)cc31)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2,7-dichloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (described in example 35d) (3.25 g, 10.2 mmol) in tetrahydrofuran/methanol (1:1, 70 mL) was added an aqueous solution (35 mL) of lithium hydroxide monohydrate (4.28 g, 102 mmol, 10 eq). A slight exotherm occurred on addition. The reaction was stirred vigorously for 18 h at room temperature over which time a cloudiness develops. The solvents are removed and replaced with 3 N HCl (50 mL) saturated with sodium chloride. The aqueous phase was extracted with ethyl acetate (3×50 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and reduced to an oil. The procedure yielded 3.11 g (quantitative) of the title compound and did not require addition purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([B:9]2[O:13][CH2:12][CH2:11]O2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:15]1C=[CH:19][C:18]([F:21])=[CH:17][C:16]=1COCOC>>[F:21][C:18]1[CH:17]=[CH:16][C:15]2[B:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[O:13][CH2:12][C:11]=2[CH:19]=1
Reactant: COCOCc1cc(F)ccc1Br
Reactant: N#Cc1cccc(B2OCCO2)c1
Product: N#Cc1cccc(B2OCc3cc(F)ccc32)c1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(3-cyanophenyl)-[1,3,2]-dioxaborolane and 1-bromo-4-fluoro-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@H:14](/[CH:17]=[CH:18]/[CH:19]([OH:26])[CH:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[CH2:12]2)([O:3]C)=[O:2]>CO.[OH-].[Na+]>[C:1]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@H:14](/[CH:17]=[CH:18]/[CH:19]([OH:26])[CH:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[CH2:12]2)([OH:3])=[O:2]
Reactant: CCCCC(F)C(O)/C=C/[C@H]1[C@H]2C/C(=C/CCCC(=O)OC)C[C@H]2C[C@H]1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(F)C(O)/C=C/[C@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(1S,2S,3R,5S)-(E)-7-(4-Carbomethoxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy(E)-1-octenyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (12') (0.129 g) was dissolved in methanol, into which 1N aqueous solution of sodium hydroxide (2 ml) was added, and stirred at room temperature for 6 hours. After a usual work-up (1S,2S,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (13') was obtained as a colorless oily product. Yield: 0.140 g
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.7 g (10.2 mmol) of ethyl 4-hydroxybenzoate, 1.76 g (9.3 mmol) of 1-t-butoxycarbonyl-4-hydroxypiperidine, and 2.44 g (9.3 mmol) of triphenyl phosphine were dissolved in 40 ml of tetrahydrofuran, and 1.62 g (9.3 mmol) of diethyl azodicarboxylic acid was added thereto, and they were stirred at room temperature overnight. It was treated in an ordinary manner by treatment with ethyl acetate as the extractant to obtain the crude product. Then, it was purified by silica gel column chromatography to obtain the title compound.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[N:31]=[N:32][N:33]([CH:36]2[CH2:39][CH:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:37]2)[C:34]=1I)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:44]1(B2OC(C)(C)C(C)(C)O2)[CH2:46][CH2:45]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C(=O)C>O>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[N:31]=[N:32][N:33]([CH:36]2[CH2:39][CH:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:37]2)[C:34]=1[CH:44]1[CH2:46][CH2:45]1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC1CC(n2nnc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2I)C1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)CC1CC(n2nnc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
tert-Butyl 5-(tert-butyldiphenylsilanyloxy)-3-[5-iodo-1-(3-isobutylcyclobutyl)-1H-[1,2,3]triazol-4-yl]valerate (340 mg), 2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.16 mL), tripotassium phosphate (403 mg), N,N-dimethylacetamide (3.4 mL) and water (0.85 mL) were mixed. The mixture was degassed by bubbling argon gas. To the mixture was added PdCl2(PPh3)2 (50 mg). The mixture was stirred at 80° C. for 1 hr. To the reaction mixture was added ethyl acetate at ice temperature, and then the mixture was filtered. The filtrate was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/20) to give the title compound (238 mg).