Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C@@H:21]1[CH2:25][C:24]([C:26](OC)=[O:27])=[CH:23][CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]([NH:20][C@@H:21]1[CH2:25][C:24]([CH2:26][OH:27])=[CH:23][CH2:22]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCC1=CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: -7.5 °C
Yield: 116.8 %

Procedure:
A reactor was charged with methyl (4S)-4-(tritylamino)cyclopent-1-ene-1-carboxylate (4.75 kg, 12.4 mol). The reactor was charged with anhydrous toluene (9.5 L), cooled to −5 to −10° C. and the agitation started. While maintaining the temperature between −10° C. and +10° C., diisobutylaluminum hydride (1M solution in toluene, 23.4 kg, 27.3 mol) was added. Upon completion of the addition, the reaction mixture was analyzed by HPLC, which confirmed a complete conversion of the starting material to the product. The reaction mixture was quenched into cold 2 N NaOH solution (−5 to −10° C.) at a rate to keep the internal temperature below 20° C. The organic phase was separated and filtered through a pad of diatomaceous earth. The pad was washed with toluene (2×1 L), and the filtrate was concentrated under reduced pressure to afford the title compound as a thick oil (5.15 kg). The product was diluted with methylene chloride and stored as a solution at 0 to 5° C. 1H NMR (300 MHz, CDCl3, δ): 7.60-7.56 (m, 5H), 7.35-7.17 (m, 10H), 5.38 (bs, 1H), 4.03-4.02 (d, J=3.7 Hz, 2H), 3.49-3.36 (m, 1H), 2.40 (s, 2H), 2.19-1.79 (m, 4H), 1.32-1.29 (t, J=5.8 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[F:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (R)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 198.1) and pyrimidin-5-ylboronic acid to afford a white powder. HPLC (Condition 4) tR=4.88 min, UPLC-MS (Condition 3) tR=0.96 min, m/z=464.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.77 (m, 1H) 1.79-1.92 (m, 1H) 2.78-2.94 (m, 1H) 3.15-3.25 (m, 2H) 3.32-3.48 (m, 1H) 4.13-4.26 (m, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.46-7.65 (m, 2H) 7.91-8.00 (m, 1H) 8.07 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.87 (s, 2H) 9.18 (s, 1H) 10.30 (s, 1H).
Reaction SMILES: C[C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[O:9].[CH2:10]1[CH2:14]O[CH2:12][CH2:11]1>O.C(O)(=O)C.C=O>[N:4]1([CH2:3][CH2:2][CH:6]2[CH2:5][CH2:7][CH2:7][C:5]3[NH:4][C:3]([CH:8]=[O:9])=[CH:2][C:6]2=3)[CH2:14][CH2:10][CH2:11][CH2:12]1
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: C1CCOC1
Agent: C=O
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1cc2c([nH]1)CCCC2CCN1CCCC1
Temperature: 95 °C

Procedure:
A mixture of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (20 mmol) in THF (40 mL), water (20 mL), acetic acid (3 mL), formaldehyde (37% wt. % solution in water, 5 mL) and the appropriate amine (30 mL) was heated to reflux (oil bath 90-100° C.) for 6 hours. The reaction was concentrated to a volume of 30 mL, basified with 2N NaOH and extracted with ethyl acetate (2×150 mL) and DCM (4×100 mL). The combined organic layers were concentrated and the residue was purified on a silica gel column to give the desired product
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]2[CH:3]=[CH:4][C:5]3[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=3[CH:16]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2SCC1
Reactant: COc1ccc(OB([O-])[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc(OC)cc3)ccc2SCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.5 g), 4-methoxyphenyl borate (0.84 g) and potassium carbonate (1.39 g) in toluene/ethanol/water (50/5/5 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphine palladium (0.17 g), and the mixture was refluxed for 24 hours and then cooled. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:15→1:9→1:4→1:2) to give pale yellow crystals of methyl 7-(4-methoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (1.40 g).
Reaction SMILES: C[Si](C)(C)[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5].Cl[Si:11]([Cl:14])(Cl)Cl>C(Cl)Cl.CN(C)C(=O)N(C)C>[Cl:14][Si:11]([O:3][Si:4]([CH3:5])([CH3:6])[CH3:7])([O:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[O:3][Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Si](C)(C)O[Si](C)(C)C
Reactant: Cl[Si](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C(=O)N(C)C
Product: C[Si](C)(C)O[Si](Cl)(O[Si](C)(C)C)O[Si](C)(C)C
Reaction time: 21 h
Yield: 27 %

Procedure:
About 4.6 g (0.2% by weight) of tetramethylurea and 183.4 g of a 25% solution of phosphonitrile chloride in methylene chloride are added to a mixture containing 1707 g (10.5 mol) of hexamethyldisiloxane and 595 g (3.5 mol) of tetrachlorosilane with stirring in a 4 liter multineck flask fitted with internal thermometer, stirrer and a reflux condenser. The reaction temperature is kept at 45° C. by cooling. After 21 hours, the volatile components of the reaction mixture are removed by distillation at 200 mbar and 100° C. The crude distillate contains 56% of 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane, 29% of 3,3-dichlorohexamethyltrisiloxane and 16% of 3,3-bis(trimethylsiloxy)hexamethyltrisiloxane. The crude distillate is fractionally distilled, and gives, at 20 mbar and 83° to 87° C., 313 g (27% of theory) of 3-chloro-3-trimethylsiloxyhexamethyltrisiloxane in a purity, determined by gas chromatography, of 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:25]=[CH:24][C:14]2[C:15]([C:18](N(OC)C)=[O:19])=[N:16][S:17][C:13]=2[CH:12]=1.Cl>C1COCC1>[Br:10][C:11]1[CH:25]=[CH:24][C:14]2[C:15]([C:18]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:19])=[N:16][S:17][C:13]=2[CH:12]=1
Reactant: CON(C)C(=O)c1nsc2cc(Br)ccc12
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1nsc2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
4-Chlorophenyl magnesium bromide (1.0 N in THF, 16 mL, 16 mmol) was added to a stirred solution of 6-bromo-N-methoxy-N-methylbenzo[d]isothiazole-3-carboxamide (3.5 g, 12 mmol) in THF (100 mL). The reaction mixture was stirred at 0° C. for 1 hour. The reaction was poured into 1N HCl and extracted into ether. The combined organic layers were washed with brine, dried and concentrated. The crude product was suspended in ether and stirred for 15 minutes. The solid was collected by filtration to give (6-bromobenzo[d]isothiazol-3-yl)(4-chlorophenyl)methanone (3.3 g, 81%). 1H NMR (CDCl3, 400 MHz) δ 8.60 (d, J=8.8 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.19 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:4][CH:3]=1.[S:18]([O:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH:33]=[CH:32][O:31]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>O=P(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:17][C@@H:32]2[O:31][C@@H:30]([CH2:29][O:28][S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[CH2:35][CH2:34][CH2:33]2)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OC(c3ccc(Cl)cc3)c3ccc(Cl)cc3Cl)O2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2.10 g of α-(4-chlorophenyl)-2,4-dichlorobenzyl alcohol and 1.78 of 2-tosyloxymethyl-3,4-dihydro-2H-pyran were dissolved in 40 ml of diethyl ester, and a catalytic amount (2 drops) of phosphorus oxytrichloride was added to the solution. The mixture was then stirred at room temperature for 4 days, after which 3 drops of triethylamine were added. The mixture was then concentrated by evaporation under reduced pressure and the residue was purified by column chromatography through silica gel eluted with a 15:5:1 by volume mixture of hexane, benzene and ethyl acetate, to give 3.41 g of the title compound in the form of a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([C:14]3=[S:21])[CH2:12]1)[CH2:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C:11]12[CH2:12][CH:13]3[CH2:19][CH:17]([CH2:16][CH:15]([CH:14]3[SH:21])[CH2:20]1)[CH2:18]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC12CC3CC(C1)C(=S)C(C3)C2)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC12CC3CC(C1)C(S)C(C3)C2)OCc1ccccc1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
Ketone 10B (100 mg, 0.317 mmol) in 5 ml of absolute MeOH was added NaBH4 (23 mg, 0.62 mmol) in portions at 0° C. The reaction was stirred for 1 h, at which time the solution was carefully quenched with water. The reaction mixture was extracted with EtOAc twice and the organic phases were combined, dried (anhydrous Na2SO4), and concentrated. The crude mixture was purified by column chromatography (0˜10% MeOH in EtOAc) to yield 51 mg of the desired mixture of alcohols 11A LC-MS (ESR): m/z=318 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)=[CH:6][C:5]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)=[O:24])=[C:4]([F:34])[CH:3]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:71][NH2:72]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:72][CH3:71])[CH:12]=3)=[CH:6][C:5]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)=[O:24])=[C:4]([F:34])[CH:3]=1
Reactant: CN
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(C#N)c3)c(F)cc2Cl)cc2cnc(Cl)cc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(C#N)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
A mixture of 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-cyanophenyl)urea (0.210 g, 0.423 mmol), t-butyl X-Phos (0.020 g, 0.047 mmol), Pd2(dba)3 (0.020 g, 0.022 mmol), Cs2CO3 (0.400 g, 1.228 mmol) and methylamine (2.0M in THF, 4.0 mL, 8.0 mmol) in dioxane (5 mL) was heated at 90° C. for 5 h, then cooled to RT stirred overnight. The solids were removed via filtration, washed with DCM, then MeCN and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/DCM) to afford 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-cyanophenyl)urea (33 mg, 15% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.40 (s, 1H), 8.83 (s, 1H), 8.41 (s, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.97 (t, J=1.8 Hz, 1H), 7.74 (s, 1H), 7.61-7.45 (m, 4H), 7.05 (d, J=5.1 Hz, 1H), 6.24 (s, 1H), 4.14 (d, J=7.4 Hz, 2H), 2.86 (d, J=4.9 Hz, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 491.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH:14]1[C:19](=[O:20])[C:18]([OH:21])=[CH:17][O:16][C:15]=1[CH2:22]Cl>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:22][C:15]1[O:16][CH:17]=[C:18]([OH:21])[C:19](=[O:20])[CH:14]=1)=[O:6]
Reactant: O=c1cc(CCl)occ1O
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(OCc1cc(=O)c(O)co1)c1ccc(O)c(O)c1
Yield: 43.3 %

Procedure:
By following the procedure of Example 1 by employing 4.22 g(27.4 mmole) of 3,4-dihydroxybenzoic acid, 1.1 g (27.5 mmole) of sodium hydroxide and 4 g(24.9 mmole) of chlorokojic acid, there was obtained 3.0 g(43.3%) of 2-(3,4-dihydroxybenzoyl)oxymethyl-5-hydroxy-4H-pyran-4-one as as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[CH:8]=[N:9]O)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C.C(OCC)C>[C:15]([C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]=1[OH:14])[C:8]#[N:9])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(C=NO)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)c1cc(C#N)cc(C(C)(C)C)c1O
Temperature: 0 °C
Yield: 54 %

Procedure:
A solution of 3,5-Di-tert-butyl-4-hydroxy-benzaldehyde oxime (3.0 grams, 8.4 mmole) in acetic anhydride (6 ml) was was refluxed for 2 hours. The mixture was cooled to 0° C. and saturated sodium hydrogencarbonate was added. The mixture was extracted with methylene chloride. The combined extracts were washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated to give a solid. This was dissolved in diethyl ether and extracted with 1 N sodium hydroxide which was then acidified to pH 1 and extracted with ethyl acetate. The extract was dried and concentrated to a yellow solid which was recrystalized from ethyl acetate/hexane to give white crystals (1.05 g). MW 231; MS (m/e) 249 (M++NH4+).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=CC=1.C1CCCC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(Cl)Cl.CO.CCOC(C)=O.CCCCCC.CCN(CC)CC>[CH:13]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:14][CH2:15][CH2:10][CH2:16]1
Reactant: OCc1ccccc1I
Reactant: Cc1ccccc1
Agent: C1=CCCC1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCc1ccccc1C1CCCC1
Temperature: 100 °C
Yield: 74 %

Procedure:
A 300 mL Parr bomb was charged with 10.0 g of 2-iodobenzyl alcohol (Aldrich), 80 mL of toluene, 30 mL of cyclopentene (Aldrich), 2.60 g of tri-ortho-tolylphosphine (Aldrich), and 6.6 mL of Et3N. The mixture was deoxygenated by bubbling N2 through for 10 min and was then treated with 0.96 g of Pd(OAc)2 (Aldrich). The bomb was flushed with N2, sealed, and heated to 100° C. for 18 h. The vessel was cooled to RT, purged with N2 and opened. The dark red reaction mixture was concentrated in vacuo to give a red-brown syrup. This material was dissolved in 200 mL of CH2Cl2, washed with water (4×100 mL), dried over anhydrous MgSO4, and concentrated in vacuo to afford a brown oil. Analysis by tlc (SiO2, 8:2 hexane:EtOAc) indicated two new major components at Rf =0.45 and 0.50, tri-o-tolyphosphine at Rf =0.90, and 4 minor components at Rf =0.60, 0.70, 0.85 and 0.0. The crude product was purified by flash chromatography (twice) on 200 g of silica gel (9:1 hexane:EtOAc) to afford 6:1 g (82%) of a mixture of the Rf =0.45 and 0.50 materials. This material was determined to be a mixture of double bond isomers by 1H-NMR. The product (6.0g ) was then hydrogenated at 40 psi in 40 mL of MeOH in the presence of 0.60 g of 5% Pt(C) (Aldrich) for 4 h. The catalyst was removed by filteration through celite and the filtrate was concentrated in vacuo to afford 5.47 g (74% from 2-iodobenzyl alcohol) of 2-cyclopentylbenzyl alcohol as a light yellow-brown liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH2:14][C:13]([CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])([C:15]([O:17]C)=[O:16])[O:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[Li+].[OH-]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH2:14][C:13]([CH2:19][NH:20][S:21]([CH3:24])(=[O:22])=[O:23])([C:15]([OH:17])=[O:16])[O:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: COC(=O)C1(CNS(C)(=O)=O)CC(c2ccc(F)c(C#N)c2)=NO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)NCC1(C(=O)O)CC(c2ccc(F)c(C#N)c2)=NO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-cyano-4-fluorophenyl)-5-(methylsulfonylaminomethyl)-5-(carbomethoxy)isoxazoline (1.13 g) in THF (50 mL) was added LiOH (3.50 mL of 1N aqueous solution). The mixture was stirred at RT under N2 for ½ h. The solvent was removed, the resulting material was diluted with water and acidified with concentrated HCl. It was then extracted with EtOAc, and the organic solution was dried over MgSO4 and concentrated to a light yellow foam (0.98 g). 1H NMR (DMSO-d6) δ 8.17 (m, 2H), 7.56 (t, 1H), 3.98-3.79 (m, 2H), 3.69 (bs, 2H), 3.01 (s, 3H) ppm; ESI mass spectrum z (rel. intensity) 339.8 (M−H, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:22]4=[C:23]5[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][C:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:14]5[CH:13]=[CH:12][C:11]4=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:31]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:31][C:17]1[CH:16]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:14]2[C:23]3=[C:22]4[C:11]([CH:10]=[CH:9][C:8]([C:5]5[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=5)=[C:21]4[CH:20]=[CH:19][C:18]=13)=[CH:12][CH:13]=2
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)cc5)ccc5ccc2c3c54)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)cc5)cc(Br)c5ccc2c3c54)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
Next, a mixed solution of 2.6 g of 1,6-bis(4-methylphenyl)pyrene, 1.2 g of N-bromosuccinimide and 60 ml of dimethylformamide was stirred under a nitrogen gas stream at 60° C. for 5 hours. The solution was cooled to room temperature and 60 ml of water was poured into the solution, followed by extraction with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then evaporated. The resulting solid was recrystallized from toluene and then vacuum-dried to obtain 1.4 g of 3-bromo-1,6-bis(4-methylphenyl)pyrene.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:13]C(=O)N(C)C)=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].C[O-].[Na+].CO.Cl>CN(C)C=O>[SH:13][C:4]1[C:3]([C:1]#[N:2])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: CN(C)C(=O)Sc1cc2c(cc1C#N)CCCC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cc2c(cc1S)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of dimethylthiocarbamic acid S-(3-cyano-5,6,7,8-tetrahydronaphthalen-2-yl) ester (1.00 g, 3.84 mmol) in anhydrous N,N-dimethylformamide (10 mL) under argon was added dropwise 25% sodium methoxide in methanol (2.6 mL, 11.5 mmol, 3.0 eq) at 0° C. The resultant yellow reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into cold 2N HCl (100 mL) and then extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated at reduced pressure to give 700 mg (96%) of crude 3-mercapto-5,6,7,8-tetrahydronaphthalene-2-carbonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(#N)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(S([N-][C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.Cl[Ru+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12]([OH:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(=O)CS(C)(=O)=O)ccc1OC
Agent: Cl[Ru+]
Agent: Cc1ccc(S(=O)(=O)[N-][C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CC#N
Solvent: Cc1ccc(C(C)C)cc1
Product: CCOc1cc([C@@H](O)CS(C)(=O)=O)ccc1OC
Temperature: 22.5 °C
Reaction time: 40 h
Yield: 87 %

Procedure:
A mixture of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (1.2 g, 4.4 mmol), RuCl(p-cymene)[(S,S)-Ts-DPEN] (28 mg, 0.044 mmol), and 5:2 formic acid-triethylamine complex (2.2 mL) in acetonitrile (7.2 mL) was stirred at 20-25° C. for 40 h. The mixture was evaporated to dryness and the residue was chromatographed on a silica gel column, using a hexanes-ethyl acetate gradient. The appropriate fractions were pooled and evaporated. The residue was triturated with heptane (25 mL) and the resulting slurry was filtered and dried under vacuum to provide (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol as a white solid (1.05 g, 87% yield); achiral HPLC (Hypersil BDS C8, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 12.37 (99.8%); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 85:15 heptane-i-PrOH): 18.07 (0.51%), 20.43 (99.4%); 1H NMR(CHCl3-d) δ 1.48 (t, J=7.0 Hz, 3H), 2.77 (dd, J=1.1, 2.6 Hz, 1H), 3.05 (s, 3H), 3.17 (dd, J=0.9, 14.7 Hz, 1H), 3.46 (dd, J=10.1, 14.6 Hz, 1H), 3.88 (s, 3H), 4.11 (q, J=7.0 Hz, 2H), 5.27-5.32 (m, 1H), 6.82-6.95 (m, 3H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:29][N:28]=[C:27]([CH3:30])[C:26]=4[CH2:31]O)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:9])[CH3:6].C([O-])(O)=O.[Na+]>COCCOC>[CH2:5]([O:7][C:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:29][N:28]=[C:27]([CH3:30])[C:26]=4[CH2:31][Br:2])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CO)cc3)cc2)CC1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus tribromide (0.43 mL, 4.53 mmol) was added to a solution of 1-[4′-(4-hydroxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (1.14 g, 3.02 mmol) in DME (30 mL) at 0° C. The reaction was stirred overnight at room temperature, and then cooled to 0° C. and neutralized with saturated aqueous NaHCO3 to pH 7. The mixture was partitioned between CH2Cl2 and H2O, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([S:12][S:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[C:8]([S:12][S:13][CH2:14][CH2:15][NH2:16])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCSSC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)SSCCN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 335.3 %

Procedure:
A solution of TFA (1.0 ml) in DCM (1.0 ml) was added to tert-butyl (2-(tert-butyldisulfanyl)ethyl)carbamate (Compound 6b-A, 100 mg, 0.377 mmol), and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure to afford the title compound (209 mg, quant.).