Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7](O)=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:37]=[C:36]([OH:38])[C:35]([C:39]([OH:41])=[O:40])=[CH:34][N:33]=2)=[CH:28][CH:27]=1.C(N(CC)CC)C.C[Si](Cl)(C)C>ClCCl.C(#N)C>[C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:37]=[C:36]([OH:38])[C:35]([C:39]([OH:41])=[O:40])=[CH:34][N:33]=2)=[CH:30][CH:31]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC(=O)O
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: -10 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A solution of 4.6 g (35 mmol) of N-acetyl-beta-alanine, 100 ml acetonitrile, and 3.9 ml (35 mmol) of N-methylmorpholine is stirred at -15° C. and 5.0 ml (38.5 mmol) of isobutyl chloroformate is added. After 30 minutes at -15° C. a solution prepared from 4.05 g (17.5 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid, 7.35 ml (52.5 mmol) of triethylamine, and 7.96 ml (62.7 mmol) of trimethylsilyl chloride in 100 ml of dichloromethane is added and the mixture stirred at -10° C. for 1 hour and at room temperature overnight. The mixture is evaporated to near dryness in vacuo and treated with 200 ml of water. The product is precipitated by acidifying to pH 2.0 and is filtered, washed with water, isopropanol, ether, and dried to give 5.8 g of 2-[4-(N-acetyl-beta-alanylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid.
Reaction SMILES: S(Cl)([O:4][CH2:5][Cl:6])(=O)=O.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])=[O:14])([CH3:11])([CH3:10])[CH3:9].C([O-])(O)=O.[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O.O.C(Cl)Cl>[Cl:6][CH2:5][O:4][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][NH:15][C:13]([O:12][C:8]([CH3:10])([CH3:9])[CH3:11])=[O:14]
Reactant: O=S(=O)(Cl)OCCl
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC(=O)OCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of chloromethyl chlorosulfate (1.1 equivalent) and 4-tert-Butoxycarbonylamino-butyric acid (1 equivalent) was added NaHCO3 (3.6 equivalents) and Bu4NHSO4 (catalytic amount) in water/CH2Cl2 (1:1). The mixture was stirred at room temperature overnight. The organic phase was thereafter separated and the aqueous phase was extracted with CH2Cl2 (three times). The combined organic layer was washed with NaHCO3 (×3), brine (×3), dried with MgSO4, filtered and evaporated.
Reaction SMILES: C(OC([NH:11][CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:23]=[CH:24]/[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:19]=2)[O:14]1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[Na+].[OH-].[OH-].[Pd+2]>[NH2:11][CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:19]=2)[O:14]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc2c(c1)CC[C@H](CNC(=O)OCc1ccccc1)O2
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc2c(c1)CC[C@H](CN)O2
Temperature: 50 °C

Procedure:
A mixture of carbamate of Example 12 (10.8 g, 23.6 mmol), ammonium formate (29 g, 460 mmol) and palladium hydroxide on carbon (Pearlman's catalyst) (4.3 g) in absolute ethanol (250 mL) was heated at 50° C. for 4 hours under argon. Some white solid appeared in the condenser. The reaction mixture was vacuum filtered through a pad of Celite. The filtrate was concentrated in vacuo to obtain an off-white solid which was subsequently dissolved in 1 N sodium hydroxide solution (200 mL). The mixture was extracted with ethyl acetate (200, 200, 100 mL). The combined organic layer was washed with brine (100 mL) and dried over anhydrous sodium sulfate. Removal of solvent in vacuo afforded the desired product cleanly as an oil (6.0 g, 88%): 1H NMR (CDCl3) δ1.40 (s, 9H), 1.70-1.81 (m, 1H), 1.90-2.00 (m, 1H), 2.46-2.51 (t, J=6.9 Hz, 2H), 2.70-2.85 (m, 4H), 2.93 (d, J=5.4 Hz, 2H), 3.90-4.00 (m, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.87 (s, 1H), 6.90 (d, J=8.1 Hz, 1H); CI-MS m/z 292 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[CH:10]3)[C:6]=2[CH:23]=1.[C:24]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>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]>[C:24]([N:28]1[CH2:33][CH2:32][CH:31]([S:34][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)[N:8]=[C:7]4[C:6]=3[CH:23]=2)[CH2:30][CH2:29]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)N1CCC(S)CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C)CC3)ccc1OCC2
Temperature: 120 °C

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (100 mg, 0.27 mmol), 1-tert-butylpiperidine-4-thiol (120 mg, 0.69 mmol), Pd2(dba)3 (24 mg, 10 mol %), XantPhos (31 mg, 20 mol %) and DIPEA (186 μL, 1.07 mmol) in dioxane (3 mL) was purged with argon and heated at 120° C. for 40 min using microwave irradiation. The reaction mixture was diluted with DCM and purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM then C18, gradient 20-50% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The residue was triturated with Et2O affording 139 as a white solid (16 mg, 51%). LCMS: RT 3.11 min [M+H]+ 467.4. 1H NMR (DMSO, 400 MHz): δ 8.54 (1H, d, J=2.35 Hz), 7.94 (1H, d, J=0.67 Hz), 7.77 (1H, s), 7.36 (1H, dd, J=8.49, 2.37 Hz), 7.02 (1H, d, J=8.48 Hz), 5.92-5.91 (1H, m), 4.55-4.49 (4H, m), 3.06-3.04 (3H, m), 2.30 (2H, t, J=11.23 Hz), 2.08-1.96 (2H, m), 1.65-1.64 (2H, m), 1.58 (6H, d, J=6.65 Hz), 1.08 (9H, s)
Reaction SMILES: C([C@](C([O-])=O)(O)[C@](CC)(O)C([O-])=[O:6])C.C(N)(=S)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=2[CH2:28][S:29][CH2:30][C:31]([NH2:33])=[O:32])=[CH:22][CH:21]=1.C(N(CC)CC)C.[O-]O.C1(C(C)C)C=CC=CC=1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.O.O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=2[CH2:28][S:29]([CH2:30][C:31]([NH2:33])=[O:32])=[O:6])=[CH:24][CH:25]=1
Reactant: NC(=O)CSCc1ccccc1-c1ccc(Cl)cc1
Reactant: CC[C@@](O)(C(=O)[O-])[C@@](O)(CC)C(=O)[O-]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(C)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)CS(=O)Cc1ccccc1-c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of (S,S)-(−)-diethyl-tartrate (2.47 g; 0.012 mol; 0.4 eq.) in a solvent (3.5 vol. vs thioacetamide) was introduced in a reactor with an impeller, containing 6.5 vol (vs thioacetamide) of the same solvent. The solution was stirred and heated to 50° C. before adding 0.2 equivalent of titanium (IV) tetraisopropoxide (1.71 g; 1.77 mL; 0.006 mol; 0.2 eq) and water (QSP to achieve 0.095 eq. in the mixture) and kept stirring at 50° C. for one hour. In these conditions, the resulting chiral titanium complex had the stoichiometry of DET/Ti(OiPr)4/H2O:2/1/0.475 and corresponded to 0.2 eq. with respect to the thioacetamide. After stirring at 50° C. for one hour, 1.0 eq. (8.75 g; 0.03 mol) of 2-[2-(4-chlorophenyl)benzyl]sulphanyl acetamide was added and contacted for 30 min. After cooling to 20° C., were successively added 0.2 eq. (0.61 g; 0.84 mL; 0.006 mol) of triethylamine and around 10 minutes later, 1.0 eq (4.57 g; 5.0 mL; 0.03 mol) of cumene hydroperoxide within less than 5 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].O.[CH:11]1(B(O)O)[CH2:13][CH2:12]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:11]1([C:2]2[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=2)[NH2:7])[CH2:13][CH2:12]1
Reactant: Cc1ccc(Br)cc1N
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C2CC2)cc1N
Temperature: 100 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
To a mixture of 5-bromo-2-methylaniline (3.51 g), cyclopropylboronic acid monohydrate (2.55 g), tricyclohexylphosphine (about 0.6 mol/L toluene solution, 3.14 mL), tripotassium phosphate monohydrate (15.2 g), toluene (52.4 mL), and water (5.24 mL) was added palladium(II) acetate (212 mg), and this mixture was stirred at 100° C. for 15 hours. The reaction mixture was left to be cooled, and filtrated through a Celite (registered trademark) pad. The pad was washed with ethyl acetate (100 mL). The filtrate and the washing liquid were mixed, and washed with water/saturated brine (1/1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (2.25 g). 1H-NMR (CDCl3) δ ppm: 0.58-0.67 (2H, m), 0.83-0.93 (2H, m), 1.73-1.84 (1H, m), 2.12 (3H, s), 3.54 (2H, br s), 6.35-6.50 (2H, m), 6.93 (1H, d, J=7.5 Hz).
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[CH3:14][Mg]Cl.O>[Ni+2].ClC(Cl)(CP(C1C=CC=CC=1)C1C=CC=CC=1)CP(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O1CCCC1>[CH3:13][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[C:11]([F:12])[C:2]=2[CH3:14])[N:7]=1
Reactant: Cc1ccc2c(Br)c(F)ccc2n1
Reactant: C[Mg]Cl
Agent: [Ni+2]
Agent: ClC(Cl)(CP(c1ccccc1)c1ccccc1)CP(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(C)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Under a nitrogen atmosphere, 28.0 g (0.05 mole) of dichloro[1,3-bis(diphenylphosphino)propane] nickel (II) catalyst (prepared by the method of G. R. Van Hecke and W. DeW. Horrocks, Inorganic Chemistry, 5, 1968 (1966), incorporated herein by reference) was added to a solution of 240 g (1.0 mole) of 5-bromo-6-fluoro-2-methylquinoline in 3.8 liters of toluene. 440 ml (1.4 mole) of 3.17 molar methylmagnesium chloride in tetrahydrofuran was added rapidly to the above mixture, the resulting exotherm being controlled with an ice bath. The reaction was allowed to stir at room temperature overnight. The reaction was treated with 1 liter of water to destroy the excess Grignard reagent, and the organic layer and aqueous layers were then separated. The organic layer was extracted twice with 1 liter portions of 3N hydrochloric acid. The acid extracts were combined, extracted twice with 1 liter portions of methylene chloride, and made basic (pH>9) with ammonium hydroxide and ice. The product was collected as a tan solid (156.4 g, 0.894 mole). This material was recrystallized from 1 liter of hexane to give 77.1 g (0.44 mole) of 2,5-dimethyl-6-fluoroquinoline which was 98.7% pure as determined by gas chromatography analysis.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:4]([CH:5]=[N:6][O:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]1[C:12]([OH:14])=[O:13].S(C1C=CC(C)=CC=1)(O[CH:20]([C:34]#[N:35])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]=1)(=O)=O>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])[O-].[K+].[K+].O>[CH3:15][C:2]1([CH3:1])[CH:4]([CH:5]=[N:6][O:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH:3]1[C:12]([O:14][CH:20]([C:34]#[N:35])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:22]=1)=[O:13]
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(Oc3ccccc3)n2)cc1
Reactant: CC(C)CON=CC1C(C(=O)O)C1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CON=CC1C(C(=O)OC(C#N)c2cccc(Oc3ccccc3)n2)C1(C)C
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 9.6 %

Procedure:
To a solution of 0.95 g of 2,2-dimethyl-3-((isobutoxyimino)methyl)cyclopropanecarboxylic acid and 1.70 g of cyano(6-phenoxy-2-pyridinyl)methyl tosylate in 30 ml of toluene was added 200 mg of tetrabutylammonium hydrogen sulfate. To this mixture was added in one portion 0.75 g of potassium carbonate dissolved in 10 ml of water. The reaction mixture turned from yellow to bright purple in 30 seconds. The reaction mixture was stirred vigorously and heated to 75° C. The purple color disappeared after 10 minutes. The reaction mixture was heated for four hours at 70° C. and then cooled to room temperature. The resulting mixture was washed with 100 ml of 5% potassium carbonate solution and extracted thrice with 50 ml portions of diethyl ether. The combined extract was stripped to give 440 mg of a crude oil. This crude product was chromatographed using 30% diethyl ether in hexane as eluent. The product was washed off the silica with ethyl acetate and the eluate was stripped to give 180 mg of the desired product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=O)=[N:6][CH:7]=1.O.[NH2:35][NH2:36]>C(O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C:4]2[C:5]([C:8]3[C:10]4[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:12](=[O:14])[NH:36][N:35]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:21])=[O:22])=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: O=C(O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc12
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A mixture of 2-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-benzoic acid (18 mg, 0.0347 mmol) and 2.3 mg of hydrazine hydrate in 1.0 ml of ethanol was refluxed for 4 hours. After cooled to room temperature the mixture was concentrated and the residue was purified via preparative TLC to afford 12 mg of title compound as a white powder. MS: (M+H)/z =515.2.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([O:34]C)=[O:33])[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([OH:34])=[O:33])[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)(=[O:22])=[O:23])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl)-sulfonyl]-4-piperidine carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl)-sulfonyl]-4-piperidinecarboxylate (545 mg, 1.04 mmol) in 8 ml of tetrahydrofuran:methanol (1:1, and 1N sodium hydroxide (2.09 ml, 2.09 mmol) to obtain 446 mg (85%) of the acid. HR-MS: m/z Calculated for C23H25NO8S2 509.1094; Found 508.1073.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[O:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[OH-].[OH-].[Pd+2].CO.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[C:10]([O:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:35][CH:36]=1)=[C:9]([OH:8])[CH:18]=[CH:17]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OCc3ccccc3)ccc2c1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(O)ccc2c1
Yield: 98.7 %

Procedure:
Add 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-piperidine (12.4 g, 25.5 mmol) to a methanol/ethyl acetate mixture (1:1, 490 mL) and heat to form a solution. Remove the heat and add ammonium formate (4.83 g, 76.6 mmol) and Pd(OH)2 on carbon (20% ww, 1.58 g, 1.12 mmol). Reflux for 50 minutes then filter the mixture. Concentrate the filtrate to provide 9.9 g of 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalene-2-ol (98.5%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:25]>C(OCC)C.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:25])=[C:11]([F:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1F
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: O
Solvent: CCOCC
Product: Fc1cc(OCc2ccccc2)ccc1CBr

Procedure:
A stirred, cooled (ice bath) solution of 4-benzyloxy-2-fluoro-benzyl alcohol (Compound 9, 15 g, 64.6 mmol) in anhydrous diethyl ether (100 mL) was treated with pyridine (5.75 mL, 71.1 mmol) followed by phosphorus tribromide (6.13 mL, 64.6 mmol). After 90 min. the reaction mixture was diluted with water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as an oil that solidified on standing (18 g, 89.5%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:38](=[CH2:40])=[N-:39]>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10](=[O:12])[CH:40]=[N+:38]=[N-:39])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)C=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
To a 0° C. solution of 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g, 4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4 mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol). The reaction mixture is stirred at 0° C. for 20 minutes and filtered. The filtrate is treated with an ether solution of diazomethane (˜16 mmol) at 0° C. The reaction mixture is stirred at room temperature for 3 hours then concentrated in vacuo. The resulting residue is dissolved in EtOAc and washed successively with water and brine, dried (Na2SO4), filtered and concentrated. The residue is purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product as a slightly yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz, 2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd, J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz, 1H), 1.41 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Li][Li].[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C(O)=O>>[CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([CH2:15][C:14]([O:20][CH2:21][CH3:22])=[O:19])=[O:5]
Reactant: CCOC(=O)CC(=O)O
Reactant: Cc1cc(Br)ccc1C(=O)Cl
Agent: [Li][Li]
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1C

Procedure:
2-Methyl-4-bromobenzoyl chloride (29.1 g, 0.13 mol) was treated with the dilithium salt of ethyl hydrogen malonate (28.0 g, 0.21 mol) and the product was isolated by the procedure described in Example 1 (ii). The crude product was purified on flash silica, eluting with dichloromethane-hexane (1:1 then 3:2) to give ethyl 2-methyl-4-bromobenzoylacetate as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9]#[CH:10])[O:6][CH2:5][CH2:4][O:3]1.[Cl:11][CH2:12][CH2:13][CH2:14]I.[NH4+].[Cl-].N>[NH2-].[Li+]>[CH3:1][C:2]1([CH2:7][CH2:8][C:9]#[C:10][CH2:14][CH2:13][CH2:12][Cl:11])[O:6][CH2:5][CH2:4][O:3]1
Reactant: ClCCCI
Reactant: C#CCCC1(C)OCCO1
Agent: N
Agent: [Cl-]
Agent: [Li+]
Product: CC1(CCC#CCCCCl)OCCO1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 89.5 %

Procedure:
A solution of lithium amide (prepared from 3.5 g-atoms of lithium in 500 ml liquid NH2) was stirred at -30° C. while 2-methyl-2-(3-butynyl)-1,3-dioxolane (70.0 g, 0.5 mol) was added thereto dropwise over a 45 minute period. The solution was allowed to stir at -30° C. for 1 hour and subsequently cooled to -60° C.; 1-chloro-3-iodo-propane (103 g, 0.5 mol) then was added dropwise over a 30 minute period. After the addition was completed, the reaction was stirred at -30° C. for 4 hours. Solid NH4Cl (25 g, 0.47 mol) was added and the ammonia allowed to evaporate overnight. Water (200 ml) and ether (300 ml) were added to the solid residue and stirred for 15 minutes. The solution was filtered through infusorial earth (CELITE®) and the layers separated. The aqueous layer was further extracted with ether (2 × 200 ml) and the combined organic layers washed with water, brine, and dried over anhydrous MgSO4. Evaporation of the solvent gave 97 g of 2-methyl-2-(7-chloro-3-heptynyl)-1,3-dioxolane as an orange oil, bp 87°-88° C/ 0.15 mm. Yield: 65 g, 60%. NMR (CDCl3): 1.28(s, 3H); 1.67-2.52(m, 8H); 3.62(s, 2H); and 3.9(s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](OS(C(F)(F)F)(=O)=O)=[CH:8][CH:7]=1.[CH2:29]([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH2:31].[Cl-].[Li+]>CN(C)C=O.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:31][CH:30]=[CH2:29])=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Yield: 92.2 %

Procedure:
Argon was passed through a solution of 7.0 g (0.0164 mol) of (S)-4-[[(trifluoromethyl)sulfonyl]oxy)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]benzenepropanoic acid methyl ester, 5.7 g (0.0165 mol) of allyltributyl tin, and 1.42 g (0.04 mol) of lithium chloride in 50 mL of dimethylformamide for 10 minutes and 210 mg (0.0003 mol) of bis(triphenylphosphine)palladium dichloride was added. The bath temperature was raised to 90°-95° C. for 40 minutes and the mixture was allowed to cool. The mixture was diluted with ether and washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The residue obtained after filtration and evaporation was purified by preparative liquid chromatography using silica gel cartridges on a Waters Prep 500 chromatograph, eluting with 10% ethyl acetate-hexane to give 4.83 g (92%) of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-(2-propenyl)benzenepropanoic acid methyl ester, mp 56°-59° C.