Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([O:5]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.N1C=CC=CC=1.[O:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>O1CCCC1>[C:2]([Cl:1])(=[O:5])[O:25][CH:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: OC1CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cl)OC1CCOCC1
Yield: 92.9 %

Procedure:
To a solution (40 mL) of bis(trichloromethyl)carbonate (2.97 g) in tetrahydrofuran was dropwise added a solution (10 mL) of pyridine (2.43 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 10 min., a solution (20 mL) of tetrahydropyran-4-ol (1.91 g) in tetrahydrofuran was dropwise added slowly. After stirring at room temperature for 2 hrs., the mixture was concentrated under reduced pressure, and ethyl acetate (50 mL) and water (50 mL) were added to the residue. The ethyl acetate layer was separated and taken, washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave tetrahydropyran-4-yl chlorocarbonate (1.53 g). To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.40 g) obtained in Reference Example 1 and tetrahydrofuran (20 mL) was added pyridine (0.78 mL), and a solution (10 mL) of tetrahydropyran-4-yl chlorocarbonate (1.53 g) obtained above in tetrahydrofuran was dropwise added, and the mixture was stirred overnight at room temperature. After concentration of the reaction mixture under reduced pressure, water (50 mL) was added, the mixture was extracted with ethyl acetate (50 mL). The residue was washed with a 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=4:1, then 3:2). The obtained colorless oil (2.03 g) was dissolved in diethyl ether (2 mL), and a 4N hydrogen chloride-ethyl acetate solution (5 mL) was added. After stirring at room temperature for 30 min., diethylether (10 mL) was added and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.20 g) as a white solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@H:14]2[O:16][CH2:15]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[C:17](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:17][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C@H:14]2[O:16][CH2:15]2)=[CH:10][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1ccc(OC[C@@H]2CO2)cc1)S(C)(=O)=O
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of compound 3-S (0.243 g, 1 mmol) and potassium carbonate (0.166 g, 1.2 mmol) in 20 ml acetone was stirred for 1 hour at room temperature, then methyl iodide (0.142 g, 0.062 ml, 1 mmol) was added dropwise at room temperature. After stirring for 8 hours, the reaction was filtered and the solvent evaporated to furnish a white solid that was used directly in the next step (0.2 g, 78% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Al](C)C.[Cl:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C@H:32]1[CH2:36][CH2:35][O:34][C:33]1=[O:37].Cl>ClCCCl>[Cl:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C@@H:32]([CH2:36][CH2:35][OH:34])[C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:6][N:7]=1)=[O:37]
Reactant: O=C1OCC[C@@H]1N1CCc2c1ccc(F)c2Cl
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cn1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCCl
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cn1)[C@H](CCO)N1CCc2c1ccc(F)c2Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
Prepared using General Procedure 2. To a stirring suspension of the 6-amino-N-(thiazol-2-yl)pyridine-3-sulfonamide (92 mg, 0.36 mmol) and DCE (2.0 mL) under N2, at RT, was added 2 M trimethylaluminum in hexanes (0.18 mL, 0.36 mmol) dropwise over 5 minutes. The solution was stirred at ambient temperature for 30 minutes. To this solution was added, a solution of (S)-3-(4-chloro-5-fluoroindolin-1-yl)dihydrofuran-2(3H)-one (92 mg, 0.36 mmol) in DCE (1.0 mL) over 5 minutes. The solution was stirred at 70° C. for 19 hours. The solution was cooled to 0° C. and aqueous 1.0 M HCl was added dropwise. The organic portion was washed with 1.0 N aqueous HCl (2×5.0 mL) and evaporated to dryness under reduced pressure. The residue was purified via silica gel chromatography using 5%-10% MeOH in CH2Cl2 to obtain (S)-2-(4-chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-(5-(N-thiazol-2-ylsulfamoyl)pyridine-2-yl)butanamide (47 mg, 26%) as a yellow solid.
Reaction SMILES: CO[C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C@H:11]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[OH-:36].[Na+]>C(O)C>[CH:13]1([CH2:12][C@@H:11]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([NH:21][CH2:20][CH2:19][C:11]([OH:10])=[O:36])=[O:35])=[CH:9][CH:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(O[C@@H](CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCNC(=O)c1ccc(O[C@@H](CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1

Procedure:
or (S)-4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-benzoic acid methyl ester (85 mg) is taken into ethanol (2 mL), treated with 5N NaOH (1 mL) for 2 h at 40° C., concentrated, acidified with 5 N HCl, extracted with ethyl acetate, dried over sodium sulfate. Concentration gives 80 mg of (R) or (S)-4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-benzoic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:17]1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(CNS(C)(=O)=O)c1ccc(-c2ccsc2)cc1
Temperature: 100 °C
Yield: 26.5 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.0 g (7.7 mmol) of thiophene-3-boronic acid and 1.1 g (7.7 mmol) of potassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) of tetrakis(triphenyl-phosphine)palladium(0). The mixture was heated to 100° C. for 4 hours, cooled to ambient temperature and diluted with 20 mL of ethyl acetate. The mixture was then washed once with water, and the organic portion was separated. The aqueous portion was extracted twice with ethyl acetate and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (35% ethyl acetate/hexane) afforded a solid which was recrystallized from bromobutane, filtered and dried in vacuo at 60° C. to afford 0.4 g (27%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C:16]3[CH:25]=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>O1CCOCC1>[CH:10]12[N:11]([C:16]3[CH:25]=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:12][CH:13]1[CH2:14][CH2:15][NH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CCC2CN(c3cnc4ccccc4n3)C2C1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a solution of 8-quinoxalin-2-yl-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (1.84 g, 5.40 mmol) in dioxane (30 mL) was added trifluoro acetic acid (8.0 mL). The reaction mixture was stirred at rt for 16 h. The solvent and excess trifluoro acetic acid were removed under reduced pressure. The crude product was purified on HPLC (Agilent, basic system) to yield the title compound (925 mg, 72%). MS (ESI) mass calcd. for C14H16N4, 240.3; m/z found, 241.2 [M+H]+. 1H NMR (CDCl3): 1H NMR (400 MHz, CDCl3) 8.12 (s, 1H), 7.86 (dd, J=8.4, 1.0, 1H), 7.67 (dd, J=8.4, 1.0, 1H), 7.54 (dd, J=8.4, 1.5, 1H), 7.37 (dd, J=8.3, 1.4, 1H), 4.45-4.37 (m, 1H), 4.17-4.03 (m, 1H), 3.90-3.82 (m, 1H), 3.57 (dd, J=14.3, 2.0, 1H), 3.19-3.04 (m, 2H), 2.98 (s, 1H), 2.81-2.62 (m, 2H), 2.14-2.03 (m, 1H), 1.85-1.73 (m, 1H).
Reaction SMILES: [OH-].[K+].CO.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[CH:11]=[CH:10]2>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2
Reactant: CCOC(=O)C(C)c1ccc2cc(OC)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 25 °C

Procedure:
A solution of 6.0 g. of potassium hydroxide, 6 ml. of water and 60 ml. of methanol is added to the ethyl 2-(6-methoxy-2-naphthyl)propionate, and the mixture is heated at reflux for 45 minutes, cooled to ambient temperature, acidified and mixed with 60 ml. of water. Methanol is removed by evaporation in vacuo, and the resultant solution is extracted with two 60 ml. portions of methylene chloride. The combined methylene chloride extracts are evaporated to dryness to yield 2-(6-methoxy-2-naphthyl)propionic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:19]=1.[Li]CCCC.CN([CH:28]=[O:29])C>C1COCC1>[CH:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([CH:28]=[O:29])=[CH:19][C:6]=3[N:7]=2)[CH2:11][CH2:12]1)([CH3:18])[CH3:17]
Reactant: CN(C)C=O
Reactant: CC(C)N1CCN(c2nc3cc(Br)ccc3s2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2nc3cc(C=O)ccc3s2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-2-(4-isopropylpiperazin-1-yl)benzothiazole (300 mg, 0.88 mmol) in dry THF was added n-BuLi dropwise over 10 min at −78° C. After 30 min, DMF was added dropwise at −78° C. The reaction mixture was then stirred for 1.5 h at −78° C., quenched with water and extracted with ethyl acetate to give a residue which was purified by column chromatography on silica gel (eluent: 1% dichloromethane in methanol). This afforded 240 mg (94%) of 2-(4-isopropylpiperazin-1-yl)benzothiazole-5-carbaldehyde.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+].O1CCOCC1>O>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[C:9]=1[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(O)ccc(C=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(OCc2ccccc2)ccc(C=O)c1O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-dihydroxy-3-methyl-benzaldehyde (3.31 g, 21.8 mmol), benzylbromide (4.09 g, 23.9 mmol), NaHCO3 (5.49 g, 65.4 mmol), 1,4-dioxane (30 mL) and water (12 mL) was stirred at 60° C. for overnight. Then the reaction mixture was cooled to RT, water (100 mL) was added, extracted with EtOAc (2×200 mL). The extract was dried over Na2SO4, evaporated. The residue was purified on SiO2 (25 g) column, hexane-EtOAc (0 to 5%). Yield 1.57 g (6.48 mmol, 29%) as off-white solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.Br[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]>O>[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)CCCCBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCCCC#N
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
7.5 g (154 mmol) of sodium cyanide was added to 80 mL of dimethyl sulfoxide, and dissolved therein under heat at 90° C. 25.0 g (128 mmol) of methyl 5-bromovalerate was dropwise added to the solution at an inner temperature of 130° C. or lower, and stirred at 100° C. for 2 hours. After cooled to room temperature, 50 mL of water was added to this, which was then extracted with 60 mL of ethyl acetate. The organic layer was dried with magnesium sulfate, and the solvent was evaporated away under reduced pressure to give 18.0 g (yield 99%) of methyl 5-cyanovalerate.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:12]Br.O>C(O)(=O)C>[Br:12][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]([NH2:9])=[N:5][CH:6]=1
Reactant: BrBr
Reactant: Nc1ncccc1C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncc(Br)cc1C(F)(F)F
Yield: 74 %

Procedure:
3-(trifluoromethyl)pyridin-2-amine (20 g, 123 mmol) was stirred in acetic acid (200 ml) at RT. Bromine (19.72 g, 123 mmol) was added drop wise with stirring. The reaction mixture was stirred for 2 h; followed by dilution with water. The product was extracted with ethyl acetate. Organic layer was washed with water, dried over sodium sulfate and concentrated to obtain the title product in 74% yield.
Reaction SMILES: [H-].[K+].[CH:3]1[C:13]2[CH2:12][S:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:20]1>COCCOC>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][S:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:32][CH:31]=1
Reactant: COc1ccc(CCN2CCC[C@@H](Cl)C2)cc1
Reactant: c1ccc2c(c1)CSc1ccccc1N2
Agent: [H-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Temperature: 25 °C
Yield: 12 %

Procedure:
Potassium hydride (35% dispersion in oil, 229 mg) was added to a solution of 5,11-dihydrodibenzo[b,e][1,4]thiazepine (see U.S. Pat. No. 3,188,322 [Chem. Abs., 63, 8384h (1965)] and I. Udea and S. Umio, Bull. Chem. Soc. Japan, 48(8), 2323 (1975)) (425 mg) in DME (1,2-dimethoxyethane) (20 ml) and the mixture stirred at room temperature for 30 minutes, treated with a solution of (R)-3-chloro-1-(4-methoxyphenethyl)piperidine (see Preparation 1) (507 mg) in DME (5 ml) and heated under reflux for 18 hours. The mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, performing a gradient elution using initially dichloromethane as eluant and changing to dichloromethane/saturated methanolic ammonia (98:2). The appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil, (100 mg, 12%), [α]58925 -60.9° (c=0.57 in ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(NC(C)C)(C)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)c(O)c1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of methyl 3-hydroxy-4-iodobenzoate (1 eq.) in dry THF were added trimethylsilylacetylene (5 eq.), tetrakis(triphenylphosphine)palladium (0.03 eq.), copper iodide (0.02 eq.) and diisopropylamine (2.1 eq.) under argon. The reaction mixture was stirred at 60° C. for 15 h, cooled to 20° C. and the solvents removed under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 9/1) to afford methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:14][CH2:15]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CC1
Yield: 97.4 %

Procedure:
To a 500 mL round-bottomed flask equipped with magnetic stirring was added 1-(2-nitrophenyl)piperazine (Emka-Chemie) (30 g, 145 mmol) in CH2Cl2 (300 mL). A solution of Na2CO3 in H2O (61.2 g in 100 mL) was added, and the reaction mixture was stirred for 5 min. Stirring was stopped, benzyl bromide (18.6 mL, 159 mmol) was added, and the reaction was heated at reflux for 4 h. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). All organic fractions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(2-nitrophenyl)-4-benzylpiperazine as an orange oil (42 g). MS (ESI, pos. Ion) m/z: 298 (M+H); MS (ESI, neg. Ion) m/z: 296 (M−H). Calc'd for C17H19N3O2: 297.15.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[F:20]C1C=CC=C(OC)C=1C=O>>[F:20][C:7]1[CH:2]=[CH:3][CH:4]=[C:5]([O:18][CH3:19])[C:6]=1[CH:8]([OH:17])[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1cccc(F)c1C=O
Product: COc1cccc(F)c1C(O)C#Cc1ccccc1
Yield: 77 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2-fluoro-6-methoxy-benzaldehyde (947 mg, 6.14 mmol) was reacted to give the title compound (1.21 g, 77%). 1H NMR (400 MHz, DMSO-d6): δ 7.41-7.30 (m, 6H), 6.91-6.79 (m, 2H), 5.97-5.94 (m, 1H), 5.90-5.87 (d, 1H), 3.86 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.Br[CH:20]1[CH2:23][CH2:22][CH2:21]1.[I-].[Na+]>CN(C=O)C>[CH:20]1([S:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)(=[O:11])=[O:10])[CH2:23][CH2:22][CH2:21]1
Reactant: O=S(O)c1ccc(F)c(F)c1
Reactant: BrC1CCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(F)c(F)c1)C1CCC1
Temperature: 100 °C

Procedure:
To 5.6 mmol 3,4-difluoro-benzenesulfinic acid and 6.2 mmol triethylamine in 10 ml DMF were added 8.4 mmol bromocyclobutane and 0.2 mmol sodium iodide and the mixture heated at 100° C. for 48 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 233.1 (M+H+, 100%)
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:26][CH3:27])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[CH3:28]I>>[CH3:28][O:1][CH:2]1[C:7]([O:26][CH3:27])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: CI
Reactant: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOCC1O
Product: COC1COCCC1(OC)c1cccc(OCc2ccc3ccccc3c2)c1
Yield: 90 %

Procedure:
Using the procedure described in Example 1, (3RS,4SR)-3-hydroxy-4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran [Example 7, Compound No. 3] was reacted with methyl iodide to give (3RS,4SR)-3,4-dimethoxy-4-[3-(naphth-2ylmethoxy)phenyl]tetrahydropyran (90%), m.p. 131°-133° C.
Reaction SMILES: CC1C(OC2C=C(CC(O)=O)C=C(C(F)(F)F)C=2)=NC=C([S:8](C2C=CC=CC=2)(=O)=O)C=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH2:40][C:41]([OH:43])=[O:42])[CH:36]=[C:37](O)[CH:38]=1>>[Cl:32][C:33]1[CH:34]=[C:35]([CH2:40][C:41]([OH:43])=[O:42])[CH:36]=[C:37]([SH:8])[CH:38]=1
Reactant: Cc1cc(S(=O)(=O)c2ccccc2)cnc1Oc1cc(CC(=O)O)cc(C(F)(F)F)c1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: O=C(O)Cc1cc(S)cc(Cl)c1

Procedure:
The subtitle compound was prepared as described in example 58 steps (i) to (iii) but instead using the product from example 18 step (iv).
Reaction SMILES: C([N:4]([CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[C:23]([F:35])[CH:22]=2)[CH2:16]1)[C:5]([O:7][CH2:8][O:9]C(=O)CC)=[O:6])(=O)C.C(Cl)(=O)OC[O:39][C:40](=O)[CH2:41][CH:42]([CH3:44])[CH3:43]>ClCCl>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([N:17]3[CH2:16][C@H:15]([CH2:14][NH:4][C:5]([O:7][CH2:8][O:9][C:40](=[O:39])[CH2:41][CH:42]([CH3:44])[CH3:43])=[O:6])[O:19][C:18]3=[O:20])=[CH:22][C:23]=2[F:35])[CH2:28][CH2:29]1
Reactant: CC(C)CC(=O)OCOC(=O)Cl
Reactant: CCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Solvent: ClCCl
Product: CC(C)CC(=O)OCOC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Yield: 93 %

Procedure:
Following general procedure C, (S)-5-aminomethyl-3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-oxazolidin-2-one (2) (760.0 mg, 2.2 mmol) in dichloromethane (21 mL) and 3-methyl-butyroxymethyl carbonochloridate (7d) gave the titled product in 93% yield (1030.0 mg, 2.06 mmol). 1H NMR (400 MHz, CDCl3): δ 7.47 (dd, 1H), 7.23 (t, 1H), 7.16 (dd, 1H), 5.73 (q, 2H), 5.37 (t, 1H) 4.76-4.82 (m, 1H), 4.05 (t, 1H), 3.78 (dd, 1H), 3.67 (ddd, 1H), 3.55 (dt, 1H), 3.12-3.19 (m, 4H), 3.09 (dt, 1H), 2.34-2.45 (m, 2H), 2.14-2.21 (m, 2H), 2.07 (sept, 1H), 0.92 (dd, 6H). MS-APCI (m/z+): 501 (M+H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:6]=1.CCN(C(C)C)C(C)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[C:4]1([N:7]2[CH2:8][CH2:9][N:10]([C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:24])[CH2:11][CH2:12]2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
To a solution of phenylpiperazine (12.0 g, 74.0 mmol) and DIPEA (13.5 mL, 81.6 mmol) in DCM (70 mL) at 0° C. add 4-nitrophenyl chloroformate (16.5 g, 81.71 mmol). The reaction mixture was stirred for 30 minutes at 0° C. and then washed with saturated sodium hydrogen carbonate solution (3×200 mL), dried (MgSO4) and concentrated in vacuo to give a 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (24.8 g, 102%) as a yellow solid which was used without further purification.