Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9](OCC)[CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.[CH2:15]([NH2:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:15]([NH:23][C:9](=[N:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH3:11])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCN
Reactant: CCOC(CC)=Nc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCCCCCNC(CC)=Nc1cccc(Cl)c1

Procedure:
Ethyl N-(3-chlorophenyl)propionimidate (1 part), n-octyl-amine (1 part), and a catalytic amount of p-toluenesulfonic acid monohydrate were charged to a flask fitted with a condenser and drying tube (CaSO4) and the mixture was refluxed for 15 hours, after which the flask was fitted with a 10 cm Vigreaux column and the ethanol that had formed (0.8 part) distilled off slowly (3 hours). The reaction mixture was then distilled at reduced pressure (0.15 mm Hg) to give N-n-octyl-N'-(3-chlorophenyl)propionamidine (0.7 part). The fraction boiling at 167.5° - 169° C. was collected and analyzed.
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][C:3]1[O:4][C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=S(Cl)Cl
Reactant: O=c1cc(CO)oc2ccccc12
Solvent: ClC(Cl)Cl
Product: O=c1cc(CCl)oc2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The 2-(hydroxymethyl)-4H-chromen-4-one was dissolved in 30 ml of anhydrous chloroform at room temperature, 1 ml of thionyl chloride was added to the solution, and reaction mixture was stirred at room temperature for 24 hours. The solvent was thereafter evaporated, and the obtained liquid was dissolved in anhydrous hexane, which was also evaporated again to give 2-(chloromethyl)-4H-chromen-4-one which was further reacted without purification.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].C[O-].[Na+].COCCOC.C1(C)C=CC(S(O[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=2)[C:26]#[N:27])(=O)=O)=CC=1>CO.O>[CH2:1]([S:5][CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:29]=1)[C:26]#[N:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: CCCCSC(C#N)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 1 h
Yield: 30.7 %

Procedure:
Butylmercaptan (105 mg) was dissolved in 1 ml of methanol, and 0.4 ml of a 2.7 M methanol solution of sodium methoxide was added at room temperature. The solution was added dropwise to 2 ml of a 1,2-dimethoxyethane solution of 391 mg of O-(p-toluenesulfonyl)-m-benzoylmandelonitrile in an argon atmosphere under ice cooling. The mixture was stirred for 1 hour under ice cooling, and 20 ml of water was added. The mixture was extracted with 20 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel; benzene) to afford 95 mg (yield 31%) of alpha-(butylthio)(m-benzoylphenyl)acetonitrile as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH3:18].[C:19]([O-:22])(=O)[CH3:20].[K+].C(OC(=O)C)(=O)C.[N:31](OCCC(C)C)=O>C1(C)C=CC=CC=1>[C:19]([N:1]1[C:2]2[C:3](=[CH:4][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=3[C:9]#[N:10])=[CH:16][CH:17]=2)[CH:18]=[N:31]1)(=[O:22])[CH3:20]
Reactant: CC(C)CCON=O
Reactant: Cc1cc(Oc2ccc(F)cc2C#N)ccc1N
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a 2 L flask, 2-(4-amino-3-methylphenoxy)-5-fluorobenzonitrile (277.1 ml, 221.7 mmol) was taken up in toluene (0.8 M) and treated with potassium acetate (26.11 g, 266.0 mmol) at ambient temperature. The reaction mixture was cooled to 0° C. and acetic anhydride (63.91 mL, 676.1 mmol) was added over 2 minutes. The ice bath was removed, the flask was fitted with a reflux condenser and the reaction was heated to 40° C. Isoamyl nitrite (59.29 mL, 443.3 mmol) was added dropwise. The reaction was heated to reflux for 15 hours, cooled to ambient temperature, and concentrated. The resulting solids were suspended in 2 L water, stirred vigorously for 15 minutes, filtered, and washed with water (1 L). The resulting solid (75 g, still wet) was used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[Cl:22])[C:12]2[C:11](=[O:23])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2].ClCCl.F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34].CO>O>[C:1]([C:4]1[CH:13]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[Cl:22])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[O:23][CH2:33][CH3:34])[NH:6][C:5]=1[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc(C#N)cc1Cl
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1Cl)C(C(C)=O)=C(C)N2
Reaction time: 2 h

Procedure:
245 mg (0.721 mmol) of 4-(3-acetyl-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-4-yl)-3-chlorobenzonitrile are dissolved under an argon atmosphere in 15 ml of abs. dichloromethane, and 273 mg (1.442 mmol) of triethyloxonium tetrafluoroborate are added. After a reaction time of two hours at room temperature (reaction checked by HPLC), the mixture is mixed with 5 ml of methanol and 0.5 ml of water and stirred for a further 2 h. It is then diluted with 20 ml of water and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 127 mg (47.9% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+].CN(C)CCN>>[CH3:29][S:30]([C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1)(=[O:32])=[O:31]
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1
Reactant: CS(=O)[O-]
Agent: CN(C)CCN
Agent: [Na+]
Product: CS(=O)(=O)c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 125 °C
Yield: 29.9 %

Procedure:
A stirred suspension of (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.22 mmol) (prepared as described in Example 108, steps 1 through 6), sodium methane sulfinate (89 mg, 0.9 mmol) and N,N-dimethylethylenediamine (9.6 μL, 0.9 mmol) was degassed under a stream of argon for 5 min. Copper (I) trifluoromethane-sulfonate benzene complex (22 mg, 0.04 mmol) was added and the mixture was sealed and heated at 125° C. for 7 h. The mixture was cooled to rt, filtered, and the filtrate subjected to purification by reverse-phase preparative HPLC eluting with a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and a Varian diphenyl column as the stationary phase, to afford (1R,2R)-2-((6-((5-(methylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (30 mg, 30%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.20 (s, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.84 (m, 1H), 7.76 (m, 1H), 7.69 (s, 1H), 7.30 (m, 1H), 7.21 (m, 1H), 5.56 (s, 2H), 4.82 (m, 1H), 3.50 (m, 1H), 3.36 (m, 1H), 3.19 (s, 3H), 2.01 (m, 1H), 1.87 (m, 1H), 1.56-1.67 (m, 2H), 1.11-1.31 (m, 4H); LCMS (ESI) m/z 457 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.[CH3:18][C:19]([CH3:23])([CH3:22])[C:20]#[CH:21]>C(NCC)C.C(Cl)CCl.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.[Cu]I>[CH3:18][C:19]([CH3:23])([CH3:22])[C:20]#[C:21][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: CN1Cc2c(Br)ncn2-c2ccccc2C1=O
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCCl
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)C)ncn2-c2ccccc2C1=O

Procedure:
2.92 g (10 mmol) of 3-bromo-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to 80° in a pressure tube for 24 hours with 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride, 30 mg of copper(I) iodide and 2.5 ml (20 mmol) of 3,3-dimethyl-1-butyne in 30 ml of diethylamine and 10 ml of ethylene chloride. The reaction mixture was evaporated, the residue was taken up in methylene chloride and washed with water. The organic solution was dried over magnesium sulphate and filtered through a silica gel pad. By crystallization from hexane there was obtained 3-(3,3-dimethyl-1-butynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 148°-150°.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][C:4]1=[O:9].C(N(CC)C(C)C)(C)C.[CH3:19][C:20]([O:23][C:24]([N:26]1C(C2C=CC(C#N)=CC=2)O1)=[O:25])([CH3:22])[CH3:21]>ClCCl>[C:20]([O:23][C:24](=[O:25])[NH:26][N:6]1[CH2:7][CH2:8][N:3]([CH3:2])[C:4](=[O:9])[CH2:5]1)([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Reactant: CN1CCNCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(NC(=O)OC(C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
Methyl-2-piperazinone hydrochloride (1:1) (300 mg, 1.99 mmol) was combined with dichloromethane (20 mL) to give a light yellow suspension. N,N-Diisopropylethylamine (309 mg, 417 μl, 2.39 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (441 mg, 1.79 mmol) in dichloromethane (10 mL) was added during 35 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 5 g, ethyl acetate/n-heptane 1/1) to give the title compound (67 mg, 15%) as white solid; GC-MS (EI) 229.0 (M)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=3[CH2:9][O:8][CH2:7][C:6]=2[CH:17]=1.C([Sn](CCCC)(CCCC)[CH:23]=[CH:24][O:25]CC)CCC.O.C1C(=O)N([Br:44])C(=O)C1>O1CCOCC1.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>[Br:44][CH2:23][C:24]([C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[CH:12]=[CH:13][C:14]([Br:16])=[CH:15][C:10]=3[CH2:9][O:8][CH2:7][C:6]=2[CH:17]=1)=[O:25]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: Brc1ccc2c(c1)COCc1cc(Br)ccc1-2
Reactant: O=C1CCC(=O)N1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc2c(c1)COCc1cc(Br)ccc1-2
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 25.2 %

Procedure:
To the solution of 3,9-dibromo-5,7-dihydro-dibenzo[c,e]oxepine (416 mg, 1.2 mmol) and tributyl(ethoxyvinyl)stannane (878 μl, 2.6 mmol) in dioxane (6 ml) was added PdCl2(PPh3)2 (30 mg). The mixture was heated at 80° C. for 16 hours and was cooled to 0° C. Water (2 ml) was added, followed by slow addition of NBS (464 mg, 2.6 mmol) over 5 minutes period. The mixture was stirred at 0° C. for additional 40 minutes, and the solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc) gave 2-bromo-1-(9-bromo-5,7-dihydro-dibenzo[c,e]oxepin-3-yl)-ethanone (120 mg).
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])(=O)=O.[CH3:20][C:21]1[N:22]=[C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:24][C:25]=1[C:26](O)=[O:27].C(=O)([O-])O.[Na+]>O>[CH3:20][C:21]1[N:22]=[C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:24][C:25]=1[C:26]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:17])[F:18])=[O:27]
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)O
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCCCOC(=O)c1sc(-c2ccccc2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 6 h
Yield: 73.7 %

Procedure:
To 10 ml of N,N-dimethylformamide were dissolved 0.50 g (2.2 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.53 g (2.4 mmol) of 4-methyl-2-phenylthiazole-5-carboxylic acid, followed by the addition of 0.37 g (4.4 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 6 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 0.57 g (yield: 74%) of 6,6-difluoro-5-methyl-5-hexenyl 4-methyl-2-phenylthiazole-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[C:25]([O:28][CH2:29][C:30](Cl)=O)(=[O:27])[CH3:26]>O1CCCC1>[C:25]([O:28][CH2:29][C:30]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:24])[C:10]2[N:11]=[C:12]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[S:13][C:14]=2[C:15](=[O:16])[N:17]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Solvent: C1CCOC1
Product: CC(=O)OCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (200 mg, 0.545 mmol) in Tetrahydrofuran (THF) (2726 μl) at 0° C. was added acetoxyacetyl chloride (117 μl, 1.090 mmol). The mixture was stirred at 50° C. for 3 h, then quenched with methanol and concentrated. The residue was subjected to silica gel chromatography (0-5% methanol/dichloromethane) followed by reversed-phase HPLC purification to provide [4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-7-oxo-4,7-dihydro[1,3]thiazolo[4,5-d]pyrimidin-5-yl]methyl acetate. (49 mg, 20%); LC/MS: MS (ES+) m/e 449 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 (s, 3H), 2.42 (s, 3H), 3.52 (m, 4H), 3.67 (m, 4H), 5.03 (s, 2H), 5.50 (s, 2H), 6.54 (d, J=7.6 Hz, 1H), 7.17 (m, 1H), 7.39 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:17]=[CH:16][C:9]([C:10](N(OC)C)=[O:11])=[C:8]([CH3:18])[CH:7]=1.[Cl-].[NH4+]>C1COCC1>[Br:5][C:6]1[CH:17]=[CH:16][C:9]([C:10](=[O:11])[CH2:1][CH3:2])=[C:8]([CH3:18])[CH:7]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1C
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Br)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethylmagnesium bromide (2.35 ml of 3M in diethyl ether, 7.05 mmol) is added slowly to a stirred solution of 4-bromo-N-methoxy-N,2-dimethylbenzamide (0.91 g, 3.53 mmol) in dry THF (40 ml) at 0° C. The reaction is stirred at 0° C. for 1 h followed by RT for 18 h. The reaction mixture is poured into saturated ammonium chloride solution to quench the reaction and concentrated in vacuo to remove most of the THF. The product is extracted with diethyl ether and the combined organic extracts are dried (MgSO4). The solvent is removed in vacuo and the resulting oil is purified by chromatography on silica eluting with iso-hexane:ethyl acetate (3:1) give the title product as a colourless oil. MS m/z 227.0 [M+H]+1H NMR (400 MHz, CDCl3) δ 1.18 (3H, t), 2.45 (3H, s), 2.88 (2H, d), 7.40 (1H, d), 7.43 (1H, s), 7.50 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[CH:17]=[C:16]([CH:18]=[O:19])[NH:15][C:14]1=[S:20])[CH2:7]2.[CH3:21][Mg]Cl.S(=O)(=O)(O)O>>[OH:19][CH:18]([C:16]1[NH:15][C:14](=[S:20])[N:13]([C@H:6]2[CH2:5][CH2:4][C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[CH2:7]2)[CH:17]=1)[CH3:21]
Reactant: O=Cc1cn([C@H]2CCc3c(F)cc(F)cc3C2)c(=S)[nH]1
Reactant: C[Mg]Cl
Agent: O=S(=O)(O)O
Product: CC(O)c1cn([C@H]2CCc3c(F)cc(F)cc3C2)c(=S)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
A mixture of (S)-3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-carbaldehyde (178 mg, 0.6 mmol), prepared as in Example 22, and methylmagnesium chloride (3M, 0.4 mL, 1.2 mmol) was stirred at approximately 0° C. for 1 hour and at approximately 25° for an additional 1 hour. The mixture was treated with 5 mL of dilute sulfuric acid and extracted with ethyl acetate (2×). The combined extracts were dried (MgSO4) and concentrated and the residue was purified by flash chromatography on silica gel eluting with methylene chloride/methanol (98:2). The purified residue was further purified by preparative thin layer chromatography on silica gel eluting with methylene chloride/methanol (95:5) to give (S)-4-(1-hydroxy)ethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (22 mg, 0.1 mmol), m.p. 210°-211° C.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[C:25](Cl)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]CC.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH2:1][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(=O)Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC(=O)Oc1ccc(-c2ccc(O)cc2)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 39.2 %

Procedure:
To a solution of 4-methylcarbonyloxy-4'-hydroxybiphenyl (2.3 g) and triethylamine (1.1 g) in methylene chloride (50 ml) was gradually added dropwise undecanoyl chloride (n-C10H21COCl) (2.1 g). Dimethylaminopyridine (0.3 g) was further added thereto and the mixture was stirred for 24 hours. After the solvent was distilled off, the residue was added to tetrahydrofuran containing tert-butylamine and the mixture was refluxed at 70° C. for 2 hours and hydrolyzed. After the solvent was distilled off, dilute hydrochloric acid was added to the residue to render the solution neutral and the solution was extracted with diethyl ether. After the solvent was distilled off, the residue was washed with hexane and recrystallized from water/ethanol (1/9) solution to obtain the titled compound (about 1.4 g).
Reaction SMILES: [H-].[Na+].O1CCCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1>O.CS(C)=O>[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:17][CH2:18][C@H:19]([O:22][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=2)[CH2:20][CH2:21]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.04 g of 60% sodium hydride was gradually added to 150 ml of a tetrahydrofuran solution containing 10.0 g of trans-4-(tert-butoxycarbonylamino)cyclohexanol and 7.35 g of 2-chloro-5-nitropyridine, and 30 mL of dimethylsulfoxide was further added thereto, and then, the mixture was stirred at room temperature for 1 day. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and then, the solvent was removed under reduced pressure. The residue was applied to silica gel column chromatography (solvent: chloroform alone to chloroform-ethyl acetate (20:1)). The obtained powder crystals were suspended in ethyl acetate-hexane mixed solution and collected by filtration to obtain 12.20 g of trans-1-tert-butoxycarbonylamino-4-(5-nitro-2-pyridyloxy)cyclohexane. To 10 ml of an ethanol suspension containing 800 mg of this compound was added 2 ml of 2N hydrochloric acid-dioxane solution, and the mixture was stirred at room temperature for 18 hours. The precipitates were collected by filtration to obtain 568 mg of trans-4-(5-nitro-2-pyridyloxy)cyclohexylamine.hydrochloride (Reference Example 9-1 in Table 6).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:12][C:4]1[CH:3]=[C:2]([OH:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: COC(=O)CBr
Reactant: Oc1cc(O)c2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cc(O)c2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
A mixture of 1.5180 g of 1,3-dihydroxynaphthalene and 1.70 g of anhydrous potassium carbonate in 10 ml of anhydrous acetone was stirred at room temperature for 1 hour. Methyl bromoacetate (0.91 ml) was added and stirring at room temperature was continued for 50 hours. The solvent was removed in vacuo and the residue was acidified and extracted with ethyl acetate. The dried (magnesium sulfate) extract was concentrated in vacuo and the product was purified by high pressure liquid chromatography using 20% ethyl acetate-toluene to give 0.419 g (19% yield) of [(4-hydroxy-2-naphthalenyl)oxy]acetic acid methyl ester as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([F:35])[CH:29]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][C:30]=2[F:35])=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Cl)cc1F
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(Cl)cc1F)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-chloro-2-fluorophenol: 1H-NMR (CDCl3) δ 8.53 (1H, d, J=2.7 Hz), 8.10 (1H, d, J=2.7 Hz), 7.97–7.94 (3H, m), 7.42–7.39 (2H, m), 7.31–7.21 (3H, m), 5.37 (1H, quint, J=7.0 Hz), 1.61–1.58 (12H, m); MS (ESI) m/z 505 (M+H)+, 503 (M−H)−.