Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.ClC(OCC)=O.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH2:33][CH3:34])[CH:27]=1>C(#N)C>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:9]([C:6]2([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][CH2:8]2)=[O:11])=[C:28]([CH2:33][CH3:34])[CH:27]=1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Reactant: CCc1cc(Cl)ccc1N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)Nc2ccc(Cl)cc2CC)CC1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a stirred solution of 1.54 grams (0.01 mole) of 1-carboethoxycyclopropanecarboxylic acid (the monocarboxylic acid intermediate described in Example XVIII) and 0.99 gram (0.01 mole) of triethylamine in 75 milliliters of acetonitrile was added a solution of 1.06 grams (0.01 mole) of ethyl chloroformate in 25 milliliters of acetonitrile dropwise with cooling to 0° C.-5° C. After stirring at ice temperature for 30 minutes a solution of 1.52 grams (0.01 mole) of 4-chloro-2-ethylaniline in 20 milliliters of acetonitrile was fed dropwise with stirring and continued cooling. The reaction mixture was allowed to warm to room temperature, then stirred for approximately sixteen hours following which it was filtered and the filtrate freed of solvent by evaporation. The residue was dissolved in dichloromethane and extracted, successively, with water (2×50 milliliters), 2N HCl (2×50 milliliters) and water (1×50 milliliters). After drying (MgSO4), solvent was removed by evaporation and the solid recrystallized from hexane to give 1.15 grams (0.004 mole) of ethyl 1-(4-chloro-2-ethylphenylaminocarbonyl)cyclopropanecarboxylate as cream colored prisms having a melting point of 77° C.-80° C. Elemental analysis of the product indicated the following:
Reaction SMILES: O[C:2]([CH2:4][CH2:5][S:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:3]>O>[Cl:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]2[C:16]=1[C:2](=[O:3])[CH2:4][CH2:5][S:6]2
Reactant: COC(=O)c1ccc(Cl)cc1SCCC(=O)O
Solvent: O
Product: COC(=O)c1ccc(Cl)c2c1SCCC2=O
Reaction time: 0.5 h

Procedure:
At 70° C., 50 g (0.18 mol) of methyl 2-(2-hydroxycarbonyleth-1-yl)thio-4-chlorobenzoate were against [sic] to 500 g of polyphosphoric acid, and the mixture was stirred for 30 minutes. The reaction mixture was subsequently added to water with stirring, and the resulting precipitate was filtered off with suction and dried. This gave 41.1 g (88%) of methyl 5-chloro-4-oxothiochromane-8-carboxylate.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>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.CN(C=O)C.CCN(CC)CC>[CH3:1][N:2]([CH2:4][C:5]#[C:6][C:9]1[C:8]([F:7])=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:18]/[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24])/[C:12](=[O:17])[NH:13]2)[CH3:3]
Reactant: C#CCN(C)C
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN(C)C)c21

Procedure:
Using Method C above, N,N-dimethyl propargylamine (42.2 mg, 0.51 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (75 mg, 0.203 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-1,3-dihydro-4-[3-(N,N-dimethylamino)-1-propynyl]-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 40 mg, 61%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13](OC(OCC)=O)=[O:14])[CH2:10][S:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.[Cl-].[NH4+]>[OH:14][CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][S:11][CH3:12]
Reactant: CCOC(=O)OC(=O)[C@H](CSC)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CSCC(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethoxycarbonyl N-(tert-butoxycarbonyl)-S-methylcysteinate (18.5 g, 60.3 mmol) in methanol (300 mL) was added sodium borohydride (9.12 g, 0.240 mol) at 0° C., and then the reaction mixture was allowed to warm to ambient temperature. After 2 hours, the reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl [1-hydroxy-3-(methylsulfanyl)propan-2-yl]carbamate which was used without further purification.
Reaction SMILES: Br.[Br:2][CH:3]([CH3:7])[CH2:4][CH2:5][NH2:6].[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1>N1C=CC=CC=1>[Br:2][CH:3]([CH3:7])[CH2:4][CH2:5][NH:6][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)=[O:17]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(Br)CCN
Agent: Br
Solvent: c1ccncc1
Product: CC(Br)CCNC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To a solution of 3-bromobutane-1-aminehydrobromide (2270 mg, 9.7 mmol) in pyridine (18 mL) was slowly added 1-fluoro-4-isocyanatobenzene (1600 mg, 12 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and 0.5N aqueous hydrochloric acid solution were added to the residue, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×3). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane (=1/1) to give the title compound (1750 mg, 62%) as a white solid.
Reaction SMILES: [C:1]([N:9]1[CH2:12][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C4CCCCO4)=[O:26])[CH:18]=3)[O:13]2)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[C:1]([N:9]1[CH2:10][C:11]2([CH2:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=3)[O:13]2)[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)c3ccccc3)C1)O2)NO
Yield: 71.2 %

Procedure:
(E)-3-[1′-Benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (110 mg, 0.23 mmol) in DCM (8 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-[1′-benzoyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (62 mg, hydrochloride salt) as as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4](SCCC)[N:3]=1>C(O)C.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: CCCSc1cc(C(=O)OC(C)(C)C)nc(Cl)n1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccnc(Cl)n1
Reaction time: 2 h

Procedure:
To a suspension of Raney® nickel (50% slurry in water, 10 g) in ethanol (20 ml) was added a solution of the product from step (ii) (3.83 g) in ethanol (20 ml). The mixture was stirred for 2 hours and treated with a further 5 g Raney® nickel. The mixture was stirred overnight and treated with a further 20 g Raney® nickel. After 1 hour the reaction mixture was filtered through Kieselguhr and the filtrate evaporated. The residue was purified by chromatography eluting with 5-10% ethyl acetate in isohexane. Yield 1.3 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:27][CH2:28][CH3:29])[CH:9]2[CH2:18][C:17]3[CH:16]=[C:15]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=3[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(#N)C.ClCCl.CCN(C(C)C)C(C)C>[N:30]1([C:36]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:27][CH2:28][CH3:29])[CH:9]3[CH2:18][C:17]4[CH:16]=[C:15]([O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=4[CH2:11][CH2:10]3)[CH2:3][CH2:2]2)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Reactant: O=C(Cl)N1CCOCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of trifluoro-methanesulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (200 μL of a 0.19 M solution in acetonitrile, 36 μmole) was added 220 μL of a 0.25 M solution of morpholine 4-carbonyl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 48 h at 25° C. under N2, and was then concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford trifluoro-methanesulfonic acid 7-{[1-(morpholine-4-carbonyl)-piperidin-4-ylmethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester (12.8mg) 106[M+H]+=548.
Reaction SMILES: COC(OC)CC(OC)OC.C(N[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH3:23])=O)CCC.Cl.C([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)(=O)C.N1C=CC=CC=1.C(O)=O.C([O-])=O.[NH4+].[OH-].[Na+]>CC(O)C>[N:31]1[CH:32]=[CH:33][CH:28]=[CH:29][C:30]=1[C:22]1[CH:23]=[CH:17][N:19]=[CH:20][CH:21]=1
Reactant: CCCCNC(=O)NCCCC
Reactant: CC(=O)c1ccncc1
Agent: COC(CC(OC)OC)OC
Agent: Cl
Agent: O=C[O-]
Solvent: c1ccncc1
Solvent: O=CO
Solvent: CC(C)O
Product: c1ccc(-c2ccncc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
15.0 g (92 mmol) of 1,1,3,3-tetramethoxypropane and 20.5 g (119 mmol) of 1,3-di(n-butyl)urea were dissolved in 20 ml of 2-propanol, 13.0 g (125 mmol) of 35% hydrochloric acid was added thereto, and the mixture was refluxed for 1 hour. The reaction solution was cooled to room temperature, and 10.0 g (83 mmol) of 4-acetylpyridine and 7.1 g (89.8 mmol) of pyridine were added thereto. After 30 minutes of stirring at room temperature, 19 ml (416 mmol) of formic acid and 31.5 g (500 mmol) of ammonium formate were added to the reaction solution to carry out the reaction at 100° C. for 8 hours. After completion of the reaction, this was cooled to room temperature, neutralized with 200 g (1.2 mol) of 25% sodium hydroxide aqueous solution and then extracted three times with 200 ml of toluene. The organic layer was concentrated and then purified by distillation under a reduced pressure to obtain 9.9 g (yield 76.5%) of the title compound (purity 99.9%, melting point 55-57° C.).
Reaction SMILES: [Cl:1][C:2]([Cl:18])([Cl:17])[CH2:3][O:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])=[O:6].S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:18])([Cl:17])[CH2:3][O:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:21])=[O:12])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1cccc(C(=O)O)c1)OCC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(C(=O)Cl)c1)OCC(Cl)(Cl)Cl
Yield: 95 %

Procedure:
To a toluene solution (10 ml) of 1.0 g of 3-[(2,2,2-trichloroethoxy)carbonylamino]benzoic acid produced in Example 9-1 was added 2 ml of thionyl chloride, and the resultant mixture was stirred at 100° C. The solvent was distilled off under reduced pressure, and the residue was dissolved in toluene. The solvent was again distilled off under reduced pressure to obtain 1.0 g (yield 95%) of the title compound as a solid.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.C1(C)C=CC(S([C:20]2[NH:24][CH:23]=[N:22][C:21]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)(=O)=O)=CC=1.[H-].[Na+].[CH3:34][Si:35]([CH2:38][CH2:39][O:40][CH2:41]Cl)([CH3:37])[CH3:36]>C1COCC1.CN(C=O)C.O>[CH3:34][Si:35]([CH3:37])([CH3:36])[CH2:38][CH2:39][O:40][CH2:41][N:24]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:22]=[CH:23]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1ccc(S(=O)(=O)c2[nH]cnc2-c2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 2.2 %

Procedure:
To a stirred solution of naphthalene (5.8 g, 45.3 mmol) in dry THF (20 mL) was added Na (0.85 g, 37.0 mmol) under N2. After 15 minutes stirring at room temperature, the resultant green suspension was cooled to −78° C. A cooled (−78° C.) solution of 2-[5-(Toluene-4-sulfonyl)-1H-imidazol-4-yl]-pyridine (Tetrahedron Lett. 1976, 285) (1 g, 3.34 mmol) in dry THF (20 mL) was then added through a cannula. Stirring was continued at −78° C. for 30 minutes and then at room temperature for 10 minutes. The reaction was quenched with the addition of H2O at 0° C. The reaction mixture was diluted with ethyl acetate (80 mL), washed successively with H2O (50 mL) and brine (50 mL), dried over Na2SO4. After removal of the volatile components in vacuo, the residue was dissolved in dry DMF (5 mL) with stirring. NaH (60% with mineral oil, 0.2 g, 5.0 mmol) was then added. After stirring at room temperature for 15 minutes, a solution of SEM-Cl (0.58 g, 3.5 mmol) in dry DMF (1 mL) was then added slowly. After stirring at room temperature for 3 hours, the reaction mixture was poured into cold H2O (50 mL); any undissolved materials were filtered off. The filtrate was then extracted with dichloromethane (3×30 mL) washed with H2O (3×50 mL), brine (50 mL) and dried (Na2SO4). Flash chromatography on silica gel column (4:1 hexane/ethyl acetate to 2:1 hexane/ethyl acetate to 4:1 ethyl acetate/hexane) afforded the intermediate 2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridine as a colorless syrup (20.5 mg, 2.1%). 1H NMR (CDCl3) δ 0.10 (s, 9H), 1.00 (t, 2H, J=7), 3.62 (t, 2H, J=7), 5.40(s, 2H), 7.22(t, 2H, J=4), 7.70–7.85 (m, 2H), 8.10 (d, 1H, J=6),8.65(d, 1H, J=4) ppm; the other isomer shows chemical shift at d 0.10 (s, 9H), 1.00 (t, 2H, J=7), 3.70 (t, 2H, J=7), 5.90(s, 2H), 7.22(t, 2H, J=4), 7.70–7.85 (m, 2H), 8.15 (d, 1H, J=6),8.72(d, 1H, J=4)ppm; LCMS calcd for (C14H21N3OSi): 275.1; found: 276.1 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>C(O)(=O)C>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:20][CH:21]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Solvent: CC(=O)O
Product: O=C(O)COc1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c2c1CCC2

Procedure:
Preparation of Indan-4-ol (compound 12A) A mixture of 4-hydroxy-indan-1-one (5.0 g, 33.7 mmol), sodium cyanoborohydride (6.4 g, 101.1 mmol), and zinc iodide (32.3 g, 101.1 mmol) in dichloromethane, was heated at reflux for two hours. The reaction mixture was then filtered through 50 g SiO2 while still warm, eluting further with dichloroethane. The filtrate was collected and concentrated under vacuum. The residue was added to diethyl ether and the resulting white precipitate was filtered off. The filtrate was collected and concentrated in vacuo to give 4.2 g of the title, compound with purity high enough for subsequent use. 400 MHz 1H NMR (DMSO-d6) δ 9.06 (s, 1H), 6.86 (t, 1H, J=7.8 Hz), 6.59 (d, 1H, J=7.8 Hz), 6.48 (d, 1H, J=7.8 Hz), 2.75 (t, 2H, J=7.3 Hz), 2.67 (t, 2H, J=7.3 Hz), 1.92 (m, 2H). Step 2. Preparation of 7-Thiocyanato-indan-4-ol (compound 12B) The title compound was prepared in the manner analogous to Example 1B using 12A. MS m/z 192 (M+1). Step 3. Preparation of (7-Mercapto-indan-4-yloxy)-acetic acid methyl ester (compound 12C) 7-Thiocyanato-indan-4ol (Example 12B) (1.47 g, 7.7 mmol), cesium carbonate (3.77 g, 11.6 mmol) and methyl bromoacetate (1.24 g, 8.08 mmol) were stirred in 20 ml acetonitrile at ambient temperature for 4 h. The reaction was filtered and concentrated. The crude product was treated under the conditions of Example 1D to afford the title product. MS m/z 239 (M+1). Step 4. Preparation of [7-(4′-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-acetic acid methyl ester (compound 12D) The title compound was prepared in the manner analogous to Example 1F using 12C and 3B. MS m/z 473 (M+1). Step 5. Preparation 17-(4′-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-acetic acid (compound 12) The title compound was prepared in the manner analogous to Example 1 using 12D. mp 158-159° C.; 400 MHz 1H NMR (DMSO-d6) δ 12.94 (br(s), 1H), 7.82 (d, 2H, J=8 Hz), 7.74 (d, 2H, J=8.8 Hz), 7.60 (d, 2H, J=6.4 Hz), 7.31 (d, 2H, J=8 Hz), 7.08 (d, 1H, J=8.8 Hz), 6.58 (d, 1H, J=8.4 Hz), 4.61 (s, 2H), 4.06 (s, 2H), 2.72 (m, 4H), 1.90 (q, 2H); MS m/z 457 (M−1).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:21]([O:25][C:26](Cl)=[O:27])[CH2:22][CH2:23][CH3:24]>ClCCl>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:26]([O:25][CH2:21][CH2:22][CH2:23][CH3:24])=[O:27])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 10.9 g tert-butyl 1-piperazinecarboxylate in 145 ml dichloromethane were added 17.8 ml triethylamine. The solution was cooled to 0° C. and 8.3 ml butylchloro-formate added dropwise at this temperature. After stirring for 1 h the reaction mixture was diluted with dichloromethane and washed with 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was directly used in the next reaction step. Yield: 18.0 g.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH2:17]([NH:21][C:10]1[C:11]([I:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=[C:8]([NH2:16])[N:9]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: CCCCN
Solvent: C1CCOC1
Product: CCCCNc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine and butylamine in THF. ES-MS m/e (%): 359 (M+H+, 100).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[C:14]([O:20][CH2:21][CH3:22])[CH:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([O:20][CH2:21][CH3:22])[CH:13]=1
Reactant: CCOc1cc(Cl)ccc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(Cl)ccc1C=O

Procedure:
Oxalyl chloride (4.87 g, 38.4 mmol) is added to dry dichloromethane (80 ml) cooled to below −60° C. under an atmosphere of nitrogen followed by dropwise addition of a solution of dry dimethyl sulphoxide (6.25 g, 80.10 mmol) in dry dichloromethane (25 ml) with stirring. After stirring for 15 min. at −78° C., a solution of 4-chloro-2-ethoxybenzyl alcohol (5.97 g, 32.0 mmol) in dry dichloromethane (35 ml) is added dropwise to give a white suspension. The suspension is stirred at −78° C. for 0.5 h then added triethylamine (16.18 g, 0.16 mol) rapidly. The mixture is stirred at room temperature for 1.5 h before quenching with aqueous saturated sodium bicarbonate (100 ml). The aqueous phase is separated and extracted with dichloromethane (2×). The combined organic phases is washed with aqueous HCl (1M) and then with brine, dried over magnesium sulphate, filtered and evaporated to a yellow solid. The solid is dissolved in diethyl ether and purified by eluting through a short plug of flash silica. Evaporate to give 4-chloro-2-ethoxybenzaldehyde as a pale yellow solid.
Reaction SMILES: S(C)C.[CH3:4][C:5]1[N:6]=[C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([S:17][CH:18]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][C:12]=2[O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:8][CH:9]=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH3:4][C:5]1[N:6]=[C:7]([NH:10][C:11]2[C:12]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:13][C:14]([S:17][CH:18]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:15][N:16]=2)[S:8][CH:9]=1
Reactant: Cc1csc(Nc2ncc(SC(c3ccccn3)C3CCN(C(=O)OC(C)(C)C)CC3)cc2Oc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: Cc1csc(Nc2ncc(SC(c3ccccn3)C3CCNCC3)cc2Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Placed Me2S (0.0072 g, 0.12 mmol) in Trifluoroacetic acid (10 mL) followed by tert-butyl 4-((6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)(pyridin-2-yl)methyl)piperidine-1-carboxylate (0.068 g, 0.12 mmol) stirred at ambient temperature for 30 minutes, then concentrated to give the title compound (0.086 g, 90% yield). 1H NMR (d6-DMSO) δ 8.52 (bs, 1H), 8.42 (m, 1H), 8.17 (bs, 1H), 8.00 (d, 1H), 7.70 (dt, 1H), 7.41 (t, 2H), 7.25-7.16 (m, 3H), 6.92 (d, 2H), 6.90 (s, 1H), 6.63 (s, 1H), 4.22 (d, 1H), 3.32 (d, 1H), 3.17 (d, 1H), 2.98-2.74 (m, 2H), 2.30 (m, 2H), 2.23 (s, 3H), 1.45 (m, 2H), 1.30 (m, 1H).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:46])=O>C1COCC1>[C:1]12([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([Cl:46])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(C(=O)Cl)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2.0 g (5 mmoles) of 4-[3-(1-adamantyl)-4-methoxy benzamido] benzoic acid are dissolved in 60 ml of THF. 1.1 g (6 mmoles of dicyclohexylamine are slowly added. A white precipitate is immediately formed. The reaction mixture is then cooled to 0° C. and 0.7 g (6 mmoles) of thionyl chloride is slowly added. The reaction mixture is stirred for 3 hours at ambient temperature. The solid that forms is filtered and then the filtrate is evaporated. The resulting residue is used, as is, in the following synthesis.