Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[C:8]([CH3:26])([CH3:25])[O:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[CH:14][CH:13]=[C:12]([NH2:24])[CH:11]=2>N1C=CC=CC=1>[F:6][C:7]1[C:8]([CH3:26])([CH3:25])[O:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)=[CH:14][CH:13]=[C:12]([NH:24][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=2
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)Oc2cc(N)ccc2C(c2ccc(F)cc2)=C1F
Solvent: c1ccncc1
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2C(c2ccc(F)cc2)=C1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, pyridine (4 mL) and Methanesulfonyl chloride (60 μL) were added dropwise to a solution of [3-fluoro-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-7-yl]amine (a compound of Reference Example 7(7), 105 mg) in pyridine (4 mL) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo, the residue was diluted with ethyl acetate, and the solution was washed successively with a saturated aqueous solution of citric acid, water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was filtered through a column of porous diatomite (Chem Elut), and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, Solvent: chloroform/methanol=100/0 to 90/10) to give the titled compound (105 mg) as a colorless powder.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)=[O:25])=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)=[O:25])=[CH:21][CH:22]=1)=[O:16]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(NC(=O)c2ccco2)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(NC(=O)c2ccco2)cc1
Temperature: 100 °C
Yield: 81 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl]-2-furamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 81 mg of the title compound (81%) as a yellow powder in 96.7% purity by HPLC (Rt: 4.05, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][CH3:13])[C:5]#[N:6].Cl.[Cl:15][CH2:16][C:17](=N)OCC>C(O)C>[ClH:15].[CH2:11]([N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[C:17]1[CH2:16][Cl:15])[CH2:12][CH3:13]
Reactant: CCOC(=N)CCl
Reactant: CCCNc1ccc(C#N)cc1N
Agent: Cl
Solvent: CCO
Product: CCCn1c(CCl)nc2cc(C#N)ccc21

Procedure:
A solution of 3-amino-4-n-propylaminobenzonitrile (7.38 g, 42.1 mmol) and ethyl chloroacetimidate hydrochloride (9.92 g, 63.2 mmol) in ethanol (100 mL) is heated at reflux for 17 h, then cooled and concentrated to give 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole hydrochloride. Prior to use in the next step, this material is converted to free base by adding aqueous bicarbonate and extracting with dichloromethane, drying (Na2SO4), and concentrating. ii) Alternatively, chloroacetylchloride rather than ethyl chloroacetimidate can by used: To a solution of 3-amino-4-n-propylaminobenzonitrile (5.15 g, 29.4 mmol) and triethylamine (4.51 mL) in ethyl acetate (52 mL) at room temperature, chloroacetyl chloride (2.57 mL) is added slowly. After stirring the reaction mixture for 30 minutes at room temperature, acetic acid (5 mL) is added and the reaction mixture heated to reflux. After heating for 20 h, the reaction mixture is cooled to room temperature and diluted with water (50 mL). The organic solution is washed twice with 1.0 M sodium hydroxide (2×50 mL), then washed with an aqueous solution of 0.25 M KH2PO4 (50 mL), followed by brine (50 mL). The organic layer is dried (sodium sulfate), concentrated in vacuo, and the solid recrystallized by heating in ethyl acetate (20 mL), adding hexane (40 mL) and cooling to room temperature with stirring to afford 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole as brown crystals. 1H NMR (CDCl3): δ 8.08 (d, J=0.8 Hz, 1H), 7.57 (dd, J=1.65, 8.52 Hz, 1H), 7.45 (d, J=8.24 Hz, 1H), 7.26 (s, 1H), 4.84 (s, 2H), 4.24 (t, J=7.6 Hz, 2H), 1.94 (pentet, J=7.4. 7.6 Hz, 2H), 1.03 (t, J=7.4 Hz, 3H). (B) Preparation of 1-Propyl-2-{([2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([SH:8])=[N:6][N:7]=1.[H-].[Na+].FC(F)(F)S(O[CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])(=O)=O>C1COCC1>[CH3:1][S:2][C:3]1[S:4][C:5]([S:8][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[N:6][N:7]=1
Reactant: CSc1nnc(S)s1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CSc1nnc(SC)s1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-methylthio-1,3,4-thiadiazole-5-thiol (1 mmole) in THF (5 mL) was treated with sodium hydride (60%, 1.1 mmole) at 0° C. and the resulting mixture was stirred at room temperature for 30 min. The reaction was then cooled to 0° C. and treated with diethylphosphonomethyl trifluoromethanesulfonate (1.1 mmole). After stirring at room temperature for 12 h, the reaction was quenched with saturated ammonium chloride. Extraction and chromatography gave 2-methylthio-5-diethylphosphonomethylthio-1,3,4-thiadiazole as an oil.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18]N1CCNCC1.C(N(C(C)C)CC)(C)C>CC(O)CC>[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: Fc1cccc(CN2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)O
Product: O=c1cc(N2CCN(Cc3cccc(F)c3)CC2)nc[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
A mixture of 6-chloro-3H-pyrimidin-4-one (Intermediate 4; 100 mg, 0.77 mmol), 1-(3-fluorobenz-yl)piperazine (Aldrich; 194 mg, 1.0 mmol), and diisopropylethylamine (200 μL, 1.1 mmol) in 2-butanol (5 mL) was heated in a sealed scintillation vial on a hot plate at about 80° C. for 8 hours and then allowed to cool and stand at room temperature overnight. The mixture was filtered. The solid was washed with 2-butanol and air-dried to give 6-[4-(3-fluoro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one (145 mg, 65%), as a white solid, mp 273-275° C. (dec.). 1H NMR (d6-DMSO) δ 2.36-2.39 (m, 4H), 3.44-3.47 (m, 4H), 5.23 (s, 1H), 7.04-7.16 (m, 3H), 7.32-7.40 (m, 1H), 7.86 (s, 1H), 11.60 (s, 1H). LRMS ES+M+H 289. HRMS Calcd. for C15H18FN4O (M+H), 289.1459. Found, 289.1459.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[S:14]([Cl:18])(=O)(=[O:16])[OH:15].O=S(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([C:9](=[O:11])[CH3:10])[CH3:12])[CH:5]=[CH:6][C:7]=1[S:14]([Cl:18])(=[O:16])=[O:15]
Reactant: CC(=O)C(C)(C)c1cccc(Cl)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(=O)C(C)(C)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of 3-(3-chlorophenyl)-3-methylbutan-2-one (15 g, 76 mmol) in CHCl3 (100 mL) was added chlorosulfuric acid (101 mL, 20 eq) at 0° C. over 2 h. Next SOCl2 (20 mL) was added dropwise to the reaction mixture over 30 min under nitrogen. The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was slowly added to ice-water and then extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4 and evaporated. The residue was purified by chromatography (silica, Hex/EtOAc=9:1 to 4:1) to give 2-chloro-4-(2-methyl-3-oxobutan-2-yl)benzene-1-sulfonyl chloride as a yellow solid (9.8 g, 43%). 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=8.4 Hz, 1H), 7.54 (s, 1H), 7.37 (d, J=2.2 Hz, 1H), 2.03 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][CH:9]2[C:15]3=[N:16][C:17]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][N:22]=4)=[CH:18][C:19](=[O:20])[N:14]3[CH2:13][CH2:12][NH:11][CH2:10]2)=[O:7])=[C:4]([O:29][CH3:30])[CH:3]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CO.C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][CH:9]2[C:15]3=[N:16][C:17]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][N:22]=4)=[CH:18][C:19](=[O:20])[N:14]3[CH2:13][CH2:12][N:11]([CH3:33])[CH2:10]2)=[O:7])=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(Cl)ccc1C(=O)NC1CNCCn2c1nc(-c1ccncn1)cc2=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(Cl)ccc1C(=O)NC1CN(C)CCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 162.9 %

Procedure:
To a solution of 0.040 g (0.09 mmol) of (+/−)-4-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-benzamide in 1.9 ml of methanol was added 0.003 g (0.04 mmol) of paraformaldehyde, 0.022 g (0.10 mmol) of sodium triacetoxyborohydride and 40 μL (0.20 mmol) of hydrochloric acid (5-6N in isopropanol). The reaction mixture was stirred at room temperature for 12 hours. To the resulting mixture was added 0.006 g (0.07 mmol) of paraformaldehyde 0.042 g (0.20 mmol) of sodium triacetoxyborohydride and pH was adjusted to 6 with glacial acetic acid. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated; the residue was dissolved in dichloromethane, washed with a saturated aqueous solution of sodium carbonate, saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The free base was transformed into its hydrochloride salt to give 0.035 g of pure product.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][CH2:6][C:7](Br)=[O:8].[CH3:10][O:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=[O:13]>C(Cl)Cl>[CH3:10][O:11][C:12]([C:14]1[CH:18]=[C:17]([C:7](=[O:8])[CH2:6][Br:5])[S:16][CH:15]=1)=[O:13]
Reactant: O=C(Br)CBr
Reactant: COC(=O)c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1csc(C(=O)CBr)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
Aluminium trichloride (4.26 g, 32.0 mmol) was dissolved in DCM (15 mL) and cooled to 0° C. Bromoacetyl bromide (1.78 mL, 20.4 mmol) was added slowly as a solution in DCM (7 mL) and stirred at 0° C. for 1 hour. Thiophene-3-carboxylic acid methyl ester (2.89 g, 20.4 mmol) was then added slowly as a solution in DCM (15 mL) and the mixture stirred overnight warming to room temperature. The mixture was poured into ice/water and extracted with DCM (×2) then the organics were washed with water, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on a 50 g silica II cartridge, eluting with 2:1 pentane:DCM to neat DCM, to give the title compound as a white solid (2.1 g). 1H NMR (400 MHz, CHCl3-d): δ 8.4 (d, 1H), 8.2 (d, 1H), 4.4 (s, 2H), 3.9 (s, 3H).
Reaction SMILES: Br[C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH3:16].CCCCCC.C([Li])CCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C.Cl>O1CCCC1>[CH3:16][C:3]1[CH:4]=[C:5]([O:6][CH:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)[CH:13]=[C:14]([CH3:15])[C:2]=1[B:28]([OH:33])[OH:29]
Reactant: Cc1cc(OC2CCSCC2)cc(C)c1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OC2CCSCC2)cc(C)c1B(O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of 4-(4-bromo-3,5-dimethylphenoxy)tetrahydro-2H-thiopyran (3.01 g, 10.0 mmol) in tetrahydrofuran (50 mL) was added dropwise n-butyllithium hexane solution (1.6 M, 6.57 mL, 10.5 mmol) at −78° C., and the reaction mixture was stirred for 1.5 hr at the same temperature. Triisopropyl borate (6.92 mL, 30.0 mmol) was added, and the mixture was stirred overnight, during which the mixture was allowed to warm to room temperature. The reaction mixture was ice-cooled, 2 M hydrochloric acid (50 mL) was added, and the mixture was stirred for 2.5 hr. The aqueous layer and the organic layer were separated, and the organic layer was washed with saturated brine and saturated aqueous sodium hydrogencarbonate while simultaneously adjusting to neutral. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with cool hexane to give the title compound (1.89 g, yield 71%) as colorless crystals.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:26]=[CH:25][C:20]4[NH:21][C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:27]>CO>[C:1]1([S:7]([CH2:8][CH2:9][NH:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]3[CH:26]=[CH:25][C:20]4[NH:21][C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[CH2:15][CH2:16]2)=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCSc4ccccc4)CC3)cc2o1
Reactant: O
Solvent: CO
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCS(=O)c4ccccc4)CC3)cc2o1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirred, ice—Cold, suspension of NaIO4 (0.13 g, 0.62 mmol) in H2O (1.2 mL) was added 6-[trans-4-(2-phenylsulfanylethylamino)cyclohexyl]-3H-benzoxazol-2-one (0.25 g, 0.62 mmol). The viscous reaction mixture was diluted with H2O (1.5 mL), warmed to room temperature, and then further diluted with MeOH (15 mL). After 21 hours, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (silica, 89:10:1 CH2Cl2:MeOH:NH4OH) gave the free base of 6-[trans-4-(2-benzenesulfinylethylamino)cyclohexyl]-3H-benzoxazol-2-one, which was converted to the HCl salt (0.13 g, 49%): mp 107-110° C.; IR (KBr): 2936, 2783, 1768, cm−1; 1H NMR (500 MHz, DMSO-d6): δ 9.03 (br s, 2H), 7.74-7.60 (m, 5H), 7.16 (s, 1H), 6.99-6.97 (m, 2H), 3.48-3.43 (m, 1H), 3.33-3.29 (m, 1H), 3.18-3.04 (m, 4H), 2.54-2.52 (m, 2H), 1.86-1.84 (m, 2H), 1.51-1.44 (m, 4H); API-MS (m/z): 385 [M+H]+; HPLC: method A, 7.01 minutes (98.1%); method B, 12.83 minutes (99.2%); Anal. Calcd for C21H24N2O3S.HCl.1.25H2O: C, 56.88; H, 6.25; N, 6.32. Found: C, 56.86; H, 6.18; N, 6.22.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:20])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:5]([OH:7])=O.[N+:21]([C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>>[Br:20][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:5]([NH:33][S:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=1)(=[O:32])=[O:31])=[O:7]
Reactant: O=C(O)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Product: O=C(NS(=O)(=O)c1cccc([N+](=O)[O-])c1)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Yield: 54.4 %

Procedure:
3,5-dibromo-4-(3-bromobenzyloxy)benzoic acid (0.17 mmol) was coupled with 3-nitrobenzenesulphonamide (0.89 mmol) using the procedure described in Example 31. Purification on column (silica gel, chloroform/methanol 9:1) gave 60 mg (54%) of N-[3,5-dibromo-4-(3-bromobenzyloxy)benzoyl]-3-nitrobenzenesulphonamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cu](C#N)[C:20]#[N:21].[OH-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[N:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: N#C[Cu]C#N
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.55 g, 5.0 mmol) in N,N-dimethylformamide (12.5 mL) was treated with copper cyanide (672 mg, 7.5 mmol). This mixture was heated at reflux for 21 h. The reaction mixture was cooled to 25° C. and poured into aqueous ammonium hydroxide (25 mL). The resulting solution was diluted with water (25 mL). This solution was extracted with ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous sodium chloride solution (3×75 mL), dried over sodium sulfate and magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.17 g, 91.3%) as a clear oil; EI-HRMS m/e calcd for C16H19NO2 (M+) 257.1415 found 257.1406.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[C:28]([CH2:30][CH3:31])[CH:27]=[CH:26][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH3:24])(=[O:20])=[O:19])=[CH:14][C:13]=1[F:25])C1C=CC=CC=1.O1CCCC1>C(O)C>[CH2:30]([C:28]1[CH:27]=[CH:26][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH3:24])(=[O:20])=[O:19])=[CH:14][C:13]=2[F:25])=[C:9]([OH:8])[CH:29]=1)[CH3:31]
Reactant: CCCNS(=O)(=O)c1ccc(Oc2ccc(CC)cc2OCc2ccccc2)c(F)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCNS(=O)(=O)c1ccc(Oc2ccc(CC)cc2O)c(F)c1
Yield: 61.9 %

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for 4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-propyl-benzenesulfonamide (140 mg; 0.32 mmol) and tetrahydrofurane for ethanol (3 mL), the title compound (70 mg; 62%) was obtained as a clear oil, after purification on preparative TLC (dichloromethane)
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2cccs2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(-c2cccs2)s1

Procedure:
20 g of 5-formyl-2,2'-bithiophene was dissolved in 50 ml of methanol, followed by adding NaBH4 and stirring until bubbling stopped. The reaction was monitored by thin layer chromatography to determine whether the reaction was completed. After the methanol was removed under reduced pressure and the reaction solution was extracted with dichloromethane, the solution was washed with saturated NaCl solution, dried over anhydrous magnesium sulfate, condensed and 20.10 g of product (melting point 52°-53° C., 99%) was thus obtained.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][Br:20])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=O)(C)(C)C.[C:21]([NH:28][C@H:29]([C:38]([OH:40])=O)[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:24]([O:23][C:21]([NH:28][C@H:29]([C:38]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][Br:20])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:40])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1)=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound (U) (3.51 g, 10 mmol) was dissolved in a solution of 25% TFA in DCM (10 ml) and stirred at room temperature for 30 mins. The solution was evaporated to dryness in vacuo and the residue evaporated from DCM three more times to remove residual traces of TFA. This residue was coupled to Boc-tyrosine (2.8 g, 10 mmol) using the procedure described for the synthesis of compound (U). The resultant product was purified by column chromatography (silica; 50% ethyl acetate in hexane (Rf =0.19)) as a colourless powder (4.9 g, 96%), mp 96-100° C. 1H NMR (CDCl3): δ 6.7-7.1 (m, 6H, ArH, Ile-NH, NH), 5.15 (d, J=8.2 Hz, 1H, Tyr-NH), 4.30 (m, 1H, αCH), 4.2 (m, 1H, αCH), 3.35-3.50 (m, 1H, NCH), 3.40 (t, J=6.0 Hz, 2H, CH2Br), 3.25 (m, 1H, NCH), 3.01 (dd, J=6.1, 13.6 Hz, 1H, Tyr-βCH), 2.93 (dd, J=6.1, 13.6 Hz, 1H, Tyr-βCH), 2.05 (m, 2H, CH2), 1.9 (m, 1H, Ile-βCH), 1.4 (m, 10H, Ile-γCH, (CH3)3), 1.05 (m, 1H, Ile-γCH), 0.89 (d, J=6.32 Hz, 3H, Ile-γCH3), 0.83 (t, J=7.37 Hz, 3H, Ile-δCH3). ISMS 514/516 (M+H). HRMS calcd for C23H35N3O5 (M-HBr), 433.2577; found 433.2573.
Reaction SMILES: [CH3:1][C@H:2]1[N:7](CC2C=CC=CC=2)[C@@H:6]([CH3:15])[CH2:5][N:4]([C:16]2[CH:17]=[C:18]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[O:35][C:36]([CH3:39])=[CH:37][CH:38]=4)=[C:30]([F:40])[CH:29]=3)(=[O:27])=[O:26])[C:19]([O:22][CH3:23])=[N:20][CH:21]=2)[CH2:3]1.[H][H].[ClH:43]>C(O)C.[Pd]>[ClH:43].[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:15])[CH2:5][N:4]([C:16]2[CH:17]=[C:18]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[O:35][C:36]([CH3:39])=[CH:37][CH:38]=4)=[C:30]([F:40])[CH:29]=3)(=[O:26])=[O:27])[C:19]([O:22][CH3:23])=[N:20][CH:21]=2)[CH2:3]1
Reactant: [H][H]
Reactant: COc1ncc(N2C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)c(F)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ncc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)c(F)c1

Procedure:
A solution of N-[5-[cis-3,5-dimethyl-4-(phenylmethyl)-1-piperazinyl]-2-(methyloxy)-3-pyridinyl]-3-fluoro-4-(5-methyl-2-furanyl)benzenesulfonamide (D31) (60 mg, 0.1 mmol) in ethanol (5 ml) and 2M hydrochloric acid (0.5 ml) containing 10% palladium on carbon (10 mg) was stirred in a hydrogen atmosphere for 2 hours. The mixture was filtered through ‘celite’ and the solvent evaporated. Purification of the residue by flash chromatography eluting with 5% methanol in dichloromethane followed by treatment with 1.0M hydrogen chloride in diethyl ether gave the title compound (E13). MS (ES+) m/e 475 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH2:32][C:33]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNC(=O)Cc3ccccc3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 14 mL (0.11 mmol) phenylacetyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[CH:28][C:29]=1[Cl:30].Cl>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([S:31]([N:6]2[CH2:7][CH2:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]2[CH2:4][C:3]([O:2][CH3:1])=[O:15])(=[O:32])=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CC1NCCc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1c2ccccc2CCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)acetic acid methyl ester (7.49 g, 36.5 mmol) was dissolved in DCM (200 ml), and triethylamine (11.7 ml, 83 mmol) was added thereto. The reaction solution was cooled to 0° C., and a solution of 3,4-dichlorobenzenesulfonyl chloride (8.14 g, 33.2 mmol) in DCM (100 ml) was added dropwise. After 3 h, 0.5 M HCl (100 ml) was added. After phase separation, the organic phase was washed with water, dried (sodium sulfate) and concentrated. Purification was carried out by column chromatography on silica gel (heptane/ethyl acetate 4:1).