Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[NH:10]C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[NH2:10])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 137.9 %

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-(tert-butoxycarbonyl)amino-thiophene-2-carboxylic acid methyl ester (4.344 g, 9.58 mmol) in CH2Cl2 (30 mL) is added trifluoroacetic acid (30 mL), and the mixture is stirred at room temperature overnight. Then it is evaporated to dryness, obtained residue is redissolved in CH2Cl2 and washed with aqueous NaHCO3 and brine. Organic fraction is separated, dried over Na2SO4, and concentrated to give 3.135 g of crude 5-(3,3-dimethyl-but-1-ynyl)-3-amino-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.[CH3:14][C:15]1[CH:16]=C(O)C=[CH:19][CH:20]=1.Cl>ClCCl>[C:5]([O:4][C:1]1[CH:14]=[C:15]([CH3:16])[CH:20]=[CH:19][CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Acetic anhydride (519 mg) and pyridine (439 mg) were added to a solution of 3-methylphenol (500 mg) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/8) to give the title compound (583 mg).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][CH:37]([F:44])[C:38](N(OC)C)=[O:39]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:38](=[O:39])[CH:37]([F:44])[F:36])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)C(F)F
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(F)F)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and 2,2-difluoro-N-methoxy-N-methylacetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:16])[C:6](I)=[CH:7][O:8]2.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:7]2[O:8][C:9]3[C:4]([C:5](=[O:16])[CH:6]=2)=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)=[N:18]1
Reactant: COc1cc(OC)c2c(=O)c(I)coc2c1
Reactant: c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3n[nH]c4ccccc34)oc2c1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
A mixture of 5,7-dimethoxy-3-iodochromone (166 mg) prepared in Example 16, indazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted from chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and recrystallized from benzene/hexane to give the titled compound (117 mg; yield=73.0%) as light yellow needle crystals. Melting point: 253°-255° C. Mass spectrum (M+): 332. 1 H-NMR(CDCl3, δ ppm): 6.62 (s, 1H, H6), 8.26 (s, 1H, H8), 6.71 (s, 1H, H3), 6.43 (s, 1H, H3'), 7.80 (d, 1H, H4'), 7.58 (d, 1H, H5'), 7.34 (t, 1H, H6'), 8.11 (d, 1H, H7'), 3.96 (s, 3H, 5MeO), 3.97 (s, 3H, 7MeO).
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.C(C1C=CC([N+]([O-])=O)=CC=1N[S:25]([CH3:28])(=[O:27])=[O:26])C>>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH:6][S:25]([CH3:28])(=[O:27])=[O:26])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1N
Reactant: CCc1ccc([N+](=O)[O-])cc1NS(C)(=O)=O
Product: Cc1cc(Cl)c([N+](=O)[O-])cc1NS(C)(=O)=O

Procedure:
Intermediate 79A was prepared from 4-chloro-2-methyl-5-nitroaniline following the procedure employed in the preparation of Intermediate 78A. HPLC: Rt=1.618 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=265 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)NC1CCC(=O)NC1=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C1CCC(n2cnc3ccc(Cl)cc3c2=O)C(=O)N1
Yield: 74 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-chloro-benzamide (0.31 g, 1.1 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (50 mg) was heated to 150° C. in a microwave oven for 10 minutes. The suspension was filtered and washed with ethyl acetate (10 mL), methanol (5 mL) and ethyl acetate (10 mL) to give 3-(6-chloro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (230 mg, 74% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.01 min (100%); mp: 302-305° C.; 1H NMR (DMSO-d6) δ 2.13-2.20 (m, 1H, CHH), 2.62-2.93 (m, 3H, CH2, CHH), 5.52 (br, 1H, NCH), 7.76 (d, J=9 Hz, 1H, Ar), 7.91 (dd, J=2, 9 Hz, 1H, Ar), 8.10 (d, J=2 Hz, 1H, Ar), 8.41 (s, 1H, CH), 11.19 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.39, 30.87, 56.29 (br), 122.56, 125.05, 129.47, 131.59, 134.82, 146.19, 147.75, 158.73, 169.68, 172.39; LCMS: MH=292, 294; Anal Calcd for C13H10N3O3Cl: C, 53.53; H, 3.46; N, 14.41. Found: C, 53.43; H, 3.21; N, 14.27.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:27]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:28])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)[C@@H](NC(=O)C2CCCCC2)N=C(c2ccccc2)c2ccccc21
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, cyclohexane carboxylic acid chloride and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white solid after removal of the solvent: m.p. 212°-214° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N[CH:9]=[N:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:13][CH:12]=1)#N>O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH:9]=[N:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: N#CNC=Nc1ccc(-c2c[nH]cn2)cc1
Reactant: COCCN
Solvent: O
Product: COCCNC=Nc1ccc(-c2c[nH]cn2)cc1

Procedure:
5 ml of 2-methoxy-ethylamine were added all at once to a suspension of N-cyano-N'-[4-(imidazol-4-yl)-phenyl]-formamidine (1.8 g) in water (2 ml). When the exothermic reaction subsided, a solution was obtained from which the title compound quickly crystallized out. The product was filtered off and purified via its maleate in acetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:5](=[C:6]([C:22](=[O:24])[CH3:23])[N:7](COCC[Si](C)(C)C)[N:8]=2)[CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][N:7]=[C:6]2[C:22](=[O:24])[CH3:23]
Reactant: COc1cc2nn(COCC[Si](C)(C)C)c(C(C)=O)c2cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2[nH]nc(C(C)=O)c2cc1OC

Procedure:
The title compound was prepared in a similar manner as described by G. Luo et al., J. Org. Chem. 2006, 71, 5392-5395: To a solution of 1-(5,6-dimethoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-3-yl]ethanone (200 mg, 0.57 mmol) in THF (6 mL) was added a 1M solution in THF of TBAF (2.85 mL, 2.85 mmol), and the mixture was heated to reflux for 16 h. The reaction mixture was then diluted with EtOAc and successively washed with water and brine, then dried (Phase separator) and evaporated. The crude product was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give after lyophilization of the purified fractions the title compound. MS (LC-MS): 221 [M+H]+; tR (HPLC conditions k): 2.61 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[N:6][CH:7]=1.[H-].[Na+].[C:17](Cl)#[C:18][CH2:19][CH2:20][CH3:21].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[N:12]([CH2:17][C:18]#[C:19][CH2:20][CH3:21])[N:13]=2)=[N:6][CH:7]=1
Reactant: CCCC#CCl
Reactant: O=C1CCC(c2ccc(Cl)cn2)=NN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC#CCN1N=C(c2ccc(Cl)cn2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a 100 mL 3 neck flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 200 milligrams (mg) of 6-(5-chloropyridin-2-yl)-4,5-dihydropyridazin-3(2H)-one (0.95 mmol), 3.8 mg of 60% sodium hydride (oil dispersion) (0.95 mmol), and 20 mL of dry DMF. The reaction mixture was stirred for about 30 minutes at ambient temperature followed by the dropwise addition of 0.1 ml of pentynyl chloride (0.95 mmol) in about 5 mL of dry DMF. The reaction was stirred overnight at ambient temperature, and checked by TLC and GC the next morning. No starting material remained, and one new product was formed. The reaction was poured into about 100 mL of water, and extracted with 3×50 mL of ethyl acetate. The combined ether extract was washed with 100 mL of water, 100 mL of saturated aqueous sodium chloride solution, dried, and stripped to afford 240 mg of a tan solid 92% isolated yield. The NMR data is a 1 follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 1.15 (t, 3H); 2.20 (m, 2H); 2.60 (t, 2H); 3.25 (t, 2H); 4.70 (s, 2H); 7.75 (d, 1H); 8.15 (d, 1H); 8.50 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: C1CSCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCSCC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
To an ice-cold solution of chloroacetyl chloride (2.87 g, 25 mmol) in 15 mL of methylene chloride was added thiomorpholine (2.50 g, 24 mmol) and triethylamine (4.9 g, 48 mmol) slowly. The reaction mixture was stirred at 5° C. for 30 minutes, then warmed to room temperature and stirred for 18 hours. After quenching with water (20 mL) at 5° C., additional methylene chloride (200 mL) was added. The organic layer was separated, washed with saturated aqueous NaHCO3 (2×100 mL), brine (2×100 mL), dried over MgSO4, filtered, and the filtrate was concentrated at reduced pressure. The concentrated residue was dried in vacuo to give 1.83 g (42.0%) of 4-(2-chloroacetyl) thiomorpholine as a brown liquid. 1HNMR (300 MHz / CDCl3):δ 2.62 (t, 2H, J=5.03 Hz), 2.68 (t, 2H, J=4.93Hz), 3.75 (t, 2H, J=5.04 Hz), 3.85 (t, 2H, J=5.04 Hz), 4.04 (s, 2H); mass spectrum, m/z =180.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15].C(O)(=O)C>C(OCC)(=O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][CH2:12][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[C:2]([F:1])[CH:7]=1
Reactant: CN(C)C(=O)CCCc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CCCc1ccc(N)cc1F
Temperature: 21 °C
Yield: 89.2 %

Procedure:
A solution of compound 4-(2-Fluoro-4-nitrophenyl)-N,N-dimethylbutanamide (77) (15 mg, 0.06 mmol), Fe (20 mg, 0.37 mmol) and acetic acid (1 mL) in ethyl acetate (3 mL) was heated under reflux for 2 h. The reaction mixture was allowed to cool to 21° C. and then filtered. The organic layer was concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 9:1) to give desired 4-(4-Amino-2-fluorophenyl)-N,N-dimethylbutanamide (76) (12 mg, 87%): 1H NMR δ 6.95 (dd, 1H, J=8.3, 8.2 Hz), 6.40 (dd, 1H, J=8.3, 2.2 Hz), 6.35 (dd, 1H, J=11.6, 2.2 Hz), 3.66 (br s, 2H), 2.95 (s, 3H), 2.93 (s, 3H), 2.58 (t, 2H, J=7.4 Hz) 2.30 (t, 2H, J=7.6 Hz) 1.85-1.95 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:9]([CH3:10])=[CH:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].ClC1C=CC=CC=1.[C:19]1([CH3:26])[CH:24]=[CH:23][CH:22]=[C:21](Cl)[CH:20]=1>[Cl-].[Zn+2].[Cl-].O>[C:19]1([CH3:26])[CH:24]=[CH:23][CH:22]=[C:21]([C:8]2[C:6](=[O:7])[N:5]([CH3:11])[C:3](=[O:4])[N:2]([CH3:1])[C:9]=2[CH3:10])[CH:20]=1
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Reactant: Cc1cccc(Cl)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1cccc(-c2c(C)n(C)c(=O)n(C)c2=O)c1
Reaction time: 3 h
Yield: 14 %

Procedure:
In a 100 mL round bottom flask equipped with a condenser and an air lock was placed compound 2 (see FIG. 3) (5.00 g, 32.4 mmol), anhydrous zinc chloride 3 (4.45 g, 32.6 mmol), dry chlorobenzene (20 mL) and m-tolyl chloride (4.6 mL, 5.38 g, 34.8 mmol). The reaction was brought to reflux in an oil bath and vigorously stirred for 3 h. After cooling, water (40 mL) was added through the condenser, dropwise at first and then with increasing speed. The condenser was then rearranged for distillation and the chlorobenzene was removed by azeotropic distillation. The solution was then cooled in an ice bath, and diethyl ether (30 mL) was added while stirring to give a precipitate. The precipitate was filtered and recrystallized from 2-propanol to yield 3d (1.11 g, 26.3%); m.p. 136.8-139° C. 1H NMR (600 MHz, CD2Cl2) δ 7.68-7.66 (m, 1H), 7.65-7.62 (m, 1H), 7.44-7.40 (m, 1H), 7.35 (t, J=7.6, 1H), 3.46 (s, 3H), 3.30 (s, 3H), 2.40 (s, 3H), 2.18 (s, 3H). 13C NMR (151 MHz, CD2Cl2) δ 194.00, 161.07, 152.22, 151.98, 139.22, 138.16, 134.94, 130.03, 129.01, 126.93, 113.36, 32.36, 28.32, 21.54, 17.99. MS (ES+) (m/z): [M+1]+ calculated for C15H17N2O3, 273.12. found 237.10.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][CH:12]1[CH2:14][O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][SH:29].C(N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[C:18]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][CH:12]([OH:13])[CH2:14][S:29][CH2:28][CH2:27][C:26]([O:25][CH3:24])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2c(CC3CO3)cccc2C2CCCC2)cc1
Reactant: COC(=O)CCS
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1

Procedure:
20 g (59 mmol) of (2-benzyloxy-3-cyclopentylbenzyl)-oxirane, 24.5 g (0.204 mol) of methyl-3-mercaptopropionate and 26.1 g (0.257 mol) of triethylamine are stirred in 150 ml of dry methanol at room temperature and under protective gas (argon or nitrogen) overnight. The solvent is removed by distillation in vacuo, and the residue is chromatographed on a silica gel column (gradient dichloromethane→ethyl acetate). 19.0 g (65% of theory) or methyl 7-(2-benzyloxy-3-cyclopentylphenyl)-6-hydroxy-4-thiaheptanoate are obtained.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[CH3:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(COCc3ccc(F)cc3)n2)cc1Cl

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 3-chloro-4-methyl-benzenesulfonyl chloride (0.062 g) as a light yellow gum (0.09 g). MS (ESI−): 419.0. ([M−H]−)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[CH:21]=[CH:22][S:23][C:14]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[CH:21]=[CH:22][S:23][C:14]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: Nc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc2ccsc2c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A mixture of 2,4-dichloroaniline (333.8 mg, 2.06 mmol) and 60% sodium hydride (82.4 mg, 2.06 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chlorothieno[3.2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) is added. The resulting reaction mixture is heated at reflux for 7 hours, cooled to room temperature, and concentrated in vacuo. The residue is treated with water for 1 hour. The precipitate is filtered, washed with water, and air dried. The resultant solid is purified by flash column chromatography eluting with a gradient of 1% ethyl acetate in hexane to 8% ethyl acetate in hexane to provide 173.1 mg of 7-[(2,4-dichlorophenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 198–200° C.; 1H NMR (DMSO-d6) δ 7.47 (d, J=4 Hz, 1H), 7.54 (dd, J=6, 2 Hz, 1H), 7.59 (d, J=6 Hz, 1H), 7.81 (d, J=2 Hz, 1H), 8.12 (d, J=4 Hz, 1H), 8.61 (s, 1H), 9.67 (s, 1H); MS 318.1, 320.2 (M+H)+.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29](=[O:36])[N:28]([CH3:37])[CH:27]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Cl.CO>CO.C(Cl)Cl>[OH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][C:17]=2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29](=[O:36])[N:28]([CH3:37])[CH:27]=2)[CH2:11][CH2:10]1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OC2CCC(O[Si](C)(C)C(C)(C)C)CC2)c2ccccc2c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2O[C@H]2CC[C@H](O)CC2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the title compound from step 1 (180.0 mg, 0.33 mmol) in dry MeOH (5 mL) and DCM (3 mL) was added dropwise HCl/MeOH (0.3 mL, 1.2 mmol, 4M) at 0° C. and then stirred at r.t. for 20 min. TLC showed the starting material was consumed completely. The mixture was concentrated and the residue was purified by prep-HPLC to afford the title compound (130.0 mg, 97.8%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.50 (d, J=7.6 Hz, 1H), 7.98 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.55 (t, J=6.8 Hz, 1H), 7.51 (t, J=6.8 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.05 (s, 1H), 4.42-4.35 (m, 1H), 3.67 (s, 3H), 3.65-3.62 (m, 1H), 3.10 (s, 3H), 2.01-1.89 (m, 2H), 1.71-1.65 (m, 2H), 1.36-1.34 (m, 4H). LCMS (M+H)+=428.1 (M+1)+
Reaction SMILES: [Cl:1]Cl.[CH3:3][CH:4]1[C:8]2[CH:9]=[CH:10][C:11]([N:13]([CH3:18])[CH:14]([CH2:16][CH3:17])[CH3:15])=[CH:12][C:7]=2[O:6][C:5]1=[O:19]>C(Cl)(Cl)Cl>[Cl:1][C:10]1[C:11]([N:13]([CH3:18])[CH:14]([CH2:16][CH3:17])[CH3:15])=[CH:12][C:7]2[O:6][C:5](=[O:19])[CH:4]([CH3:3])[C:8]=2[CH:9]=1
Reactant: ClCl
Reactant: CCC(C)N(C)c1ccc2c(c1)OC(=O)C2C
Solvent: ClC(Cl)Cl
Product: CCC(C)N(C)c1cc2c(cc1Cl)C(C)C(=O)O2

Procedure:
A cold solution of chlorine in chloroform is added dropwise at 0° to 5° C., while stirring, to a mixture of 14.7 g (0.063 mole) of 3-methyl-6-(N-methyl-N-2-butylamino)-benzofuran-2(3H)-one in 100 ml of chloroform until no more educt is visible in the thin layer chromatograph. The reaction mixture is washed with methylene chloride, dilute sodium bicarbonate solution and water. The crude product remaining after drying and concentration by evaporation of the organic phase is chromatographed over silica gel with petroleum ether/ether. Recrystallisation of the pure fractions from ether/petroleum ether yields 5-chloro-3-methyl-6-(N-methyl-N-2-butylamino)-benzofuran-2(3H)-one in the form of a colourless oil, b.p. 0.05, 190° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:26][C:27]([F:31])([F:30])[CH2:28]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][CH2:28][C:27]([F:31])([F:30])[F:26]
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(O)c(Br)c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Temperature: 100 °C
Yield: 569 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate (2 g, 0.57 mmol) and K2CO3 (1.58 g, 0.011 mol) in dry DMF (20 mL), slowly added trifluoroethyl iodide (7.2 g, 3.39 ml, 0.034 mol) at room temperature. Upon completion of the addition, the reaction mixture was slowly heated to 100° C. for 4 h. Upon completion, the reaction mixture was poured into water and extracted with ethyl acetate (2×50 mL). The combined organic layer were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1.4 g, 60% yield). 1HNMR (CDCl3, 400 MHz): 7.43 (s, 1H); 7.34 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);