Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](OC)=[N:6][CH2:5][CH2:4]1)[CH3:2].[Cl-:11].[NH4+:12]>CO>[ClH:11].[CH2:1]([CH:3]1[CH2:4][CH2:5][NH:6][C:7](=[NH:12])[CH2:8]1)[CH3:2]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: CCC1CCN=C(OC)C1
Solvent: CO
Product: CCC1CCNC(=N)C1
Product: Cl

Procedure:
The product of EXAMPLE 147 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [NH2:1][CH:2]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4][CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>CN(C)C=O>[N+:15]([C:14]1[C:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:21](=[O:23])[CH3:22])[CH2:20][C:6]=2[C:7]2[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=2[CH:13]=1)([O-:17])=[O:16]
Reactant: NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 9-amino-6-nitro-1,4,7,8,9,10-hexahydro-benzo[f]quinoxaline-2,3-dione (0.15 g, 0.5 mmol), acetic anhydride (0.1 g, 1 mmol) and triethylamine (0.2 g, 2 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 3 h. The solvent was removed by rotoevaporation, and the residue suspended in water and 2N HCl. The solid which formed was collected by filtration, washed with diethyl ether and dried to give the acetamide (0.14 g) in 88% yield. Anal. calc'd for C14H14N4O5.H2O: C, 50.00; H, 4.80; N, 16.66; found-C, 49.92; H, 4.77; N, 16.04.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:5](=[C:10]([CH3:26])[C:11]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:12][C:13]=1[O:14]CC=C)[C:6]([O:8][CH3:9])=[O:7].C(NCC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:5](=[C:10]([CH3:26])[C:11]([O:18][S:19]([C:22]([F:23])([F:25])[F:24])(=[O:21])=[O:20])=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=CCOc1cc(OS(=O)(=O)C(F)(F)F)c(C)c(C(=O)OC)c1C(=O)OC
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: COC(=O)c1c(O)cc(OS(=O)(=O)C(F)(F)F)c(C)c1C(=O)OC
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of 6-allyloxy-3-methyl-4-trifluoromethanesulfonyloxy-phthalic acid dimethyl ester (8.39 g, 20.3 mmol) in toluene (20 mL) was added tetrakistriphenylphosphine palladium (0.47 g, 0.40 mmol) and diethylamine (2.97 g, 40.86 mmol) at room temperature under an atmosphere of nitrogen. Stirring at room temperature was continued until all starting material was consumed. The crude reaction mixture was partitioned between diethyl ether and HCl (0.1 N). The organic layer was washed with brine and dried over sodium sulfate. Filtration and evaporation of solvents in vacuo yielded a crude material, which was purified by silica gel chromatography to provide 4.16 g (55%) of the desired product as an off-white solid. NMR (300 MHz, CDCl3): δ=2.20 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 7.01 (s, 1H) ppm; 19F NMR (282 MHz, CDCl3): δ=−74 ppm.
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:14]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:23]([CH2:26][C:27](=[O:29])[CH3:28])(=[O:25])[CH3:24]>C(O)(=O)C.Cl.O.C(O)C>[N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9][N:14]=[C:26]([C:27](=[O:29])[CH3:28])[C:23](=[O:25])[CH3:24])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=N[O-]
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C(=NNc1ccccc1N1CCOCC1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a solution of 2-morpholin-4-ylaniline (1000 mg, 5.62 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (465 mg, 6.74 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2764 mg, 33.71 mmol) and acetylacetone (730 mg, 7.30 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(2-morpholin-4-ylphenyl)hydrazono]pentane-2,4-dione (1000 mg, 62%).
Reaction SMILES: [CH2:1]=O.[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:9]([C:17]1[CH:18]=[C:19]([OH:24])[C:20](=[CH:22][CH:23]=1)[OH:21])([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:10]>C(O)(C)C>[O:6]1[CH2:7][CH2:8][N:3]([CH2:1][C:22]2[CH:23]=[C:17]([C:9]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:10])[CH3:11])[CH:18]=[C:19]([OH:24])[C:20]=2[OH:21])[CH2:4][CH2:5]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(O)c1
Reactant: C=O
Reactant: C1COCCN1
Solvent: CC(C)O
Product: CC(C)(C)CC(C)(C)c1cc(O)c(O)c(CN2CCOCC2)c1
Temperature: 60 °C

Procedure:
To paraformaldehyde (40 g, 1.3 mole) in 100 ml isopropanol at 25° C. was added morpholine (88 ml) in 0.5 liter isopropanol. The reaction mixture was refluxed for 30 minutes to effect solution. To the solution 4-t-octylcatechol (222 g, 1.0 mole) dissolved in 0.5 liter isopropanol was added dropwise while maintaining the solution temperature at 60° C. The reaction mixture was stirred at reflux overnight. The reaction was cooled to 25° C. and the solvent was removed in vacuo to give a white solid which was triturated with 750 ml petroleum ether and collected. Overall yield from two crops was 86%, 280 g.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH3:14][NH:15][C:16]([C:18]1([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O)=[S:17].C(OCC)(=O)C>O1CCCC1.O>[C:1]([CH:3]=[C:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C:18]1([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[C:16](=[S:17])[NH:15][CH3:14])#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CNC(=S)C1(c2cccnc2)CCCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=S)C1(c2cccnc2)CCCCC1=CC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of diethyl cyanomethylphosphonate (215 mg, 1.2 mmol) at room temperature in dry tetrahydrofuran (20 ml) was treated with a 60% oil dispersion of sodium hydride (40 mg, 1 mmol). After 15 mins at room temperature (±)-N-methyl-2-oxo-1-(pyrid-3-yl)cyclohexane carbothioamide (245 mg, 1 mmol) was added and the resulting solution stirred for 3 hours at room temperature. Ethyl acetate (50 ml) and then water (50 ml) were added to the reaction mixture. The layers were separated and the organics washed with water (50 ml). The organic extract was dried over magnesium sulphate and concentrated in vacuo to give a crude gum. Purification by flash chromatography, eluting with a 1:1 (v/v) mixture of ethyl acetate/hexane gave (±)-2-cyanomethylene-N-methyl-1-(pyrid-3-yl)cyclohexane carbothioamide as a colourless gum (190 mg, 0.7 mmol). Trituration with ether yielded a white solid (190 mg, 0.7 mmol), m.p. 182°183° C.;
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][C:10]([Cl:23])=[CH:11][C:12]=1[C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=2)(=O)=O.[Li+].[Cl-].[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC>CN(C=O)C.O>[Cl:23][C:10]1[CH:11]=[C:12]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([F:22])[CH:18]=[CH:17][CH:16]=3)[C:7]([CH:28]=[CH2:29])=[CH:8][N:9]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Temperature: 65 °C
Reaction time: 10 h
Yield: 458.4 %

Procedure:
To a solution of 6-chloro-4-(4-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (50 mg, 0.12 mmol), LiCl (8 mg, 0.19 mmol) in DMF (0.8 mL) was added tributyl(vinyl)stannane (80 mg, 0.25 mmol) dropwise at 25° C. under nitrogen. The mixture was stirred at 65° C. for 10 hours. The mixture was diluted with H2O, extracted with EtOAc, then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product. It was purified by column (PE:EA=5:1) to obtain the product of 2-(2-chloro-5-vinylpyridin-4-yl)-4-fluoro-1H-indole (150 mg, yield: 40%). 1H-NMR (CDCl3, 400 MHz) δ 8.45 (s, 1H), 7.41 (s, 1H), 7.15 (d, J=2.4 Hz, 1H), 6.88 (d, J=6.0 Hz, 1H), 6.79 (t, J=6.0 Hz, 1H), 6.35˜6.41 (m, 1H), 6.07˜6.10 (m, 1H), 5.77 (d, J=17.6 Hz, 1H), 5.49˜5.62 (m, 2H). MS (M+H)+: 273/275.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:32][CH2:33][C:34](=N)OCC.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>ClCCCl>[Cl:32][CH2:33][C:34]1[N:12]([C@H:13]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=N)CCl
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNS(C)(=O)=O)Nc1c(N)cnc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNS(C)(=O)=O)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 65 °C
Yield: 99.9 %

Procedure:
tert-Butyl (4S)-4-[(3-aminoquinolin-4-yl)amino]-5-[(methylsulfonyl)amino]pentylcarbamate (7.13 g, 16.3 mmol) was dissolved in 100 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (7.73 g, 48.9 mmol) was then added and the reaction mixture was heated to 65° C. After stirring overnight, the reaction mixture was cooled and treated with 100 mL of saturated NaHCO3 solution and 200 mL of CHCl3. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (4S)-4-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-5-[(methylsulfonyl)amino]pentylcarbamate (8.08 g) as an orange foam. The crude material was used in the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11](=[O:12])[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:13]
Reactant: NCc1cccs1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1cccs1
Yield: 94.7 %

Procedure:
A solution of thiophene-2-methylamine (4.203 g, 37.13 mmol) and of phtalic anhydride (5.00 g, 33.76 mmol) in toluene (100 mL) was stirred and heated at reflux for 3 h to remove the formed water by azeotropic distillation (Dean-Stark). The solvent was then evaporated under vacuum. The residue was dissolved in DCM (100 mL), washed with water (3×30 mL), dried over MgSO4, filtered and concentrated to afford the title compound as a white solid (7.78 g, 95%). 1H NMR (CDCl3, 300 MHz) δ 7.84 (d, 1H. J=5.4 Hz), 7.83 (d, 1H. J=5.4 Hz), 7.69 (d, 1H, J=5.4 Hz), 7.68 (d, 1H, J=5.4 Hz), 7.20 (d, 0.5H, J=5.2 Hz), 7.19 (d, 0.5H, J=5.2 Hz), 7.14 (m, 1H), 6.92 (d, 0.5H, J=5.1 Hz), 6.91 (d, 0.5H, J=5.1 Hz), 5.01 (s, 2H). HPLC (Condition A), Rt: 4.11 min (HPLC purity: 99.2%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[N:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1)[C:6]1[CH:11]=[C:10]([Br:12])[N:9]=[C:8](Br)[C:7]=1[N+:14]([O-:16])=[O:15])[CH3:2].[NH3:27]>>[CH2:1]([O:3][C:4](=[O:26])[N:5]([C:6]1[CH:11]=[C:10]([Br:12])[N:9]=[C:8]([NH2:27])[C:7]=1[N+:14]([O-:16])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(Br)nc(Br)c1[N+](=O)[O-]
Product: CCOC(=O)N(Cc1cccc(C#N)c1)c1cc(Br)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 68 using (3-cyano-benzyl)-(2,6-dibromo-3-nitro-pyridin-4-yl)-carbamic acid ethyl ester (2.32 g), aqueous ammonia (10.2 ml), and 2-methyl-THF (10.2 ml). This gave the product (1.51 g) as a yellow solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9][CH:8]=[CH:7]1.[C:21](=O)([O-])[O-:22].[K+].[K+]>CN(C)C=O>[CH:21]([C:10]1[N:6]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][CH:9]=1)=[O:22]
Reactant: COC(=O)c1cccc(-n2cccc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2cccc2C=O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Phosphoryl chloride (5.5 ml) was dropwise added to N,N-dimethylformamide (4.6 ml) under ice-cooling and the mixture was stirred for 15 minutes at 40°-50° C. To the mixture was added a solution of methyl 3-(pyrrol-1-yl)benzoate (6.0 g) in N,N-dimethylformamide (30 ml) at ambient temperature and the whole was stirred for 3 hours at 110°-120° C. An ice-cooling mixture was poured into ice-water and the mixture was adjusted to pH 9 with potassium carbonate. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 3-(2-formylpyrrol-1-yl)benzoate (5.31 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].CCN(C(C)C)C(C)C.[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)/C=C/c1cc(Br)ccc1N
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Temperature: 80 °C
Yield: 72.5 %

Procedure:
To a solution of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 2.29 mol, 1.0 equiv) in 1,4-dioxane (4.0 L) was added DIPEA (1.26 L, 8.88 mol, 3.9 equiv, GLR) and degassed with nitrogen for 20 mins. XantPhos (92.9 g, 106 mmol, 0.05 equiv, GLR), and tris(dibenzylideneacetone)dipalladium (84 g, 91.0 mmol, 0.04 equiv, Hindustan Platinum) was added to the reaction mixture. The mixture was purged with nitrogen and heated to 80° C. for 30 mins. The reaction was cooled to RT and benzyl mercaptan (455.5 g, 3.67 mol, 1.6 equiv, Alfa Aesar) was added and the reaction was heated at 80° C. for an additional 4 h. The reaction was cooled to room temperature and diluted with ethyl acetate (4.0 L). The mixture was filtered through celite and the celite bed was washed with ethyl acetate (2×1.0 L). The filtrate was concentrated under reduced pressure to obtain the crude material which was purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether) to obtain (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (520 g, 72.0%), as yellow solid. TLC solvent system: 30% ethyl acetate in hexanes. Product's Rf: 0.4. MS (ESI, positive ion) m/z; 314.1 (M+1). NMR (400 MHz, DMSO) δ 7.79 (d, J=16.1 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.25-7.17 (m, 5H) 7.10 (dd, J=8.4, 2.1 Hz, 1H), 6.61 (d, J=8.3 Hz, 1H), 6.32 (d, J=15.2 Hz, 1H), 5.75 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 4.01 (s, 2H), 1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][CH3:27]>CC#N>[Br-:23].[CH2:24]([N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: CCCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 70 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0496 g, 0.169 mmol) and 1-bromobutane (0.030 mL, 0.279 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0509 g, 70.7%). EI-MS m/z 350 (M+) Rt (1.83 min).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:13]=[C:14]([C:18]3[NH:19][C:20]4[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:15]=[CH:16][CH:17]=2)[CH:8]=1)=O.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:13]=[C:14]([C:18]3[NH:19][C:20]4[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:15]=[CH:16][CH:17]=2)[CH:8]=1
Reactant: NC(=O)c1cccc2nc(-c3cccc(-n4ccc(CNC(=O)C(F)(F)F)c4)c3)[nH]c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccn(-c2cccc(-c3nc4cccc(C(N)=O)c4[nH]3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.3 g (5.4 mmol) of the compound from Example 29 were dissolved in 100 ml of tetrahydrofuran and mixed with 0.26 g (10.8 mmol) of lithium hydroxide, dissolved in 50 ml of water. The entire mixture was stirred at room temperature for 2 hours. The mixture was subsequently neutralized by addition of dilute hydrochloric acid and the organic solvent was removed under reduced pressure. The precipitate, which slowly crystallized out, was filtered off with suction. This gave 0.61 g of the product.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]1[S:15][C:13](=[O:14])[NH:12][C:10]1=[O:11]>[O-2].[O-2].[Mn+4]>[CH:1](=[C:9]1[S:15][C:13](=[O:14])[NH:12][C:10]1=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CSC(=O)N1
Agent: [Mn+4]
Agent: [O-2]
Product: O=C1NC(=O)C(=Cc2ccccc2)S1

Procedure:
The sulfonamide derivatives 2-5 and 2-6 are prepared as depicted in Scheme 2. The bis-aryl iodonium tetrafluoroborate 2-1 is coupled with 4-hydroxybenzoate 1-2 at room temperature in dichloromethane in the presence of copper bronze and a suitable base such as triethylamine (TEA) to afford diaryl ether 2-2. Reduction of ether 2-2 with DIBAL furnishes the corresponding alcohol which is oxidized to benzaldehyde 2-3 with manganese dioxide. Condensation of aldehyde 2-3 with thiazolidinedione produces an intermediate benzylidene thiazolidinedione which is hydrogenated to furnish benzyl thiazolidinedione 2-4. A subsequent chlorosulfonylation reaction yields a 3′-sulfonyl chloride which is then reacted with a primary or secondary amine to afford 3′-sulfonylamide 2-5. Demethylation of 2-5 with boron tribromide gives hydroxysulfonamide 2-6.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)=[O:4].[O-][CH2:17][CH3:18].[Na+].C([OH:22])C>>[NH:6]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[C:5]1[C:3]([O:4][CH2:17][CH3:18])=[O:22]
Reactant: CC[O-]
Reactant: O=C(c1cc2c([nH]1)CCCC2)C(Cl)(Cl)Cl
Reactant: CCO
Agent: [Na+]
Product: CCOC(=O)c1cc2c([nH]1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 101g (6.50 g, 24.8 mmol), sodium ethoxide (17.0 mg, 0.25 mmol) and ethanol (40 mL). The solution was stirred at room temperature for 1 h. After that time, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford a 100% yield (4.80 g) of 101h as a brown solid: mp 70-72° C.; 1H NMR (300 MHz, CDCl3) d 9.08 (s, 1H), 6.75 (s, 1H), 4.25 (q, 2H, J=7.2 Hz), 2.65 (t, 2H, J=6.0 Hz), 2.56 (t, 2H, J=6.0 Hz), 1.85 (m, 4H), 1.28 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 194.1 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12].CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 6.85 g (44 mmol) of 6-chloronicotinic acid dissolved in 50 mL of tetrahydrofuran was added ethanol (6 mL), dimethylaminopyridine (700 mg) and 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDCl) (9.4 g, 49 mmol). The reaction was stirred at ambient temperature for 4 hours and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water (2×), saturated sodium bicarbonate (2×) and brine, dried over sodium sulfate and concentrated in vacuo. The residue obtained was flash chromatographed on silica gel eluting with 10% ethyl acetate in hexane to afford 6.00 g of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.40 (t, 3H), 4.40 (q, 2H), 7.40 (d, 1H), 8.25 (dd, 1H), 9.00 (d, 1H). MS (DCl/NH3) m/e 186/188 (M+H)+, 203/205 (M+H+NH3 )+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[OH:12]>CO>[O:12]1[C@@H:4]2[CH2:5][C:6]3[C:11]([C@H:3]12)=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH3:1][O:2][C@@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[OH:12]
Reactant: COC1c2ccccc2CC1O
Solvent: CO
Product: CO[C@@H]1c2ccccc2C[C@H]1O
Product: c1ccc2c(c1)C[C@H]1O[C@@H]21

Procedure:
Trans-1,2-indandiol can be obtained by a reaction of trans-2-bromo-1-indandiol with a dilute aqueous sodium carbonate solution in accordance with the method of A. Gagis, et al [J. Org. Chem., 37, 3181 (1972)]. Cis-1,2-indandiol can be obtained by peroxidation of indene with formic acid in accordance with the method of J. E. Taylor [Synthesis, 1142, (1985)]. Cis-1-methoxy-2-indanol can be obtained by a reaction of cis-1,2-epoxyindan with a copper-pyridine complex in methanol in accordance with the method of M. Imuta, et al [J. Am. Chem. Soc., 101, 3990 (1979)]. As reported by G. H. Posner, et al. [J. Am. Chem. Soc., 99, 8214 (1977)], a mixture of 1-methoxy-2-indanol with a cis/trans ratio of 50/50 can be obtained by a reaction of cis-1,2-epoxyindan with hydrochloric methanol whereas trans-1-methoxy-2-indanol is obtained by a reaction of cis-1,2-epoxyindan with sodium methoxide. The method of G. H. Posner, et al. [J. Am. Chem. Soc., 99, 8208 (1977)] can be used to obtain trans-1-acetoxy-2-indanol by a reaction of cis-1,2-epoxyindan with dilute acetic acid in the presence of neutral alumina.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1OC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 3.66 g (12 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 1.08 ml (12 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.12 ml (1.2 mmol) of piperidine was added, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=2/1→1/2) to yield 1.05 g (24.3%, light yellow oily substance) of the desired product.