Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@H:5]1[C:17]2[C:16]3[C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)#[N:2].[OH:33][Li].O.OO>CO>[C:1]([CH2:3][CH2:4][C@H:5]1[C:17]2[C:16]3[C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:21][CH2:20]4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=[O:33])[NH2:2]
Reactant: [Li]O
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCC#N)CCC4)CC1
Agent: OO
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCC(N)=O)CCC4)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a solution of tert-butyl N-(4-[[(13S)-13-(2-cyanoethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (300 mg, 0.66 mmol, 1.00 equiv) in methanol (15 mL) was added LiOH.H2O (82 mg, 1.95 mmol, 3.00 equiv) and H2O2 (30%, 0.5 mL) at 0° C. and the resulting solution was stirred for 2 h at 30° C. The reaction was quenched with saturated aqueous sodium sulfite, extracted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to give 240 mg (77%) of tert-butyl N-(4-[[(13S)-13-(2-carbamoylethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH3:24][O:25][CH:26]([O:30][CH3:31])[CH2:27][NH:28][CH3:29]>ClCCl>[CH3:24][O:25][CH:26]([O:30][CH3:31])[CH2:27][N:28]([CH3:29])[C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[S:3]
Reactant: CNCC(OC)OC
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(NC(=S)N(C)CC(OC)OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 15 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 6.5 parts of 2,2-dimethoxy-N-methyl-ethanamine and 195 parts of dichloromethane was stirred for 1 hour at room temperature. The reaction mixture was evaporated and the residue was triturated in 4-methyl-2-pentanone. The product was filtered off and dried, yielding 19.4 parts (95%) of N-(2,2-dimethoxyethyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-N-methylthiourea; mp. 155.0° C. (40).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:10][C:9](=[O:11])[CH:8]2[CH2:12][CH:5]1[CH2:6][CH2:7]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24]>CCCCCC.O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:10]2[C:4](=[O:3])[CH:5]3[CH2:12][CH:8]([CH2:7][CH2:6]3)[C:9]2=[O:11])=[O:22])=[CH:16][C:15]=1[C:23]([F:24])([F:25])[F:26]
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.064 g, 1.59 mmol) was washed with dry hexane under a nitrogen atmosphere to remove mineral oil. It was then suspended in dry tetrahydrofuran (3 mL). To the suspension was added a solution of 2,4-dioxobicyclo[3.2.1]octane (0.20 g, 1.45 mmol) in dry tetrahydrofuran (10 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. It was then treated with 4-fluoro-3-(trifluoromethyl)phenyl isocynate (0.31 mL, 2.17 mmol) via syringe. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction mixture was then concentrated on a rotary evaporator and the residue was partitioned between dichloromethane (150 mL) and 1N aqueous HCl (100 mL). The aqueous layer was extracted twice with additional portions of dichloromethane ((25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatrography on silica gel (2% methanol/dichloromethane) to yield the title compound as a light yellow solid (0.36 g, 73% yield), mp=97–100° C.; MS (−) ESI m/z=342 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH:8]([NH:9][C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:35])[CH:18]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[C:26]([Cl:28])[C:25]([O:29]CC=C)=[C:24]([Cl:33])[CH:23]=2)[CH3:19])=[O:11])[CH2:7][C:6](=[O:36])[O:5]1)[CH3:2].CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1.C(Cl)Cl.CO>C(Cl)Cl.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>[CH2:1]([O:3][CH:4]1[CH:8]([NH:9][C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:35])[CH:18]([NH:20][C:21](=[O:34])[C:22]2[CH:23]=[C:24]([Cl:33])[C:25]([OH:29])=[C:26]([Cl:28])[CH:27]=2)[CH3:19])=[O:11])[CH2:7][C:6](=[O:36])[O:5]1)[CH3:2]
Reactant: C=CCOc1c(Cl)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCC)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Solvent: CO
Solvent: ClCCl
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a solution of 110 (194 mg, 0.36 mmol) in CH2Cl2 (5 ml) was added DMBA (70.7 mg, 0.45 mmol) and Pd(PPh3)4 (50.3 mg, 0.044 mmol) at 0° C. The solution was warmed to room temperature after 15 mins, stirred for 2 hours, diluted with CH2Cl2 then washed with water (2×) and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated to give the crude product. Flash chromatography using CH2Cl2/MeOH (99/1 to 95/5%) afforded the title compound (138.6 mg, 77% yield). 1H-NMR (500 MHz, CD3OD) δ 1.13-1.31 (m, 3H), 1.35-1.49 (m, 3H), 1.84-2.35 (m, 4H), 2.43-3.05 (m, 2H), 3.48-3.93 (m, 4H), 4.22-4.80 (m, 3H), 5.38 (d, 0.4H), 5.46 (s, 0.1H), 5.55-5.61 (m, 0.5H), 7.76-7.94 (m, 2H). Analytical HPLC 8.70 min. LC-MS (ES+) m/e=502.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:12]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([CH3:12])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(C)c(C=O)c1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a degassed solution of 2-bromo-5-methoxybenzaldehyde (1.5 g, 7.04 mmol, Fluorochem) and trimethylboroxine (0.98 mL, 7.04 mmol) in 1,4-dioxane (80 mL) was added potassium carbonate (2.91 g, 21.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.813 g, 0.70 mmol). The mixture was heated under reflux for about 20 h, then more tetrakis(triphenylphosphine)palladium(0) (0.200 g, 0.17 mmol) and trimethylboroxine (0.25 mL, 1.8 mmol) were added and the mixture was heated under reflux for about another 3 h. After cooling to rt the mixture was filtered over diatomaceous earth and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:3) to give 5-methoxy-2-methyl-benzaldehyde (0.97 g, 92%) as a colorless liquid. 1H-NMR (CDCl3, Bruker 400 MHz) 2.60 (3 H, s); 3.83 (3 H, s); 7.04 (1 H, dd, J=8.5 Hz, 2.4 Hz); 7.16 (1 H, d, J=8.5 Hz); 7.33 (1 H, d, J=2.4 Hz); 10.2 (1 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH:5](C#N)[N:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1.N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: N#CC1CC(Cl)=NN1c1cccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
3-Chloro-1-(pyridine-3-yl)-4,5-dihydro-1H-pyrazole-5-carbonitrile (0.500 g, 2.42 mmol) was stirred in N,N-dimethylformamide (6.05 mL). 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.543 mL, 3.63 mmol) was added and the dark mixture was stirred at room temperature overnight. LC/MS analysis indicated that the reaction was complete. The mixture was concentrated and the dark oil was dissolved in ethyl acetate and washed with 15% aqueous lithium chloride (LiCl) and brine. The organic portion was dried over sodium sulfate (Na2SO4) and concentrated. The residue was purified by flash column chromatography using ethyl acetate. The pure fractions were concentrated and the residue was vacuum dried at 45° C. to yield the desired product as a white solid (450 mg, 93%): mp: 66-68° C.; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=27 Hz, 1H), 8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.47-7.34 (m, 1H), 6.45 (d, J=2.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 148.01, 142.72, 140.12, 135.99, 128.64, 126.41, 124.01, 108.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:13][CH:14]=1.[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[C:22](=[O:29])[N:21]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:26]([C:23]2[C:22](=[O:29])[N:21]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:20]([CH3:19])[C:24]=2[CH3:25])=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:13][CH:14]=1
Reactant: Nc1ccc(Oc2ccnn3cccc23)c(F)c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnn4cccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 50 °C
Yield: 29.2 %

Procedure:
To a solution of 3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)-phenylamine (50 mg, 0.206 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (32 mg, 0.137 mmol) dissolved in dimethylformamide (3 mL), HATU (78 mg, 0.206 mmol) and triethylamine (0.05 mL, 0.343 mmol) were sequentially added and heated at 50° C. for 7 hours. The resulting mixture was concentrated and the resulting residue was extracted with dichloromethane and water. After phase separation, the organic layer was washed with sodium chloride aqueous solution, dried with magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=1:3) to give the target compound as a white solid (16 mg, 0.04 mmol, 25% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][N:9]=1.Br[CH:20]([CH3:22])[CH3:21]>O>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH:20]([CH3:22])[CH3:21])[N:9]=1
Reactant: CC(C)Br
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)n1nc(Cl)c2ccccc2c1=O
Temperature: 50 °C
Yield: 102.7 %

Procedure:
Potassium carbonate (459 mg, 3.32 mmol) was added to a solution of 4-chlorophthalazin-1(2H)-one (300 mg, 1.661 mmol) and 2-bromopropane (409 mg, 3.32 mmol) and heated to 50° C. for 3 hrs. After 3 hrs the reaction was diluted with water and extracted with EtOAc (2×). The organic layer was washed with water followed by brine, dried over MgSO4, filtered and evaporated to give the crude product 4-chloro-2-isopropylphthalazin-1(2H)-one (380 mg, 103% yield), which was used as is in the next step. MS: MS m/z 223.15(M++1).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[N:13][N:14]=2)[CH:5]=1.[C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH3:26].[Li]>>[C:29]([O:28][C:25](=[O:27])[CH2:26][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[N:13][N:14]=2)[CH:5]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2nnc(CCOC3CCCCO3)s2)c1
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nnc(CCOC3CCCCO3)s2)c1

Procedure:
3-(5-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-[1,3,4]thiadiazol-2-yl}-benzoic acid methyl ester (1.60 g) was treated with lithium tert.-butyl acetate according to general procedure K (method b) to give 3-oxo-3-(3-{5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-[1,3,4]thiadiazol-2-yl}-phenyl)-propionic acid tert-butyl ester (2.1 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]([O:4][CH:5]([Cl:9])[CH:6]([CH3:8])[CH3:7])=O.C[S-:11].[Na+]>ClCCl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]([O:4][CH:5]([Cl:9])[CH:6]([CH3:8])[CH3:7])=[S:11]
Reactant: C[S-]
Reactant: CC(=O)OC(Cl)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=S)OC(Cl)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-chloro-2-methylpropyl methylformate in dichloromethane (DCM) was added a solution of sodium methanethiolate (CH3—SNa) (1.0 eq.) in water at 0° C. and 0.02 eq. of tetrabutylammonium bromide. The reactants were stirred at 0° C. for 30 min and then diluted with dichloromethane (DCM). The dichloromethane layer was allowed to separate, then washed with water and brine, and dried with anhydrous sodium sulfate (Na2SO4). After rotary evaporation to remove the solvent, the title compound (6a) was obtained. 1H-NMR (CDCl3): δ 1.05 (d, J=5.6 Hz, 3H), 1.07 (d, J=5.6 Hz, 3H), 2.18 (m, 1H), 2.38 (s, 3H), 6.34 (d, J=5.6 Hz, 1H) ppm.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]=NC(C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(Cl)Cl.[OH2:31]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)N=Cc1ccccc1CCCCCCCCc1ccccc1
Reactant: O
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccccc1CCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of N-[(2-(8-phenyloctyl)phenyl)methylene]-1,1-dimethylethanamine (0.51 g, 0.0146 mol) in tetrahydrofuran (5 mL) was added 10% aqueous hydrochloric acid (5 mL) and the mixture stirred for 15 h at room temperature. Methylene chloride (10 mL) and water (10 mL) were added and the layers separated. The aqueous layer was extracted with methylene chloride (1×15 mL) and the combined organics were dried (magnesium sulfate), filtered and concentrated in vacuo to an oil (0.405 g, 97.4% pure by HPLC assay, 92% corrected yield): IR (neat) 2920, 2880, 1695, 1600, 1455 cm-1 ; 1H NMR (CDCl3, 400 MHz) δ 10.25 (s, 1 H), 7.80 (dd, 1 H, J=1.2 and 7.7 Hz), 7.45 (m, 1 H), 7.33-7.13 (m, 7 H), 2.98 (t, 2 H, J=7.7 Hz), 2.58 (t, 2 H, J=7.7 Hz), 1.58 (m, 4 H), 1.30 (m, 8H).
Reaction SMILES: Cl.CO.[OH:4][C:5]1[CH:15]=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[CH:21]=O>O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:21]=[C:10]2[C:9](=[O:13])[C:8]3[CH:14]=[CH:15][C:5]([OH:4])=[CH:6][C:7]=3[O:12][CH2:11]2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28]
Reactant: CCOc1ccc(C=O)cc1OC
Reactant: O=c1ccoc2cc(O)ccc12
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOc1ccc(C=C2COc3cc(O)ccc3C2=O)cc1OC
Reaction time: 18 h
Yield: 10.7 %

Procedure:
After a saturated hydrogen chloride-methanol solution 20 ml was added to 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3-methoxy-4-ethoxybenzaldehyde 1.30 g, the mixture was srtirred for 18 hours, water 100 ml was added, and the precipitated crystals were filtered. The crystals were added to methanol 100 ml of 55° C., and the mixture was stirred for 15 minutes and filtered. The resulting crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.216 g.
Reaction SMILES: [C:1]([S-:4])(=[S:3])[CH3:2].[Na+].Cl[CH:7]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)C>[C:1]([S:4][CH:7]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[S:3])[CH3:2]
Reactant: CC(=S)[S-]
Reactant: CCOC(=O)C(Cl)c1ccc2cc(OC)ccc2c1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(SC(C)=S)c1ccc2cc(OC)ccc2c1

Procedure:
A mixture of 0.2 moles of sodium dithioacetate and 0.12 moles of ethyl α-chloro-6-methoxy-2-naphthylacetate in 300 ml. of absolute ethanol is stirred at room temperature for 15 hours. The reaction mixture is filtered, washed with absolute ethanol and evaporated to dryness in vacuo. The residue is treated with ether, filtered and evaporated to dryness to obtain ethyl α-thioacetylthio-6-methoxy-2-naphthylacetate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:25])=[O:24]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
2.0 g (0.01045 mol) of 1-benzyl-4-hydroxypiperidine were dissolved in 20 ml of dichlormethane and 5.1 ml (0.0366 mol) of triethylamine, cooled to 00 and treated with a solution of 1 ml (0.01255 mol) of methanesulfonyl chloride in 5 ml of dichloromethane. The mixture was stirred at 0° for 1/2 hr. Then, 10ml of 1N aqueous HCI were added, the mixture was stirred for 5 min. and the organic phase was washed with 1N aqueous HCI, with saturated bicarbonate solution and saturated sodium chloride solution and dried over magnesium sulfate. 0.97 g (35%) of 1-benzylpiperidin-4-yl methanesulfonate was obtained as yellow crystals. MS: me/e=270 (C13 H20NO3S+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][N:7]([CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)[CH2:6][CH2:5][C:4]1[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=1[O:2][CH3:1])[CH3:32]
Reactant: COC(=O)c1ccc(CNCCc2ccccc2OC)cc1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CCCCN(CCc1ccccc1OC)Cc1ccc(C(=O)OC)cc1

Procedure:
15.0 g (50.0 mmol) of methyl 4-{[(2-methoxyphenethyl)amino]methyl}benzoate from Example I.1., 11.52 g (55.0 mmol) of ethyl 5-bromovalerate and 6.37 g (106.0 mmol) of sodium carbonate are dissolved in 30 ml of acetonitrile and heated at reflux for 18 hours. After cooling, most of the solvent is distilled off under reduced pressure and the residues are mixed with water. The mixture is extracted repeatedly with ethyl acetate, the organic phases are washed with saturated sodium chloride solution and, after drying over magnesium sulphate, the solvent is removed under reduced pressure. The crude product is purified by flash chromatography over silica gel (0.04-0.063 nm) using the mobile phase cyclohexane/ethyl acetate 4/1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:14])SCCCS1.ClN1C(=[O:34])CCC1=O>C(#N)C.C(OCC)(=O)C.[N+]([O-])([O-])=O.[Ag+]>[O:34]=[C:7]([C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C2(c3ncccn3)SCCCS2)CC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C(=O)c2ncccn2)CC1
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl 4-{[2-(pyrimidin-2-yl)-1,3-dithian-2-yl]carbonyl}piperidine-1-carboxylate (0.51 g, 1.24 mmol) in acetonitrile (10 ml) was added quickly to a well stirred solution of N-chlorosuccinimide (1.10 g, 8.24 mmol) and silver nitrate (1.54 g, 9.06 mmol) in aqueous 80% acetonitrile (30 ml) at room temperature. The mixture was stirred 10 min, then diluted with ethyl acetate, and washed successively with aqueous Na2S2O3 (2 N), 2 N sodium carbonate and brine. The organic layer was separated, dried (MgSO4) and concentrated. The resulting residue was purified on a silica gel column (ethyl acetate/hexane) to give the title compound. LC-MS m/e 320.15 [M+1]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].[CH2:28]([N:32]=[C:33]=[O:34])[CH2:29][CH2:30][CH3:31].C(NS(C1SC(CC(C)C)=CC=1C1C=CC(CN2C=CN=C2)=CC=1)(=O)=O)(C)(C)C>CC(C)=O.C(OCC)(=O)C>[CH2:28]([NH:32][C:33]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)(=[O:24])=[O:23])=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reactant: CCCCN=C=O
Agent: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Reaction time: 0.17 h
Yield: 33 %

Procedure:
The crude product from step (c) above was dissolved in acetone (5 mL) under N2 (g). NaOH (0.20 mL, 1M, 0.20 mmol) was added to the mixture, which was then stirred for 10 min. Butyl isocyanate (109 μL, 0.97 mmol) was then added and the mixture was stirred overnight at room temperature. The reaction mixture was then diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried over MgSO4 and the solvent was removed in vacuo. Purification using column chromatography with CHCl3:MeOH (10:1) as eluent yielded the title compound (15.1 mg, 0.032 mmol) in 33% yield (from 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonic acid tert-butylamide).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7](OCC)=[O:8].C(O)=O.[CH3:16][N:17](C=O)C>C(N)=O>[CH3:12][C:4]1[NH:3][C:2]2[N:1]=[CH:16][N:17]=[C:7]([OH:8])[C:6]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(C)[nH]c1N
Solvent: O=CO
Solvent: NC=O
Product: Cc1cc2c(O)ncnc2[nH]1
Yield: 51 %

Procedure:
In a sealed tube, ethyl 2-amino-5-methyl-1H-pyrrole-3-carboxylate (150 mg, 0.9 mmol, prepared according to literature procedures, J. Heterocyclic Chem., 23:1555 (1985)) was dissolved in formamide (4.5 ml), formic acid (2.3 ml) and DMF (1.0 ml) and heated to 155° C. for 12 h. The reaction was concentrated, taken up with NaHCO3 solution, and extracted with DCM to afford 6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (70 mg, 0.46 mmol, 51%, MS (ES+) [M+H]+=150). This material was dissolved in phosphorous oxychloride (5 ml) and heated to 110° C. for 1 h. The reaction was concentrated, taken up with NaHCO3, and extracted with DCM to give 4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.23 mmol, 50%). MS (ES+) [M+H]+=168.