Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].CC1(C)C(C)(C)OB(/[CH:22]=[CH:23]/[CH2:24][O:25][CH3:26])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[CH3:26][O:25][CH2:24]/[CH:23]=[CH:22]/[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(C=O)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.5 eq.) in DMF (0.2 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was stirred at 100° C. for 2 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10](SC)=[N:9]2)=[CH:4][CH:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[C:16]([O:15][C:13]([N:11]1[C@H:12]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[C:10]1[NH:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CSC1=NC(c2ccc(F)cc2)CN1C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2ccccc2)=N[C@@H](c2ccc(F)cc2)[C@H]1c1ccc(F)cc1
Temperature: 100 °C
Yield: 123.2 %

Procedure:
A mixture of intermediate 62 (0.5 g, 1.24 mmol), benzylamine (0.680 mL, 6.2 mmol) and MeOH (0.1 mL) is heated at 100° C. overnight. The reaction mixture is cooled to RT and purified by chromatography on silica gel; gradient elution with heptane:EtOAc (75:25-60:40) gives 0.354 g of the product 160. 1H NMR (CDCl3) δ 7.55-7.25 (m, 6 H), 6.95-6.85 (m, 2 H), 6.80-6.60 (m, 6 H), 5.45-5.20 (m, 2 H), 4.75-4.55 (m, 2 H), 1.16 (s, 9 H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([CH3:12])[CH2:10]O)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)Cl>[Br:13][CH2:10][C@@H:9]([CH3:12])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H](CO)Cc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@H](CBr)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of (2S)-3-(4-chlorophenyl)-2-methylpropan-1-ol (300 mg) in DCM (20 mL) were added N-bromosuccinimide (347 mg) and triphenylphosphine (511 mg) under ice-cooling. The reaction liquid was stirred at room temperature for 2 hours, and then the reaction liquid was poured into water, followed by extraction with chloroform. The organic layer was washed with brine and dried over MgSO4, and then vehicle was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:EtOAc=100:0 to 90:10) to obtain 1-[(2S)-3-bromo-2-methylpropyl]-4-chlorobenzene (373 mg) as a colorless liquid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]1([S:12]([N:15]2[CH:26]=[CH:25][C:24]3[C:16]2=[N:17][CH:18]=[C:19]2[C:23]=3[N:22]([C@H:27]3[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]3)[N:21]=[N:20]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[NH:32][C@H:29]1[CH2:30][CH2:31][C@H:27]([N:22]2[C:23]3[C:19](=[CH:18][N:17]=[C:16]4[C:24]=3[CH:25]=[CH:26][N:15]4[S:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:14])=[O:13])[N:20]=[N:21]2)[CH2:28]1
Reactant: N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Reaction time: 4 h
Yield: 99.5 %

Procedure:
Methyl chloroformate (31.0 μL, 0.40 mmol) was added to a stirred mixture of racemic trans 3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentylamine (150 mg, 390 μmol) and diisopropylethylamine (135 μL, 790 μmol) in DCM (3 mL) at ambient temperature. Stirring was continued for 4 hours. The mixture was concentrated under vacuum and the residue obtained purified by column chromatography on silica gel (gradient: 0 to 100% ethyl acetate in pentane) to afford 171 mg (98%) of racemic trans [3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-carbamic acid methyl ester as a colourless foam. LCMS (Method B, ESI): RT=3.48 min, m+H=441.3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[C:14]([S:16]Cl)=[O:15]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:14](=[O:15])[S:16][N:8]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(N)=O
Reactant: O=C(Cl)SCl
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1-c1nsc(=O)o1
Yield: 71.7 %

Procedure:
In tetrahydrofuran (100 ml), 4-chloro-2-methoxybenzamide (5.67 g, 30.5 mmol) prepared in the Step 7-1-1 and chlorocarbonylsulfenyl chloride (4.40 g, 33.6 mmol) were suspended, and the mixture was heated under reflux for 1.5 hours. After being allowed to cool, the mixture was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:1) to give the title compound (5.33 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[O:20][C:19](=[O:21])[CH2:18][C:17](=[O:22])[CH2:16]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C.[CH3:54][N:55]1[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[N:57]=[C:56]1[CH:64]=O.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[O:20][C:19](=[O:21])[C:18]([CH2:64][C:56]3[N:55]([CH3:54])[C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=4[N:57]=3)=[C:17]([OH:22])[CH2:16]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: O=C1CC(=O)OC(CCc2ccc(OCC3CC3)c(Cl)c2)(C2CCCC2)C1
Reactant: Cn1c(C=O)nc2ccccc21
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: Cn1c(CC2=C(O)CC(CCc3ccc(OCC4CC4)c(Cl)c3)(C3CCCC3)OC2=O)nc2ccccc21

Procedure:
The title compound was prepared analogously to Example B(31), carbaldehyde where 6-[2-(3-Chloro-4-cyclopropylmethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione was substituted in place of 6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 1-methyl-2-formylbenzimidazole was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of that example.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([N:6]([S:9]([NH:12][C:13](=O)[O:14]C1C=CC=CC=1)(=[O:11])=[O:10])[O:7][CH3:8])(=[O:5])=[O:4].[CH3:23][C:24]1[CH2:28][CH:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:26][N:25]=1>C1C=CC=CC=1>[CH3:22][N:2]([CH3:1])[S:3]([N:6]([S:9]([NH:12][C:13]([N:26]1[CH:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][C:24]([CH3:23])=[N:25]1)=[O:14])(=[O:11])=[O:10])[O:7][CH3:8])(=[O:4])=[O:5]
Reactant: CC1=NNC(c2ccccc2)C1
Reactant: CON(S(=O)(=O)NC(=O)Oc1ccccc1)S(=O)(=O)N(C)C
Solvent: c1ccccc1
Product: CON(S(=O)(=O)NC(=O)N1N=C(C)CC1c1ccccc1)S(=O)(=O)N(C)C
Yield: 23.8 %

Procedure:
4.24 g (12 mmol) of phenyl N-[(N-dimethylsulfamoyl-N-methoxyamino)sulfonyl]carbamate was dissolved in 30 ml of dry benzene, and 1.6 g (10 mmol) of 3-methyl-5-phenyl-2-pyrazoline was added thereto. The mixture was refluxed for 5 minutes. The mixture was left to cool, and the solvent was distilled off under reduced pressure. The residue was purified by reverse phase column chromatography (CH3CN: H2O=7:3) to obtain 1.0 g of the desired 1-[(N-dimethylsulfamoyl-N-methoxyamino)sulfonylcarbamoyl]-3-methyl-5-phenyl-2-pyrazoline.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:16]1[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=1)[CH2:10][CH2:9]2.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1)#[N:20]>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:18])[C@@:3]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:27](=[O:28])[C:24]4[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][N:25]=4)[CH:15]=3)[CH2:10][CH2:9]2)[N:4]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@@]2(CCc3ccc(N)cc32)C(F)(F)CO1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CC3)N=C(N)OCC2(F)F)nc1
Yield: 27 %

Procedure:
The condensation of (R)-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazine]-2′,6-diamine (intermediate A7.3) and 5-cyanopicolinic acid yielded the title compound (27% yield) as an off-white solid. MS (ISP): m/z=384.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)c1ccc2nc[nH]c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ncn(Cc3cccc(C(F)(F)F)c3)c(=O)c2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-oxo-3,4-dihydroquinazoline-6-carboxylate (30.6 mg, 0.15 mmol) in DMF (2 mL) was added potassium carbonate (41.5 mg, 0.30 mmol) and 3-(trifluoromethyl)benzyl bromide (45.8 μL, 0.30 mmol). The reaction mixture was heated to 60° C. and stirred overnight. The mixture was then cooled to rt and concentrated. Water was added and the reaction mixture was extracted with DCM (5 mL, 3×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford methyl 4-oxo-3-[3-(trifluoromethyl)benzyl]-3,4-dihydroquinazoline-6-carboxylate. LC-MS: (FA) ES+ 363.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>CO.C(Cl)Cl>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[CH:13]=2)=[N:4][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Oc1ccnc(NC(=O)C2CC2)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N)cnc1Oc1ccnc(NC(=O)C2CC2)c1
Yield: 29.7 %

Procedure:
Dissolve N-[4-[(3-methyl-5-nitro-2-pyridyl)oxy]-2-pyridyl]cyclopropanecarboxamide (269 mg, 0.83 mmol) in MeOH (5 mL) and DCM (5 mL). Add Pd/C (10%, 104 mg), flush with H2. Stir the reaction under H2 at room temperature for 2 hrs. After the reaction, flush with N2, filter the reaction mixture; concentrate the filtrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (70 mg, 30%). MS: (M+1): 285.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:15]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(-c2ccccc2)ccc1CBr
Yield: 97.2 %

Procedure:
A mixture of 3-fluoro-4-methylbiphenyl (6.00 g), N-bromosuccinimide (5.73 g), 2,2′-azobisisobutyronitrile (0.075 g) and carbon tetrachloride (120 ml) is refluxed by heating for five hours. The reaction solution is washed with water. The residue, which is obtained by concentrating the organic layer, is purified using silica gel column chromatography (eluate: hexane/ethyl acetate=9/1) and thus, oily 4-bromomethyl-3-fluorobiphenyl (8.30 g) is obtained. 1H-NMR (CDCl3, δ): 4.57 (2H, s), 7.30 (1H, d, J=11.0 Hz), 7.34-7.40 (2H, m), 7.45 (3H, m), 7.56 (2H, d).
Reaction SMILES: [C:1]12[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=1[S:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]([OH:14])[C:2]2=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[C:1]12[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]([OH:14])[C:2]2=1
Reactant: Oc1ncnc2sc3c(c12)CCCC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: Oc1ncnc2sc3ccccc3c12
Temperature: 90 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A solution of 8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-ol (2.06 g, 9.99 mmol, 1.00 equiv) in 1,4-dioxane (30 mL) was added DDQ (5.68 g, 25.02 mmol, 2.50 equiv) ar room temperature under nitrogen and the resulting solution was stirred overnight at 90° C. in an oil bath. After cooling to room temperature, the reaction was quenched with saturated aqueous sodium bicarbonate, and extracted with 3×100 mL of dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to provide 1.8 g (crude) of 8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-3-ol as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][CH2:10][O:11][CH3:12].C([Mg]Br)(C)C.[N+:18]([CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O-:20])=[O:19]>C1COCC1>[CH3:12][O:11][CH2:10][O:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: COCOCc1ccccc1I
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COCOCc1ccccc1C(C[N+](=O)[O-])c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirring solution of 1-iodo-2-((methoxymethoxy)methyl)benzene (4.51 g, 16.22 mmol) in THF (40 mL) under argon was added dropwise a solution of i-PrMgBr (9.5 mL, 2.12M in Et2O, 20.14 mmol) via syringe. The stirring was maintained at 0° C. After 1 hour, a solution of nitrostyrene (2.014 g, 13.50 mmol) in THF (40 mL) was added via cannula over 10 minutes and the stirring was maintained at 0° C. After 30 minutes, the reaction was quenched with saturated NH4Cl and extracted with EtOAc (2×). The combined extracts were dried (MgSO4), filtered and concentrated to an oil which was purified on Biotage Horizon (10-50% EtOAc:hexane, SiO2, 40+M) to afford the product (2.93 g) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.35-7.39 (m, 1H), 7.27-7.34 (m, 3H), 7.22-7.27 (m, 5H), 5.34 (t, J=8.08 Hz, 1H), 4.94-5.03 (m, 2H), 4.73 (d, J=11.87 Hz, 1H), 4.68 (q, J=6.57 Hz, 2H), 4.57 (d, J=11.87 Hz, 1H), 3.42 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH3:15][O:16][C:17]1[C:21](OC)=[N:20][S:19](=[O:25])(=[O:24])[N:18]=1>CO>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:21]2[C:17]([O:16][CH3:15])=[N:18][S:19](=[O:25])(=[O:24])[N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CO
Product: COC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2.41 g; 11.2 mmoles) [prepared according to the procedure described in Belgian Pat. No. 857,388] in 20 ml of dry methanol was added all at once to a well stirred, cold (8°) suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in 200 ml of methanol. After stirring at 8°-10° for 15 minutes, a methanolic solution of the title compound is produced.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]=1)[CH:6]=[CH:5]2>C(O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[CH:6]=[CH:5]2
Reactant: Fc1ccc2cc(C3=CCNCC3)ccc2c1
Agent: O=[Pt]
Solvent: CCO
Product: Fc1ccc2cc(C3CCNCC3)ccc2c1
Reaction time: 20 h
Yield: 82.1 %

Procedure:
To a mixture of 4-(6-fluoronaphth-2-yl)-1,2,5,6-tetrahydropyridine (0.691 g, 3.04 mmol) in ethanol (20 mL) was added platinum oxide (0.03 g). The mixture was hydrogenated at one atmosphere for 20 hours. The mixture was carefully filtered and evaporated to give 4-(6-fluoronaphth-2-yl)piperidine as a white amorphous solid (0.572 g, 82%). A small portion was converted to the oxalate salt to give the title compound. FDMS m/e=230 (M++1 of free base).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]([S:21](Cl)(=[O:23])=[O:22])=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1(/[CH:14]=[CH:13]/[S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)/C=C/c2ccccc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and beta-styrenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (21.3 mg) with purity >90%. MS (pos) m/z 353.1.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O1.[CH2:16]([N:18]1[CH:22]=[C:21](I)[C:20]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[N:19]1)[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH2:16]([N:18]1[CH:22]=[C:21]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[C:20]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[N:19]1)[CH3:17]
Reactant: CCn1cc(I)c(-c2cccs2)n1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1cc(-c2ccncc2)c(-c2cccs2)n1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.60 mmol) and bis(tricyclohexylphosphine)palladium(II) chloride (0.05 mmol) were weighed into a microwave vial (reaction volume 2-5 mL). A solution of 1-ethyl-4-iodo-3-(2-thienyl)-1H-pyrazole (0.50 mmol) in 3.3 mL degassed dioxane and 1.1 mL of a degassed 2 M aqueous sodium carbonate solution were added. The reaction mixture was purged with argon, the microwave vial was capped with a septum and transferred to a laboratory microwave oven. The reaction mixture was irradiated to a reaction temperature of 120° C. for 15 min. After cooling to room temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:ethyl acetate 95:5 to 0:100) to afford 105 mg 4-[1-ethyl-3-(2-thienyl)-1H-pyrazol-4-yl]pyridine (82% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]4)=[CH:4][CH:3]=2)(=[O:36])=[O:35])=[CH:32][CH:33]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NS(=O)(=O)c4ccc(OC)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 296 was prepared analogous to compound of example 284 by reaction of compound of example 223 with 4-methoxy benzene sulfonyl chloride. The compound of example 296 was used directly without isolation, for the preparation of compound of example 297.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1>[Ni].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Cl)cnc1N
Reaction time: 3 h
Yield: 96.5 %

Procedure:
A mixture of the nitropyridine 2 (22.0 g 126.8 mmol), Raney Ni (2.2 g) and MeOH (220 mL) was shaken under H2 (20-40 psi) for 3 h, then filtered. The filtrate was rota-evaporated and the residual solid was dried to give 17.57 g (96%) of 3 as a tan powder, mp 169°-171° C. (lit. 172°-173° C, (Israel, M. & Day, A. R., J. Org. Chem. 24:1455-1460 (1959))). 1H NMR (DMSO-d6), 4.991 (bs, 2H), 5.555 (bs, 2H), 6.675 (d, 1H, J=2), 7.196 (d, 1H, J=2).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:23]2[CH:22]=[CH:21][C:20]([C:11]3[CH:12]=[CH:13][C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:10]=3)=[CH:25][CH:24]=2)=[N:3][CH:4]=[C:5]([CH3:9])[N:6]=1
Reactant: Cc1cnc(Cl)c(C)n1
Reactant: OB(O)c1ccc(-c2ccc3ccccc3c2)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cnc(-c2ccc(-c3ccc4ccccc4c3)cc2)c(C)n1
Yield: 85 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were placed 0.55 g of 2-chloro-3,5-dimethylpyrazine, 0.96 g of 4-(2-naphthyl)phenylboronic acid, 0.41 g of sodium carbonate, 0.018 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 10 mL of water, and 10 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was irradiated with microwaves (2.45 GHz, 100 W) for 50 minutes, so that heating was performed. Then, the reaction container was cooled to 50° C. or less. Water was added to the reaction solution, and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution which had been dried was filtered. The solvent of this solution was distilled, and recrystallized using methanol, whereby Hdm2nppr, which is the pyrazine derivative to be produced, was obtained (as a white powder in 85% yield). Note that the microwave irradiation was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). The synthesis scheme of Step 3 is illustrated in the following (c-2).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[CH2:28](OP(Cl)(Cl)=O)C>>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[C:14](=[CH2:28])[CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CCOP(=O)(Cl)Cl
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(C)=O)[C@@]2(C)CCC(=O)C=C12

Procedure:
Analogously to Example 42, 1.0 g of 17α-acetoxy-4-pregnene-3,20-dione is reacted with 3.8 ml of ethyldichlorophosphate and worked up, thus obtaining 510 mg of 17α-acetoxy-6-methylene-4-pregnene-3,20-dione, mp 231°-233° C.