Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:17])[N:4]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[N:5]=[CH:6][C:7]=1Cl.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[O:17]=[C:3]1[N:4]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[N:5]=[CH:6][C:7]([C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:18]#[N:19])=[C:2]1[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:9]#[N:4].[O:17]=[C:3]1[N:4]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[N:5]=[CH:6][C:7]([C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:18]#[N:19])=[C:2]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]#[N:4]
Reactant: CC(c1ccccc1)n1ncc(Cl)c(Cl)c1=O
Reactant: N#Cc1cccc(B(O)O)c1
Product: CC(c1ccccc1)n1ncc(-c2cccc(C#N)c2)c(-c2cccc(C#N)c2)c1=O
Product: CC(c1ccccc1)n1ncc(-c2ccccc2C#N)c(-c2ccccc2C#N)c1=O
Yield: 7.4 %

Procedure:
Compound 5 is prepared from intermediate 1a and 3-cyanophenylboronic acid under the conditions described for example 4. The minor product formed (solid) corresponds to compound 4 (yield:7.4%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)C=[CH:6][CH:7]=1.[Cl:19]N1C(=O)CCC1=O.[C:27]([Cl:31])(Cl)(Cl)Cl>>[NH2:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[C:27]([Cl:31])=[CH:6][C:7]=1[Cl:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cccn2nc(SCc3ccccc3)nc12
Reactant: ClC(Cl)(Cl)Cl
Product: Nc1c(Cl)cc(Cl)n2nc(SCc3ccccc3)nc12
Reaction time: 1 h

Procedure:
8-Amino-2-benzylthio[1,2,4]triazolo[1,5-a]pyridine (20.0 g, 0.078 mol), N-chlorosuccinimide (10.4 g, 0.078 mol) and carbon tetrachloride were combined and heated to reflux with stirring for 1 hour. The reaction mixture was cooled, more N-chlorosuccinimide (10.4 g) was added, and the reaction heated to reflux with stirring for another hour. The reaction mixture was then cooled and filtered. The filtrate was concentrated by evaporation under reduced pressure and the residue obtained was purified by column chromatography on silica gel eluting with dichloromethane. The product fractions were concentrated by evaporation under reduced pressure and the residues were combined and mixed with ether. The insoluble solids were collected by filtration and dried to obtain 18.0 g (71 percent of theory) of the title compound as a light tan powder melting at 118°-119° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[C:9]([SH:11])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12]N(C)C=O.[H-].[Na+].IC>O>[CH3:12][S:11][C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=2[N:10]=1
Reactant: Nc1ncnc2sc(S)nc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CSc1nc2c(N)ncnc2s1
Reaction time: 4 h

Procedure:
To a stirred and cooled (below 25° C.) mixture of 13.9 parts of 7-aminothiazolo[5,4-d]pyrimidin-2-thiol and 180 parts of N,N-dimethylformamide were added portionwise 4.3 parts of a sodium hydride dispersion 50% while cooling. After stirring for 1 hours, 11.5 parts of iodomethane were added dropwise at a temperature below 25° C. Upon completion, stirring was continued for 4 hours at room temperature. The reaction mixture was poured into water. The product was filtered off (the filtrate was set aside) and dried, yielding a first fraction of 5.9 parts of 2-(methylthio)thiazolo[5,4-d]pyrimidin-7-amine (intermediate 46). From the filtrate, the aqueous layer was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding a second fraction of 3.9 parts of 2-(methylthio)thiazolo[5,4-d]pyrimidin-7-amine (Intermediate 46). Total yield: 9.8 parts (65.6%) of 2 -(methylthio)thiazolo[5,4-d]-pyrimidin-7-amine (intermediate 46).
Reaction SMILES: [OH:1][CH:2]([C:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[OH:19])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl(O)(=O)(=O)=O.C([O-])(O)=O.[Na+]>C(OC(C)(C)C)(=O)C>[C:8]([O:1][CH:2]([C:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[OH:19])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:17])([CH3:9])[CH3:2]
Reactant: CCOC(=O)C(O)c1c(C)cc2ccccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccccc2c1O
Reaction time: 3 h

Procedure:
A solution of ethyl 2-hydroxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate (622 mg, 2.39 mmol) in tert-butyl acetate (12 mL) was treated with 70% HClO4 (20 μL) at 23° C.). After 3 h, the reaction was added slowly over 5 min to saturated NaHCO3 (25 mL). The resulting system was extracted with DCM (3×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. Hexane (10 mL) was added, and the mixture was concentrated again. The residue was dissolved in benzene. The solution was loaded onto a 24 g “gold” ISCO silica gel column and purified by flash chromatography (hexane→ethyl acetate) giving the desired product. 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.2, 8.0 Hz, 1H), 7/39 (dd, J=8.8, 8.0 Hz, 1H), 7.17 (s, 1H), 5.52 (s, 1H), 4.25-4.06 (m, 2H), 2.59 (s, 3H), 1.33 (s, 9H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C([OH:19])C>O>[NH2:1][C:2]1[N+:7]([O-:19])=[C:6]([NH:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: CCO
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CCCCCCN
Solvent: O
Product: CCCCCCNc1ccnc(N)[n+]1[O-]
Reaction time: 0.5 h
Yield: 62 %

Procedure:
50 g of 2-amino-4,6-dichloropyrimidine were suspended in 350 ml of absolute ethanol in a reactor. 181.5 ml of hexylamine (reagent A) were added in a single portion and the mixture was refluxed for 3 h. The medium was evaporated under vacuum. The oil obtained was taken up in 600 ml of water with stirring for 1 h, 30 min. The precipitate was filtered off, washed and dried in a heated desiccator. 43.5 g of the expected compound were thus obtained, for a yield of 62%.
Reaction SMILES: [N+:1]([C:4]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[Br:17]Br>[Zn].CC(O)=O>[Br:17][C:7]1[CH:8]=[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([NH2:1])=[N:5][CH:6]=1
Reactant: O=[N+]([O-])c1ncccc1Sc1ccccc1
Reactant: BrBr
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1Sc1ccccc1
Reaction time: 0.08 h
Yield: 92.2 %

Procedure:
mL 2-Nitro-3-(phenylthio)pyridine (16.3 g, 70.2 mmol) and AcOH (250 mL) were cooled in a water bath. Zinc (22.9 g, 351 mmol) was slowly added and stirred for 5 minutes. Filtered through celite and the cake washed with CH2Cl2. The CH2Cl2 was removed and to the solution was added bromine (3.6 mL, 70.2 mmol). After 10 minutes, the HOAc was removed and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (1.5 L SiO2 and 30% EtOAc in hexanes) to afford the title compound (18.2 g, 92.21% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:13])=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:8]=1)#N.[C:14]([NH:17][C:18]1C=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)(=[O:16])[CH3:15].[CH:27]1([CH:33]=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH:33]2[NH:13][C:6]3[CH:5]=[CH:4][C:3]([C:1]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[NH:17][C:14](=[O:16])[CH3:15])=[CH:8][C:7]=3[S:9](=[O:11])(=[O:10])[NH:12]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=CC1CCCCC1
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CC(=O)Nc1ccccc1B(O)O
Product: CC(=O)Nc1ccccc1-c1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)N2

Procedure:
5-Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H (using 2-Acetamidophenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). M. p. 245–249° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])C=O)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].[C:25](O)(=O)C>>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:24]2[S:18](=[CH2:25])[C:19](=[S:20])[NH:21][C:22]2=[O:23])[CH:10]=[C:11]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:12]=1[OH:13])([CH3:3])[CH3:2]
Reactant: O=C1CSC(=S)N1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CC(=O)O
Product: C=S1C(=S)NC(=O)C1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
Form I is the predominant crystal form at temperatures from about 60° C. to about 155° C. Substantially pure Form I can be obtained in a laboratory setting by refluxing 3,5-di-tert-butyl-4-hydroxybenzaldehyde with rhodanine in glacial acetic acid using fused sodium acetate as a catalyst to form 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]}-methylene-2-thioxo-4-thiazolidinone. The resultant 2-thioxo-4-thiazolidinone can then be reduced with hydrogen in the presence of palladium on carbon. The product is isolated by chromatography, and the solvent is removed to afford Form I Tazofelone. In an alternate preparation, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]}-methylene-2-thioxo-4-thiazolidinone can be refluxed with diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate and activated silica gel to form (±)-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methyl}-2-thioxo-4-thiazolidinone. The methyl-2-thioxo-4-thiazolidinone can then be reduced using hydrogen in the presence of palladium on carbon.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:15][N:14]=3)=[C:8]1[CH2:7][CH2:6]2.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([NH2:37])=[O:36].C(N(CC)CC)C.CN([CH:48]=[O:49])C>C(OCC)(=O)C>[OH:36][C:48]([C:18]([F:21])([F:20])[F:19])=[O:49].[CH3:31][N:32]([CH2:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:15][N:14]=3)=[C:8]1[CH2:7][CH2:6]2)[CH2:33][CH2:34][C:35]([NH2:37])=[O:36]
Reactant: CN(C)C=O
Reactant: CNCCC(N)=O
Reactant: FC(F)(F)c1c(-c2onc3c2CCc2cc(CBr)ccc2-3)noc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(CCC(N)=O)Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A mixture of 7-(bromomethyl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (6C, 0.025 g, 0.053 mmol), 3-(methylamino)propanamide (5.37 mg, 0.053 mmol) and triethylamine (7.33 mL, 0.053 mmol) in DMF (3.0 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (3×1.0 mL). The ethyl acetate extract was concentrated, and the residue was chromatographed using reverse-phase preparative HPLC (Column: LUNA 5 u C18, 21×100 mm:Solvent MeOH(B)—H2O(A), 0.1% TFA: 0% B-100% B, Gradient Time 12 min, Stop Time 20 min, Flow Rate 20 ml/min, Wavelength 220 nM) to give 3-(methyl((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)amino)propanamide TFA (0.012 g., 0.493 mmol, 48%) as a viscous tan liquid. The product had an HPLC ret. time=4.02 min. (condition B). LC/MS M+1=497.07. 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (1H, d, J=7.92 Hz), 7.79 (2H, d, J=7.26 Hz), 7.32-7.77 (5H, m), 4.54 (2H, s), 3.23-3.44 (4H, m), 2.98-3.21 (4H, m), and 2.89 (3H, s).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C@@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[CH2:7][C@@H:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:23]I.O>CN(C=O)C>[CH3:23][O:3][C@H:4]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C@@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[CH2:7][C@@H:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1cccs1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H](c1cccs1)[C@H]1[C@@H](c2ccccc2)CC(=O)N1C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a slurry of NaH (60%, 32 mg, 1.0 mmol) in DMF (15 mL) was added (±)-(4R*,5R*)-5-((1S)-hydroxy-2-thienylmethyl)-1-methyl-4-phenylpyrrolidin-2-one (Example 5 step 1, 250 mg, 0.9 mmol). The resulting mixture was stirred for 30 min, then methyl iodide (0.08 mL, 1.3 mmol) was added. After 2 h water was added and the resulting mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc) to give (±)-(4R*,5R*)-5-((1S*)-methoxy-2-thienylmethyl)-1-methyl-4-phenylpyrrolidin-2-one (125 mg, 46%) as a white solid: mp 101-102° C.; TLC (EtOAc/hex) Rf 0.50.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[N:7][N:8]([CH3:22])[C:9]([N:11]([N:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH3:12])=[NH:10])=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:10]=[C:9]([N:11]([N:13]=[CH:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH3:12])[N:8]([N:7]=[CH:6][C:5]1[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:22])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CN(N=Cc1ccc(Cl)cc1)C(=N)N(C)N=Cc1ccc(Cl)cc1
Product: CC(=O)N=C(N(C)N=Cc1ccc(Cl)cc1)N(C)N=Cc1ccc(Cl)cc1

Procedure:
When 1,3-bis(p-chlorobenzylideneamino)-1,3-dimethylguanidine free base is submitted to the above reaction conditions with acetic anhydride, there is obtained the corresponding 2-acetyl-1,3-bis(4-chlorobenzylideneamino)-1,3-dimethylguanidine.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:31][OH:32])[CH:24]=[CH:23]1>ClCCl>[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[CH:31]=[O:32])[CH:24]=[CH:23]1
Reactant: OCc1cccc2cc[nH]c12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cccc2cc[nH]c12
Reaction time: 2 h

Procedure:
Solid pyridinium dichromate (1.77 g, 5.1 mmol) was added in portions over 3 hours to a stirred solution of 7-indolemethanol (0.5 g, 3.4 mmol) in dichloromethane (50 ml). The mixture was stirred for a further 2 hours then filtered through a pad of Celite filter aid. The filtrate was evaporated and the residue purified by chromatography on silica in ethyl acetate-hexane (1:3).
Reaction SMILES: [I:1][C:2]1[C:7]([NH2:8])=[C:6]([I:9])[N:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:12]S(OC)(=O)=O.C(OCC)(=O)C>O1CCCC1>[I:1][C:2]1[C:7]([NH:8][CH3:12])=[C:6]([I:9])[N:5]=[CH:4][N:3]=1
Reactant: COS(C)(=O)=O
Reactant: Nc1c(I)ncnc1I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1c(I)ncnc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,6-diiodopyrimidin-5-amine (1.0 g) in tetrahydrofuran (10 mL) was added sodium hydride (60%, 138 mg) under ice-cooling. The mixture was stirred at room temperature for 30 min. To the reaction system was added dropwise a solution of methyl methanesulfonate (0.256 mL) in tetrahydrofuran (4.0 mL). The mixture was stirred at room temperature for 3 hrs and ethyl acetate was added. The mixture washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to give the title compound (600 mg) as pale-yellow crystals.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: O=C(CCC(O)c1ccccc1)N1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CCC(=O)N1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 92.1 %

Procedure:
A mixture of 4-hydroxy-4-phenyl-1-piperidin-1-yl-butan-1-one (4.00 g, 16.2 mmol), prepared in the previous step, and pyridinium chlorochromate (5.23 g, 24.3 mmol) in 150 ml of methylene chloride was stirred at room temperature for 2.25 hours. The reaction was poured onto 400 g of silica gel (230-400 mesh) and the material eluted with methylene chloride-ethyl acetate. Isolation of the major component gave 4-oxo-4-phenyl-1-piperidin-1-yl-butan-1-one (3.66 g, 92%) as a green solid. Recrystallization of a portion of this solid from ethyl acetate-hexane gave an analytically pure sample, mp 52-54° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([S:16](=[O:32])(=[O:31])[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)=[CH:8][CH:7]=1)=[O:5].[CH3:34][Mg]Br>C1COCC1>[CH2:24]([N:21]1[CH2:20][CH2:19][CH:18]([NH:17][S:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]([C:4](=[O:5])[CH3:34])=[CH:7][CH:8]=2)(=[O:32])=[O:31])[CH2:23][CH2:22]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a 0° C. solution of 4-(1-benzyl-piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid methoxy-methyl-amide 35 (200 mg, 0.43 mmol) in THF (5 mL) was slowly added methylmagnesium bromide (5.71 mL, 17.1 mmol, 1M THF solution). After stirring at 25° C. for 4 h, the resultant mixture was quenched with saturated ammonium chloride solution. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by Flash column chromatography (hexane/EtOAc) to provide 118 mg of 4-acetyl-naphthalene-1-sulfonic acid (1-benzyl-piperidin-4-yl)-amide 36 in 56% overall yield (for two steps).LC/MS showed m/z : 423 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]1[CH3:46]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:32]([NH:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]2[CH3:46])=[S:33])=[C:18]([CH3:24])[CH:17]=1
Reactant: S=C(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CC1CCCCN1CCCN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=S)NCCCN4CCCCC4C)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (51 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 6 hr. Next, 1-(3-aminopropyl)-2-methylpiperidine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 16 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (46 mg, yield 56%).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1>C(O)C>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH:13]1[NH:12][C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1csc2c(Cl)ncnc12
Reactant: NC1Cc2ccccc2C1
Solvent: CCO
Product: Cc1csc2c(NC3Cc4ccccc4C3)ncnc12
Yield: 75 %

Procedure:
4-chloro-7-methylthieno[3,2-d]pyrimidine (74 mg, 0.40 mmol) and 2-aminoindan (270 mg, 2.0 mmol) in dry ethanol (3 ml) were heated to reflux under an argon atmosphere for 1 hour. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (83 mg, 0.30 mmol) having the following physical properties:
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:24][CH2:23][CH2:22][O:21][CH3:20])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: COCCN
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(NCCOC)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2-methoxyethanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (400 MHz, CD3CN): δ 7.55-7.49 (m, 5H), 5.83 (bs, 1H), 3.67 (t, 2H), 3.27 (t, 2H), 3.21 (s, 3H), 3.05-3.00 (m, 2H), 1.80-1.72 (m, 2H), 1.48-1.38 (m, 2H), 0.97 (t, 3H); Mass Spectrum: M+H+ 339.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=3)[N:10]=2)[N:3]=[CH:2]1.[ClH:18].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:42][C@H:43]1[CH:48]2[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]2)[CH2:44]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[ClH:18].[N:45]12[CH2:50][CH2:49][CH:48]([CH2:47][CH2:46]1)[C@H:43]([NH:42][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:4]4[N:3]=[CH:2][S:1][CH:5]=4)=[N:10][C:9]=13)=[O:17])[CH2:44]2
Reactant: O=C(O)c1cccc2oc(-c3cscn3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(-c3cscn3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.8 %

Procedure:
A mixture of 2-(thiazol-4-yl)benzoxazole-4-carboxylic acid (80 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg, 0.64 mmol), 1-hydroxybenzotriazole (86 mg, 0.64 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (81 mg, 0.41 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.13 mL, 1.0 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organics were washed with water (5×25 mL), brine (25 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford the desired product (41 mg, 37%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.52 (d, J=7.1 Hz, 1H), 9.03 (d, J=2.1 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.78 (dd, J=8.1, 1.0 Hz, 1H), 7.53 (t, J=7.9 Hz, 1H), 4.42-4.35 (m, 1H), 3.60-3.53 (m, 1H), 3.25-3.05 (m, 2H), 3.02-2.90 (m, 3H), 2.28-2.10 (m, 2H), 1.87-1.80 (m, 2H), 1.75-1.67 (m, 1H); MS (ESI+) m/z 355 (M+H).