Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[H-].[Na+].Br[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:4](=[O:8])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Nc1cc[nH]c(=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(N)cc1=O
Temperature: 78 °C
Yield: 41 %

Procedure:
To a solution of 4-aminopyridin-2(1H)-one (Molbridge)(0.9 g, 8.17 mmol) in DMF (30 mL) was added NaH (60%, 490 mg, 12.3 mmol). The mixture was stirred at room temperature for 30 min before (2-bromoethoxy) (tert-butyl)dimethylsilane (2.15 g, 8.99 mmol) was added. The reaction mixture was heated at 78° C. for 15 h. The mixture was cooled and poured into H2O (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with H2O (5×50 mL), brine (50 mL), dried over MgSO4 and concentrated. The residue was purified by flash chromatography (silica gel, 40+S, 0% to 10% MeOH in EtOAc) to give 4-amino-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyridin-2-one as a white solid (0.9 g, 41%).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.Cl[CH2:36][C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1>CN(C=O)C.C1(C)C=CC=CC=1>[S:40]1[CH:41]=[C:37]([CH2:36][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]1=2
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: ClCc1csc2ccccc12
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3csc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 15 mL DMF at 0° C. is added dropwise over 5 min 1.45 mL (0.72 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, and then a solution of 132 mg (0.72 mmol, 1.1 equiv) of 3-chloromethylbenzo[b]thiophene (Wolf, G.; Zymalkowski, F. Arch. Pharm. 1976, 279) in 1 mL DMF is added. The resulting solution is stirred 2 h at RT and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 5/2 as eluent followed by lyophilization in acetonitrile/H2O afforded 222 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.79 (m, 2H), 7.44-6.93 (m, 15H), 6.88 (dd, 1H, J=1.5, 8.1), 5.03 (m, 1H), 4.42 (d, 1H, J=16.6), 4.09 (d, 1H, J=16.6), 3.85 (s, 3H), 3.80 (t, 1H, J=6.6), 3.61 (m, 2H), 1.10 (t, 6H, J=6.8); low resolution MS (FAB)m/e 604 (MH+), 439.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]([N:17]=[C:18]=[S:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[C:9]([NH:17][C:18]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)=[S:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1ccnc(N)c1
Solvent: CC(C)=O
Product: Cc1ccnc(NC(=S)NC(=O)c2ccccc2)c1

Procedure:
A solution of 2-amino-4-methylpyridine (1.08 g, 10 mmol) and benzoyl isothiocyanate (1.63 g, 10 mmol) in acetone (15 mL) was stirred at RT for 1.5 h. The precipitate formed was filtered and washed with acetone to afford 1-benzoyl-3-[4-methylpyridin-2-yl]-thiourea as a solid. This material was stirred with 2 N NaOH solution (15 mL) at 110° C. for 1 h, then cooled to RT, and the precipitate formed was washed with water and dried to provide (4-methylpyridin-2-yl)-thiourea (0.90 g, 53%). MS m/z 168 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[SH:15])=[N:8][CH:9]=1)([O-:3])=[O:2].[O:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH2:24]Cl)[CH2:18][CH2:17]1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[S:15][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[N:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2S)nc1
Reactant: ClCc1ccccc1N1CCOCC1
Product: O=[N+]([O-])c1ccc(-n2ccnc2SCc2ccccc2N2CCOCC2)nc1

Procedure:
1-(5-nitro-2-pyridyl)-2-mercaptoimidazole and 2-morpholinobenzyl chloride are treated in the same manner as described in Example 1-(1) to give 1-(5-nitro-2-pyridyl)-2-(2-morpholinobenzylthio)imidazole.
Reaction SMILES: C1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16]3)=[CH:11][C:10]=2[CH3:24])[NH2:8])CCCCC1.F[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:9]1([N:8]([CH2:7][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[N:16]3)=[CH:11][C:10]=2[CH3:24])[C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1C(N)C1CCCCC1
Reactant: COC(=O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of (+/−)-cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine (80.0 mg, 0.237 mmol) in N,N-dimethylformamide (3 mL) was added methyl 6-fluoronicotinate (55.2 mg, 0.356 mmol) and potassium carbonate (98.4 mg, 0.712 mmol). The reaction was heated to 110° C. and stirred overnight. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave (+/−)-methyl 6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinate (20 mg, 15%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.63 (s, 1H), 8.06 (s, 1H), 7.79-7.82 (m, 2H), 7.43 (s, 1H), 7.33-7.36 (m, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.03 (d, J=8.8 Hz, 1H), 5.39 (d, J=6.8 Hz, 1H), 4.74 (m, 1H), 3.75 (s, 3H), 2.49 (s, 3H), 1.85-1.88 (m, 1H), 1.58-1.72 (m, 5H), 1.05-1.19 (m, 5H).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[S:16][CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:19])([O-:5])=[O:4].[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:7]=1[S:16][CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH:19][C:31]([O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32])([O-:5])=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CSc1ccc(C(F)(F)F)cc1[N+](=O)[O-])C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](CSc1ccc(C(F)(F)F)cc1[N+](=O)[O-])C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 67 ml of 2.5N aqueous sodium hydroxide and 5.3 g of S-(2-nitro-4-trifluoromethylphenyl)-L-cysteine obtained in Reference Example 10 is stirred at room temperature for 30 minutes. Two point seven ml of benzyloxycarbonyl chloride and 19 ml of 1N aqueous sodium hydroxide are simultaneously added dropwise to the mixture at ice bath temperature over a period of 30 minutes. The resulting mixture is stirred at room temperature for further 2.5 hours and extracted with ethyl ether. The aqueous layer is acidified slightly with 1N hydrochloric acid and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl ether to yield 5.5 g of S-(2-nitro-4-trifluoromethylphenyl)-N-benzyloxycarbonyl-L-cysteine as pale yellow crystals, m.p. 150°-153° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:4]=2[N:3]=1.Cl>CCO.O1CCOCC1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCOC)cc3C)cc12
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Reaction time: 3 h

Procedure:
Ethyl 3-(5-amino-2-(4-(methoxymethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-12) (1.0 equiv.) was dissolved in EtOH (0.2 M), then added a solution of 4M HCl in dioxane (0.2 M). The product precipitated out as a yellow salt. After stirring for 3 hours, the reaction was poured into a stirring solution of ether. The mixture was stirred for 10 minutes, then filtered and washed with ether. Ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-13) was obtained as a yellow solid which was dried on vacuum overnight (bis-HCl salt). Alternatively, the crude product was purified by Combiflash using 0-5% MeOH in DCM to give the free base.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH2:5]1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:28][CH2:27][CH2:26]1>O1CCCC1>[N:25]1([C:2]([N:4]2[CH2:7][CH:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[CH2:5]2)=[O:3])[CH2:28][CH2:27][CH2:26]1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(N1CCC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5.6 g (0.02 mole) of 1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine and 3 g (0.027 mole) of potassium carbonate in 50 ml of tetrahydrofuran was treated with 1.26 g (0.022 mole) of azetidine added dropwise to the stirred mixture. After stirring for 15 min, the reaction was treated with 10 g of ice and stirred for an additional 72 hr. The tetrahydrofuran was decanted from the salt-paste and concentrated on a rotary evaporator to yield an oil, 6.3 g. This oil crystallized when cooled to -70° C. and was recrystallized from hexane yielding 5.1 g (85%) of fine white crystals, m.p. 65°-68° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8][CH:7]=1.[CH3:15][O:16][C:17](=[O:23])[CH:18](Cl)[C:19]([CH3:21])=O>CO.ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:14][C:18]([C:17]([O:16][CH3:15])=[O:23])=[C:19]([CH3:21])[N:13]=2)=[CH:8][CH:7]=1
Reactant: NC(=S)c1ccc(OCCCCl)cc1
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1sc(-c2ccc(OCCCCl)cc2)nc1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 4-(3-chloropropoxy)benzenecarbothioamide ax71 (34.67 mmol, 1 eq, 7.96 g), and 2-chloroacetoacetic acid methyl ester (34.67 mmol, 1 eq, 5.2 g) in methanol is stirred at 70° C. for 2 hours. The reaction mixture is then poured into a sealed tube and stirred at 100° C. for 3 hours. The mixture is taken up in dichloromethane and washed with water then dried over magnesium sulfate. The solvent is removed under reduced pressure to give 11.8 g of methyl 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate i105. The product is used as such in the next step.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([F:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C1COCC1>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][N:6]=1)([F:4])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(F)(F)c1cc(N)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
3-(1,1-Difluoro-ethyl)-isoxazol-5-ylamine (100 mg, 0.68 mmoles) from the previous step was dissolved in 6 mL of dry THF. To this solution was added potassium carbonate (122 mg, 0.88 mmoles) and phenyl chloroformate (138 mg, 0.88 mmoles) and the reaction stirred overnight at room temperature. The reaction was filtered and concentrated to a yellow oil, and purified using silica gel chromatography with and ethyl acetate/hexane gradient 0-20% over 70 minutes to give phenyl 3-(1,1-difluoroethyl)isoxazol-5-ylcarbamate (141 mg) as an oil. 1H NMR (300 MHz, CDCl3) δ 8.1 (s, 1H), 7.4-7.1 (m, 5H), 6.9 (m, 1H), 6.4 (s, 1H), 4.9 (s, 1H), 2.0 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:14][C:15]([C:18]3[S:19][CH:20]=[C:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:22]=3[CH3:23])=[N:16][N:17]=2)=[CH:8][C:7]=1[CH3:28].[C:30](O)(=[O:33])[CH2:31][OH:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:33][CH2:30][C:31]([NH:1][CH2:2][CH:3]([OH:29])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:14][C:15]([C:18]3[S:19][CH:20]=[C:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:22]=3[CH3:23])=[N:16][N:17]=2)=[CH:8][C:7]=1[CH3:28])=[O:32]
Reactant: Cc1cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc(C)c1OCC(O)CN
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc(C)c1OCC(O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 1.7 %

Procedure:
To a solution of crude 1-amino-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl phenoxy}-propan-2-ol (0.22 mmol) in DMF (1 mL) are added glycolic acid (25 mg), DIPEA (0.1 mL) and finally TBTU (60 mg). The mixture is stirred for 15 h at rt, evaporated and the residue purified by TLC (SiO2, EA) to give 2-hydroxy-N-(2-hydroxy-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propyl)-acetamide (1.8 mg); LC-MS: tR=0.97 min, [M+1]+=474.26.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16](=[O:22])[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1>O1CCCC1>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([OH:22])([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C2(O)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
A solution of 3-methoxyphenyl magnesium bromide in tetrahydrofuran (1.0 M, 25 mL, 25 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (1.82 g, 10 mmol) in tetrahydrofuran (40 mL) under argon with cooling in a −25° C. bath at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 2 hour, 15% aqueous ammonium chloride solution (25 mL) and water (50 mL) were added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-hydroxy-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as an off-white powder. This was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:16]1([CH:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH:3]3[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH2:26][CH2:27]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(c3ccccc3)CC2)CC1

Procedure:
A mixture of 3.081 g (11.075 mM) of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate, 1.96 g (12.2 mM) of 4-phenylpiperidine, and 3.06 g (22.2 mM) of potassium carbonate was stirred in 20 ml of N,N-dimethylformamide at 110° C. for 4 hours. This reaction mixture was poured in water and extracted with 2 portions of diethyl ether. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@H:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:17])[CH3:2].Br[CH2:27][C:28]1[C:32]2[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=2[S:30][N:29]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[C@H:5]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:27][C:28]2[C:32]3[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=3[S:30][N:29]=2)[C:7]1=[O:17])[CH3:2]
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Reactant: CCOC(=O)[C@H](c1ccc(Cl)cc1)n1c(=O)[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](c1ccc(Cl)cc1)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Temperature: 100 °C
Yield: 66.9 %

Procedure:
To a solution of (S)-(4-Chloro-phenyl)-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid ethyl ester (50 mg, 0.14 mmol) (prepared according to example 1, steps 1-3) in DMF (10 mL) are added 3-Bromomethyl-4,6-dimethyl-1,2-benzisothiazole (54 mg, 0.21 mmol) (prepares according to example 5, steps 1-6) and K2CO3 (58 mg, 0.42 mmol) at room temperature under nitrogen atmosphere. The solution is heated to 100° C. for 2 hours. The solution is cooled down and water is added. The solution is extracted with EtOAc and the combined organic layer is dried with MgSO4. The solution is filtered and the filtrate is concentrated. The residue is purified by flash chromatography with 20% EtOAc in Hexane as the eluent to afford (S)-(4-Chloro-phenyl)-[1-(4,6-dimethyl-1,2-benzisothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetic acid ethyl ester (50 mg, 67%) as a colorless foam.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28]CC2C=CC=CC=2)=[C:24]([O:36]CC2C=CC=CC=2)[CH:23]=1)[C:10]([O:12][C@H:13]([CH3:20])[C@H:14]([O:16][C:17](=[O:19])[CH3:18])[CH3:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[OH:36][C:24]1[CH:23]=[C:22]([CH2:21][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([O:12][C@H:13]([CH3:20])[C@H:14]([O:16][C:17](=[O:19])[CH3:18])[CH3:15])=[O:11])[CH:27]=[CH:26][C:25]=1[OH:28]
Reactant: [H][H]
Reactant: CC(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of (1R,2R)-2-acetoxy-1-methylpropyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (33) (2.0 g, 3.4 mmol) in 20 mL of methanol, 10% Pd—C (100 mg) pre-mixed with 10 mL of methanol was added under a nitrogen atmosphere. The nitrogen was exchanged with hydrogen using the evacuation refill cycle method. The mixture was stirred under hydrogen atmosphere at room temperature for 4 hours. After filtration and washing with methanol, the filtrate was concentrated to provide 1.4 g (100% yield) of the title compound (34). 1H NMR (400 MHz, CDCl3): δ 1.14 (d, J=6.4 Hz, 3H), 1.16 (d, J=6.4 Hz, 3H), 1.42 (s, 9H), 2.06 (s, 3H), 2.92 (dd, J=12.8, 6.4 Hz, 1H), 2.96 (dd, J=12.8, 6.4 Hz, 1H), 4.46 (dd, J=12.4, 6.4 Hz, 1H), 4.95 (m, 2H), 5.05 (d, J=8.8 Hz, 1H, NH), 6.65 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 6.73 (d, J=8.0 Hz, 1H). MS (ESI) m/z 434.1 (M+Na)+ and 410.1 (M−H)−.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[C:15]1([O:21][CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[N+](C1C=CC=CC=1)([O-])=O>[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:18]2[CH:19]=[CH:20][C:15]([O:21][CH3:22])=[CH:16][CH:17]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(I)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Nitrobenzene (45 ml) was cooled in an ice-bath and treated portionwise with aluminum chloride (13.5 g, 101 mmol, 1.15 eq.) and followed by 4-iodobenzoic acid chloride (25 g, 94 mmol, 1.07 eq.) in nitrobenzene (25 ml) at a maximum of 10° C. The mixture was stirred at 0° C. for 10 minutes, where upon anisole (9.5 g, 88 mmol, 1 eq.) was added dropwise in such a manner that the temperature didn't excess 10° C. The solution then was left to warm to room temperature overnight. The yellow suspension was poured into ice-water (750 ml). The precipitate was collected by filtration and washed with water and then dissolved in dichloromethane (2 L), which was washed NaHCO3 (aq.) (150 ml×2), dried over MgSO4. Evaporation of solvent under reduced pressure to provide the title product in (26.7 g, 90%); 1H NMR (400 MHz, CDCl3) δ 3.89 (s, 3H), 6.96 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H);
Reaction SMILES: [OH:1][CH:2]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:17]C1C=C(C=CC=1)C=O>>[F:17][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH:2]([P:9](=[O:16])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])[OH:1]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOP(=O)(OCC)C(O)c1ccccc1
Product: CCOP(=O)(OCC)C(O)c1cccc(F)c1
Yield: 79 %

Procedure:
The procedure described for the preparation of Compound 19 is used except that 3-fluorobenzaldehyde (1.49 g, 0.012M) is used in place of benzaldehyde. The solid obtained is recrystallized from hexane to obtain 2.474 g (0.009 M, 79%) of colorless short needles: mp 81°-82° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.[CH:11]1[CH:12]=[CH:13][C:14]2[S:19][CH:18]=[CH:17][C:15]=2[CH:16]=1>>[S:19]1[C:18]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([Br:1])[CH:3]=2)=[CH:17][C:15]2[CH:16]=[CH:11][CH:12]=[CH:13][C:14]1=2
Reactant: Cc1ccc(C=O)cc1Br
Reactant: c1ccc2sccc2c1
Product: Cc1ccc(Cc2cc3ccccc3s2)cc1Br

Procedure:
The above 3-bromo-4-methylbenzaldehyde and thianaphthene were treated in a manner similar to Reference Example 7 to give (Benzo[b]thiophen-2-ylmethyl)-3-bromo-4-methylbenzene as a colorless solid.