Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[C:10](O)[CH:9]=[N:8][CH:7]=1.IC.CN(C)[CH:18]=[O:19]>>[CH3:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:19][CH3:18])=[N:8][CH:7]=1
Reactant: COC(=O)c1cncc(O)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC(=O)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 90 %

Procedure:
To sodium hydride (0.42 g, 10.5 mmol, washed with hexanes ×3) in dimethylformamide (15 mL) was added 5-hydroxy-nicotinic acid methyl ester (1.53 g, 10.0 mmol) in dimethylformamide (10 mL). After three minutes, iodomethane (0.65 mL, 10.5 mmol) was added dropwise while stirring at room temperature. After 1 h, the reaction was quenched with methanol and concentrated to a brown oil. The solution was dissolved in 20% isopropanol/chloroform, washed with saturated aqueous sodium bicarbonate solution, brine (×3), dried over magnesium sulfate and concentrated to give 1.46 g of 6-methoxynicotinic acid methyl ester. The resulting oil was dissolved in tetrahydrofuran (50 mL), and added to a solution of 5N NaOH (20 mL, 100 mmol) and water (5 mL). After 30 minutes, an additional 25 mL of 5N NaOH was added to the solution. After one hour, the reaction was acidified to pH 3 with 5N HCl and concentrated. To the resulting white solids was added 20% MeOH/CHCl3 and the mixture was sonicated for 20 minutes. The mixture was filtered, and the mother liquor was dried over MgSO4 and concentrated to give 1.38 g as a light yellow solid, 90% yield.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[OH:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][O:10][N:11]1[C:12](=[O:21])[C:13]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]2[C:15]1=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCc1ccccn1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 46 %

Procedure:
2-Chloromethylpyridine hydrochloride (514 mg, 3.13 mmol), N-hydroxyphthalimide (515 mg, 3.18 mmol), and triethylamine (1.3 mL, 9.3 mmol) were mixed in acetonitrile (5 mL) and stirred at 80° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with 1N NaOH(aq), water, and brine. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was recrystallized from ethyl acetate and hexanes to provide N-(pyridine-2-ylmethoxy)phthalimide (364 mg, 1.44 mmol).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[C:6]([O:11][CH3:12])(=[O:10])[C:7]([CH3:9])=[CH2:8]>CO>[CH3:12][O:11][C:6](=[O:10])[CH:7]([CH3:9])[CH2:8][NH:5][CH:1]1[CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)C(=O)OC
Reactant: NC1CCC1
Solvent: CO
Product: COC(=O)C(C)CNC1CCC1
Yield: 80.4 %

Procedure:
A solution of 10.72 g (0.10 mole) of cyclobutylamine, 12.01 g (0.12 mole) of methyl methacrylate and 50 mL of methanol was heated at 90 degrees for 20 hours in a pressure bottle. After cooling the mixture was concentrated, then distilled under vacuum to give 13.77 g of (rac)-3-cyclobutylamino-2-methyl-propanoic acid methyl ester as colorless oil. b.p. 70-75 degrees at 0.5 mm Hg.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:37]2[C:38]([C:43]3[CH:48]=CC=CC=3F)=N[O:40][C:41]=2C)=NC=1.[NH2:51]C1CCOCC1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH2:51])=[O:25])=[C:5]([CH:38]4[CH2:43][CH2:48][O:40][CH2:41][CH2:37]4)[N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)noc2C)nc1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cn3)noc2C)nc1
Product: Cc1onc(-c2ccc(Cl)cn2)c1COc1ccc(C(N)=O)c(C2CCOCC2)n1
Yield: 47 %

Procedure:
As described for example 84f, 6-[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (108 mg, 0.3 mmol) was converted, instead of [6-[3-(2-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (61 mg, 47%) which was obtained as a white solid. MS: m/e=429.5 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]([C:12]1[S:13][C:14]([Br:17])=[CH:15][CH:16]=1)(=[O:11])[CH3:10].Cl>C1COCC1.O>[Br:17][C:14]1[S:13][C:12]([C:9](=[O:11])[CH2:10][C:3]([O:6][CH3:7])=[O:8])=[CH:16][CH:15]=1
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(Br)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(=O)c1ccc(Br)s1
Yield: 99 %

Procedure:
Sodium hydride (1.95 g of 60% dispersion in oil, 0.045 mol), dimethyl carbonate (50 mL) and THF (40 mL) were added to a flame dried flask equipped with stirrer and dropping funnel. 2-Acetyl-5-bromothiophene (5.0 g, 0.024 mol) in 20 mL THF was added dropwise. The mixture was then heated at reflux for 2 hours, then poured into 250 mL of water, acidified to pH 2.0 with 1N HCl and extracted 3×200 mL ether. The organic layers were combined, dried (MgSO4) and stripped to yield 6.4 g (99%) of present title product as an oil; tlc Rf 0.42 (CHCl3).
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.C([Li])CCC.[C:25](=[O:27])=[O:26].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:17][C:13]1[CH:12]=[C:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:25]([OH:27])=[O:26])[C:3]=3[O:18][CH3:19])[NH:7][N:6]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1c(Br)ccc2[nH]nc(-c3cccc(F)c3)c12
Reactant: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C(=O)O)ccc2[nH]nc(-c3cccc(F)c3)c12
Temperature: -78 °C

Procedure:
A total of 230 mg of 5-bromo-3-(3-fluoro-phenyl)-4-methoxy-1H-indazole obtained in Production Example II-2-c was dissolved in 4.78 ml of tetrahydrofuran, and 0.99 ml of a 1.59 M solution of n-butyllithium in hexane was added under stirring at −78° C. After stirring at −78° C. for 30 minutes, dry ice was added. After stirring at the same temperature for 10 minutes, saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:1), to give 41.1 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.N1(CO)C2C=CC=C[C:27]=2N=N1.C[Si](Cl)(C)C.Br[C:41]([F:48])([F:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(O)C.O1CCCC1.[Zn]>[F:47][C:41]([F:48])([CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1)[C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: FC(F)(F)COc1cccc2onc(OCC3CCNCC3)c12
Reactant: OCn1nnc2ccccc21
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CN1CCC(COc2noc3cccc(OCC(F)(F)F)c23)CC1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
A mixture of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole (0.51 g, 1.5 mmol, EXAMPLE 2, Step 2) and 1H-benztriazole-1-methanol (0.22 g, 1.5 mmol) in ethanol (6 mL) was stirred at 50° C. for 20 min. The mixture was concentrated in vacuo to give a solid. The residual solid was dissolved with tetrahydrofuran (2 mL) and this solution was added to a mixture of zinc powder (0.20 g, 3.0 mmol), trimethylsilylchloride (0.19 mL, 1.5 mmol), and ethyl bromodifluoroacetate (0.46 g, 2.3 mmol) in tetrahydrofuran (6 mL) at room temperature. The mixture was refluxed for 2 h and then cooled to room temperature. The mixture was filtered and the filtrate was diluted with ethyl acetate and sat. aq. sodium hydrogencarbonate (30 mL). The mixture was extracted with ethyl acetate (50 mL×2) and washed with brine. The combined extract was dried over magnesium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 4:1) to give 0.34 g (49%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([N+:15]([O-:17])=[O:16])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]1CCN2C(=NCCC2)CC1.CI>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([N+:15]([O-:17])=[O:16])[N:9]=1)[CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c([N+](=O)[O-])n1
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)c([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.4 %

Procedure:
To a solution of (5-bromo-6-nitro-pyridin-2-yl)-carbamic acid tert-butyl ester (11) (4.2 g, 13.2 mmol) in dry DMF (21 mL), DBU (5.02 g, 33.0 mmol)! was added at 0° C. Methyl iodide (3.75 g, 26.4 mmol) was added slowly at 0° C. After stirring for 3 hours at 0° C. the reaction mixture was quenched and the product was precipitated upon addition of aqueous NaHSO4 (1M). The crude product was isolated by filtration and purified by recrystallisation from a mixture of MeCN and water to afford (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester 12 (1.55 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:12](=[C:14]([C:18]([OH:20])=O)[CH:15]=[CH:16][CH:17]=2)[N:13]=1.Cl.Cl.[NH2:23][C@H:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:26]12[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27]1)[C@H:24]([NH:23][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[N:13][C:12]=13)=[O:20])[CH2:25]2
Reactant: O=C(O)c1cccc2oc(-c3ccc(Cl)cc3Cl)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(-c3ccc(Cl)cc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
A mixture of 2-(2,4-dichlorophenyl)benzo[d]oxazole-4-carboxylic acid (100 mg, 0.32 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (64 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (1.5 mL) was stirred at room temperature for 5 min, then triethylamine (0.17 mL, 1.28 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2,4-dichlorophenyl)benzoxazole-4-carboxamide (63 mg, 47%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.40 (d, J=7.0 Hz, 1H), 8.25 (dd, J=7.5, 1.0 Hz, 1H), 8.17 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.0, 1.0 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.47 (dd, J=8.5, 2.0 Hz, 1H), 4.32-4.26 (m, 1H), 3.50 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.10-2.72 (m, 5H), 2.15-2.10 (m, 1H), 2.02-1.95 (m, 1H), 1.82-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z 416 (M+H); HPLC>99% (AUC), tR=13.23 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([C:15]([OH:17])=[O:16])[C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C1(C)C=CC=CC=1.CO>[Cl:25][C:20]1[CH:19]=[C:18]([C@@H:12]2[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][C@H:13]2[C:15]([O:17][CH3:26])=[O:16])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(=O)O)C1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a mixed solution of (6R,7R)-4-(tert-butoxycarbonyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-6-carboxylic acid (0.82 g) in toluene (10 ml) and methanol (2 mL) was added trimethylsilyldiazomethane (1.576 mL, 2 mol/l hexane solution) at 0° C. and the mixture was stirred for 30 min. Acetic acid was added until the solution became colorless. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.51 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:2]([NH:1][C:32]([C:23]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)=[O:33])[CH:7]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2N)c1=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2NC(=O)c2ccc3ccccc3c2)c1=O
Yield: 70.8 %

Procedure:
A solution of 3-(2-amino-4-chlorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.4 g), 2-naphthoyl chloride (0.29 g) and triethyl amine (0.19 g) in anhydrous tetrahydro furan (30 ml) was heated at reflux temperature overnight under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (200 ml), washed with brine (×2) and dried over anhydrous sodium sulfate. The solvent was removed unded reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate and hexane (1:3) as the eluent give a pale yellow solid. The solid was recrystallized from ethyl acetate-hexane to give the title compound as a white crystal (0.42 g).
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl.O>[CH3:1][O:2][N:3]([CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
To a solution of O-Methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (0.65 g, 2.4 mmol) prepared as described in example P15d, in dichloromethane (5 ml) was added triethylamine (0.844 ml, 6.0 mmol) followed by drop wise addition of a solution 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.519 g, 2.67 mmol) in dichloromethane at 0° C. After complete addition of acid chloride the mixture was stirred 18 hours at ambient temperature. When the TLC confirmed completion of the reaction, the reaction mass was diluted with water and extracted with dichloromethane (3×60 ml). The combined dichloromethane layer were washed with 2N HCl, followed by saturated NaHCO3, then with water and finally with brine solution before drying over sodium sulfate and evaporation of the solvent. The resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 30% ethyl acetate in hexane as eluent to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (0.51 g, 49%) as off white solid. m.p: 110-112° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>O1CCCC1>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[CH:12]=[CH:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH2:20][CH2:21]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(N3CCNCC3)cccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1ccc2c(N3CCN(Cc4ccccc4)CC3)cccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(phenylsulfonyl)-4-piperazin-1-yl-1H-indole (71 mg, 0.18 mmol) in tetrahydrofuran is treated sequentially with benzyl bromide (21 μl) and triethyl-amine (75 μl), shaken at room temperature for 16 hr and concentrated in vacuo to give a residue. The residue is purified by RP-HPLC to give the title product, 37 mg, identfied by HPLC and mass spectral analyses (2.81 min; 432 M+H) using the LCMS conditions described in Table I.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N+:19]([O-:21])=[O:20])[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH2:31])[CH3:30])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([N+:19]([O-:21])=[O:20])[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:14]([CH:29]([NH:31][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:30])[CH:13]=1
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol), 1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanamine (54 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.06 mL, 0.35 mmol) in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C20H17ClFN6O2 (M+H)+: m/z=427.1. found: 427.1.
Reaction SMILES: O=[C:2]([CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH2:8][C:9]#[N:10])=[O:5].[NH2:12]/[C:13](/[CH3:19])=[CH:14]\[C:15]([O:17][CH3:18])=[O:16].[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([O-:22])=[O:21]>CO>[CH3:19][C:13]1[NH:12][C:2]([CH3:11])=[C:3]([C:4]([O:6][CH2:7][CH2:8][C:9]#[N:10])=[O:5])[CH:26]([C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: COC(=O)/C=C(/C)N
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)C1c1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A mixture of 2-cyanoethy 3-oxobutanoate (83.3 g, 0.54 mol), methyl 3-aminocrotonate (61.9 g, 0.54 mol), and 3-nitrobenzaldehyde (81.3 g, 0.54 mol) in methanol (540 mL ) was heated at reflux for 8 hours, then stirred overnight. The resulting precipitate was filtered, washed with methanol, and dried to produce racemic 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(2-cyano)ethoxycarbonyl-1,4-dihydropyridine (mp=123° C.).
Reaction SMILES: [CH2:1]([C@H:5]1[NH:10][C:9](=O)[CH2:8][NH:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([C@@H:5]1[CH2:6][NH:7][CH2:8][CH2:9][NH:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1NC(=O)CNC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[C@@H]1CNCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled to −78° C. solution of (3R)-3-butyl-2,5-piperazinedione from step (b) above (600 mg, 2.52 mmol) in THF (10 mL) was added dropwise lithium aluminum hydride (21 mL, 21.1 mmol, 1M in THF, Aldrich). The mixture was stirred at room temperature for 1 h, and then heated at reflux for 16 h. The mixture was cooled to 0° C. and quenched with sodium sulfate decahydrate until the gas evolution ceased. The mixture was stirred at room temperature for 3 h, filtered and the filter cake was washed with THF (2×10 mL). The filtrate was concentrated in vacuo to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 143 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][C:11](OCC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>>[O:12]=[CH:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a dry, cooled (−78° C.) solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate from Step A (1.00 g, 3.41 mmol) was added a solution of DiBAl-H (6.82 mL, 6.82 mmol, 1 M in CH2Cl2) slowly over 30 min. After an additional 30 min of stirring at −78° C., the reaction was quenched by the rapid addition of saturated aqueous Rochelle's salt (32 mL). The cooling bath was then removed and the reaction was allowed to rapidly stir until a noticeable decrease in the amount of emulsion was observed. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×30 mL). Combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of EtOAc:hexanes 5:95 to 40:60, to give the title compound. MS: m/z=150 (M−CO2C4H7).
Reaction SMILES: [F:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[N:20][OH:21])=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:30][C:31]1[CH:36]=[C:35]([C:37](=[CH2:42])[C:38]([F:41])([F:40])[F:39])[CH:34]=[C:33]([Cl:43])[C:32]=1[Cl:44].C(=O)(O)[O-].[K+]>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH2:42][C:37]([C:35]4[CH:34]=[C:33]([Cl:43])[C:32]([Cl:44])=[C:31]([Cl:30])[CH:36]=4)([C:38]([F:41])([F:40])[F:39])[O:21][N:20]=3)=[CH:17][CH:18]=2)[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=NO)cc2)C1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a DMF (8 mL) solution of tert-butyl 3-fluoro-3-(4-((hydroxyimino)methyl)-phenyl)azetidine-1-carboxylate (Preparation 7, 486 mg, 1.65 mmol) was added NCS (232 mg, 1.65 mmol) in two portions over 10 minutes. The reaction was stirred at room temperature overnight. The reaction was diluted with EtOAc (8 mL) and 1,2,3-trichloro-5-(1,1,1-trifluoroprop-2-en-2-yl)benzene (546 mg, 1.98 mmol) was added, followed by potassium bicarbonate (248 mg, 2.48 mmol). The reaction was stirred at room temperature for 3 days. The reaction was concentrated under vacuum. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were dried and condensed. The crude material was adsorbed on silica and chromatographed on a 40 g silica column eluting with a gradient of 0%-40% EtOAc/hexanes over 20 minutes. Fractions containing the desired material were combined and concentrated to yield 526 mg of a white solid. 1H NMR (CDCl3) δ 7.74 (d, 2H), 7.67 (s, 2H), 7.56 (d, 2H), 4.39-4.51 (m, 2H), 4.24 (m 2H), 4.12 (d, 1H), 3.72 (d, 1H), 1.5 (s, 9H).