Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH2:37][CH:38]([CH3:40])[CH3:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: CC(C)CBr
Product: COc1ccc(CC2c3c(OC)ccc(OCC(C)C)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 1-bromo-2-methyl-propane
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:24]2[CH2:28][NH:27][C:26](=[O:29])[CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].[CH2:30](O)[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:30]([O:15][C:16]1[CH:17]=[C:18]([CH:24]2[CH2:28][NH:27][C:26](=[O:29])[CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:31]=[CH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCC=Cc1ccccc1
Reactant: COc1ccc(C2CNC(=O)C2)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C2CNC(=O)C2)cc1OCC=Cc1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
Diisopropylazodicarboxylate (61 mg, 0.6 mmol) was added to a solution of 4-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidone (63 mg, 0.3 mmol), cinnamyl alcohol (43 mg, 0.3 mmol) and triphenyl phosphine (157 mg, 0.6 mmol) in 3 mL of tetrahydrofuran and the reaction mixture was stirred at 70° C. After 12 hours, the same work-up procedure as described in Example 1 gave 70 mg (70%) of 4-(3-cinnamyloxy-4-methoxyphenyl)-2-pyrrolidone: 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J=6.8 Hz, 2H), 7.31 (t, J=6.8 Hz, 2H), 7.25 (d, J=7.2 Hz, 1H), 6.86-6.81 (m, 2H), 6.71 (d, J=15.6 Hz, 1H), 6.42 (m, 1H), 5.92 (b, 1H), 4.76 (dd, J=6.0, 1.2 Hz, 2H), 3.87 (s, 3H), 3.71 (t, J=8.8 Hz, 1H), 3.64-3.56 (m, 1H), 3.35 (t, J=8.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][C:27]([NH:29][CH:30]([CH:44]([CH3:46])[CH3:45])[CH:31]([O:36][Si](C(C)(C)C)(C)C)[C:32]([F:35])([F:34])[F:33])=[O:28])[C:10](=[O:25])[C:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[O:16])=[CH:12][N:13]=2)=[CH:4][CH:3]=1.CO>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][C:27]([NH:29][CH:30]([CH:44]([CH3:46])[CH3:45])[CH:31]([OH:36])[C:32]([F:34])([F:35])[F:33])=[O:28])[C:10](=[O:25])[C:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[O:16])=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccncc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccncc2)c1=O)C(O)C(F)(F)F

Procedure:
2-[2-(4-Fluorophenyl)-6-oxo-5-(4-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide was subjected to a procedure similar to that described in Example 2.d. Chromatography with methanol:dichloromethane (gradient, 5:95, 7:93) as the eluent, gave 2-[2-(4-fluorophenyl)-6-oxo-5-(4-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide as a white solid; MS: m/z=552(M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][C:10]=2I)[CH:7]=1.C([Mg]Cl)(C)C.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][C:10]=2[Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=1
Reactant: Fc1ccc2c(I)ncn2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncn2cc(F)ccc12
Temperature: 25 °C

Procedure:
To a −16° C. solution of 6-fluoro-1-iodoimidazo[1,5-a]pyridine (158 mg, 603 μmol) in THF (4.64 mL) was added isopropylmagnesium chloride (368 μL, 736 μmol) dropwise. After 20 min tributylchlorostannane (232 mg, 193 μL, 712 μmol) was added dropwise at −16° C. and allowed to warm to room temperature. After 2 h the reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The phases were separated and the organic phase washed with brine. The organic layer was collected, concentrated in vacuo, and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([CH:38]=O)[N:37]=[C:30]2[N:29]=1.N(C)C.Cl>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[C:17]([CH2:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)=[C:16]([OH:21])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: CNC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(OC(C)C)c(Cl)c4)(C4CCCC4)OC3=O)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (0.3 g, 0.79 mmol) and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.17 g, 0.95 mmol, described in Step 3 of example B(75)) were dissolved in 3:1 MeOH/CH2Cl2 (4 mL). To this suspension, Me2NH.BH3 (0.07 g, 1.19 mmol) was added as a solid from top. After stirring 1 h at room temperature, the reaction mixture became clear and it was stirred for an additional 5 hours. After this time, 1 M HCl (1 mL) was added and the reaction stirred for 30 minutes at room temperature, the solvent was the evaporated to half the volumen and extracted 3 times with 10% MeOH/CH2Cl2 (10 mL). The organic phase was dried over MgSO4 and evaporated. The residue purified by flash column chromatography (80% EtOAc in hexanes) to eliminate unreacted pyrone and reduced 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde, then 3% MeOH/CH2Cl2 to give the product (0.1 g, 24%) as a white solid. 1H NMR (DMSO-d6): δ 1.14 (d, J=6.3, 6H), 1.4-1.53 (m, 8H), 1.7-1.75 (m, 2H), 1.95-1.98 (m, 1H), 2.35-2.44 (m, 8H), 3.19 (s, 2H), 3.57 (d, J=16 Hz, 1H), 3.69 (d, J=16 Hz, 1H), 4.41-4.47 (m, 1H), 6.91-6.93 (s, 1H), 7-7.07 (m, 2H), 7.10 (d, J=2.0, 1H), 10.7 (brs, 1H). Anal. Calcd. For C29H35N4O4: C, 64.61; H, 6.54; N, 10.39. Found: C, 64.30; H, 6.81; N, 10.35. ESIMS (MH+): 540
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccccc1O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1Oc1ncccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 90.9 %

Procedure:
A solution of 2-chloro-3-nitropyridine (21.05 g, 132.7 mmol) in DMF (100 mL) was treated with 2-tert-butylphenol (23.5 mL, 152.6 mmol) and cesium carbonate (129.8 g, 398.3 mmol). The mixture was heated at 80° C. for 30 h. The reaction was cooled to rt, and the mixture was poured in water (1 L) with stirring. The yellow precipitate formed was filtered and washed with water, and recrystallized from ethanol to afford 1a as beige crystals (32.83 g, 90%). 1H NMR (400 MHz, CD3OD) δ ppm 1.34 (s, 9H), 6.93 (m, 1H), 7.22 (m, 3H), 7.47 (m, 1H), 8.31 (dd, J=4.82, 1.75 Hz, 1H), 8.46 (dd, J=7.89, 1.75 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1.[CH2:33](Br)[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35].C(=O)([O-])[O-].[K+].[K+]>>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:21][CH:9]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:33][C:34](=[O:35])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to the procedure described in Example 14, by alkylating tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with phenacyl bromide in the presence of potassium carbonate there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(2-oxo-2-phenyl-ethoxy)-phenyl]-piperidine-1-carboxylate as a yellowish solid; MS: 551 (M)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1COCC1.[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[C:33]([F:40])[CH:32]=1.Cl.[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47]>CCOC(C)=O.Cl>[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:47][CH2:46][CH2:45][C:44]([O:43][CH3:42])=[O:48])=[O:37])=[C:33]([F:40])[CH:32]=1
Reactant: COC(=O)CCN
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCNC(=O)c1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
Solid HATU (1.6 g, 4.2 mmol) was added to a THF solution (7 mL) of 4-bromo-2-fluorobenzoic acid (750 mg, 3.2 mmol), i-Pr2Net (1.1 mL, 6.4 mmol), and β-alanine methyl ester hydrochloride (584 mg, 4.2 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was diluted with EtOAc and 1N aqueous HCl. The organic layer was separated, washed with brine, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:6][CH2:5]1)[CH3:3]>CCO>[CH3:3][CH:2]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:8][CH2:9]1)[CH3:1]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1[N+](=O)[O-]
Solvent: CCO
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 101 %

Procedure:
In a pressure vessel was placed a solution of 1-(1-methylethyl)-4-[3-(methyloxy)-4-nitrophenyl]piperazine (4.0 g, 14.3 mmol) in EtOH (100 mL). The solution was purged with N2 for 15 min before the addition of 10% Pd/carbon (0.5 g). The reaction was stirred at rt for 5 h under 60 psi H2. After releasing H2 pressure, filtration removed the solid resin, and the filtrate was concentrated and purified with silica gel chromatography to furnish the title compound of step B (3.6 g, 99% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.09 (d, J=6.6 Hz, 6H), 2.66-2.75 (m, 5H), 3.05-3.10 (m, 4H), 3.47 (s, 3H), 3.83 (s, 2H), 6.42 (dd, J=8.2, 2.4 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:11][C:12]1[N:13]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:14]=[CH:15][N:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 88.8 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (10 g, 70.9 mmol), 2-methyl-1H-imidazole (5.8 g, 70.9 mmol), and Cs2CO3 (34.7 g, 106.4 mmol) in degassed DMF (200 mL) was heated at 100° C. under nitrogen overnight. When TLC indicated that 1-fluoro-4-nitrobenzene was consumed, the reaction mixture was concentrated in vacuo. The residue was diluted with water (300 mL), and a grey precipitate was formed and was isolated to give 2-methyl-1-(4-nitrophenyl)-1H-imidazole (12.8 g, yield 89%).
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C[Si]([N:18]=[C:19]=[O:20])(C)C.CO>C(#N)C>[S:1]([C:5]1[S:13][C:8]2[CH2:9][N:10]([C:19](=[O:20])[NH2:18])[CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: C[Si](C)(C)N=C=O
Reactant: NS(=O)(=O)c1cc2c(s1)CNCC2
Solvent: CC#N
Solvent: CO
Product: NC(=O)N1CCc2cc(S(N)(=O)=O)sc2C1
Reaction time: 19 h
Yield: 95 %

Procedure:
To a warm (40° C.) solution of 2-sulfamoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (1.42 g, 6.5 mmol) in acetonitrile (80 ml), under a nitrogen atmosphere, was added trimethylsilyl isocyanate (1.0 ml, 7.4 mmol). This solution was stirred for 19 hours and then methanol (2 ml) was added. After 2 hours the precipitated pure product was collected by filtration (1.62 g, 95% yield); m.p. 205°-208° C.
Reaction SMILES: [C:1]([N:5]1[C@H:9]([CH2:10]O)[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])(=[O:4])[CH2:2][CH3:3].C(N(CC)C(F)(F)C(F)C(F)(F)[F:30])C>C(Cl)Cl>[C:1]([N:5]1[C@H:9]([CH2:10][F:30])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])(=[O:4])[CH2:2][CH3:3]
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Reactant: CCC(=O)N1[C@H](CO)[C@@H](c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Solvent: ClCCl
Product: CCC(=O)N1[C@H](CF)[C@@H](c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Temperature: 22.5 °C

Procedure:
(4R,5R)-3-propionyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound V: R1 is methylsulfonyl, R2 and R3 are methyl and R4 is ethyl) (70 g, 0.2050 moles) in methylene chloride (450 ml) reacts with N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) (73.2 g, 0.328 moles) at 95-105° C. for 2-4 hours. Cooling to 20-25° C., quenching with 25% aqueous sodium hydroxide and water (2000 mL) and separation of the methylene chloride layer gives a solution of (4S,5R)-3-propionyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound IX: R1 is methylsulfonyl, R2 and R3 are methyl and R4 is ethyl) for use in the next step.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH3:23])[C:6]([O:8][N:9]=[C:10]([NH2:22])[C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([F:21])[CH:12]=1)=O)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[C:1]([O:4][C@H:5]([C:6]1[O:8][N:9]=[C:10]([C:11]2[CH:12]=[C:13]([F:21])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[N:22]=1)[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)C(=O)ON=C(N)c1cc(F)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H](C)c1nc(-c2cc(F)cc(C(F)(F)F)c2)no1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-2-[3-fluoro-5-(trifluoromethyl)phenyl]-1-azavinyl (2S)-2-acetyloxypropanoate (5.19 g, 15.43 mmol) in anhydrous tetrahydrofuran (20 ml) at 0° C. was added a solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (3 ml) dropwise under nitrogen. The reaction mixture was stirred for 3 hours at 0° C., then poured into ethyl acetate (50 ml), washed with water (2×20 ml), brine (30 ml) and dried over sodium sulfate. Solvent was removed under reduced pressure, and the residue purified by flash chromatography, eluting with methylene chloride, to provide (1S)-1-{3-[5-fluoro-3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-yl)}ethyl acetate, LCMS 319.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:21]O)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1>[Pd].C(O)C>[NH2:21][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1)[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=1)[OH:10]
Reactant: O=C(C(=NO)c1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: NC(c1ccnc(F)c1)C(O)c1cccc(C(F)(F)F)c1
Reaction time: 10 h
Yield: 91.3 %

Procedure:
10% Palladium on carbon (3.0 g) was added to a solution of 1-(2-fluoropyridin4yl)-2-(3-trifluoromethylphenyl)-ethane-1,2-dione 1-oxime (8.0 g, 27 mmol) in ethanol (400 mL) at ambient temperature. The reaction vessel was vacuum purged, refilled with hydrogen and vigorously stirred for 10 hrs. After the reaction was complete, the solution was filtered through a pad of celite, and concentrated to give a solid. The residue was purified by recrystallization from methylene chloride and hexane to give 7.4 g of the title compound. m.p. 128-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([C:7]1[CH:12]=[C:11]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH:22][C:23](=O)[CH3:24])=O.[NH3:29].CC(O)C>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([C:11]2[CH:12]=[C:7]3[C:8](=[CH:9][CH:10]=2)[N:22]=[C:23]([CH3:24])[N:29]=[C:5]3[C:4]2[CH:26]=[CH:27][CH:28]=[C:2]([Cl:1])[CH:3]=2)=[O:21])=[CH:15][CH:16]=1
Reactant: N
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1C(=O)c1cccc(Cl)c1
Solvent: CC(C)O
Product: Cc1nc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Temperature: 0 °C
Yield: 36 %

Procedure:
A mixture of N-[2-(3-chlorobenzoyl)-4-(4-chlorobenzoyl)phenyl]acetamide (0.008 mol), described in International Patent Specification WO97/16443, in NH3/iPrOH (4.5M) (17 ml) was stirred at 160° C. for 6 hours in a small bomb, cooled, poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 80/20; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (1.2 g) was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 1.13 g (36%) of (4-chlorophenyl)[4-(3-chlorophenyl)-2-methyl-6-quinazolinyl]-methanone, mp. 182° C. (intermediate 4).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-:3])=[O:2].[CH3:12][CH:13]([S-:15])[CH3:14].[Na+]>C(#N)C>[CH:13]([S:15][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:14])[CH3:12]
Reactant: CC(C)[S-]
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)SCc1ccccc1[N+](=O)[O-]
Temperature: 35 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
In a 250 ml three-necked flask equipped with a stirrer, dropping funnel and thermometer, 17.2 g (0.1 mol) 2-nitrobenzylchloride in 20 ml acetonitrile are added dropwise to 10.3 g (0.105 mol) sodium 2-propanethiolate in 75 ml acetonitrile, with cooling to maintain the temperature at 30-40° C. The suspension is stirred for another 16 hours at 40-50° C. To complete the reaction, another 6 g sodium 2-propanethiolate (0.061 mol) are added and stirring is continued another 24 hours at 40-50° C. The reaction is cooled and the solvent removed under vacuum. The residue is dissolved in methyl tert-butyl ether, washed and dried over sodium sulfate. The sodium sulfate is removed by filtration, and the solution is concentrated under vacuum. The crude product is purified by column chromatography (silica gel, 50:1 cyclohexane/ethyl acetate). 11.8 g (92% purity by HPLC, 51.2% theoretical yield) of 1-[1-(isopropylthio)methyl]-2-nitrobenzene are obtained as a brown oil [logP (pH 2.3)=3.28].
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[NH2:6].[OH-].[Na+].[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>C1(C)C=CC=CC=1>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([NH:6][C:27](=[O:28])[N:26]([CH3:30])[CH3:25])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 45.4 %

Procedure:
3-Trifluoromethyl-4-(2-naphthyloxy)aniline (9.1 g) was dissolved in 200 ml of toluene, and 30 ml of 40% aqueous sodium hydroxide solution and 6.5 g of N,N-dimethylcarbamyl chloride were added thereto. The reaction mixture was heated under reflux for 10 hours and then cooled to room temperature. The toluene layer was washed with water, the solvent was removed by distillation under reduced pressure and the residue was rerecrystallized from ethanol to obtain 5.1 g of N'-[3-trifluoromethyl-4-(2-naphthyloxy)phenyl]-N,N-dimethylurea as white needles. M.P. 210°-211° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:19])[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.C([O-])(=O)C.[Na+].[H][H]>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][C:4]1[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]2=[CH:2][N:3]=1
Reactant: Cc1nc(Cl)c2c(c1-c1ccccc1)CCOC2=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ncc2c(c1-c1ccccc1)CCOC2=O
Yield: 96.4 %

Procedure:
8-chloro-6-methyl-5-phenyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (120 mg, 0.438 mmol), palladium acetate (5.0 mg, 0.022 mmol) and sodium acetate (72 mg, 0.877 mmol) were suspended in 5 mL of anhydrous methanol and then stirred at room temperature for about 2 hours under the hydrogen atmosphere. The mixture was filtered and then concentrated under reduced pressure, added with 15 mL of a saturated solution of sodium hydrogen carbonate and then extracted twice with 20 mL of methylene chloride. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated. A silica gel column chromatography (2% MeOH/MC) was performed on the resulting residue and 101 mg (96%) of 6-methyl-5-phenyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([N:12]2[CH:11]=[CH:10][N:9]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Brc1ccccc1-c1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccnc2-c2ccccc2Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.50 g (11.6 mmol ) of 2-(2-bromophenyl)imidazole in 10 mL of methylene chloride was treated with 1.9 mL of triethylamine (13.8 mmol), 2.64 g (13.8 mmol) of p-toluenesulfonyl chloride and 100 mg of 4-dimethylaminopyridine. The reaction mixture was stirred at room temperature for 15 minutes then transferred to a separatory funnel and washed with water, 5% aqueous citric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The crude product was chromatographed on silica, eluting with hexane/ethyl acetate (1:1), to give 4.16 g (11.0 mmol 95%) of the product which was recrystallized from hexane. FAB-MS: calculated for C16H13BrN2O2S 376,378; found 377,379 (M+H, 50%). 1H NMR (200 MHz, CDCl3): 2.32 (s, 3H), 7.09 (d, 2 Hz, 1H), 7.12 (d, 8 Hz, 2H), 7.28 (m, 5H), 7.46 (m, 1H), 7.57 (d, 2 Hz, 1H).