Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[C:1]([O:10][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCCC(=O)O
Reactant: C=CCCCCCCCCO
Product: C=CCCCCCCCCOC(=O)CCCCCC=C

Procedure:
Following the aforementioned procedure, diene was prepared from oct-7-enoic acid and dec-9-en-1-ol. The resulting yellow oil was purified by silica gel chromatography (50:1 hexanes: diethyl ether) to afford the desired product as a colorless oil. IR (neat): 3077 (m), 2926 (s), 2855 (s), 1736 (s), 1641 (m), 1462 (m), 1417 (m), 1351 (m), 1255 (s), 1168 (s), 1113 (m), 1076 (m), 993 (s), 909 (s), 734 (m), 632 (m); 1H NMR (400 MHz, CDCl3): δ 5.86-5.75 (2H, m), 5.02-4.91 (4H, m), 4.05 (2H, t, J=6.8 Hz), 2.29 (2H, t, J=7.6 Hz), 2.08-2.01 (4H, m), 1.67-1.59 (4H, m), 1.42-1.27 (14H, m); 13C NMR (100 MHz, CDCl3): δ 174.0, 139.2, 138.9, 114.5, 114.3, 64.5, 34.4, 33.9, 33.7, 29.5, 29.3, 29.1, 29.0, 28.8, 28.7, 28.6, 26.0, 25.0; HRMS (ESI+) [M+H]+ calcd for C18H33O2: 281.2481. found: 281.2475.
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@@:6]([OH:24])([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:5](=[O:25])[CH2:4]2)[CH3:2].[CH3:26][Li].[I-].[Li+]>O1CCCC1>[CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([OH:24])[C@:5]([CH3:26])([OH:25])[CH2:4]2)[CH3:2]
Reactant: CC[C@@]12CC(=O)[C@](O)(c3cccnc3)C[C@H]1CCc1cc(O)ccc12
Reactant: [Li]C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3cccnc3)C[C@H]1CCc1cc(O)ccc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 6.3 %

Procedure:
A solution of (2R,4aR,10aR)-4a-Ethyl-2,7-dihydroxy-2-pyridin-3-yl-1,4,4a,9,10,10a-hexahydro-2H-phenanthren-3-one (30 mg, 0.09 mmol) in tetrahydrofuran (8 mL) was cooled to 0° C. A 1.0 M solution of methyllithium/lithium iodide complex in tetrahydrofuran (0.43 mL, 0.43 mmol) was added and the mixture was allowed to stir from 0° C. to room temperature over 5 hours. The solution was cooled to 0° C. and additional 1.0 M methyllithium/lithium iodide solution (0.2 mL, 0.2 mmol) was added. After the mixture was allowed to stir overnight at room temperature, it was again cooled to 0° C. and more methyllithium/lithium iodide solution (0.3 mL, 0.3 mmol) was added. After stirring the mixture for a further 4 hours at room temperature, it was quenched with water and saturated aqueous ammonium chloride solution. The mixture was extracted six times with ethyl acetate, and the combined extracts were washed with brine, dried over magnesium sulfate and concentrated. The title compound (2 mg, 6%) was isolated by chromatography on silica gel eluting with a gradient of 2% to 10% methanol in chloroform. Mass spectrum (m/e) 354 (M++1).
Reaction SMILES: [CH3:1][C:2]([C@H:18]1[C:21](=[O:22])[NH:20][C@@H:19]1[CH2:23]C(O)=O)([O:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])[CH3:3].[C:27]([OH:33])(=[O:32])[CH2:28][C:29]([OH:31])=O>O1CCCC1>[CH3:1][C:2]([C@H:18]1[C:21](=[O:22])[NH:20][C@@H:19]1[CH2:23][C:29](=[O:31])[CH2:28][C:27]([O:33][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:32])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)=[O:6])[CH3:3]
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 153.4 %

Procedure:
To a solution of [(2R,3S)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-acetic acid (56.4 mg) in tetrahydrofuran (1.13 ml) was added N,N'-carbonyldiimidazole (27.5 mg) at ambient temperature. After stirring for 6 hours at ambient temperature, the magnesium salt of the mono-p-nitrobenzyl ester of malonic acid (84.8 mg) was added and the resulting mixture was stirred overnight at ambient temperature. The solvent was distilled off and the residue was dissolved in ethyl acetate (30 ml) and filtered with a diatomaceous earth. The filtrate was washed with 1N hydrochloric acid, water, phosphate buffer solution (pH 6.8), and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residual oil (78.8 mg) was chromatographed on silica gel (1.6 g) eluting with a mixture of methylene chloride and ethyl acetate (10:1 to 2:1) to give 4-nitrobenzyl 4-[(2R,3S)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate (64.2 mg) as an amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])(=[O:12])=[O:11])([O-:3])=[O:2].CO.[OH-].[Na+].Cl>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: COC(=O)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: O=C(O)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of methyl 3-(2-nitrobenzenesulfonylamino)-propionate (6.15 g) in ethanol (20 mL)-methanol (5 mL) was added 5 mol/L aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid (55 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with n-hexane and ethyl acetate. The precipitated crystals were collected by filtration, washed with n-hexane and dried under reduced pressure to give 3-(2-nitrobenzenesulfonylamino)propionic acid (5.83 g). To a solution of the obtained 3-(2-nitrobenzenesulfonylamino)propionic acid (0.5 g) in tetrahydrofuran (5 mL) was added 1,1′-carbonylbis-1H-imidazole (0.35 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1-methylpiperazine (0.46 g), and the mixture was stirred at 50° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: dichloromethane/methanol=40/1) to give the title compound (0.61 g).
Reaction SMILES: [C:1]([N:4]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]([CH2:25][CH:26]4[CH2:28][CH2:27]4)[N:23]=[N:24][C:20]=3[C:19]=2[C:31]([F:34])([F:33])[F:32])=[CH:14][CH:13]=1)[CH2:5][C:6]([O:8]CC)=O)(=[O:3])[NH2:2]>ClCCl.O>[CH:26]1([CH2:25][N:22]2[C:21]3[CH:29]=[CH:30][C:18]([C:15]4[CH:16]=[CH:17][C:12]([CH2:11][N:4]5[CH2:5][C:6](=[O:8])[NH:2][C:1]5=[O:3])=[CH:13][CH:14]=4)=[C:19]([C:31]([F:32])([F:33])[F:34])[C:20]=3[N:24]=[N:23]2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)CN(Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1)C(N)=O
Solvent: ClCCl
Solvent: O
Product: O=C1CN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3C(F)(F)F)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl N-carbamoyl-N-{4-[1-(cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]benzyl}glycinate was dissolved in a dichloromethane/1 N hydrochloric acid solution and the reaction mixture placed into an oil-bath preheated to 100° C. The mixture was stirred for 1.5 hours, cooled to ambient temperature, diluted with water and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to afford the titled compound as a white solid. H1-NMR (400 MHz, CDCl3): δ 8.87 (1H, s), 7.70 (1H, d, J=8.6 Hz), 7.35 (1H, d, J=8.6 Hz), 7.30 (2H, d, J=8.3 Hz), 7.26 (2H, d, J=8.3 Hz), 4.55 (2H, s), 4.53 (2H, d, J=7.2 Hz), 3.80 (2H, s), 1.60-1.49 (1H, m), 0.69-0.57 (2H, m), 0.52-0.41 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 430.1509 [(M+H)+; calculated for C21H19F3N5O2: 430.1485].
Reaction SMILES: [CH2:1]([N:5]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:6]([CH3:19])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[H][H]>C(O)C.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][CH:6]([CH3:19])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CCCCCCCN(CCCC)C(C)CCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCN(CCCC)C(C)CCCc1ccc(N)cc1
Yield: 90.6 %

Procedure:
A solution of 16.2 g (0.045 mol) of N-butyl-N-heptyl-α-methyl-4-nitrobenzenebutanamine in 182 ml of ethanol was hydrogenated at room temperature overnight in the presence of 1.6 g of 5% palladium-on-carbon. hydrogen uptake observed was 74% of theoretical. The reaction mixture was filtered through Celite and the filtrate was evaporated under reduced pressure. The resulting material indicated the presence of one spot by thin-layer chromatography and afforded 13.56 g of 4-amino-N-butyl-N-heptyl-α-methylbenzenebutanamine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].OS(O)(=O)=O.[CH3:24][CH2:25]O>>[CH2:24]([O:13][C:12](=[O:14])[CH:11]([C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:25]
Reactant: CCO
Reactant: CC(C)CC(C(=O)O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(CC(C)C)c1ccc([N+](=O)[O-])c(F)c1
Yield: 97 %

Procedure:
2-(3-Fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid (29.0 g, 0.12 mmol) was dissolved in EtOH (100 mL) and H2SO4 (96%, 5 mL) was added. The reaction mixture was refluxed for 3 h and the solvent evaporated. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases were washed with saturated NaHCO3 solution (50 mL), water (100 mL) and brine (100 mL), and then dried over MgSO4. Evaporation of the solvent under reduced pressure gave a brown oil (31.0 g, 97%), which was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03 (t, J=8.4 Hz, 1H), 7.33-7.26 (m, 2H), 4.17-4.11 (m, 2H), 3.73 (t, J=7.6 Hz, 1H), 2.10-1.94 (m, 1H), 1.71-1.62 (m, 1H), 1.51-1.42 (m, 1H), 1.25 (t, J=7.0 Hz, 3H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 172.2, 155.3 (d, 1JCF=265.0 Hz), 148.3 (d, 3JCF=8.4 Hz), 136.5, 126.1, 124.1 (d, 3JCF=3.6 Hz), 117.8 (d, 2JCF=21.6 Hz), 61.3, 49.4, 42.3, 25.9, 22.5, 22.1, 14.1.
Reaction SMILES: S(O[CH2:12][C:13]1[N:17]([C:18]2[S:19][C:20]([CH2:32][CH3:33])=[CH:21][C:22]=2[C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:16]([CH3:34])=[N:15][N:14]=1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44]>C(O)C>[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:12][C:13]2[N:17]([C:18]3[S:19][C:20]([CH2:32][CH3:33])=[CH:21][C:22]=3[C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:16]([CH3:34])=[N:15][N:14]=2)[CH2:38][CH2:37]1
Reactant: CN1CCNCC1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2COS(=O)(=O)c2ccc(C)cc2)s1
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN2CCN(C)CC2)s1
Yield: 49.8 %

Procedure:
To a suspension of 7 g of 3-tosyloxymethyl-4-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole in 100 ml of ethanol is added 2 g of N-methyl-piperazine, and the mixture is refluxed for 5 hours. Aftr the completion of the reaction, the solvent is distilled off and water is added to the residue. The residue is made alkaline with potassium carbonate and extracted with ethyl acetate. The extract is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue obtained is allowed to react with 2.2 g of oxalic acid in ethanol. The crude crystals formed are recrystallized from aqueous ethanol to give 3.8 g of 3-(4-methyl-1-piperazinylmethyl)-4-(3-o-chlorobenzoyl-5-ethyl-2-thienyl)-5-methyl-4H-1,2,4-triazole dioxalate 1/2 hydrate as colorless crystals melting at 164° - 165°C (decomposition).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[C:8]([NH2:12])[CH:7]=[CH:6][CH:5]=2.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=[C:22]=[O:23])=[CH:16][CH:15]=1.CCCCCC>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([NH:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([CH3:11])=[C:2]([CH3:1])[NH:3]3)=[O:23])=[CH:18][CH:19]=1
Reactant: Cc1[nH]c2cccc(N)c2c1C
Reactant: O=C=NCc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1[nH]c2cccc(NC(=O)NCc3ccc(Br)cc3)c2c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,3-Dimethyl-4-aminoindole (0.11 g, 0.7 mmol) in THF (3 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.17 g, 0.8 mmol) at ambient temperature. After stirring for 3 hours at ambient temperature, hexane was added to the reaction mixture to precipitate the title compound as a tan solid (0.12 g). mp 190° C. 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 2.25 (s, 3H), 4.25 (d, 2H), 6.51 (t, 1H), 6.82 (t, 1H), 6.85 (d, 2H), 6.95 (m, 2H), 7.25 (d, 2H), 7.53 (d, 2H), 7.78 (s, 1H), 11.04 (s, 1H); MS (DCI+) m/z 346 (M+H)+; Anal. Calcd. for C18H18N3BrO: C, 58.08; H, 4.87; N, 11.29. Found: C, 57.97, H, 4.92; N, 11.30.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-])=O.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>C1COCC1.O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: CCOP(OCC)OCC
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1cccc(N)c1)OCC

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with diethyl 3-aminobenzylphosphonate to generate the title compound. The diethyl 3-aminobenzylphosphonate was prepared by sequential treatment of commercial 3-nitrobenzyl bromide with triethyl phosphite at 125° C. for 6 hours followed by reduction with Na2S2 O4 in THF/H2O at 100° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].P(Br)(Br)[Br:12].O>C(Cl)(Cl)Cl>[Br:12][CH2:8][C:7]1[C:2]([Cl:1])=[C:3]([OH:10])[CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cccc(O)c1Cl
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Oc1cccc(CBr)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 2-chloro-3-(hydroxymethyl)phenol (400 mg, 2.5 mmol) in anhydrous chloroform (8 mL) was added dropwise a solution of phosphorus tribromide (240 μL, 2.5 mmol) in anhydrous chloroform (2 mL) at 0° C. The mixture was stirred for 2 hours at room temperature. Water was added and extracted 3 times with dichloromethane. The combined organic phase was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, 3-(bromomethyl)-2-chlorophenol was obtained (373 mg, 67% yield) and used for next step without further purification; 1H NMR (400 MHz, DMSO-d6): δ 4.70 (s, 2H), 6.94-6.97 (m, 1H), 7.02-7.04 (m, 1H), 7.13 (t, J=7.8 Hz, 1H), 10.32 (bs, 1H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][N:12]=[C:11]([CH2:14]O)[CH2:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:20][CH2:14][C:11]1[CH2:10][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[O:13][N:12]=1
Reactant: OCC1=NOC(c2ccc(C(F)(F)F)cc2)C1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C2CC(CCl)=NO2)cc1
Reaction time: 15 h
Yield: 21.2 %

Procedure:
To a stirred mixture of (5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazol-3-yl)methanol (245 mg, 1.0 mmol) in methylene chloride (15 mL) was added thionyl chloride (200 μL, 2.74 mmol) dropwise at 0° C. The resulting mixture was stirred under an atmosphere of nitrogen for 15 hours, concentrated under reduced pressure, and purified by preparative chromatography (3:7 EtOAc:hexane) to yield 3-(chloromethyl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole (56 mg, M+1=264.1).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:29]1([P:35](Cl)(Cl)=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCCC.C1CCCCC1>[C:29]1([P:35]2(=[O:36])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: O=P1(c2ccccc2)c2ccccc2CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (8.0 g, 0.125 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature at 0° C., a solution of dibenzylamine (11.8 g, 0.06 mol) in 30 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2 hours at 26° C. and then cooled to -76° C. using a solid carbon dioxide-acetone bath. A solution of phenylphosphonic dichloride (12.5 g, 0.064 mol) in 30 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to 0° C. The reaction mixture was allowed to cool to -76° C., after which time the reaction mixture was stirred for 0.25 hours. The solid carbon dioxide-acetone bath was then removed and the reaction mixture was stirred for an additional 2 hours at 26° C. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 12 ml. of acetic acid. The cyclohexane was removed on a rotary evaporator, and the resulting residue partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was dried and concentrated in vacuo to yield an orange glass. The orange glass was distilled at 220° C. and 0.25 torr and the resulting solid residue was chromatographically separated on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was crystallized from diethyl ether and petroleum ether to yield 1-phenyl-2-(phenylmethyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (6.15 g, 32% yield) as a white solid having a melting point of 99°-101° C. and the following analysis:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[CH3:6][Si:7](Cl)([CH3:9])[CH3:8]>O1CCCC1>[CH3:6][Si:7]([CH3:9])([CH3:8])[O:4][C:1]([O:5][Si:7]([CH3:9])([CH3:8])[CH3:6])=[CH:2][O:3][Si:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: O=C(O)CO
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C[Si](C)(C)OC=C(O[Si](C)(C)C)O[Si](C)(C)C

Procedure:
The reagent 1,1,2-tris-trimethylsilyloxyethylene (80) and its use for the conversion of acid chlorides to hydroxyketone (for example 96 to 98 and 90 to 92) are claimed in this invention. The reagent preparation is described hereinbelow in Flowsheet M. The reaction of glycolic acid with 1,1,1,3,3,3-hexamethyldisilazane and trimethylsilylchloride in pyridine gives bis-trimethylsilated glycolic acid (113). Addition of (113) to a tetrahydrofuran solution of one equivalent of lithium 1,1,1,3,3,3-hexamethyldisilazane amide at -78° C. generates a lithium enolate which is trapped with trimethylsilylchloride to produce the desired reagent (80). ##STR119##
Reaction SMILES: [CH:1]([N:3]([CH3:5])[NH2:4])=[O:2].[F:6][C:7]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[CH:21][C:8]=1[C:9]([C:11](=[CH:17]OCC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10].O>C(O)C>[F:6][C:7]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[CH:21][C:8]=1[C:9]([C:11](=[CH:17][NH:4][N:3]([CH:1]=[O:2])[CH3:5])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: CN(N)C=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=CNN(C)C=O)C(=O)c1cc(F)c(F)c(F)c1F
Yield: 69 %

Procedure:
3.8 g of 1-formyl-1-methylhydrazine are added dropwise to a solution of 16 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxy-acrylate in 60 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 1 hour, 60 ml of water are added, the mixture is cooled with ice and the precipitate is filtered off with suction and washed with water/ethanol (1:1). 12 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-(2-formyl-2-methylhydrazino)-acrylate of melting point 92° C. are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=23)[N:3]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([NH2:26])[CH3:25])=[N:22][CH:23]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([NH:26][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH:9]=[N:10][N:11]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=34)[N:3]=2)[CH3:25])=[N:22][CH:23]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: Clc1ccnc(-c2cnn3ccncc23)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ccnc(-c2cnn3ccncc23)n1)c1ccc(F)cn1
Yield: 4.4 %

Procedure:
A solution of 3-(4-chloropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 31, 170 mg, 0.61 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine (85 mg, 0.61 mmol, prepared as described in WO2006/82392A1) and diisopropylethylamine (122 μL, 0.70 mmol) in N,N′-dimethylformamide (5 mL) was heated to 150° C. in a microwave oven for 75 min. The solvent was then removed under reduced pressure and the residue was partitioned between 4% aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phase was separated, washed with brine, dried (MgSO4) and concentrated to give a crude which was purified by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 5% to 50%) to give the title compound (9 mg, 4%) as an oil. The corresponding fumarate salt was prepared by adding a solution of fumaric acid (3.1 mg, 0.027 mmol) in ethanol (0.5 mL) to a solution of the title compound (as free base, 9 mg, 0.027 mmol) in ethanol (2 mL) followed by evaporation of the solvent. The resulting solid was dried in an oven under vacuum to give 11 mg of the desired fumarate salt.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C:10](=[O:12])[CH3:11])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:9][C:10](=[O:12])[CH3:11])=[N:4][C:5](=[O:8])[N:6]([C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH:7]=1
Reactant: CC(=O)Nc1nc(=O)[nH]cc1F
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(=O)n(C(=O)c2ccc(C)cc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 2.7 %

Procedure:
To a round-bottomed flask containing N-(5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)acetamide (350 mg, 2.04 mmol) in CH2Cl2 (20 mL) was added 4-methylbenzoyl chloride (316 mg, 2.2 mmol) and Et3N (454 mg, 4.5 mmol) at 0° C. The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with CH2Cl2 (30 mL), washed with saturated aqueous sodium chloride (satd aq NaCl) solution (1×15 mL), dried over Na2SO4 and concentrated in vacuo. The crude solid was purified by reverse phase chromatography to yield N-(5-fluoro-1-(4-methylbenzoyl)-2-oxo-1,2-dihydropyrimidin-4-yl)acetamide as a white solid (16 mg, 3%): mp 146.9-148.2° C.; 1H NMR (acetone-d6) δ 9.75 (s, 1H), 8.64 (d, J=2.5 Hz, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 2.47 (s, 3H), 2.32 (s, 3H).