Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CCOCC>[CH2:30]([O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[CH:2][O:3][CH3:4])=[CH:41][CH:40]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(C=COC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methoxymethyl triphenylphosphonium chloride of 34.28 g was suspended in anhydrous ether of 190 ml, and potassium t-butoxide of 11.22 g was added thereto. A solution prepared by dissolving 4-n-octyloxybenzaldehyde of 22.26 g in anhydrous ether of 110 ml was added thereto, and the solution was stirred at room temperature for 12 hours. Resulting triphenylphosphine oxide was removed by filtration, and the filtrate was poured into ice and water of 300 ml. An ether layer was separated and washed with water, followed by drying the ether layer with anhydrous sodium sulfate. Then, ether was distilled off to obtain crude (4'-n-octyloxyphenyl)-2-methoxyethylene. Further, the crude product was refined by distillation under reduced pressure to obtain (4'-n-octyloxyphenyl)-2-methoxyethylene of 25.4 g. Next, a mixed solution of triethyl orthoformate of 240 g and boron trifluoride ethyl ether complex salt of 6.53 g was cooled down to 0°C., and (4'-n-octyloxyphenyl)-2-methoxyethylene of 25.39 g was added thereto. Then, after stirring the solution at room temperature for 12 hours, toluene of 200 ml and a 10 weight % sodium hydrogencarbonate aqueous solution of 150 ml were added and mixed, and then a toluene layer was separated. The toluene layer was dried with anhydrous sodium sulfate, and then toluene was distilled off to obtain 4-n-octyloxyphenyl malonotetraethyl acetal. This 4-n-octyloxyphenyl malonotetraethyl acetal of 21.2 g was added to water of 12 ml and p-tolenesulfonic acid of 0.05 g, and the reaction was carried out at 80° C. for 3 hours. After cooling the solution down to room temperature, sodium carbonate of 0.52 g was added for neutralization, and then the product was extracted with toluene. The extract was washed with a 10 weight % sodium hydroxide aqueous solution and further washed with water. Then, a toluene layer was separated and dried with anhydrous sodium sulfate, and toluene was distilled off to obtain α-(4-n-octyloxyphenyl)-β-ethoxyacrolein of 16.62 g.
Reaction SMILES: Cl.Cl.[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:10]=[CH:11][C:12]=1[Cl:13].[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:34][C:35](O)=[O:36])[N:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:34][C:35]([N:17]2[CH2:18][CH2:19][N:14]([C:9]3[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([O:6][CH2:5][CH2:4][F:3])[CH:8]=3)[CH2:15][CH2:16]2)=[O:36])[N:26]=1
Reactant: FCCOc1cc(N2CCNCC2)ccc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2ccc(Cl)c(OCCF)c2)CC1
Temperature: 20 °C
Yield: 19.7 %

Procedure:
To a vial containing 1-(3-(2-fluoroethoxy)-4-chlorophenyl)piperazine dihydrochloride (70 mg, 0.21 mmol) was added 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (51 mg, 0.21 mmol), HBTU (83 mg, 0.22 mmol), DMF (0.7 mL), and DIPEA (0.20 mL, 1.2 mmol). The reaction mixture was maintained at 20° C. for 24 h. The solution was diluted with EtOAc (30 mL) and washed with 1N HCl (2×10 mL) and sat. aq. NaCl (2×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resultant residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the indicated compound (20 mg, 20% yield): MS (ES) [M+H]+ expected 484.2. found 484.4; 1H NMR (CDCl3, 400 MHz) d 9.94 (br s, 1H), 8.78 (dd, J=1.2, 8, 1H), 8.55 (dd, J=1.2, 4.6, 1H), 7.16-7.26 (m, 4H), 6.45-6.53 (m, 2H), 5.44 (s, 2H), 4.77 (dt, J=4.0, 46.8, 2H), 4.26 (dt, J=4.0, 26.8, 2H), 3.69-3.78 (m, 4H), 3.10-3.21 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:13])[C:5]([CH:14]=[N:15]O)=[CH:4][CH:3]=1.Cl>CO.[Zn]>[NH2:15][CH2:14][C:5]1[C:6]([F:13])=[C:7]([C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)ccc(C=NO)c1F
Agent: Cl
Agent: [Zn]
Solvent: CO
Product: CCOC(=O)c1c(Cl)ccc(CN)c1F
Temperature: 60 °C
Yield: 79.5 %

Procedure:
To a solution of ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (0.800 g, 3.26 mmol) in MeOH (5 mL) was added Zn (0.850 g, 13.06 mmol), followed by dropwise addition of conc. HCl (catalytic) and the reaction mixture was heated at 60° C. for 2-3 h. Excess of solvent was removed under vacuum and the residue was diluted with water and basified with NaHCO3, extracted with EtOAc and concentrated to afford 0.600 g of the product. 1H NMR (300 MHz, DMSO d6): δ 1.31 (t, J=7.2 Hz, 3H), 3.76 (s, 2H), 4.38 (q, J=6.9 Hz, 2H), 7.41 (d, J=8.1 Hz, 1H), 7.65 (t, J=8.1 Hz, 1H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[C:12]23[C@:28]([CH3:33])([CH2:29][CH2:30][C:31](=[O:32])[CH:11]12)[C@@H:27]1[C@H:15]([C@H:16]2[C@:24]([CH3:34])([CH2:25][CH2:26]1)[C@@H:19]([C@H:20]([CH3:23])[CH2:21][OH:22])[CH2:18][CH2:17]2)[CH2:14][CH2:13]3.[N-:35]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.O>CS(C)=O>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][C:11]1[C:31](=[O:32])[CH2:30][CH2:29][C@@:28]2([CH3:33])[C:12]=1[CH:13]=[CH:14][C@@H:15]1[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:34])[C@H:16]1[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:23])[CH2:21][OH:22]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a vigorously stirred solution of (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one benzoate (1.0 g, 2.22 mmole) in dimethyl sulfoxide (35 mL), heated to 60° C., there was added sodium azide (2.7 g) and the concentrated sulfuric acid (0.2 mL). The mixture was quickly brought to a temperature of 100° C. and held at that temperature for 1 hour. The cooled mixture was then poured onto cold water (250 mL). The resulting mixture was extracted with ether (300 mL) and the ether solution was washed with brine, dried over magnesium sulfate and filtrate and the filtrate was concentrated to give a yellow solid which was purified by chromatography to give (20S)-4-amino-21-hydroxy-20-methylpregna-4,6-dien-3-one benzoate (0.8 g, 80.1%) melting at 163°-167° C. with decomposition. IR 3470, 3366, 1718, 1682 (m), 1656, 1608 (m), 1586 (m), 1567 (m), 1274, 1268, 718 cm-1 ; MS (CI) 448 (100%, M+1), 326 (35%, M+1 - PhCOOH); 1H NMR (CDCl3) δ 0.82 (3H, s, C18 -Me), 1.07 (s, C19 -Me), 1.15 (d, C22 -Me), 3.71 (2H, v br, NH2)4.07 (1H, dd, 1/2 C21 -CH2), 4.35 (1H, dd, 1/2 C21 -CH2), 5.98 (1H dd), 6.30 (1H dd), 7.35 (2H, t), 7.57 (1H, t), 8.04 (2H, dd).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:13](=[O:15])[CH3:14])[CH:8]=[C:9]([I:12])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].CI.[C:18](=O)([O-])[O-].[K+].[K+].Cl>O.C(OCC)(=O)C.CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([C:13](=[O:15])[CH3:14])[CH:8]=[C:9]([I:12])[C:10]=1[O:11][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cc(I)c(O)c(C(C)(C)C)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(I)cc(C(C)=O)cc1C(C)(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
1-(3-tert-Butyl-4-hydroxy-5-iodophenyl)ethanone (616 mg, 1.93 mmol) was added to N,N-dimethylformamide (2.5 mL), and then methyl iodide (684 mg, 4.84 mmol) and potassium carbonate (401 mg, 2.90 mmol) were added, followed by 3 hours of stirring at 60° C. After cooling the mixture to room temperature, ethyl acetate (6 mL), water (3 mL), and 2 N hydrochloric acid (2 mL) were added, and the solution was separated. The organic layer was washed with a mixed solution of water (3 mL) and saturated brine (1 mL), followed by saturated brine (3 mL). The organic layer was dried and concentrated under reduced pressure (50° C.) to obtain 587 mg of the subject compound as a yellow oily substance (yield: 91.3%, HPLC purity: 94.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=O)=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].C1COCC1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[O:18][C:6]([C:5]3[CH:19]=[CH:20][C:2]([NH2:1])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=3)=[N:8][N:9]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(C(=O)NNC(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a 20 mL microwave vial was added 1.00 g (2.99 mmol) of 4-Chloro-benzoic acid N′-(4-amino-3-nitro-benzoyl)-hydrazide (A in Example 1-28), 12 mL of THF, and 1.9934 g (8.36 mmol) of burgess reagent. The suspension was placed in the microwave at 150° C. for 30 min. To the orange/yellow suspension was added 5 mL of MeOH and the precipitates were collected by filtration to yield the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.31 (d, J=8.97 Hz, 1H) 7.80 (d, J=8.59 Hz, 2H) 8.12-8.19 (m, 2.7H) 8.25 (d, J=8.59 Hz, 2H) 8.77 (d, J=2.02 Hz, 1H). MS (m/z) 317.0 M (+1), tR=1.33, Meth 10
Reaction SMILES: C([O:4][CH:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]=[N+:25]=[N-:26])(=O)C.C1(C)C=CC=CC=1.N1C=CN=C1.[Si:39](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]>C1COCC1.CO.C(Cl)Cl.CCOC(C)=O>[C:9]([O:8][C@H:7]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]([O:4][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C@@H:6]1[N:24]=[N+:25]=[N-:26])(=[O:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
1,3,4,6-Tetra-O-acetyl-2-azido-2-deoxy-D-glucopyranose (30.2 g, 80 mmol) was coevaporated twice with toluene and dissolved in THF and methanol (7:3, 300 mL). The solution was cooled to 0° C. and gaseous anhydrous ammonia was bubbled through at a modest rate. After 15 min, nitrogen was bubbled through the solution to remove excess ammonia and the solvent was removed in vacuo to afford a brown oil. The residue was coevaporated twice with toluene and dissolved in CH2Cl2 (150 mL). Imidazole (10.9 g, 160 mmol) and tert-butyldimethylsilyl chloride (13.3 g, 88 mmol) were added. After 2 h, the mixture was diluted with EtOAc, washed with water, 1 N HCl (2×) and water. The organic layer was dried over MgSO4, filtered, and the solvent was removed in vacuo. Crystallization from ethanol afforded 2 (29.8 g, 67 mmol, 84%) as colorless crystals. 1H-NMR (300 MHz, CDCl3) δ 5.00-4.90 (m, 2H), 4.63 (d, J=7.6 Hz, 1H), 4.20 (dd, J=5.9, 12.1 Hz, 1H), 4.09 (dd, J=2.6, 12.1 Hz, 1H), 3.70-3.64 (m, 1H), 3.48-3.40 (m, 1H), 2.10 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 0.95 (s, 9H), 0.15 (s, 6H). The spectral data was in agreement with the reported data. (W. Kinzy, R. R. Schmidt, Liebigs Ann. Chem. 1985, 1537-1545; for the procedure see: B. La Ferla, L. Lay, M. Guerrini, L. Poletti, L. Panza, G. Russo, Tetrahedron 1999, 55, 9867-9880).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:15](=[O:16])[CH2:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(=O)OC(C)(C)C)=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>ClCCl.FC(F)(F)C(O)=O.C(OCC)(=O)C>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH:12]2[CH2:13][CH2:14][C:15](=[O:16])[CH:11]2[C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CCC(=O)C2c2ccc(C(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C2C(=O)CCC2c2ccc(N)cc2)cc1
Yield: 59.7 %

Procedure:
A mixture of Example 7G (1.3 g, 3.19 mmol) in dichloromethane (12 mL) and trifluoroacetic acid (4 mL) was stirred at ambient temperature for 1 hour. The mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 solution (30 mL×3) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=2:1, v/v) to afford the title compound (586 mg, 1.906 mmol, 59.8% yield) as a solid. LC/MS (ESI) m/z 308 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH2:22][CH2:23][CH3:24])=O)[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O1CCCC1>[C:7]1([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][NH:21][CH2:22][CH2:23][CH3:24])[CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCNC(=O)c1cc(-c2ccccc2)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCNCc1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
Lithium aluminum hydride was added to a solution of 4-phenyl-N-propylpyridine-2-carboxamide (350 mg) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 1 hr, followed by stirring with heating at 70° C. for 2 hr. After the mixture was cooled in ice, 10% aqueous sodium hydroxide solution was added, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was dried over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=50:50-0:100) to afford the title compound (107 mg).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[NH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1>>[C:14]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:4](=[O:6])[C@@H:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:17][CH:16]=1)#[N:13]
Reactant: CO[C@H](C(=O)O)c1ccccc1
Reactant: N#Cc1ccc(CN)cc1
Product: CO[C@H](C(=O)NCc1ccc(C#N)cc1)c1ccccc1

Procedure:
(S)-(+)-Methoxyphenylacetic acid was coupled with 4-aminomethyl benzonitrile (CAS No: 10406-25-4) according to general procedure C to give (S)-N-(4-cyano-benzyl)-2-methoxy-2-phenyl-acetamide as an off-white solid. MS 281.2 ([M+H]+)
Reaction SMILES: [C:1]12[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=1)[C:13](=[O:19])[NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3][C:2]2=[O:20].Cl>CO.O.[Pt](=O)=O>[CH:14]12[NH:18][CH:1]([CH2:17][CH2:16][CH2:15]1)[C:2](=[O:20])[NH:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13]2=[O:19]
Reactant: O=C1NCCNCCNCCNC(=O)c2cccc1n2
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1NCCNCCNCCNC(=O)C2CCCC1N2
Temperature: 60 °C
Yield: 73 %

Procedure:
3,6,9,12,18-Pentaazabicyclo[12.3.1]octadeca-1(18),14,16-trien-2,13-dione prepared as in Example 38A (1.0 g, 3.6 mmol) was dissolved in methanol (75 ml) and concentrated hydrochloric acid (2.14 g, 21.7 mmol) was added, then the catalyst platinum dioxide hydrate (0.5 g, 2 mmol). The mixture was heated to 60° C. and hydrogenated at 60 psi for 24 h. A white crystalline solid formed during the hydrogenation. The reaction mixture was filtered, and the precipitate was washed with water to dissolve it. The filtrate was concentrated to remove the alcohol and sodium hydroxide (1.0N) was added to raise the pH to 11. This solution was extracted five times with dichloromethane (75 ml each), the solvent was removed under reduced pressure, and the resulting white solid was dried on the vacuum line to give 0.74 g (73% yield) of product: mp 193°-195.5° C. (dec); 1H NMR (CD2Cl2) δ 0.79-1.48 (several m, 5 H), 1.88 (m, 2 H), 2.01 (m, 2 H), 2.63-2.88 (several m, 8 H), 3.10 (m, 2 H), 3.24 (m, 2 H), 3.36 (m, 2 H), 7.71 (s, 2 H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)C)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+]>CCO>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)c2cccc(OC(F)(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2cccc(OC(F)(F)F)c2)cc1
Temperature: 80 °C

Procedure:
To a solution of N-(4-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)acetamide (104 mg, 0.29 mmol) in EtOH (8 mL) is added NaOH (10 M in water, 0.6 mL, 6 mmol). The mixture is heated at 80° C. for 4 h and the solvent is evaporated. The residue is partitioned between EtOAc (15 mL) and brine (10 mL) and the layers are separated. The aqueous layer is extracted with EtOAc (10 mL) and the combined extracts are dried (Na2SO4) and evaporated. The white solid obtained (86 mg, 93%) is used to the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([O:24][C:25](=[O:29])[CH2:26][CH2:27][NH2:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25](=[O:29])[CH2:26][CH2:27][NH:28][C:11]([CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:14]([NH:28][CH2:27][CH2:26][C:25]([O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:29])=[O:16])=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NCCC(=O)OCc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1

Procedure:
N-(t-butoxycarbonyl)-L-aspartic acid is coupled with two equivalents of β-alanine benzyl ester to give N,N'-[[(S)-(1-t-butoxyformamido)ethylene]dicarbonyl]di-β-alanine dibenzyl ester, m.p. 109°-110° C.
Reaction SMILES: [OH-].C[N+](C)(C)C.[C:7]([OH:11])(=[O:10])[CH2:8][OH:9].Br[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[OH:9][CH2:8][C:7](=[O:11])[O:10][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=C(O)CO
Reactant: COC(=O)C(C)Br
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)C(C)OC(=O)CO
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Tetramethylammonium hydroxide (25% in methanol) was added to a stirring solution of glycolic acid (3.8 g, 50 mmol) in 5 mL dimethylformamide cooled on ice until a pH of 7 was indicated by moistened pH paper. Methyl 2-bromopropionate (6.1 mL, 55 mmol) was added and the reaction was stirred at room temperature for 5 d. The reaction mixture was filtered, the solids were washed with ethyl ether, and the combined filtrate and ether solution was washed with 5% NaCl/5% NaHCO3. Sufficient ethyl ether was added to effect rapid separation of the phases, the aqueous phase was extracted with CH2Cl2, and the organic phases were combined and dried with MgO4. The solvent was removed and the resulting residue was distilled under reduced pressure to give the title compound: b .p. 64° C./0.05 mm Hg; 1H NMR δ1.53 (d, 3H, J=7.2 Hz), δ2.78 (bs, 1H), δ3.77 (s, 3H), δ4.24 (d, 1H, J=17.4 Hz), δ4.31 (d, 1H, J=17.4 Hz), δ5.22 (q, 1H, J=7.1 Hz), HRMS calcd for C6H9O5Tms (M-CH3) 219.0688, obsd 219.0708.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[N:18]([CH3:19])[C:17]2[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]=1)[CH2:11][C:12]#[CH:13]>>[Cl:24][C:20]1[C:17]2[N:18]([CH3:19])[C:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)=[N:15][C:16]=2[CH:23]=[CH:22][CH:21]=1
Reactant: C#CCCc1nc2cccc(Cl)c2n1C
Reactant: FCc1cccc(Br)n1
Product: Cn1c(CCC#Cc2cccc(CF)n2)nc2cccc(Cl)c21

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (30 mg, 0.16 mmol) and 2-(but-3-ynyl)-7-chloro-1-methyl-1H-benzo[d]imidazole (35 mg, 0.16 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 99/1 as eluent) to afford 43 mg of a light brown solid. The resulting solid was triturated into isopropyl ether to give 6 mg of 7-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole (Yield: 10%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12]([NH:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33])[N:13]=1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reactant: NC(CO)CO
Product: O=c1ccc2c(-c3ccccc3Cl)nc(NC(CO)CO)nc2n1-c1ccccc1Cl

Procedure:
The product of Example 47, and serinol were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.44 (m, 1H), 3.68 (m, 4H), 6.30 (br s, 1H), 6.48 (d, 1H, J=9.7 Hz), 7.24-7.65 (m, 9H). LC MS (m/e)=457 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][NH2:8])[CH:3]=1.[C:9]([N:13]1[C:17](=[O:18])[C:16](Cl)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:14]1(=[O:27])=[O:26])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([N:13]1[C:17](=[O:18])[C:16]([NH:8][CH2:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:14]1(=[O:26])=[O:27])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Cc1cc(CN)no1
Product: Cc1cc(CNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)no1
Yield: 56 %

Procedure:
The title compound was prepared as described for Example 24 from 1 equivalent of [(5-methylisoxazol-3-yl)methyl]-amine, 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1 equivalent TEA with a reaction time of 45 mins. The mixture was evaporated and purified by silica gel column chromatography (Horizons Biotage) using 35% EtOAc in pentane as eluent to give the title compound (0.070 g, 56%). 1H NMR (500 MHz CDCl3): δ 7.52-7.48 (m, 2H), 7.46-7.41 (m, 3H), 5.73 (s, 1H), 5.66 (t, 1H), 5.07 (d, 2H), 2.39 (s, 3H), 1.74 (s, 9H); 13C NMR (125 MHz CDCl3): δ 170.7, 159.9, 159.4, 134.8, 131.6, 130.1, 128.9, 124.7, 109.3, 100.4, 61.9, 40.4, 27.8, 12.5; Mass Spectrum: M+H+ 376
Reaction SMILES: [C:1]([O:11][CH2:12][CH:13]=[CH2:14])(=[O:10])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].CCC(OO)=[O:18].C1C=CC=CC=1>>[C:4]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:11][CH2:12][CH:13]1[O:18][CH2:14]1)=[O:10]
Reactant: CCC(=O)OO
Reactant: C=CCOC(=O)/C=C/C(=O)OCC=C
Solvent: c1ccccc1
Product: C=CCOC(=O)/C=C/C(=O)OCC1CO1

Procedure:
9.8 kg (50 mol) of diallyl fumarate were reacted with 26.18 kg of a 22% strength solution of perpropionic acid in benzene (64 mol) at 60° C. in a manner analogous to that described in Example 1. After a reaction time of 6.8 hours, a percarboxylic acid conversion of 96.8% resulted. The conversion of diallyl fumarate was 90%. Allyl glycidyl fumarate was formed with a selectivity of 46.2% and diglycidyl fumarate was formed with a selectivity of 42.3%, in each case based on the diallyl fumarate reacted.