Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([CH3:21])([CH3:20])[CH2:8][C:9]1[N:10]=[CH:11][N:12]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:13]=1.[F:22][C:23]([F:43])([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)=[CH:32][CH:31]=1)[C:24](N(OC)C)=[O:25]>O1CCCC1>[F:43][C:23]([F:22])([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][N:37]=2)=[CH:34][CH:35]=1)[C:24]([C:11]1[N:12]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:13]=[C:9]([CH2:8][C:7]([CH3:21])([CH3:20])[CH3:6])[N:10]=1)=[O:25]
Reactant: CON(C)C(=O)C(F)(F)c1ccc(-c2ccc(F)cn2)cc1
Reactant: CN(C)S(=O)(=O)n1cnc(CC(C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)C(F)(F)c1ccc(-c2ccc(F)cn2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (1.6 M in hexane) (0.60 mL, 0.96 mmol) was added to a −78° C. solution of 4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (234 mg, 0.96 mmol) in tetrahydrofuran (10 mL). After stirring at −78° C. for 10 min, 2,2-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-N-methoxy-N-methylacetamide (296 mg, 0.96 mmol) was added and the reaction allowed to warm to ambient temperature, quenched with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 2-{difluoro[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH2:29])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:22]([C:24]1[S:28][C:27]([NH:29][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])=[N:26][C:25]=1[CH3:30])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccccc2C(F)(F)F)sc1C(=O)NCc1ccccc1
Yield: 36 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-trifluoromethylbenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 36% yield; 1H NMR (CDCl3, 300 MHz) δ 7.79-7.26 (m, 10H), 5.94 (s, br, 1H), 4.59 (d, J=5.8 Hz, 2H), 2.22 (s, 3H); MS (ES+) m/z 420.0 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=[O:23])[CH2:19][CH2:20][O:21][CH3:22])[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)C>C1COCC1>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=[O:23])[C:19]([CH2:20][O:21][CH3:22])=[CH:29][N:30]([CH3:32])[CH3:31])[CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COCCC(=O)c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Solvent: C1CCOC1
Product: COCC(=CN(C)C)C(=O)c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1

Procedure:
4-(3-Methoxy-propionyl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide was treated with an excess of Bredereck's reagent in THF at room temperature to 50° C. for 3 days. The solvent was removed under reduced pressure and the concentrate was used directly in the next step. HPLC Method B, Rt=5.0 minutes “broad peak”.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:15]1[CH2:20][CH2:19][CH:18]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl piperidin-4-ylcarbamate (45 g) and dihydro-2H-pyran-4(3H)-one (24.74 g) in dichloromethane (1000 mL) was treated with sodium triacetoxyborohydride (61.9 g), stirred at room temperature for 16 hours, washed with 1M sodium hydroxide and dried with anhydrous sodium sulfate, filtered and concentrated. The concentrate was flash column chromatographed on silica gel with 10-20% methanol/dichloromethane.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([NH:12][C@H:13]([C:22]([OH:24])=O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>ClCCl.CN(C=O)C>[C:8]([O:7][C:5](=[O:6])[NH:12][C@H:13]([C:22](=[O:24])[N:3]([CH3:4])[CH3:2])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (79 mmol) and Boc-L-tyrosine (66 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 12:1 dichloromethane/DMF reaction solvent, 60 hour reaction time) and the product purified by chromatography on silica gel eluted with 10, 20, 30, 50 and 70% ethyl acetate in hexanes. Yield 20.6 g, 102%; HPLC (60/40) 3.21 minutes (96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.C(Cl)Cl.N1C=CC=CC=1.[C:29]1([C@@H:35]2[CH2:37][C@H:36]2[C:38](Cl)=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:38]([CH:36]4[CH2:37][CH:35]4[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:39])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C3CC3c3ccccc3)ncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a mixture of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (50.5 mg, 0.200 mmol) in methylene chloride (2.0 mL, 31 mmol) was added pyridine (0.04 mL, 0.5 mmol) and trans-2-phenyl-1-cyclopropanecarbonyl chloride (35.0 uL, 0.225 mmol). The reaction mixture was stirred at room temperature for one hour and then evaporated in vacuo. The resulting residue was purified via reverse phase HPLC and lyophilized to yield 29.1 mg (37%) of N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)-2-phenylcyclopropanecarboxamide (mixture of trans stereoisomers). LCMS (ESI): RT (min)=6.288, M+H=397.1, Method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.17 (s, 1H), 8.54 (s, 1H), 8.04 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.38 (t, J=7.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 2H), 7.25-7.12 (m, 5H), 2.47-2.40 (m, 2H), 2.25 (s, 3H), 1.60-1.48 (m, 1H), 1.39 (dd, J=11.0, 7.4 Hz, 1H).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[C:12](=O)([O-:14])[O-:13].[K+].[K+].C(=O)=O>>[NH2:1][C:5]1[CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 185 °C
Yield: 35 %

Procedure:
p-Acetaminophenol 15 g, and potassium carbonate 37.5 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 3.0 MPa and heated to 185° C., maintained for 14 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve potassium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the yield is 35%.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4][OH:5].[H][H]>CO>[CH3:1][CH:2]([CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][OH:5]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: [H][H]
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CCC(C)CCO
Yield: 98 %

Procedure:
A nitrogen-purged 200-ml autoclave was charged with 22.1 g (0.1 mole) of (2E, 6E)-3,7,11-trimethyl2,6,10-dodecatrien-1-ol and 40 ml of methanol. To the solution, 4.8 mg (0.005 mmole) of the [Ru((-)-T-BINAP)](BF4)2 as prepared in Referential Example 6 was added, and hydrogenation was conducted at a hydrogen pressure of 30 kg/cm2 and at a reaction temperature of 20° C. for 10 hours. When it was confirmed that 0.1 mole of hydrogen had been absorbed, the solvent methanol was distilled off, and the residue was subjected to vacuum distillation to obtain 22 g of a (+)-(6E)-3,7,11- trimethyl-6,10-dodecadien-1-ol having a boiling point of 115 to 118° C./0.2 mmHg. The yield of this fraction was 99.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:6]
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)c2cccc(Cl)c2)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 15.1 gm (86 mmol) of 3-chlorobenzoyl chloride in 70 mL of dichloromethane was added 10.0 gm (66 mmol) of methyl 3-aminobenzoate. Triethylamine (9.38 gm, 13 mL, 93 mmol) was then added slowly to the mixture. After the addition was complete, the solution was warmed to 45° C. and stirred overnight. Ice was added to the solution to quench excess benzoyl chloride. After one hour, the layers were separated. The organic fraction was washed with 5% aqueous hydrochloride acid, saturated sodium bicarbonate, and finally with saturated sodium chloride solution. The dichloromethane solution was dried over magnesium sulfate. The drying agent was filtered off, and the solvent was removed by rotoevaporation to give the desired methyl 3-(3-chlorobenzamido)benzoate. 1H NMR (CDCl3): δ3.91 (s, 3H), 7.61 (d of t, 1H), 7.78 (d of t, 1H, 7.87 (d of t, 1H), 8.40 (d of d, 1H), and 8.94 ppm (br s, 1H). MS m/z: 290.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[C:40]1([S:46](Cl)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:25][CH2:26][N:27]([S:46]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)(=[O:48])=[O:47])[CH2:28][CH2:29]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(S(=O)(=O)c4ccccc4)CC3)s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) was dissolved in CH2Cl2 (1 mL). N,N-diisopropylethyl-amine (50 μL, 0.287 mmol) and benzenesulfonyl chloride (29 μL, 0.230 mmol) were added sequentially. The solution was stirred overnight at room temperature, then concentrated in vacuo on a Genevac. The resultant residue was dissolved in DMSO and purified via HPLC (48-82% CH3CN:H2O) to provide 4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1-(phenylsulfonyl)piperidin-4-ol. MS ESI: [M+H]+ m/z 576.1. 1H NMR (600 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.80 (d, J=5.2 Hz, 1H), 7.93 (d, J=9.2 Hz, 2H), 7.75 (dd, J=8.7, 10.3 Hz, 2H), 7.73 (s, 1H), 7.65 (t, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.25 (d, J=5.1 Hz, 1H), 7.12 (s, 1H), 6.10 (s, 1H), 3.54 (d, J=12.3 Hz, 1H), 2.58 (t, J=12.3 Hz, 2H), 2.54-2.37 (m, 1H), 2.28 (s, 3H), 2.08 (t, J=16.1 Hz, 2H), 1.80 (d, J=14.6 Hz, 2H). rhSYK activity=++
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3]>C(OC(=O)CCC)(=O)CCC.[Cl-].[Zn+2].[Cl-]>[OH:3][C:2]1[CH:4]=[CH:5][C:6]([C:2](=[O:3])[CH2:1][CH2:7][CH3:6])=[CH:7][C:1]=1[O:8][CH3:9]
Reactant: COc1ccccc1O
Agent: CCCC(=O)OC(=O)CCC
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCC(=O)c1ccc(O)c(OC)c1

Procedure:
100 g of guaiacol are dissolved in 136.4 g of butyric anhydride, treated with 120 g of zinc chloride, heated for 3 minutes as given in Example 6.a and then worked-up as described there. The crude product obtained after high vacuum distillation is chromatographed with toluene on 600 g of silica gel. After recrystallization from ether/n-hexane there is obtained 4'-hydroxy-3'-methoxy-butyrophenone in the form of colorless crystals of m.p. 40°-41°.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][OH:21]>C(O)C>[F:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]([CH:7]=1)[NH:16][C:17]1[CH:18]=[C:19]([CH2:20][OH:21])[CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1F
Reactant: Nc1cccc(CO)c1
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1Nc1cccc(CO)c1
Yield: 88.5 %

Procedure:
With ice-cooling, 1,5-difluoro-2-nitro-4-trifluoromethylbenzene (1.50 g) and 3-aminobenzyl alcohol (1.62 g) were dissolved in ethanol (50 ml) and subjected to 3 hours of the reaction at room temperature. The reaction solution was concentrated and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=100:1) to give [3-(5-fluoro-2-nitro-4-trifluoromethylanilino)phenyl]methanol (1.93 g). The resulting anilinophenylmethanol (1.75 g) and imidazole (3.61 g) were allowed to react with each other in DMF (50 ml) at 140° C. for 30 minutes, and the resulting reaction solution was spontaneously cooled down to room temperature. Then, saturated sodium chloride aqueous solution (150 ml) was added. The thus formed orange solid was collected by filtration, washed with water and then dried under a reduced pressure. The resulting crude crystals were purified by a silica gel column chromatography (chloroform:methanol=10:1) to give [3-[5-(1H-imidazol-1-yl)-2-nitro-4-trifluoromethylanilino]phenyl]methanol (1.46 g). In an atmosphere of hydrogen, the thus formed product (1.37 g) in methanol was subjected to reduction under ordinary pressure using palladium-carbon as the catalyst. The reaction solution was filtered and concentrated under a reduced pressure to give amorphous residue. Then, oxalic acid (0.13 g) and 1 N hydrochloric acid aqueous solution (10 ml) were added, followed by heating at 100° C. for 15 hours. When the reaction solution was concentrated to about half in volume, the thus formed crystals were collected by filtration, washed with ethyl acetate and then dried under a reduced pressure to give 1-(3-hydroxymethylphenyl)-7-(1H-imidazol-1-yl)-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione hydrochloride (1.20 g).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][C:4]=1[F:11])#[N:2].[CH3:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH3:12])=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: Cc1ncc[nH]1
Reactant: N#Cc1ccc(CBr)cc1F
Product: Cc1nccn1Cc1ccc(C#N)c(F)c1

Procedure:
The titled product was prepared from the product of Step B and 2-methylimidazole using the same procedure described in Step B of Example 1.
Reaction SMILES: [CH2:1]([O:17][CH:18]([CH3:23])[CH:19]([OH:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:21][CH2:20][CH:19]([OH:22])[CH:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:23])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCOC(C)C(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOC(C)C(O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.3 %

Procedure:
In 100 ml of dry dimethylformamide, 17.67 g of 3-hexadecyloxybutane-1,2-diol was treated with 2.36 g of 60% sodium hydride under chilling with ice. To the chilled mixture was added 6.77 g of benzyl chloride, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was recovered in a conventional manner and purified by silica gel column chromatography to give 4.33 g of 1-benzyloxy-3-hexadecyloxy-2-butanol.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[N:6]([CH2:12][CH:13]=[CH2:14])[C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[CH2:16]([OH:18])[CH3:17]>>[CH2:12]([N:6]1[C:7]([CH3:11])=[CH:8][C:9]([OH:10])=[C:4]([C:1](=[O:3])[CH:2]=[CH:8][C:9]2[CH:4]=[CH:1][CH:2]=[C:16]([O:18][CH2:11][C:7]#[N:6])[CH:17]=2)[C:5]1=[O:15])[CH:13]=[CH2:14]
Reactant: CCO
Reactant: C=CCn1c(C)cc(O)c(C(C)=O)c1=O
Product: C=CCn1c(C)cc(O)c(C(=O)C=Cc2cccc(OCC#N)c2)c1=O

Procedure:
According to the same manner as that of Example a-5 except that 0.20 g of 3-acetyl-1-allyl-4-hydroxy-6-methyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone, and 6 ml of ethanol was used in place of pyridine, 0.23 g of 1-allyl-3-[3-[3-(cyanomethoxy)phenyl]-1-oxo-2-propenyl]-4-hydroxy-6-methyl-2(1H)-pyridinone [Compound No. (1c)] was obtained as a yellow crystal.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[N:14]=[C:13]([OH:15])[CH:12]=[C:11]([OH:16])[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[N+:17]([C:12]1[C:13]([OH:15])=[N:14][C:9]([S:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:10][C:11]=1[OH:16])([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(O)nc(SCc2ccccc2)n1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)nc(SCc2ccccc2)nc1O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
The product of example 2, step (a) (2 g) was added to a mixture of glacial acetic acid (50 ml) and concentrated nitric acid (20 ml) and the reaction mixture heated to 50° C. A further 28 g of the product of step (a) was added in portions over 2 hours whilst maintaining the reaction temperature between 50 and 60° C. After stirring the reaction mixture for a further 1 hour at 50° C. it was poured onto crushed ice and the subtitled product isolated by filtration as a yellow solid (12.3 g).
Reaction SMILES: C([O:4][C:5]([CH2:7][N:8]1[C@H:11]([C@@H:12]([CH3:31])[C:13](N2C3(CCCCC3)OC3C=CC=CC=3C2=O)=[O:14])[C@@H:10]([C@H:32]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH3:33])[C:9]1=[O:42])=[O:6])C=C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C[Si](Cl)(C)C.[C:58]1([P:64](Cl)([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[O:65])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.P([O-])([O-])([O-])=O>O1CCCC1>[Si:35]([O:34][C@@H:32]([C@H:10]1[C:9](=[O:42])[N:8]2[C:7]([C:5]([OH:4])=[O:6])=[C:13]([O:14][P:64]([C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:65])[C@H:12]([CH3:31])[C@H:11]12)[CH3:33])([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:36])[CH3:37]
Reactant: C=CCOC(=O)CN1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)N1C(=O)c2ccccc2OC12CCCCC2
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)O)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Temperature: -50 °C
Reaction time: 0.03 h
Yield: 95.8 %

Procedure:
A solution of 1.2 g of 3-{(2R)-2-[(3S, 4R)-1-allyloxycarbonylmethyl-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl]propionyl}-spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one in 6 ml of tetrahydrofuran is added dropwise to 4.4 ml of 1M sodium bis(trimethylsilyl)amide solution (solvent:tetrahydrofuran) at a temperature from -20° C. to -30° C. during one minute. 261 mg of trimethylsilyl chloride are added thereto at -50° C. and the mixture is stirred for 2 minutes. Then, 645 mg of diphenylphosphoryl chloride are added thereto at -50° C. and the mixture is stirred for 2 hours at 0° C. The reaction mixture is poured into 50 ml of 0.2M phosphate buffer (pH 7.0) and the mixture is extracted with ethyl acetate. The extract is washed, dried and evaporated to remove the solvent. Isopropyl ether is added to the residue and the resulting precipitates of 355 mg of spiro[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one are removed by filtration. The filtrate is condensed to obtain 1.04 g of (1R, 5R, 6S)-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-1-methyl-2-diphenylphosphoryloxy-carbapen-2-em-3-carboxylic acid.allyl ester as syrup.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:13]=[CH:12][N+:11]([O-])=[C:10]([CH3:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([C:22]#[N:23])(C)C.CN(C)C(Cl)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[C:10]([CH3:15])[N:11]=[C:12]([C:22]#[N:23])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)cc[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)cc(C#N)n1
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
To a stirred solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-pyridine 1-oxide (11.2 g, 44 mmol) in dichloromethane (100 ml) at room temperature, was added trimethylsilyl cyanide (7.1 ml, 53.2 mmol). After 15 min., dimethylcarbamyl chloride (4.8 ml, 53.2 mmol) was added and the stirring was continued for 24 hr. The mixture was then cooled in an ice bath and saturated aqueous sodium bicarbonate solution (100 ml) was added. After 1 hr., organic layer was separated, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexane (1:1)) to afford 8.8 g (76%) of 4-(tert-butyl-dimethyl-silanyloxymethyl)-6-methyl-pyridine-2-carbonitrile as a white solid. 1H NMR (200 MHz, CDCl3) δ 0.11 (6H, s), 0.94 (9H, s), (3H, s), 2.52 (3H, s), 4.67 (2H, s), 6.97 (1H, d, J=6.7 Hz), 7.08 (1H, s), 8.10 (1H, d, J=6.7 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[N:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:27]=2)O1.C([O-])(=O)C.[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O.O>[N+:12]([C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[N:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:27]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1cc(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
Add 1-bromo-3-nitro-5-(trifluoromethyl)benzene (0.165 g, 0.61 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (0.18 g, 0.61 mmol), sodium acetate (0.1 g, 1.2 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (22 mg, 0.03 mmol) to 1,4-dioxane (15 mL) and water (2 mL). Stir the mixture at 100° C. under N2 for 6 hrs. TLC (EtOAc:PE=1:1) shows that the reaction is complete. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (0.17 g, 80.9%). MS: (M+1): 358.2.