Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O>[CH2:7]([O:14][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[C:25]([F:26])([F:28])[F:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of potassium t-butoxide (27.5 g) in N,N-dimethylformamide (120 ml) was added dropwise a solution of benzyl alcohol (15.9 ml) in N,N-dimethylformamide (60 ml) over min. The mixture was stirred for 30 min, and a solution of 4-fluoro-3-trifluoromethylbenzoic acid (20.0 g) in N,N-dimethylformamide (90 ml) was added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and further at 50° C. for 1 hr. The reaction mixture was added to ice water, and acidified with 1M hydrochloric acid (300 ml). The precipitated solid was collected by filtration, and washed with water and then hexane to give the object product (28.2 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:31]2[O:30][CH2:29][C:21]3([CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:32][CH3:33])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:31]2[O:30][CH2:29][C:21]3([CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:32][CH3:33])=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(CO2)COC(C)(C)OC1
Reactant: Cc1c(Cl)cncc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(CO2)COC(C)(C)OC1

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (93 mg, 0.58 mmol) with compound 522 (150 mg, 0.44 mmol) in THF (2 mL) in the presence of LiHMDS (1.3 mL, 1.3 mmol) afforded compound 129 as a white solid material after purification by column chromatography (55-60% EtOAc in light petroleum). LC-MS: RT=3.95 min.; m/z 468.19, 470.23 (M+H)+, 466.36, 468.33 (M−H)−. 1H NMR (DMSO-d6): δ 8.65 (2H, s), 7.42 (1H, d, J 8.8), 6.89 (1H, d, J 9.1), 4.63 (2H, s), 4.33 (2H, s), 4.08 (2H, s), 3.84 (3H, s), 3.82 (4H, s), 1.39 (3H, s), 1.37 (3H, s).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]([F:26])([CH3:25])[C:13](=[O:27])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@:14]([F:26])([CH3:25])[CH:13]([OH:27])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(F)C(=O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Product: C[C@]1(F)C(O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a stirred solution of ((2R,3R,4R)-3-benzoyloxy-4-fluoro-4-methyl-5-oxo-tetrahydrofuran-2-yl)methyl benzoate (about 60 g, 161 mmol) in tetrahydrafuran (about 300 ml) cooled to about −10° C., then lithium tri tertiary butoxy aluminum hydride (about 241.9 ml, 241 mmol) was added and stirred at about 0° C. for 1 hour. Completion of the reaction was monitored by thin layer chromatography, quenched with saturated ammonium chloride solution. Tetrahydrafuran was removed under reduced pressure and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water, brine and dried over sodium sulphate. The organic layer was removed under reduced pressure and the residue was purified by silica gel column chromatography using 16% ethyl acetate: hexane as eluent furnished title compound (about 60 g) as a colorless liquid. Yield: 99.46%; 1H NMR (300 MHz, CDCl3): δ 8.11-8.00 (m, 4H), 7.61-7.37 (m, 6H), 5.65 (dd, 1H, J=23.4 Hz, 7.8 Hz, 7.5 Hz), 5.34 (dd, 1H, J=9.6 Hz, 2.7 Hz), 4.69-4.66 (m, 1H), 4.57-4.53 (m, 2H), 3.40 (brs, 1H, —OH), 1.60-1.56 (m, 3H, J=22.5); Mass: [M+Na]+: 397 (100%); IR cm−: 3439, 3070, 2940, 2868, 1733, 1729, 1453, 1274, 1115, 710.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:15][O:16][CH3:17])[C:12]([OH:14])=O)[N:10]=1)=[O:4].P(Cl)(Cl)(Cl)=O.Cl.[NH2:26][CH:27]1[C:39](=[O:40])[N:29]2[C:30]([C:36]([OH:38])=[O:37])=[C:31]([O:34][CH3:35])[CH2:32][S:33][C@H:28]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[F:18][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:15][O:16][CH3:17])[C:12]([NH:26][CH:27]2[C:39](=[O:40])[N:29]3[C:30]([C:36]([OH:38])=[O:37])=[C:31]([O:34][CH3:35])[CH2:32][S:33][C@H:28]23)=[O:14])[N:10]=1)=[O:4]
Reactant: CON=C(C(=O)O)c1csc(NC(=O)C(F)(F)F)n1
Reactant: COC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OC)CS[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
A mixture of 2-{2-(2,2,2-trifluoroacetamido)-4-thiazolyl}-2-methoxyiminoacetic acid (syn isomer, 0.8 g.), dimethylformamide (0.20 g.), phosphorus oxychloride (0.41 g.) and ethyl acetate (10 ml.) was stirred for 30 minutes under ice-cooling to prepare the activated acid solution in a similar manner to that of Example 2-(1). On the other hand, a solution of 7-amino-3-methoxy-3-cephem-4-carboxylic acid hydrochloride (0.6 g.) and trimethylsilylacetamide (3 g.) in ethyl acetate (15 ml.) was stirred at 40° C. for 3 hours. To the solution was added dropwise the activated acid solution at -10° to -20° C. in 2 minutes, and the mixture was stirred at the same temperature for 1.5 hours. After water (10 ml.) was added to the resultant mixture, the ethyl acetate layer was separated and allowed to stand. The precipitates were collected by filtration to give 7-[2-{ 2-(2,2,2-trifluoroacetamido)-4-thiazolyl}-2-methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 0.3 g.). The aqueous layer, which was separated from the ethyl acetate layer, was extracted with ethyl acetate, and the extract was combined with the mother liquor obtained above. The ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was washed with diethyl ether to give the same object compound (0.25 g.), Total yield 0.55 g.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:7][C@H:6]1[C:8]([OH:10])=O)=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>ClCCl>[N:1]([CH2:4][C@@H:5]1[CH2:7][C@H:6]1[C:8]([Cl:14])=[O:10])=[N+:2]=[N-:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: [N-]=[N+]=NC[C@@H]1C[C@H]1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1C[C@H]1C(=O)Cl
Yield: 97.5 %

Procedure:
A solution of trans-2-azidomethyl-1-cyclopropane carboxylic acid (2.188 g, 15.50 mmol) in dry dichloromethane (25 ml) was treated at room temperature with oxalyl chloride (1.57 ml, 18.60 mmol) and a drop of N,N-dimethylformamide. After the evolution of gas has ceased (2.5 h), the solvent was evaporated under reduced pressure and the residue was distilled under vacuum (bulb to bulb distillation) to give 2.411 g (98%) of a clear oil: bp 70°-75° C./0.8 mm Hg (air bath temperature); ir (film) νmax : 2100 (N3), 1775 cm-1 (C=O); 1Hmr (CDCl3) δ: 3.33 (2H, d, J=6, CH2N3) ~2.2 - 1.0 ppm (4H, m, cyclopropyl).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C:6]1[N:7]=[CH:8][C:9]([C:12](=[O:18])[CH2:13][O:14]C(=O)C)=[N:10][CH:11]=1)=[O:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[OH-].[Na+]>COC(C)(C)C.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>[OH:18][C@@H:12]([C:9]1[N:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:19])([CH3:1])[CH3:20])=[N:7][CH:8]=1)[CH2:13][OH:14]
Reactant: CC(=O)OCC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CC(C)(C)C(=O)Nc1cnc([C@H](O)CO)cn1
Temperature: 37 °C
Reaction time: 11.2 h
Yield: 105.1 %

Procedure:
50 g of acetic acid 2-[5-(2,2-dimethylpropionylamino)-pyrazin-2-yl]-2-oxo-ethyl ester (178 mmol) was stirred in 150 ml tert-butyl methyl ether (TBME). Subsequently the reaction buffer, 674 mL 20 mM of 2-(4-morpholino)-ethansulfonic acid, and 100.1 g of D-glucose (658 mmol) were added. The temperature was adjusted to 29° C. and the pH to 6.25. The reaction—deacetylation—was started by the addition of 2.01 g lipase AH. Directly afterwards, 40 mg of glucose dehydrogenase GDH 102, 201 mg of ketoreductase KRED 101 and 202 mg of cofactor NADP were added to initiate the asymmetric reduction. The reaction temperature was increased up to 37° C. The stirred suspension was maintained at pH 6.25 (and 37° C.) by the controlled addition (pH-stat) of 1.0 N sodium hydroxide solution. After 11.2 h, after a total consumption of 354.1 mL of 1.0 N sodium hydroxide, and after complete conversion, the reaction mixture was stirred for further 10.5 h. For the product extraction 300 g of sodium chloride were added into the reaction mixture and the pH was adjusted to 7.5. Subsequently, the reaction mixture was extracted 5 times with 1 L of ethyl acetate. The phase separation occurred spontaneously. The combined organic phases were dried over anhydrous sodium sulfate, evaporated and dried on HV over night. 44.76 g (S)—N-[5-(1,2-dihydroxy-ethyl)-pyrazin-yl]-2,2-dimethyl-propionamide (4) (96.4% HPLC purity, [SupelcoSil ABZ+, 250×4.6 mm, eluent 20-90% acetonitrile/water+0.1% TFA over 10 min at 1 mL/min, detection at UV 300 nm, retention time 5.3 min], ee>99.9% [Chiralpak IA, 250×4.6 mm, 5 μm, eluent 50% Heptane 50% Ethanol/Methanol 1:1 over 20 min at 1 mL/min, detection at UV 240 nm, retention time enantiomers 9.3 and 10.9 min]) were isolated as a light orange, highly viscous oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:12]2[N:13]=[CH:14][N:15]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C.CO.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CCOC(C)=O.[Cl-].[Na+].O>[F:1][C:2]1[C:3]([C:12]2[N:13]=[CH:14][N:15]([C:17]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH:5]=[O:6]
Reactant: COC(=O)c1cccc(F)c1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cccc(F)c1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
To a solution of methyl 3-fluoro-2-(1-trityl-1H-imidazol-4-yl)benzoate (62 mg, 0.134 mmol) in toluene (4 mL) at −78° C. was added dropwise a solution DIBAH (1 M, 0.161 mL, 0.161 mmol) Stirring was continued at for 10 min. At this temperature, dry methanol was added. The mixture was poured into saturated aqueous NH4Cl (5 mL), diluted with EtOAc (15 mL), shaken vigorously for 3 min, added brine (5 mL), shaken again, the phases separated and the organic layer dried over Na2SO4, filtered, and evaporated to give the desired aldehyde which was used without further purification.
Reaction SMILES: [CH:1]1([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([O:17][CH2:18][CH2:19][CH3:20])=[N:11][C:12]=3[NH2:16])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1>C(O)C>[CH:1]1([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([O:17][CH2:18][CH2:19][CH3:20])=[N:11][C:12]=3[NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Solvent: CCO
Product: CCCOc1nc(N)c2ncn(C3CCCCC3)c2n1

Procedure:
A solution of 2.21 g. (7.8 mmoles) of 9-(2-cyclohexenyl)-2-n-propoxy-9 H-adenine in 30 ml. of 90% ethanol was hydrogenated overnight with 250 mg. of 10% Pd-C and then filtered. The filtrate was evaporated in vacuo, giving a residue which was crystallized from ethyl acetate-n-hexane. Yield 1.85 g. (76%); m.p. 148°-150° C. IR(KBr): 3510, 2930, 1670, 1640, 1595, 1405 cm-1. UV: λmaxMeOH 252 nm(ε8360), 269 nm(ε13200). NMR(CDCl3): δ1.03 (3H, t, J=7 Hz), 1.80(12H, m), 4.20(2H, t, J=7 Hz), 4.35(1H, m), 6.02(2H, s), 7.55(1H, s).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2OCC(C)(C)C[O:15]2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([S:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)SCCCc1ccc(C2OCC(C)(C)CO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCCCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.8 %

Procedure:
Compound 14 (525 mg, 1.70 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (2.0 mL) was added together with a drop of water. The solution was stirred for 15 h at rt. Then aq NaHCO3 (5%, 35 mL) was added and the phases were separated. The organic phase was washed twice with aq NaHCO3 (5%), once with brine and dried (Na2SO4). The solvents were removed under reduced pressure and the oily residue was purified by column chromatography (silica, ether/hexanes, 1:2), affording a yellow oil (279 mg, 74%). IR (neat): {tilde over (v)} 3037, 2928, 2849, 2731, 1693, 1605; 1H NMR δ 1.88-1.99 (m, 2H), 2.35 (s, 3H), 2.78 (t, 3J=7.3Hz, 2H), 2.89 (t, 3J=7.3Hz, 2H), 7.35, 7.81 (AA′BB′, 2×2H), 9.98 (s, 1H); 13C NMR (APT) δ 28.1 (+), 30.4 (+), 34.7 (+), 128.8 (−), 129.7 (−), 134.4 (+), 148.3 (+), 191.6 (−), 195.2 (+); GC-MS (EI) obsd 222, 180, 146, 133, 117, 105, 91, 43.
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[C:36](=[O:37])[CH2:35][O:34][C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:32]3)=[CH:26][CH:25]=2)[C:9]([NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21]CC)=[O:20])[CH2:15][CH2:14]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1>O1CCOCC1>[CH:3]1([CH:8]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][N:31]3[C:36](=[O:37])[CH2:35][O:34][C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:32]3)=[CH:28][CH:29]=2)[C:9]([NH:11][CH2:12][CH:13]2[CH2:14][CH2:15][CH:16]([C:19]([OH:21])=[O:20])[CH2:17][CH2:18]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C1CCC(CNC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1CCC(CNC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.55 ml (1.11 mmol) of 2 M aqueous sodium hydroxide solution was added to a solution of 31 mg (55 μmol) of ethyl 4-{[(cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl)amino]methyl}cyclohexanecarboxylate (Example 127A) in 3 ml of dioxane, and the mixture was stirred at room temperature overnight. The reaction mixture was then extracted once with tert-butyl methyl ether. The aqueous phase was then adjusted to pH 2 with 1 M hydrochloric acid and extracted twice with ethyl acetate. The ethyl acetate phases were combined and dried over sodium sulfate. After filtration, the solvent was removed to dryness. This gave 25 mg (47 μmol, 85% of theory) of the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18].O>CN(C=O)C>[Si:21]([O:4][CH2:3][C:2]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)([F:1])[F:11])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: OCC(F)(F)c1ccncc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(F)(F)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2-difluoro-2-(pyridin-4-yl)-ethanol (0.15 g) prepared in (2) in DMF (3.0 mL) were added imidazole (0.076 g) and tert-butyldimethylchlorosilane (0.15 g). The reaction mixture was stirred at RT for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: ethyl acetate) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:10](CC([O-])=O)=[CH2:11].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH:10]([O:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)=[CH2:11]
Reactant: C=CCC(=O)[O-]
Reactant: Oc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COc1cc(F)cc(F)c1
Temperature: 100 °C
Yield: 70.3 %

Procedure:
To a 100 ml round bottom flask was added 3,5-difluorophenol (3.85 g, 29.6 mmol), vinylacetate (5.1 g, 59.2 mmol), Na2CO3 (1.88 g, 17.8 mmol), chloro-1,5-cycooctadiene iridium (I) dimmer (199 mg, 0.296 mmol) and 10 ml toluene. The resulting reaction mixture was flushed with nitrogen and heated at 100° C. overnight. After cooling to room temperature, the reaction mixture was diluted with 60 ml hexane and washed with 60 ml water. The organics were dried over sodium sulfate, filtered through a pad of silica gel, rinsed with 60 ml hexane. The filtrates were concentrated to give 3.25 g desired product as colorless liquid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:4]=1>C1COCC1.C(O)(=O)C.O=[Pt]=O>[CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH2:15][CH2:14][CH2:13]3)[CH:4]=1
Reactant: CNc1cc(Oc2ccc3ncccc3c2)ncn1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1cc(Oc2ccc3c(c2)CCCN3)ncn1

Procedure:
In the presence of 1 g of PtO2 (Engelhard 7018), a solution of 2.63 g (10.4 mM) 6-methylamino-4-(quinolin-6-yloxy)-pyrimidine in 175 ml of THF/acetic acid 4:1 is hydrogenated. The catalyst is filtered off and the filtrate concentrated in vacuo. The residue is diluted with EtOAc and sat. Na2CO3 solution and extracted 3× with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and partially concentrated in vacuo. The crystallized title compound can be filtered off and washed with EtOAc and DIPE: TLC(EtOAc): Rf=0.18; MS: [M+1]+=257. More product can be isolated from the filtrate by column chromatography (SiO2; EtOAc).
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([OH:22])=O)[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25][N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([CH2:35][NH2:36])[CH2:32]2)=[N:27]1>>[CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([NH:36][CH2:35][CH:31]2[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][N:26]([CH3:25])[N:27]=3)[CH2:32]2)=[O:22])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Reactant: Cn1cc2c(n1)CCC(CN)C2
Agent: Cl
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NCC1CCc2nn(C)cc2C1

Procedure:
The title compound was prepared from 2-[3-[(benzylsulfonyl)amino]-6 -methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethanamine hydrochloride using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a faint yellow solid compound.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@H:10]([CH3:11])[CH2:9][CH2:8][N:7]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:6]1)=[N+]=[N-]>[Pd].C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][N:7]2[CH2:8][CH2:9][C@@H:10]([CH3:11])[C@H:5]([CH2:4][NH2:1])[CH2:6]2)=[CH:15][CH:16]=1
Reactant: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN
Reaction time: 4 h

Procedure:
A mixture of trans-3-azidomethyl-1-[2-(4-fluorophenyl)-ethyl]-4-methylpiperidine (252 mg, 911 μmol) and 10% palladium on charcoal (90 mg) in ethanol (25 mL) was shaken under a hydrogen atmosphere (60 psig) for 4 hours. The mixture was filtered and the filtrate was concentrated under vacuum to provide a sticky solid (226 mg, quantitative). 1H NMR (300 MHz, CDCl3) δ7.16 (m, 2H), 6.97 (t, J=9 Hz, 2H), 3.12 (m, 1H), 2.98 (m, 1H), 2.93 (dd, J=13, 3 Hz, 1H), 2.80 (m, 2H), 2.58 (m, 3H), 1.99 (m, 1H), 1.80 (m, 1H), 1.8-1.6 (m, 3H), 1.5-1.1 (m, 3H), 0.97 (d, J=6 Hz, 3H). Mass spec (ES+) m/z 251.1 (M+H+, 100%).
Reaction SMILES: O[CH2:2][C@@:3]([C@@H:6]1[CH2:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[CH3:26])=[CH:14][CH:13]=2)=[C:9]([CH3:28])[CH2:8][CH2:7]1)([OH:5])C.I([O-])(=O)(=O)=O.[Na+]>C(O)(C)C.O>[CH3:26][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[CH2:11][C@H:6]([C:3](=[O:5])[CH3:2])[CH2:7][CH2:8][C:9]=2[CH3:28])=[CH:17][CH:16]=1)=[O:27]
Reactant: CC1=C(c2ccc(NC(=O)c3ccncc3C)cc2)C[C@@H]([C@@](C)(O)CO)CC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)[C@@H]1CCC(C)=C(c2ccc(NC(=O)c3ccncc3C)cc2)C1
Temperature: 25 °C

Procedure:
A solution of Compound 9 was dissolved in 2:1 isopropyl alcohol and water and stirred at room temp. Sodium periodate (1 eq.) was added and the reaction was stirred overnight, quenched with water and washed with ethyl acetate. The organic layer was dried and concentrated to yield 38.0 mg Compound 6.
Reaction SMILES: Cl.[OH:2][CH:3]([C:11]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15](=[O:22])[NH:16]2)[CH:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:5].[CH3:23][O-:24].[Na+].[Na]>CO>[CH2:23]1[O:21][C:18]2[CH:19]=[CH:20][C:11]([C:3]([O:21][C:18]3[CH:19]=[CH:20][C:11]([CH:3]([OH:2])[CH:4]([NH:6][C:7]([CH3:10])([CH3:8])[CH3:9])[CH3:5])=[C:12]4[C:17]=3[NH:16][C:15](=[O:22])[CH:14]=[CH:13]4)=[O:2])=[CH:12][C:17]=2[O:24]1
Reactant: CC(NC(C)(C)C)C(O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CC(NC(C)(C)C)C(O)c1ccc(OC(=O)c2ccc3c(c2)OCO3)c2[nH]c(=O)ccc12
Reaction time: 1 h

Procedure:
1 g of 5-(1-hydroxy-2-tert-butylaminopropyl)-8-hydroxycarbostyril hydrochloride was suspended in 15 ml of methanol, and sodium methylate prepared from 155 mg of sodium metal and 3.3 ml of absolute methanol was added to the suspension. The mixture was then concentrated to dryness, and the resulting residue was dissolved in 10 ml of dimethylformamide. 593 mg of piperonylyl chloride dissolved in 5 ml of dimethylformamide was then added dropwise to the mixture while cooling with ice-water. The mixture was then stirred for 1 hour, and water was added to the mixture followed by extraction with chloroform. Chloroform was removed by distillation, and diethyl ether was added to the residue to crystallize the product. The crystals thus obtained were separated by filtration, washed with diethyl ether and recrystallized from a mixture of chloroform and diethyl ether to obtain 520 mg of 8-(3,4-methylenedioxyphenylcarbonyloxy)-5-(1-hydroxy-2-tert-butylaminopropyl)carbostyril having a melting point of 156°-157° C.