Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[C:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)(=[O:12])[CH3:11].[Cl-].[Na+]>C1(C)C(C)=CC=CC=1>[C:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1)(=[O:12])[CH3:11]
Reactant: Oc1ccccc1
Reactant: CC(=O)OCc1cccc(Br)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(=O)OCc1cccc(Oc2ccccc2)c1
Yield: 71 %

Procedure:
28.29 g. (0.3 mole) of phenol, 11.2 g. (0.2 mole) of potassium hydroxide and 20 cm3. of xylene are weighed together. The water is azeotropically distilled with stirring and boiling then the xylene is also distilled. To the reaction mixture 1.0 g. of copper(I) chloride and 1.0 g. of activated copper are added and in oil bath of 180° C. 22.91 g. (0.1 mole) 3-bromobenzyl acetate are dropped during 25 minutes while stirring. The reaction mixture is stirred at the same temperature for an additional two hours. After cooling 50 cm3. of 15% sodium chloride solution are added to the reaction mixture, then the reaction mixture is filtered off. The filtrate is extracted twice with 30 cm3 of toluene. The united organic phase is washed with a mixture of 30 cm3. of 15% sodium chloride solution and 10 cm3. of 40% sodium hydroxide solution. The organic phase is evaporated and the residue distilled in vacuo. 17.2 g. of 3-phenoxybenzyl acetate are obtained. Boiling point 142°-145° C./53.2 Pa, nD20 : 1.5621, yield 71%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[NH:14]C(=O)OC(C)(C)C)=[CH:6][CH:5]=1)[CH3:2].Cl>O1CCOCC1.C(OCC)C>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[NH2:14])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2cccc(NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOc1ccc2cccc(N)c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 51.7 %

Procedure:
To a solution of the product of Example 1C (14.47 g, 50.4 mmol) in dioxane (30 mL) at 0° C. was added 4N HCl in dioxane (60 mL, 240 mmol). The reaction mixture was stirred at room temperature for 3.5 hours, diluted with 3 volumes of diethyl ether. The resulting dark brown precipitate was collected by filtration. It was then treated with saturated NaHCO3 solution and was extracted with ethyl acetate. The solution was dried over MgSO4, filtered and evaporated in vacuo to yield the title compound (4.88 g, 52%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:59][C:60]1[S:61][CH:62]=[CH:63][N:64]=1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([NH:59][C:60]3[S:61][CH:62]=[CH:63][N:64]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 0.25 h

Procedure:
Procedure-C: 2-(4-cyclopropanesulfonylphenyl)-2-(2,4-difluorophenoxy)acetic acid (1 equi) (obtained in step III) and HATU (1.5 equi) was dissolved in DCM. To this solution was added DIPEA (2 equi.) and stirred for 15 minutes followed by addition of 2-aminothiazole (1 equi.) and continued to stir over night at room temperature. Reaction mixture was diluted with dichloromethane, washed with water, brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by flash chromatography to get the title product.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1.C(N(CC)CC)C.C(O)CCC>ClCCl>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1cccc(N)c1
Solvent: CCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2ncccc2[N+](=O)[O-])c1

Procedure:
2-chloro-3-nitropyridine (25 g, 158 mmol), m-toluidine (20.5 mL, 189 mmol), triethylamine (26.4 mL, 189 mmol), and 400 mL butanol were added to a 1 L 3-neck round-bottom flask. The reaction mixture was heated overnight under nitrogen. The solvent was evaporated leaving a bright orange solid. The solid was triturated with hexanes and filtered. The filtrate was not pure and contained product, so it was evaporated and purified by column chromatography eluting with 10 and 20% ethyl acetate/hexanes. A total of 3.15 g was obtained from the column. The bulk of the material was dissolved in dichloromethane and washed twice with water, dried over magnesium sulfate, filtered, and evaporated to an orange solid (31.2 g). The total amount obtained was 34.35 g (95%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].O>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=1
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccnc1
Yield: 32.5 %

Procedure:
To a suspension of 0.22 g of sodium hydride (60% oil dispersion, 5.5 mmol) in 2 mL of DMF was added dropwise a solution of 0.48 g of 3-hydroxypyridine (5.0 mmol) in 2 mL of DMF at room temperature, and the mixture was stirred for an hour. The resulting brown solution was ice-cooled, 0.81 mL of tert-butyl bromoacetate (5.5 mmol) was added, and the mixture was stirred under ice-cooling for an hour followed by stirring at room temperature for 2 hours. After addition of water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: chloroform:ethyl acetate=5:1), to give 0.34 g of tert-butyl 3-pyridyloxyacetate (Yield: 32.5%) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][O:18][CH3:19]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][O:18][CH3:19])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 4-bromophenol (41, 5.0 g, 28.9 mmol) in dimethylformamide (15 mL) were added potassium carbonate (4.40 g, 31.8 mmol) and 1-bromo-2-methoxyethane (5.00 g, 36.0 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at ambient temperature overnight and concentrated under reduced pressure. The residue was slurried in ethyl acetate (50 mL) and filtered. The filtrate was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered. Silica gel column chromatography (0-10% ethyl acetate in hexanes) gave the desired compound as a colorless oil (42, 3.2 g, 48%).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-:28].[Na+]>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)NCCc2csc(C(F)(F)F)n2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CC(Cc1ccc(OCC(=O)O)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared analogously to Example 16 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine in methanol with 1N sodium hydroxide solution. After neutralisation with 1N hydrochloric acid, the mixture is extracted by shaking with methylene chloride, the extract is evaporated to dryness, and the remaining residue is triturated with petroleum ether and filtered off with suction.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Br)cnn1C
Yield: 72.6 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.027 g, 0.095 mmol) was treated with 2,4-difluorophenyl isocyanate (0.015 g, 11.5 μL, 0.095 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 8 (0.030 g, 0.069 mmol, 71%) as a white solid. LCMS m/z (%)=437 (M+H79Br, 100), 439 (M+H81Br, 91). 1H NMR (400 MHz, acetone-d6) δ: 8.45 (s, 1H), 8.23 (dt, J=6.1, 9.2 Hz, 1H), 7.93 (s, 1H), 7.68 (dd, J=2.6, 9.0 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J=2.6 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 7.07 (ddd, J=2.7, 8.7, 11.3 Hz, 1H), 6.93-7.02 (m, 1H), 3.82 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1
Reactant: C1CNCCN1
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1cncc(N2CCNCC2)c1
Yield: 26.3 %

Procedure:
A mixture of 1.0 g (6.3 mmol) of 3-bromopyridine, 2.2 g (25 mmol) of piperazine, 16 mg of tris(dibenzylideneacetone)-dipalladium(0), 32 mg of (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1.3 g (13.4 mmol) of sodium t-butoxide, and 50 ml of toluene was heated under reflux for 24 hours in a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with chloroform. The combined organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated off, and the residue was purified by silica gel column chromatography using a 9:1 mixture of chloroform and methanol as a developing solvent to give 0.27 g (29%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH2:17])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.[NH2:20][NH2:21]>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH2:17])=[C:7]([CH:16]=1)[C:8](=[N:20][NH2:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NN
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Product: NN=C(c1ccccc1)c1cc(C(F)(F)F)ccc1N

Procedure:
In the manner given in Preparation 1, 5-(trifluoromethyl)-2-aminobenzophenone is refluxed with hydrazine hydratein diethylene glycol to give 5-trifluoromethyl-2-aminobenzophenone hydrazone.
Reaction SMILES: [P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:26])[C@@H:12]1[OH:27])([O:4][P:5]([OH:8])([OH:7])=[O:6])(=[O:3])[OH:2]>C(OP(O)(O)=O)[C@H]1O[C@H](OP(OP(O)(O)=O)(O)=O)[C@H](O)[C@@H]1O>[P:1]([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[C@H:13]([OH:26])[C@@H:12]1[OH:27])([O:4][P:5]([O:7][P:1]([OH:4])([OH:3])=[O:2])([OH:8])=[O:6])(=[O:2])[OH:3]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=P(O)(O)OC[C@H]1O[C@H](OP(=O)(O)OP(=O)(O)O)[C@H](O)[C@@H]1O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reaction time: 0.47 h

Procedure:
The following additions were made to each reaction: 2 μl of PRPP, 2 μl of PRPP Synthetase, and 20 μl PRPP Synthetase buffer. The reactions proceeded at 37° C. for 28 minutes at which time the reactions were transferred to 100 μl containing 2 μl of ADP and 2 μl of NDPK. This second reaction was allowed to proceed at room temperature for 20 min. The amount of ATP produced was measured by the addition of 10 ng of Luciferase followed by measuring light output with a luminometer. The data is presented in Table 30.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:10][C:4]1[CH:3]=[C:2]([Br:1])[C:7]([F:8])=[CH:6][C:5]=1[OH:9]
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(Br)c(F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a solution of 4-bromo-5-fluoro-2-nitrophenol (40.0 g, 169 mmol) in MeOH (250 mL) and THF (250 mL) was added zinc powder (91.0 g, 1700 mmol) and ammonium chloride (111.0 g, 1700 mmol) and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was washed with cold water to give 2-amino-4-bromo-5-fluorophenol (38.0 g, crude) which was used in the next step directly without further purification. 1H NMR (DMSO-d6, 400 MHz): δ 9.82 (br s, 1H), δ 6.76 (d, J=7.2 Hz, 1H), 6.60 (d, J=10.0 Hz, 1H), 4.65 (br s, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[Br:11][C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17].[OH-].[Na+]>>[Br:11][C:12]1[S:13][C:14]([CH:8]=[O:9])=[CH:15][C:16]=1[CH3:17]
Reactant: Cc1ccsc1Br
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)sc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6250.6 %

Procedure:
Phosphoryl chloride (5.3 ml, 0.57 mmol) was added dropwise to N,N-dimethylformamide (8.8 ml, 0.11 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. 2-Bromo-3-methylthiophene (5.00 g, 28.2 mmol) was added dropwise thereto under ice-cooling and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was neutralized with a 2N aqueous sodium hydroxide solution under ice-cooling. The reaction mixture was extracted with diethyl ether and the organic layer was dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=5/1) to give 5-bromo-4-methyl-2-thiophenecarbaldehyde (1.41 g, yield: 24%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:24][CH3:25])[C:15]([NH:17][C:18]([CH2:22][OH:23])([CH3:21])[C:19]#[CH:20])=[O:16])=[CH:8][CH:7]=2)#[CH:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:24][CH3:25])[C:15]([NH:17][C:18]([CH:22]=[O:23])([CH3:21])[C:19]#[CH:20])=[O:16])=[CH:8][CH:7]=2)#[CH:2]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#C)CO)cc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#C)C=O)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
2-(3-Ethynyl-quinolin-6-yloxy)-N-(1-hydroxymethyl-1-methylprop-2-ynyl)-2-methylsulfanyl acetamide (0.513 g) in dichloromethane (25 ml) was treated with Dess-Martin periodinane (0.737 g). The reaction mixture was stirred at room temperature for 2 hrs and then, quenched with sat. aqueous NaHCO3 and sat. aqueous sodium thiosulphate. The reaction mixture was vigorously stirred at rt. for 40 minutes after which time the two phases were separated. The organic layer was washed thrice with sat. aqueous. NaHCO3. After separation, the organic phase was dried over sodium sulphate, filtered and evaporated to yield 0.523 g of 2-(3-Ethynyl-quinolin-6-yloxy)-N-(1-formyl-1-methyl-prop-2-ynyl)-2-methylsulfanyl acetamide as a crude product along with minor impurities. The crude mixture was used in the next step without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCCO)cc1
Reaction time: 18 h

Procedure:
2-(4-Nitrophenoxy)ethanol (1.83 g, 10 mmol) was dissolved in EtOH (100 mL) under air at RT. A catalytic amount of 10% Pd/C was added. The air was replaced with a H2(g) atmosphere and the reaction was stirred vigorously for 18 h. The reaction was quenched by filtering it through Celite® with EtOH. The filtrate was concentrated under reduced pressure and the recovered material was purified by eluting it through a 17×2.5 cm column of silica gel (5% and 10% MeOH/CH2Cl2 step gradient) giving 2-(4-amino-phenoxy)ethanol as a black solid: MS m/z 154=[M+H]+. Calc'd for C8H11NO2: 153.08.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1.C(O)(=O)C>CCCCCC.CO>[C:14]([OH:16])(=[O:15])/[CH:13]=[CH:2]/[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C(O)CC(=O)O
Solvent: CO
Solvent: CCCCCC
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C(=O)O)ccc1O
Yield: 65 %

Procedure:
A mixture of vanillin (2.50 g, 0.0164 mol), malonic acid (3.41 g; 0.0328 mol), piperidine (3–5 mL) and acetic acid (10–20 mL) were taken in a round bottom flask and the reaction mixture was refluxed for 5–6 hours instead of microwave irradiation as mentioned in Example I. The cooled mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with dil HCl., saturated sodium chloride and then organic layer dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain solid which was recrytallised with mixture of methanol and hexane, provided ferulic acid as a solid compound mp 169° C. (lit mp 168–171° C.) in 65% yield; 1H NMR (DMSO-d6) δ 12.13 (1H, s, COOH), 7.48 (1H, d, Ar—CH═CH—COOH), 7.27 (1H, s, H-3), 7.07 (1H, d, H-6), 6.78 (1H, d, H-5), 6.36 (1H, d, —CH═CH—COOH), 3.81 (3H, s, 2-OCH3); δ168.9 (COOH), 149.8 (C-1), 148.7 (C-2), 145.4 (CH═CH—COOH), 126.6 (C-4), 123.7 (C-5), 116.4 (C-3 & C-6), 111.8 (CH═CH—COOH), 56.4 (2-OCH3).
Reaction SMILES: CC([O:7][C:8]([C:10]1[N:15]2[C:16]([C@@H:18]([NH:19][C:20](/[C:22](/[C:26]3[O:30][CH:29]=[CH:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C@H:14]2[S:13][CH2:12][C:11]=1[CH2:31][O:32][C:33]([NH2:35])=[O:34])=[O:17])=[O:9])OC(C)=O.[O-]CC.[Na+].Cl>O1CCCC1.C(O)C>[CH3:25][O:24]/[N:23]=[C:22](\[C:20]([NH:19][C@@H:18]1[C:16](=[O:17])[N:15]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([CH2:31][O:32][C:33]([NH2:35])=[O:34])[CH2:12][S:13][C@H:14]12)=[O:21])/[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Temperature: -60 °C
Yield: 89.6 %

Procedure:
Sodium metal (1.8 gm) was reacted under nitrogen atmosphere with ethyl alcohol (40 ml) at room temperature, resulting in a clear solution of sodium ethoxide. A solution of cefuroxime axetil (20.4 gm, S-isomer >90%, R-isomer <10%) in a mixture of tetrahydrofuran (204 ml) and ethyl alcohol (20 ml) was cooled to −60° C. A solution of sodium ethoxide in ethanol was slowly added to this mixture at −60° C. Progress of the reaction was monitored by high pressure liquid chromatography (HPLC). Stirring was continued until cefuroxime axetil almost disappeared (45 minutes). Thereafter, 15% aqueous hydrochloric acid (20 ml) was added and the solvent was evaporated under reduced pressure at low temperature. Water and ethyl acetate (water-immiscible solvent) were added to the reaction mass (basifying agent) and the pH level was adjusted to 6.0 using 5% aqueous potassium bicarbonate solution. The aqueous layer was separated and acidified with 15% aqueous hydrochloric acid to pH 1.0. The resulting solid was filtered, washed with water and dried to yield cefuroxime (15.2 gm).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5C(OC)=CC=C2[C@]5(C=34)CC1>C(O)=O.OO.N.C(O)(=O)C.[Pd]>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][CH:13]5[C:14]([CH:16]=[CH:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: [Pd]
Agent: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: N
Solvent: CC(=O)O
Solvent: O=CO
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314

Procedure:
Oxycodone may be prepared from thebaine by: dissolution of the thebaine in aqueous formic acid, oxidation treatment with 30% hydrogen peroxide (Seki, 18 Chem. Pharm. Bull. 671-676, 1970), neutrlztion with aqueous ammonia to yield 14-hydroxycodeinone and hydrogenation of the 14-hydroxycodeinone in acetic acid with the aid of a palladium-charcoal catalyst (Remington's Pharmaceutical Sciences 1041, 1975). Oxidation of thebaine may alternatively be performed using potassium dichromate in acetic acid (Freund et al., 94 J. Prakt. Chem. 135, 1916) or performic acid (Iljima et al., 60 Helv. Chim. Acta 2135-2137, 1977). Inproved yield, however, has been reported to be obtained by oxidizing with m-chloroperbenzoic acid in an acetic acid-trifluoroacetic acid mixture (Hauser et al., 17 J. Med. Chem. 1117, 1974; See also, U.S. Pat. No. 4,795,813 to Schwartz, Col. 1, Lines 22-26). Yield may also be improved by hydrogenation of 14-hydroxycodeinone under a pressure of about 30 psi (Kraβnig et al. 329 Arch. Pharm. Pharm. Med. Chem. 325-326,1996).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:13]2[CH2:14][C:15](=[CH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][C:29]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)([OH:32])[CH2:28][CH2:27]3)[C:16]3[C:17]([O:22][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[N:18][CH:19]=[CH:20][CH:21]=3)(=O)C.[OH-].O.C(OCC)(=O)C>C(O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:29]2([OH:32])[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][CH:23]=[C:15]3[C:16]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[O:22][C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:13]=4[CH2:14]3)[CH2:31][CH2:30]2)=[CH:34][CH:35]=1
Reactant: CC(=O)OCCOc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: OCCOc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2

Procedure:
To a solution of 1-[3—(7-(2-acetoxyethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4—(4-chlorophenyl)piperidin-4-ol (Example 50)(140 mg) in ethanol (5 ml) were added 15% sodiun hydroxide aqueous solution (2ml) and the mixture was heated to reflux for hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate.