Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@@H:7]([NH2:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]1[C:12]([CH3:14])([CH3:13])[CH2:11]1>>[CH:1]1([C@@H:7]([NH:9][CH2:11][C:12]([CH3:14])([CH3:13])[OH:10])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CO1
Reactant: C[C@H](N)C1CCCCC1
Product: C[C@H](NCC(C)(C)O)C1CCCCC1

Procedure:
(1S)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-((1S)-1-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2,4-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,4-dichlorophenylimino)-3-((1S)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[2-(phenyl)ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-aminoethylbenzene, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=O.[CH3:19][S:20][C:21](SC)=[CH:22][N+:23]([O-:25])=[O:24].O>C(O)(=O)C>[Cl:18][C:15]1[CH:14]=[C:4]2[C:3](=[CH:17][CH:16]=1)[N:2]=[C:21]([S:20][CH3:19])[C:22]([N+:23]([O-:25])=[O:24])=[C:5]2[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc2ccc(Cl)cc2c(-c2ccccc2Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of 2-amino-2',5-dichlorobenzophenone hydrochloride (1.6 g, 5.3 mmol) and 1,1-bis(methylthio)-2-nitroethylene (875 mg, 5.3 mmol) in 12 ml acetic acid was heated at 120° C. overnight. The reaction mixture was cooled to room temperature, 30 ml of water was added and the resulting mixture was extracted with 2×60 ml ethyl acetate. The ethyl acetate extracts were washed with 2×50 ml water, 2×50 ml saturated sodium bicarbonate solution and 50 ml brine, and then dried (anhydrous sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed on silica gel (440 g, 230-400 mesh), eluting with 85:15 hexane/ethyl acetate to yield the title compound as a yellow solid (1.65 g, 72% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 2-amino-4-(3-chlorophenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 4 & 5, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) was heated at reflux overnight. After cooling to room temperature, the acetic acid was removed in vacuo and the residue triturated with petroleum ether. The crude product was collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue was dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization from petroleum ether afforded the desired product as a yellow solid in 80% yield.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]CC)=O)[NH:6]2.[OH-:17].[Na+]>C(O)C>[C:12]([C:5]1[NH:6][C:7]2[C:3]([C:4]=1[CH2:5][C:12]([OH:14])=[O:17])=[C:2]([Cl:1])[C:10]([Cl:11])=[CH:9][CH:8]=2)(=[O:14])[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cc2c(Cl)c(Cl)ccc2[nH]1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2ccc(Cl)c(Cl)c12
Temperature: 25 °C
Yield: 94 %

Procedure:
To a suspension of ethyl 4,5-dichloroindole-2-carboxylate (Ishii et al., Chem. Pharm. Bull., 1974, 22, 1981., 1.8 g, 7.0 mmol) in ethanol (40 ml) was added 2N aqueous NaOH (10 ml) and the mixture was heated at reflux temperature for 2 h. The mixture was cooled to room temperature and concentrated. The residual solid was acidified with 2N aqueous HCl (30 ml) and extracted with diethyl ether (80 ml×2). The organic extracts were dried (MgSO4) and concentrated to give 1.5 g (94%) of the title compound as yellow solids.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]([CH3:39])[C:21]([OH:38])([C:26]3[CH:27]=[CH:28][C:29]4[O:34][CH2:33][C:32](=[O:35])[N:31]([CH3:36])[C:30]=4[CH:37]=3)[C:22]([F:25])([F:24])[F:23])[CH:14]=2)=[CH:7][CH:6]=1)C.[Li+].[OH-].Cl>O1CCCC1.CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:40])=[O:3])=[CH:10][CH:9]=2)=[CH:14][C:15]=1[CH:20]([CH3:39])[C:21]([OH:38])([C:26]1[CH:27]=[CH:28][C:29]2[O:34][CH2:33][C:32](=[O:35])[N:31]([CH3:36])[C:30]=2[CH:37]=1)[C:22]([F:23])([F:24])[F:25]
Reactant: CCOC(=O)c1ccc(COc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(c1cc(OCc2ccc(C(=O)O)cc2)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: 0 °C
Reaction time: 5.5 h
Yield: 62 %

Procedure:
To a solution of 4-{4-chloro-3-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-phenoxymethyl}-benzoic acid ethyl ester (Example 1, 83 mg) in tetrahydrofuran (0.3 ml) and methanol (0.3 ml) was added a 1 M aqueous LiOH solution (0.29 ml) at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 5.5 h. The mixture was cooled in an ice bath and acidified using 1 M aqueous HCl. The mixture was concentrated to dryness. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>85:15) to give the title compound (49 mg) as colorless foam. MS (m/e, ISP neg. ion)=548.2 [M−H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[NH:21][C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1.[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[N:21]([CH3:31])[C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A mixture of 3-[3-(6-methoxy-m-tolyl)-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (160 g, 0.369 mol), potassium carbonate (76.6 g, 0.554 mol) and iodomethane (34.5 mL, 0.554 mol) in N,N-dimethylformamide is stirred at room temperature for 4 hours, and poured onto ice. The resultant aqueous mixture is extracted with methylene chloride. The organic extract is diluted with hexanes, washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as an orange foam (163 g, 98.8%) which is identified by NMR spectral analyses.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:19])[N:12]([CH2:16][CH2:17][OH:18])[CH:13]([CH3:15])[CH3:14])[N:10]=2)[CH2:3]1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.CO>CN(C)C=O>[Si:20]([O:18][CH2:17][CH2:16][N:12]([CH:13]([CH3:14])[CH3:15])[C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:19])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)N(CCO)C(=O)c1csc(N2CC(O)C2)n1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of 3-hydroxy-1-{4-[N-(2-hydroxyethyl)-N-isopropyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (1.33 g, 4.66 mmol) (obtained as described in Reference Example 59(2)) in dimethylformamide (40 ml) were added t-butyldimethylsilyl chloride (738 mg, 4.89 mmol) and imidazole (333 mg, 4.89 mmol) in an ice bath, and the mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, methanol was added thereto and the mixture was stirred for 30 minutes. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) ethyl acetate as the eluant to afford 1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)-3-hydroxyazetidine (1.26 g, yield 69%) as a pale yellow oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH2:14]([O:17][C:18]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=1[NH2:20])[CH:15]=[CH2:16].Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:14]([O:17][C:18]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=1[NH:20][C:1](=[O:3])[CH3:2])[CH:15]=[CH2:16]
Reactant: C=CCOc1cc(OC)ccc1N
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCOc1cc(OC)ccc1NC(C)=O
Temperature: 25 °C

Procedure:
3 mg of 4-(dimethylamino)pyridine and 1 ml of acetic anhydride were successively added to 2 ml of pyridine containing 1.09 g of 2-allyloxy-4-methoxyaniline, and the reaction solution was then stirred at room temperature. After the disappearance of the raw material had been confirmed, 5 N HCl and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was then solidified from t-butyl methyl ether-hexane, so as to obtain 1.04 g of the subject compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>O1CCCC1>[CH3:20][S:21]([O:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(C#N)=NO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(C#N)=NOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
33.6 g (0.21 mol) of α-hydroxyimino-4-methylbenzylcyanide and 31.9 g (0.31 mol) of triethylamine are dissolved in 425 ml of tetrahydrofuran and to this solution is then added dropwise a solution of 26.44 g (0.23 mol) of methanesulfonyl chloride at 0-5° C. After the addition is complete, the mixture is stirred for 30 minutes at 0° C. and then overnight at room temperature. Subsequently, the reaction mixture is filtered and the filtrate is washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent is then distilled off on a rotary evaporator, giving a solid residue which is recrystallised from toluene. 37.3 g (75%) of α-(methylsulfonyloxyimino)-4-methylbenzylcyanide are obtained in the form of a colourless powder having an m.p. of 97.5-102.5° C. The 1H-NMR spectrum shows it to be a pure stereoisomer.
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N+:7]([O-])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O.[NH3:23]>C(Cl)(Cl)Cl>[NH2:23][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2][S:1][C:5]=12
Reactant: [O-][n+]1ccc2ccsc2c1
Reactant: N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nccc2ccsc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 16.6 g of thieno[2,3-c]pyridine-N-oxide in 500 ml of chloroform was added 25 g of p-toluenesulfonyl chloride portionwise with ice-cooling over a period of 1 hour. After the reaction mixture was stirred for further 30 minutes under the same conditions, 250 ml of 10% ammonia water was added, and stirred at ambient temperature for 16 hours. The reaction mixture was diluted with 400 ml of chloroform, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 2.8 g of the title compound as a brown oily material.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][N:14]([CH3:18])[CH2:15][C:16]#[CH:17]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:5][C:4]1[CH:3]=[C:2]([CH2:17][C:16]#[C:15][N:14]([CH3:18])[CH3:13])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: C#CCN(C)C
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CN(C)C#CCc1cc(N)cc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-5-trifluoromethylaniline (1.4 g, 5.9 mmol), 1-dimethylamino-2-propyne (1.3 mL, 0.76 mmol), PdCl2(PPh3)2 (0.26 g, 0.29 mmol) and CuI (114 mg, 0.60 mmol) in 10 mL of TEA was heated at 100° C. in a sealed tube for 3 h. The resulting mixture was filtered over Celite®. The filtrate was concentrated, and the residue was purified by prep-HPLC (reverse phase) to give the aniline. MS (ES+): 243 (M+H)+; (ES−) : 241 (M−H)−. Calc'd C12H13F3N2−242.24.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C>[Cl:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:1]([CH2:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]#[N:7]
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(N)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 191.4 %

Procedure:
To a solution of 4-amino-3-chlorobenzonitrile (1.0 g, 6.56 mmol, 1 eq) and benzyl bromide (3.12 mL, 26.2 mmol, 4.0 eq) in dry DMF (10 mL) was added at rt NaH (1.31 g, 32.8 mmol, 5 eq) portionwise under Ar(g). The reaction mixture was stirred at rt overnight, and was subsequently partitioned with H2O (30 mL) and extracted with EtOAc (5×20 mL) and CH2Cl2 (20 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:0-9:1) to furnish 2 as a white solid (2.09 g, 96%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:17])=[C:10]([F:16])[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(O)cc1F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Yield: 96.6 %

Procedure:
A solution of (2-fluoro-4-hydroxy-benzyl)-carbamic acid t-butyl ester (0.47 g, 1.95 mmol), methyl bromoacetate (0.203 mL, 2.15 mmol) and potassium carbonate (0.431 g, 3.12 mmol) in DMF (5 mL) was stirred at ambient temperature overnight. The reaction mixture was partitioned with water and ethyl acetate. The organic phase was washed with water and dried (Na2SO4). Removal of solvent in vacuo afforded 0.59 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11])([O-])=O>C(OCC)(=O)C.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(O)cc1F
Yield: 980 %

Procedure:
A mixture of 4-nitro-3-fluorophenol (0.314 g, 2 mmol) and iron (0.56 g, 10 mmol) in ethyl acetate (4 ml) and acetic acid (2 ml) was refluxed for 3 hour. The solid particles were filtered off. The filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated to yield 4-amino-3-fluorophenol (53a) (0.25 g, 19.6 mmol, 98%) as a brown solid. 1H NMR (CDCl3, 400 MHz) δ 6.48-6.58 (m, 2H), 6.61-6.70 (m, 1H), 7.87 (bs, 3H).
Reaction SMILES: C1(=O)[NH:5]C(=O)C2=CC=CC=C12.[K].Br[CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].[OH-].[Na+]>CN(C=O)C>[Si:17]([O:16][CH2:15][CH2:14][NH2:5])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN
Temperature: 75 °C
Reaction time: 5 h
Yield: 150.1 %

Procedure:
Nine grams (9 g) of potassium phthalimide was suspended in 100 mL of DMF to which 10 g of 1-bromo-2-t-butyldimethylsilyloxyethane (BrCH2CH2OTBDMS) was added and the mixture heated at 75° C. overnight. The mixture was added to 300 mL of a 5% sodium hydroxide (NaOH) solution and extracted with 300 mL of ether. The ether phase was washed twice with water, dried over Na2SO4 and the solvent removed under reduced pressure. The resulting solid was dissolved in 100 mL of CH3OH, then 3 mL of hydrazine (H2NNH2) was added. After 5 hr, 300 mL ether was added and the organic phase separated from the white precipitate by filtration. Removal of the solvent under reduced pressure yielded 11 g of O-(t-butyldimethylsilyl)ethanolamine. Five grams (5 g) of O (t butyldimethylsilyl)ethanolamine was dissolved in 40 mL of THF and 8 mL of (i-Pr)2NEt. Five milliliters (5 mL) of diphenylphosphinic chloride (Ph2P(O)Cl) was slowly added which produced a white precipitate. After 2 hr, the THF was removed under reduced pressure and the residue dissolved in 200 mL of CH2Cl2. The CH2Cl2 solution was washed with a saturated bicarbonate solution and brine. Removal of CH2Cl2 under reduced pressure followed by flash chromatography on SiO2 gel using CH2Cl2 produced the product (9 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([C:22]1[CH:23]=[N:24][CH:25]=[C:20]([Cl:19])[N:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(F)c1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)c1cncc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of (3-fluoro-benzyl)-carbamic acid tert-butyl ester I-4a (1.21 g, 5.37 mmol) in DMF (50 mL) was treated with 60% NaH in mineral oil (430 mg, 10.7 mmol). The resulting mixture was stirred at ambient temperature until the gas evolution ceased. The solution was treated with 2,6-dichloro-pyrazine (800 mg, 5.37 mmol) and the reaction mixture was heated to 80° C. under N2 and stirred for 5 h. The reaction was cooled and concentrated in vacuo to approximately ⅓ volume. The reaction mixture was poured into H2O (50 mL) and extracted with Ethyl Acetate (1×200 mL). The organic layer was washed with H2O (4×50 mL), brine, dried (Na2SO4), and concentrated to dryness. The crude product was purified by chromatography (EtOAc/Hex 5:95) to afford the title compound I-4b (1.14 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]#[N:12])=[CH:5][CH:4]=1.O.[NH2:15][NH2:16]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:16][N:15]=[C:11]([NH2:12])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)CC#N)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(N)n[nH]2)cc1
Temperature: 60 °C
Yield: 88 %

Procedure:
A suspension of 3-(4-methoxyphenyl)-3-oxopropanenitrile in ethanol was heated to 60° C. Hydrazine hydrate was added dropwise over a minimum of 30 min at 60° C. The resulting solution was held at 60° C. until reaction completion, generally 15-18 hr. The reaction mixture was quenched with water. Ethanol was removed by distillation to about 5 volumes. The product was isolated by filtration, washed with water and dried in a vacuum oven. The yield was 88-95%.
Reaction SMILES: OO.[C:3]1([O:13][CH3:14])[C:4](=[CH:6][CH:7]=[C:8]([CH:12]=1)[CH:9]=[CH:10][CH3:11])[OH:5].S(=O)(=O)(O)[OH:16].C1(C)C=CC=CC=1>C(O)=O>[CH3:11][C:10]([CH2:9][C:8]1[CH:7]=[CH:6][C:4]([OH:5])=[C:3]([O:13][CH3:14])[CH:12]=1)=[O:16]
Reactant: O=S(=O)(O)O
Reactant: CC=Cc1ccc(O)c(OC)c1
Agent: OO
Solvent: O=CO
Solvent: Cc1ccccc1
Product: COc1cc(CC(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of 30% aqueous hydrogen peroxide (9 ml, 85.5 mm) and formic acid (16 ml, 88%) is added to a solution of isoeugenol (8.1 gm, 50 mm) in formic acid (4 ml). The reaction mixture is stirred at 35° C.-40° C. under nitrogen atmosphere for 3 hours. The resulting 1-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol-monoformate is treated with 10% aqueous sulfuric acid (125 ml.) and toluene (125 ml.). After refluxing with mixing for 6 hours, the reaction mixture is cooled to room temperature, and the toluene layer separated. The aqueous layer is extracted with fresh toluene and the toluene layers are combined, washed with saturated aqueous sodium sulfate, dried over anhydrous sodium sulfate and concentrated to give methylvanillyl ketone in 48% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[C:9]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccnc(N)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C)ccn1

Procedure:
To a solution of 2-amino-4-methylpyridine (20 g) in acetic acid (80 ml) was added acetic anhydride and the resulting solution was refluxed for 3 h. The solution was concentrated in vacuo and the solid obtained was triturated with about 50 ml of water and carefully neutralised with solid sodium bicarbonate. The solid was filtered, washed with water and dried under vacuum to give the crude title compound as a white solid (20 g).