Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O)=O.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC1CCc2ccccc2N1
Temperature: -20 °C
Reaction time: 20 h
Yield: 102.1 %

Procedure:
In 60 ml of methylene chloride, 1.00 g of 2-methylquinoline was dissolved, and 66.5 mg (2.0 mol %) of crystalline (S)-chloro[(1,2,3,4,5-η)-pentamethyl-2,4-cyclopentadien-1-yl](2-pyrrolidinecarboxamidato-κN1, κN2)iridium(III) (Cp*Ir(Cl−)(S-PA-H+)) was added. After cooling to −20° C., 8.4 ml of a mixed solvent of formic acid/triethylamine (molar ratio: 5/2) was added dropwise, and the mixture was continuously stirred at the same temperature for 20 hours. Then, the reaction was completed. The reaction mixture was basified with an aqueous potassium carbonate solution and then the resulting layers were separated. The organic layer was washed with water and concentrated to give 1.05 g of 2-methyl-1,2,3,4-tetrahydroquinoline as an oil.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:3]=1.[Li+].[OH-].Cl>C1COCC1.CO.O>[I:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:3]=1
Reactant: CCOC(=O)c1cn(C2CCCCO2)nc1I
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cn(C2CCCCO2)nc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
To a solution of ethyl 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (5 g, 14.2 mmol) in (1:1) THF/MeOH (32 mL) was added a solution of LiOH (1.8 g, 4.28 mmol) in water (16 mL). The reaction was stirred at rt for 4 h then evaporated under vacuum and the residue was treated with water (25 mL) and washed with ethyl acetate (30 mL×2). The aqueous layer was isolated acidified to ˜pH5 with 2N HCl and extracted with DCM (30 mL×3). The combined extracts were washed with brine (30 mL), dried and concentrated to afford 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylic acid (3.5 g, yield: 76%). LCMS (method B): RT=2.18 min, m/z=321.0 [M−H]−.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH2:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:13]([NH:5][CH2:4][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:12])[CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)C(CN)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)C(CNCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound is prepared from 3-methyl-2-phenyl-butylamine and benzaldehyde: A solution of 3-methyl-2-phenyl-butylamine (1.3 g, 8 mmol) and benzaldehyde (0.81 mL, 8 mmol) in CH2Cl2 (50 mL) is stirred at RT for 20 min. Sodium triacetoxyborohydride (2.52 g, 11.3 mmol) is then added, followed by acetic acid (0.46 mL, 8 mmol). The reaction mixture is stirred at RT for 16 h, then quenched by the addition of saturated NaHCO3 solution. The organic layer is separated and the aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated. The residue is purified by flash chromatography (hexane/ethyl acetate) to afford benzyl-(3-methyl-2-phenyl-butyl)-amine as a colourless oil. MS: 254.3 [M+H]+; tR (HPLC, C18 column; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.03 min.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[H-].[Na+]>N1C=CC=CC=1>[O:7]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccsc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: c1ccc(Oc2ccsc2)cc1
Yield: 73 %

Procedure:
Cuprous chloride (3.08 g, 31.1 mmol) and phenol (8.78 g, 93.3 mmol) were sequentially added to a solution of 3-bromothiophene (5.06 g, 31.1 mmol) in pyridine (150 ml). Sodium hydride (3.73 g, 93.3 mmol, 60% dispersion in mineral oil) was then slowly added. The reaction was heated at reflux for 20 hours under Argon. The pyridine was removed under reduced pressure. The residue was diluted with Et2O (200 ml) and washed with 1N NaOH (3×100 ml), 1N HCl (2×150 ml) and 1N NaOH (150 ml). The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was chromatographed using hexanes to give 3-phenoxy-thiophene as a clear oil (4.0 g, 74% yield).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6]O.[NH:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: OC[C@H]1CCCO1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C[C@H]1CCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a mixture of (R)-(tetrahydrofuran-2-yl)methanol (Fluka, 4.0 g, 39.2 mmol) and di-tert-butyl hydrazine-1,2-dicarboxylate (9.1 g, 39.2 mmol) in THF (50 mL) was added triphenylphosphine (14.4 g, 54.8 mmol) followed by (E)-di-tert-butyl diazene-1,2-dicarboxylate (12.6 g, 54.8 mmol), portionwise. This mixture was stirred at ambient temperature for 16 h then was concentrated under reduced pressure and purified by column chromatography (SiO2, 99% hexane/EtOAc to 25% hexane/EtOAc) to give the title compound (11.8 g, 37.3 mmol, 95% yield). MS (DCI/NH3) m/z 317 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.CC(C)([O-])C.[K+].CN(C=O)C.[F:23][C:24]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][OH:26]>C(OCC)(=O)C.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[O:26][CH2:25][C:24]([F:31])([F:23])[C:27]([F:30])([F:29])[F:28]
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Reactant: OCC(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Br)c(OCC(F)(F)C(F)(F)F)n1
Temperature: 140 °C
Yield: 19.8 %

Procedure:
5-Bromo-6-chloro-2-pyridinecarboxylic acid (CAN 959958-25-9; 0.6 g, 2.54 mmol) and potassium tert-butoxide (712 mg, 6.34 mmol) were combined with DMF (30 mL) and THF (10 mL) to give a yellow suspension. To this suspension was added 2,2,3,3,3-pentafluoro-1-propanol (CAN 422-05-9; 3.01 g, 2 ml, 20.1 mmol) and the mixture was heated to 140° C. for 20 hours. After cooling the mixture was poured was poured into ethyl acetate (75 mL) and the combined mixture was washed with cold 1 M HCl (1×10 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 20 g, 0% to 100% ethyl acetate in heptane) and further purified by preparative HPLC to give the title compound (0.176 g 20%) as off white solid; MS (EI) 350.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]3)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[CH3:24][C:23]1[N:19]([CH2:18][C:17]([N:14]2[CH2:15][CH2:16][CH:11]([C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=3)[CH2:12][CH2:13]2)=[O:29])[N:20]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:22]=1
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (2.67 g, 6.2 mmol) in THF (20 mL) is added aqueous solution of sodium hydroxide (2 M, 4.65 mL, 9.3 mmol) at RT. After stirring 3 h at RT, the reaction mixture is acidified with 2M aqueous solution of HCl until pH 2-3, and the solution is extracted with ethylacetate (20 mL). The aqueous layer is re-extracted with ethylacetate (20 mL) and the combined organic layers are washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid (2.33 g, 94%), which can be used in the next step without further purification. 1H-NMR (400 MHz, d6-acetone): δ=1.69-1.82 (m, 1H), 1.87-2.02 (m, 1H), 2.16-2.37 (m, 2H), 2.38 (s, 3H), 2.89-2.99 (m, 1H), 3.38-3.48 (m, 2H), 4.14-4.22 (m, 1H), 4.50-4.69 (m, 1H), 5.20-5.36 (2d, 2H (diastereotopic)), 6.41, (s, 1H), 8.34 (s, 1H). MS: m/z=403 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](=O)[CH2:25][CH3:26])=[CH:23][C:18]=2[N:17]=[CH:16]1.O>CO>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](=[N:2][OH:3])[CH2:25][CH3:26])=[CH:23][C:18]=2[N:17]=[CH:16]1
Reactant: NO
Reactant: CCC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(=NO)c1ccc2c(c1)ncn2C1CCCCO1
Yield: 89.1 %

Procedure:
Hydroxylamine hydrochloride (54 mg, 0.78 mmol) and sodium acetate (100 mg, 1 mmol) were added to a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)propan-1-one (100 mg, 0.39 mmol) in MeOH (5 mL). The mixture was refluxed overnight. The mixture was poured into water and extracted with EtOAc. The organics were washed sequentially with water and brine, then (Na2SO4). Removal of solvent followed by SiO2 chromatography afforded 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)propan-1-one oxime (95 mg, 90% yield) as a light yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[I:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1>CN(C=O)C.ClCCl>[I:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([Cl:3])=[O:15])=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (39.53) and DMF (2 drops) were added to a solution of 4-iodophenylacetic acid (26.2 g), in dichloromethane (150 ml). The reaction mixture was stirred at ambient temperature for 18 hours and the solvent removed by evaporation to give 4-iodophenylacetyl chloride as an oil (23 g) which was purified by vacuum distillation; b.p. 118-119° C. (0.35 mmMg)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[C:10]([OH:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.B(O)(O)O.[CH3:18]O>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[C:10]([O:12][CH3:18])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CO
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Agent: OB(O)O
Product: COC(=O)C(O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
25.0 g of 3,5-difluorophenylhydroxyacetic acid (D2) are dissolved in 325 ml of methanol. 3.9 g of boric acid are subsequently added, and the reaction mixture is stirred at room temperature for 18 hours. The resultant solution is then evaporated to dryness. The residue is extracted using 100 ml of ethyl acetate and 100 ml of water. The aqueous phase is subsequently extracted twice with 50 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate and filtered. The filtrate is evaporated to dryness in vacuo, giving 25.5 g of the title compound as crude product. Recrystallisation from 17 ml of ethyl acetate and 170 ml of cyclohexane give 23.5 g of the pure compound C2 having a melting point of 61.8° C. (MS 201.9 (M+)).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH3:11]I>CCCCCC.CN(C)C=O>[CH3:11][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ccc(O)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To sodium hydride (50% oil dispersion, 43.2 g, 21.6 g of active NaH, 900 mmol), prewashed in dry hexane, in 800 ml of dimethylformamide (DMF) is added 5-hydroxy-2-methylpyridine (98.8 g, 906 mmol) in 700 ml of DMF at 15° and over 0.75 hour. The reaction is allowed to warm to RT and is stirred for 2 hours. It is then cooled to 10°, and methyliodide is added over 0.5 hour. The reaction is again allowed to warm to RT and is stirred overnight. It is then filtered through celite, and the solid is washed with chloroform, filtered and rotoevaporated. The resulting solid is washed with chloroform 3X, and is stirred with chloroform overnight. It is filtered and rotoevaporated, after which ether is added, followed by 10% sodium hydroxide and water. The mixture is extracted with ether (3X). The combined ether extracts are washed with water and with brine, dried over calcium sulfate, filtered and rotoevaporated to give 5-methoxy-2 -methylpyridine.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.FC(F)(F)C1C=CC(C(O)=O)=CC=1.N1C=CC=CC=1>O=S(Cl)Cl.C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([C:7]([F:18])([F:17])[F:6])=[CH:9][CH:10]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(O)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
To a cold (0° C.) solution of N,O-dimethylhydroxylamine hydrochloride (2.5 g, 25.6 mmol) and 4-(trifluoromethyl)benzoyl chloride (prepared by refluxing a solution of 4-(trifluoromethyl)benzoic acid in SOCl2, 4.86 g, 23.3 mmol) in DCM (50 mL) was added dropwise pyridine (4.06 g, 51.26 mmol). The reaction mixture was stirred overnight and evaporated. The residue was dissolved in a mixture of DCM/Et2O (1/1) (45 mL) and brine (45 mL) was added. The aqueous layer was separated and extracted twice with DCM/Et2O (1/1) (45 mL). The combined organic layers were washed with brine (45 mL), dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a yellow oil (4.88 g, 90%). 1H NMR (CDCl3, 300 MHz) δ 7.90-7.70 (m, 2H), 7.76-7.60 (m, 2H), 3.65-3.45 (m, 3H), 3.43-3.33 (m, 3H). HPLC (Condition A), Rt: 3.41 min (HPLC purity: 98.0%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].O.[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:23](=[O:26])([O-])O.[Na+]>C([O-])([O-])OC.CO>[CH3:12][O:6][CH:5]([O:26][CH3:23])[C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(OC)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A total of 21.6 g of 3-bromo-4-fluorobenzaldehyde was dissolved in a mixture of 50 ml of methyl orthoformate and 50 ml of methanol, and 0.2 g of p-toluenesulfonic acid monohydrate was added, followed by stirring at room temperature for 1 hour. To the reaction mixture was added aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 24.3 g of 3-bromo-4-fluorobenzaldehyde dimethylacetal as a colorless oil. The product was dissolved in 150 ml of dry tetrahydrofuran. After cooling to −78° C. in an atmosphere of nitrogen gas, 59 ml of a 2.5 M solution of n-butyllithium in hexane was added. After stirring for 30 minutes, 12.7 ml of 3-fluorobenzaldehyde was added and the mixture was heated to room temperature. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:15), to give 24.3 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][NH:26][C:25]2=O)=[CH:20][CH:19]=1.N1C=CNC1=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:25]2[N:24]([C:21]3[CH:20]=[CH:19][C:18]([O:17][C:16]([F:31])([F:15])[F:30])=[CH:23][CH:22]=3)[CH:28]=[CH:27][N:26]=2)[CH3:13])[CH2:11][O:10]1
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: O=c1[nH]cc[nH]1
Product: C[C@@H](Oc1nccn1-c1ccc(OC(F)(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 20 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.36 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.32 g of 1-(4-trifluoromethoxyphenyl)-2-(1H,3H)-imidazolone, 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-trifluoromethoxyphenyl)-(2(1H,3H)-imidazolone (0.60 g) and 0.46 g of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-trifluoromethoxyphenyl)-2-imidazolyloxy]ethyl]oxirane were obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:12]C)(=O)[CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(O)(=O)CCCC(C)(C)C.[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>C1(C)C(C)=CC=CC=1>[C:27]1([C:24](=[O:26])[CH2:25][C:3]([CH2:4][CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:12])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)CCCC(C)(C)C
Agent: CC(C)(C)CCCC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(C)(C)CCCC(=O)CC(=O)c1ccccc1
Temperature: 135 °C
Yield: 53 %

Procedure:
A 500 mL, 4 neck round bottom flask equipped with mechanical stirring, a nitrogen inlet, a thermometer, a condenser and an addition funnel was charged with 60% sodium hydride in mineral oil (20.5 g. 0.51 mol), methyl neo-octanoate (92.3 g., 0.58 mol, prepared from neo-octanoic acid, a product of Exxon), and xylene (42.8 g.). The mixture was heated to reflux (135° C.), and then a solution of acetophenone (32.4 g. 0.27 mol) in xylene (19.1 g.) was added over 1.25 h. The mixture was kept at reflux for an additional 1 h. After cooling to room temperature, the reaction was quenched by the careful addition of methanol (20 mL), and then acidified with 150 g/L sulfuric acid (180 mL). After separation of layers, the organic phase was washed with water (2×100 mL) and brine (100 mL). After drying by passing through anhydrous sodium sulfate, the solution was concentrated in vacuo at 70° C. down to 12 mbar to yield an orange liquid containing product in a crude yield of 63%. Vacuum distillation (200 mtorr) through a 15 cm Vigreux column yielded the product in the heart cut: 1-phenyl-3-neoheptyl-1,3-propanedione (X) (37.2 g., 96% pure, 0.14 mol; 53% yield; bp: 94-135° C.). Dypnone, the self-condensation product of acetophenone was undetectable in the product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[O-:13][C:14]#[N:15].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]([NH2:15])=[O:13])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: N#C[O-]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Water (2.5 mL) is added slowly to a mixture of 4-fluoro-3-(trifluoromethyl)aniline (500 mg, 2.79 mmol) in glacial acetic acid (1.5 mL). A solution of sodium cyanate (200 mg, 3.07 mmol) in water (2.5 mL) is added slowly, and the mixture is stirred at room temperature for 4 h. The mixture is extracted twice with dichloromethane, and the combined organic layers are concentrated under reduced pressure. Yield: 588 mg; ESI mass spectrum [M+H]+=223; Retention time HPLC: 0.87 min (Z018_S04).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](CC=O)[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Br)C>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCOC1(C)C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid tert-butyl ester (15.5 g; CAS 147959-19-1) in dry diethyl ether (100 ml) under an argon atmosphere at room temperature was added dropwise a solution of ethylmagnesium bromide in diethyl ether (42.6 ml, 3 M solution) and stirring continued for 1 hour. The reaction mixture was then quenched by careful addition of water (10 ml) and the mixture was then filtered through decalite. The filtrate was washed sequentially with water and with saturated brine and then the organic phase was separated, dried over sodium sulphate, filtered and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0→50:50) to give (S)-4-(R)-2-hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (7.30 g) from fractions eluting first and (S)-4-(S)-2-hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (6.44 g) from fractions eluting later, both compounds as colourless oils. (S)-4-(R)-2-Hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester: 1H NMR δ (CDCl3, 300 MHz): 4.52 (1H, br. D, J=3.3 Hz), 4.23 (1H, m), 4.00 (1H, dd, J=8.7 & 5.4 Hz), 3.66 (1H, d, J=8.7 Hz), 3.40 (1H, m), 1.79 (1H, td, J=11.4 & 2.1 Hz), 1.60-1.44 (16H, m), 0.95 (3H, t, J=7.5 Hz). (S)-4-((S)-2-Hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester: 1H NMR δ (CDCl3, 300 MHz): 4.12 (1H, m), 3.98 (1H, dd, J=9.0 & 5.7 Hz), 3.82 (1H, m), 3.55 (1H, m), 2.88 (1H, br. s), 1.79 (1H, m), 1.70-1.40 (16H, m), 0.95 (3H, t, J=7.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
To 4-bromo-2-methylphenol (1.25 g, 6.67 mmol) in 20 ml MeCN were added dry K2CO3 (1.84 g, 13.34 mmol, 2 equiv) and benzylbromide (0.872 ml, 7.34 mmol, 1.1 equiv) and reaction is stirred for 24 h at room temperature. Reaction mixture was filtered through Celite, solution was concentrated and purified by silica gel column chromatography (Hexane to 8% EtOAc/Hexane) to give 1.65 g 17 in 89% yield. Rf=0.90 (20% EtOAc/Hexane);
Reaction SMILES: CCCCCC.[H-].[Na+].[CH3:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.CN(C=O)C>[CH3:9][C:10]1[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2
Reactant: BrCc1ccccc1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: Cc1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
Hexane was used to wash 80 mg (2.0 mmol) of 60% NaH/mineral oil and 6 mL of DMF was added followed by 352 mg (2.0 mmol) of 2-methyl-5-nitro-1H-indole. After 0.33 hours, 0.24 mL (2.0 mmol) of benzyl bromide was added, stirred 0.5 hours and diluted with water. The mixture was extracted with EtOAc, the EtOAc washed with a saturated NaCl solution, dried MgSO4) and on concentrating at reduced pressure, crystals formed. These were washed with MeOH to give 400 mg (75% yield) of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole, mp, 150°-152° C.