Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 102.4 %

Procedure:
To a solution of N-Boc-4-piperidinemethanol (5.69 g, 26.43 mmol, Aldrich) in pyridine (50 mL) cooled to 0° C. was added tosyl chloride (10.077 g, 52.86 mmol). The reaction mixture was stirred for 3 h. The mixture was then poured into ice water and stirred vigorously. The product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated to give a light pink oil as crude product of 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (10 g). It was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[I:11]I.Cl>[NH4+].[OH-].O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: II
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
3-Hydroxybenzoic acid (13.8 g, 100 mmol) is dissolved in concentrated NH4OH (200 mL) using an overhead stirrer and is treated slowly dropwise with a solution of iodine (23.4 g, 92 mmol) and KI (18.26 g, 110 mmol) in water (100 mL). The solution is stirred for 1 h at rt and then treated rapidly dropwise with concentrated HCl (180 mL). The white solid is collected via filtration, rinsed with water and dried overnight [by pulling air through the solid] in vacuo to afford 13.05 g (54%) of 3-hydroxy-4-iodobenzoic acid as a tan solid. 1H NMR (DMSO-d6): δ 7.13, 7.43, 7.80, 10.71, 12.98 ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[NH:6][C:7]1[S:8][C:9]([CH3:14])=[CH:10][C:11]=1[C:12]#[N:13])([O-])=O.[ClH:19]>C(OCC)(=O)C.C(O)(C)C.[Pd]>[ClH:19].[NH2:13][C:12]1[C:11]2[CH:10]=[C:9]([CH3:14])[S:8][C:7]=2[NH:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:1]=1
Reactant: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N
Temperature: 81 °C
Reaction time: 15 h

Procedure:
2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile (100 g) is taken in ethyl acetate (1000 ml). 5% Pd/C (15 g) is added and hydrogenated at 50° C. for 15 hours. Ethyl acetate is distilled off to get the solid. The solid is taken in isopropyl alcohol (500 ml), concentrated hydrochloric acid (102 ml) is added at room temperature and the mixture is heated up to 80-82° C. for 12 hours under stirring. The solution is cooled to precipitate the solid, filtered and dried under vacuum at 55-60° C. to give the title compound (80 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].O1CCOCC1.[Br:24]Br>[Cl-].[Al+3].[Cl-].[Cl-].O1CCCC1>[Br:24][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Yield: 76 %

Procedure:
After dissolving 4.0 g of 4-benzyloxyacetophenone into 20 ml of 1,4-dioxane and 20 ml of tetrahydrofuran, 0.1 g of anhydrous aluminum chloride and 3.1 g of bromine were added under ice cooling and stirring. Further, after stirring for 5 hours under ice cooling, the reaction solution was concentrated to solid. Water and chloroform were added to the residue to separate liquid layers. Then, the chloroform layer was dried over anhydrous sodium sulfate and then concentrated to solid followed by purification by silica gel column chromatography using benzene/n-hexane (1:1) as an elute, to obtain 4.1 g of 2-bromo-1-(4-benzyloxy-phenyl)-ethanone. Then, using 3.0 g of the thus obtained bromide, 2.2 g of (Z)-2-(4-methyl-piperazin-1-yl)-1-(4-benzyloxy-phenyl)-ethanone oxime hydrochloride with the melting point of from 208° to 210° C. (decomposition) and 0.7 g of (E)-2-(4-methyl-piperazin-1-yl)-1-(4-benzyloxy-phenyl)-ethanone oxime hydrochloride with the melting point of from 210° to 212° C. were obtained in the same manner as in Example 1.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][CH2:19][CH2:20][CH2:21]I.CCCCCCC>C(#N)C>[Cl:18][CH2:19][CH2:20][CH2:21][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: O=C1COc2ccccc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC#N
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2H-1,4 benzoxazine-3(4H)one (1.0 g, 6.70 mmol) and Cs2CO3 (3.28 g, 10.1 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.58 g, 7.38 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give 1.65 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the pure title compound as a colorless oil. Yield 1.36 g, 89.2%. Rf=0.24 [Heptane:EtOAC(4:1)], 1H NMR (CDCl3): δ 2.16 (m, 2H), 3.62 (t, 2H), 4.10 (t, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.05 (m, 2H), 13C NMR (CDCl3): δ 30.16, 39.04, 42.45, 67.72, 114.80, 117.38, 123.07, 124.14, 128.49, 145.47, 164.58.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.F.[N+:18]([O-])([OH:20])=[O:19]>>[N+:18]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: F
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
1,000 g of anthraquinone and 500 ml of hydrogen fluoride (90 percent strength) are initially introduced into a 4 liter Venuleth vessel and stirred for 15 minutes. A mixture of 500 ml of hydrogen fluoride (90 percent strength) and 240 ml of nitric acid (98 percent strength) is added at room temperature over the course of 5 minutes. The bath temperature of the Venuleth vessel is then raised to 50°C and the mixture is stirred at this temperature for 4 hours. Working up takes place as in Example 6. 1,200 g of nitro-anthraquinone of the following composition are obtained:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C=O)C>[N:19]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 48 h
Yield: 98.1 %

Procedure:
A mixture of the title compound of Example 2 (57.1 g, 205 mmol) and NaN3 (39.9 g, 614 mmol, 3.0 eq) in DMF (200 mL) was heated and stirred at 70° C. for 48 h when TLC (solvent system C) indicated the reaction to be complete. The reaction mixture was cooled to rt and poured into cold water (200 mL). The aqueous mixture was extracted with Et2O (500 mL) and the organic extract was back-washed with water (2×100 mL), dried (Na2SO4) and the solvent was evaporated in vacuo to afford the product (45.5 g, 98%) as a colorless oil: 1H-NMR (CDCl3) ∂3.66-3.80 (m, 1H), 3.57 (m, 1H), 3.46 (m, Japp=4.0 Hz, 1H), 3.12 (m, 2H), 1.90-2.05 (m, 2H), 1.69-1.83 (m, 2H), 1.47 (s, 9H). No attempt was made to further purify or characterize this compound.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([OH:12])[CH:6]=1)#[N:4].[CH2:13](I)[CH3:14].O>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=1)#[N:4]
Reactant: CCI
Reactant: Cc1ccc(C#N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C#N)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Into a reaction vessel was charged sodium hydride (4.8 g, 0.12 mol) and N,N′-dimethylformamide (40 ml), and a solution obtained by dissolving 4-cyano-2-hydroxytoluene (14) (13.3 g, 0.1 mol) in N,N′-dimethylformamide (40 ml) in an ice bath was dropped on this, and the solution was stirred for 1.0 hour at room temperature. Subsequently, ethyl iodide (18.7 g, 0.12 mol) was dropped in an ice water, and the solution was stirred for 1.5 hours at room temperature. To the reaction liquid was added water and extracted with ethyl acetate, then, washed with saturated saline, dried, and the solvent was distilled off under reduced pressure, to obtain 4-cyano-2-ethoxytoluene (15) (16.1 g, yield from (14) is 99%).
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].OCC[C:14]#[N:15]>>[O:4]=[C:1]([CH2:2][CH3:3])[CH2:5][C:6]([O:8][CH2:9][CH2:10][C:14]#[N:15])=[O:7]
Reactant: N#CCCO
Reactant: CCOC(=O)CC(=O)CC
Product: CCC(=O)CC(=O)OCCC#N
Temperature: 192.5 °C
Yield: 55.5 %

Procedure:
A mixture of 4.86 g of ethyl propionylacetate (33.7 mmol) and 2.00 g of 3-hydroxypropionitrile (28.1 mmol) were placed in a round bottom flask (magnetically stirred) equipped with a short distillation path. The resulting mixture was gradually heated to 180-205° C. in an oil bath. The distillate was collected (1.2 mL). The mixture was then cooled to room temperature and the residue was distilled under reduced pressure to give 2.64 g of product: bp 95-98° C. (0.5 mm Hg). The product was used in the next step after spectral characterization.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:26])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C[O:28][C:29](=O)[O:30]C>C1COCC1>[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH2:26][C:29]([OH:30])=[O:28])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)OC
Reactant: Cc1cc(C(C)(C)C)ccc1C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)O)c(CC(=O)O)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a magnetically stirred solution of diisopropyl amine (0.75 g, 7.4 mmol) in THF (5 mL) at −30° C. is added BuLi (3.4 mL, 2.5 M in hexanes, 8.5 mmol). The mixture is stirred for 10 minutes at this temperature and cooled to −78° C. A solution of 4-tert-Butyl-2-methyl-benzoic acid [J. Am. Chem. Soc. 1944, 66, 154] (250 mg, 1.3 mmol) and dimethylcarbonate (150 mg, 1.67 mmol) in THF (3 mL) is added dropwise at −78° C. The mixture is allowed to stir at this temperature for 2 hours before it is allowed to warm to room temperature. The mixture is quenched with MeOH and water once it reached room temperature. After removal of THF, the water layer is extracted with ether. The water layer is acidified with HCl and the product is extracted from ether. After chromatography, the title compound is isolated pure (125 mg, 41%). MS (ESI): 237.1 (M+1)+1.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+:15]>C(Cl)Cl.C1COCC1>[N+:1]([C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([O-:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Na+:15]
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc([O-])c1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
A commercially available dinitrophenol (10.0 g, 54.3 mmol) was dissolved in 250 mL of methylenechloride, and water was removed on anhydrous magnesium sulfate. Solvent was removed by filtration under the reduced pressure. After the anhydrous dinitrophenol (10.0 g, 54.3 mmol) was dissolved in anhydrous THF (300 mL), NaH (0.782 g, 32.6 mmol) was added slowly. After all NaH was added, the solution was stirred for 3 hrs. Solvent was removed under reduced pressure to obtain 60 mol % sodium dinitrophenolate.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](O)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Pd].C1(C)C=CC=CC=1>[C:1]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)c1ccccc1

Procedure:
The oxidation of toluene appears to follow an obvious path as inferred from the kinetics of the product yields (Table IV). The intermediate products are benzyl alcohol, benzaldehyde, benzoic acid; whereas, benzyl benzoate is the final product by esterification of benzyl alcohol and benzoic acid. In a separate test at the same reaction conditions, but without the Pd catalyst, benzyl alcohol and benzoic acid were esterified in toluene to produce benzyl benzoate. The following reaction scheme explains these results:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>O1CCOCC1>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 100 %

Procedure:
5.0 g of 2-amino-5-bromo-3-nitropyridine are dissolved in 120 ml of anoxic dioxane under a nitrogen atmosphere. Subsequently, 69 ml of an aqueous sodium bicarbonate solution (2.0 M), 5.4 g of 4-fluorophenyl-boronic acid, and 1.0 g of trans-dichloro-bis(tricyclohexylphosphane)palladium-(II) are added. The reaction mixture is refluxed at 110° C. for 17 hours. Thereafter, the volatile components are removed in vacuo and the remaining residue is redissolved in 2.0 l of a mixture of water/dichloromethane (1:1). The aqueous phase is extracted four times each with 625 ml of dichloromethane. The organic layer is separated, dried using sodium sulfate, and evaporated to dryness to yield a colorless, crude solid. Subsequently, the residue is purified by flash chromatography on silica gel (eluent: toluene/ethyl acetate 20:1) to afford 5.35 g of the title compound as a colorless solid of m.p. 232° C. MS: 234.2 (MH+). TLC: Rf=0.30 (toluene/ethyl acetate 20:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[I:9]I>C1COCC1>[F:1][C:2]1[C:7]([I:9])=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: II
Reactant: Cc1ccc(F)nc1
Solvent: C1CCOC1
Product: Cc1cnc(F)c(I)c1
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A solution of 2-fluoro-5-methyl-pyridine (1.0 g, 9.000 mmol) in dry THF (10 mL) was added dropwise and the solution was stirred at this temp for 2 hours. A solution of iodine (2.284 g, 463.3 μL, 9.000 mmol) in THF (10 mL) was then added and the resultant mixture stirred for a further 1 hour at this temp before being quenched with water. The resulting mixture was partitioned between sodium thiosulfate solution and Et2O, organics separated and washed further with saturated NaCl. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a colourless oil. The resulting mixture was purified by column chromatography (30% EtOAc in hexanes, ˜200 mL silica) to give a colourless foam (1.409 g, 66% Yield).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[I:14]I>C1COCC1>[F:6][C:7]1[C:12]([I:14])=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1
Reactant: II
Reactant: Cc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cnc(F)c(I)c1
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
A solution of dilsopropylamine (7.0 mL, 50.0 mmol) in THF (100 mL) at −78° C. was treated with 2.5M n-butyllithium in hexanes (20 mL, 50.0 mmol), stirred for 15 minutes, treated dropwise with a solution of 2-fluoro-5-methylpyridine (5.55 g, 50.0 mmol) in THF (20.0 mL), stirred for 4 hours, treated slowly with a solution of iodine (12.7 g. 50.0 mmol) in THF (50 mL), quenched with water, and extracted with diethyl ether. The combined extracts were washed sequentially with Na2S2O3, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/diethyl ether to provide 7.24 g (61%) of 2-fluoro-3-iodo-5-methylpyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][CH:11]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Na]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:11]([NH:10][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH3:9])[C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: C[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1cccc(F)c1
Agent: Cl[Ni]Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: C[C@@H](NC(c1ccc(F)cc1)c1cccc(N)c1)c1cccc(F)c1

Procedure:
Following a similar procedure to that described in Example (1b), 2.82 g of isomer A of N-[(R)-1-(3-fluorophenyl)ethyl]-N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 3.64 g of nickel chloride hexahydrate, 1.16 g of sodium borolydride and 30 ml of methanol were reacted, to obtain 2.52 g of isomer A of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>CCN(CC)CC>[F:8][C:4]1[N:3]=[C:2]([NH:1][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(F)n1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccc(F)n1

Procedure:
A solution of 2-amino-6-fluoropyridine (4.2 g) in CH2C2 (100 ml) was treated with Et3N (8 ml) and pivaloyl chloride (5 ml) at 0° C. to room temperature overnight. The reaction mixture was washed with water (50 ml), 2N H2SO4 (50 ml), water (50 ml) and dried (Na2SO4). Evaporation of the solvent afforded 6-fluoro-2-pivaloylaminopyridine (6 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[I:20]I.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: II
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1I
Temperature: -75 °C
Reaction time: 3.75 h

Procedure:
In heat-dried argon purged 4-neck flask was placed a solution of pyridin-3-yl-carbamic acid tert-butyl ester (10 g, 51.5 mmol, CAS RN 56700-70-0) in THF (100 mL). After cooling down to −75° C., tert-butyllithium (1.7M solution in n-pentane, 66.6 mL, 113 mmol) was added dropwise over 15 min keeping the temperature below −60° C. The resulting light brown suspension was stirred at −75° C. for 3.75 h. A solution of iodine (28.7 g, 113 mmol) in THF (50 mL) was added dropwise over 20 min. below −63° C. The reaction mixture was stirred at −75° C. for 1.5 h and then poured on saturated aqueous NH4Cl solution (1000 mL) and EtOAc (500 mL). The layers were separated. The organic layer was washed once with 10% aqueous Na2S2O3 solution (300 mL) and once with brine (250 mL), dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 120 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Yellow solid (11.7 g; 71%). MS (ESI): m/z=321.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(C(C)(C)C)cc1N
Temperature: 35 °C

Procedure:
A solution of (239 g, 1.2 mol) 4-tert-butyl-1-methyl-2-nitro-benzene (M. S. Carpenter, W. M. Easter, T. F. Wood, J. Org. Chem. (1951), 586) in MeOH (1.0 L) was treated with Raney nickel (25 g) in a Parr shaker. The apparatus was sealed under hydrogen pressure to 52 psi, heated to 35° C. for 15 hours, and cooled to room temperature. The apparatus was vented and the contents filtered. The filtrate was concentrated in vacuo and distilled, collecting the major fraction (75°-85° C., 1.0 torr). 1H NMR (CDCl3) δ 1.26 (s, 9 H), 2.11 (s, 3 H), 3.54 (bs, 2 H), 6.69 (d, 1 H), 6.72 (dd, 1 H), 6.96 (d, 1 H).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:17]([OH:19])=[O:18])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[C:10]([C:17]([OH:19])=[O:18])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccnc(C(=O)O)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccnc(C(=O)O)c1O
Reaction time: 0.5 h
Yield: 81 %

Procedure:
3-Benzyloxy-4-methoxypicolinic acid (5.3 g) was suspended in 25 ml of ethanol. 10% palladium-carbon (0.5 g) was added to the suspension. The mixture was then catalytically hydrogenated under atmospheric pressure for 30 min. The reaction solution was filtered under the reduced pressure. The filtrate was concentrated under the reduced pressure to give 2.8 g (yield 81.6%) of the title compound as colorless powder.
Reaction SMILES: C(O)C.[CH:4]1([CH3:14])[CH2:9][CH2:8][CH:7]([CH:10]([CH3:12])[CH3:11])[CH:6]([OH:13])[CH2:5]1>O>[CH3:14][C@H:4]1[CH2:5][C@@H:6]([OH:13])[C@H:7]([CH:10]([CH3:12])[CH3:11])[CH2:8][CH2:9]1
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: O
Solvent: CCO
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Yield: 0.1 %

Procedure:
A 0.1% 1-menthol solution is prepared by mixing 30 g of ethyl alcohol, 1.2 g of a surface active agent, 145.65 g of distilled water and 0.15 g of menthol. The mixed solution is diluted twice with distilled water to prepare a control solution. A separate test solution is prepared by dissolving 0.15 g of menthyl glucoside in 100 g of distilled water.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Cl.[CH3:14][NH2:15]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][NH:15][CH3:14]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: CN
Product: CNCC(=O)Nc1c(C)cccc1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A closed stainless-steel reactor is charged with 80 g of N-(2,6-dimethylphenyl)-2-chloro-acetamide and 600 ml of a 40% aqueous methylamine solution. The mixture is heated with stirring at 80° C. for 4 h and then concentrated under vacuum. The crude product is taken up in water and washed with dichloromethane. The aqueous solution is basified using sodium hydroxide solution and extracted with dichloromethane. The organic, phase is dried over sodium sulphate and concentrated to give 60 g of a colourless oil.