Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]2[O:15][CH2:14][CH2:13][O:12]2)=[CH:6][CH:5]=1)([O-])=O>CO>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CC2OCCO2)cc1
Solvent: CO
Product: Nc1ccc(CC2OCCO2)cc1
Reaction time: 0.75 h
Yield: 93.2 %

Procedure:
Compound III (231 mg), from Example 6, was dissolved in methanol (about 3 ml) and the mixture flushed with nitrogen. Pd/C (120 mg) was added to the mixture and the sides of the reaction flask were rinsed with methanol (about 2 ml). The mixture was flushed with nitrogen and then flushed with hydrogen. The reaction mixture was stirred for 45 minutes, and then filtered through Celite. The Celite was rinsed several times with methanol and the filtrate and rinses were rotoevaporated to yield 184.4 mg (90.6 percent yield) of Compound IV.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[B-](CC)(CC)CC>C1COCC1>[OH:15][CH2:14][C:12]1[N:13]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[S:10][CH:11]=1
Reactant: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(CO)cs1
Temperature: -45 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
Ethyl 2-aminothiazole-4-carboxylate (55; 10.0 g, 58.1 mmol) was taken up in 150 mL of anhydrous THF along with di-tert-butyl carbonate (BOC2O, 12.67 g, 58.1 mmol) along with 10 mg of 4-(dimethyl)aminopyridine (DMAP). The reaction mixture was stirred at 50° C. for 4 h and then at room temperature for 18 h. It was then concentrated under reduced pressure to obtain a thick oil. Pentane was added and the resulting crystalline materials were collected by filtration and dried to afford 10.5 g of ethyl 2-(tert-butoxycarbonylamino)thiazole-4-carboxylate 56. This material 56 (10.5 g, 38.5 mmol) was dissolved in 300 mL of anhydrous THF and cooled in Dry Ice-acetonitrile bath. A solution of 1 M Super Hydride™ in THF (85 mL) was then added over a period of 10 min. The resulting reaction mixture was stirred at −45° C. for 2 h. Another portion of 1 M Super Hydride™ in THF (35 mL) was then added and the reaction mixture was stirred for an additional 2 h at −45° C. The reaction was quenched at −45° C. by the addition of 50 mL of brine. Upon warming to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 6.39 g of tert-butyl 4-(hydroxymethyl)thiazol-2-ylcarbamate 57 (72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:17])O[C:11](C)(C)[O:12][C:13]=1[CH3:14].C=[N:19][C:20]([CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH3:21]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:17])[N:19]([C:20]([CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH3:21])[CH2:11][O:12][C:13]=1[CH3:14]
Reactant: C=NC(C)(C)c1cccc(Cl)c1
Reactant: CC1=C(c2ccccc2F)C(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2cccc(Cl)c2)CO1
Yield: 83.2 %

Procedure:
Xylene (2 ml ) was added to a mixture of 5-(2-fluorophenyl)-2,2 ,6-trimethyl-2H,4H-1,3-dioxin-4-one (compound of Example 1 ) (0.71 g) and N-methylene-1-methyl1-(3-chlorophenyl)ethylamine (compound of Example 3) (0.6 g), and the resulting mixture was heated at reflux for 20 minutes for reaction. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.9 g).
Reaction SMILES: C1(C(=[N:14][C:15]2[N:20]=[C:19]([CH2:21][N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]4([C:42]5[C:33](=[CH:34][C:35]6[O:40][CH2:39][CH2:38][O:37][C:36]=6[CH:41]=5)[O:32][CH2:31]4)[C:23]3=[O:43])[CH:18]=[CH:17][CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:14][C:15]1[N:20]=[C:19]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]3([C:42]4[C:33](=[CH:34][C:35]5[O:40][CH2:39][CH2:38][O:37][C:36]=5[CH:41]=4)[O:32][CH2:31]3)[C:23]2=[O:43])[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1N(Cc2cccc(N=C(c3ccccc3)c3ccccc3)n2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
To a solution of 1′-({6-[(diphenylmethylidene)amino]pyridin-2-yl}methyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.18 g, 0.32 mmol) in tetrahydrofuran (10 mL) was added 2 M aqueous hydrochloric acid (0.5 mL). The reaction mixture was stirred at ambient temperature for 10 min, cooled to 0° C. and saturated aqueous sodium bicarbonate (10 mL) was added. The mixture was diluted with ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layers was washed with brine (45 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with 65% ethyl acetate in hexanes to afford 1′-[(6-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.10 g, 76%) as a colorless solid: mp 240-241° C.; 1H NMR (300 MHz, CDCl3) δ7.45-7.35 (m, 1H), 7.25-7.14 (m, 2H), 7.06-6.98 (m, 1H), 6.91-6.86 (m, 1H), 6.59-6.54 (m, 1H), 6.50 (s, 1H), 6.45-6.39 (m, 1H), 6.37 (s, 1H), 5.12-5.03 (m, 1H), 4.99-4.92 (m, 1H), 4.80-4.63 (m, 4H), 4.25-4.05 (m, 4H); 13C NMR (300 MHz, CDCl3) δ 177.5, 157.9, 155.2, 153.0, 144.6, 142.1, 139.0, 138.2, 132.2, 128.8, 123.7, 123.4, 121.2, 111.7, 111.1, 109.6, 107.9, 99.3, 80.0, 64.5, 63.9, 58.1, 45.2; MS (ES+) m/z 401.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:25]([CH:30]=O)=[N:26][CH:27]=[CH:28][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:30][C:25]2[C:24]([CH3:23])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of 4-[(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester, 3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 in CH2Cl2 gave 4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.84-1.88 (m, 4H), 2.09 (s, 6H), 2.50-2.66 (m, 3H), 3.81 (s, 4H), 4.14-4.17 (m, 2H), 7.05-7.09 (m, 2H), 7.36 (d, 2H, J=9.0 Hz), 8.34 (d, 2H, J=3.0 Hz). Deprotection with TFA using General Procedure F gave COMPOUND 249 as a white solid. 1H NMR (CDCl3) δ 1.56-1.70 (m, 2H), 1.75 (s, 1H), 1.90 (d, 2H, J=12.0 Hz), 2.10 (s, 6H), 2.31-2.51 (m, 2H), 2.55-2.58 (m, 1H), 3.12 (d, 2H, J=12.0 Hz), 3.84 (s, 4H), 7.05-7.09 (m, 2H), 7.35 (d, J=7.5 Hz), 8.34 (d, 2H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.42, 28.86, 47.07, 55.13, 58.17, 122.64, 133.81, 138.29, 146.21, 157.93. ES-MS m/z 311 (M+H). Anal. Calcd. for C19H26N4.0.3H2O: C, 72.25; H, 8.49; N, 17.74. Found: C, 72.11; H, 8.41; N, 17.58.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.COC1C=CC2SC(B(O)O)=CC=2C=1.Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[N+:35]([O-:37])=[O:36]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][C:8]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=3[N+:35]([O-:37])=[O:36])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: COc1ccc2sccc2c1
Agent: COc1ccc2sc(B(O)O)cc2c1
Product: COc1ccc(-c2cc3cc(OC)ccc3s2)c([N+](=O)[O-])c1

Procedure:
Synthesized from 5-methoxybenzo[b]thiophene according to an analogous synthetic method to Preparation Example 78, (5-methoxybenzo[b]thiophen-2-yl)boronic acid (6.2 g) and 4-bromo-3-nitroanisole (5.5 g) were used according to an analogous synthetic method to Preparation Example 79 to provide 5-methoxy-2-(4-methoxy-2-nitrophenyl)benzo[b]thiophene (2.7 g). The total amount of this compound was used according to an analogous synthetic method to Example 22 to provide the title compound (2.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-])=O)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1>C(O)C.[C].[Pd]>[NH2:10][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[C:6]([CH3:9])[N:5]=1
Reactant: COc1ccc(C)nc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C)nc1N
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 3-methoxy-6-methyl-2-nitropyridine (3.85 g) in ethanol (91.6 ml) was added 10% palladium-carbon (50% wet, 0.96 g), and the mixture was stirred under hydrogen atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to dryness. The residue was recrystallized from ethyl acetate/hexane to give the title compound (2.89 g).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=1.O>CN(C=O)C>[I:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12]2[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: Nc1ccc(I)cc1
Reactant: COc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccnc(Nc2ccc(I)cc2)n1
Temperature: 125 °C
Reaction time: 21 h
Yield: 14 %

Procedure:
Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of 4-iodoaniline (220 mg) and 2-chloro-4-methoxypyrimidine (145 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125° C. for 21 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=10/1) to obtain N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg). (2) Under an argon atmosphere, N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg) was added to a suspension of sodium hydride (11 mg) in anhydrous DMF (5 ml), and the resulting mixture was stirred at room temperature for 5 minutes. Methyl iodide (0.0096 ml) was added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 23 hours. Water was added thereto and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=3/1) to obtain N-(4-iodophenyl)-4-methoxy-N-methylpyrimidin-2-amine (46 mg).
Reaction SMILES: O.P([O-])([O-])([O-])=O.[CH2:7]([O:9][C:10]([CH:12]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=2[O:13]1)=[O:11])[CH3:8].[OH-]>O1CCCC1>[CH2:7]([O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=2[O:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CCc2ccc(O)cc2O1
Yield: 45.5 %

Procedure:
A 250 mL 3-necked, round-bottomed flask equipped with a mechanical stirrer, a pH electrode connected to a pH control unit and an addition tube connected to a peristaltic pump, was charged with 60 mL of deionized water, 15 mL of 0.05M phosphate buffer (pH 7.0) and 2.2 g racemic 3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester dissolved in 7.5 mL of tetrahydrofuran. The pH was adjusted to 8.0 with 0.1N aqueous hydroxide solution, and 0.4 g of Pseudomonas lipase enzyme (P-30, Amano International Enzyme Co., Inc., Troy, Va.) was added while the mixture was stirred at a fast rate. The reaction flask was stoppered to avoid loss of the co-solvent by evaporation and the stirring was continued at the same rate. The pH was maintained at 8.0 by adding 0.1N aqueous sodium hydroxide solution via the peristaltic pump. The reaction was discontinued when 55 mL of 0.1N aqueous sodium hydroxide had been consumed (at about the 10 hour mark) and the tetrahydrofuran was removed by evaporation at 35° C. under 10 mm Hg of vacuum. The remaining mixture was extracted 3 times with 50 mL (for a total of 150 mL) of ethyl acetate. The combined organic layers were washed with 50 mL of saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solution was filtered and concentrated at 40° C. under 10 mm Hg of vacuum, to obtain 1.0 g (45% yield, 100% of theory) of (R)-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester as an off-white solid; m.p. 77°-78° C., (α)D25 -20.2° (c 1.0, CHCl3), 99.6% e.e.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[Cl:37])[C:17]([CH:19]1[C:24](=O)[C@@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[Cl:37][C:31]1[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=1[N:16]1[C:17](=[O:18])[C:19]2[C@@H:20]3[C:26]([CH3:27])([CH3:28])[C@@:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]=2[NH:15]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1cc(Cl)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cc(Cl)ccc3Cl)c(=O)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
Trifluoroacetic acid (100 mL) was added slowly to a cooled (0° C.) solution of N′-(2,5-dichloro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜46.9 mmol) in dichloromethane (100 mL), and the resulting solution was stirred at 0° C. for 10 min and then at room temperature for 2 h. The solvent was evaporated and dichloromethane (200 mL) was added. The solution was washed with water (4×80 mL) and brine (80 mL), dried (magnesium sulfate), filtered, and evaporated to give a brown foam. This was triturated with 10% ethyl acetate/hexane (100 mL) and the mixture was stirred at room temperature for 20 min and then cooled in an ice-bath at 0° C. for 1 h. The solid was filtered off, washed with hexane, and dried to give (4S,7R)-2-(2,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (13.55 g, 86%) as a tan solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:34].[Na+].Cl>CO.O>[NH2:34][C:2]1[CH:3]=[CH:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: NC1=CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C=C1
Yield: 89.7 %

Procedure:
3-(4-(4-Oxopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (375 mg, 1 mmol) was dissolved in MeOH (10 ml), treated with ammonium acetate (771 mg, 10 mmol) and sodium cyanoborohydride (440 mg, 7 mmol) and refluxed 4 hours. The mixture was neutralised with 1 N hydrochloric acid, water (15 ml) added, and extracted with dichloromethane (3×15 ml), and dried (magnesium sulfate). Evaporation gave the desired product (334 mg).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([O:21][CH3:22])[C:14]([C:23]3[N:24]=[CH:25][O:26][CH:27]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:21][CH3:22])[C:14]([C:23]3[N:24]=[CH:25][O:26][CH:27]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2cocn2)c1OC
Solvent: CO
Product: COc1c(-c2cocn2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O

Procedure:
Prepared by proceeding in a similar manner to Example 3, starting from crude methyl 6-(benzenesulphonylmethyl)-3-(oxazol-4-yl)-2-methoxybenzoate (Intermediate 49) and using methanol in place of dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:7]=1.[Cl-].[NH4+].C(OCC)(=O)C>C(O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1-c1ccc(F)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1-c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a solution of the above 5-chloro-4′-fluoro-2-nitrobiphenyl (4.20 g, 15.7 mmol) and iron powder (2.75 g, 49.3 mmol) in ethanol (20 mL), a saturated aqueous ammonium chloride solution (aq., 8.0 mL) was added, and the mixture was stirred at 90° C. for 30 minutes. After the reaction, the reaction mixture was cooled to room temperature and ethyl acetate (30 mL) was added. After the organic phase was washed with water (30 mL), it was dried with sodium sulfate. After the filtration and concentration, the residue was purified by silica gel column chromatography (ethyl acetate/hexane, 1:20-1:3, v/v) to give the title compound (2.43 g, 11.0 mmol, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:6][CH:7]=1.Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=3)[CH2:24][CH2:23]2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: O=C(O)c1cc(Cl)ccn1
Product: COC(=O)c1ccc(NCC2CCN(c3ccnc(C(=O)O)c3)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Yield: 82.5 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-5-methoxycarbonyl-2-[(4-piperidinylmethyl)amino]benzamide (0.30 g, 0.74 mmol) and 4-chloropicolinic acid (0.23 g, 1.5 mmol) afforded 320 mg (82%) of the title compound.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][CH:13]([CH2:19][CH:20]=C)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:10]([Cl:24])[CH:9]=1>C1COCC1.O.O=[Os](=O)(=O)=O>[Br:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][CH:13]([CH2:19][CH:20]=[O:2])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:10]([Cl:24])[CH:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(Cc1ccc(Br)cc1Cl)C(=O)OCC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CC=O)Cc1ccc(Br)cc1Cl
Reaction time: 2 h
Yield: 75.7 %

Procedure:
Add sodium periodate (41 g, 190 mmol) into a solution of ethyl 2-(4-bromo-2-chlorobenzyl)pent-4-enoate (21 g, 63 mmol), 2.5 wt % OsO4 (64 g, 6.3 mmol) in THF (400 mL) and water (160 mL) and stir for 2 hours. Extract the reaction mixture with ethyl acetate, wash the organic layer with sodium thiosulfate solution and brine. Dry over sodium sulfate, filter and concentrate. Purify the residue with silica gel column to afford the title compound (15.9 g, 75%) as colorless oil: 1H NMR (CDCl3) 9.73 (s, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.32 (dd, J=8.20, 2.0 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 4.05-4.15 (m, 2H), 3.20-3.28 (m, 1H), 3.07-3.15 (m, 1H), 2.84-2.92 (m, 2H), 2.53-2.61 (m, 1H), 1.51-1.21 (m, 3H).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].C1(N[S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])C=CC=CC=1.CCOCC.CCCCCC>CN(C)C=O.CCOCC.O>[F:26][C:25]([F:28])([F:27])[S:22]([O:1][C:2]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:24])=[O:23]
Reactant: CCCCC(=O)CC(=O)OCC
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCCCC(=CC(=O)OCC)OS(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
Ethyl 3-ketoheptanoate (2.07 g, 12 mmol) was dissolved in dimethylformamide (60 mL) under argon and sodium hydride (357 mg, 14.4 mmol) was added. After 30 minutes at room temperature the solid N-phenyltrifluoro-methanesulfonamide (Tetra. Letters, (1983), 24, 979) (4.97 g, 13.8 mmol) was added. The reaction was stirred for 2 hours, diluted with ether/water and the usual workup gave after chromatography with 5:95 ether/hexane 3.45 g (94%) of ethyl 3-trifluoromethanesulfonyloxy-2-heptenoate.
Reaction SMILES: BrC1C=CC(O)=C(C(C2C=CC=CC=2)=O)C=1.COC1C=CC(CN)=CC=1.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([C:35](=[N:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH:35]([NH:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:29]=1
Reactant: COc1ccc(CN=C(c2ccccc2)c2cc(Br)ccc2O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COc1ccc(CN)cc1
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1ccc(CNC(c2ccccc2)c2cc(Br)ccc2O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5-Bromo-2-hydroxy-phenyl)-phenyl-methanone (5.0 g, 17.68 mmol) is dissolved in dichloromethane (20 mL). 4-Methoxybenzylamine (3.00 mL, 22.02 mmol) is added and the mixture stirred at room temperature for 2 hours. 4-Bromo-2-[(4-methoxy-benzylimino)-phenyl-methyl]-phenol (700 mg, 1.766 mmol) is dissolved in dichloromethane (6 mL) and treated with sodium triacetoxyborohydride (2.0 g, 8.96 mmol). The mixture is stirred at room temperature over the weekend. The mixture is poured into saturated aqueous sodium bicarbonate solution. The aqueous phase is exhaustively extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, the drying agent is filtered off. The filtrate is concentrated to dryness in vacuo. The residue is purified by column chromatography on silica gel using dichloromethane as an eluant. The product fractions are evaporated to dryness in vacuo. This affordes the desired compound as a colourless oil.
Reaction SMILES: N[C:2]1[CH:7]=CC=C[CH:3]=1.C=CC.[NH2:11][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH:2]([CH3:7])[CH3:3])[C:12]=1[NH2:11]
Reactant: Cc1ccccc1N
Reactant: Nc1ccccc1
Solvent: C=CC
Product: Cc1cccc(C(C)C)c1N

Procedure:
2-Methyl-6-isopropyl aniline was prepared by the method of Example 2 using an H-Y zeolite catalyst for the condensation of aniline and propylene. The ortho-toluidine and propylene were fed to the reactor in a 1:5 molar ratio and at an LHSV of 0.25 based on o-toluidine. The reaction was conducted at 250° C. and 861 psig. The effluent product stream was analyzed by gas chromatography. Conversion of o-toluidine was 81.5%.