Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]#[N:12].N.[H][H]>C(O)C.[Ni]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: [H][H]
Reactant: N#CCCc1ccc(F)cc1F
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCCCc1ccc(F)cc1F

Procedure:
33.4 g (0.20 mol) of 3-(2,4-difluorophenyl)propionitrile are dissolved in 200 ml of ethanol and, after 2.8 g of Raney nickel in ethanol have been added and after 34 g (2.0 mol) of ammonia gas have been injected, are hydrogenated using hydrogen gas in a pressurized reactor at 75°-80° C. The take-up of hydrogen is complete after about 3 hours. The reaction mixture is cooled, decompressed and filtered and then freed from solvent on a vacuum rotary evaporator. The resultant oil is subjected to fractional distillation at 89°-90° C. in vacuo (13 mbar). 26.0 g (76% of theory) of a colourless oil are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[C:32](Cl)=[O:33]>O1CCCC1>[C:6]1([N:5]([CH2:4][CH2:3][N:2]([CH3:12])[CH3:1])[C:32]([C:22]2[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][O:25][C:21]=2[CH3:20])=[O:33])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: CN(C)CCNc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1C(=O)N(CCN(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of 24.6 grams (0.15 mole) of N,N-dimethyl-N'-phenyl-ethylenediamine and 18.2 grams (0.18 mole) of triethylamine in 500 milliliters of tetrahydrofuran (THF) is cooled to 0° C. and 39.8 grams (0.18 mole) of 5-methyl-3-phenyl-4-isoxazole carbonyl chloride in 100 milliliters of tetrahydrofuran is added dropwise. After the addition is complete, the mixture is warmed to room temperature and stirred for 4 hours. The resulting suspension is filtered and the THF removed in vacuo. The residue is dissolved in methylene chloride and washed with 2N sodium hydroxide and water and then dried over magnesium sulfate. The mixture is filtered and the solvent removed by evaporation. The residue is then treated with hexane to yield crystals of N-phenyl-N-(2-dimethylaminoethyl)-5-methyl-3-phenyl-4-isoxazole carboxamide; M.P. 88°-89° C.
Reaction SMILES: [CH3:1][SH:2].Br[C:4]1[C:14]([O:15][CH3:16])=[C:13]([Br:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:17][C:13]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:2][CH3:1])[C:14]=1[O:15][CH3:16]
Reactant: CS
Reactant: CCOC(=O)c1ccc(Br)c(OC)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OC)c1SC

Procedure:
A solution of methanethiol (47 ml) in dimethyl formamide was added to a mixture of ethyl 2,4-dibromo-3-methoxybenzoate (105 g) and potassium carbonate (131 g) in dimethyl formamide and the resultant suspension was stirred at room temperature overnight. Water was added and the mixture was extracted into ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography eluted with a mixture of ethyl acetate and cyclohexane to give as the minor component ethyl 4-bromo-3-methoxy-2-(methylsulphenyl)benzoate (4.5 g) as a white solid, NMR (CDCl3) 1.5(t,3H), 2.6(s,3H), 4.05(s,3H), 4.5(q,2H), 7.35 (m,2H).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:14])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]([CH:12]=[CH2:13])([NH2:11])[CH2:4]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1.C(OCC)C>[CH3:2][C:3]1([CH3:14])[CH2:8][C:7]([CH3:9])([CH3:10])[CH2:6][C:5]([NH:11][C:22](=[O:23])[O:24][CH3:25])([CH:12]=[CH2:13])[CH2:4]1
Reactant: C=CC1(N)CC(C)(C)CC(C)(C)C1
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC1(NC(=O)OC)CC(C)(C)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A mixture of amine hydrochloride 5 (0.25 g, 1.2 mmol) and Na2CO3 (0.73 g, 6.9 mmol) in THF (6 ml) was stirred at room temperature for 1 h. Methyl chloroformate (0.27 ml, 3.45 mmol) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was diluted with diethyl ether (20 ml), filtered and evaporated to the dryness. The crude product was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10:1) to give 6 (0.24 g, 87%) as a colorless solid with m.p. 61-63° C. 1H-NMR (CDCl3, TMS): 0.92 and 1.15 (total 12H, both s, 3,5-CH3); 1.00-1.40 (4H, m, 4-CH2 and 2,6-CH); 2.00 (2H, d, 14 Hz, 2,6-CH); 3.62 (3H, s, CH3N); 4.72 (1H, br s, NH); 5.00 and 5.06 (total 2H, both d, 10.5 and 17 Hz, ═CH2) and 5.83 ppm (1H, dd, 10.5 and 17 Hz, ═CH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)([CH2:22][CH2:23]O)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)([CH2:22][CH2:23][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: C1CCNC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCN2CCCC2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 178 using pyrrolidine in Step 2. LC-MS Method 2 tR=1.225 min, m/z=491.1; 1H NMR (CD3OD) 1.62 (d, 3H), 2.01 (m, 2H), 2.14 (m, 2H), 2.22-2.49 (m, 4H), 2.56 (m, 1H), 2.92-3.13 (m, 3H), 3.19 (m, 1H), 3.41 (m, 1H), 3.69 (m, 2H), 5.64 (m, 1H), 7.12 (d, 2H), 7.21 (m, 3H), 7.43 (m, 4H), 7.57 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].Br[CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13].[C:15]([O-:27])(=[O:26])[CH2:16][C:17]([CH2:22][C:23]([O-:25])=[O:24])([C:19]([O-:21])=[O:20])[OH:18].[Na+].[Na+].[Na+]>C(#N)C>[C:15]([O-:27])(=[O:26])[CH2:16][C:17]([CH2:22][C:23]([O-:25])=[O:24])([C:19]([O-:21])=[O:20])[OH:18].[CH3:13][C:12]([CH3:14])=[CH:11][CH2:10][N+:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1.[CH3:13][C:12]([CH3:14])=[CH:11][CH2:10][N+:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1.[CH3:13][C:12]([CH3:14])=[CH:11][CH2:10][N+:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: CC(C)=CCBr
Reactant: N#Cc1cccnc1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)=CC[n+]1cccc(C#N)c1

Procedure:
3-Cyanopyridine is reacted with 1-bromo-3-methyl-2-butene in acetonitrile; and the halide intermediate is reacted with sodium citrate.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17](=[S:19])[NH2:18])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:19][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(C(N)=S)c1-c1ccc(F)cc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Yield: 4.2 %

Procedure:
A solution of the compound (710 mg, 2.56 mmol) obtained in Example 1, step 4 and ethyl bromopyruvate (0.322 mL, 2.56 mmol) in ethanol (15 mL) was stirred at 80° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give ethyl 2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazole-4-carboxylate (50 mg, 0.108 mmol, 64.6%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21])([O-])=O.[OH-].[Na+].[H][H]>[C].[Pd]>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21]
Reactant: O=C1c2ccccc2C(=O)c2c1ccc(C(=O)O)c2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(C(=O)O)ccc2c1C(=O)c1ccccc1C2=O
Reaction time: 5 h
Yield: 91.3 %

Procedure:
A 500 ml. electromagnetically stirred glass reactor was charged with 5.0 g (0.0168 mole) of 1-nitro-2-carboxyanthraquinone, 100 g of a 4% aqueous solution of sodium hydroxide and 0.25 g of 5% palladium-carbon. The inside of the reactor was purged with hydrogen, and the 1-nitro-2-carboxyanthraquinone was hydrogenated at 50° C. with stirring. In 5 hours, 0.0504 mole of hydrogen was absorbed, whereupon the reaction was stopped. The reaction mixture was filtered to separate the catalyst. The filtrate was oxidized with air with stirring at 20° to 30° C. for 2 hours, and then neutralized with 20% sulfuric acid to a pH of 2 to 3. The crystals precipitated were filtered, washed with water, and dried to afford 4.1 g of 1-amino-2-carboxyanthraquinone in a yield of 91.3%.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C@@H:8]1[CH2:12][CH2:11][O:10][CH2:9]1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](F)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20].Cl>CN(C)C=O.O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:7][C@@H:8]4[CH2:12][CH2:11][O:10][CH2:9]4)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O[C@@H]1CCOC1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@@H]1CCOC1
Reaction time: 1 h

Procedure:
13.80 g of potassium tert-butoxide are added batchwise to a solution of 10.80 g of (R)-3-hydroxytetrahydrofuran in 100 ml of N,N-dimethylformamide while cooling with an ice bath. The reaction mixture is stirred for about one hour, then 10.40 g of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-fluoroquinazoline are added batchwise. The cooling bath is then removed and the deep red reaction mixture is stirred for two hours at ambient temperature. For working up the reaction mixture is poured onto about 500 ml of water and neutralized with 2 N hydrochloric acid. The yellowish precipitate formed is suction filtered and dried at 70° C. in a circulating air drier. Yield: 12.80 g; melting point: 244° C.; mass spectrum (ESI−): m/z=403, 405 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:28])[C:8]=2[N:29]=1)[CH3:2].C(#N)C>[Pt].CO>[NH2:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:13]1[CH:14]=[CH:15][C:16]2[C:7]3[N:6]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:5]([CH2:4][O:3][CH2:1][CH3:2])=[N:29][C:8]=3[C:9]([NH2:28])=[N:10][C:11]=2[CH:12]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4cccc([N+](=O)[O-])c4)ccc3c2n1CC(C)C
Agent: [Pt]
Solvent: CO
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3cc(OCc4cccc(N)c4)ccc3c2n1CC(C)C
Yield: 9.8 %

Procedure:
2-Ethoxymethyl-1-(2-methylpropyl)-7-(3-nitrobenzyloxy)-1H-imidazo[4,5-c]quinolin-4-amine (980 mg, 2.2 mmol), prepared as described in Example 27, was mixed with acetonitrile (30 mL), and 5% platinum on carbon (˜25 mg) was added. The reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) overnight. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of starting material; additional 5% platinum on carbon (˜25 mg) was added. The reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for an additional three hours. An analysis by LC/MS again indicated that the reaction was incomplete; methanol (100 mL) and 5% platinum on carbon (200 mg) were added. The reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) overnight. The reaction mixture was filtered through a layer of CELITE filter aid, the filter cake washed with hot methanol, and the filtrate concentrated under reduced pressure to yield a solid. The solid was purified by column chromatography on silica gel (45 g, eluting with chloroform:methanol ranging in ratios from 99:1 to 95:5) to provide two products. The first product was recrystallized from 2-propanol to provide 90 mg of 7-(3-aminobenzyloxy)-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as off-white crystals, mp 228.0-230.0° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>>[C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])[CH2:13][CH2:14]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCCCCBr
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OCCCCCCCBr)CC1

Procedure:
In analogy to examples 1.4 and 1.5, trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester was reacted with 1,7-dibromoheptane to yield trans-[4-(7-Bromo-heptyloxy)-cyclohexyl]-methyl-carbamic acid tert-butyl ester which was reacted with N-allylmethylamine to yield trans-(4-[7-(Allyl-methyl-amino)-heptyloxy]-cyclohexyl)-methyl-carbamic acid tert-butyl ester as colorless oil, MS: 397 (MH+).
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)[CH3:2].C(N=C=S)C.[NH2:13][C:14]1[C:15]([Cl:30])=[N:16][C:17]2[C:22]([C:23]=1[NH:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])=[CH:21][CH:20]=[CH:19][CH:18]=2>N1C=CC=CC=1>[Cl:30][C:15]1[C:14]2[N:13]=[C:4]([NH:3][CH2:1][CH3:2])[N:24]([CH2:25][C:26]([CH3:27])([OH:28])[CH3:29])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Solvent: c1ccncc1
Solvent: CCN=C=S
Product: CCNc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Temperature: 80 °C
Yield: 77.2 %

Procedure:
Triethylamine (3.15 mL, 22.6 mmol) and ethyl isothiocyanate (1.19 mL, 13.6 mmol) were sequentially added to a solution of 1-[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (3.00 g, 11.3 mmol) in pyridine (50 mL), and the reaction was heated for five minutes at 80° C. 1,(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.60 g, 13.6 mmol) was added slowly, and the reaction was heated overnight at 80° C., allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), and the resulting solution was washed with brine (3×) and water (1×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 2-3% methanol in dichloromethane) to provide 2.78 g of 1-[4-chloro-2-(ethylamino)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13](OCC)=[O:14].C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]2[C:13](=[O:14])[CH:12]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1nc(N)sc1C
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Product: Cc1sc2nc(CCl)cc(=O)n2c1C
Yield: 144 %

Procedure:
This compound was synthesized from 2-amino-4,5-dimethylthiazole (5.0 g, 30.365 mmol) and ethyl chloroacetoacetate (6.519 g, 42.511 mmol) in polyphosphoric acid (40.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 10.0 g of the desired compound as a black solid; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.60 (s, 3H), 4.52 (s, 1H), 6.25 (s, 1H); ESI-MS (m/z) 229.60 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12](=[O:18])[NH:13][CH:14]=[CH:15][C:16]=1[I:17])=O.O=P(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[NH:1]1[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]=[C:9]1[C:11]1[C:12](=[O:18])[NH:13][CH:14]=[CH:15][C:16]=1[I:17]
Reactant: Nc1ccncc1NC(=O)c1c(I)cc[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=c1[nH]ccc(I)c1-c1nc2cnccc2[nH]1
Reaction time: 2 h

Procedure:
To a solution of 4-iodo-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (4-amino-pyridin-3-yl)-amide (281 mg, 0.79 mmol) in 9 mL pyridine at 0 C was added (slowly) 0.5 mL POCl3 (5.3 mmol). The mixture was stirred at 0 C for 2 hours, then poured on a mixture of ice and saturated aqueous sodium bicarbonate solution. The product precipitates as a colloid. All attempts to filter or extract the product failed. The mixture was concentrated in vacuum, water removed by aceotropic destillation with n-propanol and the crude mixture used as it is. LCMS [M+H]+ 339, T=0.54 min product and [M+H]+ 357, T=0.29 min unreacted starting material [YMC ODS-A C18 S7 3.0×50 mm column; 0-100% gradient over 2 min*; 5 mL/min flow rate]. * Gradient begins with 10% methanol/90% water (0.1% TFA) and end with 90% methanol/10% water (0.1% TFA)
Reaction SMILES: [CH3:1]C1C=C(O)C=CC=1O.[O-2].[La+3].[O-2].[O-2].[La+3].CC1C(C)=C(C=CC=1O)O.[CH3:25][C:26]1[C:27]([OH:35])=[C:28]([CH3:34])[C:29]([CH3:33])=[C:30]([CH:32]=1)[OH:31]>CO>[CH3:25][C:26]1[C:27]([OH:35])=[C:28]([CH3:34])[C:29]([CH3:33])=[C:30]([OH:31])[C:32]=1[CH3:1]
Reactant: Cc1cc(O)ccc1O
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: Cc1c(O)ccc(O)c1C
Agent: [La+3]
Agent: [O-2]
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into an autoclave (inner volume: 9 ml, made of SUS 316, equipped with a manometer) were charged 0.098 g of methylhydroquinone, 3.491 g of methanol and 7 mg of lanthanum oxide (manufactured by High Purity Chemicals Co.). The reaction was started by elevating the temperature up to 350° C. with sand bath. The pressure during the reaction was 18 MPa. After 2 hours, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of methylhydroquinone was 32% by mole, the selectivity of dimethylhydroquinone was 80% by mole, the selectivity of trimethylhydroquinone was 10% by mole and no tetramethylhydroquinone was produced.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:14]([CH3:21])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])[CH:11]=[CH:12][CH:13]=1.[CH2:22]([C:24]([C:43]1[CH:56]=[CH:55][C:46]([O:47][CH2:48][C@@H:49]2[O:53][C:52](=[O:54])[CH2:51][CH2:50]2)=[C:45]([CH3:57])[CH:44]=1)([C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([CH3:42])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(OCC)(=O)C>CN(C)C=O>[CH2:22]([C:24]([C:43]1[CH:56]=[CH:55][C:46]([O:47][CH2:48][C@@H:49]2[O:53][C:52](=[O:54])[CH2:51][CH2:50]2)=[C:45]([CH3:57])[CH:44]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:21])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:15])[CH:9]=2)=[C:29]([CH3:42])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CC(C)(O[Si](C)(C)C)c1cccc(Br)c1
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2cccc(C(C)(C)O[Si](C)(C)C)c2)c(C)c1
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 51.5 %

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.49 mg, 0.002 mmol), a 2 M Na2CO3 solution (0.1 mL, 0.2 mmol) and [1-(3-bromo-phenyl)-1-methyl-ethoxy]-trimethylsilane (Example 16-(1); 26.3 mg, 0.091 mmol) were added to a solution of (R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(3); 30 mg, 0.061 mmol) in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 85° C. for 13.5 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1, developed twice) to give the title compound (18 mg, 49.2%).
Reaction SMILES: C([N:8]1[CH2:29][CH2:28][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12]2=[CH2:27])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=[O:31]>[Pd]>[CH2:17]([N:13]1[C:12]([OH:31])([CH3:27])[C:11]2([CH2:28][CH2:29][NH:8][CH2:9][CH2:10]2)[O:15][C:14]1=[O:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C=C1N(CCCCCCCCCC)C(=O)OC12CCN(Cc1ccccc1)CC2
Reactant: O=CO
Agent: [Pd]
Product: CCCCCCCCCCN1C(=O)OC2(CCNCC2)C1(C)O
Yield: 78 %

Procedure:
4.0 g of 8-benzyl-3-decyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane are stirred together with 4.0 g of 10% by weight palladium-on-carbon catalyst in 40 ml of 50% aqueous formic acid for 2 hours at room temperature. After filtering off the catalyst the solution is evaporated under reduced pressure, the residue is treated with aqueous sodium hydrogen carbonate solution and the solid product is filtered off. After recrystallizing this product from a mixture of chloroform with n-hexane the title substance is obtained in 78.0% yield, m.p. 139°-140° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[S:17]([O:1][CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6])([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CC(C)(CO)CS(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)CS(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of 5.0 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide in 18 ml of pyridine was added 6.3 g of p-toluenesulfonyl chloride under ice-cooling and stirring. After 2 hours, the reaction mixture was poured to a mixture of 300 ml of chloroform and 100 ml of ice-water. The separated chloroform layer was washed in turn with diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate and to obtain 8.5 g of 3-tosyloxy-2,2-dimethyl-1-propanesulfonamide.
Reaction SMILES: [C:1]([O:12]CC)(=[O:11])[C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[OH-].[Na+].Cl.C(OCC)(=O)C>C1COCC1>[C:5]1([NH:4][C:2](=[O:3])[C:1]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(=O)Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
Ethyl oxanilate 83 (Aldrich, 1.0 g, 1.0 eq) in 12 mL of THF was treated dropwise with a 1N NaOH solution (5.70 mL, 1.1 eq) resulting in a white precipitate. After stirring for 3 hours at RT, 0.5N HCl and ethyl acetate were added, the organic layer separated, washed with 0.5N HCl and brine and then dried over sodium sulfate, filtered, and concentrated to give 712 mg (68%) of N-phenyl oxalamic acid 84 as a white solid with consistent analytical data. FIA M+H=166.0, M−H=163.9; 1H NMR (DMSO-d6) δ 10.70 (s, 1H), 7.75 (m, 2H), 7.35 (m, 2H), 7.15 (m, 1H) ppm.