Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].CC(O)CCCCCC.[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1(C)C=CC=CC=1.O>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Cc1cccc(C2CC2)c1[O-]
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC(C)O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a mixture of 25.5 g (150 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 12.5 g of 2-octanol was added 2.5 g (purity: 99%; 15.0 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 100 g of pure water and 100 g of toluene were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 3.11 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 75.2%) and 10.0 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.2%) were obtained.
Reaction SMILES: ClC1C=C(C=CC=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[Cl:83][C:84]1[CH:85]=[C:86](B(O)O)[CH:87]=[CH:88][C:89]=1[Cl:90]>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:86]4[CH:87]=[CH:88][C:89]([Cl:90])=[C:84]([Cl:83])[CH:85]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2ccc(Cl)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 4 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 3,4-dichlorophenylboronic acid (50 mg, 0.2625 mmol) to produce the title compound (5 mg, 4% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6].[Cl:10][C:11]1[N:16]=[C:15]([C:17]([NH2:19])=[O:18])[CH:14]=[C:13](Cl)[N:12]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:17]([C:15]1[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([NH:2][CH2:3][C@H:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6])[CH:14]=1)(=[O:18])[NH2:19]
Reactant: COC(=O)[C@@H](O)CN
Reactant: NC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](O)CNc1cc(C(N)=O)nc(Cl)n1
Temperature: 50 °C
Yield: 76.1 %

Procedure:
To a mixture of the (S)-methyl 3-amino-2-hydroxypropanoate hydrochloride (0.333 g, 2.14 mmol) in acetonitrile (10 mL) was added 2,6-dichloropyrimidine-4-carboxamide (0.385 g, 2.01 mmol) and iPr2NEt (0.77 mL, 4.4 mmol). The mixture was heated at 50° C. overnight then cooled. The precipitated solid was filtered off, rinsed once with 2 mL acetonitrile, and air-dried to give (S)-methyl 3-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)-2-hydroxypropanoate as a pale peach-colored powder (0.421 g, 1.53 mmol, 76% yield). LC/MS: m/z=275.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21]O)=[CH:13][CH:12]=3)=[O:5])[CH3:2].S(Cl)([Cl:25])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21][Cl:25])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCO)cc12
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCCl)cc12

Procedure:
78 mg of 6-(3-hydroxy-1-propinyl)-beta-carboline-3-carboxylic-acid-ethylester in 2 ml of thionyl chloride is stirred for 3 h at room temperature. After evaporating till dry, the mixture is heated in ethanol and evacuated. By recrystallization from acetic-acid/cyclohexane, 40 mg of 6-(3-chloro-1-propinyl)-beta-carboline-3-carboxylic-acid-ethylester is obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].C(C(C)=O)C.[CH3:15][O:16][C:17]1[C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[C:20]([C:27](Cl)=[O:28])=[CH:19][CH:18]=1>O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:27]([C:20]1[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:28])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)c2c1OCCO2
Reactant: CCN1CCCC1CN
Solvent: CCC(C)=O
Solvent: O
Product: CCN1CCCC1CNC(=O)c1ccc(OC)c2c1OCCO2
Yield: 103.4 %

Procedure:
87 g of 1-ethyl-2-aminomethyl pyrrolidine and 775 cm3 of methyl ethyl ketone were introduced into a balloon flask provided with an agitator and a thermometer and then, in portions, 155 g of 8-methoxy-1,4-benzodioxane-5-carbonyl chloride was added, with the temperature being maintained at from 5°-10° C. After agitation the mixture was dissolved with 1,500 cm3 of water and then the methyl ethyl ketone was distilled. The remaining solution was filtered and then treated with sodium hydroxide. The oil was decanted and then extracted with methylene chloride. The solution was dried on potassium carbonate and then the methylene chloride was distilled under vacuum. 224.5 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamide was produced. 197.5 g of the base produced was dissolved in 760 cm3 of absolute alcohol, and then 67 g of oxalic acid in solution in 195 cm3 of absolute alcohol was added. The crystals formed were dried off, washed with absolute alcohol and then dried. 208.5 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamide oxalate was produced (M.P. 129°-130° C.; yield: 82%).
Reaction SMILES: [N:1]#[N:2].[C:3]([NH:6][C:7]1[NH:8][C:9](=[O:37])[C:10]2[N:11]=[CH:12][N:13]([CH2:16][O:17][CH:18]([CH2:28][O:29]CC3C=CC=CC=3)[CH2:19][O:20]CC3C=CC=CC=3)[C:14]=2[N:15]=1)(=[O:5])[CH3:4].[H][H]>CO.O.[OH-].[OH-].[Pd+2]>[N:1]#[N:2].[C:3]([NH:6][C:7]1[NH:8][C:9](=[O:37])[C:10]2[N:11]=[CH:12][N:13]([CH2:16][O:17][CH:18]([CH2:19][OH:20])[CH2:28][OH:29])[C:14]=2[N:15]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1nc2c(ncn2COC(COCc2ccccc2)COCc2ccccc2)c(=O)[nH]1
Reactant: [H][H]
Agent: [Pd+2]
Agent: N#N
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Yield: 44.5 %

Procedure:
To a solution of N2 -acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine (4.62 g, 9.67 mmol) in 150 ml of methanol plus 40 ml of water was added 20% palladium hydroxide on carbon as a slurry in 10 ml of water. The mixture was hydrogenated on a Parr hydrogenator at 60 psi of hydrogen for 38 hours then filtered through celite and concentrated to a white solid. Recrystallization from methanol/ethyl acetate gave 1.4 g of N2 -acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp 205°-208° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][N:15]([C:31](=[O:33])[CH3:32])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ncc3n2CNc2ccccc2-3)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(-c2ncc3n2CN(C(C)=O)c2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-(4-methoxyphenyl)-5,6-dihydroimidazo[1,5-c]quinazoline (100 mg) and diisopropylethylamine (50 ml) in THF (20 ml) is added acetyl chloride (50 ml) and the mixture stirred at RT for 5 hours. The reaction is extracted with ethyl acetate (200 ml), the solvent evaporated, and the residue is purified by preparative-plate chromatography (75% ethyl acetate/hexane) to afford 3-(4-methoxyphenyl)-5,6-dihydro-6-acetylimidazo[1,5-c]-quinazoline (Compound 49) as a light yellow solid. m.p. 80°-82° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[CH:4][N:3]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1.N1C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([C:22]3[CH:23]=[CH:24][S:20][CH:21]=3)[CH:18]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Reactant: OB(O)c1ccsc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Nc1ncc(-c2ccc(=O)n(-c3ccsc3)c2)c(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 51.3 %

Procedure:
In a reaction vessel, 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (50 mg, 0.197 mmol), thiophene-3-boronic acid (50 mg, 0.393 mmol), and copper acetate (4 mg, 0.0197 mmol) were suspended in N,N-dimethylformamide (3 ml). Pyridine (31 mg, 0.393 mmol) was added thereto, followed by stirring at room temperature for 14.5 hours in the air. After the reaction was terminated, the mixture was concentrated and suspended in dimethylsulfoxide. Subsequently, the insoluble matters were removed by filtration and the resulting filtrate was purified by HPLC, to give the title compound (34 mg, 51%) as a pale yellow solid.
Reaction SMILES: [C:1]1([P:7]([C:14]2C=C[CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].Cl.ClCC1C=C[NH:26][N:25]=1>O1CCCC1>[C:1]1([P:7]([CH2:14][C:15]2[CH:16]=[CH:17][NH:26][N:25]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1cc[nH]n1
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: c1ccc(P(Cc2cc[nH]n2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of tetrahydrofuran (100 ml) and triphenylphosphine (3.56 g, 13.6 mmol) at room temperature is added lithium (0.100 g, 14.5 mmol). The reaction mixture is stirred at room temperature for 2 hours at which time the lithium has dissolved. The bright red solution is cooled to 0° C., and 3-(chloromethyl)pyrazole hydrochloride (0.960 g, 6.8 mmol) is added at once. The ice bath is removed and the reaction solution is allowed to stir an additional 2 hours. Degassed ethanol (40 ml) is added to the reaction mixture followed by diethyl ether (100 ml). The organic phase is separated and the aqueous phase extracted with diethyl ether (2×25 ml). The organic phases are combined and dried over magnesium sulfate, filtered and concentrated. The crude residue is purified by chromatography (SiO2, 50% ethyl acetate/petroleum ether) to give purified 3-(diphenylphosphinomethyl)pyrazole as a cloudy white oil in 77% yield (2.81 g, 10.6 mmol). This material is characterized as follows: 1H NMR (CDCl3, 500 MHz) δ7.43 (m,4H), 7.41 (d, J=2.0 Hz, 1H), 7.34 (m, 6H), 5.99 (d, J=2.0 Hz, 1H), 3.47 (s, 2H); 13C{1H} NMR (CDCl3, 125 MHz) δ138.16 (d, 14.3 Hz), 132.97 (d, J=18.6 Hz), 129.11, 128.73 (d, J=6.6 Hz), 105.18 (d, J=5.1 Hz), 27.14 (d, J=6.2 Hz) MS m/z 265.9, 182.9 (M—C4H3N2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=C(C3C=NC=CN=3)C=[CH:20][N:19]=2)=[CH:12][CH:11]=1.N1C=CN=CC=1C(=O)C.[CH3:40][C:41]1[O:42][C:43]([C:47](=O)[CH3:48])=[C:44]([CH3:46])[N:45]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=[C:47]([C:43]3[O:42][C:41]([CH3:40])=[N:45][C:44]=3[CH3:46])[CH:48]=[CH:20][N:19]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Reactant: CC(=O)c1oc(C)nc1C
Agent: CC(=O)c1cnccn1
Product: Cc1nc(C)c(-c2ccnc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)n2)o1

Procedure:
Title compound was obtained according to the scheme 6 similarly to the compound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone as the starting material 1-(2,4-dimethyl-oxazol-5-yl)-ethanone (Table 11). Characterization of the title compound is provided in the Table 12.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl[CH2:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)=[O:18])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
To a solution of 4-(4-fluorobenzyl)piperidine (4.25 g, 22.0 mmol) in DMF (50 mL) were added 2-chloro-N-(3,4-dichlorophenyl)acetamide (Reference Example 70-1, 4.77 g, 20.0 mmol) and potassium carbonate (3.04 g, 22.0 mmol), successively, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added ethyl acetate (70 mL). The organic layer was washed with water (20 mL, 10 mL×2), saturated sodium chloride solution (10 mL), successively, dried over magnesium sulfate and concentrated under reduced pressure. To the concentrate was added a mixed solvent of diisopropyl ether/diethyl ether (2/1)(30 mL), and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether (15 mL×4), and dried under reduced pressure to give the titled compound (5.90 g) as white crystals. The filtrate was concentrated. To the concentrate was added a mixed solvent of diisopropyl ether/diethyl ether (2/1)(15 mL), and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether (5 mL×4), and dried under reduced pressure to give the titled compound (1.20 g) as white crystals. Yield: 7.10 g, 90%, 7.10 g, 18.0 mmol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCCCCBr
Reactant: N#CCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(F)c(F)c2)CCCCC1
Reaction time: 0.08 h
Yield: 87.2 %

Procedure:
To a solution of 2-(3,4-difluorophenyl)acetonitrile (2 g, 13.06 mmol) in 20 mL of DMF at 0° C. was added 60% sodium hydride (1.149 g, 28.7 mmol), and the mixture was stirred at the same temperature for 5 mins. Then a solution of 1,5-dibromopentane (1.779 mL, 13.06 mmol) in 20 mL of DMF was added dropwise and the mixture was stirred at a temperature in the range 0° C. to room temperature for 5 hrs. The reaction was quenched with water, and extracted with EtOAc. The mixture was washed with water and brine. The combined aqueous layers were back extracted with EtOAc once and washed with brine. The combined extracts were dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (120 g silica gel) eluting with 1:9 EtOAc-hexane to give 1-(3,4-difluorophenyl)cyclohexanecarbonitrile (2.52 g, 11.39 mmol, 87% yield). 1H NMR (400 MHz, CCl3D) δ ppm 7.12-7.35 (3H, m), 2.14 (2H, d, J=11.86 Hz), 1.75-1.95 (6H, m), 1.64-1.75 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:20]O>CC(OC)(C)C>[CH3:20][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:10][C:2]=1[NH2:1]
Reactant: CCCCOc1ccc(C(=O)O)c(N)c1
Reactant: CO
Solvent: COC(C)(C)C
Solvent: O=S(Cl)Cl
Product: CCCCOc1ccc(C(=O)OC)c(N)c1

Procedure:
A mixture of 2-amino-4-butoxybenzoic acid (2.0 g), thionyl chloride (1.2 g) and methanol (33 mL) was boiled under reflux for 24 hours. The reaction solution was diluted with MTBE and washed with sodium hydroxide solution. The organic phase was dried and concentrated. The product with the molecular weight of 223.27 (C12H17NO3) was obtained in this way; MS (ESI): 224 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:28])[N:4]([CH2:14][C:15]([NH:17][CH:18]([CH:25]([CH3:27])[CH3:26])[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=[O:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:29]1([S:35]([N:38]=[C:39]=[O:40])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[O:28]=[C:3]1[C:2]([NH:1][C:39]([NH:38][S:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)(=[O:37])=[O:36])=[O:40])=[CH:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[CH2:14][C:15]([NH:17][CH:18]([CH:25]([CH3:26])[CH3:27])[C:19](=[O:24])[C:20]([F:22])([F:23])[F:21])=[O:16]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(=O)C(F)(F)F
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)NS(=O)(=O)c2ccccc2)c1=O)C(=O)C(F)(F)F
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To 2-(3-amino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.5 g) in dichloromethane (40 mL) was added benzenesulfonyl isocyanate (0.23 g), and the resulting solution was allowed to stir for 1 h. The solvent was evaporated and the product was purified by chromatography to provide the title compound (0.7 g); chromatography solvent: methanol:dichloromethane (5:95); TLC: Rf =0.6, methanol:dichloromethane (10:90); MS: m/z=579(M+1), 577(M-1) by FAB.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[SH:14][CH2:15][C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)CS
Reactant: O=[N+]([O-])c1cc(CCO)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CSc1ccc(CCO)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 59.6 %

Procedure:
A mixture of 2-(4-fluoro-3-nitro-phenyl)ethanol [RN20274-69-5](1.1 g, 6 mmol), mercaptoacetic acid (0.61 g, 6.6 mmol), potassium carbonate (2.8 g, 20 mmol) and N,N-dimethylformamide (12 ml) was heated at 70° C. for 4 hours. The mixture was poured onto water (200 ml) and the aqueous phase was washed with ethyl acetate. The aqueous phase was then acidified with 1M aqueous hydrochloric acid and extracted three times with dichloromethane. The extracts were dried and evaporated to give an oil (0.92 g, 60%).
Reaction SMILES: O=[CH:2][C:3](=[CH2:5])[CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([NH2:16])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=[O:12].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].S(=O)(=O)(O)O>O>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:8]=1[CH:2]=[C:3]([CH3:5])[CH:4]=[N:16]2
Reactant: C=C(C)C=O
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Cc1cnc2c(C(=O)O)ccc(Cl)c2c1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
14 g of methacrolein were added dropwise, at 100° C., to a solution of 17 g of 4-chloroanthranilic acid and 19 g of sodium m-nitrobenzenesulfonate in 200 g of 57% strength sulfuric acid. The mixture was stirred for 1 hour at 130° C., after which it was diluted with 450 g of water and filtered under suction while hot. The pH was brought to 2-3 with concentrated sodium hydroxide solution, while cooling. The precipitated solid was filtered off under suction, washed with water and dried.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.[CH:21]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22].O>O1CCCC1>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:15]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reaction time: 0.08 h
Yield: 92 %

Procedure:
Lithium hexamethyldisilazane [1.0 M] (44.7 mL, 44.4 mmol) was added to a solution of 5-bromo-1H-indole (7.30 g, 37.0 mmol) in tetrahydrofuran (50 mL) at room temperature. After stirring for 5 minutes, triisopropylsilyl chloride (8.62 g, 44.4 mmol) was added to reaction mixture and stirred for 30 minutes. Water was added to quench the reaction and the solvent was removed under reduced pressure to give the crude mixture, which was purified via column chromatography on silica gel (9:1 hexane/ethyl acetate) to give the title compound in 92% yield. 1H NMR (CDCl3) δ 7.74 (d, J=1.8, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.22 (m, 2H), 6.55 (d, J=3.1 Hz, 1H), 1.65 (m, 3H), 1.12 (d, J=7.5 Hz, 18H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([CH:34]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.[Sn](Cl)(Cl)(Cl)Cl.CN(C)C=O.C(O)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:10]2[C:9]([CH2:8][O:7][C:6]3[CH:34]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:35])=[C:18]3[C:13]([NH:14][C:15]([CH3:22])([CH3:21])[C:16](=[O:20])[N:17]3[CH3:19])=[CH:12][CH:11]=2)=[C:24]([O:32][CH3:33])[CH:25]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 72 h
Yield: 49.5 %

Procedure:
A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(2-methoxy-4-nitrophenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 8-6, 26.1 mg, 0.0544 mmol) and tin chloride (II) (64.8 mg, 0.342 mmol) was suspended in mixed solvent of anhydrous N,N-dimethylformamide (0.25 ml) and anhydrous ethanol (0.5 mL), and stirred at 80° C. for 3 days. After cooling down, the reaction mixture was diluted with ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution was added thereto until the pH became 9. After the precipitated solids were filtered out, the filtrate was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (12.1 mg) as a brown solid. (Yield 50%)