Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[OH:25][CH2:26][C:27](=O)[CH3:28].[BH3-]C#N.[Na+]>C(Cl)Cl.C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:27]([CH3:28])[CH2:26][OH:25])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Reactant: CC(=O)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(CO)Nc1cccc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c1
Reaction time: 8 h

Procedure:
To a mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (100 mg, 0.32 mmol) and hydroxyacetone (0.03 mL, 1.5 eq) in CH2Cl2 (12 mL) and THF (5 mL) was added NaCNBH3 (28 mg, 1.5 eq) and the reaction mixture was stirred overnight. The volatiles were removed under vacuo and the residue was purified by preparatory TLC to give 3-(1-methylindol-3-yl)-4-[3-(2-hydroxy-1-methylethylamino)phenyl]-1H-pyrrole-2,5-dione (8 mg). LC/MS: M+ 375(85.6%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][C:11]1[CH:12]=[C:13]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[CH:28][CH:29]=[C:30]4[C:34]=3[N:33]([CH3:35])[CH:32]=[C:31]4[CH:36]=O)[N:22]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH3:20])[CH3:19].[OH-].[Na+]>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[CH:28][CH:29]=[C:30]4[C:34]=3[N:33]([CH3:35])[CH:32]=[C:31]4[CH2:36][NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:22]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH3:19])[CH3:20]
Reactant: CCOC(=O)CCN
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCNCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
ethyl β-alaninate hydrochloride (768 mg) and 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (396 mg) was added to a solution of NaOH (200 mg) in ethanol (10 mL). After stirring for 0.5 hour, ethanol was evaporated off and then dichloromethane (40 mL) containing AcOH (0.5 mL) was added to the residue. NaBH(OAc)3 (1.06 g) was added to the above mixture. The reaction mixture was stirred at room temperature overnight and then terminated by saturated NaHCO3 solution. The organic layer was separated and washed with water and brine. After the solvent was evaporated off the residue was purified by Mass Directed AutoPrep to afford ethyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-6-alaninate (D78) (288 mg) as a yellow solid. δH (CDCl3, 400 MHz): 1.24 (3H, t), 1.46 (6H, d), 1.74 (1H, br s), 2.78 (2H, t), 3.25 (2H, t), 3.74 (3H, s), 4.31 (2H, s), 4.69-4.76 (1H, m), 7.07 (1H, d), 7.70 (1H, t), 7.60 (1H, d), 7.80 (1H, dd), 8.02 (1H, dd), 8.22 (1H, d). MS (ES): C26H29ClN4O4 requires 496; found 380.2 (M—NHCH2CH2COOEt+).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].S(Cl)([Cl:10])=O.[CH2:12](OCC)[CH3:13]>C(O)C>[ClH:10].[NH2:1][CH:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:12][CH3:13])=[O:4]
Reactant: CCOCC
Reactant: O=S(Cl)Cl
Reactant: CCC(N)C(=O)O
Solvent: CCO
Product: CCOC(=O)C(N)CC
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A slurry of 2-aminobutyric acid (100 g, Aldrich) in absolute ethanol (300 ml) was stirred under nitrogen at 0° C. and thionyl chloride (120.8 g) was added dropwise. The reaction was stirred overnight at 0° C. and then gradually warmed to room temperature. The resulting white slurry was heated under reflux for 3 hours, left to cool for 10 minutes, then poured into chilled diethyl ether (600 ml) with hand stirring. The suspension was filtered and the solid product dried to give the desired product (150 g) as a white solid. 1H NMR consistent with proposed structure.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>O.C(O)C>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccnc3)c2cc1OC
Temperature: 70 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
N,N-Dimethylformamide (1 ml), ethanol (0.5 ml), and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-pyridylboronic acid (44 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (33 mg, yield 75%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][NH:4][C:3]1=[O:8].BrBr.[C:11]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[CH3:18][O:17][C:11]1[CH:16]=[CH:15][C:14]([CH:5]2[NH:4][C:3](=[O:8])[N:2]([CH3:1])[C:6]2=[O:7])=[CH:13][CH:12]=1
Reactant: COc1ccccc1
Reactant: CN1C(=O)CNC1=O
Agent: BrBr
Solvent: CC(=O)O
Product: COc1ccc(C2NC(=O)N(C)C2=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
4.56 g (40 mmol) of 3-methyl-hydantoin, 30 ml of acetic acid, and 2.0 ml (40 mmol) of bromine were mixed at room temperature. The reaction mixture was then vigorously stirred at a temperature of 40° C. for 2 hours. The reaction mixture was then allowed to cool to room temperature. To the reaction mixture was then added 60 mmol of anisole. The reaction mixture was then allowed to undergo reaction at a temperature of 100° C. for 6 hours. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 4.22 g (yield: 48%) of 5-(p-methoxyphenyl)-3-methyl-hydantoin.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:31][CH:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)[CH:12]=3)[CH:7]=1
Reactant: CN1CCC(N)CC1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC3CCN(C)CC3)cc21
Temperature: 180 °C
Yield: 19.5 %

Procedure:
To a solution of Example A3 (2.1 g, 5.96 mmol) in NMP (10 mL) was added 1-methyl-piperidin-4-ylamine (1.36 g, 11.9 mmol) and DBU (1.7 g, 11.4 mmol). Nitrogen was bubbled through the mixture for 5 min and then it was heated at 180° C. for 12 h. The reaction mixture was cooled to RT, poured into water and extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to yield 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpiperidin-4-ylamino)-1,6-naphthyridin-2(1H)-one (0.50 g, 19.5% yield) which was 70% pure (30% de-methylated by-product) and used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1.[CH2:20](Br)[CH:21]=[CH2:22]>O1CCCC1>[CH2:20]([O:19][CH2:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:5][O:4][CH3:3])[CH2:7][CH2:8]2)[CH2:17][CH2:16]1)[CH:21]=[CH2:22]
Reactant: C=CCBr
Reactant: COC[C@H]1CC[C@H]([C@H]2CC[C@H](CO)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC[C@H]1CC[C@H]([C@H]2CC[C@H](COC)CC2)CC1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
150 mg of sodium hydride (as a 50 percent suspension in oil) is suspended in 10 ml of absolute tetrahydrofuran and then treated dropwise at room temperature within 3 minutes with a solution of 0.5 g of [trans-4-[trans-4-(methoxymethyl)cyclohexyl]cyclohexyl]methanol in 8 ml of absolute tetrahydrofuran. The mixture is stirred for a further 5 minutes, then treated with 0.755 g of allyl bromide and stirred under reflux (bath temperature 70° C.) for 16 hours. Thereafter, the reaction mixture is partitioned in diethyl ether/water and extracted three times with diethyl ether. The organic phases are washed twice with water, dried over magnesium sulphate, filtered and evaporated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gives [trans-4-[trans-4-(methoxymethyl)cyclohexyl]cyclohexyl]methyl allyl ether.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[C:10](Br)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29]B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[C:10]([CH3:29])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(-c2cccc3c2c(=O)c(Br)cn3Cc2ccccc2)c(C)c1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(-c2cccc3c2c(=O)c(C)cn3Cc2ccccc2)c(C)c1
Temperature: 95 °C
Reaction time: 22 h
Yield: 59.5 %

Procedure:
1-Benzyl-3-bromo-5-mesitylquinolin-4(1H)-one (0.277 g, 0.64 mmol), methyl boronic acid (0.384 g, 6.4 mmol), potassium carbonate (0.443 g, 3.2 mmol), and Pd(PPh3)4 (0.37 g, 0.32 mmol) were diluted in dioxane (4 mL). Water (0.11 mL, 6.4 mmol) was added and the reaction stirred at 95° C. for 22 hr. The solution was then cooled and filtered through GF/F paper and concentrated. Flash chromatography (40% ethyl acetate/hexanes) gave the title compound as a white solid (0.14 g, 60%).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:36][C:37]1[N:41]2[C:42](=[O:51])[N:43]([CH:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[CH2:44][C:40]2=[CH:39][N:38]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:36][C:37]1[N:41]2[C:42](=[O:51])[N:43]([CH:45]3[CH2:50][CH2:49][N:48]([C:10](=[O:12])[CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:47][CH2:46]3)[CH2:44][C:40]2=[CH:39][N:38]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)CNC(=O)OC(C)(C)C)CC1)C2
Yield: 66 %

Procedure:
To a solution of Boc-glycine (0.44 g) and HOBt (0.58 g) in acetonitrile (15 ml) was added WSC (0.72 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, a solution of 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.73 g), DBU (0.75 ml) and triethylamine (1.1 ml) in acetonitrile (5 ml) was added thereto. The reaction mixture was mixed at room temperature for 15 hours, the solvent was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound as a colorless solid (0.62 g, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH3:12]C(C)([O-])C.[K+].IC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([CH3:12])[N:6]=[CH:5]2
Reactant: Cc1cc(Br)cc2cn[nH]c12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(Br)cc2cnn(C)c12

Procedure:
2.11 g (10.0 mmol) 5-bromo-7-methyl-1H-indazole and 1.20 g (10.7 mmol) potassium-tert-butoxide in 50 mL THF were stirred overnight with 0.700 mL (11.2 mmol) iodomethane at RT. Then the precipitate was filtered off and the filtrate was evaporated down i. vac. The residue was purified by flash chromatography.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[N:3]=1.[C:20](B1OC(C)(C)C(C)(C)O1)([CH3:22])=[CH2:21].C(NC(C)C)(C)C>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:21]=[C:20]([C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[N:3]=1)[CH3:22]
Reactant: COC(=O)c1ccc2c(Br)nn(-c3ccsc3)c2c1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1nn(-c2ccsc2)c2cc(C(=O)OC)ccc12
Temperature: 100 °C
Yield: 86.9 %

Procedure:
Methyl 3-bromo-1-(thiophen-3-yl)-1H-indazole-6-carboxylate (1.414 g, 4.19 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.58 ml, 8.41 mmol), diisopropylamine (1.18 ml, 8.40 mmol), triphenylphosphine-3,3′,3″-trisulfonic acid trisodium salt hydrate (275.8 mg, 0.431 mmol), and palladium(II) acetate (48.3 mg, 0.215 mmol) were dissolved in N,N-dimethylformamide (15 ml)/water (5 mL), placed in a sealed tube and heated to 100° C. for 4 h. The reaction was stopped, cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride (20 mL), and the mixture extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×15 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 330 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-15%). The title compound (1.0847 g, 3.64 mmol, 87% yield) was recovered as a white solid. LC-MS: [M+1]=299.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].S([O-])([O-])=O.[Na+].[Na+].[C:20](=O)(O)[O-].[Na+].BrCC(O)=O>O>[F:9][C:5]1[CH:4]=[C:3]([S:10]([CH3:20])(=[O:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Reactant: O=C([O-])O
Agent: O=C(O)CBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cc(F)c(F)cc1F
Temperature: 150 °C
Yield: 66.5 %

Procedure:
2,4,5-Trifluorophenyl sulfonyl chloride (279 mg) was added to a solution of sodium sulfite (306 mg) and sodium bicarbonate (153 mg) in water (4 mL). The mixture was heated to 150° C. in a sealed microwave vial for 400 seconds and allowed to cool. The mixture was treated with bromoacetic acid (253 mg) in water (1 mL), and heated to 150° C. for 300 seconds then allowed to cool, following which the precipitate was removed by filtration and dried in vacuo to give the desired compound (169 mg). The material was used without further purification. 1H NMR δ (d6-DMSO): 3.35 (s, 3H), 7.87-8.01 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:13]2[O:14]CC(C)(C)N=2)=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:20](O)[CH3:21].S(=O)(=O)(O)[OH:24]>O>[C:1]([C:5]1[CH:12]=[C:9]2[C:8](=[CH:7][CH:6]=1)[C:13](=[O:14])[O:24][CH:10]2[O:11][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCO
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2C=O)=N1
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCOC1OC(=O)c2ccc(C(C)(C)C)cc21

Procedure:
3.66 g (14.1 mmol) of 5-tert-Butyl-2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-benzaldehyde was weighed into a 200 mL round bottom flask fitted with a stir bar and reflux condenser. Added 75 mL of ethanol and stirred to obtain a clear solution. Added 50 mL of 50% aqueous sulfuric acid. Stirred at reflux for 22 hr. Poured the reaction mixture into 400 mL water. Extracted the aqueous mixture with 2×200 mL CH2Cl2. Combined the organic extracts and washed with 200 mL brine. Dried over Na2SO4 and removed the solvent on rotavap. Dried under high vacuum to obtain 2.9 g of the title compound as an off-white solid. MS (ESI) 235 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12]CC)=O)[CH:4]=[CH:5][N:6]=1.[C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH3:19].[Li]>>[C:22]([O:21][C:18](=[O:20])[CH2:19][C:10]([C:9]1[CH:15]=[CH:16][CH:17]=[C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH:8]=1)=[O:12])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cccc(-n2ccnc2C)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: Cc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
Prepared from ethyl 3-(2-methyl-imidazol-1-yl)-benzoate [prepared by reaction of ethyl 3-aminobenzoate with ethyl acetimidate hydrochloride in EtOH at 0° C., direct treatment with aminoacetaldehyde diethyl acetal in EtOH at 23° C., follwed by addition of conc. H2SO4 and refluxing.] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a brown oil (9.66 g).
Reaction SMILES: [ClH:1].[F:2][CH:3]([F:30])[O:4][C:5]1[CH:6]=[C:7]([S:11]([N:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:17]=2)[CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[ClH:1].[F:30][CH:3]([F:2])[O:4][C:5]1[CH:6]=[C:7]([S:11]([N:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]3[CH2:25][CH2:26][N:27]([CH3:33])[CH2:28][CH2:29]3)[CH:17]=2)[CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(N(C)S(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCNCC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: COc1ccc(N(C)S(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C)CC1

Procedure:
The compound was prepared by reaction of 3-difluoromethoxy-N-[4-methoxy-3-(piperazin-1-yl)-phenyl]-N-methyl-benzenesulfonamide hydrochloride (compound of example 2) with aqueous formaldehyde and sodium triacetoxyborohydride as described for example 5.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:13]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[CH:28])[C:20]=2[CH:29]=1)=[C:14]=[O:15]>>[CH2:7]([O:6][C:4]([CH:3]=[C:2]([NH:1][C:14](=[O:15])[NH:13][C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]#[CH:28])[C:20]=2[CH:29]=1)[C:9]([F:10])([F:11])[F:12])=[O:5])[CH3:8]
Reactant: C#CCN1C(=O)COc2ccc(N=C=O)cc21
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Product: C#CCN1C(=O)COc2ccc(NC(=O)NC(=CC(=O)OCC)C(F)(F)F)cc21

Procedure:
Analogously to the procedure described in Example 1, starting from ethyl 3-amino-4,4,4-trifluorocrotonate and 3,4-dihydro-6-isocyanato-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine there is obtained 6-{3-[2-(ethoxycarbonyl)-1-trifluoromethyl-vinyl]ureido}-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine (not isolated) and, after cyclization of this benzoxazine, there is obtained 3-[3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, m.p. >250° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:26])=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:33]1([S:39]([N:42]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=[CH:43]2)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>ClC(Cl)C>[Cl:22][CH2:21][CH2:20][CH2:19][O:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]([Cl:26])=[O:14].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([C:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:42]([S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])[CH:43]=2)=[O:15])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][Cl:22]
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(OCCCCl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1ccc(OCc2ccccc2)c(OCCCCl)c1
Product: O=C(c1ccc(O)c(OCCCCl)c1)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-(3-Chloropropoxy)-4-benzyloxybenzoyl chloride, which was prepared using 4-benzyloxy-3-(3-chloropropoxy)benzoic acid (2.53 g) and oxalyl chloride (1 ml), was dissolved in dichloroethane (20 ml). Aluminum chloride (2.63 g) was added to the resultant solution while cooling on ice bath, stirred for 5 minutes at room temperature, and then cooled again on ice bath. 1-(Phenylsulfonyl)indole (1.69 g) in dichloroethane (10 ml) was added dropwise to the resultant mixture and stirred for 2.5 hours at room temperature. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate. The resultant extract was sequentially washed with saturated sodium bicarbonate solution and brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), obtaining 0.76 g of 3-[4-hydroxy-3-(3-chloropropoxy)benzoyl]-1-(phenylsulfonyl) indole as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1([CH2:19][C:20]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:16]2[CH2:17][CH2:18][N:13]([CH2:19][C:20]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:21])[CH2:14][CH2:15]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=C(CN1CCNCC1)Nc1cccnc1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3cccnc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (10 ml) was added 2-(piperazin-1-yl)-N-(pyridin-3-yl)acetamide×3HCl salt (0.180 g, 0.55 mmol) followed by diisopropylethylamine (0.41 ml, 2.36 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 2.5% methanol in ethyl acetate. The title compound was obtained as a yellow solid (0.180 g, 82%); 1H-NMR (500 MHz, DMSO-d6) 2.68 (br s, 4H, piperazine N(CH2)2), 3.14 (br s, 4H, piperazine N(CH2)2), 3.24 (s, 2H, NCH2CO), 6.98 (br s, 2H, NH2), 7.34 (dd, J=8.10, 4.75 Hz, 1H, pyridyl 5-H), 8.06 (d, J=7.50 Hz, 1H, pyridyl 4-H), 8.16 (s, 1H, 6-H), 8.27 (dd, J=4.80, 1.96 Hz, 1H, pyridyl 6-H), 8.78 (d, J=2.30 Hz, 1H, pyridyl 2-H), 9.95 (s, 1H, CONH);