Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[N:44]1([CH2:50][CH2:51][NH2:52])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:36]([NH:52][CH2:51][CH2:50][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:42])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: NCCN1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)NCCN4CCCCC4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-piperidino-1-ethanamine (60 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (123 mg, yield 83%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CN(C)C=O.[H-].[Na+].Br[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nn(CCc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1.00 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.60 g), and the mixture was stirred at room temperature for 30 min. To the mixture was added (2-bromoethyl)benzene (2.22 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.72 g, 55%).
Reaction SMILES: CO[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].[C:14]1([CH3:26])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:27][O:13][C:4]1[CH:3]=[C:12]2[C:7](=[CH:6][CH:5]=1)[CH2:8][CH:9]([N:23]1[CH2:22][CH2:21][N:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH3:26])[CH2:25][CH2:24]1)[CH2:10][CH2:11]2
Reactant: COC1C(=O)CCc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1N1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCC(N1CCN(c3ccccc3C)CC1)C2

Procedure:
6 g of methoxy-2-tetralone together with 6 g of N-(o-tolyl)-piperazine are dissolved in 100 ml of toluene whilst warming, 300 mg of p-toluenesulphonic acid are added and the solution refluxed for 24 hours, whereby the water is separated using a Dean-Stark separator. The reaction mixture is then evaporated to dryness, 200 ml of dimethyl formamide and 300 mg of a 10% palladium on charcoal catalyst are added to the obtained 3,4-dihydro-6-methoxy-2-[4-(2-methylphenyl)-1-piperazinyl]-naphthalene, which is hydrogenated at normal pressure. When the take-up of hydrogen ceases the catalyst is filtered off, the solvent evaporated off and the residue chromatographed on Kieselgel with methylene chloride (methanol (99:1). The title compound is obtained as a compact residue. M.P. 286-288° [Hydrochloride salt form].
Reaction SMILES: [CH3:1][C:2]([CH:8]=[CH:9][O:10][C:11](=[O:13])[CH3:12])=[CH:3][O:4]C(=O)C.ClC1C=CC=[C:17]([C:21]([O:23]O)=[O:22])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]([O:23][C:21](=[O:22])[CH3:17])([CH:8]=[CH:9][O:10][C:11](=[O:13])[CH3:12])[CH:3]=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OC=CC(C)=COC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC=CC(C)(C=O)OC(C)=O

Procedure:
In the case of the reaction of 2-methyl-1,4-diacetoxy-buta-1,3-diene with m-chloroperbenzoic acid in chloroform, to give 2-methyl-2,4-diacetoxy-but-3-enal, the reaction can be represented by the following formulae: ##STR6##
Reaction SMILES: [CH3:1][N:2]1[C:6](SC)=[CH:5][C:4]([CH:9]([C:17]2[NH:21][C:20]([C:22]3[S:23][C:24]([CH2:27][OH:28])=[CH:25][N:26]=3)=[CH:19][CH:18]=2)[CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:3]1.O[O:30][S:31]([O-:33])=O.[K+].O.[C:36](=O)([O-])O.[Na+]>CO.O1CCCC1>[CH3:1][N:2]1[C:6]([S:31]([CH3:36])(=[O:33])=[O:30])=[CH:5][C:4]([CH:9]([C:17]2[NH:21][C:20]([C:22]3[S:23][C:24]([CH2:27][OH:28])=[CH:25][N:26]=3)=[CH:19][CH:18]=2)[CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:3]1
Reactant: CSc1cc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)nn1C
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of [2-(5-{1-[1-methyl-5-(methylsulfanyl)-1H-pyrazol-3-yl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]methanol (0.40 g), oxone (registered trade mark) (0.89 g), water (6 mL), tetrahydrofuran (6 mL) and methanol (6 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.30 g, yield 70%) as a colorless amorphous solid from the fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). MS: 451 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[C:29]([O-:37])(=[Se])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C[O:39]C1C=CC([Te](C2C=CC(OC)=CC=2)=O)=CC=1>>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1].[C:29]([O-:37])(=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [O-]C(=[Se])c1ccccc1
Reactant: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: O=C([O-])c1ccccc1

Procedure:
5α-Cholestan-3β-ol-selenobenzoate (278 mg, 0.50 mmol) was reacted with bis-(p-methoxyphenyl)-telluroxide for 0.3 h. 5α-Cholestan-3β-ol-benzoate (229 mg, 93%) was obtained after p.l.c. (petroleum ether-ethyl acetate 9:1). The product obtained was recrystallized from ethyl acetate (198 mg, 80%) m.p. 136°-137° (lit., 136°-137°).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([CH2:13][CH3:14])[C:7](=[O:12])[CH2:8][C:9](=O)[CH3:10])=[CH:2]1.C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH2:13]([C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[C:9]([CH3:10])=[CH:8][C:7]=1[OH:12])[CH3:14]
Reactant: CCC(C(=O)CC(C)=O)c1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCc1c(O)cc(C)c2sccc12

Procedure:
5-Thiophen-3-yl-heptane-2,4-dione (410 mg, 2 mmol) was dissolved inin 15 ml benzene, and p-toluene sulfonic acid monohydrate (408 mg, 2 mmol) was added. The reaction mixture was heated to reflux for 30 min, cooled, diluted with diethy ether, washed with saturated sodium bicarbonate, water, brine, and dried over magnesium sulfate. Concentration in vacuo 370 mg of 4-Ethyl-7-methyl-benzo[b]thiophen-5-ol, 98% , as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O-])([O-])=O.[K+].[K+].[CH2:15]([O:19][C:20](Cl)=[O:21])[CH:16]([CH3:18])[CH3:17].[Br:23]N1C(C)(C)C(=O)N(Br)C1=O>O.C(Cl)Cl>[Br:23][C:8]1[CH:7]=[CH:6][C:4]([NH:5][C:20](=[O:21])[O:19][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:3][C:2]=1[F:1]
Reactant: Nc1cccc(F)c1
Reactant: CC(C)COC(=O)Cl
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)COC(=O)Nc1ccc(Br)c(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 109.6 %

Procedure:
To a solution of 500 g (4.50 mol) of 3-fluoroaniline and 2 L of CH2Cl2 in a 12 L round bottom flask was added a solution of 473 g (3.42 mol, 0.76 equiv.) of K2CO3 in 2 L of water. Isobutylchloroformate (663 g, 4.86 mol, 1.08 equiv.) was added with stirring via an addition funnel over 3 h so as to allow the isotherm to warm and maintain the mixture at gentle reflux. Gas evolves vigorously near the end of the addition. The organic phase was sampled for GC analysis 1 h after completion of the addition; less than 0.5% 3-fluoroaniline remained. The mixture was quenched by addition of 72 mL of conc. NH4OH. After stirring for 15 minutes, the mixture was neutralized to pH by addition of 120 mL of conc. aq. HCl. The layers were separated, and the aqueous layer was extracted with 1.5 L of CH2Cl2. To the combined organic layers was added 987 g (3.45 mol, 0.77 equiv.) of 1,3-dibromo-5,5-dimethylhydantoin and 2.5 L of water. The mixture was allowed to isotherm to 39° C. and held at that temperature by gentle heating for 2 hours. The reaction was judged complete by HPLC analysis of the organic layer. The mixture was cooled to 32° C. by addition of 500 g of ice, and the solids not soluble in either liquid layer (mostly hydantoins and partially brominated hydantoins) were removed by filtration. The filtrate layers were separated, extracting the aqueous layer with 500 mL of CH2Cl2. the combined organic layers were added with rapid stirring to a solution of 410 g of Na2SO3 in 3 L of water. The layers were separated, extracting the aqueous layer with 3400 mL of CH2Cl2. The combined organics were distilled on a rotovap and replaced with heptane, maintaining a constant volume. The resulting thick slurry was cooled to 4° over 2.5 h. The solids were collected by filtration, washed with heptane ( 2×750 mL) and air dried, affording 1097 g (84%) of 2-Methylpropyl (4-bromo-3-fluorophenyl)carbamate as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:8]3([NH:12][CH2:11][CH2:10][NH:9]3)[C:6]=2[CH:7]=1.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl>CO>[ClH:1].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][S:13][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8]1[NH:12][CH2:11][CH2:10][N:9]=1
Reactant: Clc1ccc2c(c1)C1(NCCN1)S2
Reactant: ClCc1ccccc1Cl
Solvent: CO
Product: Cl
Product: Clc1ccc(SCc2ccccc2Cl)c(C2=NCCN2)c1

Procedure:
32 Parts of 4-chlorobenzothietane-2-spiro-2'-imidazoline is reacted with 26 parts of 2-chlorobenzyl chloride in 300 parts of methanol. The yield is 52 parts (90% of theory) and the melting point is 260° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[CH2:4][CH2:5][CH:6]([CH3:8])[CH:7]=1.[CH2:10]=[CH:11][CH:12]=C.[Cl-].[Cl-].[CH2:16]([Al+2])C>ClCCl>[CH3:8][CH:6]1[CH:7]2[C:2]([CH3:16])([CH2:1][CH:10]=[CH:11][CH2:12]2)[C:3](=[O:9])[CH2:4][CH2:5]1
Reactant: CC1=CC(C)CCC1=O
Reactant: C=CC=C
Reactant: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1CCC(=O)C2(C)CC=CCC12

Procedure:
2,4-Dimethyl-2-cyclohexen-1-one (10.0 g, 0.081 mol), Butadiene (8.75 g, 0.162 mol), Ethyl aluminium dichloride (1 molar solution in hexane, 40 ml, 0.040 mol), Dichloromethane (100 ml)
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]1[C:18]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][C:29]([OH:36])=[C:30]([OH:35])[CH:31]=3)[CH:26]2[CH3:37])=[N:19][C:20]([Cl:24])=[N:21][C:22]=1[CH3:23].[OH-].[Na+]>ClCCl>[ClH:24].[CH3:16][C:17]1[C:18]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][C:29]([OH:36])=[C:30]([OH:35])[CH:31]=3)[CH:26]2[CH3:37])=[N:19][C:20]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:21][C:22]=1[CH3:23]
Reactant: Nc1ccc(F)cc1
Reactant: Cc1nc(Cl)nc(N2CCc3cc(O)c(O)cc3C2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3cc(O)c(O)cc3C2C)c1C
Product: Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
4-fluoroaniline(0.46 ml, 4.70 mmol) and triethylamine(0.66 ml, 4.70 mmol) were added to a solution of 5,6-dimethyl-2-chloro-4-(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(1.0 g, 3.13 mmol) in dimethyifomiamide(5 ml) and then stirred for 3 hours at 120° C. The reaction mixture was cooled to a room temperature and diluted with dichloromethane. Aqueous sodium hydroxide solution was added to the reaction mixture, which was then stirred. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography and dissolved in ethanol. Ethyl ether saturated with hydrochloric acid was added to the solution. The resulting solid was filtered and dried to give 530 mg of the titled compound.
Reaction SMILES: [CH:1]([N:14]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=[C:15]1[SH:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:24](O)[CH2:25][CH3:26]>>[CH:1]([N:14]1[C:18]([C:19]([O:21][CH2:24][CH2:25][CH3:26])=[O:20])=[CH:17][N:16]=[C:15]1[SH:22])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1cnc(S)n1C(c1ccccc1)c1ccccc1
Reactant: CCCO
Agent: Cl
Product: CCCOC(=O)c1cnc(S)n1C(c1ccccc1)c1ccccc1

Procedure:
3.1 g (0.01 mol) of 1-benzhydryl-2-mercapto-5-imidazole carboxylic acid (Example 2a) and 100 cc of 1-propanol were heated to 97° C. while introducing gaseous hydrogen chloride until esterification was completed. Working up in a basic medium yielded 3.3 g (94% of the theory) of 1-benzhydryl-2-mercapto-5-propoxycarbonyl-imidazole, m.p. 133° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:31])[CH3:30]>>[CH:18]([N:13]1[C:12]([C:35]2[CH:36]=[CH:37][C:32]([CH:29]([CH3:31])[CH3:30])=[CH:33][CH:34]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: CC(C)c1ccc(-c2c3c(nn2C(C)C)CCNCC3)cc1
Yield: 94.2 %

Procedure:
The title compound (177 mg) was prepared according to Example 189 using 270 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 311 mg of 4-isopropylphenylboronic acid. MS (ESI): exact mass calculated for C19H27N3, 297.44. found, m/z 298.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.35-7.34 (m, 2H), 7.19-7.17 (m, 2H), 4.57 (br s, 1H), 4.38-4.32 (m, 1H), 3.36-3.34 (m, 1H), 3.15-3.13 (m, 1H), 2.90 (m, 1H), 2.79-2.70 (m, 2H), 1.31 (d, J=13.3 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1([CH3:19])[C:13](=O)[NH:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[O:9]1>C1COCC1>[CH3:7][C:8]1([CH3:19])[CH2:13][NH:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[O:9]1
Reactant: CC1(C)Oc2ccccc2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CNc2ccccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a stirred solution of LAH (3.01 g, 79.10 mmol) in THF (80 ml) at 0° C. was added 2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (7.00 g, 39.5 mmol) in portions and stirred the reaction mixture at 25° C. for 1 h and then 50° C. for 3 h. Reaction mixture was quenched by the addition cold saturated sodium sulfate solution and it was filtered through celite and extracted with DCM (100 ml×2), washed with brine (50 ml), dried over sodium sulfate, concentrated to give 2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine (6.09 g), which was used as such for the next reaction without purification
Reaction SMILES: O[C:2]1[CH:7]=[C:6](OCOC)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].CO[C:17]1N=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1.[OH-].[K+].O.[CH3:28]CO>>[C:20]1([CH:23]=[CH:13][C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:14])[CH:21]=[CH:28][CH:17]=[CH:18][CH:19]=1
Reactant: COCOc1ccc(C(C)=O)c(O)c1
Reactant: CCO
Reactant: COc1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 34 %

Procedure:
4.18 g (21.3 mmol) of 1-(2-hydroxy-4-(methoxymethoxy)phenyl)ethanone, 2.8 g of 6-methoxy-3-pyridine-carboxaldehyde (20.4 mmol), and 1.8 g (32.1 mmol) of KOH were reacted in 60 ml of EtOH and 20 ml of H2O ml to give 2.18 g (34%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 13.27 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 7.95-7.82 (m, 3H), 7.50 (d, J=15.6 Hz, 1H), 6.83 (d: J=8.7 Hz, 1H), 6.67 (d, J=2.7 Hz; 1H), 6.61 (d, d, J=2.4, 9.0 Hz, 1H), 5.25 (s, 2H), 4.02 (s, 3H), 3.51 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H](C2C=CC(F)=CC=2Cl)[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][Br:12])=[O:4].[CH3:26][C:27]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.[C:36](OCC)(=O)CC(C)=O>>[Br:12][CH2:11][C:10]1[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7][C@@H:29]([C:28]2[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:27]=2[CH3:26])[C:5]=1[C:3]([O:2][CH2:1][CH3:36])=[O:4]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1c(F)cccc1C=O
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1cccc(F)c1C

Procedure:
Compound C-3 was prepared in analogy to compound C by using 2-methyl-3-fluorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde and ethyl acetoacetate instead of methyl acetoacetate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[O:12][CH2:13][C:14](=[O:21])[C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:13]2[O:12][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=3)=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]2=[O:21])=[CH:23]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc3ncsc3c2)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc3ncsc3c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 45.2 %

Procedure:
To a solution of ethyl 2-(benzo[d]thiazol-6-ylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.070 g, 0.23 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.034 g, 0.23 mmol) in ethanol (6.0 mL), L-proline (0.0030 g, 0.023 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.045 g, y. 45%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[NH:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:1]=[C:19]1[NH:13][C:14](=[O:15])[NH:16][C:17]1=[O:18]
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1OC

Procedure:
It was previously reported by Deulofeu and Mendivelzua, Z. physiol. Chem. 219, 233 (1933) that the condensation of veratraldehyde (3,4-dimethoxybenzaldehyde) with hydantoin in acetic anhydride in the presence of fused anhydrous sodium acetate gave 5-(3',4'-dimethoxybenzal) hydantoin. We have now found, however, that this reaction leads to the formation of a corresponding acetylated product.
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:18])[C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:20]1[NH:22][CH2:21]1>>[N:22]1([CH2:19][CH:2]([OH:1])[CH2:3][O:4][C:5]2[C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10](=[O:18])[C:9]=3[CH:8]=[CH:7][CH:6]=2)[CH2:20][CH2:21]1
Reactant: C1CN1
Reactant: O=C1c2ccccc2-c2c(OCC3CO3)cccc21
Product: O=C1c2ccccc2-c2c(OCC(O)CN3CC3)cccc21

Procedure:
4 g of 4-(2,3-epoxypropoxy)-9-fluorenone are allowed to stand at room temperature over night together with 15 cc of ethylene imine. The excess ethylene imine is removed by evaporation, the residue is taken up in ether and the solution is concentrated by evaporation until crystallization commences. The title compound has an M.P. of 113°-116°.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[CH2:20][N:14]4[CH2:15][CH2:16][NH:17][C:18](=[O:19])[CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:20][N:14]4[CH2:15][CH2:16][N:17]([CH2:24][C:25]5[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=5)[C:18](=[O:19])[C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=C1NCCN2CC(Oc3cnc(C4CC4)cn3)CC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1[C@@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN2CCN1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 18.6 %

Procedure:
To a solution of 7-(5-cyclopropylpyrazin-2-yloxy)hexahydropyrrolo[1,2-a]-pyrazin-1(2H)-one [3:1 (7R,8aS: 7R,8aR) diastereomer ratio](112 mg, 0.408 mmol) from Example 163 Step 3 in N,N-dimethylformamide (1 mL) under nitrogen was added sodium hydride (60% weight suspension in mineral oil) (19.60 mg, 0.490 mmol), and the resulting suspension was stirred at room temperature. After 20 minutes, the suspension was treated with 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.076 mL, 0.490 mmol). The resulting solution was stirred at room temperature for 3 hours, and it was then partitioned between water and ethyl acetate (3×). The combined organic extracts were dried over sodium sulfate and then filtered. The filtrate was concentrated under a stream of nitrogen, and the crude material was purified with a 12 g silica gel cartridge eluted with a gradient 0-5% methanol/dichloromethane over 17 minutes to give an oil. The oil (54 mg) was loaded onto 2×0.25 mm silica gel prep plates and eluted with 5% methanol/ethyl acetate to give the title compound (33 mg, 0.076 mmol, 18.69% yield) as the first eluting diastereomer as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.07 (d, J=1.4 Hz, 1H), 7.94 (d, J=1.4 Hz, 1H), 7.60 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 5.49-5.39 (m, 1H), 4.71 (d, J=14.9 Hz, 1H), 4.60 (d, J=14.9 Hz, 1H), 3.71 (t, J=8.0 Hz, 1H), 3.46 (ddd, J=12.1, 7.9, 6.6 Hz, 1H), 3.38 (dd, J=10.9, 5.7 Hz, 1H), 3.20 (dt, J=12.1, 4.0 Hz, 1H), 3.07-2.99 (m, 2H), 2.88 (dd, J=10.8, 3.0 Hz, 1H), 2.53 (ddd, J=15.1, 8.0, 7.3 Hz, 1H), 2.44 (ddd, J=14.6, 7.9, 1.7 Hz, 1H), 1.99 (tt, J=7.8, 5.3 Hz, 1H), 1.01-0.90 (m, 4H); MS (ESI+) m/z 433 (M+H)+.