Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[S:18])OC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[S:18])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(C)c(C)cc1NC(=S)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc(C)c(C)cc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate(0.2 g, 0.7 mmol) and 1-(3,5-dimethoxyphenyl)piperazine(0.16 g, 0.7 mmol) were dissolved in tetrahydrofuran(10 ml) and thereto DBU(0.11 g, 0.7 mmole) was added, followed by stirring at room temperature for 2 hours. The resulting product was concentrated and purified by chromatography to obtain the titled compound.
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:27])[CH:21]([CH2:22][CH:23]=C(C)C)[O:20]3)[CH:12]2[O:28][CH3:29])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:30]=[O+][O-]>CO.ClCCl>[CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:27])[CH:21]([CH2:22][CH:23]=[O:30])[O:20]3)[CH:12]2[O:28][CH3:29])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[O+][O-]
Reactant: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CC=O

Procedure:
To a solution of 6-cyclohexylcarbamoyloxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (70 mg) in a mixture of methanol (0.1 ml) and dichloromethane (5 ml) was passed through ozone for 13 minutes at -78° C. to give 6-cyclohexylcarbamoyloxy-5-methoxy-4-[2-methyl-3-formylmethyloxiranyl)-1-oxaspiro-[2,5]octane in the reacting mixture. After babbling of nitrogen, methyl sulfide (0.2 ml) was added to the mixture at the same temperature. The mixture was stirred at -78° C. for 15 minutes and allowed to warm to 0° C. followed by the addition of carboethoxymethylene-triphenylphosphorane (150 mg). The mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with a mixture of diethyl ether and n-hexane (1:1) to yield 6-cyclohexylcarbamoyloxy-4-[3-(3-ethoxycarbonyl-2-propenyl)-2-methyloxiranyl]-5-methoxy-1-oxaspiro[2,5]-octane (53 mg) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([CH3:13])[C:5]=1[O:14][CH3:15])([O-])=O.C(O)C.[H][H].[ClH:21]>[Pd].O>[ClH:21].[ClH:21].[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([CH3:13])[C:5]=1[O:14][CH3:15]
Reactant: [H][H]
Reactant: COc1c(C)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1c(C)cc(N)cc1N

Procedure:
105 g of 2,4-dinitro-6-methylanisole, 1.35 l of ethanol, 150 ml of water and 1 g of Pd/C (5% strength) were initially introduced into the autoclave and hydrogenated at 50° C. with a hydrogen pressure of 50 bar for 12 h. Subsequently, the mixture was cooled and then poured into 1.0 l of semiconcentrated HCl. The catalyst was filtered off, and the filtrate was evaporated to dryness on a rotary evaporator. The residue was extracted by boiling with 2×150 ml of ethanol, filtered off and dried overnight under reduced pressure.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>C(N(CC)CC)C>[C:1]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.28 mL of benzoyl chloride was added to 10 mL of methylene chloride solution containing 0.50 g of methyl 2-amino-4-phenylbenzoate and 0.36 mL of triethylamine and stirred at room temperature overnight. The solvent was evaporated under reduced pressure and water and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.52 g of methyl 2-(benzamido)-4-phenylbenzoate as white solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.[Cl:14][C:15]([F:20])([F:19])[C:16](Cl)=[O:17].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:16](=[O:17])[C:15]([Cl:14])([F:20])[F:19])=[C:7]([CH3:12])[CH:6]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: O=C(Cl)C(F)(F)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc(NC(=O)C(F)(F)Cl)c(C)c1

Procedure:
According to general procedures outlined above, 3-methyl-4-aminophenyl N-methylcarbamate (2.3g., 0.0128 mole) was reacted with chlorodifluoroacetyl chloride (2.1g., 0.014 mole) in the presence of triethylamine (1.4g., 0.014 mole) and benzene. The product was a light tan solid (1.6g., m.p. 156°-58.5° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:29][C@@H:30]1[C@H:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:33][C:32](=[O:41])[NH:31]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:31]4[C@H:30]([CH3:29])[C@H:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[O:33][C:32]4=[O:41])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4C(=O)O[C@@H](c5ccccc5)[C@H]4C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-oxazolidin-2-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[CH3:21][C:22]1([CH3:37])[O:27][C:26]2[C:28](F)=[CH:29][C:30]([NH2:32])=[CH:31][C:25]=2[N:24]2[N:34]=[N:35][N:36]=[C:23]12.Cl>CC(O)C.O1CCOCC1>[CH3:21][C:22]1([CH3:37])[O:27][C:26]2[CH:28]=[CH:29][C:30]([NH:32][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:17][CH:16]5[N:12]([CH2:13][CH2:14][CH2:15]5)[C:11]([CH3:19])([CH3:18])[CH2:10]4)[C:5]([F:20])=[CH:4][N:3]=3)=[CH:31][C:25]=2[N:24]2[N:34]=[N:35][N:36]=[C:23]12
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC2CCCN21
Reactant: CC1(C)Oc2c(F)cc(N)cc2-n2nnnc21
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(Nc3ncc(F)c(NC4CC5CCCN5C(C)(C)C4)n3)cc2-n2nnnc21
Temperature: 100 °C
Yield: 83.4 %

Procedure:
A solution of (R/S,S/R)—N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (D1) (0.1 g, 0.3 mmol, single diastereomer) in 3 ml of iPrOH, 4,4-dimethyl-6-fluoro-4H-benzo[b]tetrazolo[1,5-d][1,4]oxazin-8-amine (0.093 g, 0.4 mmol) and 4N HCl in dioxane (0.1 ml) were added. The reaction mixture was heated to 100° C. in a sealed vial for 12 hours. LCMS analysis of the crude reaction mixture indicated the completion of the reaction. The crude product was purified by column chromatography to give 0.12 g (Yield=72%) of the product as a mixture of two enantiomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[NH2:12].[SH:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([N:18]([CH3:20])[CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([S:13][C:14]2[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:4]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: CN(C)C(=O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccccc1Sc1cc(N)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 74.5 %

Procedure:
A solution of 2.5-dichloro-4-nitro-phenylamine (17) (3.0 g, 14.5 mmol) and 2-mercapto-N,N-dimethyl-benzamide (3.0 g, 16.6 mmol) in DMF (50 mL) was heated to reflux with potassium carbonate (10 g) for 24 h. The mixture was poured into ice water and the precipitate was collected by a filtration. A dark colored solid was recrystalized from petroleum ether/methylene chloride yielded 3.8 g of (18) as a pale yellow powder (75%): IR (cm−1, KBr) 3461, 3376, 3153, 3154, 1627, 1575, 1492, 1135; 1H NMR (200 MHz CDCl3) δ 8.23 (s, 1H), 7.3–7.6 (m, 4H), 6.16 (s, 1H), 4.8 (br s, 2H), 3.37 (s, 3H), 2.86 (s, 3H). Anal. (C15H14ClN3O3S) C, H, N.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](F)[N:11]=1.[H-].[Na+].O>O1CCCC1>[CH2:1]([O:8][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(OCc2ccccc2)n1
Temperature: 50 °C
Yield: 100 %

Procedure:
An oven-dried 3-neck 2 L round bottom flask under nitrogen was charged with benzyl alcohol (9.04 ml, 87 mmol) and tetrahydrofuran (75 ml). Attached an addition funnel containing a solution of 2,6-difluoropyridine (10.00 g, 87 mmol) in tetrahydrofuran (30 ml). Sodium hydride (3.82 g, 96 mmol) was added in small portions with stirring. Heated in a 50° C. oil bath for 45 minutes; cooled to room temperature. Added contents of addition funnel dropwise. After 18 hours poured into water. Extracted three times with ethyl acetate, washed combined organic portions with brine, dried with anhydrous magnesium sulfate, filtered and rotary evaporated filtrate. The crude product was subjected to flash column chromatography eluting with hexane. Evaporation of fractions gave the title compound as a colorless oil. (17.70 g, 87 mmol, 100% yield). LCMS (ES+) m/z 204.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:6]2=[O:23].CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1>CC(O)=O>[O:17]=[C:8]1[N:7]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:6](=[O:23])[C:5]2[C:10](=[CH:11][C:12]([C:13]([F:15])([F:16])[F:14])=[C:3]([CH2:2][N:1]3[CH:26]=[CH:30][CH:29]=[CH:28]3)[CH:4]=2)[NH:9]1
Reactant: COC1CCC(OC)O1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CN)cc2c1=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(Cn3cccc3)cc2c1=O
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of N-(6-aminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (100 mg, 0.28 mmol) in conc. CH3CO2H (8 mL) was added 2,5-dimethoxytetrahydrofurane (41.3 μL, 0.31 mmol) and the reaction mixture was stirred for 20 min at reflux temperature. Subsequently, the solvent was evaporated and the crude brown residue was recrystallized from EtOAc/cyclohexane to yield N-(2,4-dioxo-6-pyrrol-1-ylmethyl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (108 mg, 0.27 mmol, 95%) as a light-brown solid. 1H-NMR (DMSO-d6, 400 MHz) 3.12 ppm (s, 3H, SO2—CH3); LC-MS rt=3.757 mn; MS: m/z 402.9 [M+H]+ Column: SunFireC18, 4.6*50 mn, 3.5 um; Positive MS Water/Acetonitrile 95:5 to 5:95 in 5 min, Flow: 1.5 mL/min
Reaction SMILES: O[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][N:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:23].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[Cl:23][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][N:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(c1ccc(CO)nc1)N(C1CCCC1)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccc(CCl)nc1)N(C1CCCC1)C1CCCC1
Reaction time: 0.17 h

Procedure:
To a solution of the title product of Example C (1.44 g, 5 mmol) in chloroform (30 mL), phosphorus pentachloride (1.04, 5 mmol) was added. The contents were immersed in an oil-bath at 70° C. and the temperature raised to reflux. After 18h, the pinkish colored reaction solution was cooled to room temperature. The reaction was diluted with water (75 mL) and solid potassium carbonate (2.2 g) added. The contents were stirred for about 10 min until no more effervescence was observed. More water (100 mL) was added and the reaction solution extracted with methylene chloride. The organic layer was separated, dried (MgSO4) and filtered. After removal of solvent, 1 6 g of the title product was isolated as an off-white solid. The compound was used in Example 1 without any further purification. 1H NMR (CDCl3) 1,2-2.2 (m, 16H), 3.6-3.9 (m, 2H), 4.7 (s, 2H), 7.53 (d,J=8 Hz, 1H), 7.74 (dd,J=3,8 Hz, 1H), and 8.56 ppm (d,J=3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>>[C:7]([C:4]1[N:3]=[C:2]([CH3:1])[NH:6][CH:5]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncc[nH]1
Product: CC(=O)c1c[nH]c(C)n1

Procedure:
The reaction of 2-methylimidazole with acetic anhydride to give 4-acetyl-2-methylimidazole over a catalyst may be represented for example by the following equation: ##STR7##
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+].N12CCCN=C1CCCCC2>CC(C)=O>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH2:34][CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: CCc1ccnc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)OC)c1
Temperature: 25 °C

Procedure:
A mixture of methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A, 700 mg, 1.99 mmol), 2-bromoacetyl-4-ethylpyridine* (545 mg, 2.39 mmol), potassium carbonate (1.37 g, 13.9 mmol) and acetone (20 ml) was stirred at room temperature. After stirring for 3 h, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.6 ml, 3.98 mmol) was added. The resulting mixture was stirred for an additional 19 h and then concentrated. The residue was diluted with dichloromethane (200 ml) and washed with water (100 ml×2). The organic layer was dried (MgSO4) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane/dichloromethane (1:4:1) to give the title compound including impurity. The crude product was washed with ethyl acetate to give 297 mg (42%) of the title compound as yellow solids.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:10]=1)(=[O:3])[CH3:2].[Br:18]Br>C(=S)=S>[C:12]([O:11][C:9]1[CH:8]=[C:7]([C:15](=[O:17])[CH2:16][Br:18])[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:10]=1)(=[O:14])[CH3:13]
Reactant: BrBr
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(C)=O)c1
Solvent: S=C=S
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)CBr)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4 g of 3',5'-diacetyloxyacetophenone was suspended in 75 ml of carbon disulfide. Thereto was dropwise added a solution of 0.90 ml of bromine dissolved in 25 ml of carbon disulfide, at room temperature in about 1 hour. The system was heated to about 50° C. occasionally in the course of dropwise addition and, each time when a reaction started, the system was returned to room temperature and stirred. After the completion of the dropwise addition, stirring was conducted at room temperature for 1 hour. After the completion of the reaction, the solvent was removed by distillation to obtain 5.53 g of 3',5'-diacetyloxy-2-bromoacetophenone as brown crystals.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:24])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([C:21](O)=[O:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:26][O:27][C:28](=[O:35])[C@@H:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32].[K+].[Br-]>>[CH3:26][O:27][C:28](=[O:35])[C@@H:29]([NH:34][C:21]([C:19]1[O:18][N:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:24])=[CH:15][CH:14]=2)[CH:20]=1)=[O:22])[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: O=C(Nc1ccc(-c2cc(C(=O)O)on2)cc1)NC1CCCCC1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cc(-c2ccc(NC(=O)NC3CCCCC3)cc2)no1
Yield: 67.9 %

Procedure:
The title compound was prepared from 3-[4-(3-cyclohexyl-ureido)-phenyl]-isoxazole-5-carboxylic acid and (S)-2-amino-4-methyl-pentanoic acid methyl ester hydrochloride as set forth in Example 5 and was obtained in 67.9% yield. Mass (ES+): 457 (M++1); IR (KBr): 3328, 2931, 1752 (br), 1655 (br), 1542 (br); 1H NMR (DMSO-d6) δ: 0.87, 0.91 (2×d, 6H), 1.14-1.81 (5×m, 13H), 3.47 (br, 1H), 3.65 (s, 3H), 4.49 (m, 1H), 6.17 (d, 1H), 7.52 (d, 2H), 7.59 (s, 1H), 7.77 (d, 2H), 8.59 (s, 1H), 8.96 (br, 1H), 9.32 (d, 1H).
Reaction SMILES: [Cl-].C([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:15](=[O:36])[CH2:16]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[CH:47]=O.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(#N)C>[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1/[CH:47]=[CH:16]/[C:15]([N:10]1[CH2:9][CH2:13][O:12][C:11]1=[O:14])=[O:36]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: O=C(C[PH](c1ccccc1)(c1ccccc1)c1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(/C=C/c1ccc2ccccc2c1)N1CCOC1=O
Yield: 69.8 %

Procedure:
A mixture of (4S)-4-benzyl-3-[(triphenylphosphino) acetyl]-1,3-oxazolidin-one chloride (10 mg, 0.193 mmol), 2-naphthaldehyde (30 mg, 0.193 mmol), triethylamine (0.030 ml, 0.212 mmol) and 4-(dimethylamino)pyridine in acetonitrile (5 ml) was heated under reflux for 24 h. After evaporation, the residue was dissolved in hexaneetherdichloromethane and chromatographed on flash silica eluting with hexane:ether 3:2 to give a white solid (36 mg, 52%) of 3-[(E)-3-Naphthalen-2-ylprop-2-enoyl]-1,3-oxazolidin-2-one. M/e 358 (MH+).
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:21])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:24]=1[NH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[Cl:22][C:23]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:24]=1[N:25]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:11](=[O:21])[C:2]([CH3:1])=[C:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: Cc1c(-c2ccccc2)n(-c2cc([N+](=O)[O-])ccc2Cl)c(-c2ccccc2)cc1=O

Procedure:
To 170ml of chlorobenzene were added 3.4 g (0.012 mole) of 2-methyl-1,5-diphenyl-1,3,5-pentanetrione, 10.4 g (0.060 mole) of 2-chloro-5-nitroaniline, 4.1 g (0.022 mole) of para-toluenesulfonic acid and 35.0 g of Molecular Sieves 5A, followed by refluxing for 2 hours. After cooling the reaction mixture, solid matter was removed from the reaction mixture, followed by addition of 200 ml of chloroform. The resultant mixture was washed first with 100 ml of 10% hydrochloric acid and then with 100 ml of a 10% aqueous solution of sodium hydroxide. The mixture was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate). Upon recrystallization of the resultant crystals from a 2:1 mixed solvent of acetone and hexane, 1.9 g of 1-(2-chloro-5-nitrophenyl)-3-methyl-2,6 -diphenyl-4(1H)-pyridinone having a melting point of 277°-279° C. was obtained.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:11]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:10]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)=O.C[Si]([C:41]#[N:42])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O1CCCC1>[C:27]([O:26][C:24](=[O:25])[NH:23][CH2:22][C:11]1[N:12]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:13](=[O:17])[C:14]2[C:9]([C:10]=1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[CH:8][C:7]([CH2:6][C:41]#[N:42])=[CH:16][CH:15]=2)([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(COS(C)(=O)=O)ccc2c1=O
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CC#N)ccc2c1=O
Yield: 74.8 %

Procedure:
To a mixture of (3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)methyl methanesulfonate (39 g, 0.75 mmol) in acetonitrile (5 mL) and tetrahydrofuran (4 mL) were added trimethylsilyl cyanide (0.15 mL, 1.1 mmol) and a solution of 1.0 M tetrabutylammonium fluoride: in tetrahydrofuran (1.1 mL), and then the mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:2 (v/v)) to give tert-butyl[6-(cyanomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.25 g, 75%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=[C:37]([O:39]C)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([O:39][CH3:37])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a pale yellow semi-solid. IR (liq.) 2971, 2935, 2875, 1606, 1565, 1480, 1440, 1391, 1287, 1230, 1206, 1183, 1091, 1079, 1044 cm−1; OAMS supporting ions at: ESI+ 452.1; MS (EI) m/z 451 (M+); MS (FAB) calcd for C26H30CLN3O2 +H1 452.2104, found 452.2100. [α]25D=−91 (c 0.39, methylene chloride); Anal. Calcd for C26H30ClN3O2: C, 69.09; H, 6.69; N, 9.30. Found: C, 69.04; H, 6.74; N, 9.30.