Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:50]2[CH:55]=[C:54]([O:56][CH3:57])[C:53]([O:58][CH3:59])=[C:52]([O:60][CH3:61])[CH:51]=2)=[C:8]([CH:49]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:48])[C:27]3[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:28]=3[C:36]3[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=3)[CH2:22][CH2:21]2)[CH2:13][CH2:12]1)=[O:10])([O-])=O>[Pd].C(O)(=O)C.CO>[NH2:33][C:31]1[CH:30]=[CH:29][C:28]([C:36]2[CH:37]=[C:38]([O:46][CH3:47])[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=2)=[C:27]([CH:32]=1)[C:26]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][N:11]([C:9](=[O:10])[C:8]3[CH:49]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=3[C:50]3[CH:51]=[C:52]([O:60][CH3:61])[C:53]([O:58][CH3:59])=[C:54]([O:56][CH3:57])[CH:55]=3)[CH2:12][CH2:13]2)[CH2:21][CH2:22]1)=[O:48]
Reactant: COc1cc(-c2ccc([N+](=O)[O-])cc2C(=O)N2CCN(CCCN3CCN(C(=O)c4cc([N+](=O)[O-])ccc4-c4cc(OC)c(OC)c(OC)c4)CC3)CC2)cc(OC)c1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(-c2ccc(N)cc2C(=O)N2CCN(CCCN3CCN(C(=O)c4cc(N)ccc4-c4cc(OC)c(OC)c(OC)c4)CC3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
10% Palladium on carbon (50 mg) was added to a solution in acetic acid-methanol (1 ml-i ml) of 1,3-bis[4-[5-nitro-2-(3,4,5-trimethoxyphenyl)benzoyl]-1-piperazinyl]-propane dthydrochloride (91 mg; 0.10 mmol) synthesized by the process described in Example 8. After the mixture was stirred at room temperature for 3 hours under hydrogen, the catalyst was removed from the reaction mixture by filtration. The filtrate was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resultant concentrated residue to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 29 mg (yield: 37%) of 1,3-bis[4-[5-amino-2-(3,4,5-trimethoxyphenyl)benzoyl]-1-piperazinyl]propane as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC.C([O:37][C:38](=O)[CH:39]=[CH2:40])C>CS(C)=O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH2:40][CH2:39][C:38](=[O:37])[NH:5]2
Reactant: Nc1cccc(Cl)c1I
Reactant: C=CC(=O)OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CS(C)=O
Product: O=C1CCc2c(Cl)cccc2N1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-chloro-2-iodoaniline (143-3; 1.1 g, 0.0043 mol), AIBN (0.282 g, 0.0017 mol), tributyl tinhydride (1.8 g, 0.0064 mol) in dimethyl sulphoxide (10 mL) was added ethylacrylate (1.7 g, 0.173 mol) portion wise at 0° C. Reaction mixture was allowed to stir at 120° C. for 12 h. The reaction mixture was diluted with ice cold water (150 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 7.159-7.119 (t, J=7.6 Hz, 1H), 7.021-7.002 (d, J=7.6 Hz, 1H), 6.819-6.800 (d, J=7.6 Hz, 1H), 2.941-2.651 (t, J=8 Hz, 4H). MS (M+1): 181.8.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][N:38]([C:41](Cl)=[O:42])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][N:11]([C:41]([N:38]2[CH2:37][CH2:36][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:40][CH2:39]2)=[O:42])[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccccc1
Yield: 75.8 %

Procedure:
To a solution of rac-[(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (0.76 g, 2.46 mmol) in CH2Cl2 (10 ml) was added ethyl-diisopropyl-amine (0.51 ml, 2.95 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (0.61 g, 2.7 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/Hx 1:1) afforded 0.87 g (70%) of the title compound as a white solid. ES-MS m/e: 501.4 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH:6]([CH2:8][CH2:9][OH:10])[NH2:7].C(N(CC)CC)C>C(Cl)Cl>[NH2:7][N:6]([CH2:8][CH2:9][OH:10])[C:2](=[O:3])[O:4][CH3:5]
Reactant: COC(=O)Cl
Reactant: NNCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(N)CCO
Reaction time: 3 h
Yield: 98.9 %

Procedure:
At 0-5° C., 248.4 g (2.628 mol) of methyl chloroformate were added with stirring, over a period of 30 min, to a mixture of 200 g (2.628 mol) of 2-hydrazinoethanol and 266 g (2.628 mol) of triethylamine in 1600 ml of methylene chloride. After 3 h of stirring at from 3 to 22 C, the resulting hydrochloride was removed by filtration and washed with THF. The filtrates were combined. The filter cake was suspended in 800 ml of THF and filtered again. This filtrate, too, was combined with the previous filtrate. The combined filtrates were concentrated under reduced pressure. This gave 366 g of the title compound as colorless oil having an HPLC purity of 95.3%, corresponding to a yield of 98.9% of theory. According to GC, the purity was 85.2%.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17].[CH3:18][Si:19]([CH3:22])([CH3:21])Cl>O1CCCC1>[CH3:18][Si:19]([CH3:22])([CH3:21])[O:17][C:9]1[CH2:10][C:11]2[C:16]([CH:8]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: O=C1Cc2ccccc2C1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1=Cc2ccccc2C1
Reaction time: 3 h
Yield: 71 %

Procedure:
Methyl alpha-2-[2'-(3"-cyclopropylisoxazol-5"-yl)-ethen-1'-yl]-phenyl-β-methoxyacrylate ##STR10## a) 30.3 g (0.30 mole) of triethylamine are added to a solution of 36.5 g (0.28 mole) of 2-indanone and 32.4 g (0.30 mole) of trimethylchlorosilane in 300 ml of tetrahydrofuran at room temperature while stirring. Stirring is continued for a further 3 hours at room temperature (20° C.), the precipitate which has separated out is filtered off under suction and the filtrate is evaporated down. The residue is purified by distillation (53° C., 0.3 mbar). 40.6 g (72%) of 2-trimethylsilyloxy-1H-indene are obtained as a colorless liquid in this manner.
Reaction SMILES: [F-].[K+].F[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[F:12][C:13](F)([F:22])[O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C1OCCOCCOCCOCCOCCOC1>CS(C)=O.C(OCC)(=O)C>[F:12][CH:13]([F:22])[O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: N#Cc1ccccc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1Oc1cccc(OC(F)F)c1
Temperature: 140 °C
Yield: 67 %

Procedure:
A mixture of potassium fluoride on alumina (40% w/w, Aldrich, 11 g), 2-fluorobenzonitrile (6.0 ml, 56 mmol), 3-trifluoromethoxyphenol (10 g, 56 mmol), and 18-crown-6 (1.48 g, 5.6 mmol) in dimethylsulphoxide (40 ml) was heated to 140° C. for 20 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (300 ml). The solid was filtered off through a plug of celite. The solution was washed with a mixture of water (100 ml) and brine (100 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (200 g), using ethyl acetate/heptane (1:3) as eluent, to give 9.80 g of 2-(3-(difluoromethoxy)phenoxy)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].CN([CH:16]=[O:17])C>>[Cl:1][C:2]1[CH:7]=[C:6]([O:17][CH3:16])[C:5]([CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CN(C)C=O
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Product: COc1cc(Cl)c([N+](=O)[O-])cc1C
Reaction time: 6 h

Procedure:
A solution of 2-chloro-4-floro-5-methylnitrobenzene (1 mmole) in DMF (5 mL) was treated with fresh sodium methoxy (1.1 mmole), and the mixture was stirred for 6 h. Evaporation and chromatography gave 2-chloro-4-methoxy-5-methylnitrobenzene.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([NH:10][C:11]([C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[N:5]=1.[CH3:22]I>CS(C)=O>[Br:3][C:4]1[C:9]([N:10]([CH3:22])[C:11]([C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[N:5]=1
Reactant: COc1ccc(NC(=O)c2cccnc2Cl)c(Br)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(N(C)C(=O)c2cccnc2Cl)c(Br)n1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.3 g of a 50% dispersion in mineral oil) was added to dimethylsulfoxide (10 ml) and warmed to 50° C. After cooling the mixture to room temperature, N-(2-bromo-6-methoxy-3-pyridinyl)-2-chloro-3-pyridinecarboxamide (2.0 g) was added and the resulting solution was stirred for 10 min. Methyl iodide (0.4 ml) was then added and the mixture was stirred for 30 min. The reaction mixture was quenched by the addition of water (10 ml) and ethyl acetate (100 ml) was then added. The organic phase was washed with water (4×100 ml), dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (methylene chloride followed by methylene chloride/ethanol, 98:2) to give 1.9 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].O.[Sn](Cl)Cl.[OH-].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(/C=C/c2cccc([N+](=O)[O-])c2)n1
Agent: Cl[Sn]Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1csc(/C=C/c2cccc(N)c2)n1
Yield: 81.3 %

Procedure:
A solution of 1.5 g of (E)-2-[2-(3-nitrophenyl)ethenyl]-4-thiazolecarboxylic acid ethyl ester, 3.87 g of tin(II) chloride monohydrate and 100 ml of ethanol was heated to reflux for 16 hr. The reaction mixture was then poured onto ice-water, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was washed with water, saturated brine and dried (MgSO4). Evaporation of the solvent in vacuo yielded 1.1 g of (E)-2-[2-(3-aminophenyl)ethenyl]-4-thiazolecarboxylic acid ethyl ester; m.p. 112°-113° C. from ethanol.
Reaction SMILES: Br([O-])(=O)=O.[Na+].[CH3:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.CC[O:17]CC>C(#N)C.O>[CH3:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:17])=[O:12])=[CH:9][CH:8]=1
Reactant: Cc1ccc(CO)cc1
Reactant: CCOCC
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 40 h
Yield: 96 %

Procedure:
A mixture of Ceiv catalyst from EXAMPLE 47 (0.08 g), sodium bromate (0.3 g) and 4-methylbenzyl alcohol (0.24 g, 2 mmol) in acetonitrile:water (1:1, 10 ml) was stirred at 80° C. for 40 h under an atmosphere of nitrogen. On cooling ether (70 ml) was added and the catalyst was filtered off. The organic layer was separated and the aqueous phase was extracted with ether (2×50 ml). The combined organic extracts were washed with water (25 ml), dried with anhydrous magnesium sulphate and concentrated to give 4-methylbenzoic acid as a white solid (0.26 g, 96%). M.p. 178° C., lit. 180–182° C.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])=[CH:11][CH:10]=2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.C(N(CC)CC)C.Cl[C:37](=[O:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>ClCCl>[C:37]([N:8]([CH2:7][CH2:6][N:5]1[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]2[C:1]1=[O:28])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]([F:22])([F:21])[CH:18]([F:19])[F:20])=[CH:13][CH:14]=1)([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:43]
Reactant: O=C1c2ccccc2C(=O)N1CCNc1ccc(OCC(F)(F)C(F)F)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)N(CCN1C(=O)c2ccccc2C1=O)c1ccc(OCC(F)(F)C(F)F)cc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To the mixture of the obtained N-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (3.2 g), triethylamine (1.2 ml) and dichloromethane (60 ml), was added dropwise a solution of ethyl chloroglyoxylate (0.9 ml) in dichloromethane (10 ml) at -65° C. The reaction solution was stirred for 1 hour at -40° C., and then ice-water (50 ml) was added thereto to fractionate. The dichloromethane layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-ethoxalyl-N-(2-phthalimido)ethyl-4-(2,2,3,3-tetrafluoropropoxy)aniline (3.1 g) as colorless powdery crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(OCC)=O)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13](=[O:15])[N:22]([CH3:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Solvent: ClCCl
Product: CC(C)OC(=O)C(C(=O)N(C)c1ccccc1)=C1SC=CS1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-(ethoxycarbonyloxy-carbonyl)acetate (15.9 g) and N-methylaniline (6.43 g) were dissolved in methylene chloride (100 ml). The solution was stirred at room temperature for 24 hrs. The resultant mixture was washed with aqueous sodium hydroxide solution, dil-HCl and water. After removal of solvent the residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (9:1) as an eluent to give the product (13.2 g, 78.7%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[C:7]([CH2:8][NH:13][CH2:11][CH3:12])=[CH:6][C:5]([CH3:10])=[CH:4][N:3]=1
Reactant: CCN
Reactant: Cc1cnc(Cl)c(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNCc1cc(C)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-5-methyl-pyridine-3-carbaldehyde (0.22 g, 1.41 mmol), ethylamine (2M in THF; 1.06 mL, 2.12 mmol), and sodium cyanoborohydride (0.133 g, 2.12 mmol) were combined in MeOH (2.52 mL). Acetic acid (0.12 mL, 2.12 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was dissolved in CH2Cl2, washed with saturated aqueous NaHCO3, concentrated, and purified by silica gel chromatography (0-10% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: COCCOCCOCCOC.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24])([O-:15])=[O:14].[CH3:27][C:28]1([CH3:35])[NH:32][C:31](=[O:33])[NH:30][C:29]1=[O:34]>>[F:24][C:23]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([N:30]2[C:29](=[O:34])[C:28]([CH3:35])([CH3:27])[NH:32][C:31]2=[O:33])[CH:20]=[CH:21][C:16]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: CC1(C)NC(=O)NC1=O
Solvent: COCCOCCOCCOC
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
The following were introduced into 282 ml of triglyme: 112.8 grams of 2-nitro-5-chloro-trifluoromethylbenzene, 64.1 grams of 5,5-dimethyl-hydantoin and 33.5 grams of cuprous oxide. The mixture was heated to about 215° C.±5° C. for 4 hours, then cooled to 20° C. and filtered. The triglyme solution was recovered and a 22 Be ammonia solution (1V), toluene (1V) and demineralized water (4V) were added to the solution of triglyme (1V). The solution was stirred at 20° C. for 15 minutes, then cooled to about -10° C. and stirred again at -10° C. After washing and drying, 47.6 grams of the desired product were obtained.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[C:6](#[N:9])[CH:7]=[CH2:8].[OH-].[Na+]>O1CCOCC1.O.C1(C=CC(O)=CC=1)O>[CH3:3][C:2]([CH3:4])([CH:1]=[O:5])[CH2:8][CH2:7][C:6]#[N:9]
Reactant: CC(C)C=O
Reactant: C=CC#N
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C=O)CCC#N
Temperature: 65 °C
Yield: 48042.2 %

Procedure:
To a solution of 64.8 g (0.898 mmol, 51.45 mL) of isobutyraldehyde in 300 mL of dry dioxane was added 300 mg of hydroquinone (0.0027 mmol) and 60.0 g (1.13 mmol; 1.26 eq; 48.4 mL) of acrylonitrile. To this stirred solution was added all at once a freshly prepared solution of 3 g of NaOH dissolved in 60 mL of water and the whole was heated at 65° C. during 150 min. After cooling to 20° C., removal of the solvents under aspirator vacuum gave a residue which was partitioned between water and CH2Cl2. After separation, the aqueous layer was extracted 3 times with CH2Cl2 and the combined organic layers dried over Na2SO4 and concentrated under vacuum (aspirator). The crude residue was distilled under vacuum (81° C./1 mm Hg) to yield 54 g (49%) of 4,4-dimethyl-5-oxovaleronitrile.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][C:29]=1[C:39]([F:42])([F:41])[F:40]>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:1][CH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][C:29]=1[C:39]([F:41])([F:40])[F:42]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C)c(C(F)(F)F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
N-Bromosuccinimide (1.04 g, 5.83 mmol) and benzoyl peroxide (0.12 g, 0.49 mmol) were added to a solution of ethyl 4-methyl-3-(trifluoromethyl)benzoate (1.06 g, 4.56 mmol) in carbon tetrachloride (25 mL). The reaction mixture was heated at reflux overnight. After it was cooled to room temperature, it was diluted with dichloromethane (50 mL), and washed with water (20 mL). The aqueous layer was extracted with dichloromethane (20 mL). It was dried over Na2SO4 and concentrated. It was purified by prep-TLC (Hexanes:ethyl acetate=10:1) to give the product as an oil (0.60 g, 44%) 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=1.6 Hz, 1H), 8.20 (dd, J=4.8, 1.6 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 4.64 (s, 1H), 4.40 (q, J=7.2 Hz, 2 H), 1.40 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:29]([C:26]1[CH:25]=[N:24][C:23]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:19][CH:18]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:28][CH:27]=1)[CH3:30]
Reactant: Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCc1cnc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N(CCc2ccc(O)cc2)Cc2ccc(C(F)(F)F)cc2)nc1
Yield: 85.9 %

Procedure:
Condensation of 4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenol (1.20 g; 4.06 mmol) with 2-chloro-5-ethyl-pyrimidine (0.52 ml; 4.27 mmol) as per general procedure E (conditions: 1.1 eq. DIEA, toluene, 210C, 16 hr) provided the title compound (1.40 g; 85% yield).
Reaction SMILES: CN1CCN(C)[C:3]1=[O:8].Cl[C:10]1[CH:11]=[C:12](C(C)(C)CCl)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18]>>[O:16]([C:15]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:3][OH:8])[C:17]1[CH:18]=[CH:14][CH:15]=[CH:10][CH:11]=1
Reactant: CCOc1ccc(C(C)(C)CCl)cc1Cl
Reactant: CN1CCN(C)C1=O
Product: OCc1cccc(Oc2ccccc2)c1
Yield: 500 %

Procedure:
3 l (3,156 g) of 1,3-dimethyl-2-imidazolidinone (hereinafter referred to as DMI), 618.0 g (2.50 mol) of purified 2-(3-chloro-4-ethoxyphenyl)-2-methylpropyl chloride obtained in the same manner as in Example 1, 1,251.0 g (6.25 mol) of m-phenoxybenzyl alcohol (a product of Ethyl Corp.) and 280.0 g (5.00 mol) of potassium hydroxide in the form of flakes were charged in a 5 l four-neck flask and stirred at 120° C. under nitrogen stream for 15 h to complete the reaction.
Reaction SMILES: [CH3:1][C:2]1[NH:3][NH:4][C:5](=[O:7])[CH:6]=1.[Mg].Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl>C1COCC1.CCOCC>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:2]3([CH3:1])[CH2:6][C:5](=[O:7])[NH:4][NH:3]3)=[CH:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: Cc1cc(=O)[nH][nH]1
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 9.8 g of 3-methyl-pyrazolin-5-one in 100 ml of THF is added dropwise with stirring and cooling, to a Grignard solution prepared from 4.8 g of magnesium and 20.3 g of 4-bromo-4'-fluoro-biphenyl in 800 ml of absolute ether. After stirring for 2 hours at 10°-25°, the mixture is decomposed with ice and dilute hydrochloric acid and worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:4]=1[C:5](N(C)C)=[O:6].C(O)(=[O:19])C>O.[O-2].[O-2].[O-2].[Cr+6]>[C:5]([C:4]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:3]=1[CH:2]=[O:1])([OH:19])=[O:6]
Reactant: CN(C)C(=O)c1cc([N+](=O)[O-])ccc1CO
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: O=Cc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-hydroxymethyl-5-nitro-N,N-dimethylbenzamide (17 g.) in glacial acetic acid (340 ml.) was added chromium trioxide (17 g.) in water (17 ml.) and glacial acetic acid (340-1). The reaction mixture was stirred at room temperature for 5 minutes, and then poured into ice-water (2 liters). The aqueous was extracted with chloroform (3 × 500 ml.). The chloroform extracts were combined and neutralised by washing with 10% sodium bicarbonate solution. The chloroform exracts were then washed thoroughly with water and dried over magnesium sulphate. The solution was then filtered and the solvent evaporated off to yeild a gum.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O>C1C=CC=CC=1>[CH2:11]1[O:12][CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[O:7][CH2:10]1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: c1ccccc1
Product: Brc1ccc(C2OCCO2)cc1
Yield: 100 %

Procedure:
To a solution of 4-bromobenzaldehyde (102 g, 0.55 mol) and ethylene glycol (100 g, 1.65 mol) in benzene (1l) were added a small amount of 10-camphorsulfonic acid, and the mixture was refluxed for 3 hours, while water was removed with Dean-Stark. After allowing to cool, saturated sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled to give the title compound (126 g, 0.55 mol, 100%).