Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=O)[CH:2]=1.Cl.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.C(O)(=O)C>C(O)C>[Br:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[NH:19][CH:9]=[C:8]2[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=CCCc1cccnc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Brc1ccc2[nH]cc(Cc3cccnc3)c2c1

Procedure:
A mixture of 3-pyridin-propionaldehyde (1 g; 0.0074 mol) and of 4-bromophenylhydrazin hydrochloride (1.8 g; 0.0074 mol) with acetic acid (4.44 ml) in absolute ethanol (50 ml) was refluxed for 3 hours. The reaction was then quenched with a saturated solution of aqueous sodium carbonate and the product was extracted with ethyl acetate. The organic extract was dried (MGSO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol (98/2), the desired compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:14]([S:30]([CH3:29])(=[O:32])=[O:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)[C@@H](c1ccccc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of alcohol 4 (0.94 g, 3.18 mmol) and NEt3 (0.73 g, 7.18 mmol) at 0° C. in Cl2CH2 (10 mL), methanesulfonyl chloride (418 mg, 3.65 mmol) was added. The reaction mixture was allowed to stir at 0° C. for 45 min. It was then quenched with cold dilute HCl, diluted with Cl2CH2 and the organic layer was washed with an aqueous solution of NaHCO3 followed by brine and dried over Na2SO4. The solvent was eliminated in vacuo and the crude mesylate 6 was obtained as a foamy white solid which was used in the next step without further purification. 1H NMR (CDCl3).δ1.417 (s, 9H), 2.910 (s, 3H, CH3 --OMs), 3.705 (s, 3H, CH3O--), 4.853 (dd, J=9.6, 6.6 Hz, 1H, H--C2), 5.173 (bd, J=9.6 Hz, 1H, H--N), 5.893 (d, J=6.6 Hz, 1H, H--C3), 7.389-7.400 (m, 5H); IR (KBR) 3400, 2980, 2950, 1745, 1715, 1520, 1360, 1180 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[OH:14].[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1Cl>[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[O:14][C:3]3[C:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:18][CH:17]=1
Reactant: Nc1cccc(-c2ccccc2)c1O
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(-c2nc3cccc(-c4ccccc4)c3o2)cc1

Procedure:
8.55 g of 2-(4'-methylphenyl)-7-phenyl-benzoxazole (produced by condensation of 2-amino-6-phenylphenol with 4-methyl-benzoyl chloride and subsequent cyclisation in o-dichlorobenzene in the presence of p-toluenesulfonic acid, melting point 144° to 145° C.) and 8.93 g of 4-phenylbenzaldehyde-4'-chloranil are dissolved, under nitrogen, in 150 ml of anhydrous dimethylformamide. After the addition of 6.72 g of pulverised potassium hydroxide, stirring is maintained for a further 15 minutes at room temperature. The temperature is then raised within 30 minutes to 40° to 45° C., and stirring is continued for 2 hours at this temperature. The reaction mixture is subsequently stirred into 450 ml of methanol, and the resulting precipitate is filtered off. The residue is washed with methanol, then with water and again with methanol and finally dried. The yield is 8.5 g of the compound of the formula ##STR14##
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:9][O:10][C:11]1[C:12]([Cl:29])=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:18]([C:25]([F:28])([F:27])[F:26])[O:17][C:15]=2[CH:16]=1)(C)(C)C.Cl.C(OCC)C>C(Cl)Cl>[Cl:29][C:12]1[C:11]([O:10][CH2:9][C@@H:8]([NH2:7])[CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:16][C:15]2[O:17][CH:18]([C:25]([F:27])([F:28])[F:26])[C:19]3[C:24]([C:14]=2[CH:13]=1)=[CH:23][CH:22]=[N:21][CH:20]=3
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Cl)-c1ccncc1C(C(F)(F)F)O2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C[C@H](N)COc1cc2c(cc1Cl)-c1ccncc1C(C(F)(F)F)O2
Reaction time: 14 h
Yield: 23 %

Procedure:
To a stirred solution of tert-butyl((2S)-1-((9-chloro-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.100 mmol) in DCM (10 mL) was added 1M HCl in diethyl ether (0.100 mmol) at room temperature and the solution stirred for 14 h. The solvent was removed under reduced pressure to afford a residue which was purified by preparative HPLC using 0.1% TFA in methanol. The purification afforded (2S)-1-((9-chloro-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-amine (10 mg, 0.023 mmol, 23% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J=5.2 Hz, 1 H), 8.57 (s, 1 H), 8.32 (s, 1 H), 7.98 (d, J=5.2 Hz, 1 H), 6.97 (s, 1 H), 6.45 (m, 1 H), 3.9 (m, 1 H), 3.87 (m, 1 H), 3.09 (m, 1 H), 1.83 (m, 1 H), 1.33 (m, 2 H), 1.31-1.26 (m, 6 H); LCMS (ESI) m/e 401.2 [(M+H)+, calcd for C19H21ClF3N2O2 401.1]; LC/MS retention time (Method C): tR=1.69 min; HPLC retention time (method A): tR=5.80 min, 5.87 min (diastereomeric mixture); HPLC retention time (method B): tR=6.41 min, 6.45 min (diastereomeric mixture).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].Br[C:13]#[N:14].O>C(O)C>[N+:1]([C:4]1[C:5]2[NH:11][C:13]([NH2:14])=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: N#CBr
Solvent: O
Solvent: CCO
Product: Nc1nc2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of 1.53 g (10 mmol) of 3-nitro-benzene-1,2-diamine in ethanol (20 mL) was added 1.3 g (12.5 mmol) of BrCN and water (5 mL). The mixture was refluxed for 1.0 h. After cooling to room temperature, the solvent was concentrated, then the residue was dissolved in water, the pH was adjusted to 8.0 with sat. NaHCO3 solution. The resulting solid was filtered, washed with water and dried under vacuum to afford 1.42 g (80%) of the 7-nitro-1H-benzoimidazol-2-ylamine LCMS: 179 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1OC)[CH:5]=[O:6].[H-].[CH2:13]1COCC1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[CH3:13]
Reactant: C1CCOC1
Reactant: COc1ccc(C=O)cc1F
Agent: [H-]
Product: Cc1ccc(CO)cc1F
Reaction time: 0.5 h

Procedure:
3-fluoro-p-anisaldehyde (12.5 g, 81.1 mmol) was dissolved in 100 ml THF. Under N2 a solution of diisobutylalumium hydride (100 ml, 1M in THF) was added at 0° C. over 30 min. The reaction was stirred for 30 min and quenched with 250 ml 1N HCl solution. The resulting mixture was stirred for 15 min and filtered through a short column of Celite®. The product was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried with MgSO4, and concentrated to give a viscous oil in 11.6 g. This product was used without further purification. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]([F:17])([F:16])[CH2:12][C:13](O)=[O:14].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:13](=[O:14])[CH2:12][C:11]([F:17])([F:16])[F:10])=[C:4]([F:9])[CH:3]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: Nc1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CC(F)(F)F)Nc1ccc(Cl)cc1F
Reaction time: 8 h
Yield: 90 %

Procedure:
4-Chloro-2-fluoroaniline (3 g, 20.7 mmol), 3,3,3-trifluoropropanoic acid (2.6 g, 20.7 mmol) and Et3N (5.8 mL) were dissolved in 50 mL of DCM. To this solution was added HATU (8.6 g, 22.7 mmol) slowly and then stirred overnight. The organic phases was washed with aq. NH4Cl (50 mL), NaHCO3 solution (50 mL) and brine (100 mL). The combined organic phases were evaporated and purified by column chromatography (PE/EA=5/1) to give N-(4-chloro-2-fluorophenyl)-3,3,3-trifluoropropanamide which was pure enough for next step. (4.7 g, yield: 90%) was a yellow solid. MS obsd. (ESI+) [(M+H)+] 256.
Reaction SMILES: O[C:2]1C=C[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.BrC1[S:46]C=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[NH:22]1[CH:23]=[CH:24][CH:25]=[C:21]1/[CH:20]=[C:13]1\[C:14](=[O:19])[NH:15][C:16]2[C:12]\1=[CH:11][C:10]([C:9]#[C:8][C:5]1[S:46][CH:2]=[CH:3][CH:4]=1)=[CH:18][CH:17]=2
Reactant: Brc1cccs1
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(C#Cc3cccs3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (42 mg, 0.18 mmol) (from Example 82) was coupled with 2-bromothiophene (30 mg, 0.18 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst in 1 mL DMF and 1 mL triethylamine at 70° C. for 14 hours to give (Z)-1,3-dihydro-3-[(1H-pyrrol-2-yl)-methylene]-5-(2-thiophenyl)ethynyl-2H-indol-2-one as a yellow powder. (Yield 25 mg, 44%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)(Cl)Cl>[CH3:45][S:46]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[N:13]([S:46]([CH3:45])(=[O:48])=[O:47])[CH:12]=[CH:11][N:10]=1)(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3nccn3S(C)(=O)=O)Cc3nccn3S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The compound (52.9 mg) obtained in Example 19-3 was dissolved in anhydrous chloroform (2.0 ml). The solution was added with triethylamine (0.054 ml) and then added with methanesulfonyl chloride (manufactured by Kanto Kagaku) (0.027 ml), followed by stirring at room temperature for 17 hours. After completion of the reaction, chloroform (3.0 ml) was added to the solution, and the whole was washed with water. The organic layer was dried with anhydrous magnesium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd.) (hexane/ethyl acetate), thereby obtaining the subject compound (31.7 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][O:4]1.C(N(CC)CC)C.[Br:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>C(OCC)C>[Br:15][CH:16]([CH3:20])[C:17]([O:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][O:4]1)=[O:18]
Reactant: CC(Br)C(=O)Cl
Reactant: OCC1CCCO1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)OCC1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a 250 milliliter three-necked flask were added 0.15 mole of 2-(hydroxymethyl)tetrahydrofuran, 0.15 mole of triethylamine, and 100 milliliters of diethylether. The flask was immersed in ice, and 0.15 mole of 2-bromopropanoyl chloride introduced dropwise. The ice bath was removed, and the reaction stirred at ambient temperature for two hours. The mixture was extracted with an equal volume of water, and the organic phase dried over sodium sulfate. Decantation and solvent removal resulted in 2-tetrahydrofuranylmethyl 2-bromopropanoate in 94% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[F:16][C:17]([F:24])([F:23])[C:18](B(O)O)=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([C:18]([C:17]([F:24])([F:23])[F:16])=[CH2:19])[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: C=C(B(O)O)C(F)(F)F
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(C(F)(F)F)nc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Yield: 98.8 %

Procedure:
4-bromo-2,6-bis(trifluoromethyl)pyridine (1.53 g), (3,3,3-trifluoroprop-1-en-2-yl)boronic acid (purity: 40%, 2.00 g) and potassium carbonate (1.58 g) were dissolved in the mixed solvent of THF and water, which was then degassed three times. To the solution was added dichlorobis(triphenylphosphine) palladium (II) (0.07 g), and the mixture was heated to reflux for 3 hours under argon atmosphere. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with pentane. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under reduced pressure, and the residue was then purified by silica gel chromatography to obtain 2,6-bis(trifluoromethyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (1.59 g) at a yield of 98%.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2[C:8]3[CH:17]4[NH:18][CH:14]([CH2:15][CH2:16]4)[CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.[CH3:26]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2[C:8]3[CH:17]4[NH:18][CH:14]([CH2:15][CH2:16]4)[CH2:13][C:9]=3[N:10]([CH3:26])[C:11]=2[CH:12]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc2[nH]c3c(c12)C1CCC(C3)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)cc(Br)cc31)C1CCC(C2)N1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Sodium hydride (38 mg, 0.950 mmol) was added to a solution of the product of step A (240 mg, 0.636 mol) in DMF (4 mL) at room temperature under N2. After 1 h, methyl iodide (134 mg, 0.058 mL, 0.943 mol) was added, and the reaction allowed to proceed for an additional 1 h. The mixture was quenched with H2O, upon which a solid precipitated out of solution. The solids were filtered off to provide tert-butyl 3-bromo-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (248 mg, 100%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 7.40 (s, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 5.30-5.10 (br m, 1H), 4.76-4.56 (br m, 1H), 3.54 (s, 3H), 3.49-3.19 (br m, 1H), 2.46 (d, J=16.0 Hz, 1H), 2.37-2.08 (m, 2H), 1.97-1.86 (m, 1H), 1.69-1.57 (m, 1H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:18])[N:4]([CH3:19])[C:3]1=[O:20].[N+:21]([C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CS(C)=O>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:27]3[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:18])[N:4]([CH3:19])[C:3]1=[O:20]
Reactant: Cn1c(N2CCN(CCCN)CC2)cc(=O)n(C)c1=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Product: Cn1c(N2CCN(CCCNc3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O

Procedure:
2.50 g of the previously obtained compound h and 1.90 g of 4-nitrofluorobenzene were added to 20 ml of dimethyl sulfoxide, and the resultant mixture was then heated at 80° C. for 3 hours. After the mixture was allowed to stand for cooling, the precipitated crystals were collected by filtration, washed, and then dried to obtain 2.75 g of 1,3-dimethyl-6-[4-(3-[4-nitroanilino]-propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[N+:13]([O-])=O.[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:4]=1[NH2:13]
Reactant: [H][H]
Reactant: CCCOc1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCOc1ccc(N)c(OC)c1

Procedure:
1.40 g (6.63 mmol) 2-Methoxy-1-nitro-4-propoxybenzene in 20 mL EtOAc is charged with 100 mg Pd/C (5%) and hydrogenated at rt with a hydrogen pressure of 50 psi. The mixture is filtered and the solvent is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])[CH3:3].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(C1OC1)Br>CC(N(C)C)=O>[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:3][CH:2]2[CH2:5][O:4]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: Oc1ccccc1CCCCc1ccccc1
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: c1ccc(CCCCc2ccccc2OCC2CO2)cc1
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
7.84 g of potassium t-butoxide were added at room temperature to a solution of 15.81 g of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3) in 350 ml of dimethylacetamide, and the resulting mixture was stirred at the same temperature for 20 minutes, after which 11.46 ml of epibromohydrin were added to it. The mixture was then stirred at room temperature overnight, after which the reaction mixture was partitioned between water and ethyl acetate. The organic layer was then washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 7:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 19.68 g (yield 99.8%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[O:23]=[C:24]1[CH2:29][O:28][CH2:27][CH2:26][N:25]1[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C(Cl)CCl>CN(C=O)C>[O:23]=[C:24]1[CH2:29][O:28][CH2:27][CH2:26][N:25]1[C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[CH:34][CH:35]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (26 mg, 0.082 mmol) and 4-(3-oxo-morpholin-4-yl)phenylamine (23 mg, 0.12 mmol) in DMF (3 mL), EDC (39 mg, 0.20 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (27 mg). MS 493.2 and 495.2 (M+H, Cl pattern).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)[CH:14]=[O:15]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[CH:10]=[CH:9][N:8]([CH2:2][C@H:1]2[CH2:5][CH2:6][CH2:14][O:15]2)[C:7](=[NH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1ccnc(N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: CC(C)(C)c1ccn(C[C@H]2CCCO2)c(=N)c1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 4-tert-butylpyridin-2-amine (1.0 g, 6.7 mmol, LeadGen Labs), Example 11A (2.0 g, 8.0 mmol), and tetrabutylammonium iodide (1.2 g, 3.3 mmol) in N,N-dimethylformamide (1.3 mL) was heated at 95° C. for 16 hours. The reaction was incomplete as monitored by LC/MS. One more equivalent of both Example 11A and tetrabutylammonium iodide were added. After stirring at 95° C. for 16 hours, the reaction mixture was cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with dichloromethane (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 235 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:7]=[C:6]([C:8](O)=[O:9])[N:5]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:4]=1.[NH2:23][C:24]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:25]=1[C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].C(N(CC)CC)C>C(#N)C>[CH3:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:25]([C:26]([NH:28][CH:29]([CH3:30])[CH3:31])=[O:27])[C:24]=1[NH:23][C:8]([C:6]1[N:5]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:4]=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:7]=1)=[O:9]
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1C(F)(F)F
Reactant: Cc1cccc(C(=O)NC(C)C)c1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1C(F)(F)F
Reaction time: 18 h
Yield: 78.3 %

Procedure:
A mixture of the title compound of Example 3, Step B (0.54 g, 1.1 mmol), the title compound from Example 1, Step B (0.44 g, 2.4 mmol) and BOP chloride (bis(2-oxo-oxazolidinyl)phosphinyl chloride, 0.54 g, 2.1 mmol) in acetonitrile (1.3 mL) was treated with triethylamine (0.9 mL). The mixture was shaken in a closed scintillation vial for 18 h. The reaction was partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid. The ethyl acetate layer was washed successively with 1N hydrochloric acid (50 mL), 1N sodium hydroxide (50 mL) and saturated sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel with hexanes/ethyl acetate (5:1 to 3:1) as eluent. The title compound (0.43 g) a compound of the present invention, was isolated as a white solid. m.p. 227-230° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Product: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Yield: 99.7 %

Procedure:
A solution of 2-amino-5-bromobenzotrifluoride (1.623 g, 6.76 mmol, Aldrich) in acetic anhydride (10 mL) was stirred at room temperature for 12 h to produce a white needle precipitate. It was filtered to give 1.840 g (99.7%) of title compound. Mp: 140°-2° C., 1HNMR (CDCl3): δ 2.212 (s, 3H); 7.358 (s, 1H); 7.659 (d, 1H, J =8.7 Hz); 7.726 (d, 1H, J=1.8 Hz); 8.118 (d, 1H, J=8.4 Hz).