Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.CSC.[Cl:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:21])([CH3:19])[CH3:18])=[CH:14][CH:13]=1.C[O-].[Na+]>C(#N)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2([C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([Cl:11])=[CH:30][CH:29]=3)([CH3:19])[CH3:18])[CH2:5][O:21]2)=[CH:23][CH:24]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CSC
Product: CC(C)(Oc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reaction time: 12 h
Yield: 53.9 %

Procedure:
A solution of 59.2 g (0.47 mol) of dimethyl sulphate and 32 g (0.517 mol) of dimethyl sulphide in 270 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 87 g of 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone in 80 ml of acetonitrile is then added dropwise at 20° to 25° C., in the course of approx. 2 hours. 28.7 g (0.53 mol) of sodium methylate are introduced at the same temperature, and the mixture is stirred for a further 12 hours and then concentrated. The residue is stirred overnight with a mixture of 200 ml of ethyl acetate and 150 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 49 g (76% of theory) of crude 2-(4 chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane are obtained, and this compound is directly reacted further. ##STR158## 52 g (0.3982 mol) of p-chlorophenol and 55 g (0.3982 mol) of potassium carbonate in 400 ml of toluene are heated under reflux for 2 hours in a water separator. The mixture is cooled to 40° C., and a solution of 2-bromo-prop-2-yl 4-chlorophenyl ketone in 170 ml of toluene is added dropwise. This reaction mixture is stirred for a further 5 hours at 100° C. and then cooled, water is added and the organic phase is separated off. This is washed with dilute sodium hydroxide solution and water, dried over sodium sulphate and concentrated. 87 g (85% of theory) of crude 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone are obtained, and this compound is directly reacted further. ##STR159## 1 ml of hydrogen bromide/glacial acetic acid is added to 65.5 g (0.36 mol) of 4-chlorophenyl isopropyl ketone in 200 ml of chloroform, and 57.5 g (0.36 mol) of bromine are then added dropwise at 30° C. The mixture is stirred for a further 30 minutes at room temperature, and thereafter concentrated in vacuo. 86.6 g (92% of theory) of crude 2-bromo-prop-2-yl 4-chlorophenyl ketone are obtained, and this compound is directly reacted further.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)=[O:13])[CH:9]=2)[NH:4][CH2:3]1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[Cl:64][C:65]1[CH:66]=[C:67]([CH:69]=[CH:70][CH:71]=1)[NH2:68]>CN(C)C=O>[Cl:64][C:65]1[CH:66]=[C:67]([N:68]2[C:16](=[O:18])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]2([C:8]2[CH:9]=[C:10]3[C:5]([NH:4][CH2:3][C:2](=[O:1])[NH:11]3)=[CH:6][CH:7]=2)[OH:13])[CH:69]=[CH:70][CH:71]=1
Reactant: O=C1CNc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Reactant: Nc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C1CNc2ccc(C3(O)c4ccccc4C(=O)N3c3cccc(Cl)c3)cc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
To a solution of 2-[(3-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)carbonyl]benzoic acid (50 mg, 0.16 mmol) in N,N-dimethylformamide (2.0 mL), HOAt (40 mg, 0.28 mmol), HATU (90 mg, 0.23 mmol) and NMM (0.1 mL, 0.80 mmol) was added and the reaction mixture was stirred for 20 minutes at room temperature, followed by the addition of 3-chloro-aniline (24 μL, 0.23 mmol). The reaction mixture was stirred for 15 hours at room temperature. The solvent was evaporated and the resulting crude was purified by reverse phase preparative HPLC (CH3CN/H2O with 0.1% TFA). The fractions were collected and the aqueous solution was lyophilized to give 7-[2-(3-chlorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-3,4-dihydroquinoxalin-2(1H)-one (36 mg, 39% yield.). 1H NMR (400 MHz, DMSO-d6): 12.25 (s, 1H), 10.44 (s, 1H), 8.04 (d, 1H), 7.78 (t, 1H), 7.59 (d, 1H), 7.47 (m, 2H), 7.43 (dd, 1H), 7.33 (m, 3H), 7.08 (m, 3H), 4.22 (s, 2H); MS (EI) for C22H16ClN3O3: 406 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1.CN(C)C=O.[H-].[Na+]>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:11][CH:12]=1
Reactant: Oc1ccc(F)cc1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
To a mixture of 4-fluorophenol (2.1 g, 19 mmol), 2,5-dibromopyridine (3.0 g, 13 mmol) and N,N-dimethylformamide (30 mL) was added sodium hydride (730 mg, 15 mmol, 50% in oil) at 0° C., which was stirred for 10 minutes at room temperature. The reaction mixture was then stirred for 5 hours at 110° C. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water twice, and then washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=15:1) to obtain the title compound (2.6 g, 75%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(=O)([O-])O.[Na+].[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>O.C(OCC)(=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: C=C(C)C(=O)Cl
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)C(=O)NCc1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitrobenzylamine hydrochloride (1.51 g) and sodium hydrogencarbonate (4.13 g) were dissolved in water (25 mL), to which ethyl acetate (25 mL) was added, followed by being stirred in an ice bath. Methacryloyl chloride (1.26 g) was added dropwise thereto. After stirring for 10 minutes, the mixture was extracted with ethyl acetate. After washing with water and brine, the organic layer was dried over anhydrous sodium sulfate and evaporated. After that, the recrystallization was performed by using a mixture solvent of hexane and ethyl acetate. N-(4-Nitrobenzyl)methacrylamide was obtained as pale yellowish crystals. The yield was 1.05 g (60%). Spectrum data of 1H-NMR (400 MHz, CDCl3) is shown for the obtained compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([CH3:14])[CH2:12]O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Br)(Br)[Br:16].O>C(OC(C)C)(C)C>[Br:16][CH2:12][C:11]([CH3:14])=[CH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=Cc1ccc(C(C)C)cc1)CO
Reactant: BrP(Br)Br
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC(=Cc1ccc(C(C)C)cc1)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 136.4 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-2-methyl-2-propen-1-ol (6.30 g, 33.1 mmol) in isopropyl ether (50 ml) was added under ice cooling phosphorus tribromide (5.98 g, 22.1 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted with isopropyl ether. The organic layer was washed with water and an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 7.63 g (91% yield) of the oily title compound.
Reaction SMILES: [N:1]1([C:10]2[C:11](=[O:26])O[C:13](=[O:25])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Si](C)(C)[NH:29][Si](C)(C)C.CO>C1(C)C=CC=CC=1>[N:1]1([C:10]2[C:11](=[O:26])[NH:29][C:13](=[O:25])[C:14]=2[C:15]2[C:19]3[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]([CH3:24])[CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: Cn1cc(C2=C(n3ccc4ccccc43)C(=O)OC2=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CO
Product: Cn1cc(C2=C(n3ccc4ccccc43)C(=O)NC2=O)c2ccccc21
Reaction time: 1 h
Yield: 46.1 %

Procedure:
A mixture, 163 mg of 3-(1-indolyl)-4-(1-methyl-3-indolyl)furan-2,5-dione, 2.6 g of hexamethyldisilazane, 0.6 g of methanol and 50 ml of toluene was stirred at 40° C. for 1 hour and then at 110° C. for 1 hour. The mixture was evaporated and the residue was chromatographed on silica gel with 10% methanol in dichloromethane to give 75 mg of 3-(1-indolyl)-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 235°-236° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:32][OH:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:32][O:33][C:41](=[O:43])[CH3:42])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1ccc(CC(=O)NC(CO)c2ccccc2N2CCCCC2)cc1OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(CC(=O)NC(COC(C)=O)c2ccccc2N2CCCCC2)cc1OCC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of ethyl 2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (0.227 g, 0.5 mmol) and absolute triethylamine (0.126 ml, 0.9 mmol) in absolute chloroform (3 ml), a solution of acetyl chloride (0.063 ml, 0.9 mmol) in absolute chloroform (1 ml) is added dropwise. After 4 days' stirring at ambient temperature the mixture is diluted with chloroform, washed with dilute aqueous sodium bicarbonate solution, the chloroform solution is dried and filtered and evaporated down in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone=4/1).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>CO.O>[C:1]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2=NCCN=C2c2ccccc2)cc1
Reactant: COc1ccc(C=O)cc1
Solvent: O
Solvent: CO
Product: COc1ccc(Cc2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1

Procedure:
The same procedures as in Example 3 were repeated using 2,3-diphenyl-5,6-dihydropyrazine and p-anisaldehyde. 2,3-Diphenyl-5-(p-methoxybenzyl)pyrazine was obtained as colorless prisms, m.p. 102°-103° C. (recrystallized from methanol-water). Physical properties of the product support a chemical structure of the below formula (VIII).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=S)[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:37][OH:38].C([O-])(=O)C.[Na+]>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[N:37][OH:38])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=S)cc2)CCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=NO)cc2)CCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
A mixture of {1-[4-(2-phenyl-4-thioxo-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (33.4 mg, 0.069 mmol), hydroxylamine hydrochloride (14.4 mg, 0.207 mmol) and sodium acetate (17 mg, 0.207 mmol) in IMS (5 mL) was stirred at 80° C. for 16 hours. The cooled reaction mixture was partitioned between DCM and water. The aqueous phase was isolated and extracted with DCM. The combined organic extracts were evaporated to dryness. The resultant residue was subjected to flash chromatography (SiO2, 2% MeOH in DCM) to afford the title compound (27.2 mg, 82%) as a pale yellow solid. LCMS (Method A): RT=4.96 min, [M+H]+=483.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.[NH3:12].O>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:12])[C:5]([O:9][CH3:10])=[C:4]([Cl:11])[N:3]=1
Reactant: N
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1c(N)nc(Cl)nc1Cl
Yield: 88 %

Procedure:
2,4,6-Trichloro-5-methoxypyrimidine (1.0 g, 4.7 mmol, see U.S. Pat. No. 3,984,411 for preparation) was dissolved in 15 mL dry dimethyl sulfoxide (DMSO) and treated with a stream of ammonia gas for 30 min. The mixture was poured into 30 mL water and the precipitated product was collected by filtration and washed with water. This solid was dissolved in 40 mL ethyl acetate, washed twice with water, washed once with brine, dried and evaporated to give the title compound (800 mg, 88% yield): mp 155-156° C.: 1H NMR (DMSO-d6+D2O) δ 3.71 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([N:7](C=O)[NH2:8])=[NH:6])[CH3:2].[CH3:12]OCCOCCOC>>[CH2:1]([O:3][C:4]([C:5]1[N:6]=[CH:12][NH:8][N:7]=1)=[O:11])[CH3:2]
Reactant: CCOC(=O)C(=N)N(N)C=O
Reactant: COCCOCCOC
Product: CCOC(=O)c1nc[nH]n1
Yield: 85 %

Procedure:
A suspension of (N-Formylhydrazino)-imino acetic acid ethyl ester (9.62 g, 60.4 mmol) in diglyme (40 ml) was refluxed for 30 minutes. After cooling, the precipitated crystal was collected by filteration and washed with hexane to give 1H-1,2,4-triazol-3-carboxylic acid ethyl ester (7.28 g). Yield: 85%.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc2ccccc12
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1-c1cncc2ccccc12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 4-bromoisoquinoline (2.06 g, 10 mmol), prepared as described in the Journal of Organic Chemistry 2003, 68, 9412-9415, 2-methoxyphenylboronic acid (2.79 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: ClC1C=C[C:5]([C:8]2[CH:12]3[CH2:13][N:14]([C:16]4[N:25]=[C:24]5[C:19]([C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22][N:23]5[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[CH:18][C:17]=4[F:38])[CH2:15][CH:11]3[O:10][N:9]=2)=CC=1.C(O)(C(F)(F)F)=[O:40]>>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:23]1[C:24]2[C:19](=[CH:18][C:17]([F:38])=[C:16]([N:14]3[CH2:15][CH:11]4[CH:12]([C:8]([CH2:5][OH:40])=[N:9][O:10]4)[CH2:13]3)[N:25]=2)[C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(Cl)cc5)C4C3)c(F)cc2c1=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(CO)C4C3)c(F)cc2c1=O

Procedure:
The title compound was prepared in an analogous manner to acid 101, but using a suitably substituted TFA salt 11. Acid 107 was isolated as a beige solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.[N+](C1C=C[C:26]([N:29](C)[C:30](=O)[O-:31])=CC=1)([O-])=O>CN(C)C=O>[CH3:26][NH:29][C:30](=[O:31])[NH:1][CH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1
Reactant: CN(C(=O)[O-])c1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Solvent: CN(C)C=O
Product: CNC(=O)NCc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Temperature: 20 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
A mixture of 1 g of 8-aminomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one and 1.8 g of 4-nitrophenyl-N-methylcarbamate in 40 ml of dimethylformamide is stirred for 18 hours at a temperature in the region of 20° C. The reaction mixture is filtered and washed with 5 ml of dimethylformamide. The solid is taken up in 25 ml of dimethylformamide and the suspension is heated at 100° C. for 30 minutes. The insoluble material is filtered and washed with 5 ml of dimethylformamide and then with 20 ml of acetone. After drying under reduced pressure (1 mbar) at 60° C., 1.2 g of 8-(3-methylureido)methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a yellow solid, the melting point of which is greater than 260° C. (Analysis; % Calculated C: 62.13, H: 4.89, N: 22.64; % Found C: 62.0, H: 4.5, N: 22.6).
Reaction SMILES: O[CH2:2][C:3]([CH3:25])=[CH:4][CH2:5][CH2:6][C:7]([CH3:24])=[CH:8][CH2:9][CH2:10][C:11]([CH3:23])=[CH:12][CH:13]=[C:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(Cl)(Cl)(Cl)[Cl:52]>>[Cl:52][CH2:2][C:3]([CH3:25])=[CH:4][CH2:5][CH2:6][C:7]([CH3:24])=[CH:8][CH2:9][CH2:10][C:11]([CH3:23])=[CH:12][CH:13]=[C:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=CC=C(C)CCC=C(C)CCC=C(C)CO)C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)C(=CC=C(C)CCC=C(C)CCC=C(C)CCl)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 14-hydroxy-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenoate (713 mg, 2.03 mmol) in dry carbon tetrachloride (2 ml) was added triphenylphosphine (787 mg, 3.00 mmol), and the mixture was heated under reflux with stirring for 2 hours. After confirmation of disappearance of the starting material, the mixture was cooled to room temperature, and n-hexane was added thereto. Insoluble triphenylphosphine oxide was filtered and washed with n-hexane. The liltrate and the washing were combined and condensed. The resultant residue was added to a small amount of n-hexane, filtered, and washed to remove the residual triphenylphosphine oxide. The filtrate and the washing were combined and condensed to give as a residue the aimed ethyl 14-chloro-2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenoate. The product was used in the subsequent reaction without purification.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH:17][C:41](=[O:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1)c1ccccc1
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a stirred solution of 44 mg (0.095 mmol) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine in 5 mL of THF, 19 μL (0.114 mmol, 1.2 eq) of Huenig's base and 11 μL (0.095 mmol, 1 eq) of benzoyl chloride were added at 0° C. After 2 hours, the reaction mixture was quenched by addition of an aqueous solution of NaHCO3 and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel EtOAc/Heptane 1:1 gave 28 mg (51%) of (RS,SR)-N-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-benzamide as a white solid, MS: 565 (M).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:11][CH2:10][CH:9]([CH:12]3[CH2:14]C3)[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[O:18]1[CH2:17][CH2:16][N:15]([C:4]2[C:5]3[O:11][CH2:10][C:9]4([CH2:12][CH2:14]4)[O:8][C:6]=3[N:7]=[C:2]([C:29]3[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=3)[N:3]=2)[CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Clc1nc2c(c(N3CCOCC3)n1)OCC(C1CC1)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2nc3c(c(N4CCOCC4)n2)OCC2(CC2)O3)cn1
Temperature: 120 °C
Yield: 35.2 %

Procedure:
A mixture of 2-chloro-7-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (98 mg, 0.34 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (144 mg, 0.65 mmol), Pd(PPh3)2Cl2 (25 mg, 0.035 mmol) and sodium carbonate (1.0 mL, 1.0 mmol, 1M aqueous solution) in acetonitrile (4 mL) was degassed then heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 106 as a white solid (41 mg, 35%). LCMS: RT=3.24 min, [M+H]+=343. 1H NMR (400 MHz, CDCl3): δ 9.12 (2H, s), 5.20 (2H, broad s), 4.16 (2H, s), 3.82 (8H, s), 1.29 (2H, t, J=6.89 Hz), 0.88 (2H, t, J=6.88 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][C:23](=[O:24])[C:18]=3[O:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[C:30]([F:32])[CH:31]=1>C1COCC1>[F:25][C:26]1[CH:27]=[C:28]([C:23]2([OH:24])[C:18]3[O:17][N:16]=[C:15]([C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[C:19]=3[CH2:20][CH2:21][CH2:22]2)[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: COc1cc(-c2noc3c2CCCC3=O)ccc1-n1cnc(C)c1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cc(-c2noc3c2CCCC3(O)c2cc(F)cc(F)c2)ccc1-n1cnc(C)c1
Reaction time: 3 h
Yield: 69.6 %

Procedure:
To a mixture of 3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (880 mg, 2.72 mmol) in THF (15 ml) at 0° C., was added slowly (3,5-difluorophenyl)magnesium bromide (6.54 mL of 0.5 M solution in THF, 3.27 mmol) and the reaction was stirred for 3 hr. Additional amount of (3,5-difluorophenyl)magnesium bromide (6.0 mL of 0.5 M solution in THF, 3.0 mmol) was added and stirring was continued at 0° C. for 2 hr. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography using 0-6% MeOH in DCM as solvent to afford the 828 mg of the title product.