Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)C(O)=O.CN(C)C=O.C(Cl)(=O)[C:38]([Cl:40])=[O:39]>ClCCl>[O:1]=[C:2]1[C:10]2([C:11]3=[CH:21][C:20]4[CH2:19][CH2:18][O:17][C:16]=4[CH:15]=[C:12]3[O:13][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:25][C:24]=1[C:38]([Cl:40])=[O:39]
Reactant: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (2.13 g, 5.1 mmol) and N,N-dimethylformamide (0.001 mL, catalytic amount) in anhydrous dichloromethane (30 mL) was treated with oxalyl chloride (4.50 mL, 5.1 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The crude product was concentrated in vacuo to afford 3-(((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride as a light yellow solid. A solution of 3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.27 g, 0.6 mmol), cyclohexanemethylamine (0.17 mL, 1.3 mmol), triethylamine (0.44 mL, 3.2 mmol), and 4-(dimethylamino)pyridine (0.005 g, catalytic amount) in anhydrous dichloromethane (5 mL), was stirred at ambient temperature for 20 h under nitrogen. The reaction mixture was diluted with dichloromethane (10 mL) and aqueous citric acid (10 mL) and the phases were separated. The organic phase was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate in hexanes (0% to 100% gradient) to afford N-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.33 g, 65%) as a colourless solid: 1H NMR (300 MHz, CDCl3) δ7.80 (s, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.48-7.37 (m, 2H), 7.23-7.15 (m, 2H), 7.08-7.00 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 6.19-6.09 (m, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H), 3.33-3.23 (m, 2H), 3.07-2.95 (m, 2H), 1.82-1.64 (m, 5H), 1.34-1.13 (m, 4H), 1.07-0.86 (m, 2H); MS (ES+) m/z 509.0 (M+1).
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[C:14]([S:17][CH3:18])=[N:13][N:12]=2)=[CH:7][CH:6]=1.[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:32]=[C:28]([C:29]([NH2:31])=[O:30])[C:27]([OH:33])=[CH:26][CH:25]=1.O>CS(C)=O>[C:29]([C:28]1[CH:32]=[C:24]([CH:25]=[CH:26][C:27]=1[OH:33])[O:23][CH2:22][CH2:21][NH:20][CH2:19][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[C:14]([S:17][CH3:18])=[N:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:30])[NH2:31]
Reactant: NCCOc1ccc(O)c(C(N)=O)c1
Reactant: CSc1nnc(-c2ccc(OCC3CO3)cc2)n1C
Solvent: CS(C)=O
Solvent: O
Product: CSc1nnc(-c2ccc(OCC(O)CNCCOc3ccc(O)c(C(N)=O)c3)cc2)n1C

Procedure:
Analogously to Example 12, 19.5 g of 3-[4-(2,3-epoxypropoxy)-phenyl]-4-methyl-5-methylthio-4H-1,2,4-triazole are reacted with 11.0 g of 5-(2-aminoethoxy)-salicylamide in 70 ml of dimethyl sulphoxide. The resin-like crude product that is obtained on mixing with water is extracted by boiling with dioxan, the dioxan solution is concentrated by evaporation and the residue is recrystallised from methanol. 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(4-methyl-5-methylthio-4H-1,2,4-triazol-3-yl)-phenoxy]-2-propanol having a melting point of 123°-125° is obtained.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc([N+](=O)[O-])cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, yellow solid (41 mg, 47%), MS (ISP) m/z=347.5 [(M+H)+], mp 312° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-nitro-phenylboronic acid (54.3 mg, 0.325 mmol).
Reaction SMILES: S(=O)(=O)(O)O.C([C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15](C(=O)C)=[CH:16][CH:17]=3)[CH:12]([CH3:25])[C:11]=2[CH:10]=1)(=O)C.C([O:29][C:30](=[O:32])[CH3:31])(=O)C.OO>O.ClCCl>[C:30]([O:32][C:16]1[CH:15]=[CH:14][C:13]2[C:12]3[C:11](=[CH:10][C:9]([O:29][C:30](=[O:32])[CH3:31])=[CH:21][CH:25]=3)[CH:19]([CH3:20])[C:18]=2[CH:17]=1)(=[O:29])[CH3:31]
Reactant: CC(=O)c1ccc2c(c1)C(C)c1cc(C(C)=O)ccc1-2
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1ccc2c(c1)C(C)c1cc(OC(C)=O)ccc1-2
Temperature: 24 °C
Reaction time: 7 h
Yield: 36.9 %

Procedure:
36M-sulfuric acid (12 mL) was slowly dropwise added to a mixture of 2,7-diacetyl-9-methylfluorene (30 g), dichloromethane (30 mL), acetic anhydride (35 g) and a 34% hydrogen peroxide aqueous solution (34.6 g) while maintaining 3° C. or lower. The resulting mixture was stirred at 24° C. for 7 hours and then poured into water. The separated organic layer was sufficiently washed in order with saturated sodium hydrogencarbonate, 10% saturated sodium hydrogensulfite and water, and then dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure, and the resulting residue was purified by means of column chromatography (silica gel, eluting solvent: heptane/toluene [6/4]) and recrystallization (ethanol) to obtain 2,7-diacetyloxy-9-methylfluorene (12.4 g) of colorless crystal. Melting point: 138.6-139.7° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]([O:13][C:14]([N:16](C)[C@H:17]([C:19]([OH:21])=O)[CH3:18])=[O:15])([CH3:12])([CH3:11])[CH3:10].[CH3:23]N(C)CCCN=C=NCC>ClCCl>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:19](=[O:21])[C:17]([NH:16][C:14]([O:13][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:15])([CH3:18])[CH3:23]
Reactant: O=C1CCC(=O)N1O
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)ON1C(=O)CCC1=O

Procedure:
A stirred solution of N-hydroxysuccinimide (112 g, 0.973 mol), N-t-butoxycarbonyl-methylalanine (197 g, 0.969 mol), and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (186 g, 0.970 mol) in anhydrous dichloromethane (1.4 L) was stirred at room temperature for about 18 hours under nitrogen atmosphere. The reaction mixture was washed three times each with saturated sodium bicarbonate solution and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound of part 1-D as a white solid (256 g, 88%): PBMS (M+18)+ 318; 1H NMR=250 MHz (CDCl3) δ: 4.91 (NH, br s, 1H), 2.84 (—CO(CH2)2CO—, s, 4H), 1.67 (Me, s, 6H), 1.48 (BOC, s, 9H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH2:11][OH:12])=[N:7][C:8]=1[O:9][CH3:10].[Br:14][C:15]1[CH:16]=[C:17]([C:28](O)=[O:29])[C:18]2[C:19]([CH3:27])=[CH:20][N:21]([CH:24]([CH3:26])[CH3:25])[C:22]=2[CH:23]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl.CN(C=O)C>[Br:14][C:15]1[CH:16]=[C:17]([C:28]([NH:1][CH2:2][C:3]2[C:8]([O:9][CH3:10])=[N:7][C:6]([CH2:11][OH:12])=[CH:5][C:4]=2[CH3:13])=[O:29])[C:18]2[C:19]([CH3:27])=[CH:20][N:21]([CH:24]([CH3:25])[CH3:26])[C:22]=2[CH:23]=1
Reactant: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Reactant: COc1nc(CO)cc(C)c1CN
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1nc(CO)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methanol (0.29 g, 1.591 mmol), 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (0.48 g, 1.621 mmol), and HOAt (0.22 g, 1.616 mmol) in Dichloromethane (15 mL) and DMF (5 mL) was added EDC free base (0.30 g, 1.932 mmol). The reaction was stirred at RT for 3 h then evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 20% EtOAc in CH2Cl2) to give the product 6-bromo-N-((6-(hydroxymethyl)-2-methoxy-4-methylpyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (0.73 g, 1.586 mmol, 100% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.46 (t, J=4.9 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 7.33 (d, J=1.0 Hz, 1H), 6.99 (d, J=1.5 Hz, 1H), 6.90 (s, 1H), 5.31 (t, J=5.9 Hz, 1H), 4.74 (quin, J=6.6 Hz, 1H), 4.45 (d, J=5.1 Hz, 1H), 4.43 (d, J=5.8 Hz, 2H), 3.83 (s, 3H), 2.40 (s, 3H), 2.10 (s, 3H), 1.38 (d, J=6.8 Hz, 6H). MS(ES)+ m/e 460.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:28])([C:7]1[CH:11]=[C:10]([NH:12][C:13](=O)[O:14]C2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)[C:3]([F:6])([F:5])[F:4].COC1C=C2C(=CC=1OC)N=C[N:35]=C2OC1C=C(C=CC=1)N.C(N(C(C)C)CC)C>C1COCC1>[F:28][C:2]([F:1])([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:14])[NH2:35])[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=1)[C:3]([F:5])([F:6])[F:4]
Reactant: O=C(Nc1cc(C(F)(F)C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CCN(CC)C(C)C
Solvent: C1CCOC1
Product: NC(=O)Nc1cc(C(F)(F)C(F)(F)F)nn1-c1ccccc1
Temperature: 60 °C
Yield: 73.5 %

Procedure:
A stirred mixture of phenyl 3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (199 mg, 0.50 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (100 mg, 0.34 mmol), N,N-diethylisopropylamine (88 mg, 0.68 mmol) in THF (1 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to afford the crude product. Purification via preparative HPLC afforded 14346,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-yl)urea (80 mg, 39%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) 89.35 (s, 1H), 8.82 (s, 1H), 8.54 (s, 1H), 7.55-7.61 (m, 7H), 7.36-7.40 (m, 2H), 7.18 (m, 1H), 6.95 (m, 1H), 6.88 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z 601 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH:6]([CH2:8][NH:9][CH:10]([CH3:12])[CH3:11])[O:5][C:4]1=[O:13])[CH3:2].[CH:20](O)=O.C=O>C(O)C.O>[CH2:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH:6]([CH2:8][N:9]([CH3:20])[CH:10]([CH3:12])[CH3:11])[O:5][C:4]1=[O:13])[CH3:2]
Reactant: O=CO
Reactant: CCC1(c2ccccc2)CC(CNC(C)C)OC1=O
Agent: C=O
Solvent: O
Solvent: CCO
Product: CCC1(c2ccccc2)CC(CN(C)C(C)C)OC1=O
Yield: 73 %

Procedure:
A solution containing 1.3 g of 3-ethyldihydro-5-[[(1-methylethyl)amino]methyl]-3-phenyl-2(3H)-furanone, 1.3 g of 90% formic acid, and 1.1 g of 37% formaldehyde in 15 ml of ethanol was refluxed 2.5 hrs. The solution was cooled and then diluted with water and washed with diethyl ether. The aqueous layer was made basic with dilute sodium hydroxide and extracted with diethyl ether. The ether extract was washed with saturated sodium chloride solution, dried over anhydrous potassium carbonate, and concentrated in vacuo to an oil. The oil was dried at 40°/1 mm to yield 1.0 g of the title compound, having the following elemental analysis:
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[CH2:22][CH3:23].CCN(C(C)C)C(C)C.O>CC(O)C>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)([NH:31][C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:21][CH2:22][CH3:23])=[CH:30][CH:29]=3)[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: CCCOc1ccc(N)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) (from example 1c supra), 4-propoxy-phenylamine (61 mg, 0.41 mmol) and DIPEA (104.5 mg, 0.81 mmol) in propan-2-ol (10 mL) was stirred at room temperature for 2 h. Then water (10 mL) was added and the desired product was precipitated out, then filtrated and dried to give 98 mg of rac-6-chloro-3-(3-chloro-benzyl)-3-(4-propoxy-phenylamino)-1,3-dihydro-indol-2-one as a white solid. MS: 441 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li+].CCC[CH2-].C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[C:5]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)=[CH:4][CH:3]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: FC1(F)Oc2cccc(Cl)c2O1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)OB(c2ccc(Cl)c3c2OC(F)(F)O3)OC1(C)C
Temperature: -75 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
4-Chloro-2,2-difluorobenzo[d][1,3]dioxole (3 g, 15.58 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −75° C. N-Butyllithium (2.5 M in hexanes; 6.86 mL, 17.14 mmol) was added dropwise keeping the temperature below −65° C. The reaction mixture was then stirred at −75° C. for 1 h to ensure complete deprotonation. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.19 g, 17.14 mmol) was then added to the reaction mixture dropwise keeping the temperature below −65° C. The reaction mixture was then allowed to warm to room temperature, added to diethyl ether (200 mL) and extracted with water (2×100 mL). The aqueous phases were combined and acidified to pH 4 with concentrated HCl. The product was extracted with diethyl ether and the organic phase was dried and concentrated under vacuum to provide the title compound as an off-white solid (3.82 g, 77%): 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 1.36 (s, 12H); EIMS m/z 318.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1.[O:27]=[C:28]1[NH:32][CH2:31][C:30](=[O:33])[N:29]1[CH2:34][C:35](O)=[O:36]>>[O:27]=[C:28]1[NH:32][CH2:31][C:30](=[O:33])[N:29]1[CH2:34][C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:6][CH:7]=1)=[O:36]
Reactant: O=C(O)CN1C(=O)CNC1=O
Reactant: Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Product: O=C(CN1C(=O)CNC1=O)Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1

Procedure:
1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with 2-(2,5-dioxo-imidazolidin-1-yl acetic acid as described in example 217. The product with the molecular weight of 483.49 (C26H21N5O5); MS (ESI): 484 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[C:23]3[CH2:29][CH2:28][NH:27][CH2:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1)=[O:12])[CH3:9].CCN(C(C)C)C(C)C.[CH:46]1([C:49](Cl)=[O:50])[CH2:48][CH2:47]1>C(Cl)Cl>[CH:46]1([C:49]([N:27]2[CH2:28][CH2:29][C:23]3[C:22]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]4[CH3:36])=[N:21][C:20]([C:17]4[CH:16]=[CH:15][C:14]([NH:13][C:11]([NH:10][CH2:8][CH3:9])=[O:12])=[CH:19][CH:18]=4)=[N:25][C:24]=3[CH2:26]2)=[O:50])[CH2:48][CH2:47]1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)C2CC2)C3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
To a stirred solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea 2,2,2-trifluoroacetate (100 mg, 0.20 mmol) in DCM was added iPr2NEt (70 uL, 0.40 mmol) and cyclopropanecarbonyl chloride (20 uL, 0.22 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and purified by prep. HPLC to give a white solid (14 mg, 0.03 mmol, 15% yield).
Reaction SMILES: [C:1]([CH2:4][PH:5](=[O:7])[O-:6])(=O)[CH3:2].[Na+:8].[NH2:9][NH:10][C:11]([NH2:13])=[S:12]>C(O)C>[C:1](=[N:9][NH:10][C:11]([NH2:13])=[S:12])([CH2:4][PH:5](=[O:7])[O-:6])[CH3:2].[Na+:8]
Reactant: CC(=O)C[PH](=O)[O-]
Reactant: NNC(N)=S
Agent: [Na+]
Solvent: CCO
Product: CC(C[PH](=O)[O-])=NNC(N)=S

Procedure:
A mixture of sodium acetylmethylphosphinate (3.5 g) and thiosemicarbazide (2.2 g) was stirred in ethanol (15 ml) for 4 days. The precipitated hydrazone was filtered off and dried (4.6 g). The n.m.r spectrum supports the required structure. The compound slowly decomposes above 125°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N+:10]([O-])=[CH:11]2)=[CH:6][CH:5]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:13]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2cc[n+]([O-])cc2c1
Agent: Cl
Product: COc1ccc2ccnc(Cl)c2c1
Temperature: 90 °C

Procedure:
7-Methoxy-isoquinoline-N-oxide hydrochloride (38.2 g) was added in portions to phosphoryl chloride (275 mL) and the mixture heated at 90° C. for 6 h. Excess of phosphoryl chloride was removed in vacuo. The remaining white solid was washed with water, filtered and dried in vacuo.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>C1(C)C=CC=CC=1.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>[CH:11]([C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH2:12]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1nc2ncccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1nc2ncccc2[nH]1

Procedure:
A solution of bromoimidazo[4,5-b]pyridine (1 eq.), tributyl(vinyl)tin (1.5-3 eq.), and tetrakis(triphenylphosphine)palladium(0) (0.1 eq.) in toluene (deoxygenated with N2, 20 ml/mmol ml) is stirred under reflux for 4 h. Concentration in vacuo and chromatographic purification (EtOAc/hexane gradient) yields the corresponding vinylimidazo[4,5-b]pyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].[CH3:10][CH:11]([CH3:15])[CH2:12][C:13]#[CH:14]>N1C=CC=CC=1>[Br:8][C:4]1[C:3]2[O:9][C:13]([CH2:12][CH:11]([CH3:15])[CH3:10])=[CH:14][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCC(C)C
Reactant: Oc1c(Br)cccc1Br
Solvent: c1ccncc1
Product: CC(C)Cc1cc2cccc(Br)c2o1

Procedure:
A stirred mixture of 2,6-dibromophenol (946 mg, 3.76 mmol), Cu2O (322 mg, 2.25 mmol), 4-methylpentyne (0.5 mL, 3.9 mmol) and pyridine (5 mL) was heated at vigorous reflux for 0.5 h. The mixture was concentrated under reduced pressure to remove pyridine, diluted with ether (100 mL), washed with water (50 mL), 5% aq HCl (2×50 mL) and 1M aq NaOH (50 mL) and dried over MgSO4. Removal of the solvent left an oil (650 mg) containing 7-bromo-2-isobutylbenzofuran (˜70% pure).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7]/[C:8](=[CH:12]\[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C1(N)CCCCC1>CO>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C/C(=C\CCc1ccccc1)C(=O)O
Solvent: CO
Solvent: NC1CCCCC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A stirred solution of (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid (100 g, 0.34 mol), cyclohexylamine (39 ml, 0.34 mol) and [(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)ruthenium chloride (0.64 g, 0.69 mmol) in methanol (1000 ml) was heated to 60° C., under hydrogen (60 p.s.i.), for 42 hours and then allowed to cool to room temperature. The mixture was filtered through celite and then concentrated in vacuo to a yellow solid which was purified by re-crystallisation from acetone (850 ml). The resulting solid was partitioned between ethyl acetate (1200 ml) and citric acid solution (10%, 1200 ml) and the organic phase was separated, washed with demineralised water (1200 ml) and concentrated in vacuo to leave the title compound as an oil (80 g).
Reaction SMILES: Br[C:2]1[C:19]2[C:20]3[C:5]([C:6]4[C:21]5[C:10]6=[C:11]([C:22]([N:24]([C:27]7[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=7[CH:36]([CH3:38])[CH3:37])[C:25](=[O:26])[C:9]6=[CH:8][CH:7]=4)=[O:23])[CH:12]=[CH:13][C:14]=5[C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.[C:39]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]#[CH:48])(=[O:41])[CH3:40].Cl>O1CCCC1.N1CCCCC1.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.[Cu]I>[CH:36]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([CH:33]([CH3:35])[CH3:34])[C:27]=1[N:24]1[C:25](=[O:26])[C:9]2[C:10]3[C:21]4[C:6](=[CH:7][CH:8]=2)[C:5]2[C:20]5[C:19]([C:2]([C:48]#[C:47][CH2:46][CH2:45][CH2:44][CH2:43][O:42][C:39](=[O:41])[CH3:40])=[CH:3][CH:4]=2)=[CH:18][CH:17]=[CH:16][C:15]=5[C:14]=4[CH:13]=[CH:12][C:11]=3[C:22]1=[O:23])([CH3:38])[CH3:37]
Reactant: C#CCCCCOC(C)=O
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccc3c4cccc5c(Br)ccc(c6ccc(c2c36)C1=O)c54
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CC(=O)OCCCCC#Cc1ccc2c3ccc4c5c(ccc(c6cccc1c62)c53)C(=O)N(c1c(C(C)C)cccc1C(C)C)C4=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
2.0 g (3.56 mmol) of 9-bromo—N-(2,6-diisopropylphenyl)perylene-3,4-dicarboximide (prepared in analogy to Example 6a of WO 96/22 332 using N-(2,6-diisopropylphenyl)perylene-3,4-dicarboximide from Example 28 of WO 97/22 607 as starting material) was dissolved in 500 ml of a mixture of one part by volume of absolute tetrahydrofuran (THF) and one part by volume of dry piperidine under inert gas, admixed in succession with 4 mol % of Pd(PPh3)4 (164 mg, 0.14 mmol), 5 mol % of CuI (32 mg, 0.18 mmol) and 1.14 g (7.12 mmol) of 6-acetoxy-1-hexyne; this mixture was slowly heated to 70° C. and held at this temperature for 1 h. After cooling to room temperature, the reaction mixture was added to three times the volume of a mixture of ice and concentrated hydrochloric acid in a volume ratio of 3:1, the organic phase was separated off, the aqueous phase was extracted with 3 times 200 ml of methylene chloride, the combined organic extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Chromatography on silica gel using methylene chloride as eluent gave 1.98 g (90%) of N-(2,6-diisopropylphenyl)-9-(6-acetoxy-1-hexynyl)perylene-3,4-dicarboximide as a red powder having a melting point >300° C.