Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[O:11][N:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]=1[CH2:7][CH2:6]2)=C.C[N+]1([O-])CC[O:24]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.[Os](=O)(=O)(=O)=O.O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[O:11][N:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]=1[CH2:7][CH2:6]2)=[O:24]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c(C(=O)OC)noc1-2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1noc2c1CCc1cc(C=O)ccc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of methyl 7-vinyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (Preparation 45B, 65 mg, 0.255 mmol) in THF (4 mL) were sequentially added N-methylmorpholine-N-oxide in water (0.084 mL, 0.407 mmol) and osmium tetroxide in water (0.062 mL, 10.19 μmol) at room temperature. The solution was stirred vigorously at room temperature overnight. Sodium periodate (109 mg, 0.509 mmol) in water (1 mL) was added and the mixture was stirred at room temperature under nitrogen for two hours. Water (2 mL) was then added and the mixture was concentrated to remove THF. The resulting solid was filtered, washed with water (2×2 mL), and dried to give 72 mg of product as a yellow solid. The compound had an HPLC ret. time=0.88/2.0 min. (condition E).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[C:14]1([CH:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCCO)C.O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[N:22]1[CH2:23][CH2:24][CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21]1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1cc(Cl)c2cc(Cl)ccc2n1
Solvent: O
Solvent: CCOCCO
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(Cl)ccc2n1

Procedure:
4,6-Dichloro-2-methylquinoline (0.1 g) and 3-phenylpyrrolidine (0.15 g) in 2-ethoxy-ethanol (1.5 mL) was heated in a microwave at 240° C. for 10 minutes. The mixture was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with a mixture of methanol and dichloromethane. Evaporation of the desired fractions gave the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([S:27]([NH2:28])(=[O:30])=[O:29])[CH:25]=[CH:26][C:18]=3[Cl:17])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(N)(=O)=O)ccc3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step 2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-Chloro-5-sulfamoyl-benzoic acid (CAS: 97-04-1; Basu; D.-G.; J.Indian Chem. Soc.; 16; 1939; 100, 106) (42%, white solid), MS (m/e): 438.1 (M−H, 100%)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N:13]1([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]([NH:26][NH2:27])=[O:25])[N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:27][NH:26][C:24](=[O:25])[CH2:23][N:21]1[N:20]=[N:19][C:18]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[N:22]1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)Cn1nnc(N2CCCC2)n1
Solvent: CC(=O)O
Product: O=C(Cn1nnc(N2CCCC2)n1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 72 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-[5-(1-pyrrolidinyl)-2H-tetrazol-2-yl]acetohydrazide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 67 mg of the title compound (72%) as a yellow powder in 95% purity by HPLC (Rt: 4.24, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:10][CH2:9][C:7]([C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCC(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NCC(=O)c1cccs1)c1ccc(Cl)cc1
Yield: 99.5 %

Procedure:
5.0 g of N-[(2-thienylcarbonyl)methyl]amine hydrochloride, 10.0 g of sodium bicarbonate and 4.78 g of 4-chlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(3). 7.6 g of N-(4-chlorobenzoyl)-N-[(2-thienylcarbonyl)methyl]amine are thereby obtained.
Reaction SMILES: [BH4-].[Na+].[O:3]([C:10]1[CH:11]=[C:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O>CO>[F:18][C:17]([F:19])([F:20])[CH:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:11]=1)[OH:21]
Reactant: O=C(c1cccc(Oc2ccccc2)c1)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(c1cccc(Oc2ccccc2)c1)C(F)(F)F
Reaction time: 0.42 h

Procedure:
2.71 g of sodium borohydride were added in small fractions over 35 minutes at 0° C. to a solution of 56.1 g of the raw product of Step A in 235 ml of methanol and the mixture was stirred for 25 minutes while allowing the temperature to rise to room temperature. The mixture was added to aqueous 1N hydrochloric acid solution and water was added with stirring. The decanted aqueous phase was extracted with methylene chloride and the organic phase was washed with water and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with methylene chloride to obtain 13.3 g of (R, S) 2,2,2-trifluoro-1-(m-phenoxy-phenyl)-ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]OCCOC)=[C:7]([O:15][CH3:16])[N:6]=[C:5]([C:17]([F:20])([F:19])[F:18])[C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[ClH:26]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:26][CH2:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([C:17]([F:20])([F:19])[F:18])=[N:6][C:7]=1[O:15][CH3:16]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(OC)c(COCCOC)c1OC
Reactant: Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)(F)F)nc(OC)c(CCl)c1OC
Reaction time: 0.33 h
Yield: 97 %

Procedure:
To a solution of 15.5 g (0.0289 mol) of product of Example 26 in 30 ml of CH2Cl2 cooled in a ice water bath was added 12.0 g of titanium tetrachloride. The reaction mixture turned brown with formation of a white precipitate. After stirring at 10°-15° C. for 20 minutes, then at 20° C. for 20 minutes, the reaction mixture was poured into 70 ml of 6N HCl. The CH2Cl2 layer was separated, dried (MgSO4) and concentrated. The residue was kugelrohr distilled at 2 torr (pot temperature 140° C.) to give 9.1 g (97%) of product as a colorless liquid: nD25 1.4738.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:27]([CH:28]=1)[C:8]1[N:9]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[C:10](=[O:17])[C:11]3[C:16]([C:7]=1[N:6]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[C:29]([O:32][CH2:33][CH2:34]Br)(=[O:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:9]2[C:8]3[N:27]4[CH:28]=[C:2]([O:1][CH2:34][CH2:33][O:32][C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]4=[N:6][C:7]=3[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:17])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=c1c2ccccc2c2nc3ccc(O)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A mixture of compound 10 (1.0 equiv., 0.806 mmol, 0.300 g), 2-bromoethyl acetate (2.0 equiv., 1.611 mmol, 0.269 g) and K2CO3 (3.0 equiv., 2.417 mmol, 0.334 g) in dry DMF (5 ml) was stirred at 60° C. for 4 h. Water was added to the reaction mixture and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried with MgSO4 and concentrated in vacuo. Purification by column chromatography (dichloromethane/methanol 97.2:2.5) afforded 6-(4-nitrophenyl)-9-[2-[(1-oxoethyl)oxy]-ethoxy]-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (73) (0.245 g, yield=66%, purity (LC)=97%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.O.[BH4-].[Na+].C[NH2:16]>CO>[NH2:16][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: CN
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of aldehyde product from Step B (2.0 g, 14 mmol) in methanol (100 mL), 40% methylamine in water (2.27 mL, 27.6 mmol) was added at room temperature over a period of 10 min. The mixture was stirred at room temperature under nitrogen overnight and then was cooled down to 0° C. Sodium borohydride (1.05 g, 27.6 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 h. Most of methanol was removed in vacuo, and the residue was diluted with water and extracted (3×) with ether. The combined organic layers were extracted with 2 N HCl (100 mL). The HCl layer was made basic (pH˜11) with 2 N NaOH and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give crude 4-(aminomethyl)-indole as a white powder (1.95 g, 88%): 1H NMR (300 MHz, CDCl3) δ 8.29 (s, br, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.22 (t, J=2.7 Hz, 1H), 7.16 (t, J=8.0, 7.3 Hz, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.64 (t, J=2.0 Hz, 1H), 4.06 (s, 2H), 2.51 (s, 3H); CI MS m/z=160 [C10H12N2+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(O)cc1F
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(O)cc1F
Temperature: 0 °C
Reaction time: 72 h

Procedure:
4-Amino-3-fluorophenol (0.254 g; 2.0 mmol) was dissolved in 10 ml of dry pyridine under nitrogen and cooled to 0° C. Methanesulfonyl chloride (0.17 ml; 2.1 mmol) was added dropwise and stirred for three days at room temperature. The reaction was evaporated, 25 ml of toluene added and evaporated again. Toluene evaporation was repeated. Residue was dissolved in 25 ml of EtOAc, washed with 20 ml of water and evaporated to dryness to give red-brown solid N-(2-fluoro-4-hydroxyphenyl)methanesulfonamide. 1H NMR (400 MHz, DMSO-d6): 2.93 (3H, s), 6.56-6.66 (2H, m), 7.14 (1H, t, J=9.0 Hz), 9.17 (1H, s), 9.98 (1H, s).
Reaction SMILES: [Br:1]Br.[CH2:3]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)[CH:9]=[C:8]([Cl:16])[N:7]=1)[CH3:4].O.N>C(Cl)Cl>[CH2:3]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)[C:9]([Br:1])=[C:8]([Cl:16])[N:7]=1)[CH3:4]
Reactant: BrBr
Reactant: CCNc1nc(Cl)cc(NC2CC2)n1
Agent: N
Solvent: ClCCl
Solvent: O
Product: CCNc1nc(Cl)c(Br)c(NC2CC2)n1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A solution of 6.4 g of bromine (0.04 mol) in 30 ml of methylene chloride is added dropwise over the course of one hour to a solution of 8.5 g (0.04 mol) of 2-ethylamino-4-cyclopropylamino-6-chloropyrimidine in 300 ml of methylene chloride, whilst cooling with ice. The solution is left to stand overnight at room temperature, 150 ml of water are then added and the mixture is brought to pH 9-10 with dilute ammonia solution. The organic phase is separated off, rinsed with water, dried over magnesium sulphate, filtered and evaporated. The evaporation residue (12 g), when recrystallised from methanol-water (1:1), gives 10.4 g of colourless crystals of melting point 100°-101°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[Br:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[Br:29])[CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
A solution of 16 (1.77 g, 3.90 mmol) in anhydrous DMF (20 mL) under Ar was treated with NaH (206 mg, 5.1 mmol, 1.3 equiv, 60% oil dispersion) and the reaction mixture was stirred for 30 min. The mixture was cooled to 0° C. and 4-bromo-2-methyl-2-butene (1.35 mL, 11.7 mmol, 3 equiv) was added dropwise by cannula. The solution was stirred at 0° C. for 1 h before being allowed to warm to 25° C. and stirred overnight. Water (20 mL) was added and the aqueous phase was extracted with EtoAc (3×15 mL). The combined organic phases were washed with saturated aqueous NaCl (1×30 mL), dried (Na2SO4) and the solvent was removed under vacuum. Chromatography (SiO2, 4×20 cm, 10% EtOAc-hexane) afforded 17 (2.05 g, 2.03 g theoretical, >99%) as an amber oil: 1H NMR (CDCl3, 400 MHz) δ8.66 (d, 1H, J=0.5 Hz), 8.40 (d, 1H, J=8.6 Hz), 7.63 (d, 1H, J=8.6 Hz), 7.51-7.34 (m, 5H), 6.85 (s, 1H), 5.24 (d, 1H, J=9.5 Hz), 5.20 (d, 1H, J=11.7 Hz), 5.17 (d, 1H, J=11.7 Hz), 4.40 (dd, 1H, J=6.1, 14.5 Hz), 4.01 (dd, 1H, J=7.7, 14.9 Hz), 1.61 (s, 3H), 1.57 (s, 3H), 1.37 and 1.30 (two s, 9H); 13C NMR (CDCl3, 100 MHz) δ153.7, 140.9, 136.3, 135.8, 133.5, 128.8, 128.5, 127.3, 126.7, 124.1, 119.8, 119.5, 118.8, 111.7, 110.9, 81.0, 80.5, 70.8, 47.7, 46.3, 28.5, 28.2, 25.7; IR (film) vmax 3467 (br), 2928, 2229, 1701, 1676, 1596, 1503, 1438, 1387, 1335, 1255, 1164, 1090, 863, 738 cm-1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH2:30][CH3:31])=[O:27])=[C:21]([Cl:32])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>CN(C)C=O>[Cl:32][C:21]1[CH:20]=[C:19]([O:18][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH3:17])=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:43]4[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:24]=[CH:23][C:22]=1[NH:25][C:26]([NH:28][CH2:29][CH2:30][CH3:31])=[O:27]
Reactant: CN1CCNCC1
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCCBr)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCCN4CCN(C)CC4)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
N-{2-Chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (500 mg), potassium carbonate (857 mg), and 1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 451 mg (yield 71%) of N-(4-{[6-(3-bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea. N-(4-{[6-(3-Bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea (50 mg), potassium carbonate (40 mg), and N-methylpiperazine (50 μl) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 20 mg (yield 44%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37].C[O-].[Na+:41].CO>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O-:38])=[O:37].[Na+:41]
Reactant: COc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4Cl)C(C(=O)O)CCO5)cc3)n2)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4Cl)C(C(=O)[O-])CCO5)cc3)n2)cn1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 6-chloro-7-(4-(6′-methoxy-2,3′-bipyridin-6-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.080 g, 0.150 mmol) in 1:1 THF/methanol (2 ml) was added a 0.5 M solution of sodium methoxide in methanol (0.301 ml, 0.150 mmol), and the reaction was stirred for 2 hours, then concentrated to yield the desired compound (0.080 g, 0.144 mmol, 96.0% yield). MS (apci) m/z=532.2 (M-Na+2H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH2:17][N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19]2)[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
N-Benzylmaleimide (5.0 g, 26.7 mmol), and N-(methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (7.0 g, 29.4 mmol) were dissolved in toluene (150 mL). Trifluoroacetic acid (500 μL, 6.5 mmol) was added at room temperature. The reaction was allowed to stir for two hours at room temperature, and the precipitate was filtered off (˜440 mg). The filtrate was concentrated and purified by silica gel column chromatography (20-50% ethyl acetate in hexanes) to afford a white solid (6.2 g, 72%). 1H NMR (400 MHz, CDCl3): δ 7.22-7.05 (m, 8H), 7.01-6.96 (m, 2H), 4.45 (s, 2H), 3.95 (s, 2H), 3.50 (d, J=11.0 Hz), 3.37 (d, J=8.8 Hz), 3.10 (app t, J=9.1 Hz); 13C NMR (400 MHz, CDCl3): δ 175.8 (C═O), 134.8 (Ph), 130.6 (Ph), 129.6 (Ph), 129.3 (Ph), 128.8 (Ph), 128.6 (Ph), 128.3 (Ph), 127.7 (Ph), 57.3 (CH2), 54.0 (CH2), 42.9 (CH), 42.6 (CH2).
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[O:28]=[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31][NH:30]1.O>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]=[CH:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29](=[O:28])[NH:30][CH:31]=2)[CH:11]=1
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1c[nH]c(=O)c2ccccc12
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]cc(C=Cc2cccnc2)c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under an N2 atmosphere,147 g (377 mmol) of triphenyl-(pyridin-3-yl-methyl)-phosphonium chloride in 2.2 l of THF are mixed with 44.1 g (393 mmol) of potassium-tert-butylate and stirred for 30 min. The suspension is heated to 50° C. and a mixture of 50.0 g (289 mmol) of 1-oxo-1,2-dihydro-isoquinoline-4-carbaldehyde and 2.2 l of THF is added dropwise and finally stirred for 10 h at 60° C. To the cooled reaction mixture is added 700 ml of water and then the THF is evaporated off on a RE. The residue is taken up in 5 l of water and 8 l of EtOAc, the water phase is separated and extracted 3 more times with EtOAc. The organic phases are washed with water and with brine, combined, dried (Na2SO4) and left to stand over night. A solid separates from the mixture and is filtered off and washed with EtOAc [→(E) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one]. The filtrate is extracted twice with 1 N HCl and then discarded. The acidic aqueous phases are immediately rendered basic with sat. Na2CO3 solution and extracted 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2, EtOAc/ethanol 19:1→9:1) yields first of all (Z) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one, followed by an (E/Z) mixture of 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one. (E) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one: m.p. 222-224° C.; 1H NMR (DMSO-d6) δ11.57 (sb, HN), 8.80 (s, 1H), 8.44 (d, 1H), 8.26 (d, 1H), 8.12 (m, 2H, m), 7.79 (t, 1H), 7.68 (d, J=16.3 Hz, 1H), 7.56 (m, 2H), 7.39 (dd, 1H), 7.07 (d, J=16.3 Hz 1H). (Z) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one: 1H NMR (DMSO-d6) δ11.24 (sb, HN), 8.39 (s, 1H), 8.32 (d, 1H), 8.25 (d, 1H), 7.71 (t, 1H), 7.65 (d, 1H), 7.54 (m, 2H), 7.21 (dd, 1H), 6.90 (s, 1H), 6.81 (s, 2HOlef.).
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:14]=[C:15]([F:31])[CH:16]=[C:17]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=2)[CH:18]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[C:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]=[CH:19][C:17]2[CH:18]=[C:13]([OH:12])[CH:14]=[C:15]([F:31])[CH:16]=2)=[CH:22][CH:23]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Oc1ccc(C=Cc2cc(F)cc(OCc3ccccc3)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Oc1ccc(C=Cc2cc(O)cc(F)c2)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
A 1 M solution of BBr3 (9 ml, 9 mmol) in CH2Cl2 was added to a well-stirred solution of 5-benzyloxy-3-fluoro-4′-acetoxystilbene (1.09 g, 3 mmol) in dry CH2Cl2 (120 mL) at −78° C. The mixture was warmed to −20° C. and stirred for 10 minutes. Then MeOH was added at −78° C. The mixture was washed with saturated NaHCO3, and water, dried over Na2SO4, filtered and evaporated. The 4′-acetoxy-3-fluoro-5-hydroxystilbene (0.50 g, 61%) was obtained as white solid. To a solution of the crude 4′-acetoxy-3-fluoro-5-hydroxystilbene (0.50 g, 1.8 mmol) in MeOH (7.5 ml) was added 3.7 ml 4M HCl in 1,4-dioxane. The mixture was stirred for 20 minutes at ambient temperature. After purification by flash column, 3-fluoro-5,4′-dihydroxystilbene (0.33 g, 780%) was obtained. Data are: 1H NMR (Aceton-d6, 300 MHz) δ 8.624 (s, 2H), 7.46 (m, 2H), 7.06 (q, 2H), 6.84 (m, 4H), 6.66 (dt, 1H); 13C NMR (Aceton-d6, 75 MHz) δ 164.90 (d), 159.96 (d), 158.57, 142.02 (d), 130.84, 129.63, 129.10, 125.55 (d), 116.53, 110.28 (d), 104.44 (d), 102.00 (d); 19F NMR (Aceton-d6, 282 MHz) δ-32429.72 (t); HRMS (EI+) found 230.0738, calcd 230.0743 for C14H, FO2.