Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:21][Mg]Br.C1COCC1>>[F:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C:12](=[O:20])[C:13]([CH3:19])([CH3:18])[C@:14]([OH:17])([CH3:21])[C@H:15]2[CH3:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)C(C)(C)C(=O)C2C)ccc(C#N)c1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)C(C)(C)[C@@](C)(O)[C@H]2C)ccc(C#N)c1F

Procedure:
Using 2-fluoro-3-methyl-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (60 mg) and methylmagnesium bromide-THF solution (2.19 mL, 1.0 mol/L), and in the same manner as in Example 2, the title compound was obtained as colorless crystals (yield: 40 mg, 63%).
Reaction SMILES: [CH3:1][CH:2]([CH2:15][CH3:16])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:6].[CH2:17]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH2:15][CH3:16])[CH2:3][O:4][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:37]([C:34]2[CH:33]=[CH:32][C:31]([C:28]3[CH:29]=[CH:30][C:25]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)=[CH:36][CH:35]=2)=[O:38])=[CH:12][CH:13]=1)=[O:6]
Reactant: CCC(C)COC(=O)Oc1ccc(O)cc1
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(OC(=O)OCC(C)CC)cc3)cc2)cc1
Temperature: 60 °C

Procedure:
p-(2-Methylbutyloxycarbonyloxy)phenol (0.25 g) prepared in the above (i) was dissolved in pyridine (5 ml) and cooled with ice, followed by dropwise adding a solution of 4'-octyl-4-biphenylcarboxylic acid chloride (0.37 g) dissolved in toluene (5 ml), heating on a water bath at 60° C., reacting the mixture, adding toluene (50 ml), separating the toluene layer, washing with 6N-hydrochloric acid, further with 2N-NaOH aqueous solution, then with a saturated NaCl aqueous solution to make the layer neutral, drying over sodium sulfate, concentrating, and twice recrystallizing from a mixed solution of ethyl acetate (20 ml) and ethanol (10 ml) to obtain the objective 4'-octyl-4-biphenylcarboxylic acid p-(2-methylbutyloxycarbonyloxy)phenyl ester. This product exhibited SA phase and Ch phase and its phase transition points, C-SA point, SA-Ch point, and Ch-I point were 78.3° C., 150.2° C. and 165.2° C., respectively. Further its values of elemental analysis accorded well with its calculated values as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][C:33]([Br:36])=[CH:32][N:31]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Br:36][C:33]1[N:34]=[CH:35][C:30]([NH:29][C:13](=[O:14])[CH:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:31][CH:32]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1Cl
Reactant: Nc1cnc(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (prepared as in Example 20, 470 mg, 1.36 mmol) in methylene chloride (25 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.78 mL, 1.56 mmol) and then was stirred at 0° C. for 30 min. At this time, the reaction was concentrated in vacuo to yield a light yellow oil. This oil was dissolved in tetrahydrofuran (10 mL) and then treated with a solution of 2-amino-5-bromopyrazine (472 mg, 2.71 mmol, prepared according to Tetrahedron 1988, 44, 2977-2983) in tetrahydrofliran (20 mL) and pyridine (0.55 mL, 6.78 mmol). The reaction was then stirred at 25° C. for 16 h. At this time, the reaction was diluted with water (15 mL) and extracted with methylene chloride 3×25 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 40/60 hexanes/ethyl acetate) afforded N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide (477 mg, 70%) as a yellow foam: (ES)+-HRMS m/e calcd for C19H21ClBrN3O4S (M+H)+ 502.0198. found 502.0205.
Reaction SMILES: [C:1]([Si:5]([O:18][CH2:19][C@H:20]1[O:27][CH:26]2[C@:22]([CH3:30])([O:23][C:24]([CH3:29])([CH3:28])[O:25]2)[C@H:21]1I)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([Si:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:18][CH2:19][C@H:20]1[O:27][CH:26]2[C@:22]([CH3:30])([O:23][C:24]([CH3:29])([CH3:28])[O:25]2)[CH2:21]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OC2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H](I)[C@@]2(C)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)OC2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C[C@@]2(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A solution of tert-butyl(((5R,6S,6aS)-6-iodo-2,2,6a-trimethyl-tetrahydrofuro[3,2-d][1,3]dioxol-5-yl)methoxy)diphenylsilane (from step 6) (10.3 g, 0.0186 mol), Bu3SnH (5.9 mL, 0.0224 mol) and AIBN (5 mol %) in 120 mL anhydrous toluene was refluxed for 7 h. The reaction mixture was cooled to room temperature and 100 mL of 1N NaOH was added and stirred for one h. This mixture was then finally washed with brine and extracted with ethyl acetate. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. Purification was performed by column chromatography using hexane and ethyl ether as a gradient mixture to give 6.8 g of viscous title compound in 86% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:22])=[C:4]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[CH2:24][C:25]([O:27]CC)=[O:26]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[O:10])[C:3]=1[O:22][CH2:24][C:25]([OH:27])=[O:26]
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1cc(Cl)cc(Cl)c1O
Reactant: CCOC(=O)CBr
Product: O=C(O)COc1c(Cl)cc(Cl)cc1C(=O)c1cnn(-c2ccccc2)c1

Procedure:
Prepared from (3,5-dichloro-2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)methanone and ethyl bromoacetate according to GP2 and GP3: LC/MS (an10p8): Rt 3.27 min, m/z 390.5 [M+1]+; 1H NMR (CDCl3): δ 4.72 (s, 2H), 7.38-7.51 (m, 4H), 7.57-7.58 (m, 1H), 7.70 (d, J=8.1 Hz, 2H), 8.06 (s, 1H), 8.36 (s, 1H), 9.23 (br s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][N:16]=2)[CH2:11][CH:10]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][N:16]=2)[CH2:11][CH:10]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccccc3)cnc2N1Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(NC1Cc2cc(-c3ccccc3)cnc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a suspension of 1K (80 mg, 0.17 mmol) in THF (1 mL) at RT under argon was added borane-tetrahydrofuran complex (0.85 mL, 0.85 mmol) dropwise. After the addition, the reaction became a clear solution. The reaction was allowed to stir at RT under argon for 30 min. After this time, no starting material was detected by LC-MS. MeOH (1 mL) was added carefully to the reaction and the reaction mixture was stirred at RT for 40 min, then concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. The layers were separated. The aqueous layer was extracted with CH2Cl2 (20 mL). The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The resultant residue was purified by silica gel (10 g) column chromatography eluting with a gradient of EtOAc (0-50%) in hexane to give the title compound as a white foam (74 mg, 96%). LC/MS (method A): retention time=3.96 min, (M+H)+=456. 1H-NMR (CDCl3, 400 MHz): δ8.30 (s, 1H), 7.70 (dd, J1=8.2 Hz, J2=1.2 Hz, 2H), 7.52-7.60 (m, 1H), 7.40-7.52 (m, 6H), 7.20-7.40 (m, 7H), 4.75 (dd, J1=48.2. Hz, J2=15.0 Hz, 2H), 4.71 (d, J=8.6 Hz, 1H), 3.80-3.92 (m, 1H), 3.30 (dd, J1=15.9 Hz, J2=2.2 Hz, 1H), 3.00-3.13 (m, 2H), 2.75-2.85 (m, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[NH:6])(=[O:3])[CH3:2].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=1)=O>CN(C=O)C>[F:20][CH:19]([F:21])[O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[NH:7][CH:9]=2)=[CH:13][CH:14]=1
Reactant: CC(=O)NC(=N)N
Reactant: O=C(CBr)c1ccc(OC(F)F)cc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(-c2ccc(OC(F)F)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.8 %

Procedure:
Acetyl guanidine (2.6 g, 25.7 mmol, 3.0 eq) was dissolved in DMF anhydrous (40 mL) and 2-Bromo-1-(4-difluoromethoxy-phenyl)-ethanone (2.3 g, 8.5 mmol, 1.0 eq) was added; the mixture was stirred under nitrogen at room temperature for 4 days. DMF was dried; the residue was washed with water, filtered and dried. The crude was crystallized from methanol to give 1.2 g of the title compound (yield: 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)[CH:7]=[CH:6][C:4]=1[NH2:5].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)[CH:7]=[CH:6][C:4]=1[NH:5][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2cc(-c3ccc(N)c(OC)c3)ccc2c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2cc(-c3ccc(NC(=O)c4ccccc4)c(OC)c3)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 2-methoxy-4-(6-methoxy-2-naphthyl)aniline (82 mg, 0.29 mmol, 1 eq) in 10 ml of dry dichloromethane are added benzoyl chloride (0.1 ml, 123 mg, 0.88 mmol, 3 eq) and trace amounts of DMAP. After stirring for 18 h at RT, the reaction mixture is stopped by adding a 2% sodium carbonate solution, the phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. Purification by column chromatography with a gradient of hexane/ethyl acetate 9/1 to 1/1 yielded the desired product in a yield of 90% (101 mg).
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:14][C@@H:15]([CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:16][N:17](C(OCC3C=CC=CC=3)=O)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.CCOC(C)=O.[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:14][C@@H:15]([CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:11][N:10]=[CH:9]2)=[CH:42][CH:43]=1)#[N:2]
Reactant: [H][H]
Reactant: CS(=O)(=O)CC[C@@H](CN(Cc1cccc(Cl)c1)C(=O)OCc1ccccc1)NCc1cncn1Cc1ccc(C#N)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)CC[C@@H](CNCc1cccc(Cl)c1)NCc1cncn1Cc1ccc(C#N)cc1
Reaction time: 0.33 h
Yield: 49.5 %

Procedure:
To a solution of the product from Step F (163 mg, 0.262 mmol) in 3 mL of methanol and 3 mL of EtOAc was added at room temperature 10% palladium on carbon (10 mg). A balloon of hydrogen gas was introduced to the solution via syringe needle, and the reaction was stirred for ca. 20 minutes. The solution was filtered through celite to remove the catalyst, then concentrated in vacuo. The resulting product was purified by silica gel chromatography (4% MeOH/CH2Cl2 with 1% NH4OH) to provide the titled compound (63 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].Cl.[CH:25]1([C:28]2[CH:29]=[C:30]([CH3:40])[C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:32][CH:33]=2)[CH2:27][CH2:26]1>>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:21])=[O:22])[CH:13]=[CH:12][C:8]=1[C:9]([N:37]1[CH2:36][CH2:35][N:34]([C:31]2[C:30]([CH3:40])=[CH:29][C:28]([CH:25]3[CH2:27][CH2:26]3)=[CH:33][N:32]=2)[CH2:39][CH2:38]1)=[O:10]
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCS1(=O)=O
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2N2CCCS2(=O)=O)CC1
Yield: 37 %

Procedure:
Using 2,4-bis(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (200 mg) described in Preparation Example 34 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (141 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 86, the title compound (115 mg) was obtained.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrBr.[Cl-].[K+]>ClCCl>[C:16]1([S:15][C:12]2[CH:13]=[CH:14][C:9]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:10][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(c1ccccc1)c1ccc(Sc2ccccc2)cc1
Agent: BrBr
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc(Sc2ccc(Sc3ccccc3)cc2)cc1
Reaction time: 0.5 h

Procedure:
A 500-mL, round-bottom flask with a Teflon-covered magnetic stirring bar is charged with dichloromethane (50 mL), 10% KHCO3 (43 mL), and phenyl[4-(thiophenoxy)phenyl] sulfoxide (5 g, 17.0 mmol). To the reaction mixture is added bromine (2.72 g, 17.0 mmol) in dichloromethane (50 mL) over a period of 5 min with vigorous stirring. The reaction is continued for 30 min. To the reaction mixture is added a KCl saturated solution and dichloromethane (100 mL). The aqueous layer is extracted with dichloromethane (2×50 mL). The organic layer is washed with water, dried over anhydrous sodium sulfate, and filtered. After recrystallization from ether, the solid is obtained. The solid is dried under vacuum at room temperature for 20 h and then is used without further purification for polymerization.
Reaction SMILES: COC1C=C(C=CC=1C[N:25]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[C:42]([CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1)=[N:41][NH:40][C:39]2=[O:53])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)=[O:27])OCCCC(NCC1C=CC(C)=CC=1)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:53]=[C:39]1[C:38]2[C:43](=[CH:44][CH:45]=[C:36]([NH:25][C:26]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[O:27])[CH:37]=2)[C:42]([CH2:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)=[N:41][NH:40]1
Reactant: COc1cc(OCCCC(=O)NCc2ccc(C)cc2)ccc1CN(C(=O)Nc1ccc(C)cc1)c1ccc2c(Cc3cccnc3)n[nH]c(=O)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2ccc3c(Cc4cccnc4)n[nH]c(=O)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-{3-Methoxy-4-[1-(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-p-tolyl-ureidomethyl]-phenoxy}-N-(4-methyl-benzyl)-butyramide of example 8 was suspended in a solution of 20% TFA in DCM (3 ml), and stirred at room temperature for 2 hours. The resin was filtered and the solution collected and dried up yielding 11 mg of title compound. [M+1]+=386; HPLC r.t. 4.72; 1H-NMR (DMSO-d6), diagnostic signals (ppm): 2.23 (s, 3H), 4.26 (s, 2H), 7.10 (d, 2H), 7.29 (m, 1H) 7.33 (d, 2H), 7.64 (m, 1H), 7.83 (dd, 1H), 7.89 (d, 1H), 8.40 (m, 2H), 8.56 (d, 1H), 8.70 (br. S, 1H), 9.22 (br. s, 1H), 12.38 (br. s, 1H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]([OH:24])[CH2:22][N:23]=2)=[CH:14][CH:13]=1>ClCCCl>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:19][CH:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:21]([O:24][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:22][N:23]=2)=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Solvent: ClCCCl
Product: COc1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Yield: 24.4 %

Procedure:
Phenyl isocyanate (1.25 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(4-methoxyphenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.5 g) in 1,2-dichloroethane (20 cc). The solution obtained is heated to reflux for 6 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter [eluent: cyclohexane/ethyl acetate/triethylamine (60:35:5 by volume)], collecting 20-cc fractions. Fractions 4 to 10 are combined and concentrated to dryness under reduced pressure (2. 7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-2-(4-methoxyphenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.52 g), m.p. 223° C., is obtained.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].Cl[C:7]1[C:16]([C:17]([C:19](=[CH:25]N(C)C)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:18])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([Cl:30])=[C:12]([F:29])[CH:13]=2)[N:8]=1>C(N(CC)CC)C>[Cl:30][C:11]1[C:12]([F:29])=[CH:13][C:14]2[C:9]([CH:10]=1)=[N:8][C:7]1[N:5]([CH2:4][CH2:3][F:2])[CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:17](=[O:18])[C:16]=1[CH:15]=2
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reactant: NCCF
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CCF)c2nc3cc(Cl)c(F)cc3cc2c1=O
Temperature: 75 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
2.7 cm3 of triethylamine are added to a suspension of 1.9 g of 2-fluoroethylamine hydrochloride in 25 cm3 of trichlorcmethane. 3.5 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate are added to the solution obtained at about 20° C. After stirring at this temperature for 16 hours, the solution is concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue is taken up in 20 cm3 of ethanol and 3 cm3 of triethylamine and heat at about 75° C., with stirring, for 2 hours. After cooling to about 20° C. the insoluble matter is drained and washed with twice 10 cm3 of ethanol and twice 10 cm3 of diisopropyl ether. 1.9 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(2-fluoro-ethyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 268° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.O.[N:20]#[C:21]Br>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]3[NH:17][C:21]([NH2:20])=[N:18][C:13]=3[CH:12]=2)[CH2:4][CH2:3]1
Reactant: N#CBr
Reactant: CN1CCN(CCOc2ccc(N)c(N)c2)CC1
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(CCOc2ccc3[nH]c(N)nc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 149.4 %

Procedure:
A 100 mL flasked was charged with 4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene-1,2-diamine (4.35 mmol), water (50 mL) and acetic acid (2 mL) and stirred at room temperature for 15 minutes. The reaction mixture was placed in an ice bath and then charged with cyanogen bromide (0.526 g, 5 mmol). The reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was concentrated under reduced pressure and redissolved in acetone, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 1.79 g of 5-(2-(4-methylpiperazin-1-yl)ethoxy)-1H-benzo[d]imidazol-2-amine. This material was used without any further purification. MS (EI): 276 (MH+).
Reaction SMILES: C(OO)(=[O:3])C.[CH2:6]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH3:7]>>[CH2:6]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N+:18]=2[O-:3])=[CH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: CC(=O)OO
Reactant: CCOC(=O)c1ccc(-c2ccccn2)cc1
Product: CCOC(=O)c1ccc(-c2cccc[n+]2[O-])cc1
Temperature: 25 °C

Procedure:
8.9 ml of 40% peracetic acid is added dropwise to 14.08 g of 2-(p-ethoxycarbonylphenyl)pyridine so as to maintain the reaction temperature between 80° and 85°. After the addition is complete the reaction mixture is heated at 90° for 3 h, and allowed to cool to room temperature. The excess peracetic acid is destroyed with aqueous sodium sulfite solution. The solvent is evaporated and the residue taken up in methylene chloride and refiltered through Celite®. Evaporation yields 2-(p-ethoxycarbonylphenyl)pyridine-N-oxide which is treated with 8.66 g dimethyl sulfate in 62 ml of toluene at 90° for 3 h. The solvent is evaporated and the residue redissolved in an ice-cold mixture of 8 ml of water and 9.3 ml of 1N sodium hydroxide. A solution of 13.64 g of potassium cyanide in 10 ml of water is added slowly and the reaction mixture is maintained at 0° for 24 h. Extraction with methylene chloride, drying over sodium sulfate and evaporation of solvent yields the title compound (a); IR (CH2Cl2) 2200 cm-1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[OH:10].[OH-].[Na+]>O.CC(OC)(C)C>[CH3:1][C:2]1[C:3](=[O:10])[CH:4]=[CH:5][C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: Cc1c(O)ccc(O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CC1=C(C)C(=O)C=CC1=O
Temperature: 50 °C
Yield: 88.1 %

Procedure:
A solution of FeCl3.6H2O (81.0 g, 300 mmol) in water (100 mL) was added to a solution of 2,3-dimethyl-benzene-1,4-diol (13.8 g, 100 mmol) in MTBE (150 ml) at ambient temperature. Aqueous sodium hydroxide solution (2.5M, 60 mL, 150 mmol) was added to the vigorously stirring mixture and the reaction heated to 50° C. for 5 hrs. MTBE (150 mL) and water (150 mL) were added and the aqueous layer further extracted with MTBE (2×100 mL). The combined organics were washed with brine (100 mL), dried (Na2SO4), and concentrated to give the intermediate 2,3-dimethyl-[1,4]benzoquinone as an orange-yellow solid (12.0 g, 88%), which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH3:12])[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]>ClCCl.[O-2].[Mn+4].[O-2]>[CH:2]([CH:3]=[C:4]([CH3:12])[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:1]
Reactant: CCOC(=O)C=CC(C)=CCO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)C=CC(C)=CC=O
Yield: 78.7 %

Procedure:
11.7 g of ethyl 6-hydroxy-4-methyl-2,4-hexadienoate in 200 ml of dichloromethane were stirred at room temperature for 4 hours with 30 g of manganese (IV) oxide. The solution was filtered and concentrated and the residue was then recrystallized from hexane/cyclohexane. There were obtained 9.1 g (78%) of ethyl 5-formyl-4-methyl-2,4-pentadienoate of melting point 48°-49° C.