Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:16]([C:29](O)=[O:30])=[CH:15]2.[NH2:32][C:33]1[CH:34]=[N:35][C:36]([N:39]([CH3:41])[CH3:40])=[CH:37][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:40][N:39]([CH3:41])[C:36]1[N:35]=[CH:34][C:33]([NH:32][C:29]([C:16]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)=[O:30])=[CH:38][CH:37]=1
Reactant: CN(C)c1ccc(N)cn1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Reaction time: 0.17 h

Procedure:
0.27 ml (1.67 mmol) of diethyl cyanophosphonate is added dropwise at 20° C. under argon to a solution of 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (obtained in Example 1.1) and 0.229 g (1.67 mmol) of 3-amino-6-(dimethylamino)pyridine in 3.5 ml of dry dimethylformamide. The mixture is stirred for 10 minutes and then 0.43 ml (3.06 mmol) of triethylamine is added dropwise. The mixture is stirred at ambient temperature for 18 hours and concentrated under reduced pressure, and then the residue is taken up in 50 ml of ethyl acetate. This solution is then successively washed with three times 20 ml of a saturated sodium hydrogencarbonate solution, 50 ml of water and 20 ml of a saturated sodium chloride solution and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid obtained is triturated from hot isopropyl ether. 0.423 g of a solid is collected by filtration, which solid is dried under reduced pressure and used as in the following stage.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:12])[N:3]=1.Cl[CH2:14][CH:15]([OH:36])[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:14][CH:15]([OH:36])[CH2:16][N:17]2[CH2:18][CH2:19][N:20]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)[N:3]=1
Reactant: Oc1cccc2nc(Cl)ccc12
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: OC(COc1cccc2nc(Cl)ccc12)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 51.2 %

Procedure:
Following the same procedure as in Example 23-(c), reaction and treatment were carried out using 1 g of 2-chloro-5-hydroxyquinoline and 2.88 g of 4-(3-chloro-2-hydroxypropyl)-1-diphenylmethylpiperazine synthesized in Example 23-(b), in order to obtain 1.39 g of 2-chloro-5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinoline.
Reaction SMILES: [C:1]([NH:4][C:5]([NH:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([Br:15])=[CH:10][C:9]=1F)=[S:6])(=[O:3])[CH3:2].[H-].[Na+].O>CN(C=O)C>[Br:15][C:11]1[CH:12]=[C:13]([F:14])[C:8]2[N:7]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:9]=2[CH:10]=1
Reactant: CC(=O)NC(=S)Nc1c(F)cc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2c(F)cc(Br)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
1-acetyl-3-(4-bromo-2,6-difluorophenyl)thiourea (3.356 g, 10.86 mmol) was dissolved in DMF (100 ml) and the flask was cooled under nitrogen in an ice water bath. Then, sodium hydride (60% in mineral oil, 512.6 mg, 12.82 mmol) was added, and the reaction was warmed to room temperature and stirred for 1 hour. Then, the reaction flask was put in a preheated oil bath (130° C.) and stirred under nitrogen for an additional hour. The reaction was cooled to room temperature, poured into deionized water (300 ml), and filtered. The solid was washed with water and then dried by suction overnight to afford N-(6-bromo-4-fluorobenzo[d]thiazol-2-yl)acetamide (3.205 g, ˜100%). MS (ESI pos. ion) m/z: 289 (MH+, 79Br), 291 (MH+, 81Br). Calculated exact mass for C9H6BrFN2OS 288 (79Br), 290 (81Br).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C(C)C)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (40 mg, 0.14 mmol, 1.00 equiv), 4-fluorophenylboronic acid (57.4 mg, 0.41 mmol, 3.00 equiv), Pd(PPh3)4 (31.4 mg, 0.03 mmol, 0.20 equiv), K3PO4 (116 mg, 0.55 mmol, 4.00 equiv), 1,4-dioxane (3 mL). The resulting solution was stirred for overnight at 110° C. in an oil bath. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by prep-TLC with ethyl acetate/petroleum ether (1:8). This resulted in 42 mg (87%) of methyl 2-(4-fluorophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=O)[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>>[CH:1]1[C:11]2[C:10]([NH:21][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[N:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)CCN
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Product: CN(C)CCNC1=Nc2ccccc2Nc2ccccc21
Yield: 27.1 %

Procedure:
5,10-Dihydro-dibenzo[b,e][1,4]diazepine-11-one (160FE15A) (21 mg, 0.1 mmol) and N,N-dimethylethylenediamine (88 mg, 1.0 mmol) were reacted according to GP4 to give 7.6 mg of the title compound (160FE20B). MS (ESI) 281 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[C:10](=[CH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([CH3:25])=[CH:21][C:20]3=[O:26])[C:11](=O)[CH3:12])=[CH:5][CH:4]=1.[NH2:28]/[C:29](/[CH3:36])=[CH:30]\[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:10]2[CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[O:23][C:22]([CH3:25])=[CH:21][C:20]4=[O:26])[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:29]([CH3:36])[NH:28][C:11]=2[CH3:12])=[O:27])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C(=Cc2cccc3c(=O)cc(C)oc23)C(C)=O)cc1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccc(OC)cc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
230 mg (0.63 mmol) of 1-(4-methoxyphenyl)-2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-butane-1,3-dione are heated with 81.9 mg (0.63 mmol) of ethyl 3-aminocrotonate in 5 ml of 2-propanol under reflux overnight. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 50 mg (16% of theory) of the title compound are obtained.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Cl.[NH2:16][CH:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[C:18]1=[O:35]>O>[NH2:16][C:17]1([CH2:3][CH2:2][C:1]#[N:4])[C:25]2[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[C:18]1=[O:35]
Reactant: COc1ccc2c(c1)N(c1ccccc1F)C(=O)C2N
Reactant: C=CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)N(c1ccccc1F)C(=O)C2(N)CCC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon gas atmosphere, 29.90 ml of acrylonitrile and 62.70 g of potassium carbonate were added to 210 ml of a dimethyl sulfoxide solution of 70.00 g of 3-amino-1-(2-fluorophenyl)-2,3-dihydro-6-methoxy-1H-indol-2-one hydrochloride, and the whole was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate extract was washed with water successively with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate and then filtered. The filtrate was evaporated to afford 70.70 g of 3-[3-amino-1-(2-fluorophenyl)-2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl]propanenitrile as a brown oil.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10]([O:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][CH:9]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:10]([O:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11]
Reactant: CCOC(=O)c1ccccc1OC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccccc1OC(=O)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
The ethyl 2-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)benzoate (1.2 g, 2.9 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (4 mL). The reaction was stirred (RT, 3 h) and then concentrated. The crude material was purified by silica chromatography (0-10% MeOH/CH2Cl2) to afford 0.63 g of ethyl 2-(2-amino-3-phenylpropanoyloxy)benzoate. Mass calculated for C18H19NO4=313.35. found: [M+H]+=314.1.
Reaction SMILES: [CH3:1][N:2]([CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]1)[C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:32](I)[CH:33]=[CH2:34]>CN(C=O)C.CCOC(C)=O>[CH2:34]([O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:6]1[N:7]=[N:8][C:3]([N:2]([CH3:1])[CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:4][CH:5]=1)[CH:18]=[CH:17]2)[CH:33]=[CH2:32]
Reactant: C=CCI
Reactant: CN(c1ccc(-c2ccc3cc(O)ccc3c2)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2cc(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.2 %

Procedure:
To a solution of 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol (208 mg, 0.53 mmol) in DMF (5.3 mL) was added 60% wt NaH (47 mg, 1.17 mmol) followed by allyl iodide (54 μL, 0.59 mmol). The reaction was stirred at RT for 10 min. The crude reaction mixture was diluted with EtOAc. The organic layer was washed with water (5×) and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via HPLC to give 6-(6-(allyloxy)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (85 mg). LCMS Rt=1.46 min (condition B); MS (M+1)=431.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.37 (d, J=1.5 Hz, 1H), 8.20 (dd, J=8.6, 1.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.79 (d, J=9.9 Hz, 1H), 7.20-7.25 (m, 1H), 7.19 (d, J=2.3 Hz, 1H), 6.92 (d, J=9.6 Hz, 1H), 6.09-6.23 (m, 1H), 5.51 (dd, J=17.2, 1.5 Hz, 1H), 5.36 (dd, J=10.5, 1.4 Hz, 1H), 5.16-5.31 (m, 1H), 4.66-4.74 (m, 2H), 3.03 (s, 3H), 1.76 (dd, J=12.5, 3.4 Hz, 2H), 1.45-1.53 (m, 2H), 1.41 (s, 6H), 1.24 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH3:8])[CH:7]=1.[CH3:10][N:11](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]#[N:11])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)ccc1I
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(F)ccc1C#N
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
5-Fluoro-2-iodotoluene (3 g, 12.7 mmol) was stirred in DMF (40 mL) under argon and Zn(CN)2 (1.94 g, 16.5 mmol) and Pd(PPh3)4 (1.47 g, 1.27 mmol) were added. The reaction was stirred at 80° C. for 1.5 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2-SO4. The solvent was removed under reduced pressure to afford a yellow solid (2.90 g), confirmed by GC MS.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:22]([O:24][CH3:25])=[O:23])[N:3]=1.Cl.[NH2:27][C@@H:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30].CCN(C(C)C)C(C)C>C(#N)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:7]=[C:2]([NH:27][C@@H:28]([CH3:33])[C:29]([O:31][CH3:32])=[O:30])[N:3]=[C:4]([C:22]([O:24][CH3:25])=[O:23])[N:5]=3)=[CH:9][CH:10]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1nc(Cl)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(N[C@@H](C)C(=O)OC)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
To a suspension of methyl 4-chloro-6-(4-(4-fluorophenoxy)phenyl)pyrimidine-2-carboxylate (0.719 g, 2.00 mmol) in acetonitrile (10 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (0.310 g, 2.22 mmol) and iPr2NEt (0.77 mL, 4.4 mmol). The mixture was heated at 50° C. for 2 h than 80° C. for 6 days. The mixture was evaporated in vacuo and the residue chromatographed over silica gel with 20-60% EtOAc/hexanes. The product fractions were evaporated in vacuo to give (S)-methyl 4-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-2-carboxylate as a pale tan oil (0.479 g, 1.13 mmol, 56% yield). LC/MS: m/z=426.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[C:17]([CH3:24])([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:23])[CH3:22]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-hydroxybenzaldehyde (20 g, 0.164 mol) in acetone (300 mL) was added K2CO3 (34 g, 1.5 equiv.) and the reaction was stirred at room temperature during 30 minutes. Ethyl 2-bromo-2-methylpropionate (36.2 mL, 1.5 equiv.) was added dropwise and the mixture was heated under reflux during 3 hours. K2CO3 (34 g, 1.5 equiv.) and ethyl 2-bromo-2-methylpropionate (36.2 mL, 1.5 equiv.) were added and the mixture was heated under reflux during 16 hours and then pourred into water and extracted with CH2Cl2 (3×300 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent evaporated to afford crude intermediate. After chromatography on silicagel, eluting with cyclohexane/CH2Cl2 (6/4, then 8/2) and then with CH2Cl2, the titled compound was obtained as an oil (27 g, 69.85%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(OC)c(OC)cc4nc3OC)CC2)c1
Yield: 68 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 190 to obtain the titled compound (yield, 68%) NMR (300 MHz, CDCl3) δ 3.28-3.29 (m, 4H), 3.75-3.79 (m, 4H), 3.97 (s, 3H), 4.00 (s, 3H), 4.13 (s, 3H), 6.07-6.11 (m, 3H), 7.14 (s, 1H), 7.27-7.28 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](/[CH:12]=[C:13](\[O:17]C)/[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[Cl:19].Br>C(O)(=O)C.O>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](/[CH:12]=[C:13](\[OH:17])/[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[Cl:19]
Reactant: CO/C(=C\c1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(/C=C(\O)C(=O)O)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
10.00 kg (33.82 mol) (Z)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-methoxy-acrylic acid (C) were suspended in 20.0 L acetic acid and heated to 80° C., before 57.02 kg (338.25 mol) hydrobromic acid (48%) were added. Then the reaction mixture was stirred for 1.5 hours at 80° C., then diluted with 78.0 L water and the suspension was cooled to 22° C. The product was separated off, washed with 100.0 L water and dried.
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2>CCO.O>[N+:14]([C:11]1[C:10]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:1])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(O)c2cccnc12
Temperature: 100 °C
Yield: 67.6 %

Procedure:
KOH (2.69 g, 47.9 mmol) was added to a solution of 5-chloro-8-nitro-quinoline 27 (1.0 g, 4.79 mmol) in EtOH (20 ml) and water (30 ml) and the mixture was heated at 100° C. for 2 h. The reaction mixture was cooled in the fridge for 18 h and the resulting crystals were collected by filtration and dried to give the title compound (616 mg, 68%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25]([N:29]=[C:30]=[O:31])[CH:24]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:22]=[C:16]1[CH:15]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[CH2:4][N:3]([CH3:2])[C:30]([NH:29][C:25]3[CH:24]=[C:23]([CH3:32])[CH:28]=[CH:27][CH:26]=3)=[O:31])[C:9]2=[O:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)N(C)Cc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and m-tolyl isocyanate (0.29 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH2Cl2 and slurred with acetone to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-m-tolyl-urea as a solid (0.41 g, 52%): mp 208-210° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.57 (99%); 1H NMR (DMSO-d6): δ 1.99-2.08 (m, 1H), 2.24 (s, 3H), 2.28-2.35 (m, 1H), 2.55-2.62 (m, 1H), 2.85-2.92 (m, 1H), 2.96 (s, 2H), 4.36 (d, J=17.3 Hz, 1H), 4.43 (d, J=17.3 Hz, 1H), 4.64 (s, 2H), 5.10-5.17 (dd, J=5.1, 13.2 Hz, 1H), 6.78 (d, J=7.4 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 7.29-7.25 (m, 2H), 7.45 (d, J=7.2 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H), 8.38 (s, 1H). 11.02 (s, 1H). 13C NMR (DMSO-d6) δ: 21.17, 22.56, 31.17, 34.71, 46.25, 48.38, 51.56, 117.15, 120.57, 121.71, 122.63, 128.12, 128.43, 129.87, 131.92, 133.87, 137.31, 140.13, 140.27, 155.62, 168.01, 171.01, 172.84. Anal Calcd for C23H24N4O4+0.1 H2O: C, 65.42; H, 5.78; N, 13.27. Found: C, 65.25; H, 5.50; N, 13.14.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Reactant: Brc1ccccn1
Product: O=C(c1ccccn1)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12e and 2-bromopyridine
Reaction SMILES: [C:1]([CH2:4][N:5]([S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:26])[CH:22]=2)[CH:17]=1)(=[O:15])=[O:14])[CH2:6][CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])(O)=[O:2].[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[NH:28][NH2:29].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C>[C:32]([O:31][C:27]([NH:28][NH:29][C:1](=[O:2])[CH2:4][N:5]([S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:26])[CH:22]=2)[CH:17]=1)(=[O:15])=[O:14])[CH2:6][CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=O)C=CCN(CC(=O)O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COC(=O)C=CCN(CC(=O)NNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.5 %

Procedure:
A solution of methyl 4-[carboxymethyl(6-chloro-naphthalene-2-sulfonyl)amino]-2-butenate (796 mg), tert-butyl carbazate (265 mg) and HOBt (367 mg) in acetonitrile (20 ml) was combined with WSC (575 mg) and stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water and brine, dried, concentrated to obtain a residue, which was then crystallized from ether-hexane to obtain methyl 4-[[2-(N′-tert-butoxycarbonylhydrazino)-2-oxoethyl](6-chloro-naphthalene-2-sulfonyl)amino]-2-butenoate (1.05 g) as colorless crystals.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:6]=1)([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([C:7]2[N:8]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[C:10]([Br:22])=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[N:6]=2)=[CH:16][CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc(OC(C)C)cc(OC(C)C)n2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(-c2nc(OC(C)C)c(Br)c(OC(C)C)n2)cc1
Yield: 99 %

Procedure:
111.7 g of 4,6-diisopropoxy-2-p-tolylpyrimidine and 450 ml of carbon tetrachloride are heated to 70°-75° C. To the resultant solution is added 0.5 g of dibenzoyl peroxide, followed by the addition, over 45 minutes, of a mixture of 1 g of azoisobutyronitrile and 70.8 g of N-bromosuccinimide. The mixture is refluxed for 2 hours to bring the reaction to completion. The precipitated succinimide is then filtered off and excess carbon tetrachloride is removed by distillation, affording 141 g of the title compound with a melting point of 74°-75° C. after purification with methanol.