Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.C(OCC)(=O)C>C1COCC1>[OH:14][C:9]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCC1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCCC1
Yield: 100.5 %

Procedure:
Under nitrogen atmosphere 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.84 g (10 mmol) of cyclopentanone in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 15 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of 1N hydrochloric acid, 10 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 10 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.73 g of the desired product (yield 94%).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(C)([O-])C.[K+].S(O[CH:25]([CH2:37][CH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)[CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O.O1CCCC1>[O:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]1[O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]([CH2:37][CH2:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)[S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)OC(CCCCOC2CCCCO2)CCCc2cccnc2)cc1
Reactant: CCOC(=O)CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CSC(CCCCOC1CCCCO1)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.125 ml (1.1 mmol) ethyl 2-mercaptoacetate in 2.4 ml dimethylformamide is added 0.68 ml (1.1 mmol) of 1.61M potassium t-butoxide in tetrahydrofuran. The solution is stirred at room temperature for 30 min and then a solution of 0.402 g (0.87 mmol) 5-tosyloxy-8-(3-pyridyl)-1-(2-tetrahydropyranyloxy)-octane in 1 ml dimethylformamide is added. The mixture is stirred at room temperature for 18 h, poured into water and then extracted with ethyl acetate. The organic phase is washed with water, brine, dried, filtered and evaporated to give an orange oil which is purified by preparative thin layer chromatography using ether/hexane (4:1) as the eluent to give ethyl 8-(2-tetrahydropyranyloxy)-4-[3-(3-pyridyl)propyl]-3-thia-octanoate; IR (CH2Cl2): 1729, 1134 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#N)=[N:6][CH:7]=1.[OH2:10].[OH-:11].[K+]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])=[O:10])=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1ccc(Br)cn1
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(Br)cn1
Temperature: 80 °C

Procedure:
5-Bromo-2-pyridinecarbonitrile (1 g, 5.464 mmol) was dissolved in EtOH (20 mL) and water (20 mL) and treated with potassium hydroxide (1.53 g, 27.32 mmol). The reaction mixture was heated to 80° C. for 24 h. The solvent was removed under vacuum and the residue was taken up in water and acidified to pH 4 with 2M HCl. The aqueous layer was extracted with ethyl acetate (×3) and the combined organic layers dried and concentrated to give 5-bromo-2-pyridinecarboxylic acid (0.704 g) as an orange solid which was used in step 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][Br:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-c1ccc(CBr)c(Br)c1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A solution of 1.0 g (3.7 mmol) of 3'-bromo-4'methyl-1,1'-biphenyl-2-nitrile (Step C) in 15 mL of carbon tetrachloride under a nitrogen atmosphere was treated with 0.720 g (4.04 mmol) of N-bromosuccinimide followed by 60 mg (0.37 mmol) of azobisisobutyronitrile (AIBN). The reaction mixture was heated at reflux for four hours, cooled to room temperature and filtered through Celite. The solvent was removed under vacuum and the residue was dissolved in methylene chloride and treated with decolorizing carbon. The solids were filtered through Celite and the solvent removed under vacuum. The resulting solid was triturated with cold ether, filtered and air dried to afford 920 mg (71%) of the product as an off-white solid. 1H NMR (200 MHz, CDCl3): δ 4.64 (s, 2H), 7.4-7.8 (m, 7H). EI-MS: calculated for C14H9Br2N 351; found 351 (M+, 20%); 271 (M-Br, 100%).
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[CH:10]([NH:12][C:13]1[S:14][C:15]([Br:39])=[C:16]([C:18](=[N:36][O:37][CH3:38])[C:19]([NH:21][CH:22]2[C:34](=[O:35])[N:24]3[C:25]([C:31]([O-:33])=[O:32])=[C:26]([CH2:29][OH:30])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1)=[O:11].[Na+].O.Cl>CC(C)=O.CN(C)C=O>[CH:10]([NH:12][C:13]1[S:14][C:15]([Br:39])=[C:16]([C:18](=[N:36][O:37][CH3:38])[C:19]([NH:21][CH:22]2[C:34](=[O:35])[N:24]3[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH2:29][O:30][C:6](=[O:7])[NH:5][C:3](=[O:4])[C:2]([Cl:9])([Cl:8])[Cl:1])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1)=[O:11]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1nc(NC=O)sc1Br
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)NC(=O)C(Cl)(Cl)Cl)CS[C@H]12)c1nc(NC=O)sc1Br
Reaction time: 3.5 h
Yield: 76.5 %

Procedure:
A solution of trichloroacetyl isocyanate (1.32 g.) in dry acetone (5 ml.) was added dropwise to a solution of sodium 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4-carboxylate (1.9 g.) in dry dimethylformamide at -30° C. and stirred at -40° to -20° C. for 3.5 hrs. Water (20 ml.) was added dropwise to the reaction mixture below -20° C. and the mixture was poured into water (180 ml.). The mixture was adjusted to pH 2 with 6N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diethyl ether and dried to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 1.9 g.).
Reaction SMILES: N1C=CC=CC=1.ClCCl.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@H:23]3[C@H:33]([CH2:34][CH2:35][C@:18]12[CH3:19])[C@:31]1([CH3:32])[C@H:26]([C@@H:27]([OH:36])[CH2:28][CH2:29][CH2:30]1)[CH2:25][CH2:24]3>O.[O-2].[O-2].[O-2].[Cr+6]>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]2[C@H:23]3[C@H:33]([CH2:34][CH2:35][C@:18]12[CH3:19])[C@:31]1([CH3:32])[C@H:26]([C:27](=[O:36])[CH2:28][CH2:29][CH2:30]1)[CH2:25][CH2:24]3
Reactant: C[C@]12CCC[C@H](O)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@]12CCCC(=O)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12

Procedure:
To 0.42 ml. of dry pyridine and 6.3 ml. of dry dichloromethane was slowly added 0.264 g. of chromium trioxide and the mixture was stirred for 15 min. at room temperature. To the mixture was added a solution of 175 mg. of the product of Step D in 0.7 ml. of dichloromethane and the resulting mixture was stirred for 20 min. at room temperature. The mixture was diluted with water, extracted with ethyl ether, and washed with 2.5 N sodium hydroxide, water, and brine. The mixture was then dried and evaporated to a clear oil.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:5])[CH3:4].[SH:12]([O:15]Cl)(=O)=[O:13].[Cl:17]CCl>>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:17])(=[O:15])=[O:13])=[CH:8][CH:7]=1)[C:3](=[O:5])[CH3:4]
Reactant: ClCCl
Reactant: O=[SH](=O)OCl
Reactant: CC(=O)N(C)c1ccccc1
Product: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
A solution of N-methyl-N-phenylacetamide (11 g, 73.83 mmol) in dichloromethane (20 mL) was added dropwise to HSO3Cl (80 g, 689.66 mmol) at 5° C. The resulting solution was then stirred at room temperature overnight. The reaction mixture was then quenched by adding 100 mL of iced water. The resulting solution was extracted using dichloromethane (2×50 mL) and the organic layers were combined. The residue was purified by column chromatography using a 10:1 ethyl acetate/petroleum ether solvent system to give 2.2 g (11%) of 4-(N-methylacetamido)benzene-1-sulfonyl chloride as a white solid. 1H NMR (CDCl3) δ 8.09 (d, 2H), 7.48 (d, 2H), 3.38 (s, 3H), 2.17 (s, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[C:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1.C(OCC)(=O)C>ClCCl>[CH3:13][C:2]([O:1][C:23](=[O:24])[CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CSc1ccc(C(=O)C(C)(C)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(C(=O)C(C)(C)OC(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.5 %

Procedure:
To a -30° C. solution of 2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one (1.05 g, example 1, Step 2) in dichloromethane (20 mL) was added 3-phenylpropionyl chloride (1.68 g) in dichloromethane (10 mL) followed by pyridine (791 mg) and the mixture was allowed to warm up slowly to 25° C. and stirred for 12 h. Ethyl acetate was added to the mixture and it was washed with 1N HCl, brine, dried over magnesium sulfate filtered and the solvent was evaporated under vacuum. Purification by silica gel chromatography afforded 1.36 g of the title compound.
Reaction SMILES: C1CC1.[CH2:4]([O:6][C:7]([CH:9]1[CH2:11][C:10]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH3:5].OS(O)(=O)=O.[N:29]([O-])=[O:30].[Na+]>CC(O)=O.O>[CH2:4]([O:6][C:7]([C:9]1[CH2:11][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:30][N:29]=1)=[O:8])[CH3:5]
Reactant: O=N[O-]
Reactant: CCOC(=O)C1CC1(c1ccccc1)c1ccccc1
Agent: C1CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1=NOC(c2ccccc2)(c2ccccc2)C1
Temperature: 18 °C
Yield: 91 %

Procedure:
The crude cyclopropane derivative, 2,2-diphenylcyclopropanyl carboxylate ethyl ester (generated through the reported one step procedure as a crude product in 107% yield) (1.14 g, 4.3 mmol) was dissolved in 4.0 mL AcOH at room temperature (18° C.). Into the solution was carefully added 2.0 mL concentrated H2SO4, followed by adding NaNO2 (0.33 g, 4.7 mmol, 1.1 eq) in several portions so that the reaction temperature did not excess 40° C. After addition, the reactants were stirred at room temperature (about 18° C.) for half an hour. And the reactants were poured into an iced water and extracted with diethyl ether (2×20 mL), the ethereal solutions were combined and washed with sat. NaHCO3 (2×20 mL), then water (20 mL) and brine (20 mL) in sequence. The washed ethereal solution was then dried over Na2SO4. After removing the desiccant, the ethereal solution was concentrated to furnish a thick oily crude product. The 1H NMR of the crude product showed that the reaction was clean and a virtual 100% yield. The thick oily crude product was stirred with 10 mL petrol to give a pale yellow solid 1.15 g, 91% yield (97% over yield in two steps based on diphenyl ketone hydrazine).
Reaction SMILES: [I:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O=[C:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[I:8])[N:9]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18](=[O:19])[NH:10]2
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1cc(I)c(I)cc1N
Solvent: CCO
Product: CCOC(=O)c1nc2cc(I)c(I)cc2[nH]c1=O
Reaction time: 8 h

Procedure:
A solution was prepared from 0.9 g. of 4,5-diiodo-o-phenylenediamine and 25 ml. of ethanol. Five grams of diethyl ketomalonate were added and the resulting mixture was heated to refluxing temperature with stirring overnight. The reaction mixture was then cooled. Ethyl 6,7-diiodo-3,4-dihydro-3-oxo-2-quinoxaline carboxylate formed in the above reaction precipitated and was collected by filtration; yield=0.8 g.; mp=275°-276° C.
Reaction SMILES: C(=O)C1C=CC=CC=1.[CH:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[Cl:19][C:20]([CH:23]([OH:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+]([O-])=O)[CH:25]=1)([Cl:22])[Cl:21]>>[Cl:19][C:20]([CH:23]([OH:33])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([Cl:21])[Cl:22].[Cl:19][C:20]([CH:9]([OH:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)([Cl:22])[Cl:21]
Reactant: O=[N+]([O-])c1cccc(C(O)C(Cl)(Cl)Cl)c1
Reactant: COc1ccc(C=O)cc1
Solvent: O=Cc1ccccc1
Product: COc1ccc(C(O)C(Cl)(Cl)Cl)cc1
Product: OC(c1ccccc1)C(Cl)(Cl)Cl

Procedure:
Following the procedure of Example I and substituting benzaldehyde, 4-anisaldehyde and other starting material compounds and substituting the reagents of Example II, there is obtained trichloromethylbenzyl alcohol, trichloromethyl-4-methoxybenzyl alcohol and the benzaldehyde corresponding to said starting material compound, respectively.
Reaction SMILES: [CH:1]1[C:6]([C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:8]([Cl:10])[Cl:9])=[CH:5][CH:4]=[C:3]([Cl:18])[CH:2]=1.[Cl:19]Cl>O>[CH:16]1[C:11]([CH:7]([C:8]([Cl:19])([Cl:10])[Cl:9])[C:6]2[CH:5]=[CH:4][C:3]([Cl:18])=[CH:2][CH:1]=2)=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=1
Reactant: ClCl
Reactant: ClC(Cl)=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O
Product: Clc1ccc(C(c2ccc(Cl)cc2)C(Cl)(Cl)Cl)cc1

Procedure:
Onto the p,p'-DDE obtained in Stage (b) 100 ml water is added, the mixture heated to 80° C.-85° C. and chlorine gas added over a period of 8-11 hours, until the concentration of p,p'-DDE drops to 0.2%. The upper aqueous phase is separated to afford 410 g p,p'-DDT, which was used directly in the next stage.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22])=[CH2:18].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:2]1([CH2:1][N:8]2[CH2:12][CH2:18][CH:17]([C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[C:21]#[N:22])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=Cc1ccccc1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccccc1C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.21 h
Yield: 57.6 %

Procedure:
A solution of N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (16.62 g, 70.0 mmol) in dichloromethane (15 mL) are added dropwise, over a 45-minute period, to a solution of 2-ethenylbenzonitrile (6.00 g, 46.0 mmol) and trifluoroacetic acid (0.57 g, 5.0 mmol) in dichloromethane (55 mL). The resulting solution was stirred at room temperature for an additional 10 to 15 minutes, and then heated with saturated aqueous sodium bicarbonate solution (ca 10-15 mL). The organic layer was decanted, washed with water, and dried over anhydrous magnesium sulfate. Filtration and concentration of the solution provided an orange oil which was chromatographed (silica-gel, hexanes-ethyl acetate 5:1) to afford the title compound (6.95 g, 58%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.[H-].[Na+].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1.[NH4+:24].[Cl-]>CN(C=O)C>[NH2:24][C:20]1([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]3)[C:19]([Cl:23])=[CH:18][N:17]=[C:16]([Cl:15])[NH:21]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN1Cc2cccc(N)c2C1=O
Reactant: [NH4+]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2cccc(NC3(N)NC(Cl)=NC=C3Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
At 0° C., a solution of 7-Amino-N-methyl-2,3-dihydroisoindole-1-one (232.6 mg, 1.43 mmol) in DMF (2.0 mL) is treated with 60% NaH (89.8 mg), stirred at the same temperature for 1.5 h, treated with a solution of 2,4,5-trichloropyrimidine (0.557 g) in DMF (3.5 mL), stirred for 1 h, and warmed to room temperature. After furthermore stirring for 13 h, the mixture is treated with sat. aqueous NH4Cl (6 mL), and the resulting brown precipitates are collected by a filtration, followed by washing with H2O, hexane, and CH3CN to give 7-(4-Amino-2,5-dichloropyrimidin-4-yl)amino-N-methyl-2,3-dihydroisoindole-1-one (130.2 g, 0.416 mmol) in 26%. Brown solid. Rf (CH2Cl2/EtOAc 1:1) 0.50. 1H-NMR (400 MHz, CDCl3): 3.22 (s), 4.43 (s), 7.15 (d, J=8.0), 7.59 (dd, J=8.0, 8.0), 8.24 (s), 8.71 (d, J=8.0), 11.05 (br. s).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][NH:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39]>>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH2:32][N:35]([CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH3:34])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Reactant: CNCCS(C)(=O)=O
Agent: Cl
Product: CN(CCS(C)(=O)=O)Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Yield: 38.8 %

Procedure:
In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.217 g, 0.474 mmol) was reacted with N-methyl-N-(2-methanesulphonyl-ethyl)amine (0.41 1g, 3.0 mmol). Purification by silica gel chromatography, eluting with 2-3% MeOH/CHCl3, followed by trituration with ether, gave the title compound as a pale yellow solid (0.100 g, 0.184 mmol, 39%); δH [2H6]DMSO 9.84 (1H,s), 8.63 (1H,s), 8.48 (1H,s), 8.12 (1H,d), 7.78 (1H,d), 7.68 (2H,d), 7.13-7.52 (5H,m), 7.02-7.10 (3H,m), 6.55 (1H,d), 5.14 (2H,s), 3.70 (2H,s), 3.35-3.44 (2H, obscured by water), 3.05 (3H,s), 2.84 (2H,t), 2.28 (3H,s).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1>C(O)(=O)C.O>[CH3:21][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(C2CCC3(CC2)OCCO3)cc1C
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(C2CCC(=O)CC2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the title compound from Example 13 Step C (610 mg, 2.10 mmol) in acetic acid (7.8 mL) and water (2.6 mL) was stirred at 80° C. After 2 h, the mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. The resulting oil was diluted with ether, then was washed successively with water, saturated aqueous sodium bicarbonate, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 50% EtOAc in hexanes, then 50 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 215.4 [M−CH3O]+; 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J=8.5 Hz, 1H), 7.14-7.10°(m, 2H), 3.88 (s, 3H), 3.05-3.00 (m, 1H), 2.59 (s, 3H), 2.51 (app dd, J=8.5, 4.0 Hz, 4H), 2.24-2.20 (m, 2H), 1.97-1.92 (m, 2H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1C=C2N=NN(O)C2=CC=1.O.C(N=C=NC(C)C)(C)C.[CH:42]1[C:47]([S:48]([OH:51])(=[O:50])=[O:49])=[C:46]([OH:52])[C:45]([NH2:53])=[CH:44][C:43]=1[Cl:54]>CN(C=O)C.C(N(CC)CC)C>[Cl:54][C:43]1[CH:42]=[C:47]([S:48]([OH:51])(=[O:49])=[O:50])[C:46]([OH:52])=[C:45]([NH:53][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])[CH:44]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1cc(Cl)cc(S(=O)(=O)O)c1O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: N[C@@H](CCC(=O)Nc1cc(Cl)cc(S(=O)(=O)O)c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
Boc-Glu-OtBu (100 mg, 0.33 mmol) and HOBt hydrate (65.6 mg, 0.43 mmol) were dissolved in 2 mL of DMF, and triethylamine (0.137 mL) was added thereto. After cooling the mixture down to 0° C., diisopropylcarbodiimide (66.4 μL, 0.43 mmol) and 2-amino-4-chlorophenol-6-sulfonic acid (73.7 mg, 0.33 mmol) were added thereto and stirred overnight at room temperature. After removing a solvent, purification was conducted in accordance with the purification process A. The obtained intermediate was dissolved in 2 mL of TFA and stirred at room temperature for 2 hours. 2 mL of methylene chloride was added thereto, and a precipitate was taken by filtration to obtain a title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:26])[N:4]([CH3:25])[C:5]([NH:14][CH2:15][CH:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[C:27]1(=O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[O:28]1.C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl>[NH2:24][CH:16]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:15][NH:14][C:5]1[N:4]([CH3:25])[C:3](=[O:26])[C:2]([N:1]2[C:27](=[O:28])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:36])=[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:6]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cn1c(NCC(N)Cc2ccccc2)nc(-c2ccncc2)c(N)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(NCC(N)Cc2ccccc2)nc(-c2ccncc2)c(N2C(=O)c3ccccc3C2=O)c1=O
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 5-amino-2-(2-amino-3-phenyl-propylamino)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (100 mg, 0.22 mmol), and isobenzofuran-1,3-dione (50 mg, 0.33 mmol) in DMF (0.5 mL) was heated under microwave irradiation (150° C.) for 10 min. The cooled mixture was diluted with CH2Cl2 (2 mL) followed by the addition of TFA (1 nL). After being stirred at room temperature for 6 h, the mixture was concentrated, partitioned between NaHCO3 (aq) and CH2Cl2. The organic residue was purified on silica (1–10% MeOH in CH2Cl2) to afford the desired product as a light yellow solid. M+1 481.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:16])(=O)=O>C(OC)(C)(C)C>[Cl:16][CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: COC(C)(C)C
Product: O=C(CCl)c1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 67 %

Procedure:
3′-Nitroacetophenone (2.00 g) was suspended in methyl t-butyl ether (12.1 ml), and sulfuryl chloride (4.90 g) was dropwise added thereto at 20° C. over 15 minutes. After stirring for 2 hours, precipitated solids were filtered and washed with methyl t-butyl ether. Drying under reduced pressure yielded the desired 2-chloro-3′-nitroacetophenone (1.62 g; 67.0%).