Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:19])([O:12][C@@H:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])OC1C=CC([N+]([O-])=O)=CC=1.[CH3:20][O:21][C@:22]12[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][C@H:23]1[NH:24][CH2:25][CH2:26]2>C(Cl)(Cl)Cl>[CH3:20][O:21][C@:22]12[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][C@H:23]1[N:24]([C:1]([O:12][C@@H:13]([CH3:18])[C:14]([F:15])([F:16])[F:17])=[O:19])[CH2:25][CH2:26]2
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: CO[C@@]12CCN[C@@H]1CN(C(=O)OC(C)(C)C)C2
Solvent: ClC(Cl)Cl
Product: CO[C@@]12CCN(C(=O)O[C@@H](C)C(F)(F)F)[C@@H]1CN(C(=O)OC(C)(C)C)C2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate (15 mg) prepared in Referential Example 2 in CHCl3 (2 mL) was added tert-butyl (3aR,6aR)-3a-methoxyhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (11 mg) at room temperature. The resulting mixture was stirred at 100° C. in a sealed tube for 2 hours and then cooled to room temperature. The mixture was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜0/1) to give 5-tert-butyl 1-[(2S)-1,1,1-trifluoropropan-2-yl] (3aR,6aR)-3a-methoxyhexahydropyrrolo[3,4-b]pyrrole-1,5-dicarboxylate as a pale yellow foam.
Reaction SMILES: I[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][CH2:24][C:25]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[CH:19][CH:18]=[CH:17][CH:16]=2>C(#N)C>[F:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][CH2:24][C:25]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][OH:4])[CH2:27][CH2:26]1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: OCCI
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccccc23)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccccc23)CCN(CCO)CC1

Procedure:
1.14 cm3 of 2-iodoethanol and 1.9 g of potassium carbonate were added to a solution of 4.4 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)propyl]piperidine-4-carboxylate in 100 cm3 of anhydrous acetonitrile, with vigorous stirring and under an inert atmosphere. The reaction mixture was stirred for 18 hours in the region of 20° C., filtered and washed with 3 times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. The evaporation residue was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 5 cm; height 32 cm), eluting with dichloromethane/methanol/aqueous ammonia (40/5/0.5 by volume) and collecting 100-cm3 fractions. Fractions 8 to 12 were combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 3.5 g of ethyl 4-[3-(3-fluoroquinolin-4-yl)-propyl]-1-(2-hydroxyethyl)piperidine-4-carboxylate were obtained in the form of a viscous orange-colored oil.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.O=[C:12]([CH:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)C)C(OCC)=O>>[O:4]=[C:2]([CH2:12][CH2:18][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)C(C)c1cccs1
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)CCc1cccs1

Procedure:
A mixture of phosphorous tribromide (18.95 g) and pyridine (3.76 cc) in 10 ml of benzene is chilled to -5° C. and treated with a solution of 2-(2-thienyl)-ethanol (25 g) in 10 ml of benzene containing 1.25 cc of pyridine at such a rate that the reaction temperature never exceeds 0° C. The mixture is then allowed to come to room temperature while stirring overnight. The reaction mixture is then concentrated on a water pump at 30°-40° C. to remove solvent and other volatiles, and the residue Claisen-distilled under water pump vacuum to yield 21 g of crude bromide (b.p. 115°-119° C.). This material is then fractionally distilled at 0.3 mm to provide 19 g of pure 2-(2-thienyl)-ethyl bromide (b.p. 50°-51° C.; 99.9% by gc). This bromide is dissolved in 40 ml of dry tetrahydrofuran and added, dropwise, to a stirred mixture of magnesium turnings (2.4 g) and 15 ml of dry tetrahydrofuran under nitrogen atmosphere. The mixture is then stirred and refluxed for 1 hour, cooled to room temperature, and added, dropwise under nitrogen, to a stirred mixture of diethyl oxalate (17.5 g) in 25 ml of dry tetrahydrofuran in a -15° C. bath. After completion the reaction mixture is stirred at -10° C. for 15 minutes, then allowed to warm to 10° C. and treated with 60 ml of saturated ammonium chloride solution. The aqueous layer is extracted twice with toluene; the combined organic layers dried over magnesium sulfate and concentrated in vacuo to provide 16.7 g of a mixture containing by gc analysis: solvent (26%); diethyl oxalate (10.5%); and ethyl 2-oxo-(2-thienyl)-butyrate (63.4%). The nmr spectrum (CDCl3) is consistent for this mixture, showing the presence of two specific types of ethyl esters, and the mass spectrum exhibits a peak at m/e=212 for the molecular ion of one keto-ester along with a fragmentation pattern consistent with structure.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[NH:6][CH3:7])([O-])=O.C(=O)([O-])O.[Na+].CO.[S-2].[Na+].[Na+]>O.[OH-].[Na+]>[NH2:1][C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[NH:6][CH3:7]
Reactant: CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNc1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
71 Parts of 2,4-dinitro-N-methylaniline and 53 parts of sodium hydrogen carbonate are stirred in 144 parts of methanol. The yellow suspension is heated in the course of 20 minutes to 40° C. Simultaneously, 81.9 parts of 60% sodium sulphide are dissolved in 144 parts of water of approx. 40° C and 1.2 parts of 30% sodium hydroxide solution are added to the resultant solution. The turbid yellow solution is filtered. The clear yellow filtrate is added dropwise in the course of 2 hours to the suspension of 2,4-dinitro-N-methylaniline. An exothermic reaction occurs during the dropwise addition. The contents of the flask turn dark in colour. The new suspension is heated in the course of 1 hour to 70° C and stirred for 15 minutes at this temperature (reflux). Then 144 parts of methanol are distilled off. The residue is cooled to 25° C and 50 parts of ice are added. After suction filtration at 8° C, the filter cake is washed three times with 160 parts of water and dried in vacuo at 60° C, affording 56.8 parts of 2-amino-4-nitro-N-methylaniline (94.4% of theory). The melting point of the product is 177°-178° C.
Reaction SMILES: [H-].[Na+].[C:3]([N:5]=[C:6](SC)[NH:7][C@H:8]1[C@@:13]([OH:15])([CH3:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]2[CH:18]=[CH:19][C:20]([C:22]3[N:26]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:25]=[N:24][N:23]=3)=[CH:21][C:9]1=2)#[N:4].Cl.[CH2:38]([OH:40])[CH3:39]>>[C:3]([N:5]=[C:6]([O:40][CH2:38][CH3:39])[NH:7][C@H:8]1[C@@:13]([OH:15])([CH3:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]2[CH:18]=[CH:19][C:20]([C:22]3[N:26]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:25]=[N:24][N:23]=3)=[CH:21][C:9]1=2)#[N:4]
Reactant: CCO
Reactant: CCOC(=O)CCCn1nnnc1-c1ccc2c(c1)[C@@H](NC(=NC#N)SC)[C@](C)(O)C(C)(C)O2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCn1nnnc1-c1ccc2c(c1)[C@@H](NC(=NC#N)OCC)[C@](C)(O)C(C)(C)O2
Reaction time: 16 h

Procedure:
Sodium hydride (0.03 g of an 80% dispersion in mineral oil) was added to ethanol (4 ml). After 5 minutes (3S,4R)-4-(3-cyano-2-methylisothioureido)-3,4-dihydro-6-(1-[3-ethoxycarbonylprop-1-yl]-1H-tetrazol-5-yl)-3-hydroxy-2,2,3-trimethyl-2H-benzo[b]pyran (see Example 75) (0.2 g) was added and the mixture was allowed to stand at room temperature for 16 hours. The solution was acidified to pH 3 with 2N hydrochloric acid and then was concentrated in vacuo. The residue was purified by chromatography on silica eluting with dichloromethane containing methanol (2.5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was triturated with hexane to give the title compound as a foam, 0.09 g. Found: C,57.00; H,6.46; N,19.48; C23H31N7O5.0.1 hexane requires: C,57.35; H,6.60; N,19.83%.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>C(Cl)Cl.O.S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:11][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: BrCCCCBr
Reactant: Oc1cccc2c1CCCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: BrCCCCOc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
A solution of 5,6,7,8-tetrahydronaphthalen-1-ol (4.2 g, 0.028 mol) in methylene chloride (50 ml) was mixed with a solution of sodum hydroxide (2.3 g, 0.0575 mol) in water (50 ml). After adding tetra-n-butylammonium bisulfate (9.6 g, 0.028 mol) and 1,4-dibromobutane (31 g, 0.14 mol), the reaction mixture was refluxed with vigorous stirring for 2 hrs. The reaction was cooled to room temperature, the layers separated and the organic phase washed with saturated sodium chloride solution. After drying over sodium sulfate, the organic phase was concentrated on the rotary evaporator and the residual oil heated under vacuum (0.1 mm Hg) to remove remaining 1,4-dibromobutane. The residue was chromatographed on silica gel using 100% hexane as eluent to give 8.1 g (71%) of the title compound as an oil.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.C(N(CC)CC)C.[C:29]1([P:35](Cl)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:29]1([P:35]([O:1][N:2]=[C:3]2[CH:4]=[CH:5][C:6](=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[C:10]#[N:11])[CH:7]=[CH:8]2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(C(C#N)=C2C=CC(=NO)C=C2)cc1OC
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)=C2C=CC(=NOP(=O)(c3ccccc3)c3ccccc3)C=C2)cc1OC
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 119.2 %

Procedure:
10.16 g (0.036 mol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-3,4-dimethoxyphenylacetonitrile (prepared as described in Example 13.1) and 3.64 g (0.036 mol) of triethylamine are dissolved in 180 ml of tetrahydrofuran and cooled to 0-5° C. 8.52 g (0.036 mol) of diphenylphosphoryl chloride, dissolved in 70 ml of tetrahydrofuran, are added dropwise. When the addition is completed, the ice bath is removed and the solution stirred overnight at room temperature. Water and ethyl acetate are subsequently added, the organic layer is washed several times with saturated sodium chloride solution and water and dried over magnesium sulfate. Evaporation of the solvent gives 20.7 g of a viscous red oil, which is further purified by filtration over silica gel (eluent: hexane/ethyl acetate 9:1). Yield: 11.5 g (62%) (4-diphenylphosphoryloxyimino-cyclohexa-2,5-dienylidene)-3,4-dimethoxyphenyl-acetonitrile, reddish viscous oil which solidifies upon standing. 31P-NMR (CDCl3; δ relative to H3PO4 as external reference): 37.102 and 2.9.092 ppm (P(V) of the (E) and (Z)-isomers). 1H-NM R (CDCl3, δ [ppm]): 7.9-7.75 (m, 4H); 7.55-7.35 (m, 6H), 7.4-6.65 (m, 7H); 3.91/3.90 (s, 3H, (E)/(Z) isomers); 3.89/3,88 (s, 3H, (E)/(Z) isomers).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15]Cl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C.C(Cl)Cl.CO>[CH3:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:14]=1[CH2:15][NH:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1CCl
Reactant: Cc1nc2cccc(N)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: Cc1nc2cccc(NCc3c(C)cccc3C)c2[nH]1
Yield: 30.3 %

Procedure:
4-amino-2-methylbenzimidazole (6.0 g, 0.041 mol) was dissolved in acetonitrile (120 ml). To the solution were added 2,6-dimethylbenzylchloride (6.3 g, 0.041 mol), sodium carbonate (16 g, 0.15 mol) and a cat. amount of sodium iodide and the reaction mixture was refluxed for 3 h. The sodium carbonate was removed by filtration and was washed with methylene chloride. Vacuum evaporation of the solvent gave an oily residue which was subjected to flash chromatography on silica gel, methylene chloride: methanol (10:1). The residue was crystallized by treating with ethyl acetate to obtain 3.3 g ( 30%) of the title compound.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C:13]3[CH2:14][O:15][C:16](=[O:17])[C:12]=3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C>C(O)(=O)C.[Pd]>[C:1]1([C@@H:7]([N:9]2[C@H:13]3[CH2:14][O:15][C:16](=[O:17])[C@H:12]3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](c1ccccc1)n1c2c([nH]c1=O)C(=O)OC2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.6 %

Procedure:
A solution of 3.7 g (15.16 mmol) of 1-[(S)-(1-phenylethyl)]-1H-furo[3,4-d]imidazol-2,4 (3H,6H)-dione in 100 ml of acetic acid is placed in a 250-ml autoclave and 0.4 g of palladium on activated carbon (5 percent) was added. Then the autoclave was flushed twice successively with hydrogen and filled to 50 bars. This mixture was stirred for 15 hours at room temperature. The catalyst was then filtered off. The solvent was evaporated at 20 mbars and the residue was chromatographed over silica gel with ethyl acetate, 2.0 g (54 percent yield) of the title product was eluted. Recrystallization in methanol yields white needles. Concerning the product:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][O:9][C:8]2=[O:12])=[N:3]1.[N+:13]([O-])([OH:15])=[O:14].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[C:4]([N:7]2[CH2:11][CH2:10][O:9][C:8]2=[O:12])=[N:3]1
Reactant: O=[N+]([O-])O
Reactant: Cn1ccc(N2CCOC2=O)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc([N+](=O)[O-])c(N2CCOC2=O)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(1-methyl-1H-pyrazol-3-yl)-1,3-oxazolidin-2-one (85 mg) in conc. sulfuric acid (2.5 mL) was added fuming nitric acid (32 μL) under ice-cooling, and the mixture was stirred at 0° C. for 2 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution under ice-cooling, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (58 mg).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][C:25]([C@@H:27]([NH2:29])[CH3:28])=[N:24][CH:23]=3)[CH:19]=[CH:18][CH:17]=2)[CH:10]=1>N1C=CC=CC=1>[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][C:25]([C@@H:27]([NH:29][C:5](=[O:7])[CH3:6])[CH3:28])=[N:24][CH:23]=3)[CH:19]=[CH:18][CH:17]=2)[CH:10]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc([C@H](C)N)s3)n2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](C)c1ncc(-c2cccc(Nc3cc(C)ccn3)n2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Acetic anhydride (0.02 ml, 0.24 mmol) was added to a solution of N—((S)-1-{5-[6-(4-methyllpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}ethyl)amine (50 mg, 0.16 mmol) obtained in Example 9 in pyridine (3 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and extracted with a mixed solution of ethyl acetate-tetrahydrofuran. The organic layer was washed with a saturated brine and dried over magnesium sulfate. The obtained residue was washed with diisoprpyl ether and dried in vacuo and the title compound (43 mg, 76%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH2:19][CH:18]([CH3:20])[CH2:17][C:16](=[O:21])[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].C(=O)(O)[O-].[Na+:26]>O>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH2:19][CH:18]([CH3:20])[CH2:17][C:16](=[O:21])[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O-:8])=[O:7].[Na+:26]
Reactant: CC1CC(=O)C=C(c2ccc(OCC(=O)O)c(Cl)c2Cl)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1CC(=O)C=C(c2ccc(OCC(=O)[O-])c(Cl)c2Cl)C1

Procedure:
[2,3-Dichloro-4-(5-methyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid (500 mg) is dissolved by stirring and warming with 0.25 N sodium bicarbonate solution (5.4 ml). The solution is diluted to 10 ml and sterilized by filtration. All the water that is used in the preparation is pyrogen-free. The concentration of the active agent in the final solution is 5%.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)cccc2n1
Yield: 30 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 4-chlorobenzene-sulfonyl chloride (86.5 mg; 0.41 mmol) to obtain 25.5 mg. (30% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.78 (m, 4H), 7.38 (t, J=8.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.92 (br s, 1H), 6.83 (d, J=7.6 Hz, 1H), 5.92 (br s, 2H), 3.73 (br d, J=11.6 Hz, 2H), 3.11 (br d, J=12.0 Hz, 2H), 2.84 (m, 2H), 2.62 (m, 2H). ESIMS+420.5 m/z
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][N:30]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([N:24]6[CH2:25][CH2:26][CH2:27][CH2:28]6)=[CH:34][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2ccc(N3CCCC3)nc2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(N5CCCC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-pyrrolidin-1-ylpyridine-5-boronic acid pinacol ester (Boron Molecular, Research Triangle Park, USA) to give the title compound as a white solid. (HPLC: tR 2.23 min (Method A); M+H=440 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.25-8.23 (m, 1H), 8.13-8.11 (m, 1H), 8.05-8.01 (m, 1H), 7.87-7.83 (m, 1H), 7.58-7.53 (m, 1H), 7.42-7-40 (m, 1H), 6.56-6.52 (m, 1H), 3.92 (s, 3H), 3.56 (s, 3H), 3.44-3.38 (m, 4H), 1.97-1.92 (m, 7H))
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[C:6]([CH3:17])[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:31][CH3:32])=[C:27]([Cl:30])[CH:28]=2)[N:23]=[C:22]([CH3:33])[C:21]=1[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C(Cl)Cl.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:31][CH3:32])[N:23]=[C:22]([CH3:33])[C:21]([CH3:34])=[C:20]2[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:6]=2[CH3:17])[C:2]([CH3:18])([CH3:1])[CH2:3]1
Reactant: COc1cc2nc(C)c(C)c(Cl)c2cc1Cl
Reactant: Cc1c(N2CCOCC2)ccc2c1NCC2(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nc(C)c(C)c(N3CC(C)(C)c4ccc(N5CCOCC5)c(C)c43)c2cc1Cl
Temperature: 100 °C

Procedure:
A mixture of 4-(3,3,7-trimethylindolin-6-yl)morpholine (37.9 mg, 0.154 mmol), 4,6-dichloro-7-methoxy-2,3-dimethylquinoline (made by procedures A-D, 59.1 mg, 0.231 mmol), cesium carbonate (75.3 mg, 0.231 mmol), Pd2(dba)3 (28.4 mg, 0.031 mmol), and Xantphos (26.7 mg, 0.046 mmol) in toluene (2 mL) under N2 was heated at 100° C. for 21 h. The mixture was cooled to rt and diluted with DCM-MeOH (8:2). The mixture was filtered and the filtrates were concentrated. Purification of the residue by flash chromatography over silica gel, using 40% EtOAc in hexane, and following the second purification by flash chromatography over silica gel, using 10% MeOH in DCM, gave 6-chloro-7-methoxy-2,3-dimethyl-4-(3,3,7-trimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)quinoline. 1H-NMR (DMSO-d6) δ 7.40 (1H, s), 7.09 (1H, s), 7.07 (1H, d, J=8.0 Hz), 6.72 (1H, d, J=8.0 Hz), 4.01 (3H, s), 3.93 (1H, d, J=8.0 Hz), 3.80-3.62 (4H, m), 3.53 (1H, d, J=8.0 Hz), 3.00-2.90 (2H, m), 2.75-2.69 (2H, m), 2.61 (3H, s), 2.42 (3H, s), 1.70 (3H, s), 1.33 (3H, s), 1.09 (3H, s). Mass Spectrum (ESI) m/e=466.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:13]([OH:15])=[O:14])[CH2:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH3:1][C:2]1([C:13]([O:15][CH2:21][CH3:22])=[O:14])[CH2:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C(=O)O)CC(=O)c2ccccc2O1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(C)CC(=O)c2ccccc2O1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A mixture of 152 parts of 3,4-dihydro-2-methyl-4-oxo-2H-1-benzopyran-2-carboxylic acid, 18.4 parts of concentrate sulfuric acid and 2720 parts of ethanol was stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in a mixture of 1,1'-oxybisethane and a sodium hydroxide solution. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 126 parts (72.7%) of ethyl 3,4-dihydro-2-methyl-4-oxo-2H-1-benzopyran-2-carboxylate as a residue (intermediate 26).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH3:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[CH3:23][C:21]1[S:22][C:18]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[CH:19][CH:20]=1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1ccc(C=O)s1
Product: Cc1ccc(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)s1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 5-methylthiophene-2-carbaldehyde (28 mg, 0.23 mmol) to give the title compound.