Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[O:3]1[C:7]2=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([C:16]4[C:17]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)=[N:18][C:19]5[C:24]([N:25]=4)=[CH:23][C:22]([C:26]([O:28]C)=[O:27])=[CH:21][CH:20]=5)[C:14]=3[CH:15]=[C:6]2[O:5][CH2:4]1>CO.O>[O:3]1[C:7]2=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([C:16]4[C:17]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)=[N:18][C:19]5[C:24]([N:25]=4)=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][CH:20]=5)[C:14]=3[CH:15]=[C:6]2[O:5][CH2:4]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc5c(cc43)OCO5)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc5c(cc43)OCO5)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Sodium hydroxide (35 mg, 0.88 mmol) was added to a solution of methyl 3-[2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinolin-5-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate (100 mg, 0.22 mmol) in methanol (30 ml) and water (1.0 ml) and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 ml), and adjusted to pH 5 with hydrochloric acid (3 N) to give a precipitate which was collected by filtration to afford 3-[2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinolin-5-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (70.0 mg, 72%).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:26]([CH2:29][CH2:30][CH2:31][OH:32])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH2:29][CH2:30][CH2:31][OH:32])(=[O:28])=[O:27])[CH:21]=2)[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: O=S(=O)(CCCO)c1cccc(Br)c1
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cccc(S(=O)(=O)CCCO)c1

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 3-(3-bromo-benzenesulfonyl)-propan-1-ol (Intermediate 6), the title compound was obtained as a brown solid after purification by preparative HPLC.
Reaction SMILES: NC(N)=NC(=O)C1C=C(S(C)(=O)=O)C(N2C=CC=C2)=CC=1C.Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[CH3:31].[C:32](=[O:34])=[O:33]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:32]([OH:34])=[O:33])=[C:25]([CH3:31])[CH:26]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: O=C=O
Agent: Cc1cc(-n2cccc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Product: Cc1cc(Cl)ccc1C(=O)O

Procedure:
In a process for preparing N-diaminomethylene-2-methyl- 4-(1-pyrrolyl)-5-methylsulfonylbenzamide, the step comprising reacting 2-bromo-5-chlorotoluene with a secondary or tertiary organolithium compound and CO2 to produce 4-chloro-2-methylbenzoic acid.
Reaction SMILES: [C:1]([C:3](=[CH:6][N:7]([CH3:9])[CH3:8])[CH:4]=O)#[N:2].[NH2:10]OS(O)(=O)=O.[OH-].[Na+]>O>[CH3:8][N:7]([CH:6]=[C:3]([C:4]#[N:10])[C:1]#[N:2])[CH3:9]
Reactant: NOS(=O)(=O)O
Reactant: CN(C)C=C(C#N)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)C=C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 12.4 g. of 2-cyano-3-dimethylaminoacrolein in 50 ml. of water was added in small portions 13.6 g. of hydroxylamine-O-sulfonic acid (91% pure). The resulting clear solution was stirred for an additional 10 minutes, then cooled to 0° and adjusted to pH 6.0 by addition of approximately 26 ml. of 5N sodium hydroxide solution. The mixture was heated for 20 minutes in a water bath at 70°. A pH 3 was maintained over this period by dropwise addition of 5N sodium hydroxide solution. After cooling to room temperature, the mixture was extracted with 3 × 100 ml. of methylene chloride. The combined extracts were washed with 50 ml. of water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Thus, dimethylaminomethylenemalononitrile was obtained. After recrystallization from isopropanol, the material had a melting point of 93°-95°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[CH:27]=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:1][C:2]4[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=4)=[C:28]3[CH:27]=[N:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 160 °C
Yield: 37.2 %

Procedure:
A mixture of N-(4-hydroxy-phenyl)-acetamide (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 14 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-acetylamino-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (15 mg, 35%) as a white solid. Mass spectrum MH+=453.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C@@H:21]([OH:26])[CH2:22][C@H:23]([OH:25])[CH3:24].COCCOC(N=NC(OCCOC)=O)=O.[N+:43]([C:46]1[CH:54]=[CH:53][C:49]([C:50]([OH:52])=[O:51])=[CH:48][CH:47]=1)([O-:45])=[O:44]>C1COCC1.O>[N+:43]([C:46]1[CH:47]=[CH:48][C:49]([C:50]([O:25][C@@H:23]([CH3:24])[CH2:22][C@H:21]([OH:26])[CH3:20])=[O:51])=[CH:53][CH:54]=1)([O-:45])=[O:44].[N+:43]([C:46]1[CH:47]=[CH:48][C:49]([C:50]([OH:52])=[O:51])=[CH:53][CH:54]=1)([O-:45])=[O:44]
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)C[C@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
After triphenylphosphine (565 mg, 2.16 mmol), (2R,4R)-2,4-pentanediol (226 mg, 2.16 mmol), and THF (6 ml) were added to a 50 mL flask, azodicarboxylic acid bis(2-methoxyethyl) ester (505 mg, 2.16 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C. Subsequently, 4-nitrobenzoic acid (300 mg, 1.80 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for one hour. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 mL, ×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-(4-nitrobenzoyloxy)pentane-2-ol as a pale yellow solid substance (358 mg, yield: 79%/4-nitrobenzoic acid).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[CH:7]3[CH2:14][CH2:15][CH2:16][C:5]=1[C:6]=23)(=[O:3])[CH3:2].[H-].[Na+].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CN(C=O)C>[C:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3([CH2:23][CH2:22][CH2:21][CH2:20][Br:19])[CH2:14][CH2:15][CH2:16][C:5]=1[C:6]=23)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c3c1CCCC3C(=O)N2
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c3c1CCCC3(CCCCBr)C(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A 170 ml portion of DMF solution of 6-acetyl-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (3.2 g, 14.9 mmol) was cooled to −5° C. Thereto was added 0.7 g of sodium hydride (16.4 mmol), and the resulting solution was stirred at 0° C. for 30 minutes and then cooled to −40° C. Thereto was added 8.9 ml of 1,4-dibromobutane (74.5 mmol), and the mixture was stirred overnight while gradually increasing the temperature in an atmosphere of argon. The reaction solution was extracted with ethyl acetate and washed with water. After drying (Na2SO4), the oily substance obtained by the evaporation of the solvent under a reduced pressure was purified by a silica gel column chromatography (700 cc; elution with ethyl acetate-hexane=2:3) and then recrystallized from ethyl acetate-hexane to obtain 2.26 g of the title compound (43% in yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH:9]([CH3:16])[CH:8](C(OC(C)(C)C)=O)[C:7](=[O:24])[C:6]=1[S:5]2>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH:9]([CH3:16])[CH2:8][C:7](=[O:24])[C:6]=1[S:5]2
Reactant: CC1CC2=C(Sc3cc(Br)ccc3N2)C(=O)C1C(=O)OC(C)(C)C
Solvent: CS(C)=O
Product: CC1CC(=O)C2=C(C1)Nc1ccc(Br)cc1S2

Procedure:
A mixture of 7-bromo-3-carbo-ter-butoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-one (4l R=Br, 3.09 g, 13.7 mmole) in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 3 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from MeOH and proves to be identical. An analytical sample of 4m, (R=Br), mp 250° (dec.) occurs as light orange crystals, 2.67 g (63.2%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][N:33]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:35]3[CH:34]=[N:33][C:32]([CH3:31])=[CH:37][CH:36]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)nc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(C)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 55.8 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.15 mmol), 2-methyl-5-tributylstannanyl-pyridine (86 mg, 0.23 mmol) and PdCl2(PPh3)2 (21 mg, 0.030 mmol) in 4 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (10-90% EtOAc/hexanes+1% AcOH) to give 40 mg of the title compound as a white solid. MS: (+) m/z 478.45 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1Cl)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17](Cl)=[C:16]([NH2:21])[CH:15]=2)[CH:8]=1)=[O:6].C([O-])=O.[Na+].COCCO>[Pd].O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:21])[CH:15]=2)[CH:8]=1)=[O:6]
Reactant: Nc1cc(C(=O)c2cccc(C(=O)c3ccc(Cl)c(N)c3)c2)ccc1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: Nc1cccc(C(=O)c2cccc(C(=O)c3cccc(N)c3)c2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
In the next step, to a sealed glass reaction vessel equipped with a thermometer, stirrer and reflux condenser, 156 g (0.41 mole) of the above 1,3-bis(3-amino-4-chlorobenzoyl)benzene, 145 g (2.13 mole) of sodium formate, 787 g of 2-methoxyethanol and 43 g of water were charged and heated to 100° C. with stirring. Successively, 7.8 g of a 5% palladium/activated carbon catalyst (a product of M.E. Chemcat Co.) was gradually added and the reaction was continued at 100° C. for 3 hours with stirring. The reaction mixture was cooled to 85° C. and hot filtered to remove the catalyst. The filtrate was poured into 4 l of water. The precipitated yellow crystals were filtered, washed with water and dried. Crude crystal of the desired 1,3-bis(3-aminobenzoyl)benzene were thus obtained in an amount of 126 g (97% yield). The crystals were analyzed by high performance liquid chromatography and determined to have a purity of 85.3%. The crude 1,3-bis(3-aminobenzoyl) benzene was dissolved in 630 g of toluene by heating and hot filtered to remove insoluble matter. Successively, 89 g of a 36% aqueous hydrochloric acid solution was added to the filtrate and allowed to cool. The precipitated crystal of 1,3-bis(3-aminobenzoyl)benzene hydrochloride was recrystallized from ethanol to obtain crystals of pure 1,3-bis(3-aminobenzoyl)benzene hydrochloride. The hydrochloride was dissolved in 1 l of water and neutralized with an aqueous ammonia solution. The precipitated yellow crystals were filtered, washed with water and dried. The desired product, crystals of pure 1,3-bis(3-aminobenzoyl)benzene were thus obtained in an amount of 85g (67% yield). Melting point was 114.2°~116.9° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].C([Li])CCC.[CH:17]([CH:19]=[CH2:20])=[O:18]>C1COCC1>[OH:18][CH:17]([CH:19]=[CH2:20])[CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:11])[C:8]([OH:10])=[O:9]
Reactant: Cc1ccccc1CC(=O)O
Reactant: C=CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(O)C(C(=O)O)c1ccccc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
A solution of o-tolylacetic acid (45.0 g.) in dry THF (300 ml.) was treated under argon at 5°-10° C. with a 1.60M solution (376 ml.) of butyl lithium. The suspension was stirred 2 hours at 5°-10° C. and then acrolein (dried over 3A molecular sieve) (20.0 ml., 16.8 g.) was added over 5 minutes. The mixture was stirred for 2 hours and then carefully treated with ice-water (1 1.) The aqueous mixture was washed with ether (200 ml.). The aqueous layer was separated and acidified to pH4 (HCl) and extracted with ether (3×150 ml.). The extracts were washed with water, dried (magnesium sulphate) and evaporated to give 3-hydroxy-2-o-tolyl-4-pentenoic acid (A) (55.2 g.), which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[N:16][N+:17]([O-:19])=[O:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:13]2[CH2:14][CH2:15][N:11]([CH:10]=[CH:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:23][N:22]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCN1C=Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])N=C1N(C=Cc2ccc(Cl)c(Cl)c2)CCN1Cc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A mixture comprising 7.0 g of 1-{2-(3,4-dichlorophenyl)vinyl}-2-nitroiminoimidazolidine, 7.5 g of 2-chloro-5-chloromethylpyridine, 6.4 g of potassium carbonate and 50 ml of dimethylsulfoxide was stirred at 60° C. for one hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgS04) and concentrated o give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate) to give 5.7 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(3,4-dichlorphenylvinyl) -imidazolidine.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:5].[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH2:27])=[S:26])([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC>CO>[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]1[S:26][CH:2]=[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[N:27]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCCNC(N)=S
Reactant: Cc1ccccc1C(=O)C(=O)CBr
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccccc1C(=O)c1csc(NCCCNC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Yield: 71.3 %

Procedure:
A mixture of 2.55 g (10.6 mmol) 3-Bromo-1-o-tolyl-propane-1,2-dione, 1.9 g (8.1 mmol) (3-thioureido-propyl)-carbamic acid tert-butyl ester and 5.66 ml (40.6 mmol) NEt3 in 100 ml methanol was heated to 80° C. for 2 h. The reaction mixture was evaporated under reduced pressure and the residue was purifier by flash column chromatography on silica eluting with a gradient of heptane and ethyl acetate. Evaporation of the product fractions yielded 2.17 g (71%) of the title compound as dark red oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:12]1[N:13]([CH2:25][CH2:26][CH2:27][NH2:28])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:9][CH2:10][CH3:11].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH2:8]([C:12]1[N:13]([CH2:25][CH2:26][CH2:27][NH:28][S:30]([CH3:29])(=[O:32])=[O:31])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2cnc3ccccc3c2n1CCCNS(C)(=O)=O
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Triethylamine (1.1 g, 10.6 mmol) was added with stirring to a solution of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08 mmol) in dichloromethane (˜150 mL). Methanesulfonyl chloride (892 mg, 7.79 mmol) was added and the reaction was stirred under nitrogen overnight. The reaction mixture was washed with aqueous 1% sodium bicarbonate solution (3×50 mL). The aqueous washes were extracted with dichloromethane (2×20 mL). The organics were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide 1.89 g of N-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]methanesulfonamide as a light brown solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18]Br)[CH3:15].[OH-].[K+]>CS(C)=O.O>[CH2:14]([O:16][CH:17]([O:20][CH2:21][CH3:22])[CH2:18][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH3:15]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(CBr)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(COc1ccc(-c2ccccc2)cc1)OCC
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A mixture of 4-phenylphenol (5 g, 29.4 mmol), bromoacetaldehyde diethyl acetal (4.56 mL, 29.4 mmol) and KOH (1.94 g, 29.4 mmol) in DMSO (15 mL) was stirred at reflux for 6 h. The reaction mixture was allowed to cool down to room temperature and poured over ice containing 0.60 g of KOH and diluted to 100 mL with water. The solution was extracted with Et2O (20 mL×3); the combined extracts were washed with 1N NaOH solution, water and brine, dried, and concentrated under reduced pressure to yield 7.97 g (94%) of a yellow oil that was used without further purification: 1H NMR (400 MHz, CDCl3) δ 7.56-7.50 (m, 4H), 7.41 (t, 2H), 7.30 (t, 1H), 7.00 (dt, 2H), 4.86 (t, 1H), 4.05 (d, 2H), 3.82-3.74 (m, 2H), 3.69-3.62 (m, 2H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[N:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][C:7]=1[O:17][CH3:18].[CH3:19]C(C)([O-])C.[K+].CI>CN(C=O)C.O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[N:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[N:13]2[CH3:19])=[CH:8][C:7]=1[O:17][CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: COc1cc2c(nc1C1OCCO1)NC(=O)CC2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(nc1C1OCCO1)N(C)C(=O)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 0.1 g (0.4 mmol) 7-[1,3]dioxolan-2-yl-6-methoxy-3,4-dihydro-1H-[1,8]naphthyridin-2-one in 1 ml of DMF cooled to 5° C. was added 0.5 ml (0.5 mmol) of potassium t-butoxide (1M solution in THF). The reaction mixture was stirred fo 30 minutes. To this mixture was added 0.06 ml (1 mmol) of methyl iodide and the reaction stirred at ambient temperature for 2 hours. The reaction mixture was diluted with 5 ml of water and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and evaporated to yield intermediate 7-[1,3]dioxolan-2-yl-6-methoxy-1-methyl-3,4-dihydro-1H-[1,8]naphthyridin-2-one as a dark oil. Mass spectrum: m/e=205.1 (p+1). This material was dissolved in 5 ml of acetone containing 0.1 g of para-toluenesulfonic acid and refluxed for 2 hours. The reaction mixture was evaporated and the residue triturated with saturated NaHCO3. This mixture was extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and evaporated and the residue chromatographed on silica using 3:1 chloroform/ethyl acetate as the elutant. Appropriate fractions were combined to yield 12 mg of 3-methoxy-8-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carbaldehyde as an oil. Mass spectrum: m/e=221.1 (p+1). 1H NMR (CDCl3) δ 10.1 (s, 1H), 7.25 (s, 1H), 3.95 (s, 3H), 3.50 (s, 3H), 3.0 (m, 2H), 2.90 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CCO>[O:25]1[CH2:26][CH2:27][N:22]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:21]=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:4])[CH2:23][CH2:24]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: CCO
Product: O=C(CN1CCOCC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 100 °C
Yield: 29.9 %

Procedure:
To a solution of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol) in EtOH (5 mL), morpholine (63 μL, 0.706 mmol) was added and the reaction mixture was heated at 100° C. for 20 hrs. Upon completion, the solvent was removed in vacuo and the crude oily residue was purified by preparative LCMS to afford 2-morpholino-N-(3-(quinoxalin-2-yl)phenyl)acetamide (35 mg, 30% yield). LCMS calculated for C20H20N4O2 (M+H): 349.40. found 349. 1H-NMR (DMSO-d6, 400 Mhz) δH: 9.98 (1H, br.), 9.53 (1H, s), 8.55 (1H, m), 8.13-8.20 (2H, m), 8.05-8.08 (1H, m), 7.82-7.98 (3H, m), 7.55-7.60 (1H, m), 3.70 (4H, m), 3.20 (2H, s), 2.58 (4H, m).