Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])(C)(C)C.FC(F)(F)C(O)=O>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:15]2[CH:14]=[CH:13][C:12]3[N:8]([CH2:7][C:6]([OH:31])=[O:5])[C:9]([CH2:28][CH2:29][CH3:30])=[N:10][C:11]=3[CH:16]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
The product of step d.) was treated with trifluoroacetic acid (TFA) (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ10.01 (br s, 1H), 7.74 (dd, J=5.3 Hz, J=8.7 Hz, 2H), 7.35 (t, J=8.7 Hz, 2H), 7.19 (d, J=1.8 Hz, 1H), 6.87 (dd, J=1.8 Hz, J=8.7 Hz, 1H), 4.93 (s, 2H), 2.67 (t, J=7.5 Hz, 2H), 1.72 (sextet, J=7.5 Hz, 2H), 0.95 (t, J=7.5 Hz, 3H). MS: ESI (negative): 390 (M−H).
Reaction SMILES: C([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[N:9][CH:8]=[CH:7][CH:6]=2)C.O.[OH-].[Li+]>CO.O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([S:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][N:4]2[C:5]3[C:10](=[N:9][CH:8]=[CH:7][CH:6]=3)[C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:3]2)=[CH:26][CH:27]=1
Reactant: CCc1c(C(=O)O)c(=O)c2ncccc2n1Cc1ccccc1Sc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(Cc2ccccc2Sc2ccc(Cl)cc2)c2cccnc2c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.6 %

Procedure:
To a light brown solution of ethyl 1-(2-(4-chlorophenylthio)benzyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (26) (203 mg, 0.450 mmol) in methanol (20 mL) was added the solid lithium hydroxide monohydrate (189 mg, 4.5 mmol) at room temperature. The resulting light brown solution was stirred for 15 h at room temperature at which time LCMS analysis indicated the absence of starting material. Then, it was diluted with water and the methanol was removed under vacuum. The resulting light brown solids were difficult to dissolve in 1.0N NaOH and water, but it was dissolved in dimethylformamide (approx. 10 mL) and the solution was diluted with water (approx. 100 mL). Then, the resulting basic aqueous solution was neutralized with 1.0N HCl. The resulting solids were collected by filtration and washed with water and hexanes. After air drying, 102 mg of 1-(2-(4-chlorophenylthio)benzyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (27) (53.6% yield) was isolated as an off-white solid.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=2)[C:3]=1[C:32]#[N:33].[ClH:34].N([O-])=O.[Na+]>O>[Cl:34][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:26][CH:27]=2)[C:3]=1[C:32]#[N:33]
Reactant: Cl
Reactant: CNC(=O)c1cccc(CSc2nc(N)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CNC(=O)c1cccc(CSc2nc(Cl)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2 g (4.35 mmol) of 3-[({6-amino-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]pyridin-2-yl}-sulfanyl)methyl]-N-methylbenzenecarboxamide Example 8 were dissolved in ice-cooled conc. hydrochloric acid. 0.9 g (13.06 mmol) of sodium nitrite was added, and the mixture was then stirred at 0° C. for 1 h. After 30 min, a barely stirrable solution had formed. 200 ml of water were added to the reaction mixture. The precipitate was filtered off and purified by column chromatography on silica gel 60 (mobile phase: dichloromethane/methanol 50/1→20/1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C(NCC)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:21][N+:18]([O-:20])=[O:19])=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C(/C=C/c1ccccc1)c1ccc(Br)cc1
Solvent: CCNCC
Solvent: CO
Product: O=C(CC(C[N+](=O)[O-])c1ccccc1)c1ccc(Br)cc1
Yield: 85.7 %

Procedure:
In a 1 L flask, 46.9 g (154 mmol) of (2E)-1-(4-bromophenyl)-3-phenylprop-2-en-1-one were dissolved in 450 g of methanol, admixed with 46.9 g (768 mmol) of nitromethane and 56.2 g (768 mmol) of diethylamine and refluxed for 16 h. The solvent was half distilled off in vacuo and the precipitated solid was separated off and dried to constant weight in vacuo to obtain 46 g (132 mmol) of 1-(4-bromophenyl)-4-nitro-3-phenylbutan-1-one.
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:28])=O)=[N:24][CH:25]=1.Cl.[CH3:30][O:31][NH:32][CH3:33]>C(Cl)Cl>[CH3:30][O:31][N:32]([CH3:33])[C:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][CH2:17][CH3:16])=[CH:25][N:24]=1)=[O:28]
Reactant: CNOC
Reactant: CCCCc1ccc(C(=O)O)nc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCCc1ccc(C(=O)N(C)OC)nc1
Reaction time: 19 h
Yield: 129.7 %

Procedure:
Add N-methylmorpholine (1.22 mL, 11.1 mmol) and isobutylchloroformate (1.44 mL, 11.1 mmol) to a solution of fusaric acid (2.0 g, 11.1 mmol) in methylene chloride at 0° C. After 15 minutes add O,N-dimethylhydroxylamine hydrochloride (1.1 g, 11.1 mmol) and N-methylmorpholine (1.22 mL, 11.1 mmol). Stir the reaction for at 0° C. 15 minutes and then room temperature for 19 hours. Dilute the reaction with methylene chloride and wash with water (1×50 mL), 10% aqueous citric acid (1×50 mL), brine (1×50 mL), saturated aqueous sodium bicarbonate (1×50 mL), and brine (1×50 mL). Dry the organic solution with sodium sulfate, filter, and concentrate in vacuo to provide the title compound 3.2 g (100%) as a clear yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]1[O:11][C:5]2([CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:8][CH2:9]1
Reactant: O=C1CCC(O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: OC1CCC2(CC1)OCCO2

Procedure:
A reaction mixture consisting of 10 gm. (0.085 mole) 4-hydroxycyclohexanone, 4.75 ml. ethylene glycol, 0.20 gm. p-toluenesulfonic acid, and 100 ml. benzene is heated at the reflux temperature in a reaction vessel fitted with a Dean and Stark trap for 2 hours. After the reaction mixture has cooled, it is washed first with water and then with brine. The benzene is then removed by evaporation under reduced pressure giving the intermediate 4-hydroxycyclohexanone ethylene monoketal as a viscous oil weighing 14.12 gm. The 4-hydroxycyclohexanone ethylene monoketal is dissolved in 100 ml. methylene chloride and added with stirring to a suspension consisting of 55.0 gm. chromium trioxide (predried for 24 hours under reduced pressure over phosphorous pentoxide), one liter dry methylene chloride, and 52.8 gm. 3.5-dimethylpyrazole. After continued stirring for ten (10) min. this dark reaction mixture is poured onto a two liter column of silica gel. When the reaction mixture has been completely adsorbed, the chromatogram is developed with a 1:1 mixture of ethyl acetate and technical hexane (Skellysolve B - a mixture of isomeric hexanes having a boiling range between 60° and 70° C.) The appropriate fractions as determined by TLC are collected and combined, after which the solvents are removed by evaporation under reduced pressure. The crystals thus obtained are recrystallized from technical hexane, and there is thus obtained 10.82 gm. (91% yield) of the desired cyclohexane - 1,4-dione, ethylene monoketal hving a melting point at 68° to 69° C. [The literature value is 71.5° to 72.5° C.]
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16]
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ccccc1
Reaction time: 4 h
Yield: 82.8 %

Procedure:
A 250 ml round-bottomed flask equipped with a magnetic stirrer is charged with 30 g of 2-chloroacetophenone and 36.3 g of potassium phthalimide in 120 ml of DMF. After 4 h at RT, the mixture is concentrated under vacuum. The solid obtained is taken up in 120 ml of DCM and 100 ml of 1 sodium hydroxide solution. The organic phase is washed with saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated under vacuum. The solid obtained is triturated in diisopropyl ether. The insolubles are filtered off and dried under vacuum to give 42.6 g of 2-(2-oxo-2-phenylethyl)-1H-isoindole-1,3(2H)-dione in the form of a beige solid, which is used as it is in the following step.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][OH:23])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([O:27][C:26]([F:25])([F:37])[F:38])[CH:29]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: Cc1cc(-c2cccc(OC(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (intermediate 4) was reacted with 3-trifluoromethoxy-phenyl boronic acid to give the title compound as off-white solid. MS: 477.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[NH:23]1[CH:27]=[CH:26][CH:25]=[N:24]1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:23]1[CH:27]=[CH:26][CH:25]=[N:24]1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-n1cccn1
Yield: 40.8 %

Procedure:
A mixture of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.080 g; 0.188 mmol), 1H-pyrazole (0.065 g; 0.942 mmol), copper (I) iodide (0.0036 g; 0.002 mmol), and potassium carbonate (0.032 g; 0.226 mmol) in 2-propanol (3 ml) was irradiated in a microwave oven microwave for 20 minutes at 150° C. The volatiles were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was then extracted several times with ethyl acetate. The combined organic layers were evaporated to dryness and the residue was purified by flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) to afford 0.028 g (41%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-2-(1H-pyrazol-1-yl)benzamide as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O-:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[K+].Br[CH2:14][C:15]1[N:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1.O>CN(C)C=O>[Cl:21][C:18]1[N:17]=[N:16][C:15]([CH2:14][O:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)c1ccc([O-])cc1
Reactant: Clc1ccc(CBr)nn1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(OCc2ccc(Cl)nn2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.5 %

Procedure:
To a solution of potassium 4-(methanesulfonyl)phenolate (150 mg, 0.713 mmol) in N,N-dimethylformamide (2 mL) was added a solution of 3-bromomethyl-6-chloropyridazine (221 mg, 1.07 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 2.5 hours, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→2/3) to give the title compound as a white crystal (148 mg, yield 69%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2O.[OH-].[NH4+].C(OCC)(=O)C.P(Cl)(Cl)([Cl:29])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[Cl:29]
Reactant: O=C(c1cnc2cc(F)c(Br)cc2c1O)C1CC1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(c1cnc2cc(F)c(Br)cc2c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
(6-Bromo-7-fluoro-4-hydroxyquinolin-3-yl)(cyclopropyl)methanone (3.35 g, 10.8 mmol) was suspended in phosphoryl chloride (10 mL) at 0° C. The reaction was warmed to room temperature and stirred overnight. After this time 2M ammonium hydroxide was added dropwise until a solid formed. Ethyl acetate was added and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (1.5 g, 42%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 8.63 (d, J=7.2 Hz, 1H), 7.84 (d, J=8.9 Hz, 1H), 2.70-2.45 (m, 1H), 1.55-1.35 (m, 2H), 1.35-1.05 (m, 2H).
Reaction SMILES: [OH-].[Na+].C([NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][C:13]([CH3:23])([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:11]=2[C:24]=1[CH3:25])(=O)C>CO.O>[NH2:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][C:13]([CH3:23])([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:11]=2[C:24]=1[CH3:25]
Reactant: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CCc1ccccc1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CCc1ccccc1)O2
Temperature: 200 °C
Yield: 51.6 %

Procedure:
Aqueous 6N sodium hydroxide solution (3 ml) was added to a solution of 5-acetylamino-2,4,6,7-tetramethyl-2-(2-phenylethyl)-2,3-dihydrobenzofuran (0.7 g, 2.1 mmol) in methanol (3 ml) and the mixture was heated at 200° C. in an autoclave for 18 hours. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (isopropyl ether-ethyl acetate, 2:1). The crude crystals were recrystallized from hexane to obtain the desired compound (0.32 g, yield: 54.5%), m.p. 45°-46° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([NH2:17])=[O:16].[Cl:18][CH2:19][C:20](=O)[CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+]>>[Cl:18][CH2:19][C:20]1[N:17]=[C:15]([CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])[O:16][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(N)=O
Reactant: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc(-c2ccccc2)nc1CCc1nc(CCl)co1
Temperature: 130 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
A mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propanamide (10.0 g) and 1,3-dichloro-2-propanone (5.35 g) was stirred at 130° C. for 2 hrs. An aqueous potassium carbonate solution was added to alkalize the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue was subjected to silica gel column chromatography to give crystals (2.30 g, 18%) of 4-[2-(4-chloromethyl-2-oxazolyl)ethyl]-5-methyl-2-phenyloxazole from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 71-72° C.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:31](=[O:32])[CH2:30][O:29][C:28]3[CH:34]=[CH:35][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Reactant: COc1ccc(OCC(=O)O)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Yield: 52 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 52%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]#[CH:30]>CC(C)=O>[C:28]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1)#[C:29][CH3:30]
Reactant: COc1ccc(-c2c(C)oc3cc(O)ccc3c2=O)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1ccc2c(=O)c(-c3ccc(OC)cc3)c(C)oc2c1

Procedure:
A mixture of 7-hydroxy-2-methyl-4′-methoxyisoflavone (2.82 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g, 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.24 g of a product with the following characteristics: m.p. 139-140° C.; 1H NMR (CDCl3) δ: 2.29 (s, 3H), 2.6 (m, 1H), 3.85 (s, 3H), 4.75 (s, 2H), 6.93-8.17 (m, 7H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:32]5[CH2:33][CH2:34][CH2:35][N:29]([C:26]6[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=6)[CH2:30][CH2:31]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: c1cc(N2CCCNCC2)ccn1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCN(c2ccncc2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(pyridin-4-yl)-1,4-diazepane (1.2 equiv) to give 208 (M+1 473.0)
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[S:6]1[CH2:12][C:10](=[O:11])[NH:9][C:7]1=S.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][NH:5][C:7]2[S:6][CH2:12][C:10](=[O:11])[N:9]=2)[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCC2CC2)=N1

Procedure:
Similar procedure as described in example 67(a) was used, starting from cyclopropylmethylamine, rhodanine (2-thioxo-4-thiazolidinone), mercuric chloride and DIEA to give 2-cyclopropylmethylamino-thiazol-4-one. LC-MS m/e 171 (MH+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:28]([NH:31][CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)(=[O:30])[CH3:29]>C(Cl)Cl.C1COCC1>[Cl:1][CH2:2][C:3]([N:34]1[CH2:35][CH2:36][CH:32]([NH:31][C:28](=[O:30])[CH3:29])[CH2:33]1)=[O:5]
Reactant: O=C(O)CCl
Reactant: CC(=O)NC1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NC1CCN(C(=O)CCl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of chloroacetic acid (0.715 g, 7.56 mmol, 1 eq.) in DCM (15 mL) and THF (12 mL) at r.t. was added EDC.HCl (1.89 g, 9.83 mmol, 1.3 eq.) and HOBt (1.33 g, 9.83 mmol, 1.3 eq.). The reaction mixture was stirred at r.t. for 30 min and then 3-acetamidopyrrolidine (1.26 g, 9.83 mmol, 1.3 eq.) was added. After stirring two days at r.t., the reaction mixture was diluted with water, HCl 1M, and DCM. The aqueous phase was extracted with DCM five times. The combined organic layers were washed with a saturated NaHCO3 solution, with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude oil was used as such in the next step.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[C:18](OCC)=O.[OH-].[NH4+]>O>[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[C:18]1[NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:8][C:9]=2[N:14]=1
Reactant: Nc1ccc(Cn2ccnc2)cc1N
Reactant: CCOC(=O)c1ccccc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Clc1ccccc1-c1nc2cc(Cn3ccnc3)ccc2[nH]1
Temperature: 140 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
A mixture of 5 parts of 4-(1H-imidazol-1-ylmethyl)-1,2-benzenediamine, 5 parts of ethyl 2-chlorobenzoate and 30 parts of polyphosphoric acid was stirred for 4 hours at 140° C. The whole was poured into 200 parts of water and crushed ice. The mixture was treated with ammonium hydroxide. The product was extracted three times with 120 parts of trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of trichloromethane, methanol and ammonium hydroxide (90:10:0.05 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off and dried in vacuo at 100° C., yielding 2.1 parts (26%) of 2-(2-chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-1H-benzimidazole; mp. 115.2° C. (compound 88).
Reaction SMILES: [OH:1][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH3:17][O:18][CH2:19][CH2:20]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:17][O:18][CH2:19][CH2:20][O:1][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: O=c1[nH]c2c([nH]c1=O)C(O)c1ccccc1-2
Reactant: COCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COCCOC1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Yield: 60 %

Procedure:
A suspension of 9-hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione. 1H2O (0.50 g, 2.13 mmol) in benzene (20 ml), 2-methoxyethanol (10 ml) and p-toluensulfonic acid (20 mg) was refluxed with water separation for 20 hours. The reaction mixture was evaporated in vacuo to dryness, the residue was suspended in ethanol (10 ml) and the precipitate was filtered off and washed with ethanol and dried to give 0.48 g of the crude product, which was recrystallized from ethanol to yield 0.35 g (60%) of the title compound. M.p. >300° C. 1H-NMR (DMSO-d6, δ): 3.22 (s, 3H), 3.27-3.51 (m, 4H), 5.24 (s, 1H), 7.18 (t, 1H), 7.33 (t, 1H), 7.42 (d, 1H), 7.5 (d, 1H), 2.06 (s, 1H), 12.29 (s, 1H).