Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([O:16][CH:17]([CH:20]3[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]3)[C:18]#[CH:19])[C:10]([F:15])=[C:11]2[F:14])=[CH:6][CH:5]=1)[CH3:2]>C(N(CC)C1C=CC=CC=1)C.CC(OC)(C)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[CH:19]=[CH:18][CH:17]([CH:20]4[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]4)[O:16][C:9]=3[C:10]([F:15])=[C:11]([F:14])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: C#CC(Oc1cc2ccc(OCC)cc2c(F)c1F)C1CCC(CCC)CC1
Solvent: COC(C)(C)C
Solvent: CCN(CC)c1ccccc1
Product: CCCC1CCC(C2C=Cc3c(c(F)c(F)c4cc(OCC)ccc34)O2)CC1

Procedure:
7.75 g (about 18.6 mmol) of 7-ethoxy-1,2-difluoro-3-[1-(4-propylcyclohexyl)prop-2-ynyloxy]naphthalene are heated at 205° C. for 4.5 h in 80 ml of N,N-diethylaniline. The batch is diluted with MTBE and washed a number of times with hydrochloric acid. The organic phase is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:MTBE=4:1). The further purification is carried out by recrystallisation from n-heptane, giving 8-ethoxy-5,6-difluoro-3-(4-propylcyclohexyl)-3H-benzo[f]chromene as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[C:19]([CH2:25]Br)[CH:18]=1>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:21][CH:22]=1)[CH2:23][C:3]1([C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[CH2:25]2
Reactant: BrCc1ccc(Br)cc1CBr
Reactant: O=C1Cc2ccccc2N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12Cc1ccc(Br)cc1C2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of oxindole (363 mg, 2.73 mmol) at −78° C. in THF (15 mL) was added butyllithium (2.5 M in hexanes, 2.29 mL, 5.73 mmol) drop wise, followed by the drop wise addition of tetranethylethylenediamine (0.905 mL, 6.00 mmol). The solution was stirred for 1 h at −78° C., then a solution of 4-bromo-1,2-bis(bromomethyl)benzene [Anderson et al., J. Org. Chem. 1979, 44(9), 1519-1533] (1.87 g, 5.45 mmol) in THF (5 mL) was added drop wise. The reaction solution was stirred at −10 to −20° C. for 2 h and at ambient temperature for 16 h. The reaction mixture was partitioned between saturated NH4Cl (50 mL) and EtOAc (50 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=315 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([NH2:32])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:33]([CH3:35])[CH3:34])[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([NH:32][S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:9])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:33]([CH3:35])[CH3:34])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: COc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(N)n1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(NS(=O)(=O)c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
2-Fluoro-benzenesulfonyl chloride (0.05 mL, 0.37 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-amino-6-methoxy-pyridin-4-yl)-methanone (100 mg, 0.31 mmol) in pyridine (2 mL) and stirred for 2 h at room temperature. The reaction mixture was quenched with H2O (100 mL) and extracted with hot EtOAC/MeOH (95:5 3×100 mL). The combined organic extracts were cooled to room temperature and the solid was filtered and dried to provide the title compound as a white solid (69 mg, 47%). MS: 485.3 (MH+); HPLC Rf: 2.7 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: NCCCCSc1cccc2nccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCCSc1cccc2nccn12
Yield: 50.7 %

Procedure:
To a solution of 5-[4-(amino)butylthio]imidazo[1,2-a]pyridine (440 mg, 1.99 mmoles) and triethylamine (0.42 ml, 3.01 mmoles) in methylene chloride (20 ml) was added methanesulfonyl chloride (0.19 ml, 2.45 mmoles) under ice-cooling with stirring and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was washed in turn with an aqueous saturated sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 302 mg of the desired product (50.8%, light red brown solid).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[C:3]1[CH3:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[C:3]1[CH3:11]
Reactant: C1=COCCC1
Reactant: C#CCC1=C(C)[C@@H](O)CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: C#CCC1=C(C)[C@@H](OC2CCCCO2)CC1=O
Yield: 86.5 %

Procedure:
1 To a solution of (S)-4-hydroxy-3-methyl-2(2-propynyl)cyclopent-2-ene-l-one (20.0 g) in dichloromethane (200 ml) were added with stirring 3,4-dihydro-2H-pyran (12.5 g) and a catalytic amount of p-toluenesulfonic acid hydrate under ice-water cooling, then the solution was stirred at room temperature for 1.5 hours. This solution was partitioned between diethyl ether and brine, and the organic layer was washed twice with brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1) to afford (S)-4-(2-tetrahydropyranyloxy)-3-methyl-2-(2-propynyl)cyclopent-2-ene-1-one (27 g, yield 86.6%) pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[Cl:18].[CH2:19]([Sn](CCCC)(CCCC)C=C)[CH2:20]CC.[F-].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH:19]=[CH2:20])=[CH:4][C:3]=1[C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[Cl:18]
Reactant: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1I
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cc(-c2cc(Cl)ccc2Cl)c(Cl)cc1OC
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a stirred solution of 2,2′,5′-trichloro-5-iodo-4-methoxybiphenyl (3.4 g, 8.3 mmol) in toluene (100 mL) at room temperature, tributyl(vinyl)stannane (3.1 g, 9.9 mmol) was added followed by Pd(PPh3)4 (2 g, 1.7 mmol). The reaction mixture was degassed and back-filled with nitrogen (several cycles) and then stirred at reflux for 16 h. The mixture was allowed to cool to room temperature, a solution of KF (1.72 g, 29.7 mmol) in H2O (10 mL) was added and then stirred for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-2% ethyl acetate/petroleum ether) to afford the desired product (2.4 g, 92% yield) as a white solid
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.O[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 4 h
Yield: 24.3 %

Procedure:
To a suspension of 1H-indazol-5-ol (134 mg, 0.999 mmol) in tetrahydrofuran (4 ml) were added tert-butyl 4-hydroxy-1-piperidinecarboxylate (201 mg, 0.999 mmol) and triphenylphosphine (262 mg, 0.999 mmol) at room temperature, followed by adding thereto diethyl azodicarboxylate (0.46 ml, 1.01 mmol) at 0° C., and the resulting mixture was stirred at 0° C. for 30 minutes and then at room temperature for 4 hours. Subsequently, the solvent of the reaction mixture was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=7/3) to obtain tert-butyl 4-(1H-indazol-5-yloxy)-1-piperidinecarboxylate (77 mg, 24%).
Reaction SMILES: [CH3:1][NH2:2].C([NH:6][C:7]1[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[N:9][N:8]=1)(=O)C>C1COCC1>[CH3:1][NH:2][S:12]([C:10]1[S:11][C:7]([NH2:6])=[N:8][N:9]=1)(=[O:14])=[O:13]
Reactant: CN
Reactant: CC(=O)Nc1nnc(S(=O)(=O)Cl)s1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1nnc(N)s1
Temperature: 25 °C

Procedure:
Methylamine (2M in THF, 40 mmol) was added to a suspension of 5-acetylamino-1,3,4-thiadiazole-2-sulfonyl chloride (10 mmol) (prepared as described in Bioorg. Med. Chem. 5, 515, 1997) in THF (10 mL) at −20° C. The mixture was stirred at room temperature over night and evaporated to dryness. The crude methylsulfonamide was suspended in EtOH (15 mL) and added 4N HCl in dioxane (15 mL) and heated for 4 h at 80° C. and then cooled to room temperature and evaporated to dryness to give crude 5-amino-1,3,4-thiadiazole-2-sulfonic acid methylamide.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][OH:13])[CH:6]=1)=O.[C:14]([NH:17][C:18]([NH2:20])=[S:19])(=[O:16])[CH3:15]>O1CCCC1>[OH:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]([C:3]2[N:20]=[C:18]([NH:17][C:14](=[O:16])[CH3:15])[S:19][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)NC(N)=S
Reactant: O=C(CBr)c1cccc(CCO)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(-c2cccc(CCO)c2)cs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of 2-bromo-1-[3-(2-hydroxyethyl)phenyl]ethanone (crude, 658 mg) in tetrahydrofuran (15 ml) was added 1-acetyl-2-thiourea (320 mg) at 25° C. The mixture was stirred at 60° C. for 2 h. The residual colorless crystals were collected by filtration. The crystals were washed with isopropyl ether, dried under reduced pressure to give N-{4-[3-(2-hydroxyethyl)phenyl]-1,3-thiazol-2-yl}acetamide (514 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:16][OH:17].C(Cl)Cl>>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][C:11]=2[CH2:16][OH:17])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CO
Reactant: Cc1cc(C)cc(Sc2cnc(C)[nH]2)c1
Solvent: ClCCl
Product: Cc1cc(C)cc(Sc2[nH]c(C)nc2CO)c1
Yield: 21 %

Procedure:
Heated was a solution of 7.0 g (3.2 mmol)of 5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazole (5b)in 37% aqueous formaline (20 ml)at 120° C. for 15 hours in a sealed tube. The reaction mixture was dissolved in methanol/methylene chloride, and the aqueous layer was separated off. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (methanol:ethyl acetate=2:98), and the crude product was washed with isopropyl ether to obtain 1.7 g of [5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazol-4-yl]methanol (41d)(yield 21%). mp 199-201° C.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][C:9]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20]P(Br)Br.O>C(Cl)Cl>[Br:20][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:10]=1
Reactant: OCc1ccc(CC2CCCCC2)c(C(F)(F)F)c1
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1cc(CBr)ccc1CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 198.9 %

Procedure:
To a stirred solution of (4-(cyclohexylmethyl)-3-(trifluoromethyl)phenyl)methanol (80 mg, 0.29 mmol) in dry DCM (1 mL) was added tribromophosphine (11 μL, 0.12 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h, poured into water, extracted with DCM. The combined organics were washed with saturated NaHCO3 solution and brine, dried and concentrated. The residue was purified by column chromatography to give the title compound (80 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 0.96-1.06 (m, 2H), 1.14-1.22 (m, 3H), 1.55-1.72 (m, 6H), 2.65 (d, J=6.5 Hz, 2H), 4.49 (s, 2H), 7.28 (d, J=8.0 Hz, 1H), 7.47 (dd, J=8.0 and 1.7 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH2:13].C(O)(=O)C.[Cl:18][CH2:19][C:20](Cl)=[O:21].C([O-])(=O)C.[Na+]>O>[Cl:18][CH2:19][C:20]([NH:13][C:4]1[CH:5]=[C:6]([C:9]([F:11])([F:10])[F:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:21]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1NC(=O)CCl
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a stirred and cooled (about 10° C.) solution of 11.7 parts of 2-methoxy-5-(trifluoromethyl)benzenamine in 50 parts of acetic acid were added dropwise 7.7 parts of chloroacetyl chloride at a temperature below 20° C. After stirring for 30 minutes, there was added dropwise a solution of 24.8 parts of sodium acetate in 62 parts of water (exothermic reaction). Upon completion, stirring was continued for 30 minutes at room temperature. The precipitated product was filtered off, washed with a lot of water and dried, yielding 15.5 parts (93.3%) of 2-chloro-N-[2-methoxy-5-(trifluoromethyl)phenyl]-acetamide; mp. 94.7° C. (intermediate 62).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([Li])[CH2:12]CC.CN(C)CCN(C)C.ICC.[NH4+].[Cl-]>C1COCC1>[CH2:11]([C:3]1[C:2](=[O:10])[N:1]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2)[CH3:12]
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccccc2N1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1=c2ccccc2=NC1=O
Temperature: 25 °C
Yield: 2.9 %

Procedure:
A solution of oxindole (40 g, 0.3 mol) in dry THF (400 ml) under N2 was cooled to −25° C. and treated drop wise with n-butyl lithium (2.5M in hexanes, 240 ml, 0.6 mol). To the resulting solution was added N,N,N′,N′-tetramethylethylenediamine (90.4 ml, 0.6 mol). After 30 min. iodoethane (48 ml, 0.6 mol) was added and the reaction mixture was allowed to warm to RT and stirred over night. The reaction mixture was poured into aqueous NH4Cl solution, extracted with EtOAc (2×) and the combined organic layers were washed with dil. HCl, water, brine, dried (MgSO4) and concentrated. The residual oil was triturated with hexane to afford the crude product (24.5 g, 51%). A sample (3 g) was recrystallized from EtOAc/hexane to obtain the title compound (1.4 g), mp. 100-101° C.; 1H-NMR (DMSO-d6) δ0.76 (t, 3H, J=7.5 Hz), 1.8-2.0 (m, 2H), 3.38 (t, 3H, J=5.7 Hz), 6.8 (dt, 11H, J=7.69, 0.45 Hz), 6.93 (dt, 1H, J=7.45, 1.10 Hz), 7.15 (m, 1H), 7.22 (m, 1H), 10.3 (s, 1H); MS (ESI) m/z 270 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.CC(C)([O-])C.[K+]>O1CCOCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1NCCc2ccc(Br)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2cc(Br)ccc2CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a solution of 7-bromo-3,4-dihydroisoquinolin-1(2H)-one (150 mg, 0.66 mmol) and 1-(bromomethyl)-4-fluorobenzene (151 mg, 0.80 mmol) in 1,4-dioxane (5 ml) was added potassium t-butoxide (112 mg, 1.00 mmol). The resulting mixture was stirred at RT overnight. Solids were removed by filtration. Then the mixture was concentrated in vacuo to give 7-bromo-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one (222 mg, yield: 100%). MS (M+H)+: 335.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]#[N:15].[CH2:16]([NH:18][C:19]1[C:24]([CH:25]=O)=[CH:23][N:22]=[C:21]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:20]=1)[CH3:17].O>C(OCCO)C>[CH2:16]([N:18]1[C:19]2[N:20]=[C:21]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:22]=[CH:23][C:24]=2[CH:25]=[C:13]([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[C:14]1=[NH:15])[CH3:17]
Reactant: N#CCc1ccc2ccccc2c1
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Product: CCn1c(=N)c(-c2ccc3ccccc3c2)cc2cnc(Nc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
To a suspension of NaH (60% in mineral oil, 27 mg) in 5 mL of 2-ethoxyethanol was added 2-naphthyl-acetonitrile (227 mg, 1.36 mmol). After stirring for 5 minutes at room temperature, 4-ethylamino-2-phenylamino-pyrimidine-5-carbaldehyde (300 mg, 1.24 mmol) was added and the reaction heated at 110° C. for 1 hour, resulting in a dark brown solution. Upon cooling, the solution was poured into 30 mL of water which caused precipitation. The resulting precipitate was removed by filtration and washed with water. The crude product was purified by flash chromatography, eluting with 5% methanol/methylene chloride, followed by 10% methanol/methylene chloride. Concentration of product fractions yielded 400 mg (82%) of yellow solid, (8-ethyl-7-imino-6-naphthalen-2-yl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-phenylamine; mp 236-242° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:13]=1)[C:7]([NH:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:9]
Reactant: NCCCn1ccnc1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Solvent: C1COCCO1
Product: Nc1ccc(Cl)cc1C(=O)NCCCn1ccnc1
Reaction time: 0.67 h

Procedure:
5-Chloroisatoic anhydride (26.7 g) was added in portions to a stirred solution of 3-imidazol-1-ylpropylamine (17.2 g) in dioxan (150 ml) over a period of 15 minutes. Stirring was continued for 40 minutes before the solution was evaporated in vacuo to give 5-chloro-2-amino-N-(3-imidazol-1-ylpropyl)benzamide as a buff coloured solid, used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].FC1C=CC=C2C=1[C:12]([CH2:21][C:22]([OH:24])=[O:23])=[CH:13][C:14](=[O:20])N2>>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:12]([CH2:21][C:22]([OH:24])=[O:23])=[CH:13][C:14](=[O:20])[NH:5]2)=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cc(=O)[nH]c2cccc(F)c12
Reactant: Nc1cccc(F)c1
Product: O=C(O)Cc1cc(=O)[nH]c2cc(F)ccc12

Procedure:
The compound is prepared according to the technique described in 1.1. from 3-fluoroaniline. It contains 17% of 5-fluoro-2-oxo-1,2-dihydro-4-quinolineacetic acid. This mixture melts at 224°-225° C.
Reaction SMILES: [CH2:1]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[N:20]=[C:19]([C:11]2[S:10][C:9]([CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:13][CH:12]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Clc1ncccn1
Reactant: c1ccc(CCc2cccs2)cc1
Product: Clc1nccc(-c2ccc(CCc3ccccc3)s2)n1

Procedure:
The title compound was prepared from 2-phenethyl-thiophene and 2-chloropyrimidine in a manner analogous to Example 255, Step 1. MS (M+H)+ 301.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:24]>O1CCOCC1.ClCCl>[NH2:24][C:2]1[C:11]([C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N
Reactant: COc1cccc(OC)c1C(=O)c1cc2ccccc2nc1Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cccc(OC)c1C(=O)c1cc2ccccc2nc1N
Temperature: 150 °C

Procedure:
(2-Chloroquinolin-3-yl)(2,6-dimethoxyphenyl)methanone (2.0 g, 6.1 mmol) was dissolved in dioxane (15 mL), mixed with 25% aqueous ammonia solution (10 mL) and heated to 150° C. under its own pressure for 24 hours in a pressurized reactor. The reaction mixture was diluted with dichloromethane and washed several times with water. The organic phase was dried (sodium sulfate) and concentrated. The crude product was purified by chromatography (silica gel, dichloromethane, methanol). Yield: 1.15 g (3.73 mmol, 61%).
Reaction SMILES: [NH2:1][OH:2].Cl.C([O-])([O-])=O.[K+].[K+].[O:10]1[C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH:12]=[C:11]1[C:19]#[N:20]>O.CCO>[OH:2][NH:1][C:19]([C:11]1[O:10][C:18]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[CH:12]=1)=[NH:20]
Reactant: N#Cc1cc2cnccc2o1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1cc2cnccc2o1
Temperature: 70 °C

Procedure:
A solution of NH2OH.HCl (1.22 g, 17.5 mmol) and K2CO3 (1.21 g, 8.75 mmol) in H2O (3 mL) was added to a stirred solution of furo[3,2-c]pyridine-2-carbonitrile (1.26 g, 8.75 mmol) in EtOH (6 mL). The reaction was heated to 70° C. for 2 h, before being concentrated in vacuo. The remainder was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc (8×), then the combined organic extracts were washed with brine, back-extracting with EtOAc (4×). The combined organic extracts were dried (MgSO4), filtered, and concentrated to give the title compound: m/z (ES+)=178.0 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([C:14]3[C:15](=[S:32])[NH:16][C:17](=[O:31])[N:18]([CH2:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26]C)=[O:25])[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH:10]1[C:11]2[CH:12]([C:14]3[C:15](=[S:32])[NH:16][C:17](=[O:31])[N:18]([CH2:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([OH:26])=[O:25])[CH:19]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc(Cn2cc(C3c4ccccc4-c4ccccc43)c(=S)[nH]c2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Cn2cc(C3c4ccccc4-c4ccccc43)c(=S)[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the product from step (v) (0.175 g) and lithium hydroxide monohydrate (0.034 g) in tetrahydrofuran (3 ml) and water (3 ml) was stirred at room temperature for 3 hours and partitioned between dichloromethane and 2 M HCl. The organic phase was dried (MgSO4) and evaporated under reduced pressure. Yield 0.095 g.