Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:10]1([CH2:15]O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: OCC1CCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(OCC2CCCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3,5-Dibromophenol (5.0 g; 19.8 mmol), cyclopentane-methanol (2.0 g; 19.9 mmol) and tributylphosphine (8.8 mL; 35.7 mmol) were dissolved in dry THF (250 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (9.01 g; 35.7 mmol) dissolved in dry THF (150 mL) was added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was filtered, evaporated to dryness and purified by flash chromatography (heptane→ethyl acetate:heptane 2:3). Yield: 5.68 g; 86%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14](=[O:17])[N:15]=[N:16][C:12]3=[CH:11][C:10](=[O:18])[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14](=[O:17])[N:15]=[N:16][C:12]3=[CH:11][C:10](=[O:18])[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1
Reactant: O=c1cc2nnc(=O)n-2c2ccc([N+](=O)[O-])cc2n1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)n(-c1ccccc1)c(=O)cc1nnc(=O)n2-1

Procedure:
33.5 g of 8-nitro-6-phenyl-1H-s-triazolo[4,3-a] [1,5]-benzodiazepine-1,5-dione in 100 ml of ethanol containing 2.0 g of 10% palladium-on-charcoal is hydrogenated at room temperature at an initial hydrogen pressure of 50 p.s.i. The reaction is stopped when 0.3 moles of hydrogen has been absorbed; the suspension is filtered and the filtrate evaporated to give the title compound.
Reaction SMILES: Cl.C([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:10]([OH:22])[C:9]2=[O:23])(=O)C.N>C(O)C>[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:10]([OH:22])[C:9]2=[O:23]
Reactant: CC(=O)Nc1ccc2oc(-c3ccccc3)c(O)c(=O)c2c1
Agent: Cl
Agent: N
Solvent: CCO
Product: Nc1ccc2oc(-c3ccccc3)c(O)c(=O)c2c1
Yield: 50.9 %

Procedure:
Aqueous HCl (5 M, 20 mL) was added to a suspension of 6-acetamidoflavonol (6) (1.00 g, 3.39 mmol) in ethanol (30 mL) and the mixture was heated under reflux for 1.5 h. The mixture was cooled and made basic with aqueous NH3 (litmus) and the precipitate formed was collected by filtration to afford 6-aminoflavonol as a bright yellow powder (0.437 g, 51%), m.p. 211-212° C. 1H NMR (399.7 MHz, d6-DMSO) δ 5.48 (s, 1H, NH); 7.08 (dd, 1H, J5,7 2.8, J7,8 9.2 Hz, H7); 7.14 (d, 1H, J5,7 2.8 Hz, H5); 7.47-7.57 (m, 4H, H3′,4′,5′,8); 8.17 (app. d, 2H, J=7.6 Hz, H2′,6′); 8.62 (br s, 1H, OH).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][N:6]=1.Br[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[CH2:13]([N:5]1[N:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:1])=[N:6]1)[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1n[nH]nc1C
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1nn(CC(C)C)nc1C
Temperature: 60 °C
Yield: 43.3 %

Procedure:
To av solution of ethyl 5-methyl-2H-1,2,3-triazole-4-carboxylate (0.5 g, 3.2 mmol) in acetonitrile (40 mL) were added 1-bromo-2-methylpropane (1.25 mL, 11.5 mmol), potassium carbonate (2.66 g, 19.2 mmol) and a catalytic amount of potassium iodide. The reaction mixture was heated to 60° C. for 22 h. The reaction mixture was allowed to cool to ambient temperature and was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield 293 mg (43%) of the title compound; MS (APPI/APCI) m/z 212[M+H+].
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]=[C:15]2[NH:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=1[Cl:29].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[NH:21][C:15]1[C:14]2[C:19](=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][N:2]([CH3:3])[CH3:1])[C:11]([O:30][CH3:31])=[CH:12][CH:13]=2)[NH:18][C:17](=[O:20])[CH:16]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCBr
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCN(C)C
Reaction time: 2.5 h

Procedure:
A solution of dimethylamine (1.5 mL, 2M THF, 3 mmol) was added to a solution of 8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (146 mg, 0.3 mmol) and DMSO (3 mL). After 2.5 h, the reaction was poured into 10% K2CO3 (30 mL) and extracted with dichloromethane (40 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silical gel chromatography (1:0→4:1; dichlormethane:methanol w/1% conc. NH4OH solution) and then reverse-phase HPLC (1:9→1:1; acetonitrile:water) to give 4-(3,5-dichloropyridin-4-ylamino)-8-(4-(dimethylamino)butoxy)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.81 (s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 3.99 (t, 2H), 3.90 (s, 3H), 2.27 (t, 2H), 2.13 (s, 6H), 1.73 (m, 2H), 1.54 (m, 2H); MS (ESI): 451.0.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([OH:27])=O.C(N(CC)CC)C.Cl.[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][CH2:51][CH2:52][C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][CH2:51][CH2:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][C:25]([CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)=[O:27])=[CH:55][CH:54]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccn1)Nc1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
Diphenylphosphoryl azide (0.46 ml) was added dropwise to a stirred suspension of 2-pyridylacetic acid (0.367 g) and triethylamine (0.3 ml) in N,N-dimethylformamide (10 ml) maintained at 0° C. A suspension of 4-[3-(2-benzyloxyphenyl)propyl]benzeneamine hydrochloride (0.75 g) in N,N-dimethylformamide (10 ml) containing triethylamine (0.9 ml) was added rapidly to the reaction mixture. Stirring was continued at ambient temperature for 16 hours and the reaction mixture was concentrated to small volume. The residue was partitioned between water and diethyl ether. The diethyl ether extract was washed once each with saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml) and dried. The gum obtained on removal of the solvent was subjected to chromatography on silica (Merck 9385) eluted with a mixture of ethyl acetate and hexane (1:1 v/v). The gum obtained was triturated with ether at 0° C. to give 4-[3-(2-benzyloxy-phenyl)propyl]-N-(2-pyridylmethylcarbonyl)benzeneamine (m.p. 61°-2° C.; yield 0.63 g 68%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:16]1([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[C:22]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=[CH:24][C:25]([CH2:26][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:28][CH:29]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(Cn3c4ccccc4c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Carbazole (8.25 g, 49 mmol) was dissolved in N,N'-dimethylformamide (100 ml). Under a atmosphere of nitrogen was added sodium hydride (2.56 g, 64 mmol of a 60% suspension in mineral oil) in portion during 15 minutes. The mixture was then stirred at room temperature for 0.5 h. To the resulting mixture was added 4-phenylbenzylchloride (10 g, 49 mmol) in portions during 10 minutes. Then additional N,N'-dimethylformamide (100 ml) was added and the mixture was stirred at room temperature for 3.5 h. Water (125 ml) was added and the mixture was stirred vigorously at room temperature for 0.5 h, the solid formed was filtered off, washed with water (2×100 ml) and with hexane (2×100 ml). Drying in vacuo at 50° C. for 16 h afforded 15.9 g (97%) of 9-(biphenyl-4-ylmethyl)-9H-carbazole as a solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@H:10](O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@@H:10]([N:18]3[C:14](=[O:24])[C:15]4[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:17]3=[O:19])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCN(Cc2ccccc2)C1
Reaction time: 18 h
Yield: 79 %

Procedure:
To a suspension of 8.9 g (50 mmol) of (S)-1-phenylmethyl-3-hydroxypyrrolidine [Synth. Commun., 15, 587 (1985)], 9.8 g (50 mmol) of phthalimide, 13.1 g (50 mmol) of triphenylphosphine and 100 ml of tetrahydrofuran was added, dropwise, a solution of 8.8 g (50 mmol) of diethyl azodicarboxylate at room temperature. The reaction was stirred for 18 hours and the solvent was removed in vacuo. The residue was triturated with ether and the solid was removed by filtration and chromatographed on silica gel (E. Merck-240-400 mesh) eluting with chloroform/ethyl acetate (80:20). Fractions were combined based on thin layer chromatography and evaporated in vacuo to give 12.1 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][NH:22]C(=O)C)[CH:11]=3)=[CH:9][C:2]=12.N1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC)=O>[N:22]1([CH2:21][CH2:20][CH2:19][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:8]3[NH:7][C:3]4=[N:4][CH:5]=[CH:6][N:1]=[C:2]4[CH:9]=3)=[CH:11]2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: C1COCCN1
Reactant: CC(=O)NCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2CCCN1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of 3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propylbromide [250 mg, Reference Example 4], morpholine (0.5 mL), potassium carbonate (100 mg) and potassium iodide (2 crystals) in ethyl methyl ketone was heated at reflux for 2 hours. The mixture was then allowed to cool to ambient temperature over 16 hours then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (9:1, v/v) to give a yellow glass which was triturated with ethyl acetate and pentane to give the title compound (40 mg) as a yellow solid, m.p. 180-185° C. MS: 362 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][CH2:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][NH:15][CH2:16][C@@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNC[C@H](C)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-((R)-2-phenyl-propyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=[O:21])[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([O:21][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@@H]3C)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Temperature: 0 °C

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (220 mg, 2.78 mmol) and then Tf2O (393 mg, 1.39 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of ice-water (20 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (300 mg, crude).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-])=O)[CH:26]=3)=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=3)=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccncc3)c(-c3cccc([N+](=O)[O-])c3)n2)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccncc3)c(-c3cccc(N)c3)n2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To crude 4-[3-(3-nitro-phenyl)-4-pyridin-4-yl-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.75 mmol) in methanol (20 mL) Pd/C 10% (190 mg) was added. The reaction was stirred under hydrogen atmosphere (45 psi) at room temperature for six hours. The suspension was filtered to remove the catalyst, and then concentrated to give the crude product that was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([Cl:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)[CH:7]=1.Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[Cl:20][C:5]1[CH:4]=[C:3]([Cl:21])[C:2]([NH:1][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:29])=[CH:7][C:6]=1[C:8]1[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(N)c(Cl)cc2Cl)c1=O
Solvent: O
Product: CCOC(=O)C(C)Nc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 150 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A mixture of 0.15 g of 3-(5-amino-2,4-dichlorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-334) and 172 μl of ethyl 2-bromopropionate was stirred at 150° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 92 mg (yield, 48%) of 3-{2,4-dichloro-5-[1-(ethoxycarbonyl)ethylamino]phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-336).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12](C(=O)C)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)N1CCC(c2noc3cc(Cl)ccc23)CC1
Agent: Cl
Solvent: CCOCC
Product: Clc1ccc2c(C3CCNCC3)noc2c1
Yield: 157.5 %

Procedure:
1-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethanone (1.45 g, 5.3 mmol) was diluted with an aqueous solution of HCl 6N (13.8 mL, 16 mmol) and the mixture was refluxed overnight. After cooling, 2×20 mL of ether was added and the mixture extracted. A solution of NaOH was added to the aqueous phase until pH 11 and the mixture was extracted with ethyl acetate three times. The combined ethyl acetate fractions were dried and evaporated under reduced pressure to yield 1.14 g of a light brown solid (93%). MS (m/e): 236.9 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:20])[CH2:16][C:17](=O)[CH3:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH3:21]>CO>[NH2:21]/[C:17](/[CH3:18])=[CH:16]\[C:15]([NH:14][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)=[O:20]
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: N
Solvent: CO
Product: C/C(N)=C/C(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-chloro-4-morpholinophenyl)-3-oxobutanamide (2.0 g, 6.74 mmol), MeOH (15 mL) and ammonia (15 mL) was stirred at rt overnight. The mixture was then concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH2:17][C:18]3[C:19]([CH3:34])=[N:20][C:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[CH:22][CH:23]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:34][C:19]1[C:18]([CH2:17][CH2:16][O:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:35])=[O:3])=[CH:23][CH:22]=[C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=2)[N:20]=1
Reactant: CCOC(=O)Cn1ccc2c(OCCc3ccc(-c4ccc(C(F)(F)F)cc4)nc3C)cccc21
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCOc1cccc2c1ccn2CC(=O)O

Procedure:
In analogy to the procedure described in example 5 g], (4-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-indol-1-yl)-acetic acid ethyl ester was treated with LiOH to obtain the title compound as white solid.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH3:17])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1>>[CH3:1][NH:2][C:4]1[C:13]2[N:14]=[CH:15][N:16]([CH3:17])[C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CN
Reactant: Cn1cnc2c(Cl)nc3ccccc3c21
Product: CNc1nc2ccccc2c2c1ncn2C
Temperature: 112 °C

Procedure:
A mixture of 40% aqueous methylamine (25 ml) and 5.0 g (0.023 mole) of 4-chloro-1-methyl-1H-imidazo[4,5-c]quinoline (from Example 114) was placed in a metal pressure reactor and heated at 112° C. for about 16 hours. After cooling, the solid was separated by filtration, washed with water, dried and recrystallized from ethanol to provide N,1-dimethyl-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 216°-218° C. Analysis: Calculated for C12H12N4 : %C, 67.9; %H, 5.7; %N, 26.4; Found: %C, 67.9; %H, 5.6; %N, 26.4.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:14]([CH:25](Cl)[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:14]([CH:25]([N:38]=[N+:39]=[N-:40])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:37])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(Cl)C(=O)OCc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 47 %

Procedure:
To a solution of benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]-2-chloroacetate (3.60 g.) in N,N-dimethylformamide (6 ml.) was added sodium azide (384 mg.) at 0° C., and the mixture was stirred at 0° C. for 50 minutes. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed twice with water and an aqueous solution of sodium chloride, dried over magnesium sulfate, and then evaporated to leave an oil (3.60 g.), which was chromatographed on silica gel (36 g.) with chloroform as an eluent to give an oil (1.71 g.) of benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]-2-azidoacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[Br:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.O>C1COCC1>[Br:23][C:24]1[CH:25]=[C:26]([S:30]([N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1n(S(=O)(=O)c2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
360 mg (1.17 mmol) of the compound from Example 5A were dissolved in 10 ml of THF and, at 0° C., 94 mg (2.34 mmol) of sodium hydride (60% strength dispersion in mineral oil) were added. After 20 min, 299 mg (1.17 mmol) of 3-bromobenzenesulfonyl chloride were added, and the mixture was stirred at 0° C. for 1 h. For work-up, 10 ml of water were added and the mixture was extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1, then 1:1). This gave 181 mg (27% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:17]1([CH2:23][C:24](=[NH:28])OCC)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:24](=[NH:28])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Nc1ncccc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccccc1
Yield: 15.6 %

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (2.5 g, 12.5 mmol) and ethyl phenylacetimidate hydrochloride (2.5 g, 12.5 mmol) in ethanol (100 ml) was heated under reflux for 1 hour. The solvent was evaporated in vacuo, and the residue taken up in chloroform, washed with aqueous sodium bicarbonate, dried and the chloroform evaporated. Treatment with charcoal and recrystallisation from ethyl acetate/petroleum ether gave the product (0.62 g), m.p. 114°-116° C.