Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[N:10]=2)[C:5](O)=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19].S(Cl)([Cl:22])=O>>[Cl:22][C:5]1[C:6]2[C:11](=[N:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[N:2]([CH3:1])[C:3](=[O:19])[C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1c(O)c2ccc(C)nc2n(C)c1=O
Product: CCOC(=O)c1c(Cl)c2ccc(C)nc2n(C)c1=O

Procedure:
A stirred mixture of 1 g. of 1,2-dihydro-1,7-dimethyl-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester in 25 ml. of thionyl chloride was heated under reflux for 5 hours. The thionyl chloride was removed in a rotary evaporator and the residue was triturated with 10 ml. of ethyl acetate. The insoluble material was collected to give 0.8 g. of material. A small amount of this solid was recrystallized from ethyl acetate to give the analytical sample, m.p. 180°-184° C. of 4-chloro-1,2-dihydro-1,7-dimethyl-2-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.F[B-](F)(F)F.[O:24]=[N+:25]=[O:26].O>C(#N)C>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([N+:25]([O-:26])=[O:24])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: O=[N+]=O
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(c2ccccn2)c2cc([N+](=O)[O-])ccc2O1
Yield: 15.7 %

Procedure:
1.32 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 20 ml of acetonitrile and 0.73 g of nitronium tetrafluoroborate was added at room temperature. After 1 hour the mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with sodium chloride solution, dried over sodium sulphate and evaporated to give an oil. This oil was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. 245 mg of 3,4-dihydro-2,2-dimethyl-6 -nitro-4-(2-pyridyl)-2H-1-benzopyran were obtained in the form of an oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:9]=[CH:8][CH:7]=1)O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:66]=[N+:67]=[N-:68])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:66]([CH:4]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:9]=[CH:8][CH:7]=1)[CH:3]([CH2:19][CH3:20])[CH2:1][CH3:2])=[N+:67]=[N-:68]
Reactant: CCC(CC)C(O)c1ccnn1-c1ccc(OC)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)C(N=[N+]=[N-])c1ccnn1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To 2-ethyl-1-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]butan-1-ol (1.0 g, 3.7 mmol) in THF (35 mL) at 0° C. was added triphenylphosphine (1.5 g, 5.6 mmol), diethyl azodicarboxylate (0.88 mL, 5.6 mmol) and diphenylphosphorylazide (1.2 mL, 5.6 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with EtOAc and washed twice with 1N HCl. The organic layer was dried (MgSO4), filtered, concentrated in vacuo and the resulting oil was purified by column chromatography (SiO2, EtOAc/hexane, 1:9) to give a clear oil in 80% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, 1H, J=1.9 Hz), 7.32 (m, 2H), 7.07 (m, 2H), 6.55 (m, 1H), 4.42 (d, 1H, J=8.4 Hz), 3.80 (s, 3H), 1.60 (m, 1H), 1.41 (m, 1H), 1.25 (m, 1H), 1.14 (m, 2H), 0.69 (t, 3H, J=7.4 Hz), 0.60 (t, 3H, J=7.4 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:4]([C:9]([OH:11])=O)=[N:5][CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][CH:42]=1)[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>O1CCCC1.CN(C)C=O.C(=O)([O-])O.[Na+]>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:22]=[C:21]([NH:20][C:9]([C:4]5[C:3]([C:2]([F:1])([F:13])[F:12])=[CH:8][CH:7]=[CH:6][N:5]=5)=[O:11])[CH:42]=[CH:41][CH:40]=4)=[CH:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Reactant: O=C(O)c1ncccc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To a solution of 3-(trifluoromethyl)pyridine-2-carboxylic acid (47.5 mg, 0.249 mmol) in tetrahydrofuran (5 mL) were added N,N-dimethylformamide (2 drops) and oxalyl chloride (43.2 μL, 0.498 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in N,N-dimethylacetamide (6 mL), and the solution was stirred at room temperature. N-[6-(3-Aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (66 mg, 0.214 mmol) was added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (72.5 mg, 70%) as a white solid.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:31]>CO.[OH-].[OH-].[Pd+2]>[ClH:31].[CH:22]1([CH2:21][N:19]([CH3:20])[C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=3[N:18]=2)[CH2:23][CH2:24]1
Reactant: CN(CC1CC1)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CC1CC1)c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 67 %

Procedure:
To a solution of 8-benzyl-N-(cyclopropylmethyl)-N-methyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (0.36 g) in methanol (10 mL) was added 20% Pd(OH)2/C (70 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2.5 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (300 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (197 mg, 67%) as a colorless powder.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:28]O)[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].[C:30]1(=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[NH:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:40]=[C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[N:31]1[CH2:28][C:9]1[C:10]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:6]2[N:7]([C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[N:8]=1
Reactant: CCOC(=O)CCCCc1c(CO)nn2c(CC)ccc2c1-c1cncc(C)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCCc1c(CN2C(=O)c3ccccc3C2=O)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
A mixture of ethyl 5-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (100 mg), 1H-isoindole-1,3(2H) dione (44.6 mg) diisopropyl azodicarboxylate (76.7 mg) and triphenylphosphine (99.5 mg) in tetrahydrofuran (2 mL) was stirred at ambient temperature for 1 hour. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-1:1) to give ethyl 5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (107 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C@@H:7]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[O:10])[NH2:8])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C.[NH2:30][C:31]1[C:36]([Cl:37])=[CH:35][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:33][C:32]=1[Cl:42]>C(Cl)Cl>[NH2:30][C:31]1[C:36]([Cl:37])=[CH:35][C:34]([S:38]([NH:8][CH:7]([CH2:6][C:5]2[CH:18]=[CH:19][C:2]([NH2:1])=[C:3]([N+:20]([O-:22])=[O:21])[CH:4]=2)[C:9]([N:11]2[CH2:12][CH2:13][CH:14]([CH3:17])[CH2:15][CH2:16]2)=[O:10])(=[O:40])=[O:39])=[CH:33][C:32]=1[Cl:42]
Reactant: Nc1c(Cl)cc(S(=O)(=O)Cl)cc1Cl
Reactant: CC1CCN(C(=O)[C@@H](N)Cc2ccc(N)c([N+](=O)[O-])c2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(C(=O)C(Cc2ccc(N)c([N+](=O)[O-])c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Reaction time: 2 h

Procedure:
3.06 g (10 mMol) of 4-amino-3-nitro-phenylalanyl-(4-methyl-piperidine) are dissolved in 100 ml of methylene chloride and combined with 2.8 ml (20 mMol) of triethylamine. Then at ambient temperature 3.1 g (12 mMol) of 4-amino-3,5-dichloro-benzenesulphonic acid chloride in 20 ml of methylene chloride is slowly added dropwise. After 2 hours the precipitate is suction filtered, washed with methylene chloride and dried at 70° C. For further purification the precipitate is suspended in 100 ml of ethanol, decocted and after cooling suction filtered again.
Reaction SMILES: C(OC([N:8]1[C:12]([CH3:14])([CH3:13])[CH2:11][C:10](=[O:15])[N:9]1[C:16]1[N:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[CH:18][N:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:26]1[CH:25]=[C:24]([C:23]#[C:22][C:19]2[CH:20]=[N:21][C:16]([N:9]3[C:10](=[O:15])[CH2:11][C:12]([CH3:14])([CH3:13])[NH:8]3)=[N:17][CH:18]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1N(c2ncc(C#Cc3cccc(F)c3)cn2)C(=O)CC1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(=O)N(c2ncc(C#Cc3cccc(F)c3)cn2)N1
Reaction time: 16 h
Yield: 67.8 %

Procedure:
(118 mg, 0.29 mmol) 2-[5-(3-Fluoro-phenylethynyl)-pyrimidin-2-yl]-5,5-dimethyl-3-oxo-pyrazolidine-1-carboxylic acid tert-butyl ester (Example 15, step 3) was dissolved in dichloromethane (2 ml) and TFA (0.55 ml, 7.2 mmol, 25 equiv.) was added at room temperature and stirred for 16 hours. The reaction mixture was extracted with saturated Na2CO3 solution and a small amount of dichloromethane. The organic extract was loaded directly to a silica gel column. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 2-[5-(3-fluoro-phenylethynyl)-pyrimidin-2-yl]-5,5-dimethyl-pyrazolidin-3-one (61 mg, 69% yield) was obtained as a light yellow solid, MS: m/e=311.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2>[Pt]>[Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH3:13])[NH:7]2
Reactant: Cc1ccc2c(Cl)c(C)ccc2n1
Agent: [Pt]
Product: Cc1ccc2c(c1Cl)CCC(C)N2

Procedure:
5-Chloro-6-methylquinaldine was reduced with platinum on carbon to give 5-chloro-2,6-dimethyltetrahydroquinoline.
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[CH2:18]([CH:20](C(OCC)=O)[C:21](OCC)=O)[CH3:19]>>[C:1]([CH:4]([C:16]1[CH:21]=[CH:20][CH:18]=[CH:19][CH:17]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: CCC(CCCCCC1=CCCC1=O)C(=O)O
Product: O=C1CCC=C1CCCCCC(C(=O)O)c1ccccc1

Procedure:
This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-(6-carboxyoctyl)cyclopent-2-en-1-one by substituting diethyl phenylmalonate for diethyl ethylmalonate.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][CH:10]([C:12]1[N:17]=[N:16][C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[N:14][CH:13]=1)[CH3:11])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:16]2)=[C:10]([CH3:11])[N:9]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3sccc3Br)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4sccc4Br)n3n2)cc1
Yield: 22.7 %

Procedure:
Applying the Cyclization Procedure 1, using 3-bromo-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-thiophenecarboxamide (Intermediate 49) (159 mg, 0.37 mmol), 1,2-dichloroethane (7.3 mL) and phosphorus oxychloride (0.273 mL, 2.93 mmol), to afford 7-(3-bromo-2-thienyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (35 mg) as a yellow solid. MS m/z 416/418 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15](O)[CH:16]=2)[CH:11]=1.S(=O)(O)[O-].[Na+]>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[C:10]([OH:9])[CH:19]=[CH:18]3)=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: Oc1ccc2cc(O)ccc2c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Nc2ccc3cc(O)ccc3c2)cc1
Yield: 31.1 %

Procedure:
A mixture of 300 mg (2.75 mmol, Aldrich) of 4-aminophenol, 1.5 g (90%, 8.4 mmol, Aldrich) of 2,6-dihydroxynaphthalene and 1.0 g (9.6 mmol, Aldrich) of sodium bisulfite in 30 ml of H2O was refluxed for 18 hours. The reaction mixture was cooled, added to 30 ml of H2O and extracted with two 25 ml portions of ethyl aetate. The organic extracts were combined, dried (MgSO4), and concentrated in vacuo to give a solid. The crude solid was purified by flash chromatography (15×5.0 cm, 1:2 EtOAc/pet ether) followed by recrystallization (EtOAc/pet ether) to afford 215 mg (31%) of title compound as pale pink crystals, m.p. 195°-196°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41](OS(C(F)(F)F)(=O)=O)[CH:40]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:54])[CH2:38][C:39]1[CH:40]=[C:41]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[C:42]([Cl:45])=[CH:43][CH:44]=1)[CH3:35]
Reactant: CCOC(=O)Cc1ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (4-chloro-3-trifluoromethanesulfonyloxy-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:13]([OH:15])=O)[C:3]1=2.C(N(CC)CC)C.ClC(OCC)=O.[F:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32].Cl>CN(C)C=O>[F:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH:32][C:13]([C:4]1[C:3]2[C:2](=[O:1])[CH2:10][C:9]([CH3:11])([CH3:12])[CH2:8][C:7]=2[NH:6][CH:5]=1)=[O:15]
Reactant: CC1(C)CC(=O)c2c(C(=O)O)c[nH]c2C1
Reactant: Nc1ccccc1F
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)c2c(C(=O)Nc3ccccc3F)c[nH]c2C1
Reaction time: 0.75 h
Yield: 24.4 %

Procedure:
To a stirred solution of 4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (155 mg, 0.75 mmol) and triethylamine (209 μL, 1.5 mmol) in dimethylformamide (4 mL) at 0° C. was added ethyl chloroformate (143 μL, 1.5 mmol). After stirring an additional 45 minutes, 2-fluoroaniline (145 μL, 1.5 mmol) was added. The reaction mixture was stirred for 30 minutes, then poured into aqueous 3.6N hydrochloric acid and extracted 2× with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated it vacuo. To the residue was added aqueous 5N sodium hydroxide (5 mL) and ethyl alcohol (1 mL), and the mixture was heated at reflux for 30 minutes. After cooling in an ice water bath, the reaction mixture was acidified with hydrochloric acid, the precipitate was collected, rinsed with water, and dried to give 55 mg of N-(2-fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 2).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:9]([O:8][C:6](=[O:7])[C:5]1[CH:13]=[CH:14][C:2]([O:15][C:16]2[CH:23]=[CH:22][CH:21]=[C:18]([C:19]#[N:20])[CH:17]=2)=[CH:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2cccc(C#N)c2)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 24.6 %

Procedure:
To the solution of tert-butyl 4-fluorobenzoate (500 mg, 2.55 mmol) and 3-hydroxybenzonitrile (306 mg, 2.55 mmol) in N,N-dimethylformamide (80 mL) was added potassium carbonate (528 mg, 3.8 mmol), the mixture was stirred at 130° C. for 1 hour under microwave. Then evaporated the solvent purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=10:1) to give tert-butyl-4-(3-cyanophenoxy)benzoate (185 mg, 57%), as oil, 1H-NMR (300 MHz, CD3OD) δ 8.00 (m, 2H), 7.56 (m, 2H), 7.43 (m, 2H), 7.05 (m, 2H), 1.59 (s, 9H).
Reaction SMILES: [ClH:1].C([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH3:23])=[CH:15][CH:16]=2)[CH2:11]1)C1C=CC=CC=1>C(O)C.O.[Pd]>[ClH:1].[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH3:23])=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CCOC(=O)C(CC)Oc1ccc2c(c1)CC(NCc1ccccc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC)Oc1ccc2c(c1)CC(N)CC2

Procedure:
A solution of 2-benzylamino-7-(ethoxycarbonylpropan-3-yloxy) tetralin hydrochloride (14 g), prepared as described in Example 3, in a mixture of 95% ethanol (250 ml) and water (10 ml) is hydrogenated at atmospheric pressure and 60° C. in the presence of 10% Pd/C (2 g) as the hydrogenation catalyst. After 5 hours the catalyst is filtered off, the filtrate is concentrated to dryness and the residue is taken up in absolute ethanol (100 ml) and concentrated to dryness a few times. The obtained product is then triturated with acetone, filtered and crystallized from isopropanol affording 8.8 g of the compound of the title. M.p. 134°-136° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:28]>>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:28])=[O:2])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Yield: 65 %

Procedure:
The title compound is prepared in analogy to example 3 from N-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=65%. Colorless solid. MS: m/e=353.1 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1.[C:20](Cl)(=[O:22])[CH3:21]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:20](=[O:22])[CH3:21])[CH:9]=[C:10]2[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CCCNC(C)=O)c2c1
Reactant: CC(=O)Cl
Product: COc1ccc2cc(C(C)=O)cc(CCCNC(C)=O)c2c1

Procedure:
By reacting N-[3-(7-methoxy-1-naphthyl)propyl]acetamide obtained in Example 1 with acetyl chloride, the compound of the title is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[I:18]Cl>C(O)(=O)C>[F:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([I:18])[CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2nc3c(F)cccc3s2)cc1
Reactant: ClI
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc3c(F)cccc3s2)cc1I
Reaction time: 2 h

Procedure:
A solution of the 4-fluoro-2-(4′-aminophenyl)benzothiazole prepared as described in Example 3 (4.5 mmol) in acetic acid (20 ml) was added dropwise to a solution of iodine monochloride (5.8 mmol) in acetic acid (20 ml) at 25° C. The resulting solution was stirred for 2 hr, then the solvent was removed under vacuum. The residue was dissolved in chloroform (100 ml) and washed with aqueous sodium carbonate (50 ml), aqueous sodium thiosulfate (50 ml) and water (50 ml). Evaporation of the solvent, followed by column chromatography (chloroform) and recrystallization from methanol gave pale cream needles.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[CH:13][CH:12]=2)[N:3]=1.[Cl:22][C:23]1[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[C:28]([O:29][C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[CH:20][N:19]=[CH:18]4)=[CH:13][CH:12]=3)[N:3]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Oc1cccnc1Cl
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3ccnc3)cc2)n1
Product: COc1nc(Nc2ccc(-n3ccnc3)cc2)nc(Oc2cccnc2Cl)n1
Yield: 37 %

Procedure:
This compound was prepared in analogy to example 3 from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-(4-imidazol-1-yl-phenyl)-amine and 2-chloro-3-hydroxypyridine. The title compound was isolated as a colorless solid in 37% yield.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[NH:12][N:13]=C(C1C=CC=CC=1)C1C=CC=CC=1)#[N:2].S(=O)(=O)(O)O.[CH2:32](O)[CH2:33]C>>[NH2:2][C:1]1[C:3]2[O:7][C:6]([C:8]([O:10][CH2:11][CH2:32][CH3:33])=[O:9])=[CH:5][C:4]=2[NH:12][N:13]=1
Reactant: COC(=O)c1cc(NN=C(c2ccccc2)c2ccccc2)c(C#N)o1
Reactant: CCCO
Agent: O=S(=O)(O)O
Product: CCCOC(=O)c1cc2[nH]nc(N)c2o1
Reaction time: 4 h

Procedure:
To a solution of 56.01 g (0.1624 mol) of methyl 5-cyano-4-[2-(diphenylmethylene)hydrazino]-2-furoate in 1.12 L of n-propanol was slowly added 115 mL (2.1 mol) of 98% sulfuric acid. The resulting mixture was refluxed for 2 hours obtaining a clear brown solution. The reaction mass was concentrated under reduced pressure to a small volume, cooled to 0/+4° C. and slowly diluted with 1.1 L of 25% trisodium citrate dihydrate solution over a period of 90 min. under efficient stirring. The mixture (pH=4) was extracted three times with 600 mL of cyclohexane. The organic extracts were discarded while the aqueous layer was cooled to 0/+4° C. and brought to pH 6-7 by carefully adding 1 L of 10% aqueous sodium bicarbonate and, finally, 82 mL of N-methylmorpholine. The resulting suspension was aged for 4 hours at 0/+2° C. and then filtered and washed thoroughly with water affording, after drying, 21.35 g of product as light brown solid.