Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:27](O)[CH3:28].Cl>>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH2:27][CH3:28])=[O:15])=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)NCC(O)COc1ccc(C(=O)O)cc1-c1ccc(=O)[nH]n1
Agent: Cl
Product: CCOC(=O)c1ccc(OCC(O)CNC(C)(C)C)c(-c2ccc(=O)[nH]n2)c1

Procedure:
4-(3-t-Butylamino-2-hydroxypropoxy)-3-(1,6-dihydro-6-oxo-3-pyridazinyl)benzoic acid was esterified with ethanol-hyrogen chloride to give ethyl 4-(3-t-butylamino-2-hydroxypropoxy)-3(1,6-dihydro-6-oxo-3-pyridazinyl)benzoate.
Reaction SMILES: O[C@H:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@@H:3]1[C:14]([O:16][CH3:17])=[O:15]>[Pd].CO>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][CH2:4][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:2]2
Reactant: COC(=O)[C@H]1CCc2c(OC)cccc2[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1CCc2c(cccc2OC)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 80.2 %

Procedure:
A mixture of (1R,2S)-methyl [1-hydroxy-5-methoxy-1,2,3,4-tetrahydro-2-naphthyl]formate (2.22 g) and 10% palladium on carbon in methanol (50 ml) was stirred under hydrogen (2-3 atm) at room temperature for 22 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give (S)-methyl (5-methoxy-1,2,3,4-tetrahydro-2-naphthyl)formate as a colorless oil (1.66 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[C]=O.[H][H]>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [H][H]
Agent: [Ru]
Agent: [C-]#[O+]
Agent: [C]=O
Solvent: O=[N+]([O-])c1ccccc1
Product: Nc1ccccc1
Temperature: 160 °C

Procedure:
12.3 g (0.100 mole nitrobenzene) in 75 ml of methanolic solution and 0.128 g Ru3 (CO)12 (600 microgram-atoms ruthenium) were placed in the reactor vessel. The gas volume in the vessel was replaced with carbon monoxide and then pressurized at ambient temperature with 920 psig carbon monoxide and 80 psig hydrogen (approximately 0.05 mole hydrogen). The reactor contents were then heated to 160° C. Initially, aniline was produced from nitrobenzene in 100 percent selectivity. After approximately 0.030 moles aniline had been produced, phenyl urethane production also began. After a total of 7.5 hours at 160° C., nitrobenzene conversion was complete and the solution contained 0.060 moles aniline and 0.034 moles phenyl urethane. This example demonstrates that the primary amine may be provided by reduction of the nitrogen-containing organic compound, e.g. nitrobenzene, in-situ. Note that, once the added hydrogen is utilized to reduce the nitrobenzene to aniline, the selectivity of the conversion of the remaining nitrobenzene to the urethane is greater than 50 percent.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[N:4](COCC[Si](C)(C)C)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]2[CH2:32][CH2:31][CH2:30]2)[CH:21]=1.ClC1C2C(=O)NN=CC=2N(COCC[Si](C)(C)C)C=1C1C=CC(OC(F)F)=C(OC2CCC2)C=1>>[Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[NH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]2[CH2:30][CH2:31][CH2:32]2)[CH:21]=1
Reactant: COc1ccc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OC1CCC1
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)c(Cl)c2c(=O)[nH]ncc21
Product: COc1ccc(-c2[nH]c3cn[nH]c(=O)c3c2Cl)cc1OC1CCC1
Yield: 84.3 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 32-(b) except for using 335 mg (0.70 mmol) of 3-chloro-2-(3-cyclobutoxy-4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Example 45-(a) in place of 3-chloro-2-(3-cyclobutoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 204 mg of the title compound was obtained as a white solid. (Yield: 84%)
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:22])[NH:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: CN(C)C(=O)c1ccc(N)cc1
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.1 %

Procedure:
To a solution of 4-amino-N,N-dimethyl-benzamide (3.5 g, 0.0213 mol), TEA (2.15 g, 0.0213 mol) in DCM (50 mL) was added 4-bromophenyl isocyanate (5.07 g, 0.0256 mol). The reaction mixture was stirred at room temperature for 12 h. The white solid was obtained and was filtered and dried to afford the title compound [6.8 g, 88%]; LC-MS (ESI): Calculated mass: 361.0; Observed mass: 362.0 [M+H]+ (RT: 0.17 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:26]1[N:34]2[C:29]([C:30]([NH2:35])=[N:31][CH:32]=[N:33]2)=[CH:28][CH:27]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:26]2[N:34]3[C:29]([C:30]([NH2:35])=[N:31][CH:32]=[N:33]3)=[CH:28][CH:27]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Nc1ncnn2c(Br)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccc3c(N)ncnn23)c1
Temperature: 80 °C

Procedure:
To a solution of [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-carbamic acid tert-butyl ester (7 g, 21 mmol) in DME (100 mL), 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (2.5 g, 11.7 mmol), PdCl2(dppf) complexed with CH2Cl2 (850 mg, 1.2 mmol) and 2 N Na2CO3 (12 mL) were added. The mixture was degassed for 20 min and was then heated to 80° C. for 23 hours. After cooling, the mixture was partitioned between EtOAc and H2O, and the organic layer was separated and dried. Biotage® chromatography (50-100% EtOAc) provided the title product as off white solid 2.6 g (76%). 1H NMR (300 MHz, DMSO-d6) δ 7.80-7.50 (m, 6 H), 7.20-7.0 (m, 3 H), 4.80 (s, 2 H), 1.30 (s, 9 H); ES-MS m/z 339 [M+H]+, HPLC RT (min) 2.41.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][N:26]5C(=O)C6C(=CC=CC=6)C5=O)[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:26][CH2:25][C:21]1[CH:20]=[C:19]([O:18][C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([NH:8][CH2:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[O:10][C:11]=3[CH:17]=2)[CH:24]=[CH:23][N:22]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 2-((4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridin-2-yl)methyl)isoindoline-1,3-dione (6.2 mg, 0.013 mmol, 1 eq) was dissolved in 0.5 mL of ethanol. And then hydrazine monohydrate (6.4 mg, 0.13 mmol, 10 eq) was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. And then the solvents were removed. The crude product was purified by reverse phase prep HPLC to give the title compound. MH+=353.0.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[O:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>CS(C)=O>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([NH:35][CH:32]5[CH2:33][CH2:34][O:29][CH2:30][CH2:31]5)[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(F)n1
Reactant: NC1CCOCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(NC2CCOCC2)n1
Temperature: 160 °C
Yield: 46.7 %

Procedure:
6-Fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (100 mg, 0.27 mmol) and tetrahydro-2H-pyran-4-amine (55 mg, 0.54 mmol) were dissolved in DMSO (1.5 ml) in a microwave vial. DIPEA (0.282 ml) was added and the mixture was heated at 160° C. for 3 h under microwave irradiation. The reaction mixture was concentrated under a stream of nitrogen and redissolved in methanol. This solution was loaded onto a 2 g aminopropyl column, which was been preconditioned with methanol. The column was eluted with methanol (2 column volumes) and the desired fraction was blown to dryness under nitrogen. The sample was then purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound (57 mg) as a white solid.
Reaction SMILES: [C:1]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:3]([CH3:4])[CH2:2][C:1]([N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])=[O:5])=[CH:16][CH:15]=1
Reactant: C/C=C/C(=O)N1CCOC1=O
Reactant: COc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(C)CC(=O)N2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a solution of Pd((R)-binap)(OH2)2(OTf)2 (26.6 mg, 0.025 mmol) in toluene (3 ml) were added 3-crotonoyl-1,3-oxazolidin-2-one (155 mg, 1.0 mmol) and anisidine (148 mg, 1.2 mmol). After the resulting mixture was stirred at room temperature for 3 hours, the reaction solution was concentrated and purified by a silica gel column chromatography (hexane:ethyl acetate=4:1) to give the objective 3-[3-(4-methoxyphenylamino)butyryl]-1,3-oxazolidin-2-one (228 mg, 82% yield).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=[O:13])[C:6]=2[CH:5]=[CH:4]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:14]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=[O:13])[C:6]=2[CH:5]=[CH:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=Cc1cccc2c1ccn2Cc1ccccc1
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
Sodium hydride (95%; 0.37 g) was suspended in 10 ml of dimethylformamide and cooled to a temperature ranging from 0° to 5° C. with stirring, under an argon gas atmosphere. To the resulting mixed liquid, there was dropwise added a solution of 2.00 g of indole-4-carbaldehyde in 5 ml of dimethylformamide over 15 minutes. After completion of the dropwise addition, the mixture was stirred at a temperature ranging from 0° to 5° C. for 30 minutes. To the reaction solution, there was added a solution of 2.47 g of benzyl bromide in 5 ml of dimethylformamide, followed by stirring at room temperature for 2 hours. The reaction solution was poured into 200 ml of a 10% ammonium chloride aqueous solution, followed by extraction with ethyl acetate (200 ml×2). After washing the extract with a saturated common salt solution, it was dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure to give 3.18 g of 1-benzylindole-4-carbaldehyde as brown crystals. The yield thereof was found to be 98%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:21](=[O:30])[CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:21](=[O:30])[CH:20]=1
Reactant: NCc1ccn(-c2ccsc2)c(=O)c1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccn(-c2ccsc2)c(=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (97 mg, 0.30 mmol), 4-aminomethyl-1-thiophen-3-yl-1H-pyridin-2-one (61 mg, 0.30 mmol), and triethylamine (77 μL, 0.59 mmol) in N,N-dimethylformamide (2 mL) is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure, and the residue is triturated with acetonitrile to provide (4Z)-6-iodo-4-[({[2-oxo-1-(3-thienyl)-1,2-dihydropyridin-4-yl]methyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione as a mauve powder (65 mg, 43%).
Reaction SMILES: [NH2:1]/[C:2](/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[N:3]\[NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=O>C(O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[NH:3][N:4]=[C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[N:1]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N/N=C(\N)c2ccccn2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c(-c3ccccn3)n2)CC1
Temperature: 150 °C

Procedure:
Tert-butyl 4-({(2Z)-2-[amino(pyridin-2-yl)methylidene]hydrazinyl}carbonyl)piperidine-1-carboxylate 45 g (129 mM) obtained in step II is melted at 220° C. under nitrogen atmosphere for 1 hr. Reaction is then cooled to 150° C. and added ethanol till solid get dissolved. Ethanol is then evapourated to get desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O.C(COC)OC>C(O)C>[Cl:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]2[N:3]([CH:14]=[C:12]([CH2:11][Cl:10])[N:1]=2)[CH:4]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: O=C(CCl)CCl
Solvent: COCCOC
Solvent: CCO
Product: ClCc1cn2cc(Cl)cc(Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 2-amino-3,5-dichloropyridine (Aldrich; 5.12 g), 1,3-dichloroacetone (Aldrich; 4.68 g), and dimethoxyethane (28 mL) is stirred overnight at room temperature. Ethanol (28 mL) is then added and the mixture is refluxed for 7.5 h and then stirred overnight at room temperature. The mixture is then refluxed for an additional 24 h and is then concentrated under reduced pressure and partitioned between saturated aq. sodium bicarbonate and dichloromethane. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is adsorbed to silica gel and chromatographed on silica gel using ethyl acetate/chloroform (10/90), followed by a second chromatography of the combined product fractions using methanol/dichloromethane (2/98), to give 2.22 g of 6,8-dichloro-2-(chloromethyl)imidazo[1,2-a]pyridine in three crops after crystallization from methanol/dichloromethane; mp 162-163° C.; MS m/z 234, 236, 238; IR (mineral oil) 994, 808, 861, 1522, 3056 cm-1, 1H NMR (CDCl3) δ 4.79, 7.69, 8.10.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:25])[C:11]([CH3:24])=[CH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[NH2:23])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:26](N(CC)CC)C.S(OC)(OC)(=O)=O>CCOCC>[CH2:1]([NH:9][C:10](=[O:25])[C:11]([CH3:24])=[CH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[NH:23][CH3:26])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Reactant: CCN(CC)CC
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: CNc1cc(OC)c(OC)cc1C=C(C)C(=O)NCCc1ccccc1
Reaction time: 2 h
Yield: 35.9 %

Procedure:
To a nonaqueous ether solution of 3.00 g (8.81 mmol) (E) 3-(2-amino-4,5-dimethoxyphenyl)-2-methyl-2-propenoic acid phenethyl amide and 1.34 ml (9.69 mmol) of triethylamine (manufactured by Wako Pure Chemical Industries, Ltd.), 0.92 ml (9.69 mmol) of dimethyl sulfate (manufactured by Wako Pure Chemical Industries, Ltd.) was slowly added dropwise. Thereafter, reflux was carried out for 2 hours at 34° C. to 35° C. After the completion of the reaction, the solvent was evaporated, and the resulting residue was dissolved in ethyl acetate. Thus obtained ethyl acetate layer was washed with water and was dried with sodium sulfate. The dried solution was concentrated under a reduced pressure, and the resulting crude product was refined by an aminopropyl-modified type silica gel column chromatography (n-hexane/ethyl acetate=1/1), whereby 1.12 g of the aimed compound was obtained as a yellowish crystal (yield: 35.9%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:11]N1C(=O)CCC1=O>CC(C)=O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Product: Brc1cnc2[nH]cc(I)c2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-Bromo-5H-pyrrolo[2,3-b]pyrazine (258 mg, 1.3 mmol) in acetone (5 ml) was added N-iodosuccinimide (324 mg, 1.44 mmol) in one portion. The reaction mixture was stirred at room temperature for 45 minutes. The resulting precipitate was filtered off, washed with a minimal amount of acetone, and dried in vacuum to give the title compound as a light brown solid 1H-NMR (500 MHz, d6-DMSO) δ 12.81 (s br, 1H), 8.40 (s, 1H), 8.19 (d, 3.0 Hz, 1H). MS: m/z 323.8/325.8 [MH+].
Reaction SMILES: Cl[C:2]1[N:3]2[C:7]([N:8]=[C:9]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11][C:10]=13)=[CH:6][CH:5]=[N:4]2.[NH:17]1[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]1.CCN(C(C)C)C(C)C>C(O)C>[CH3:16][N:13]1[CH2:12][CH2:11][C:10]2=[C:2]([N:17]3[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]3)[N:3]3[C:7]([N:8]=[C:9]2[CH2:15][CH2:14]1)=[CH:6][CH:5]=[N:4]3
Reactant: CN1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: O=C(O)C1CNC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Temperature: 75 °C

Procedure:
To 1.77 g (7.48 mmol) 10-Chloro-7-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene in 50 mL ethanol was added 0.83 g (8.22 mmol) 3-azetidinecarboxylic acid and 2.75 mL (15.7 mmol) DIPEA and the reaction mixture was heated at 75° C. for 4 hours. The mixture was concentrated and treated with diethyl ether and methanol. After ultrasound irradiation, a precipitate formed which was collected by filtration. The remaining solution was concentrated and the above mentioned procedure was repeated. The precipitates were combined and dried to yield the desired product as the DIPEA-salt.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[NH:26])[CH:17]=[CH:18][C:19]=1[F:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:27][C:25](=[NH:26])[CH2:24][O:23][CH2:22][CH2:21][C:16]1[CH:17]=[CH:18][C:19]([F:20])=[C:14]([Cl:13])[CH:15]=1)=[O:6]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: N=C(N)COCCc1ccc(F)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1ccc(F)c(Cl)c1)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-[2-(3-chloro-4-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride in the presence of TBTU and DIPEA to give 2,5-dichloro-N-{2-[2-(3-chloro-4-fluoro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as orange oil. MS: m/e=404.2 [M+H+].
Reaction SMILES: Cl[C:2]1[C:11](C(C(=CN(C)C)C(OCC)=O)=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6](Cl)=[C:7](F)[CH:8]=2)[N:3]=1.C1([NH2:29])CC1>ClC(Cl)Cl>[CH2:10]1[CH2:11][CH2:2][N:3]2[C:7](=[N:29][CH2:6][CH2:5][CH2:4]2)[CH2:8][CH2:9]1
Reactant: NC1CC1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Solvent: ClC(Cl)Cl
Product: C1CCC2=NCCCN2CC1
Yield: 122.8 %

Procedure:
A solution of 20.6 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate and 6 g of cyclopropylamine in 100 cm3 of trichloromethane is stirred at a temperature close to 20° C. for 24 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. The residue is taken up in 180 cm3 of ethanol and 10 g of DBU and the solution obtained is heated at a temperature close to 78° C. for 4 hours. After cooling to a temperature close to 20° C., the precipitate obtained is drained and washed with twice 60 cm3 of ethanol. 13.65 g of 8-chloro-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a pale yellow solid melting at 256° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[CH:15][C:16]([CH2:32][CH3:33])=[C:17]([CH:19]2[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[C:22](=[O:28])[C:21]([CH3:30])([CH3:29])[C:20]2=[O:31])[CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Na].[Na].[Na].S(C1C=C(P(C2C=CC=C(S(O)(=O)=O)C=2)C2C=CC=C(S(O)(=O)=O)C=2)C=CC=1)(O)(=O)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH2:32][CH3:33])=[C:17]([CH:19]2[C:20](=[O:31])[C:21]([CH3:29])([CH3:30])[C:22](=[O:28])[C:23]([CH3:27])([CH3:26])[C:24]2=[O:25])[CH:18]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 37.4 %

Procedure:
To a microwave vial is added palladium(II) acetate (1.1 mg, 0.0049 mmol), tris(3-sulfophenyl)phosphine trisodium salt (5.1 mg, 0.0099 mmol), 2,4-dichlorophenylboronic acid (0.099 g, 0.5 mmol), 6-(5-bromo-2-ethylphenyl)-2,2,4,4-tetramethylcyclohexane-1,3,5-trione (0.19 g, 0.5 mmol) and potassium phosphate (0.53 g, 2.5 mmol). Degassed water (0.75 ml) is next added (washing-down any solids from the slides of the vial), followed by stirring for 5 minutes and flushing with argon. This mixture is then heated at 160° C. under microwave irradiation for 15 minutes. A further quantity of 2,4-dichlorophenylboronic acid (0.099 g, 0.5 mmol) and potassium phosphate (0.095 g, 0.5 mmol) are added, the reaction mixture again blanketed under an atmosphere of argon, and the mixture is heated at 160° C. for a further 15 minutes. After cooling to room temperature the reaction mixture is diluted with dichloromethane (5 ml) and acidified with 2M aqueous hydrochloric acid. The organic phase is separated, dried over anhydrous magnesium sulfate, and filtered through a plug of silica gel. The filtrate is concentrated under reduced pressure and the residue is dissolved in N,N-dimethylformamide (approximately 1 ml) and purified by preparative reverse phase HPLC to afford 6-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,4,4-tetramethyl-cyclohexane-1,3,5-trione as a colourless oil (80.6 mg).