Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:17][CH2:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (31 mL) was added dropwise to a solution of 3-(4-methoxyphenyl)-1-propanol (50 g) and triethylamine (56 mL) in dichloromethane (800 mL) at 0° C. The resulting mixture was stirred overnight at room temperature. After washing with water, 2% hydrochloric acid and 4% aqueous sodium bicarbonate, the organic solution was dried over sodium sulfate and rotoevaporated to yield crude 3-(4-methoxyphenyl)-1-propyl methanesulfonate as a colourless solid (ca. 83 g). This product and sodium iodide (75 g) in acetone (800 mL) were heated at reflux in the dark for 20 hours. After cooling to room temperature, the reaction mixture was poured into n-hexane/EtOAc/water 1:1:1 (1.5 L) under stirring. The organic layer was washed with water, diluted aqueous sodium metabisulfite and 4% aqueous sodium bicarbonate, then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by passing it through a short pad of silica gel (eluting with n-hexane/EtOAc 95:5). The title compound was obtained as a pale yellow solid (75 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:31])[CH2:13][CH:14]2[C:19](=[O:20])[NH:18][CH:17]=[CH:16][N:15]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:5][CH:4]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[O:20]=[C:19]1[NH:18][CH:17]=[CH:16][N:15]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH:14]1[CH2:13][C:12]([NH:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:4][CH:5]=1)=[O:31]
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)NCCc2ccc(CCl)cc2)cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)NCCc2ccc(CN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-(4-chloromethyl-phenyl)-ethyl]-2-[3-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-pyrazin-2-yl]-acetamide (195 mg, 0.42 mmol) in CH2Cl2 (2 mL) was added piperidine (Aldrich, 0.13 mL, 1.3 mmol) at rt. The reaction mixture was stirred at rt overnight and then diluted with CH2Cl2 (50 mL). The organic solution was washed with saturated NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative TLC (7% MeOH—CH2Cl2) afforded the title compound. MS (ESI): 511 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]([CH3:39])=[C:35]([CH2:37]Cl)[N:36]=2)=[CH:28][CH:27]=1>O>[C:15]([O:14][C:12]([CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:37][C:35]3[N:36]=[C:32]([C:29]4[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=4)[O:33][C:34]=3[CH3:39])=[CH:3][CH:4]=2)[O:9][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)C1COc2cc(O)ccc2C1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1oc(-c2ccc(Br)cc2)nc1COc1ccc2c(c1)OCC(C(=O)OC(C)(C)C)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a stirred suspension of tert-butyl 7-hydroxychromane-3-carboxylate (1.1 g, 4.4 mmol) and potassium carbonate (1.1 g, 8 mmol), 2-(4-bromophenyl)-4-(chloromethyl)-5-methyl-1,3-oxazole (1.14 g, 4 mmol) was added and the reaction mixture was stirred at 60° C. for overnight. After the completion of the reaction, water (40 ml) was added and the precipitated product was extracted with ethylacetate (60 ml). The organic layer was washed with 50 ml of water twice and dried. The dried solution was evaporated to give the product as brown solid (1.55 g, 77.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:11]N1C(=O)CCC1=O.BrCC1C=CC2SC=CC=2C=1.CC1C=CC2SC=CC=2C=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2occc2c1
Agent: BrCc1ccc2sccc2c1
Agent: Cc1ccc2sccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2occc2c1

Procedure:
By brominating 5-methyl-benzo[b]furan[Synth. Commun. 19, 257(1989)] with N-bromosuccinimide in carbon tetrachloride in an analogous manner to the procedure for the preparation of 5-bromomethyl-benzo[b]thiophene [J. Med. Chem. 34(1), 65(1991)] from 5-methyl-benzo[b]thiophene there was obtained 5-bromomethyl-benzo[b]furan as a light yellow solid; MS: 210, 212 (M)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:10]=3[N:11](CC3C=CC(OC)=CC=3)[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)=[CH:4][CH:3]=1.[Br-].[Al+3].[Br-].[Br-]>C1(OC)C=CC=CC=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:10]=3[NH:11][C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccc4ccccc4c3)N=C(c3ccc(N)nc3)c3cc(Cl)ccc32)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: Nc1ccc(C2=NC(Cc3ccc4ccccc4c3)C(=O)Nc3ccc(Cl)cc32)cn1
Temperature: 80 °C
Yield: 41.8 %

Procedure:
5,7-Dichloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.10 g, 0.20 mmol) and 2-aminopyridine-5-boronic acid pinacol ester were reacted according to the corresponding procedure described in Example 12 to yield intermediate 5-(6-aminopyridin-3-yl)-7-chloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one. (77 mg, 69%). 5-(6-Aminopyridin-3-yl)-7-chloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (77 mg, 0.14 mmol) was dissolved in anhydrous anisole (2 mL) under a nitrogen atmosphere, and aluminum bromide (1M in dichloromethane, 0.70 mL, 0.70 mmol) was added. The mixture was heated to 80° C. for 1 hour then cooled to ambient temperature and an additional amount of aluminum bromide (1M in dichloromethane, 0.70 mL, 0.70 mmol) was added. The solution was heated to 80° C. for 1 hour, cooled, poured into ice, diluted with ethyl acetate and saturated sodium bicarbonate. The layers were separated and the organic layer dried with sodium sulfate, decanted and concentrated in the presence of silica gel. Column chromatography eluting with a gradient of 70-100% ethyl acetate in hexanes provided 5-(6-aminopyridin-3-yl)-7-chloro-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (25 mg, 42% yield). 1H NMR (300 MHz, d6-DMSO) δ 3.47 (m, 2H) 3.71 (m, 1H), 6.40-6.46 (m, 2H), 7.20-7.26 (m, 2H), 7.42-7.62 (m, 5H), 7.78-7.87 (m, 4H), 10.64 (s, 1H); ESI m/z measured 427.1324 [M+H]+. calculated 427.1326.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[N:9]1([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CN2CCCCC2)cc1
Reaction time: 18 h
Yield: 98.9 %

Procedure:
1-(4-Nitro-benzyl)-piperidine (0.089 g, 0.404 mmol) is dissolved in MeOH (5 mL), and to this solution is added 10% Pd/C (0.009 g, 0.404 mmol). The reaction mixture is stirred under an atmosphere of H2 for 18 h. The resulting mixture is filtered through celite, and the filtered catalyst is washed with excess EtOAc. The filtrate is concentrated under high vacuum to afford the product as a solid (0.076 g, 99%); 1H NMR (DMSO-d6) δ 1.29-1.40 (m, 2H), 1.40-1.51 (m, 4H), 2.17-2.30 (m, 4H), 3.18 (s, 2H), 4.88 (s, 2H), 6.46 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H); mass spectrum [(+) ESI], m/z 191 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:15][C@:14]([CH3:26])([O:16][CH2:17][P:18](=[O:25])([O:22]CC)[O:19]CC)[C@@H:13]([OH:27])[C@H:12]1[OH:28].N1C(C)=CC=CC=1C.C[Si](I)(C)C>C(#N)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:15][C@:14]([CH3:26])([O:16][CH2:17][P:18](=[O:19])([OH:22])[OH:25])[C@@H:13]([OH:27])[C@H:12]1[OH:28]
Reactant: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)OCC
Agent: C[Si](C)(C)I
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: C[C@]1(OCP(=O)(O)O)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 397.9 %

Procedure:
To a solution of compound 31.4 (20 mg, 0.048 mmol) in acetonitrile (2 mL) was added 2,6-lutidine (0.034 mL, 0.29 mmol) and then trimethylsilyl iodide (0.068 mL, 0.48 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was done, 0.08 mL of 2,6-lutidine was added to the mixture and the mixture was concentrated under reduced pressure. The residue was then put into solution with water (2 mL) and treated with sodium hydroxide 1N to pH=10. The solution was then acidify to pH=3 using acetic acid and subjected to a reverse phase (YMC-Pack ODS-A) to give compound 31.5 (69 mg, 72% yield). 1H NMR (300 MHz, D2O): δ 1.42 (s, 3H), 3.33 (t, 1H, J=10.7), 3.51 (t, 1H, J=11.9), 4.12 (d, 1H, J=4.6), 5.18 (m, 1H), 6.10 (d, 1H, J=7.1), 8.24 (s, 1H), 8.55 (s, 1H). LRMS (ESI) MH+ C11H16N5O7P requires 362.3. Found 361.9.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](F)=[C:22]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:21]=1.[Cl-].[NH4+]>CN(C=O)C.CCOC(C)=O>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([O:3][CH2:4][CH2:5][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)=[C:22]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CS(=O)(=O)c1cc(Br)ccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(Br)cc2S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
After 60% sodium hydride (17 mg) was added to a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (109 mg) in DMF (2 mL) at 0° C. in a nitrogen atmosphere, the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was cooled to 0° C., 4-bromo-1-fluoro-2-(methylsulfonyl)benzene (100 mg) was added thereto. The reaction mixture was stirred at 0° C. for 30 minutes, and stirred at room temperature for 3 hours. After a saturated aqueous ammonium chloride solution was added to the reaction mixture, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=80:20 to 55:45), whereby tert-butyl 4-{2-[4-bromo-2-(methylsulfonyl)phenoxy]ethyl}piperidine-1-carboxylate (169 mg) was obtained as a colorless liquid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]1[CH2:19][C@H:18]2[C@H:16]([CH2:17]2)[CH2:15][N:14]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].NN>CCO>[NH2:3][CH2:12][C@@H:13]1[CH2:19][C@H:18]2[C@H:16]([CH2:17]2)[CH2:15][N:14]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@H]2C[C@H]1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H]2C[C@H]2C[C@H]1CN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-dimethylethyl (1S,4S,6S)-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-azabicyclo[4.1.0]heptane-3-carboxylate D28 (1.8 g) was dissolved in EtOH (8 ml) then hydrazine (2.476 ml, 50.5 mmol) was carefully added and the reaction stirred at room temperature for 2 hours. All volatiles were removed under vacuum and the solid residue was purified by SCX chromatography (column size 20 g using MeOH 100% to MeOH/NH3 2M). The product recovered showed a low purity so it was purified again by silica —NH chromatography (Biotage SP—column size 28 g using EtOAc 100% as eluent). It was recovered the title compound D29 (793 mg). UPLC: (Acid Final_QC): rt=0.46 minutes, peaks observed: 227 (M+1). C12H22N2O2 requires 226. 1H NMR (400 MHz, CDCl3) δ ppm 4.41 (br. s., 1 H) 3.66 (br. s., 1 H) 2.90-2.65 (m, 2 H) 2.42-2.17 (m, 2 H) 1.60-1.40 (m, 11 H) 1.21-1.08 (m, 1 H) 1.06-0.84 (m, 2 H) 0.81-0.68 (m, 1 H) 0.30-0.04 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>>[C:25]([CH2:24][CH2:23][N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:21])[N:7]2[C:14]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CCCl
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1cc(Cl)c(Cl)cc13
Product: COC(=O)CCn1c2cc(Cl)c(Cl)cc2n2c(=O)c3ccc(C)cc3nc12

Procedure:
6-(Carbomethoxyethyl)-3-methyl-8,9-dichlorobenzimidazo-[2,1-b]quinazolin-12(6H)one is prepared with 3-methyl-8,9-dichlorobenzimidazo[2,1-b]quinazolin-12(6H)one and methyl 3-chloropropionate.
Reaction SMILES: [O-2].[O-2].[O-2].[O-2].[O-2].[V+5:6].[V+5].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10]>[O-2].[O-2].[O-2].[K+].[Nb+5].O>[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6]
Reactant: O=C(O)C(=O)O
Agent: [Nb+5]
Agent: [V+5]
Agent: [K+]
Solvent: O
Product: O=C([O-])C(=O)[O-]
Temperature: 1300 °C

Procedure:
Granulated alumina (8 - 16 mesh) is heated at 1300°C. for 4 hours. Potassium niobate (4K2O.3Nb2O5.16H2O) and vanadium pentoxide are suspended in 5 parts of water, heated to 80°C., and oxalic acid is added slowly to obtain a blue-colored vanadium oxalate solution. Sodium carbonate is added and the alumina is also placed in the solution. The mixture is dried over a water bath with agitation. While air is pumped in, it is indurated in a furnace at 400°C. for 16 hours to obtain the catalyst ready for use after cooling.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[OH:18][CH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>COCCOC.O.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]>[OH:18][CH2:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2ccc(-c3cccc(CO)c3)cc2cn1)C1CC1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 9 %

Procedure:
A mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (100 mg, 0.35 mmol), 3-(hydroxyl-methyl)phenylboronic acid (0.53 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg, 0.035 mmol) and cesium carbonate (228 mg, 0.70 mmol) in 1,2-dimethoxyethane/water (10:1, 2.0 mL) was stirred under microwave irradiation at 130° C. for 20 minutes under nitrogen. Ethyl acetate (10 mL) was added to the reaction mixture and it was filtered. The residue was extracted with ethyl acetate (5.0 mL×3). The organic layer was combined, dried with sodium sulfate, filtered and concentrated. It was purified by column chromatography to give the product (10 mg, 13%). LCMS (ESI): RT (min)=1.062, M+H+=318.2, method=A. 1H NMR (400 MHz, CDCl3) δ 10.91 (s, 1H), 9.18 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 8.01 (dd, J=1.6, 8.8 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.73 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.46 (t, J=6.8 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 5.29 (t, J=5.6 Hz, 1H), 4.58 (d, J=6.0 Hz, 2H), 2.07-2.04 (m, 1H), 0.83-0.79 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([N+:14]([O-])=O)[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[NH2:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]2[O:3][C:2]([CH3:1])([CH3:17])[C:6](=[O:7])[C:5]=2[CH:8]=1
Reactant: Cc1c([N+](=O)[O-])cc2c(c1C)OC(C)(C)C2=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1c(N)cc2c(c1C)OC(C)(C)C2=O
Yield: 92 %

Procedure:
A mixture of 2,2,6,7-tetramethyl-5-nitro-1-benzofuran-3(2H)-one obtained in Reference Example 46 (5.0 g, 21.3 mmol), 10%-palladium carbon (50% hydrous, 500 mg) and ammonium formate (7.06 g, 85.0 mmol) in methanol (100 mL) was heated under reflux for two hours. The solid material was removed and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The solvent was distilled off under reduced pressure to obtain a residue, which was crystallized with ethyl acetate-hexane to obtain 4.0 g (yield 92%) of the title compound. Melting point: 149-150° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:49]=[CH:50][CH:51]=1)[O:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]3[CH2:48][CH2:47]3)=[O:45])[N:42]=2)[N:39]=1>CN(C)C=O.CN1CCCC1=O>[CH:46]1([C:44]([NH:43][C:41]2[N:42]=[C:37]3[CH:36]=[CH:35][C:34]([O:33][C:32]4[CH:31]=[C:30]([NH:29][C:6](=[O:8])[C:5]5[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=5)[CH:51]=[CH:50][CH:49]=4)=[N:39][N:38]3[CH:40]=2)=[O:45])[CH2:47][CH2:48]1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 31 %

Procedure:
Using 3,5-bis(trifluoromethyl)benzoic acid (120 mg, 0.45 mmol), oxalyl chloride (48 μL, 0.56 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (120 mg, 0.37 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (63 mg, 31%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[S:22][C:5]2[NH:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[CH3:23]N(C)CCN(C)C.C([Li])CCC.CI>O1CCCC1.O>[CH3:1][C:2]1[S:22][C:5]2[N:6]([CH3:23])[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(s1)N(C)c1ccccc1N=C2N1CCN(C)CC1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (3.1 g) (European Patent Publication 0 454 436) in dry tetrahydrofuran (distillated from sodium/benzophenone) was stirred and cooled to -70° C. Tetramethylethylenediamine (1.16 g) was added followed by n-butyllithium (6.25 ml, 0.6M solution), keeping the temperature below -60° C. The deep red solution was stirred for 15 minutes and then methyl iodide (1.42 g) was added. The reaction was allowed to attain room temperature, during which time the red colour discharged. Water was added and the product extracted with ethyl acetate. The solvent was washed with water, dried and evaporated to dryness under reduced pressure. The product was purified by chromatography on Florisil using ethyl acetate as eluent and crystallised from acetronitrile to give the title compound, m.p. 126-128° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:25][C:26]1([CH3:51])[C:35]([CH3:36])=[CH:34][C:33]2[N:32]=[CH:31][N:30]=[C:29]([N:37]3[CH2:43][C:42]4[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:41]=4[O:40][CH2:39][CH2:38]3)[C:28]=2[CH2:27]1>>[NH2:16][C@@H:13]1[CH2:14][CH2:15][N:11]([S:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:45]3[CH:46]=[CH:47][C:41]4[O:40][CH2:39][CH2:38][N:37]([C:29]5[C:28]6[CH2:27][C:26]([CH3:25])([CH3:51])[C:35]([CH3:36])=[CH:34][C:33]=6[N:32]=[CH:31][N:30]=5)[CH2:43][C:42]=4[CH:44]=3)[CH:6]=2)(=[O:9])=[O:10])[CH2:12]1
Reactant: CC1=Cc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2CC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Product: CC1=Cc2ncnc(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)N6CC[C@@H](N)C6)c5)cc4C3)c2CC1(C)C

Procedure:
Prepared as in example 5 using (R)-tert-butyl 1-(2-amino-5-bromopyridin-3-ylsulfonyl)pyrrolidin-3-ylcarbamate (reagent preparation 25) and [4-(6,6,7-trimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1 and BOC group deprotection. 1H NMR (400 MHz, d6-DMSO) δ 8.54 (s, 1H), 8.37 (s, 1H), 8.01 (d, 1H), 7.57 (d, 1H), 7.48 (dd, 1H), 7.02 (d, 1H), 6.76 (s, 2H), 6.13 (d, 1H), 4.62 (s, 2H), 4.33 (s, 2H), 3.84 (s, 2H), 3.44-3.20 (m, 3H), 2.89 (d, 1H), 2.69 (s, 2H), 1.88 (d, 5H), 1.53 (s, 1H), 0.92 (s, 6H); MS (ES) for C29H35N7O3S: 562.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13](OS(C(F)(F)F)(=O)=O)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:29][CH2:30][C:31]1[O:35][C:34](=[O:36])[NH:33][N:32]=1.C(NC(C)C)(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([NH:29][CH2:30][C:31]3[O:35][C:34](=[O:36])[NH:33][N:32]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)cc1OC
Reactant: NCc1n[nH]c(=O)o1
Solvent: CC(=O)N(C)C
Solvent: CC(C)NC(C)C
Product: COc1ccc(-c2cc3ncccc3c(NCc3n[nH]c(=O)o3)n2)cc1OC
Temperature: 70 °C

Procedure:
97 mg Trifluoromethanesulfonic acid 7-(3,4-dimethoxy-phenyl)-[1,6]naphthyridine-5-yl ester (6.2), 30 mg 5-aminomethyl-3H-[1,3,4]oxadiazole-2-one (2.33) and 0.132 mL N,N-diisopropylamine were placed in dimethylacetamide at ambient temperature. The reaction was heated to 70° C. overnight. After this time the reaction was cooled to ambient temperature and additional 0.132 mL N,N-diisopropylamine were added. The reaction was heated to 90° C. for 6 h. After this time, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted with additional ethyl acetate (×3) and the combined organic fractions were dried over sodium sulfate, filtered and the solvent was concentrated from the filtrate under reduced pressure. Purification by and then by silica gel chromatography (ethyl acetate/methanol: 100:0 to 95:5) provided the title compound.