Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:10]([NH:12][C@@H:13]1[C:16](=[O:17])[N:15]2[C:18]([C:27]([OH:29])=[O:28])=[C:19]([CH2:22][O:23][C:24]([NH2:26])=[O:25])[CH2:20][S:21][C@H:14]12)=[O:11])/[C:5]1[O:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:37]([O:39][C:40](=[O:46])[C:41]([O:44][CH3:45])([CH3:43])[CH3:42])[CH3:38]>CN(C)C=O>[C:24]([O:23][CH2:22][C:19]1[CH2:20][S:21][C@@H:14]2[C@H:13]([NH:12][C:10](=[O:11])/[C:4](=[N:3]\[O:2][CH3:1])/[C:5]3[O:9][CH:8]=[CH:7][CH:6]=3)[C:16](=[O:17])[N:15]2[C:18]=1[C:27]([O:29][CH:37]([O:39][C:40](=[O:46])[C:41]([O:44][CH3:45])([CH3:43])[CH3:42])[CH3:38])=[O:28])(=[O:25])[NH2:26]
Reactant: COC(C)(C)C(=O)OC(C)Br
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(=O)C(C)(C)OC)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 1 h
Yield: 38.7 %

Procedure:
Cefuroxime (4.24 g) and powdered potassium carbonate (0.690 g) were stirred in anhydrous N,N-dimethylformamide (40 ml) till a solution was obtained. The solution was cooled to -3°, 2-methoxy-2-methylpropanoic acid 1-bromoethyl ester (2.50 g) was added and the solution was stirred for 1 hour. It was then partitioned between 2N hydrochloric acid (100 ml) and ethyl acetate (200 ml and 100 ml) and the combined organic layers were washed sequentially with 100 ml each of 2N hydrochloric acid (2×), water, saturated aqueous sodium bicarbonate, water (2×) and saturated brine, dried over magnesium sulphate and concentrated under reduced pressure to ca 20 ml. The solution was added slowly to petroleum ether (200 ml) and the resulting precipitate was filtered off, washed with petroleum ether and dried under vacuum to give the title ester (2.20 g); λmax (ethanol) 277.5 nm E11 342; νmax (CHBr3) 3520 and 3400 (NH and NH2), 1788 (β-lactam C=O), 1750 (ester C=O), 1732 (αβ unsaturated ester and carbamate C=O), and 1688 and 1514 cm-1 (amide C=O).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][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:4].[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23](O)=[O:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>C(Cl)Cl>[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23]([NH:1][CH2:2][C:3]([NH:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]1)=[O:4])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CN)CC1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)c2cc(Cl)ccc2N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A solution of 4-{(glycylamino)methyl}-1-(tert-butoxycarbonyl)piperidine (1.33 g, 4.90 mmol) in CH2Cl2 (25 mL) was treated with EtN (0.75 mL, 5.4 mmol), 2-amino-5-chlorobenzoic acid (840 mg, 4.9 mmol), EDCI (940 mg, 4.9 mmol) and HOBt (660 mg, 4.9 mmol). After the reaction mixture was stirred at room temperature for 3 h, 2 N aqueous NaOH solution (20 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, ethyl acetate) afforded the desired 4-[{(N-(2-amino-5-chlorobenzoyl)glycyl)amino}methyl]-1-(tert-butoxycarbonyl)piperidine (1.63 g, 78%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[NH:13])[O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[N:6][CH:7]=1.[NH2:14][C:15]#N>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[N:13][C:15]#[N:14])[O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[N:6][CH:7]=1
Reactant: N#CN
Reactant: CCCOC(=N)c1cncc(N)c1
Solvent: CC#N
Product: CCCOC(=NC#N)c1cncc(N)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.6 %

Procedure:
The propyl 5-amino-3-pyridinecarboximidate (110 mg, 0.6 mmol) was then dissolved in acetonitrile (1 ml), and an aqueous solution (2 ml) of NaH2PO4 ·2H2O(375 mg, 2.4 mmol), Na2HPO4 (85 mg, 0.6 mmol) and NH2CN (50 mg, 1.2 mmol) was added to the solution. The mixture was stirred at room temperature for 19 hours. After the completion of the reaction, the reaction mixture was extracted with chloroform (20 ml×3), and the chloroform layer was dried over- anhydrous sodium sulfate and concentrated under reduced pressure to give a crude oil of propyl 5-amino-N-cyano-3-pyridinecarboximidate (100 mg, yield 82%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.[OH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=O>>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][OH:28])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: O=CCCCCO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 50 mg (0.08 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 8 mg (0.08 mmol) of 5-hydroxypentanal.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][CH2:13][CH:14]3[CH2:18][O:17]C(C)(C)[O:15]3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[NH2:25].Cl.[OH-].[Na+]>CO.C(O)(C)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[CH2:18][OH:17])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=1
Reactant: CC1(C)OCC(CCCn2ccc3ncnc(Cl)c32)O1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Product: OCC(O)CCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.1 %

Procedure:
The crude product was obtained by the reaction in the same manner as in Example 201 (iii) using 4-chloro-5-[3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl]-5H-pyrrolo[3,2-d]pyrimidine (171 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (195 mg) and isopropyl alcohol (3.5 mL). The crude product was dissolved in methanol (1 mL), 1N hydrochloric acid (0.5 mL) was added, and the mixture was stirred at room temperature for 3.5 hrs. The reaction mixture was treated with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→95:5) to give the title compound (179 mg) as white crystals.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[CH:3][CH:2]=1.[C:17]([OH:27])(=[O:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:16][C:1]2[CH:2]=[CH:3][C:4]([C:7]3[O:8][C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[CH:11]=3)=[CH:5][CH:6]=2)=[CH:20][CH:19]=1)([OH:27])=[O:26]
Reactant: Cc1ccc(-c2cc3ccccc3o2)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C=Cc2ccc(-c3cc4ccccc4o3)cc2)cc1

Procedure:
Proceeding in a manner similar to that described in Example 1 above, 2-(p-tolyl)benzofuran (2.08 g; 0.01 mole) was interacted with 2.25 g (0.01 mole) of the anil derivative of terephthalaldehydic acid in the presence of 6.72 g (0.06 mole) of potassium tert-butoxide in 150 ml of dimethylformamide. The resulting product was purified by sublimation to obtain 2-[4-(4-carboxystyryl)phenyl]benzofuran which melted at 348°-349°C. The wavelength of maximum excitation of this compound was 365 nm and the wavelength of maximum emission was 425 nm.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH:37](OC=O)=[O:38]>C(O)=O>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][N:11]([CH:37]=[O:38])[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: O=COC=O
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Solvent: O=CO
Product: CCOP(=O)(CCN(C=O)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-{4-[6-Methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (74 mg, 0.14 mmol) in formic acid (1 mL) was added formic anhydride (1 mL) and the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the crude product carried onto the next step. The NMR data of this compound shows two rotamers with the ratio of 70:30. 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 1.18-1.28 (m, 2H), 1.28 and 1.30 (t, 6H, J=7 Hz), 1.74 (s, 3H), 1.84-2.08 (m, 2H), 2.19 (s, 3H), 3.34-3.45 (m, 2H), 3.47 (d, 2H, J=7 Hz), 3.72 and 3.87 (s, 2H), 3.78 and 3.79 (s, 3H), 4.06 and 4.07 (pent, 4H, J=7 Hz), 4.26-4.37 (m, 2H), 5.13 (s, 2H), 5.30-5.46 (m, 1H), 8.03 and 8.19 (s, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 27.5 and 28.1 ppm; MS (m/z) 570.1 [M+H]+, 592.2 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Temperature: 80 °C
Yield: 90.5 %

Procedure:
According to Scheme 13 Step 1: A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.38 mmol, 1.43 g), 1-(chloromethyl)-4-methoxybenzene (7.38 mmol, 1.00 mL) and K2CO3 (7.38 mmol, 1.02 g) in acetonitrile (10 mL) was heated at 80° C. for 5 hours. Water was added and the aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4, was filtered and was concentrated under reduced pressure to afford 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.68 mmol, 2.10 g, 91%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(S[C:15](=[O:32])[CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:17](=[O:19])[CH3:18])(C)(C)C>>[CH2:30]([S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH:16]([C:17](=[O:19])[CH3:18])[C:15]([NH:1][C:2]2[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=2[F:8])=[O:32])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[CH3:31]
Reactant: CCS(=O)(=O)c1ccc(CC(C(C)=O)C(=O)SC(C)(C)C)cc1
Reactant: Nc1cc(O)ccc1F
Product: CCS(=O)(=O)c1ccc(CC(C(C)=O)C(=O)Nc2cc(O)ccc2F)cc1

Procedure:
The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2-(4-ethanesulfonylbenzyl)-3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:50])=[C:8]([N:10]2[CH2:49][CH2:48][C:13]3[N:14]=[C:15]([C:28]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:29]=4[C:30]([CH3:47])=[CH:31][N:32]5S(C4C=CC(C)=CC=4)(=O)=O)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][C@H:21]([O:24][CH3:25])[C:20]([CH3:27])([CH3:26])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2].[OH-].[K+].[OH-].[NH4+].O>CO.ClCCl.[Cl-].[Na+].O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:50])=[C:8]([N:10]2[CH2:49][CH2:48][C:13]3[N:14]=[C:15]([C:28]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:29]=4[C:30]([CH3:47])=[CH:31][NH:32]5)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][C@H:21]([O:24][CH3:25])[C:20]([CH3:26])([CH3:27])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CO[C@H]1CCN(c2nc(-c3cccc4c3c(C)cn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2cc(C(C)C)ccc2C)CC3)CC1(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CO[C@H]1CCN(c2nc(-c3cccc4[nH]cc(C)c34)nc3c2CN(c2cc(C(C)C)ccc2C)CC3)CC1(C)C
Temperature: 80 °C

Procedure:
To a solution of (S)-6-(5-isopropyl-2-methylphenyl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (135 mg, 0.195 mmol) in methanol (2 mL) in a microwave vial was added KOH (100 mg, 1.75 mmol) followed by 28% ammonium hydroxide in water (1 mL, 7.25 mmol). The vial was sealed and heated via microwave irradiation at 80° C. for 75 minutes. The reaction mixture was cooled to room temperature and diluted with dichloromethane and brine. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (0-70% ethyl acetate/heptanes) to furnish (S)-6-(5-isopropyl-2-methylphenyl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-2-(3-methyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (s, 3 H) 0.98 (s, 3 H) 1.18 (d, J=6.8 Hz, 6 H) 1.51-1.62 (m, 1 H) 1.91-1.99 (m, 1 H) 2.01 (s, 3 H) 2.21 (s, 3 H) 2.78-2.88 (m, 2 H) 2.91-3.08 (m, 4 H) 3.29 (s, 3 H) 3.31-3.41 (m, 3 H) 3.60-3.71 (m, 1 H) 4.07 (s, 2 H) 6.86 (d, J=7.3 Hz, 1 H) 6.96 (s, 1 H) 7.07-7.15 (m, 3 H) 7.20 (d, J=7.1 Hz, 1H) 7.41 (d, J=7.8 Hz, 1 H) 10.89 (br. s., 1 H); MS (ESI+) m/z 538.4 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.[Cl:12]CC1C=CC(CC(O)=O)=CC=1>>[Cl:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][C:9]([Cl:12])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(CCl)s1
Reactant: O=C(O)Cc1ccc(CCl)cc1
Product: O=C(Cl)Cc1ccc(CCl)s1

Procedure:
When in the procedure of Example 1 (B) 5-chloromethyl-2-thienylacetic acid, is substituted for p-chloromethylphenyl acetic acid, 5-chloromethyl-2-thienylacetyl chloride is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([F:18])[CH:12]=3)=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.C(=O)([O-])O.[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]4[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=4)=[CH:3][CH:4]=3)[NH:9][C:10]2=[O:19])=[CH:15][CH:14]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cc2ccc(F)cc12
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc(-c3cc4ccc(F)cc4c(=O)[nH]3)cc2)cn1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
A suspension of 3-(4-bromo-phenyl)-7-fluoro-2H-isoquinolin-1-one (159 mg, 0.50 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (114 mg, 0.55 mmol) and sodium hydrogen carbonate (50.4 mg, 0.60 mmol) in DMF (1 ml) and water (0.5 ml) is flushed with nitrogen and heated to 40° C. Then bis(triphenylphosphine)-palladium(II)-chloride (7.0 mg, 0.01 mmol) is added. The reaction mixture is heated to 80° C. and stirred at this temperature for 20 hours. The mixture is allowed to cool to room temperature and excess water is added. The resulting precipitate is filtered off and washed with water. The residue is chromatographed on a silica gel column with methanol/dichloromethane to afford 7-fluoro-3-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-2H-isoquinolin-1-one as ochre solid; HPLC/MS 2.43 min (B), [M+H] 320;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[C@@H:11]([CH3:13])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.C1COCC1>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C@@H:11]([CH3:13])[C:10]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](Oc1cccc(C=O)c1)C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a mixture of 1.00 g of 3-hydroxybenzaldehyde, 1.80 g of tert-butyl(R)-lactate, 2.58 g of triphenylphosphine, and 40 mL of THF was added 1.71 g of diethyl azodicarboxylate at room temperature, followed by stirring for 12 hours. The reaction solution was diluted with ethyl acetate, followed by washing with a 5% aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 1.49 g of tert-butyl(2S)-2-(3-formylphenoxy)propanoate as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:25])[CH3:24])=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:25][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:24])(=[O:28])[CH3:27]
Reactant: CC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]ethanol (50.0 mg, 0.126 mmol) in pyridine (0.5 mL) was added acetic anhydride (0.3 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hrs. The mixture was concentrated. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (38.8 mg, 0.0884 mmol, 70%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C1(C)C=CC(S([N:21]2[C:29]3[C:24](=[C:25]([O:30][CH2:31][CH:32]4[O:34][CH2:33]4)[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)(=O)=O)=CC=1>C(O)C>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11][CH:2]1[NH:1][CH2:33][CH:32]([OH:34])[CH2:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:23]=[CH:22][NH:21]2
Reactant: NC1CCc2ccccc2C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(OCC4CO4)cccc32)cc1
Solvent: CCO
Product: OC(CNC1CCc2ccccc2C1)COc1cccc2[nH]ccc12
Yield: 30.6 %

Procedure:
A mixture of 2-aminotetralin (5 g) and 1-[1-(p-toluenesulfonyl)-indol-4-yloxy]-2,3-epoxypropane (11.7 g) in absolute ethanol (150 ml) is refluxed for 6 hours. The solvent is evaporated, the obtained residue is dissolved under stirring in hot isopropanol (100 ml) and the solution is made acidic by the addition of hydrochloric acid in isopropanol. The precipitate which forms is recovered by filtration, dissolved in a mixture of ethanol (250 ml) and aqueous sodium hydroxide (7.6 g in 85 ml of water). The reaction mixture is refluxed for 6 hours, the solvent is evaporated off and the residue is dissolved in ethyl acetate (200 ml). The obtained solution is washed twice with water, dried over sodium sulfate and concentrated by evaporating off the solvent. The residue is chromatographed on a silica gel column eluting with ethyl acetate. The fractions containing pure product are pooled. The solvent is evaporated and the residue is dissolved in ethyl ether (20 ml) and crystallized therefrom yielding 3.5 g of N-(1,2,3,4-tetrahydronaphth- 2-yl)-2-hydroxy-3-(4-indolyloxy)propanamine; m.p. 65°-68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[N:4]([CH3:10])[N:3]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:22][C:23]2[CH:24]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:41][CH2:40]5)=[O:38])[N:35]=4)[N:32]=3)[CH:42]=[CH:43][C:44]=2[F:45])=[O:8])[N:4]([CH3:10])[N:3]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cn1nc(Cl)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cn1nc(Cl)cc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 68.7 %

Procedure:
In the same manner as in Example 259 and using 3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (59 mg, 0.37 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (130 μL, 1.5 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.31 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (100 mg, 71%) was obtained as a white solid.
Reaction SMILES: O.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[CH2:11]1[C:16](=[O:17])[O:15][CH2:14][C:12]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:12]2[CH2:14][O:15][C:16](=[O:17])[CH:11]=2)=[CH:5][CH:4]=1
Reactant: O=C1COC(=O)C1
Reactant: NCc1ccc(Cl)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C(NCc2ccc(Cl)nc2)CO1

Procedure:
On a water separator, 5.00 g (35.1 mmol) of 1-(6-chloropyridin-3-yl)methylamine, 3.51 g (35.1 mmol) of tetronic acid and 20 mg (0.12 mmol) of 4-toluenesulphonic acid in 200 ml of toluene are heated under reflux for 24 hours. The reaction mixture is concentrated, and the residue that remains is then purified by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate. This gives 4.96 g (63% of theory) of 4-[[(6-chloropyridin-3-yl)methyl]amino]furan-2(5H)-one, which can be used for subsequent reactions.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]\[C:4](O)=[O:5].[CH2:9]([C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=1[NH2:13])[CH3:10]>C(OC(C)C)(C)C>[CH2:9]([C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=1[N:13]1[C:4](=[O:5])[CH:3]=[CH:2][C:1]1=[O:8])[CH3:10]
Reactant: CCc1cccc(C)c1N
Reactant: O=C(O)/C=C\C(=O)O
Solvent: CC(C)OC(C)C
Product: CCc1cccc(C)c1N1C(=O)C=CC1=O
Temperature: 100 °C
Yield: 88.3 %

Procedure:
196 g of maleic acid arthydride were dissolved in 2.5 l of diisopropyl ether at room temperature. A solution of 270.4 g of 2-ethyl-6-methyl-aniline in 200 ml of diisopropyl ether was added dropwise at room temperature in the course of 4 hours, the resulting suspension was cooled to 15° to 20° C. and the solid was filtered off with suction and introduced into a mixture of 670 ml of acetic arthydride and 65 g of anhydrous sodium acetate. The suspension formed was heated to 100° C., while stirring, stirred at this temperature for 30 minutes, subsequently cooled to 30° C. and introduced into 1.3 l of ice-water. The precipitate was filtered off with suction, washed with ice-water and petroleum ether and dried. 321 g of N-(2-ethyl-6-methylphenyl)-maleimide (92.9% of theory) with a content of 97.8% by weight (determined by HPLC) and a melting point of 84.5° to 85° C. were obtained.