Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]([CH:9]=[CH:10][C:11]([NH:13][CH2:14][C:15]([N:17]([C:19]2[C:20]([Cl:28])=[C:21]([C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:22]Br)[CH3:18])=[O:16])=[O:12])=[CH:7][CH:6]=1)=[O:4].[CH2:31]([O:33][C:34]1[C:43]2[C:38](=[C:39]([OH:44])[CH:40]=[CH:41][CH:42]=2)[N:37]=[C:36]([CH3:45])[CH:35]=1)[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:28][C:20]1[C:19]([N:17]([CH3:18])[C:15](=[O:16])[CH2:14][NH:13][C:11](=[O:12])[CH:10]=[CH:9][C:8]2[CH:29]=[CH:30][C:5]([C:3](=[O:4])[NH:2][CH3:1])=[CH:6][CH:7]=2)=[CH:26][CH:25]=[C:24]([Cl:27])[C:21]=1[CH2:22][O:44][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:38]=1[N:37]=[C:36]([CH3:45])[CH:35]=[C:34]2[O:33][CH2:31][CH3:32]
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CBr)c2Cl)cc1
Reactant: CCOc1cc(C)nc2c(O)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C)nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)NC)cc4)c3Cl)cccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
To a solution of 3-[N-[4-(methylcarbamoyl)-cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyl bromide (60 mg) and 4-ethoxy-8-hydroxy-2-methylquinoline (24.9 mg) in dimethylformamide (0.6 ml) was added potassium carbonate (48.5 mg), and the mixture was stirred for 5 hours at ambient temperature. Water was added thereto, and the mixture was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]-amino]benzyloxy]-4-ethoxy-2-methylquinoline (67 mg) as an amorphous powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH2:20])[CH:11]=1.[CH2:22]1[O:32][C:31]2[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][C:24]=2[O:23]1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH:20][CH2:27][C:26]2[CH:29]=[CH:30][C:31]3[O:32][CH2:22][O:23][C:24]=3[CH:25]=2)[CH:11]=1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc2c(c1)OCO2
Temperature: 80 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
A solution of 0.80 g of N-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide in 10 ml of N,N-dimethylformamide were added 0.962 g of 3,4-methylenedioxybenzyl chloride and 0.710 g of sodium hydrogencarbonate, and the mixture was stirred at 80° C. for 4 hours. Chloroform and water were added to the reaction solution, and the chloroform extraction was conducted. The organic layer was washed with water, concentrated, and purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 9:1) to give 0.49 g of N-(2-pyridylmethyl)-4-acetylamino-3-(3,4-methylenedioxybenzylamino)benzamide.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[C:16]1([OH:26])[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.C[O:28][C:29](=[O:38])[CH:30](Br)[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][CH:30]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:26][C:16]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:6]=[N:5]2)[C:29]([OH:28])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1cccc2c1CCCC2
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3c2CCCC3)cc1=O
Yield: 90 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 5,6,7,8-tetrahydro-naphthalen-1-ol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-propionic acid (13.02 g, 90%) as a white solid; LC-MS 383 [M+H+]; HPLC [acetonitrile (0.1% trifluoroacetic acid) in water (0.1% trifluoroacetic acid)=50%˜100%, gradient, 1 mL/min, Venusil MP-C18, C18-15 cm×4.6 mm-5 μm), 254 nm, 95%, 214 nm, 95%. 1H-NMR (300 MHz, CDCl3): δ 7.88 (s, 1H), 7.15 (t, J=7.8 Hz, 1H), 7.03 (d, J=7.8 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 5.88 (s, 1H), 5.50 (q, J=4.8 Hz, 1H), 2.81 (s, 2H), 2.55 (s, 2H), 2.17-2.40 (m, 1H), 2.09-2.16 (m, 1H), 1.50-1.90 (m, 11H), 1.14-1.21 (m, 2H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1>[Cl-].C([N+](CCCC)(CCCC)CC1C=CC=CC=1)CCC.O>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
196 g (4 mol) of sodium Cyanide, 12.5 g (40 mmol) of tributylbenzylammonium chloride and 660 mL of water are initially introduced into a 2 l multineck apparatus with reflux condenser, internal thermometer and dropping funnel, and the mixture is heated to 90° C. At the same temperature, 644 g (4 mol) of molten 4-chlorobenzyl chloride are added dropwise in 1 h, and the mixture is then stirred for 2 h. After having been cooled to about 35° C., the organic phase is separated off, washed with water and fractionated over a short column. 552 g of 4-chlorobenzyl cyanide (91% of theory) are obtained.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=C1)=[S:2].NCCCNC1C[CH2:22][N:21]([CH2:24][CH2:25][C@@H:26]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:27][N:28]([CH3:37])[C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:20][CH2:19]1>>[ClH:44].[ClH:44].[Cl:45][C:40]1[CH:39]=[C:38]([C@H:26]([CH2:25][CH2:24][N:21]2[CH2:22][CH2:11][CH:12]([N:8]3[CH2:9][CH2:6][CH2:7][NH:3][C:1]3=[S:2])[CH2:19][CH2:20]2)[CH2:27][N:28]([CH3:37])[C:29](=[O:36])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:43]=[CH:42][C:41]=1[Cl:44]
Reactant: CN(C[C@@H](CCN1CCC(NCCCN)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Product: CN(C[C@@H](CCN1CCC(N2CCCNC2=S)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using the procedure of Example 3, replacing 1,1′-carbonyldiimidazole by 1,1′-thiocarbonyldiimidazole, replacing (S)-N-[4-[4-(2-aminoethylamino)piperidino]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide by (S)-N-[4-[4-(3-aminopropylamino)-piperidino]-2-(3,4-dichlorophenyl)butyl]-N-methylbenzamide, and stirring overnight at room temperature instead of reflux, the title compound was obtained as a white solid; MS: m/z=533(M+1); Analysis for C27H34Cl2N4OS.2.30 HCl.0.10 (C2H5)2O: Calculated: C, 52.67; H, 6.01; N, 8.96; Found: C, 52.57; H, 6.11; N, 8.84.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[C:9]2[C:8](=[O:18])[N:7]([CH3:19])[CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:19][N:7]1[C:8](=[O:18])[C:9]2[C:10]([NH:12][C@@H:13]3[CH2:17][CH2:16][O:15][CH2:14]3)=[N:11][C:2]([C:30]3[CH:29]=[CH:28][C:27]([N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)=[CH:32][CH:31]=3)=[CH:3][C:4]=2[N:5]=[CH:6]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cn1cnc2cc(Cl)nc(N[C@@H]3CCOC3)c2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(c2ccc(-c3cc4ncn(C)c(=O)c4c(N[C@@H]4CCOC4)n3)cc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-7-chloro-3-methyl-5-(tetrahydrofuran-3-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one (16 mg, 0.057 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (19 mg, 0.063 mmol), Pd(PPh3)4 (6.6 mg, 0.0057 mmol), K2CO3 (24 mg, 0.17 mmol), 2-propanol (3 mL) and H2O (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature and worked-up. The residue was purified using slilica gel flash column chromatography (eluent: 0-10% methanol in dichloromethane) to afford (R)-3-methyl-7-(4-(4-methylpiperazin-1-yl)phenyl)-5-(tetrahydrofuran-3-ylamino) pyrido[4,3-d]pyrimidin-4(3H)-one as a slightly yellow solid. HPLC-MS calculated C23H28N6O2(M+H+): 421.24, found: 421.20.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([CH2:22][CH3:23])[CH2:13][NH:14]C(=O)OC(C)(C)C)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[ClH:1].[Cl:1][C:2]1[C:3]([CH:12]([CH2:22][CH3:23])[CH2:13][NH2:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCC(CNC(=O)OC(C)(C)C)c1ncc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CN)c1ncc(C(F)(F)F)cc1Cl
Product: Cl
Temperature: 25 °C

Procedure:
146 g of tert-butyl 2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]butylcarbamate (0.414 mol) are dissolved in 2 L of dichloromethane. 190 mL of trifluoroacetic acid are added dropwise. The reaction mixture is stirred at room temperature for twelve hours, concentrated to dryness and diluted in 300 mL of hydrochloric acid 2M.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].[CH2:41](I)[CH2:42][CH3:43]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:41][CH2:42][CH3:43])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2]
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Reactant: CCCI
Product: CCCOc1cc2nc(N3CCOCC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Yield: 46 %

Procedure:
The same procedure as in Example 48 was repeated, using 335 mg (0.61 mmol) of Compound 47 obtained in Example 47, except that propyl iodide was used in place of methyl iodide, to give 164 mg (yield: 46%) of Compound 49 as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[H-].[Na+].[H-].[H][H].O1CCN(P(Cl)(N2CCOCC2)=O)CC1.[C:41]([NH:44][NH2:45])(=O)[CH3:42]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:41]([CH3:42])=[N:44][N:45]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: CC(=O)NN
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: [H][H]
Agent: O=P(Cl)(N1CCOCC1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 610 mg. (2 mmoles) of 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 10 ml. of dry tetrahydrofuran at room temperature was added 115 mg. of a 50% dispersion of sodium hydride in oil (2.4 mmoles of hydride). The mixture was warmed gently on the steam bath for approximately 1 hour until hydrogen evolution stopped. Dimorpholinophosphinic chloride (764 mg., 3.0 mmoles) was added and the resulting mixture was stirred at room temperature for 2 hours. To this mixture was then added a solution of 296 mg. (4 mmoles) of acethydrazide in 5 ml. of dry tetrahydrofuran and stirring was continued for 15 minutes at room temperature. Solvents were evaporated and the residue was dissolved in 20 ml. of butanol and heated to reflux for 2 hours. Butanol was evaporated. The residue was partitioned between methylene chloride and water. The methylene chloride layer was dried and evaporated. Crystallization of the residue from isopropanol-ether-petroleum ether yielded, in two crops, final product having a m.p. of 225°-227°.
Reaction SMILES: [I:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1.[C:24](O)(C(F)(F)F)=O>C(OCC)(OCC)OCC>[I:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]2[O:19][CH:24]=[N:21][N:20]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)NN)cc2)c1I
Solvent: CCOC(OCC)OCC
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-c3nnco3)cc2)c1I
Temperature: 130 °C

Procedure:
4-(5-Iodo-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzohydrazide (4.9 g, 12 mmol) was suspended in 60 mL of triethyl orthoformate, to which was added 1 mL of TFA. The suspension was heated at 130° C. The reaction was cooled to rt, and the precipitate was collected, washed with hexanes and dried to give 4.8 g of the title compound. 1H NMR (500 MHz, (CDCl3): 8.62 (m, 1H), 8.57 (s, 1H), 8.11 (m, 1H), 8.09 (s, 4H), 7.82 (m, 1H), 7.32 (m, 1H), 4.13 (s, 3H). LCMS: [M+1]=430.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]1[C:7]2[N:8]([N:19]=[CH:20][N:21]=2)[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].IC.[CH3:24]C(C)([O-])C.[K+].O>C(O)(C)(C)C>[CH3:24][NH:18][C:9]1[N:8]2[N:19]=[CH:20][N:21]=[C:7]2[C:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOCCc1c(-c2ccccc2)nc(N)n2ncnc12
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)(C)O
Product: CCOCCc1c(-c2ccccc2)nc(NC)n2ncnc12
Temperature: 25 °C

Procedure:
A mixture of 3.0 g (0.01 mole) of 8-(2-ethoxyethyl)-7-phenyl-1,2,4-triazolo[2,3-c]pyrimidine-5-amine, ca. 3 g of iodomethane, and ca. 1 g of potassium t-butoxide in t-butyl alcohol was stirred with heating for five hours. The solution was cooled to room temperature and then poured into 200 ml of cold water and extracted with several portions of ethyl acetate. The organic phase was washed with aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo to dryness. Column chromatography on silica gel afforded 175 mg of the title monomethylated product.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].C(#N)C.[CH3:15][O:16][C:17]([C:19]1[C@H:20]2[CH2:28][C@@H:27]3[O:29][C@:26]3([CH3:30])[C@@H:21]2[CH:22]([OH:25])[O:23][CH:24]=1)=[O:18]>CO>[CH3:15][O:16][C:17]([C:19]1[C@H:20]2[CH2:28][C@@H:27]3[O:29][C@:26]3([CH3:30])[C@@H:21]2[C@H:22]([O:25][C:10](=[O:11])[NH:9][CH3:8])[O:23][CH:24]=1)=[O:18]
Reactant: CN=C=O
Reactant: COC(=O)C1=COC(O)[C@@H]2[C@@H]1C[C@@H]1O[C@@]12C
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
0.15 ml of triethylamine and 60 μl of methylisocyanate were added to an acetonitrile solution containing 200 mg of a known (4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-1-hydroxy-7-methylcyclopenta [c] pyrane-4-carboxylic acid methylester followed by stirring for 1 hour at room temperature. After adding 1 ml of methanol to the reaction mixture, it was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain colorless needles from the hexane-ether eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-1-methylcarbamoyloxy-7-methylcyclopenta [c] pyrane-4-carboxylic acid methylester (55 mg, yield : 22%). The physicochemical properties of this compound are described in Table 1, Compound No. 3).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[I:9][CH2:10][CH2:11][OH:12]>CN(C)C=O>[I-:9].[OH:12][CH2:11][CH2:10][N+:2]1([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: OCCI
Reactant: CN1CCC(=O)CC1
Solvent: CN(C)C=O
Product: C[N+]1(CCO)CCC(=O)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-4-piperidone (1.0 g) in N,N-dimethylformamide (10 ml) was added 2-iodoethanol (0.70 ml-1.5 g) and stirred overnight at ambient temperature. The reaction mixture was evaporated under reduced pressure and washed by ethyl acetate to afford 1-(2-hydroxyethyl)-1-methyl-4-oxopiperidinium iodide (0.94 g).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([NH:11][N:12]=[C:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:22][CH2:23][NH2:24].C(OC(C)C)(C)C.[Cl:37]CCl>>[ClH:37].[ClH:37].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:22][CH2:23][NH:24][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]2[N:6]=[N:7][C:8]([NH:11][N:12]=[C:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: ClCCl
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC(C)=NNc1ccc(OCC2CO2)nn1
Solvent: CC(C)OC(C)C
Product: COc1ccc(CCNCC(O)COc2ccc(NN=C(C)C)nn2)cc1OC
Product: Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(2,3-epoxypropoxy)-6-isopropylidenehydrazinopyridazine (20 g) and 3,4-dimethoxyphenethylamine (40 ml) was stirred at 50° C for 4 hours. After cooling, the mixture was dissolved in dichloromethane (100 ml) and poured into diisopropyl ether (800 ml). After stirring for 1 hour the precipitate was collected and triturated with diisopropyl ether (400 ml). The collected solid was dissolved in ethanol (300 ml) and 5.4N hydrochloric acid (35 ml) Was added dropwise. The solvent was evaporated under vacuum, the residue was diluted with acetone (100 ml) and toluene (100 ml) and evaporated to dryness The residue was crystallised from ethanolacetone to afford 26.6 g of the title compound as a pale yellow solid. m.p. 206°-209° C. (with decomposition).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[Cl:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[C:17]([C:7]2[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=2)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 550.4 %

Procedure:
4.08 g (30.0 mmol) of 3-trifluoromethylpyrazol, 4.75 mmol (30.0 mmol) of 2-chloro-4-fluorobenzaldehyde and 4.14 g (30.0 mmol) of potassium carbonate in 30 ml of N,N-dimethylformamide were stirred at 60° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into 100 ml of water, and the organic matters were extracted with 50 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. The residue afforded 7.18 g of 2-chloro-4-(3-trifluoromethylpyrazolyl)benzaldehyde (yield 87.2%) as a pale yellow powder, after washed with n-hexane.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: O=S1(=O)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCS(=O)(=O)CC1
Yield: 23.6 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from Example 65A (200 mg, 0.38 mmol), thiomorpholine 1,1-dioxide (154 mg, 1.14 mmol), tetrabutylammonium iodide (140 mg, 0.38 mmol) and N,N′-diisopropylethylamine (135 μL, 0.76 mmol) in N,N′-dimethylformamide (2 mL) to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-7-methoxy-quinazolin-4-ylsulfanyl}-phenyl)-urea (56.27 mg, 24%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.27 (m, 5H), 6.49 (s, 1H), 4.30 (bs, 2H), 3.99 (s, 3H), 3.12-3.04 (m, 10H), 1.27 (s, 9H); LC-MS (ESI) m/z 627 (M+H)+.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]([CH2:18][C:19]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[O:21])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: Nc1ccccn1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)Nc1ccccn1
Temperature: 0 °C
Yield: 15.8 %

Procedure:
Under a nitrogen atmosphere, oxayl chloride (2.38 g, 0.019 mole) was added slowly dropwise to a stirred and chilled (15°-20° C.) solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.70 g, 0.016 mole) in 50 ml of dimethylformamide. The reaction mixture was stirred at ambient temperature for 1/2 hr., then warmed to 60°-65° C. for 5 hrs. This acylchloride solution was added dropwise under nitrogen to a stirred and chilled (15°-20° C.) solution of 2-aminopyridine (1.76 g, 0.019 mole), triethylamine (1.89 g, 0.019 mole), and 30 ml of dimethylformamide. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was poured into 400 ml of ice water and extracted with ehtyl acetate (3×). The ethyl acetate layers were washed with 5% potassium hydroxide (2×50 ml), water (2×50 ml), dried, and filtered. The residue was treated with isopropyl alcohol and excess ethereal hydrogen chloride to give solid which was recrystallized twice from isopropyl alcohol-isopropyl ether and once from isopropyl alcohol. The solid was collected by filtration, washed with cold isopropyl alcohol, then isopropyl alcohol-water, and dried under high vacuum for 2 days to give 0.92 g (15.8%) of title compound, mp 165°-66° C.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[O:9]=[C:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH:8]1[NH:4][C:3](=[O:10])[CH2:2][CH2:1]1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: Cl[Mg]Cc1ccccc1
Solvent: ClCCl
Product: O=C(CCC1CCC(=O)N1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a solution of tetrahydro-pyrrolizine-3,5-dione (5 g, 36 mmol) in CH2Cl2 (320 mL) at 0° C. was added benzyl magnesium chloride (1M solution in THF, 39 mL, 39 mmol) dropwise. The solution was stirred at 0° C. for 3 h and was quenched with saturated aqueous ammonium chloride. After warming to room temperature, the aqueous solution was extracted with CH2Cl2 (3×). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (1% MeOH in CH2Cl2to 2% MeOH in CH2Cl2) to yield 5.9021 g of 5-(3-oxo-4-phenyl-butyl)-pyrrolidin-2-one. 1H NMR (CDCl3) δ7.35-7.18 (m, 5H), 3.69 (s, 2H), 3.56 (m, 1H), 2.50 (t, 2H), 2.27 (m, 2H), 2.15 (m, 1H), 1.73 (m, 2H), 1.61 (m, 1H).