Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][S:9](=[O:12])(=[O:11])[CH:8]([CH3:13])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:22][C@H:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][C@@H:23]2[CH3:22])[C:5]2[CH2:10][S:9](=[O:12])(=[O:11])[CH:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: CC1c2nc(Cl)nc(Cl)c2CS1(=O)=O
Reactant: C[C@H]1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1c2nc(Cl)nc(N3CCOC[C@@H]3C)c2CS1(=O)=O
Yield: 39.7 %

Procedure:
To a solution of 2,4-dichloro-7-methyl-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (Example 7, step (vi)) (160 mg, 0.63 mmol), and triethylamine (64 mg, 0.63 mmol) in DMF (3 mL) at 0° C. was added 3-(S)-methylmorpholine (57 mg, 0.57 mmol). The resultant mixture was stirred at rt for 2 h. The solvent was removed under vacuum and the residue obtained partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give the product which was purified by preparative TLC (petroleum ether/ethyl acetate=2/1) to produce 2-chloro-7-methyl-4-[(3S)-3-methylmorpholin-4-yl]-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (72 mg, 36% yield). LC-MS (Method A), (ES+) 318/320, RT=2.95 min.
Reaction SMILES: C(O)C.Cl[C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=3)[N:12]=[CH:13][C:6]=12.Cl.[O:23]1[C:28]2[CH:29]=[CH:30][C:31](NC)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1.[CH2:35]([N:37](CC)CC)C>>[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:35][NH:37][C:5]3[N:10]=[CH:9][N:8]=[C:7]4[N:11]([C:14]5[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=5)[N:12]=[CH:13][C:6]=34)=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: Cc1cc(C)cc(-n2ncc3c(Cl)ncnc32)c1
Reactant: CCN(CC)CC
Reactant: CNc1ccc2c(c1)OCCO2
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)cc(-n2ncc3c(NCc4ccc5c(c4)OCCO5)ncnc32)c1
Temperature: 27.5 °C
Reaction time: 0.29 h
Yield: 86 %

Procedure:
350.0 ml of ethanol and 25.0 g (0.096 mol) of 4-chloro-1-(3,5-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Compound No. 79) were charged into a 1.0 L 4 necked round bottom flask connected to a mechanical stirrer, thermometer socket, condenser and addition funnel. Stirred the mass at 25-30° C. for 15-20 min. 32.0 g of 2,3-dihydro-benzo[1,4]dioxin-6-yl-methylamine hydrochloride was charged at 25-30° C. under stirring. Stirred the mass at 25-30° C. for 15-20 min. 30.0 g of triethyl amine was added slowly at maintaining the mass temperature 25-30° C. during 30-45 min. Maintained the mass temperature at 25-30° C. for 30-45 min. Temperature of the reaction mass was raised to refluxing. Maintained the mass at reflux temperature for 10-11 hours. Reaction mass was cooled to 25-30° C. Maintained the mass temperature at 25-30° C. for 60-90 min. Reaction mass was cooled to 0-5° C. Maintained the mass temperature at 0-5° C. for 90-120 min. Solid was filtered and washed with 50.0 ml of chilled ethanol. Compound was dried under vacuum at 60-65° C. till constant weight is obtained. Dry weight of the compound is 35.50 g. 175.0 ml of dimethyl sulphoxide and 35.50 g of dry crude compound were charged into a 1.0 L 4-necked round bottom flask, connected to a mechanical stirrer, thermometer socket and condenser. Mass temperature was raised to 55-60° C. Maintained the mass temperature at 55-60° C. for 30-45 min. Insoluble solid was filtered through hyflow bed, washed the flask with 20.00 ml of hot dimethyl sulphoxide. Clear aerate was collected into flask. 1000.0 ml of Water is charged into a 3.0 L 4 necked round bottom flask, connected to a mechanical stirrer, thermo meter socket and addition funnel. Dimethyl sulphoxide solution was added slowly to water at maintaining the mass temperature at 25-35° C. over a period of 30-45 min. Maintained the mass temperature at 25-35° C. for 60-90 min. Temperature of the mass was cooled to 5-10° C. Maintained the mass temperature at 5-10° C. for 90-120 min. Solid was filtered and solid was washed with 150 ml of water. Compound was dried under vacuum at 60-65° C. 32.0 g Of dried compound is obtained (yield—85.5% by theory). Product purity by HPLC is 99.48%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[N:30]1(C2C=C(C=CC=2)N)[CH:34]=[CH:33][CH:32]=[CH:31]1>>[N:30]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH2:1])[N:14]=3)[CH:21]=[CH:20][CH:19]=2)[CH:34]=[CH:33][CH:32]=[CH:31]1
Reactant: Nc1cccc(-n2cccc2)c1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2cccc2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(1H-pyrrol-1-yl)aniline in step 1. MS: 392.5 (M+H).
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:6]([NH:8][CH2:9][CH2:10]O)[CH3:7]>C1C=CC=CC=1>[CH:2]([CH:1]1[N:8]([CH2:9][CH3:10])[CH2:6][CH2:7][O:5]1)([CH3:4])[CH3:3]
Reactant: CCNCCO
Reactant: CC(C)C=O
Solvent: c1ccccc1
Product: CCN1CCOC1C(C)C

Procedure:
Iso-butyraldehyde (11.1 g; 0.15 moles) was added slowly over a period of 1 hour to N-ethyl-2-hydroxyethylamine (13.3 g; 0.15 moles) at a temperature of 25°-30° C. Benzene (100 ml) was then added, and the resulting solution was heated to reflux. Continuous azeotropic distillation removed 2.8 ml of water. The benzene was then removed by vacuum distillation to give the desired 2-isopropyl-3-ethyl-1,3-oxazolidine as a yellow liquid.
Reaction SMILES: O1CCOCC1.Br[C:8]1[CH:9]=[C:10]([CH3:15])[C:11]([NH2:14])=[N:12][CH:13]=1.[I-:16].[Na+].CC(C)(N)C(C)(C)N>[Cu](I)I.O>[I:16][C:8]1[CH:9]=[C:10]([CH3:15])[C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: [I-]
Agent: I[Cu]I
Agent: CC(C)(N)C(C)(C)N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(I)cnc1N
Temperature: 110 °C
Yield: 92.7 %

Procedure:
To dioxane (10 mL) was added 5-bromo-3-methylpyridin-2-amine (2 g, 10.6 mmol), sodium iodide (3.2 g, 21.4 mmoL), copper iodide (0.190 g, 1.06 mmol) and the solution degassed followed by addition of tetramethylethane-1,2-diamine (0.803 mL, 1.06 mmol) this mixture heated at 110° C. overnight. After cooling water was added and extracted the crude product with ethyl acetate. The residue was purified by column chromatography to give 5-iodo-3-methylpyridin-2-amine as a beige solid (2.3 g, 93%).
Reaction SMILES: CN1CCOCC1.[Cl:8][CH2:9][C:10](Cl)=[O:11].[C:13]([NH:16][C:17]1[C:18]([NH2:42])=[C:19]([C:23]2[NH:24][C:25]3[C:30]([C:31]=2[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=[C:27]([C:38]([O:40][CH3:41])=[O:39])[CH:26]=3)[CH:20]=[CH:21][CH:22]=1)(=[O:15])[CH3:14]>C(Cl)Cl>[C:13]([NH:16][C:17]1[C:18]([NH:42][C:10](=[O:11])[CH2:9][Cl:8])=[C:19]([C:23]2[NH:24][C:25]3[C:30]([C:31]=2[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=[C:27]([C:38]([O:40][CH3:41])=[O:39])[CH:26]=3)[CH:20]=[CH:21][CH:22]=1)(=[O:15])[CH3:14]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc(NC(C)=O)c3N)[nH]c2c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc(NC(C)=O)c3NC(=O)CCl)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-methyl morpholine (1 eq) and chloroacetylchloride (1 eq) were added to a stirred solution of methyl 2-[3-(acetylamino)-2-aminophenyl]-3-cyclohexyl-1H-indole-6-carboxylate in CH2Cl2 (0.03 M) under N2. After stirring at RT for 1 h, further N-methyl morpholine (1 eq) and chloroacetylchloride (1 eq) were introduced. The reaction was stirred for another hour before diluting with CH2Cl2 and washing with 1N HCl (aq), water and brine. The organics were then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a brown solid that was taken on in the subsequent step without further purification (91%). MS (ES+) m/z 482 (M+H)+, 484 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].[CH3:36]C(C)=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:7][O:8][CH3:9].[C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH2:33][CH3:34])[C:5]=1[O:35][CH3:36])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(C)=O)c1O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCCc1c(OCCCOc2ccc(C(C)=O)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Product: COC

Procedure:
Methyl 7-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate (493 mg) was added to 25 ml of acetone containing 276 mg of anhydrous potassium carbonate and 282 mg of methyl iodide. The mixture was refluxed for about 24 hours and water was added and the mixture was then extracted with ethyl acetate. The extract was dried, the solvent removed under vacuum, and the residual oil was chromatographed over silica gel with a 40/60 mixture of ethyl acetate/hexane to provide pure methyl ether, methyl 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Br[CH2:20][C:21]([NH2:23])=[O:22]>>[C:17]([C:9]1[C:10]([C:13]([F:14])([F:15])[F:16])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:20][C:21]([NH2:23])=[O:22])[C:4]([CH:1]1[CH2:2][CH2:3]1)=[CH:12]2)#[N:18]
Reactant: NC(=O)CBr
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2CC(N)=O)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 2-bromoacetamide: 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J=8.4 Hz, 1H), 7.71 (bs, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.35 (bs, 1H), 6.37 (s, 1H), 5.02 (s, 2H), 1.94 (m, 1H), 0.99 (m, 2H), 0.77 (m, 2H); MS (ES) m/z 308 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][C:6]2=[O:25])#[N:2].[N-:26]=[N+:27]=[N-:28].[Na+].Cl.C(N(CC)CC)C.Cl>CCOC(C)=O.CN(C=O)C>[O:25]=[C:6]1[C:5]2[C:22](=[CH:23][CH:24]=[C:3]([C:1]3[NH:28][N:27]=[N:26][N:2]=3)[CH:4]=2)[O:21][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:7]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C#N)ccc1O2
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3nnn[nH]3)ccc1O2
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give tert-butyl 6-bromo-4-oxospiro-[chroman-2,4′-piperidine]-1′-carboxylate. Alternatively, 10 mL of pyrrolidine (121.31 mmol) may be used in this procedure. To a solution of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CN)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, 0.17 mol). The slurry was heated to 90° C. for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5° C., stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 23 g of tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (67.17 mmol), 13.10 g sodium azide (201.52 mmol), 27.74 g of triethylamine hydrochloride (201.52 mmol), and 460 mL of dry DMF was stirred under a nitrogen atmosphere at 100° C. for 12 hours. After cooling to room temperature, 506 mL of EtOAc were added, followed by 322 mL of 1M HCl (322 mmol). Alternatively, 0.5M HCl maybe added until pH=3. The resulting layers were separated, the organic layer was washed with water/methanol (115 mL/46 mL), and then concentrated to give tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 5.08 g of tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate (13.18 mmol), 8.8 mL of 12 M HCl (105.44 mmol) and 8 mL of methanol was heated to 50° C. until the reaction was complete. The resulting slurry was filtered, washed with 25 mL of methanol at room temperature, and dried to give 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-4-one hydrochloride salt.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>O1CCCC1.O>[C:28]([O:27][C:25](=[O:26])[CH2:24][C:16]1([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CC(=O)OC(C)(C)C)CCOCC1
Temperature: -35 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
Diisopropylamine (1.28 mL, 9.16 mmol) was diluted with tetrahydrofuran (2 mL) and cooled to −78° C. n-Butyllithium (2.5 M, 3.66 mL, 9.16 mmol) was added dropwise, and the solution was allowed to stir for 1 h. Methyl tetrahydro-2H-pyran-4-carboxylate (1.1 g, 7.63 mmol) was added as a solution in tetrahydrofuran (1.5 mL) at −78° C. The mixture was allowed to warm to −35° C. and stirred for 1 h. tert-Butyl bromoacetate (1.58 mL, 10.7 mmol) was added neat at −35° C. The mixture was allowed to warm to 0° C. and stirred for 2 h. The mixture was stirred at rt overnight. Water was added at 0° C. and the mixture extracted with ethyl acetate. The organic phase was washed with brine, and dried over sodium sulfate. The crude product was purified by flash chromatography (Biotage Flash 40M, 6:1 hexane/ethyl acetate) to afford methyl 4-(2-tert-butoxy-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.12 g, 56%). LC-MS ret. time 2.47 min, m/z 258.7 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 9H), 1.52-1.61 (m, 2H), 2.00-2.07 (m, 2H), 2.50 (s, 2H), 3.52-3.60 (m, 2H), 3.70 (s, 3H), 3.71-3.77 (m, 2H).
Reaction SMILES: BrCC.[Mg].Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21].[C:22]([C:24]1[CH:28]=[CH:27][O:26][N:25]=1)#N.S(=O)(=O)(O)[OH:30]>C1COCC1>[O:26]1[CH:27]=[CH:28][C:24]([C:22]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:30])=[N:25]1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(C)c(OCc2ccccc2Br)c1
Reactant: N#Cc1ccon1
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: Cc1ccc(C)c(OCc2ccccc2C(=O)c2ccon2)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 6.3 %

Procedure:
THF (2 ml) and bromoethane (0.1 ml) were added to magnesium (0.49 g, 0.02 mol) in a stream of nitrogen, and the mixture was stirred at 50° C. for 10 minutes. Then, a mixture of 1-bromo-2-(2,5-dimethylphenoxymethyl)benzene (2.91 g, 0.01 mol) and THF (8 ml) was added at 50 to 60° C. over 30 minutes, and the mixture was stirred at 50 to 60° C. for 1 hour. After completion of the reaction, the reaction mixture was added to a mixture of 3-cyanoisoxazole (1.45 g, 0.015 mol) and THF (15 ml) at 20° C. or lower over 15 minutes, and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 2N sulfuric acid (200 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl isoxazol-3-yl ketone (0.20 g, 6.3%) as colorless crystals. mp. 90.5-92° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][Cl:17])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[O:20]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.N1C=CC=CC=1.O>C(OCCO)C>[Cl:17][CH2:16][CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:33][CH:32]=3)=[C:3]([C:18]#[N:19])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cc1OCCCl
Temperature: 135 °C
Yield: 78 %

Procedure:
Following the procedure of Example 1, a mixture of 3.0 g (0.01 mol) of 4-chloro-7-(2-chloroethoxy)-6-methoxy-3-quinolinecarbonitrile (Boschelli, Diane H.; Ye, Fei; Wang, Yanong D.; Dutia, Minu; Johnson, Steve L.; Wu, Biqi; Miller, Karen; Powell, Dennis W.; Yaczko, Deanna; Young, Mairead; Tischler, Mark; Arndt, Kim; Discafani, Carolyn; Etienne, Carlo; Gibbons, Jay; Grod, Janet; Lucas, Judy; Weber, Jennifer M.; Boschelli, Frank. J. Med. Chem. 2001, 44, 3965-3977), 2.04 g (0.011 mol) of 4-phenoxyaniline and pyridine hydrochloride 1.16 g (0.01 mol) in 100 mL of 2-ethoxyethanol is heated at 135° C. for 2 hours. Water is added to the reaction mixture, and the precipitate is filtered off. After washing with water, ether and ethyl acetate, the solid is dried in vacuo to provide 3.48 g of 7-(2-chloroethoxy)-6-methoxy-4-(4-phenoxyphenylamino)quinoline-3-carbonitrile as a yellow solid, mp 148-151° C.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=S)#[N:2].CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C.[NH2:33][CH:34]([NH:39][C:40](=[O:48])[C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)[C:35]([Cl:38])([Cl:37])[Cl:36]>CN(C=O)C.C(OCC)(=O)C>[CH3:47][C:44]1[CH:45]=[CH:46][C:41]([C:40]([NH:39][CH:34]([NH:33][C:4](=[N:3][C:1]#[N:2])[NH:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C:35]([Cl:38])([Cl:36])[Cl:37])=[O:48])=[CH:42][CH:43]=1
Reactant: N#CNC(=S)Nc1cccnc1
Reactant: Cc1ccc(C(=O)NC(N)C(Cl)(Cl)Cl)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC(NC(=NC#N)Nc2cccnc2)C(Cl)(Cl)Cl)cc1
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
A solution of Example 44A (200 mg, 0.932 mmol) in DMF (7 mL) at 23° C. was treated with EDCI (250 mg, 1.30 mmol) followed by diisopropyethylamine (0.180 mL, 1.03 mmol). The mixture was stirred for 30 minutes, then treated with a solution of Example 38A (262 mg, 0.932 mmol) as a solution in DMF (2 mL) along with additonal diisopropyethylamine (0.360 mL, 2.06 mmol). The solution was stirred for 10 hours, poured into ethyl acetate (25 mL), and washed with water (25 mL). The aqueous layer was extracted with ethyl acetate (20 mL), and the combined organic portions were washed with water (3×20 mL) and brine (20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated. Purification of the residue by flash chromatography (elution with 5% ethanol/hexanes) provided 146 mg of the desired product as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[NH:9]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[N:10]1.[C:16]([CH2:18][C:19](=[S:21])N)#[N:17].C(O)(=O)C>CC(O)C>[O:8]=[C:4]1[NH:5][CH:6]=[CH:7][C:2]2[N:1]=[C:19]([SH:21])[C:18]([C:16]#[N:17])=[C:14]([C:11]3[CH:12]=[CH:13][NH:9][N:10]=3)[C:3]1=2
Reactant: N#CCC(N)=S
Reactant: Nc1cc[nH]c(=O)c1
Reactant: O=Cc1cc[nH]n1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: N#Cc1c(S)nc2cc[nH]c(=O)c2c1-c1cc[nH]n1

Procedure:
573 mg (5.20 mmol) of 4-aminopyridin-2(1H)-one, 500 mg (5.02 mmol) of pyrazole-3-carbaldehyde and 521 mg (5.20 mmol) of 2-cyanoethanethioamide were initially charged in 25 ml of 2-propanol, 0.45 ml (7.81 mmol) of acetic acid was added and the mixture was stirred at reflux for 48 h. The precipitate was removed by filtration, and the filtrate was evaporated and reacted further without further purification.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)([CH3:15])[CH3:14].[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:43])[CH:39]=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH:43][C:1]([NH:22][CH:19]4[CH2:20][CH2:21][N:16]([CH:13]([CH3:15])[CH3:14])[CH2:17][CH2:18]4)=[O:12])[CH:39]=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: CC(C)N1CCC(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-isopropyl-piperidin-4-ylamine (CAS no. 127285-08-9) and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=444.7 (M+H+).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][S:22][CH2:23][CH3:24]>CCO>[CH2:11]([O:10][C:2]([CH:3]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][S:22][CH2:23][CH3:24])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:9])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCSCCOCCCCCCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCCOCCSCC)C(=O)OCC
Yield: 60 %

Procedure:
Sodium metal (0.31 g, 0. 014 mol) was dissolved in absolute EtOH (20 mL). To this mixture was added diethyl malonate (2.2 g, 0. 014 mol) in EtOH (5 mL) and the above 7-oxa-10-thiadodecyl bromide (3g, 0.011 mol) in EtOH (5 mL) at room temperature. The reaction mixture was refluxed for 5 h. After evaporation of the solvent, the residue was dissolved in ethyl acetate (120 mL). The organic phase was washed with water (2×30 mL), brine (30 mL), and dried (Na2SO4). The crude product was purified by Kugelrohr distillation to give ethyl 2-ethoxycarbonyl- 9-oxa-12-thiatetradecanoate (2.3 g, 58%); bp 122°-128° C./0.04 torr; NMR: 1.27 (6H, t, J=7 Hz), 3.3-3.7 (5H, m), and 4.17 ppm (4H, q, J=7 Hz), 1.2-1.9 (10H, m ), 2.59 (2H, q, J=7 Hz), 2.68 (2H, t, J=7 Hz), 3.1-3.7 (5H, m), and 4.17 ppm (4H, q, J=7 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7](=O)[CH2:8][NH:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:14].[K+].[K+].[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH2:30][O:31][C:32]3[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=3)[CH2:35]Cl)=[N:27]2)=[CH:22][CH:21]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH2:30][O:31][C:32]3[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=3)[CH2:35][O:1][C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][C:8](=[O:14])[NH:9]4)=[CH:4][CH:3]=3)=[N:27]2)=[CH:22][CH:21]=1
Reactant: ClCc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reactant: O=C([O-])[O-]
Reactant: O=C1CNc2cc(O)ccc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(OCc3cccc(OCc4ccc5ccc(Cl)cc5n4)c3)cc2N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.5 %

Procedure:
A mixture of 0.326 g (2 mmol) of 7-hydroxy-1,2,3,4-tetrahydroquinolin-3-one, 0.609 g (5 mmol) of K2CO3, 0.075 g (0.25 mmol) of tetra-n-butylammonium bromide, 40 ml of DMF and 0.636 g (2 mmol) of 3-(7-chloro-2-quinolinylmethoxy)benzyl chloride was stirred at room temperature for 3 days. Insoluble matter was removed and the solvent was then distilled off. The residue was subjected to chromatography on a silica gel column. Subsequent to elution with CHCl3, recrystalization was conducted from acetone, whereby 0.245 g of the title compound was obtained as pale yellow powder (yield: 27.6%).