Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-chloroaniline (400 mg, 3.13 mmol) in anhydrous dichloromethane (40 mL) were added 3-methoxybenzenesulfonyl chloride (648 mg, 3.13 mmol) followed by pyridine (297.2 mg, 3.76 mmol). The mixture was allowed to stir for 12 h at 25° C. 10% citric acid solution (20 mL) and water (20 mL) was added. The organic phase was dried (Na2SO4), and evaporated under reduced pressure yielding the title compound as solid which was used as such in the next step. Yield: 900 mg (96%). MS (m/e): 296 (M+−H); 1H-NMR (CDCl3, 400 MHz): δ 3.76 (s, 3H), 6.48 (brs, 1H), 7.0 (d, J=8.72 Hz, 2H), 7.06 (d, J=7.76 Hz, 1H), 7.21 (m, 3H), 7.32 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].[CH2:8]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C1COCC1>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([CH:4]([C:3]#[N:7])[C:5]#[N:6])=[O:21])=[CH:23][CH:24]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CCC#N
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C#N)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.7 %

Procedure:
NaH (1.657 g, 60%, 41.4 mmol) was suspended in THF (10 mL). To this suspension was added malononitrile (1.368 g, 20.71 mmol) in THF (10 mL) at 0° C. dropwise over 10 minutes. The suspension was stirred for additional 20 minutes. To this solution was added compound 31A (5.11 g, 20.71 mmol) in THF (40 mL) portion wise. Afterwards, the solution was warmed to rt and stirred for 30 minutes. The pH of the solvent was adjusted to 1 with concentrated HCl. The reaction mixture was concentrated, and partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was triturated with 1:1 Hex/EtOAc (50 mL) to give a solid which was collected by filtration to provide 3.7 g of the desired product 31B: 1H NMR (DMSO-d6): δ 7.60-7.63 (m, 2H), 7.32-7.47 (m, 5H), 7.03-7.07 (m, 2H), 5.16 (s, 2H). MS (DCI(+)): m/z 294 (M+NH4).
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[N:11][C:10]([C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.Cl.[NH4+].[Cl-]>ClCCl>[CH2:1]([N:8]1[N:12]=[N:11][C:10]([C:13]([CH3:20])([CH3:19])[CH:14]=[O:15])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1nnn(Cc2ccccc2)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C=O)c1nnn(Cc2ccccc2)n1
Temperature: -78 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
To a stirred mixture of 2-benzyl-α,α-dimethyl-2H-tetrazole-5-acetic acid, ethyl ester acetaldehyde (step 1 of Example 9) (6.14 g, 22.4 mmol) in dichloromethane (100 mL) at −78° C. was added DIBAL (1.0 M in toluene, 50.0 mL, 50.0 mmol). The resulting mixture was stirred at −78° C. for 4 h. To the reaction mixture was added DIBAL (1.0 M in toluene, 25.0 mL, 25.0 mmol) and the resulting mixture was stirred at −78° C. for 8 h. To the mixture were added 2 M aqueous HCl (100 mL) and saturated aqueous NH4Cl (20 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (10:1) to give 3.45 g (67%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a 3-neck round-bottomed flask were added zinc powder (1.96 g, 30 mmol) followed by anhydrous THF (40 mL). To the stirred suspension was slowly added, via syringe, TiCl4 (1.6 mL, 2.77 g, 14.6 mmol) at room temperature. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 2 h. To the refluxing reaction mixture was added a solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (1.1 g, 3.61 mmol) and cyclohexanone (1.1 mL, 1.04 g, 10.6 mmol) in anhydrous tetrahydrofuran (40 mL). The stirred reaction mixture was heated at reflux under a nitrogen atmosphere for 2 h. The oil bath was removed and the reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added water (24 mL) followed by 10% aqueous K2CO3 (24 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel with the aid of water and EtOAc and the layers were separated. The organic phase was washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 60:40) to give 1.17 g (95%) of compound 6 as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.52 (m, 6H), 2.12 (m, 4H), 6.65 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 9.32 (s, 1H). HRMS (EI) Calcd for C19H19BrO: 342.0619 (M+.). Found: 342.0627.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=C.[O:13]=[O+][O-]>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:13]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc([N+](=O)[O-])cc1C
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])ccc1C=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
2Bromo-5-nitrotoluene (1.0 g, 4.54 mmol) and vinyltributyl tin (1.59 g, 4.99 mmol) were dissolved in toluene (25 mL) under argon. Palladium dibenzylidene acetone (4.15 g, 0.455 mmol) and triphenylphosphine (488 mg, 1.86 mmol) was added and the reaction refluxed overnight. The solvent was evaporated and the residue dissolved in 200 mL of methylene chloride and washed with 10% ammonium hydroxide, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography heptane-methylene chlolride 1:1) to yield 726 mg of 2-methyl-4-nitrostyrene. 2-methyl-4-nitrostyrene (700 mg, 4.5 mmol) was dissolved in methylene chloride (20 mL) and cooled to −78° C., and treated with ozone until a blue color remained, after 5 minutes the excess ozone was removed by passing a stream of oxygen through the solution. Dimethyl sulfide (1 mL) was added and the reaction mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by flash column chromatography to yield 580 mg of the 2-methyl-4-nitrobenzaldehyde. 2-Methyl-4-nitrobenzaldehyde (570 mg, 3.45 mmol) and potassium carbonate (476 mg, 3.45 mmol) were suspended in methanol. Tosylmethylisocyanide (674 mg, 3.45 mmol) was added and the reaction mixture refluxed for 3 h, cooled to room temperature and concentrated. The residue was dissolved in methylene chloride (200 mL) and the organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 710 mg (94%) of 5-(4-nitro-2-methylphenyl)oxazole. 5-(4-Nitro-2-methylphenyl)oxazole was dissolved in methanol (100 mL) and 10% palladium on carbon 200 mg was wetted with water and added. The reaction mixture was hydrogenated at 45 psi overnight. The catalyst was removed by filtration and 560 mg of 5-(4-amino-2-methylphenyl)oxazole was isolated in 92% purity by HPLC method A. Mass spectrum M+H+=175.1, 1H 400 MHz NMR (CDCl3): δ7.88 (s, 1H), 7.45 (m, 1H), 7.08 (s, 1H), 6.60 m(m, 2H), 2.38 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1.[CH3:14][S:15]([O-:17])=[O:16].[Na+].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>CS(C)=O.[Cu]I>[CH3:14][S:15]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1)(=[O:17])=[O:16]
Reactant: OC[C@H]1COc2ccc(Br)cc2O1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)O[C@@H](CO)CO2
Temperature: 140 °C
Yield: 213.6 %

Procedure:
A mixture of [(2S)-7-bromo-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (0.6 g, 2.3 mmol), sodium methanesulfinate (85%) (0.4 g, 3.4 mmol), CuI (0.043 g, 0.2 mmol), L-proline (0.052 g, 0.5 mmol) and NaOH (0.018 g, 0.5 mmol) in DMSO (3 ml) was heated under microwave radiation at 140° C. for 2 h 30 min in a nitrogen-flushed vial. The mixture was mixed with 2 other batches and water and EtOAc was added. The solution was extracted with EtOAc (3×50 ml). The combined organic phases were washed with LiCl (5%), HCl (1 N) and brine. The resulting solution was dried (Na2SO4) and evaporated to dryness. Purification on flash column chromatography (isooctane/EtOAc) gave the title compound (1.2 g). MS m/z (rel. intensity, 70 eV) 244 (M+, bp), 213 (39), 165 (26), 134 (22), 79 (23).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH3:40][CH:41]([NH:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH3:42]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:47][CH2:46][CH2:45][CH2:44][NH:43][CH:41]([CH3:42])[CH3:40])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CC(C)NCCCN
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCCNC(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 64.4 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (20 mg, 0.036 mmol) in THF(3 mL) was added N-(1-methylethyl)-1,3-propanediamine (0.025 mL, 0.179 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (14 mg, 64%). LC-MS m/z 604 (M+H)+; 1H-NMR (MeOD) δ 1.00 (d, 6H), 1.65 (m, 2H), 2.34 (s, 3H), 2.50 (m, 2H), 2.78 (m, 1H), 3.15 (m, 2H), 4.13 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1>CCCCO>[Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cccnc1C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: Cc1cccnc1C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Reaction time: 48 h
Yield: 28 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpicolinamide (197 mg, 0.566 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butyl piperidin-3-ylcarbamate (453 mg, 2.263 mmol) and stirred at 160° C. for 48 hours in a sealed tube. The mixture was concentrated in vacuo, and the residue diluted with water (25 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate concentrated in vacuo, and the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-85% CH3CN/water gradient; 25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(3-methylpicolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (83.8 mg, 28% yield) as a solid. LCMS (APCI+) m/z 429.1, 431.1, 531.1 (M+H)+, Retention time=4.32 minutes (Method 2).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[C:12](O)(=[O:16])[C:13](O)=[O:14]>Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]2[C:3]=1[NH:11][C:12](=[O:16])[C:13](=[O:14])[NH:10]2
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(F)c(F)c(F)c1N
Agent: Cl
Product: O=c1[nH]c2cc(F)c(F)c(F)c2[nH]c1=O
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a brown solution of 3,4,5-trifluoro-1,2-phenylenediamine (285 mg, 1.75 mmol) in aqueous 2N HCl (10 mL) is added oxalic acid (221 mg, 1,75 mmol). The brown mixture is brought to reflux and stirred under N2 overnight. The mixture is filtered to yield 139 mg (37%) of crude title compound. An analytical sample is prepared by dissolving 42 mg of this brown powder in 2.5 mL-boiling ethanol. Upon cooling, brown, rod-like, crystals are formed, which are filtered and dried in vacuo to-yield 15 mg (36%) of pure title compound: 1H NMR (DMSO-d6), 6.91 (m, 1H), 12.02 (s, 1H), 12.19 (s, 1H); analysis calculated for C8H3F3N2O2 : C, 44.46; H, 1.40; N, 12.96. Found: C, 44.42; H, 1.16; N, 12.76.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8]/[CH:9]=[C:10]2\[C:11](=[O:22])[NH:12][C:13](=[O:21])[C:14]3[C:19]\2=[CH:18][C:17](I)=[CH:16][CH:15]=3)=[CH:6][CH:5]=[C:4]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[N:3]=1.[O:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C)C=O.C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[C:7]([NH:8]/[CH:9]=[C:10]2\[C:11](=[O:22])[NH:12][C:13](=[O:21])[C:14]3[C:19]\2=[CH:18][C:17]([C:32]2[CH:33]=[CH:34][O:30][CH:31]=2)=[CH:16][CH:15]=3)=[CH:6][CH:5]=[C:4]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[N:3]=1
Reactant: OB(O)c1ccoc1
Reactant: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)c(F)n2)CC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(-c5ccoc5)cc43)c(F)n2)CC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A suspension of (4Z)-4-({[2-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}methylene)-6-iodoisoquinoline-1,3(2H,4H)-dione (0.10 g, 0.20 mmol), 3-furanboronic acid (55 mg, 0.50 mmol), tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) and cesium carbonate (0.13 g) in N,N-dimethylformamide (2 mL) is heated in a 120° C. oil bath for 10 minutes. Tri-tert-butylphosphine (20 mg/mL solution in N,N-dimethylformamide, 0.50 mL, 10 mg, 0.05 mmol) is added, and the mixture continued to stir in the oil bath for one hour. After cooling to room temperature, the reaction mixture is diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer is concentrated under reduced pressure and purified via reverse phase HPLC to provide (4Z)-4-({[2-fluoro-6-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}methylene)-6-(3-furyl)isoquinoline-1,3(2H,4H)-dione.3 trifluoroacetic acid salt (53 mg, 34%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:40][C:41]1[N:42]=[C:43]([CH3:46])[S:44][CH:45]=1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:12]([C:7]1[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[C:5]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:40][C:41]3[N:42]=[C:43]([CH3:46])[S:44][CH:45]=3)[CH:3]=2)[N:8]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1nc(CCl)cs1
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCc4csc(C)n4)cc23)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.4 %

Procedure:
To a solution of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.40 g, 0.95 mmol) in N,N-dimethylformamide (10 ml) were added potassium carbonate (0.28 g, 2.0 mmol), 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (0.37 g, 2.0 mmol) and triethylamine (0.31 ml, 2.2 mmol) and the mixture was stirred at room temperature for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl ({2-isobutyl-4-(4-methylphenyl)-6-[(2-methyl-1,3-thiazol-4-yl)methoxy]quinolin-3-yl}methyl)carbamate (0.32 g, yield 63%) as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[CH3:11][N:12]1[C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=[N:13]1>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:16]2[N:12]([CH3:11])[N:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Product: Cc1cc(-c2ccnn2C)cc(C)c1Br

Procedure:
The title compound is prepared from 2-bromo-5-iodo-1,3-dimethylbenzene and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following a procedure analogous to that described in Step 1 of Intermediate 17. LC (method 9): tR=1.11 min; Mass spectrum (ESI+): m/z=265 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH:28]/[CH:29]=[CH:30]/[C:31](=[O:33])[CH3:32]>>[C:31]([C:30]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:28]([CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([F:34])([F:35])[F:19])[CH:29]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)/C=C/NCc1ccccc1C(F)(F)F
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3ccccc3C(F)(F)F)C=C1C(C)=O)C2=O

Procedure:
The title compound 67 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 68 (90 mg, 0.37 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 67 as a yellow oil. (Yield 35 mg, 20%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:16]=[C:9]2[N:10]=[C:11]([CH3:15])[CH:12]=[C:13](Cl)[N:8]2[N:7]=1)(=O)C.NC(N)=[S:19]>C(O)C>[OH:4][CH2:5][C:6]1[N:16]=[C:9]2[N:10]=[C:11]([CH3:15])[CH:12]=[C:13]([SH:19])[N:8]2[N:7]=1
Reactant: CC(=O)OCc1nc2nc(C)cc(Cl)n2n1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(S)n2nc(CO)nc2n1
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
In 400 ml of ethanol was dissolved 23.7 g of 2-acetoxymethyl-7-chloro-5-methyl-s-triazolo[1,5-a]pyrimidine, and 19 g of thiourea was added thereto and the mixture was stirred for 30 minutes under reflux. The reaction mixture was ice-cooled and the precipitated crystals were collected by filtration, washed with ethanol and dried. After the obtained crystals were dissolved in a 10% potassium hydroxide aqueous solution and stirred for 30 minutes, pH was adjusted to 2 with addition of a 2N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried to obtain 15.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:23]([O:25]C)=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:11].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:23]([OH:25])=[O:24])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[O:11]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2ccccc2Cl)C(=O)O)cc1
Yield: 86 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 45 (2.9 g), 1 mol/L of an aqueous sodium hydroxide solution (12 mL), and methanol (120 mL), to give the captioned compound (2.4 g, 79%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][CH3:33])[CH:26]=2)[CH:6]=[CH:5][C:4]=1[OH:34].[NH2:35][C:36]1[CH:37]=[C:38]([CH:42]2[S:46][C:45]3=[N:47][CH2:48][CH2:49][N:44]3[CH2:43]2)[CH:39]=[CH:40][CH:41]=1.Cl.[Cl:51][C:52]1[CH:60]=[CH:59][C:55]([C:56](Cl)=[O:57])=[CH:54][N:53]=1.[OH-].[Na+]>CO.C(Cl)Cl>[CH3:33][O:32][C:27]1[CH:26]=[C:25]([CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][C:7]2[CH:6]=[CH:5][C:4]([OH:34])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:30]=[CH:29][C:28]=1[OH:31].[Cl:51][C:52]1[CH:60]=[CH:59][C:55]([C:56]([NH:35][C:36]2[CH:37]=[C:38]([CH:42]3[S:46][C:45]4=[N:47][CH2:48][CH2:49][N:44]4[CH2:43]3)[CH:39]=[CH:40][CH:41]=2)=[O:57])=[CH:54][N:53]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1cccc(C2CN3CCN=C3S2)c1
Agent: COc1cc(CNCCCNCCCCNCCCNCc2ccc(O)c(OC)c2)ccc1O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1cccc(C2CN3CCN=C3S2)c1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
dl-6-(m-Aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (dl-m-aminotetramisole) (42 g) was dissolved with stirring in aqueous methanol (200 ml methanol/50 ml water), and the pH was adjusted to 5 with 2N hydrochloric acid. The mixture was then cooled in an ice/water mixture and 6-chloronicotinoyl chloride (67 g--prepared as in Part A above) was added. The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with methylene chloride (about 500 ml), and pH adjusted to 10 with 1N sodium hydroxide. The organic layer was separated, washed to neutrality with water, and allowed to stand, when the desired product, dl-6-(m-(6-chloronicotinoylamono)phenyl)-2,3,,5,6-tetrahydroimidazo[2,1-b]thiazole (52.6 g), m.p. 135°-138°, crystallied out. The product was filtered off. Evaporation of the filtrate produced a second crop (6.8 g) of the product.