Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8].C(N(CC)CCN[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:29]=[O:30])=[O:19])C>C(Cl)(Cl)Cl>[OH:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][OH:11])[CH2:4][CH2:3][CH2:2][NH:1][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:29]=[O:30])=[O:19]
Reactant: CCCCCCCCCCCCCCCCCCN(C=O)c1ccccc1COC(=O)NCCN(CC)CC
Reactant: NCCCN(CCO)CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C=O)c1ccccc1COC(=O)NCCCN(CCO)CCO
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 41.2 %

Procedure:
N-(3-Aminopropyl)diethanolamine (0.89 g) was added to the intermediate (a) (2.62g) obtained in Example 28. After being stirred for 2.5 hours at 70° C., the reaction mixture, with chloroform added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then filtrated. The solvent was evaporated out and the residue was purified by silica gel column chromatography (silica gel 70 g, chloroform:methanol=50:1-30:1), thereby yielding 1.17 g of the aimed compound as white solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:16]([C:17]#[N:18])=[C:15]([N:19]([CH3:21])C)[N:14](N=C)[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>CO>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:16]2[C:15](=[N:19][CH:21]=[N:18][C:17]=2[NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:26]([Cl:25])[CH:27]=2)[NH:14][N:13]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C=Nn1nc(NCCNC(=O)OC(C)(C)C)c(C#N)c1N(C)C
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 35 g (108.9 mmol) of 3-[2-(Boc-amino)-ethylamino]-4-cyano-5-dimethylamino-methyleneamino-pyrazole, 17.9 g (109.1 mmol) of 3-chloro-aniline hydrochloride and 350 ml of methanol is heated under reflux for 30 hours and then stirred at RT for 15 hours. Filtration and washing the filter residue with methanol yield 3-[2-(tert-butyloxy-carbonyl-amino)-ethylamino]-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine having a water content of 2.39%; m.p. 206-208° C.; ESI-MS: (M−H)−=402.
Reaction SMILES: [CH3:1][SH:2].C[O-].[Na+].Br[CH2:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][F:11]>CO>[CH3:12][C:9]([CH3:13])([CH2:10][F:11])[C:8](=[O:14])[CH2:7][S:2][CH3:1]
Reactant: CS
Reactant: CC(C)(CF)C(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSCC(=O)C(C)(C)CF
Temperature: 20 °C
Reaction time: 12 h
Yield: 77.3 %

Procedure:
40 g (0.83 mol) of methylmercaptan were passed into 150 ml of methanol at -20° C. A solution of 45 g (0.83 mol) of sodium methylate in 200 ml of methanol was then added dropwise to the same temperature. 154 g (0.78 mol) of 1-bromo-3,3-dimethyl-4-fluoro-butan-2-one were now added dropwise at 0° C. The mixture was stirred for a further 12 hours at 20° C., the inorganic precipitate was filtered off and the filtrate was distilled. 99 g (77% of theory) of 3,3-dimethyl-4-fluoro-1-methylthio-butan-2-one of boiling point 86° C./10 mm Hg were obtained. ##STR30##
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.CC1C=CC(S(NN)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>COCCOC.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:39][CH:40]=4)=[C:14]([CH2:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=5[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1ccc(-c2c(CCc3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C

Procedure:
A mixture of compound 60a (60.0 mg, 0.112 mmol), 4-methylbenzenesulfonohydrazide (104 mg, 0.558 mmol) and sodium acetate (46.2 mg, 0.558 mmol) in 3.3 mL of 10:1 DME/water was refluxed for 4 h. After cooling to rt, the mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0:1-3:2 EtOAc/DCM) to afford compound 60b as a colorless oil. 1H-NMR (CDCl3; 400 MHz) δ 8.05 (d, J=8.6 Hz, 2H), 7.96 (d, J=5.6 Hz, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.15 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.07 (d, J=5.6 Hz, 1H), 3.96-4.03 (m, 4H), 3.89-3.96 (m, 4H), 3.15-3.30 (m, 4H), 2.83 (t, J=6.3 Hz, 2H), 2.69 (t, J=6.3 Hz, 2H), 1.82-1.91 (m, 2H), 1.73-1.82 (m, 2H), 1.61 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C32H37N5O3, 540.3 (M+H). found 540.5.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.OO.[O-:14]S([O-])=O.[Na+].[Na+].[I-].[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=S([O-])[O-]
Reactant: Cc1cnc2ccccc2c1
Agent: OO
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc2ccccc2[n+]([O-])c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
3-Methylquinoline (30.0 mL, 224 mmol) was dissolved in acetic acid (85 mL), and 30% aqueous hydrogen peroxide (30.4 mL) was added. The reaction was stirred at 80° C. for 16 h before cooling in an ice bath. 10% aq Na2SO3 (199 mL, 0.5 equiv) was added followed by sodium iodide (2.358 g, 0.05 equiv). This mixture was stirred for 5 min. A peroxide test strip indicated no peroxide remaining. 5 N aq NaOH was then added, keeping the internal temperature below 24° C. A dark color formed, indicating that the solution was basic (tested as pH 10). The solution was extracted with four portions of dichloromethane. The combined organics were dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (methanol/ethyl acetate) gave 3-methylquinoline 1-oxide (Intermediate 3, 32.09 g) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J=8.8 Hz, 1 H), 8.42 (s, 1 H), 7.77 (d, J=8.2 Hz, 1 H), 7.68 (td, J=7.8, 1.1 Hz, 1 H), 7.56-7.63 (m, 1 H), 7.52 (s, 1 H), 2.45 (s, 3 H); MS (M+1): 160.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3([CH3:15])[CH2:14][CH2:13]3)[NH:9]2)=[CH:5][C:4]=1[CH3:16].[CH:17]([C:19]1[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][CH:20]=1)=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:17][C:19]3[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3([CH3:15])[CH2:13][CH2:14]3)[NH:9]2)=[CH:5][C:4]=1[CH3:16]
Reactant: COc1cc2[nH]c(C3(C)CC3)cc2cc1C
Reactant: COC(=O)c1cccc(C=O)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(Cc2c(C3(C)CC3)[nH]c3cc(OC)c(C)cc23)n1
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 6-methoxy-5-methyl-2-(1-methylcyclopropyl)-1H-indole (586 mg) and methyl 6-formylpyridine-2-carboxylate (450 mg) in dichloromethane (13.6 mL) was added triethylsilane (1.30 mL) under ice-cooling. Trifluoroacetic acid (0.313 mL) was added dropwise thereto, and the mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was suspended in methanol. The precipitate was collected by filtration, washed with methanol, and then dried under reduced pressure at 40° C. to obtain the title compound (688 mg). 1H-NMR (CDCl3) δ ppm: 0.66-0.72 (2H, m), 0.80-0.86 (2H, m), 1.31 (3H, s), 2.19 (3H, s), 3.84 (3H, s), 4.05 (3H, s), 4.48 (2H, s), 6.78 (1H, s), 7.00 (1H, s), 7.04-7.10 (1H, m), 7.59 (1H, t, J=7.8 Hz), 7.79 (1H, br s), 7.91-7.97 (1H, m). ESI-MS (m/z): 365 (M+H)+
Reaction SMILES: C[O-].[Na+].[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:7]=1)=O.[CH3:20][O:21][C:22](=[O:27])[CH2:23][N:24]=[N+:25]=[N-:26]>CO>[N:24](/[C:23](=[CH:4]/[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])=[CH:8][CH:7]=1)/[C:22]([O:21][CH3:20])=[O:27])=[N+:25]=[N-:26]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cc1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C(=C\c1ccc(NC(=O)OC(C)(C)C)cc1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 6 h
Yield: 53.4 %

Procedure:
To a solution 13.45 mmol of sodium methoxide in 6 mL absolute methanol at 0° C. was added a solution of 717 mg (3.24 mmol) of tert-butyl 4-formylphenylcarbamate and 1.49 g (12.96 mmol) methylazidoacetate dissolved in 6 mL absolute methanol dropwise over 5 minutes. The mixture was stirred at 0° C. for 6 h, then partitioned between ethyl acetate and acetic acid until neutral. The organic phase was dried over magnesium sulfate, concentrated and purified by column chromatography, eluting with 25% ethyl acetate/hexane to provide 551 mg of methyl (2E)-2-azido-3-{4-[(tert-butoxycarbonyl)amino]phenyl}prop-2-enoate as a yellow solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[NH:10][C:11](=[O:37])[C:12]2[NH:13][CH2:14][N:15]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:40]I>O1CCCC1>[CH2:1]([S:8][C:9]1[N:10]([CH3:40])[C:11](=[O:37])[C:12]2[NH:13][CH2:14][N:15]([C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(SCc2ccccc2)nc2c1NCN2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(SCc2ccccc2)nc2c(c1=O)NCN2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
After 500 mg (0.10 mmol) of Compound o obtained in Reference Example 14 was dissolved in 20 ml of tetrahydrofuran, 0.08 g (0.20 mmol) of 60% sodium hydroxide was added to the solution under ice cooling. After 30 minutes, 0.125 ml (0.20 mmol) of methyliodide was added, and the mixture was stirred for 2 hours at 50° C. The solvent was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with chloroform, and the extract was washed with a saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silicagelcolumchromatography (eluent: chloroform) to afford 300 mg (yield, 58%) of Compound p as a white powder.
Reaction SMILES: [CH3:1][NH2:2].CO.C([O:7][C:8](=O)[CH2:9][C:10](=[O:16])[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)C>CO>[CH3:1][NH:2][C:8](=[O:7])[CH2:9][C:10](=[O:16])[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN
Reactant: CCOC(=O)CC(=O)c1cccs1
Solvent: CO
Product: CNC(=O)CC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A 9.8 g (126.26 mmol) portion of 40% methylamine/methanol solution was added to 20 ml of methanol solution containing 5 g (25.25 mmol) of 3-oxo-3-(2-thienyl)propionic acid ethyl ester obtained in Reference Example 1 and stirred at room temperature for 19 hours. After the reaction, the solvent and excess methylamine were evaporated under a reduced pressure to obtain 4.6 g of crystals of N-methyl-3-oxo-3-(2-thienyl)propionamide.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][O:8][CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCOCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
To a solution of 2-(4-trifluoromethyl-benzyloxy)-ethanol (1.0 g, 4.5 mmol) in dry DCM (20 ml) and DIPEA (2.36 ml, 13.5 mmol), at 0° C., under argon atmosphere, was added methanesulfonyl chloride (421 μl, 5.4 mmol). The reaction mixture was stirred at 0° C. for 10 minutes, then the ice-bath removed and the stirring continued for 2 hours at r.t. The mixture was then diluted with 70 ml of DCM and washed with 50 ml of NaHCO3 saturated solution, 100 ml of water, 100 ml of 2N HCl and 100 ml of water, dried over sodium sulfate and evaporated to dryness affording 1.35 g (yield: quantitative) of methanesulfonic acid 2-(4-trifluoromethyl-benzyloxy)-ethyl ester as a brown oil that was used as such for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[O:13]1[CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]1>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][C:7]=1[CH:18]([CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14][OH:13]
Reactant: CCCCC1CO1
Reactant: Clc1cccc(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(CCCCO)c1ccc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
A slurry of m-dichlorobenzene, 735 g. (5.0 mole) and anhydrous aluminium chloride, 162 g. (1.1 mole) is cooled to 10° using an ice-water bath and 1,2-epoxyhexane, 100 g. (1.0 mole) is added dropwise over a one hour period. The temperature of the reaction is kept below 15°. The reaction mixture is allowed to come to room temperature and stirring is continued overnight. The reaction mixture is then poured into a 4 liter flask containing ice and concentrated hydrochloric acid (50 ml.) with stirring. The aqueous and organic layers are separated and the aqueous layer extracted three times with ether (150 ml). The combined organic extracts are washed twice with water (50 ml) and dried over magnesium sulfate. Solvent is evaporated and vacuum distillation (160°-172°/0.1 mm) gives 114 g. (46%) of product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[N:32](C3CCCCO3)[N:31]=2)=[N:4][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[C:11]([CH3:28])[CH:10]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH3:28])[C:12]([CH:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[CH:13][N:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2ncc(Cl)c(Nc3cc(C)n(C4CCCCO4)n3)n2)ncc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cn3)ncc2Cl)n[nH]1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(6-(5-chloro-4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-4-methylpyridin-3-yl)piperidine-1-carboxylate in DCM (1 mL), was added TFA (1 mL). The mixture was stirred for 1 h and concentrated to afford 5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-methyl-5-(piperidin-4-yl)pyridin-2-yl)pyrimidine-2,4-diamine as brownish oil. The product was used directly for subsequent reactions without further purification.
Reaction SMILES: [C:1]([C:3]1([NH:9][C:10]([O:12][C@@H:13]([CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].C=O.[C:31](O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([C:3]1([NH:9][C:10]([O:12][C@@H:13]([CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])=[O:11])[CH2:8][CH2:7][N:6]([CH3:31])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(=O)O
Reactant: N#CC1(NC(=O)O[C@@H](CC2CCCCC2)C(=O)N2CCOCC2)CCNCC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C#N)(NC(=O)O[C@@H](CC2CCCCC2)C(=O)N2CCOCC2)CC1
Yield: 72 %

Procedure:
A sample of the free amine obtained from the previous step (40 mg, 0.102 mmol) is dissolved in MeOH (1 mL) and formaldehyde (6.06 mg, 0.202 mmol) is added as a solution in methanol (2 mL) with a single drop of acetic acid. Sodium cyanoborohydride (2.1 mg, 0.034 mmol) is added as a solid and the reaction is allowed to stir for half an hour. The solvent is removed in vacuo and the product is purified by preparative HPLC to afford the title material, 29.8 mg, 72% yield. HPLC-MS calculated for C21H34N4O4 (M+H+)407.3, found 407.3.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([N:27]([CH3:43])[C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][N:29]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[CH:30][N:29]=[C:28]([N:27]([CH:24]([CH3:26])[CH3:25])[CH3:43])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC(C)N(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccnc(N(C)C(C)C)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and isopropyl-methyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (Stage 130.1.1) to give the title compound as a white solid. (HPLC: tR 2.24 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.14-8.08 (m, 3H), 7.97-7.93 (m, 1H), 7.69-7.66 (m, 1H), 6.69-6.66 (m, 1H), 6.56-6.53 (m, 1H), 4.90 (hp, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 2.85 (s, 3H), 1.96 (s, 3H), 1.17-1.11 (m, 6H))
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.NC(N)=[S:14]>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:14])[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: NC(N)=S
Solvent: CO
Product: Sc1nc2ccc(Br)cc2s1
Temperature: 120 °C
Yield: 81.3 %

Procedure:
A mixture of 6-bromo-2-chlorobenzo[d]thiazole (250 mg, 1 mmol) and thiourea (228 mg, 3 mmol) in 2 mL of MeOH in a microwave tube was heated in a microwave reactor for 10 min at 120° C. The mixture was concentrated and the solid was collected through filtration and washed with water and dried under high vacuum to afford 6-bromobenzo[d]thiazole-2-thiol as a yellow solid (200 mg, 81%). MS (ESI) m/z 247.9 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)=[O:14])[CH:9]=[C:8]([F:26])[C:3]=1[C:4]([O:6]C)=[O:5]>[OH-].[Na+]>[F:26][C:8]1[CH:9]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:21])[CH3:22])[CH:19]=2)=[O:14])[CH:11]=[C:2]([F:1])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(F)cc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1F
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(C(=O)Nc2cc(F)c(C(=O)O)c(F)c2)sc1C(C)C
Yield: 86 %

Procedure:
The aforementioned ester (83 mg, 0.209 mmol) was hydrolyzed with sodium hydroxide in a conventional manner, and extraction and recrystallization were performed to obtain the title compound (43, 66 mg, 86%) as colorless prisms.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].[CH3:21][NH2:22].CO>>[NH2:1][C:2]1[N:10]=[C:9]([NH:22][CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Yield: 83 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and 40% methylamine/methanol solution (50 ml) were heated at 120° C. for 20 hours in autoclave. The reaction mixture was condensed in vacuo. To the residue was added 5N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (163 mg, yield 83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[CH3:2].[BrH:21]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([Br:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[CH3:2]
Reactant: CCOC(=O)C(C)(C)CCCC=Cc1ccccc1Cl
Reactant: Br
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)CCCCC(Br)c1ccccc1Cl
Temperature: 25 °C
Yield: 86 %

Procedure:
7-(2-Chlorophenyl)-2,2-dimethylhept-6-enoic acid ethyl ester (11.75 g, 0.040 mole) was dissolved in acetic acid (80 mL) under an argon atmosphere. The flask was cooled in an ice-water bath. Hydrogen bromide gas was passed slowly through the solution for 3 hours while the solution slowly warmed to room temperature. Ice (250 g) was added and after mixing, the product was extracted with ethyl acetate (2×100 mL). The ethyl acetate extracts were combined and washed with saturated sodium bicarbonate solution (3×75 mL) and water (100 mL). The solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The remaining oil (14.06 g) was purified by column chromatography on silica gel (250 g), eluting with 3:1 (followed by 2:1) heptane/ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure to provide 7-bromo-7-(2-chlorophenyl)-2,2-dimethylheptanoic acid ethyl ester (12.9 g, 86% yield) as a clear oil. 1H NMR (300 MHz, CDCl3/TMS): δ=7.57 (d, 1H, J=7.50 Hz), 7.33-7.15 (m, 3H), 5.43 (t, 1H, J=6.9 Hz), 4.08 (q, 2H, J=7.2 Hz), 2.30-2.21 (m, 2H), 1.55-1.42 (m, 3H), 1.34-1.19 (m, 5H), 1.13 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ=177.72, 139.41, 132.69, 129.67, 129.28, 128.92, 127.48, 60.36, 50.17, 42.26, 40.57, 39.19, 28.59, 25.38, 25.34, 24.45, 14.50. MS (HR, DIP-CI): Calculated for (MH+): 375.0726. found 375.0726.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[C:9](F)[CH:8]=2)[CH3:2].[F:23][C:24]([F:35])([F:34])[C:25]([NH:27][CH2:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)=[O:26].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[C:9]([C:31]1[NH:32][CH:33]=[C:29]([CH2:28][NH:27][C:25](=[O:26])[C:24]([F:23])([F:34])[F:35])[N:30]=1)[CH:8]=2)[CH3:2]
Reactant: CCOC(=O)c1nc2cc(F)c([N+](=O)[O-])cc2nc1OCC
Reactant: O=C(NCc1c[nH]cn1)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2cc(-c3nc(CNC(=O)C(F)(F)F)c[nH]3)c([N+](=O)[O-])cc2nc1OCC
Temperature: 130 °C
Reaction time: 15 h
Yield: 37.1 %

Procedure:
To a solution of ethyl 3-ethoxy-7-fluoro-6-nitroquinoxaline-2-carboxylate (308 mg, 999 μmol) and 4-(trifluoroacetamidomethyl)imidazole (1.72 g, 8.91 mmol) in acetonitrile (10 ml) was added triethylamine (3.00 ml, 21.5 mmol), and the mixture was stirred for 15 hours at 130° C. in sealed tube. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by means of silica gel column chromatography [methylene chloride] to obtain 179 mg of the title compound as light brown powder. Yield 37%.