Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:8]=1[C:9]([NH:11][CH2:12][C:13](=[O:29])[NH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)=[O:10])(=O)C.Cl>CO.O1CCCC1>[Cl:34][C:31]1[CH:32]=[CH:33][C:7]([OH:6])=[C:8]([CH:30]=1)[C:9]([NH:11][CH2:12][C:13](=[O:29])[NH:14][C:15]1[CH:16]=[C:17]([C:25]([F:27])([F:28])[F:26])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:10]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)NCC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CNC(=O)c1cc(Cl)ccc1O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.7 %

Procedure:
5N Aqueous sodium hydroxide (0.1 mL) was added to a solution of 2-acetoxy-5-chloro-N-({[3,5-bis(trifluoromethyl)phenyl]carbamoyl}methyl)benzamide (83.7 mg, 0.17 mmol) in methanol/tetrahydrofuran (2 mL+1 mL), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) and washed with n-hexane under suspension to give the title compound (47.7 mg, 63.7%) as a white crystal.
Reaction SMILES: [H][H].C([N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[C:17]([OH:28])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([O:26][CH3:27])=[CH:21][CH:20]=3)[CH2:12][CH2:11]1)C1C=CC=CC=1.C1COCC1>[Pd].CO>[CH3:27][O:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:28])[C:16]([CH:13]1[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1)=[CH:25]2
Reactant: COc1ccc2nc(O)c(C3=CCN(Cc4ccccc4)CC3)cc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(=O)c(C3CCNCC3)cc2c1
Reaction time: 2 h

Procedure:
In a hydrogen atmosphere 160 mg (0.46 mmol) 3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6-methoxy-quinolin-2-ol and 20 mg palladium on charcoal (10%) in 30 mL MeOH were hydrogenated for 17.5 h at 50° C. at 50 psi. Then another 10 mL THF and catalyst were added and the mixture was hydrogenated for a further 2 h. Catalyst was added again and the mixture was hydrogenated overnight at 50° C. in a hydrogen atmosphere of 60 psi. After filtration of the reaction mixture the filter cake was washed with DMF and the filtrate was evaporated down. The residue was added to EtOAc, triturated with PE and filtered. The precipitate was washed with diisopropylether and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][C:14](=[O:16])[NH:15][C:8]=23)=[CH:4][CH:3]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)Cl>N1C=CC=CC=1>[O:16]=[C:14]1[NH:13][C:9]2=[N:10][CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][C:26]([NH:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:27])=[CH:3][CH:4]=3)=[C:8]2[NH:15]1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1
Temperature: 50 °C
Yield: 68.7 %

Procedure:
Method H1 (in Pyridine). 7-(4-Aminophenoxy)-2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridine (65 mg, 0.27 mmol) was suspended in dry pyridine (3 mL) and heated at 50° C. Phenyl isocyanate (30 μL, 0.28 mmol) was added; the solution became clear. The reaction mixture was heated at reflux for 2 hours, then it was allowed to cool at room temperature. DCM (20 mL) was added, the precipitate formed was recovered by filtration and washed with more DCM, to afford 1-(4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-7-yl-oxy)phenyl)-3-phenyl-urea (67 mg, 69%). 1H-NMR (δ, ppm, DMSO-d6): 6.34 (d, 1H, HPy,5, J=7.5 Hz), 6.98 (t, 1H, Harom,Ph′,4, J=7.5 Hz), 7.13 (d, 2H, Harom,Ph,3+5, J=8.75 Hz), 7.29 (t, 2H, Harom,Ph′,3+5), 7.46 (d, 2H, Harom,Ph′,2+6), 7.53 (d, 2H, Harom,Ph,2+6), 7.76 (d, 1H, HPy,6) 8.67 (s, 1H, NHurea,1), 8.76 (s, 1H, NHurea,3), 11.19 (s, 1H, NHPy3), 11.35 (s, 1H, NHPy2). LC-MS (m/z): 362 (M+H, 100).
Reaction SMILES: O[C:2]1([CH3:29])[CH:26]=[C:25]2[C@:20]([CH3:27])([CH2:21][CH2:22][CH2:23][CH2:24]2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1.CC(C)[O-:32].[Al+3].CC(C)[O-].CC(C)[O-].CC(=O)CC.N#N>C1(C)C=CC=CC=1>[CH3:29][C:2]1[C@@H:3]2[C@@H:19]([C@:20]3([CH3:27])[C:25]([CH:26]=1)=[CH:24][C:23](=[O:32])[CH2:22][CH2:21]3)[CH2:18][CH2:17][C@@:16]1([CH3:28])[C@H:4]2[CH2:5][CH2:6][C@@H:7]1[C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: CC(C)[O-]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@@]1(C)CCCCC1=CC3(C)O
Agent: N#N
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(C)=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 89.2 %

Procedure:
A mixture of methyl 7-hydroxy-7-methylchol-5-en-24-oate (8) (2.0 g, 4.78 mmoles), aluminum isopropoxide (1.17 g, 5.72 mmoles), 2-butanone (8.6 ml, 96 mmoles) in toluene (40 ml) was heated at 80° in a N2 atmosphere for 6 hrs. About 15 ml of solvent was distilled from the reaction mixture at atmospheric pressure. Toluene (30 ml) was added, and the mixture was extracted with 3N HCl (2 times), H2O (3 times) and dried with MgSO4. Evaporation in vacuo gave 1.7 g of an orange oil that was purified by flash chromatography on silica gel with hexane-EtOAc (7:2 and 2:1 ) to give 0.62 g of pure 9 as a colorless syrup. NMR (CDCl3): δ0.76 (s, 3H, 18-Me); 0.94 (d, 3H, 20-Me); 1.08 (s, 3H, 19-Me); 3.67 (s, 3H, CO2Me); 5.59 (s, 1H, 4H); 5.95 (s, 1H, 6-H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[C:16](=[O:18])[CH3:17])([CH3:3])[CH3:2].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:19][CH2:17][C:16]([C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][C:8]([CH:10]([CH3:11])[CH3:12])=[CH:7][C:6]=1[CH:13]([CH3:15])[CH3:14])=[O:18]
Reactant: CC(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)c1cc(C(C)C)c(C(=O)CBr)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 1 (2,4,6-triisopropylphenyl)ethanone (10.0 g, 65.3 mmol) in acetonitrile (81 mL) was added tetrabutylammoniumtribromide (TBABr3, 19.6 g, 40.6 mmol). The reaction was stirred at room temperature for 3.0 h. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(2,4,6-triisopropylphenyl)ethanone (13.2 g), which was used directly for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]([CH3:33])([CH3:32])[CH2:9][C:10]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH:11]=[N:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([F:26])([F:25])[F:24])=[N:18]3)[CH:7]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]([CH3:32])([CH3:33])[CH2:9][C:10]([C:28]([F:29])([F:30])[F:31])([OH:27])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([F:26])([F:24])[F:25])=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(C(F)(F)F)ccc12)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(C(F)(F)F)ccc12)C(F)(F)F

Procedure:
Analogously to Example 37, 500 mg (0.99 mmol) of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-1-(2-(trifluoromethyl)quinolin-5-ylimino)-pentan-2-ol is reacted with 154 mg (4.04 mmol) of sodium borohydride in 5.0 ml of methanol. After purification on silica gel with hexane-ethyl acetate (0-100%), 420 mg (84% of theory) of the product is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[N+:23]([O-])([OH:25])=[O:24]>>[N+:23]([C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:7]([CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)[C:8](=[O:9])[CH2:10][CH2:11]2)([O-:25])=[O:24]
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(4-Piperidinyl)-3,4-dihydrocarbostyril (0.2 g) is added to conc. sulfuric acid (5 ml) and thereto is added fuming nitric acid (0.1 ml) under ice cooling. The mixture is stirred at room temperature for 30 minutes, and then the reaction mixture is poured into ice-water. The mixture is basified and extracted with dichloromethane. The solvent is concentrated to give 6-nitro-1-(4-piperidinyl)-3,4-dihydrocarbostyril (0.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:17])=[CH:14][CH:13]=1)#[N:11]
Reactant: COc1ccc(N)cc1
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: COc1ccc(NC(=O)c2ccc(C#N)cc2)cc1
Yield: 91.6 %

Procedure:
Using p-anisidine (1.35 g, 11.0 mmol) and 4-cyanobenzoic acid (1.47 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 2.31 g (91.7%) of the title compound in the form of colorless needle crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Br.[CH3:6][N:7]([CH3:34])[C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:17]=2)[CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:34][N:7]([CH3:6])[C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24](=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:4][CH2:3][O:2][CH3:1])=[CH:29][CH:30]=3)[CH:17]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N(C)C)c2)cc1NC(=O)c1ccc(O)cc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(=O)Nc2cc(C(=O)Nc3cccc(N(C)C)c3)ccc2C)cc1
Temperature: 25 °C

Procedure:
2-Bromoethyl methyl ether (0.033 ml) was added to a stirred suspension of N-(3-dimethylaminophenyl)-3-(4-hydroxybenzamido)-4-methylbenzamide (0.9 g) and anhydrous potassium carbonate (0.064 g) in DMF (10 ml) and the resultant mixture was stirred at 80° C. for 5 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was triturated under diethyl ether. There was thus obtained the title compound as a solid (0.073 g); NMR Spectrum: (DMSOd6) 2.28 (s, 3H), 2.87 (s, 6H), 3.31 (s, 3H), 3.67 (m, 2H), 4.18 (m, 2H), 6.43 (d, 1H) 7.12 (m, 5H), 7.37 (d, 1H), 7.78 (d, 1H), 7.97 (m, 3H), 9.87 (s, 1H), 9.96 (s, 1H); Mass Spectrum: M+H+448.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:28]([NH:31][CH:32]([CH3:34])[CH3:33])([CH3:30])[CH3:29]>CN(C=O)C>[OH:26][C@H:25]([CH2:27][N:31]([CH:32]([CH3:34])[CH3:33])[CH:28]([CH3:30])[CH3:29])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CN(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 19 h
Yield: 89 %

Procedure:
A mixture of (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.83 mmol), (prepared as described for the starting material in Example 292), and diisopropylamine (1.35 ml, 9.7 mmol) in DMF (5 ml) was stirred at 70° C. for 19 hours under an atmosphere of nitrogen then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified on silica gel using gradient elution with dichloromethane, dichloromethane/methanol (95/5), dichloromethane/methanolic ammonia (7M) (98/2 to 90/10) to give (2R)-7-(2-hydroxy-3-((N,N-diisopropyl)amino)propoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (343 mg, 86%).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([Br:20])=[CH:13][N:12]=1>C(#N)C.[F-].[K+]>[Br:20][C:14]1[CH:15]=[C:16]([C:4]2[CH:3]=[C:2]([F:1])[N:7]=[CH:6][C:5]=2[NH2:8])[C:11]([F:10])=[N:12][CH:13]=1
Reactant: Nc1cnc(F)cc1I
Reactant: OB(O)c1cc(Br)cnc1F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cnc(F)cc1-c1cc(Br)cnc1F
Temperature: 80 °C
Yield: 28.6 %

Procedure:
A mixture of 6-fluoro-4-iodopyridin-3-ylamine (1.57 g, 6.59 mmol), 2-fluoro-5-bromopyridine-3-boronic acid (2.17 g, 9.89 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.43 g, 0.53 mmol) in acetonitrile (25 mL) and 1N aqueous potassium fluoride solution (25 mL) was degassed with nitrogen for 20 minutes. The reaction mixture was heated at 80° C. for 3 h, allowed to cool to ambient temperature and then partitioned between ethyl acetate (100 mL) and water (75 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, 40 g column, ISCO, 0-50% ethyl acetate in cyclohexane) to afford the title compound as an brown solid (0.54 g, 29%). 1H NMR (CDCl3, 300 MHz): 8.37 (dd, J=2.5, 1.4 Hz, 1H), 7.99 (dd, J=8.1, 2.5 Hz, 1H), 7.79 (d, J=1.5 Hz, 1H), 6.74 (d, J=2.8 Hz, 1H), 3.62 (s, 2H). LCMS (Method B): RT=3.01 min, M+H+=286/288.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[S:7][C:6]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C@@H:35]([OH:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:5][CH:4]=1>O1CCOCC1.C(Cl)Cl>[ClH:2].[ClH:1].[Cl:2][C:3]1[S:7][C:6]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C@@H:35]([OH:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:5][CH:4]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
4.0M hydrogen chloride in 1,4-dioxane (2.508 mL) was added to a solution of tert-butyl (S)-2-(5-chlorothiophen-2-yl)-3-(4-((5R,7R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropylisopropylcarbamate (283 mg, 0.502 mmol) in 1,4-dioxane (2.5 mL) and methylene chloride (2.5 mL) at 0° C. The mixture was allowed to warm up to room temperature and stirred for 1 hour. The mixture was concentrated in vacuo. The residue was then dissolved in a minimum volume of DCM (1 mL) and added dropwise to ether (10 mL) at 0° C. with stirring. A white solid precipitated. The solvents were evaporated with a rotovap in a 25° C. bath. The off-white solid was dried under high vacuum overnight to give (S)-2-(5-chlorothiophen-2-yl)-1-(4-((5R,7R)-6,7-dihydro-7-hydroxy-5-methyl-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (537 mg, 99.9%). MS (APCI+) [M+H]+464.1. 1H NMR (D20, 400 MHz) δ 8.53 (s, 1H), 6.97 (d, J=4.0 Hz, 1H), 6.96 (d, J=4.0 Hz, 1H), 5.40 (t, J=8.0 Hz, 1H), 4.78-4.71 (m, 1H), 4.31-4.27 (m, 1H), 4.09-3.97 (m, 2H), 3.84-3.42 (m, 10H), 2.36-2.30 (m, 1H), 2.21-2.13 (M, 1H), 1.33 (d, J=6.4 Hz, 3H), 1.32 (d, J=6.4 Hz, 3H), 1.14 (d, J=6.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:16]([NH:18][C:19](=[O:37])[C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[C:23]([CH3:35])=[C:22]([F:36])[CH:21]=1)[CH3:17].C(=O)([O-])O.[Na+]>C(O)(C)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>[CH2:16]([NH:18][C:19](=[O:37])[C:20]1[CH:25]=[C:24]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:11]4[CH2:15][CH2:14][O:13][CH2:12]4)=[N:7][NH:8]3)=[CH:4][CH:3]=2)[C:23]([CH3:35])=[C:22]([F:36])[CH:21]=1)[CH3:17]
Reactant: CCNC(=O)c1cc(F)c(C)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1ccc2c(C3CCOC3)n[nH]c2c1
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: [Na+]
Solvent: CC(C)O
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4CCOC4)n[nH]c3c2)c1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
A mixture of 6-bromo-3-(tetrahydro-3-furanyl)-1H-indazole (Intermediate 9, 84 mg) N-ethyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5, 97 mg) aqueous sodium hydrogen carbonate (1M, 630 μL) and tetrakis(triphenylphosphine)palladium (7 mg) in isopropanol (4 ml) in a sealed vial was stirred at 150° C. for 15 min in a microwave oven. The solvent was removed under vacuum and the residue purified by chromatography on a silica column eluting with cyclohexane:ethyl acetate (50:50 to 0:100) to give the title compound as a white solid (44 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:6][C:21](=[O:22])[C:13]3[N:9]2[C:10]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[N:11][C:12]=3[CH3:14])=[CH:7][CH:8]=1
Reactant: Cc1cn(-c2cc(Cl)ccc2N)c(C2CCCCC2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(C2CCCCC2)n2c1c(=O)[nH]c1ccc(Cl)cc12

Procedure:
1.45 g 4-Chloro-2-(2-cyclohexyl-4-methyl-imidazol-1-yl)-aniline were stirred in 25 ml toluene. 1.0 g Carbonyldiimidazole was added and the mixture was refluxed for 6 hours. After cooling 25 ml water was added, the product was filtered off, washed with 20 ml water and 25 ml toluene and dried.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][SH:20])[CH3:15].O>CN(C=O)C>[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][S:20][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1)[CH3:15]
Reactant: Nc1ncc(Br)s1
Reactant: CCOC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCSc1cnc(N)s1
Yield: 49.3 %

Procedure:
5-Bromo-2-aminothiazole (25 g, 96 mmol) in DMF (150 mL) was added K2CO3 (26.5 g, 192 mmol) and the mixture was purged with N2 for 5 min. The mixture was cooled to 0° C. on an ice bath before 3-mercaptopropionic acid ethyl ester (12.9 g, 96 mmol) was added dropwise over the course of 30 min. The reaction mixture was stirred for 16 hours before water (400 mL) was added. The aqueous mixture was extracted with Et2O (1×500 mL, 2×250 mL). The combined organic phases was washed with saturated NH4Cl (3×150 mL), dried (MgSO4). The solvent was removed in vacuo to give a dark residue which was purified by column chromatography (SiO2, EtOAc-heptane (1:1)). The solvent was removed in vacuo to give 11 g (49%) of the desired compound.
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][CH2:11][CH2:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:19][CH:20]=O>CO>[C:2]1([C:1]2[CH:19]=[CH:20][N:9]3[C:8]=2[CH2:12][CH2:11][CH2:10]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2=NCCC2)cc1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: c1ccc(-c2ccn3c2CCC3)cc1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
2-Benzyl-1-pyrroline (Example 1b, 85%, 74 g, 0.395 mol), dissolved in MeOH (360 ml), is treated with NaHCO3 (38 g, 0.45 mol), and the mixture is cooled to 5° C. A solution of chloroacetaldehyde (45% strength in water, 68 g, 0.4 mol), dissolved in MeOH (100 ml) is added dropwise to the solution at this temperature, and the mixture is stirred for 18 h with exclusion of light.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.Cl[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]1>>[CH3:19][N:15]1[CH2:16][CH2:17][CH2:18][CH:13]([CH2:12][O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:14]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CN1CCCC(CCl)C1
Product: CN1CCCC(COc2ccc(N)cc2)C1

Procedure:
Using the procedure of Example 56, 4-nitro-phenol Compound 104a was used in place of Compound 36a and 3-chloromethyl-1-methyl-piperidine Compound 104b was used in place of Compound 56a and carried forward to provide 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine Compound 104d. MS 221 (MH+). Using the procedure of Example 1, 5-(2,4-dichloro-phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,6,8-tetraaza-acenaphthylene-2-carboxylic acid Compound 43c was used in place of Compound 1 and Compound 104d was used in place of 4-piperidin-1-ylmethyl-phenylamine Compound 1k to give Compound 32. MS 583, 585, 587 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]=[C:18]=S.[Cl:20][C:21]1[C:22]([N:30]2[CH2:35][CH2:34][CH:33]([F:36])[CH2:32][CH2:31]2)=[CH:23][C:24]([NH:28][CH3:29])=[C:25]([CH:27]=1)[NH2:26].CC(C)N=C=NC(C)C>>[F:16][C:4]1[C:3]([NH:17][C:18]2[N:28]([CH3:29])[C:24]3[CH:23]=[C:22]([N:30]4[CH2:31][CH2:32][CH:33]([F:36])[CH2:34][CH2:35]4)[C:21]([Cl:20])=[CH:27][C:25]=3[N:26]=2)=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=1[CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1F
Reactant: CNc1cc(N2CCC(F)CC2)c(Cl)cc1N
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2F)nc2cc(Cl)c(N3CCC(F)CC3)cc21
Yield: 49 %

Procedure:
The title compound is prepared from N-(4-chloro-2-fluoro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide and 5-chloro-2-methylamino-4-(4-fluoropiperidin-1-yl)-aniline and DIC in analogy to example 51.
Reaction SMILES: [NH2:1][C:2]1[NH:18][C:5]2=[CH:6][C:7]3[C:8]([CH3:17])([CH3:16])[C:9](=[O:15])[N:10]([CH2:13][CH3:14])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[CH2:13]([N:10]1[C:11]2[CH:12]=[C:4]3[N:3]=[C:2]([NH:1][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:18][C:5]3=[CH:6][C:7]=2[C:8]([CH3:17])([CH3:16])[C:9]1=[O:15])[CH3:14]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Yield: 67.9 %

Procedure:
A solution of D3 (500 mg) and benzoyl chloride (0.6 ml; 5.12 mmol) in pyridine (15 ml) is stirred at RT for 20 h. After completion, water is added and the aqueous layer is extracted with EtOAc. The combined organic layer is washed with hydrochloric acid (1 N), saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with CH2Cl2/MeOH (30:1) afford the title compound (484 mg).