Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].C[N:11]1[CH2:20][CH2:19][C@H:18]2[C@H:13]([C:14]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:15]=3[C:16](=[O:21])[CH2:17]2)[CH2:12]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH3:27][C:22]1[C:15]2[C:16](=[O:21])[CH2:17][CH:18]3[CH:13]([C:14]=2[CH:25]=[C:24]([CH3:26])[CH:23]=1)[CH2:12][N:11]([C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3])[CH2:20][CH2:19]3
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1cc(C)c2c(c1)[C@@H]1CN(C)CC[C@@H]1CC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1)C1CN(C(=O)OCC(Cl)(Cl)Cl)CCC1CC2=O
Temperature: 25 °C
Yield: 97.3 %

Procedure:
a 2.1) 0.76 ml (5.65 mmol) of 2,2,2-trichloroethyl chloroformate was added at 1000 to a suspension of 500 mg (2.26 mmol) of (+)-cis-2,7,9-trimethyl-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one and 120 mg of K2CO3 in 20 ml of toluene and the mixture was heated at reflux for 16 hours. Subsequently, the solution was cooled to room temperature and poured on to 40 ml of ice-water. The aqueous phase was extracted twice with 50 ml of ethyl acetate, dried (MgSO4), filtered and evaporated. Chromatography of the residue (silica gel, hexane/ethyl acetate 4:1) yielded 890 mg (97%) of 2,2,2-trichloroethyl 7,9-dimethyl-6-oxo-3,4,4a,5,6,10b-hexahydro-1H-benzo[h]isoquinoline-2-carboxylate as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH:25]=O.CO.[BH3-]C#N.[Na+]>CCOC(C)=O.C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:25][C:24]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:22]([O:21][CH3:20])[CH:23]=2)[N:13]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
The operation is carried out as in Stage 2 of Example 7 starting from 280 mg of the product obtained in Stage 1 of Example 7, 275 mg of 3,4,5 trimethoxybenzaldehyde in place of the benzaldehyde, 4 ml of methanol and 0.2 ml of acetic acid then the reaction medium is agitated at ambient temperature for 5 hours. Then 100 mg of NaBH3CN is added and the reaction medium is agitated at ambient temperature for approximately 1 hour. 10 ml AcOEt is added, followed by washing with 2×5 ml H2O, then 5 ml of a saturated aqueous solution of NaCl, drying and evaporating the solvent. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 95/05/0.33, 305 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][Si](C)(C)C)=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH:21]1[C:26](=[O:27])[C:25]([CH3:29])([CH3:28])[O:24][C:23]([CH3:31])([CH3:30])[C:22]1=[O:32])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[CH:16])=[CH:13][CH:14]=2)=[CH:5][C:4]=1[CH:21]1[C:22](=[O:32])[C:23]([CH3:31])([CH3:30])[O:24][C:25]([CH3:29])([CH3:28])[C:26]1=[O:27])[CH3:2]
Reactant: CCc1ccc(-c2ccc(C#C[Si](C)(C)C)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(-c2ccc(CC)c(C3C(=O)C(C)(C)OC(C)(C)C3=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a solution of 4-[4-ethyl-4′-(trimethylsilylethynyl)biphenyl-3-yl]-2,2,6,6-tetramethyl-pyran-3,5-dione (0.143 g, 0.32 mmol) in methanol (6.5 ml) is added powdered potassium carbonate (0.177 g, 1.28 mmol), and the mixture is stirred at room temperature for 1 hour. Water is then added to dissolve all inorganics, and the mixture is concentrated in vacuo. 2M hydrochloric acid is added to achieve pH 2-3, then the desired material is extracted with ethyl acetate (×3). All organics are combined, washed with brine, dried over anhydrous magnesium sulfate then concentrated in vacuo. The residue is further purified by flash column chromatography on silica gel (hexane/ethyl acetate 4:1 ratio) to afford 4-(4-ethyl-4′-ethynylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.070 g) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N:5][O:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:33]3)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:4]1[C:3]([CH2:2][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[CH:31][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:33]4)=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[C:7]([CH:8]([CH3:10])[CH3:9])[O:6][N:5]=1
Reactant: COC(=O)c1ccc2ccc(-c3ccc(O)cc3)cc2c1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2c1
Yield: 79.3 %

Procedure:
A solution of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (0.12 g, 0.36 mmol), methyl 7-(4-hydroxyphenyl)-2-naphthalenecarboxylate (0.084 g, 0.30 mmol), and cesium carbonate (137 mg, 0.42 mmol) in dimethylformamide (0.73 mL) was heated to 65° C. for 3 hours. The solution was partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered and concentrated. The filtrate was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.130 g, 68.4% as 1.0 ethyl acetate). 1H NMR (DMSO-d6): δ 8.66 (s, 1H), 8.34 (s, 1H), 8.04-8.00 (m, 2H), 7.94-7.90 (m, 2H), 7.69 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.55-7.51 (m, 1H), 6.91 (d, J=9 Hz, 2H), 4.87 (s, 2H), 3.90 (s, 3H), 3.46 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 546 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O.CC([O-])=O.[Na+]>CC(O)=O>[Cl:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]2[CH:1]=[CH:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=2[OH:21])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COc1cccc(C=O)c1O
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(C=Cc2nc3ccccc3c(=O)n2-c2ccc(Cl)c(Cl)c2)c1O
Yield: 41.7 %

Procedure:
Compound 63 (1 g, 0.028 mol), 2-hydroxy-3 methoxybenzaldehyde (9, 0.4 g, 0.003 mol) and NaOAc (0.233 g, 0.002 mol) in AcOH were heated under reflux for 10 hours. After cooling the precipitate formed was washed with water, filtered off, dried and recrystallized from EtOH to yield 64 (0.55 g, 71%). M. Wt. 439. LCMS [M+H]+=440.
Reaction SMILES: COP([CH2:7][C:8](=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)OC.[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[Cl-].[NH4+]>O1CCCC1>[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29](/[CH:30]=[CH:7]/[C:8](=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:32]=[CH:33][CH:34]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C=O)c1
Reactant: CCCCCCCCC(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCCC(=O)/C=C/c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Reaction time: 0.33 h

Procedure:
For Wittig-Horner olefination, 3.64 g of potassium-tertbutylate is added at -20° C. to a solution of 9.41 g of-2-oxo-decyl-phosphonic acid dimethyl ester in 280 ml of tetrahydrofuran and stirred for 20 minutes at this temperature. Then, a solution of 4.5 g of 3-tert-butyldimethylsilyloxymethylbenzaldehyde (see example 18A) in 150 ml of tetrahydrofuran is instilled in this solution and stirred for one hour at -20° C. It is poured on 500 ml of saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase is washed neutral with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue thus obtained is chromatographed on silica gel. With hexane/5-20% ethyl acetate, 6.5 g of 1-[3-(tert-butyldimethylsilyloxymethyl)-phenyl]-(1E)-undecen-3-one is obtained as colorless oil.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.CCN(CC)CC.[CH3:43][C:44]1([CH3:51])[C:48]([CH3:50])([CH3:49])[O:47][BH:46][O:45]1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[Cl:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([B:46]2[O:47][C:48]([CH3:50])([CH3:49])[C:44]([CH3:51])([CH3:43])[O:45]2)=[C:3]([NH2:10])[CH:4]=1
Reactant: Cc1cc(Cl)cc(N)c1Br
Reactant: CC1(C)OBOC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(Cl)cc(N)c1B1OC(C)(C)C(C)(C)O1
Temperature: 80 °C

Procedure:
2-Bromo-5-chloro-3-methyl-phenylamine (595 mg, 2.7 mmol, Example 135: step c), Pd(OAc)2 (30.3 mg, 0.14 mmol), 2-(dicyclohexylphosphino)biphenyl (189.2 mg, 0.54 mmol) and Et3N (1.5 mL, 10.8 mmol) were dissolved into dioxane (10 mL). To this was added 4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane (1.2 mL, 8.1 mmol) slowly. The reaction was heated to 80° C. overnight. The solvents were removed in vacuo and the resulting residue was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) and removal of the solvents in vacuo resulted in a mixture of the title compound and 3-Methyl-2,5-bis-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine were obtained and used with out further purification.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([NH:24][C:25](=[O:28])[CH2:26][OH:27])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:30]([C:32]1[O:33][CH:34]=[CH:35][C:36]=1B1OC(C)(C)C(C)(C)O1)=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.C(OCC)(=O)C>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([NH:24][C:25](=[O:28])[CH2:26][OH:27])[C:14]([C:36]3[CH:35]=[CH:34][O:33][C:32]=3[CH:30]=[O:31])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1NC(=O)CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C=O)c1NC(=O)CO
Temperature: 140 °C
Yield: 99.9 %

Procedure:
A mixture of tert-butyl 6-(benzenesulfonylmethyl)-3-bromo-2-(2-hydroxyacetylamino)benzoate (Intermediate 36, 0.165 g), 2-formylfuran-3-boronic acid pinacol ester (0.091 g), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride DCM complex (0.028 g) and cesium carbonate (0.311 g) in THF (4.3 mL) and water (0.7 mL) were sealed, under nitrogen, in a microwave vial and heated in the microwave at 140° C. for 10 minutes. After cooling, the mixture was diluted with ethyl acetate and water and the organic layer was separated, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give tert-butyl 6-(benzenesulfonylmethyl)-3-(2-formylfuran-3-yl)-2-(2-hydroxyacetylamino)-benzoate (0.17 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]12(O)[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>CC(O)=O.CCOC(C)=O>[C:15]12([C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=4)[CH:13]=[CH:12][C:11]=3[OH:14])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2
Reactant: Oc1ccc(-c2ccc(I)cc2)cc1
Reactant: OC12CC3CC(CC(C3)C1)C2
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2ccc(I)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To a mixture of 4′-iodobiphenyl-4-ol (0.332 g, 2 mmol) and 1-admantanol (0.15 g, 0.51 mmol) in AcOH (2 ml) concentrated H2SO4 (0.5 ml) was added and the reaction mixture was stirred for 50 h at room temperature. This was diluted to 100 ml with EtOAc and washed with NaHCO3 solution, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was crystallized from MeOH to give the product (0.195 g; 93%), as a colourless paste. 1H NMR (CDCl3) 1.78 (m, 6H); 2.07 (s, 3H); 2.15 (s, 6H); 6.69 (d, 1H, J=8.15 Hz); 7.21-7.28 (m, 3H); 7.37 (d, 1H, J=2.28 Hz); 7.69 (d, 2H, J=8.45 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10](N(CC)CC)[CH3:11].CC(C)(O)C#C>ClCCl.C1(C)C=CC=CC=1.O.[Cu]I>[Br:9][C:5]1[CH:6]=[C:7]2[C:2](=[N:3][CH:4]=1)[NH:1][CH:11]=[CH:10]2
Reactant: Nc1ncc(Br)cc1I
Reactant: CCN(CC)CC
Agent: [Cu]I
Agent: C#CC(C)(C)O
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Brc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
A suspension of 2-amino-5-bromo-3-iodopyridine (5.0 g, 16.7 mmol), bis-(triphenyl-phosphine)-palladium(II)-dichloride (43 mg, 0.061 mmol), copper(I)iodide (29.4 mg, 0.15 mmol) and triethylamine (2.21 g, 21.8 mmol) in dichloromethane (20 mL) was treated at 23 to 30° C. within 1 to 2 hours with a solution of 1,1-dimethyl-2-propyn-1-ol (1.85 g, 21.7 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at 25° C. for 4 hours. The mixture was diluted with dichloromethane (10 mL) and washed with water (2×25 mL). The organic phase was then treated with 1 M HCl (40 mL). The layers were separated and the organic layer was extracted with 1 M HCl (15 mL). The combined product containing aqueous layers were washed with dichloromethane (2×8 mL). The pH of the aqueous layer was adjusted to pH 7-9 by the drop wise addition of sodium hydroxide solution (28% in water). The resulting suspension was stirred at 20° C. over night and the crystals were then filtered off and washed with water (2×5 mL). The wet crystals were dissolved in N-methylpyrrolidone (50 mL) and treated within 2 hours at 60° C. and 50-100 mbar with an aqueous solution of lithium hydroxide (2.4 M, 32 mL). The resulting mixture was heated to 75° C. and stirred at this temperature and under reduced pressure (50-100 mbar) for 15-20 hours. Toluene (20 mL) and water (20 mL) were then added and the layers were separated. The aqueous layer was extracted with toluene (3×25 mL). The combined organic layers were washed with water (3×10 mL) and then concentrated to dryness. The residue was dissolved in N-methylpyrrolidone (50 mL) and treated at 60° C. with potassium tert.-butylate (3.52 g, 30.7 mmol). After stirring for 3 hours at 60° C., the mixture was cooled to ambient temperature and diluted with toluene (40 mL) and water (40 mL). The aqueous layer was separated and back extracted with toluene (3×50 mL). The combined toluene layers were washed with water (3×10 mL) and then concentrated to dryness. The residue was dissolved in a hot mixture of toluene and n-heptane (20 mL). The clear solution was cooled to −5° C. within 4 to 6 hours whereupon crystals precipitated. The suspension was stirred at −5° C. for 2-4 hours. The crystals were filtered off, washed with heptane and dried at 45° C./<30 mbars over night to afford 5-bromo-7-azaindole (2.05 g, 62% yield) as slightly yellow crystals with a purity of 99.6% (HPLC, area%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:17][C:16]2[N:12]([N:13]=[N:14][C:15]=2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=2[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[C:36]([O:40][C:41]([NH:43][C@H:44]([CH2:49][C:50]1[CH:55]=[C:54]([F:56])[C:53]([F:57])=[CH:52][C:51]=1[F:58])[CH2:45]C(O)=O)=[O:42])([CH3:39])([CH3:38])[CH3:37].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)CCl>[C:36]([O:40][C:41](=[O:42])[NH:43][CH:44]([CH2:49][C:50]1[CH:55]=[C:54]([F:56])[C:53]([F:57])=[CH:52][C:51]=1[F:58])[CH2:45][C:6]([N:8]1[CH2:17][C:16]2[N:12]([N:13]=[N:14][C:15]=2[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=2[CH2:9]1)=[O:7])([CH3:37])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2-n2nnc(-c3ccc(F)cc3)c2C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(CC(=O)N1Cc2ccccc2-n2nnc(-c3ccc(F)cc3)c2C1)Cc1cc(F)c(F)cc1F

Procedure:
3-(4-Fluoro-phenyl)-4H,6H-1,2,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester was deprotected using trifluoroacetic acid and the resulting salt was coupled with (R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid using HOBT, EDC and DIPEA. The desired compound was obtained as a viscous oil.
Reaction SMILES: S1C=CN=C1.[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[S:24][CH:25]=[C:26]([CH2:28][CH3:29])[N:27]=4)=[CH:18][CH:17]=3)[C:8]=12.Br[CH2:44][C:45]([C:47]1C=CC=C[CH:48]=1)=O>>[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23]4[S:24][CH:25]=[C:26]([C:28]5[CH:48]=[CH:47][CH:45]=[CH:44][CH:29]=5)[N:27]=4)=[CH:20][CH:21]=3)[C:8]=12
Reactant: O=C(CBr)c1ccccc1
Reactant: CCc1csc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)n1
Agent: c1cscn1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc(-c6ccccc6)cs5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
The procedure for thiazole synthesis, described in the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-ethyl-1,3-thiazol-2-amine, was employed with the exception that 2-bromoacetophenone (0.131 g, 0.66 mmol) was used as the alkylating agent. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 8.7-9.8 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-phenyl-1,3-thiazol-2-amine as a yellow powder (0.036 g, 0.064 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 8.22 min; MS (MH)+ 566.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][S:23]([O:15][CH2:14][C:12]1[N:13]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[O:10][CH:11]=1)(=[O:25])=[O:24]
Reactant: CC1(c2nc(CO)co2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2nc(COS(C)(=O)=O)co2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methanol (235 mg, 1.27 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.24 mL, 1.68 mmol) followed by DMAP (16 mg, 0.13 mmol) and Ms-Cl (0.13 mL, 1.65 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (2-(2-methyl-[1,3]dioxolan-2-yl)oxazol-4-yl)methyl methanesulfonate as a brown oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 4-(azidomethyl)-2-(2-methyl-1,3-dioxolan-2-yl)oxazole as a brown oil. To a solution of the crude azide in THF (6 mL) were added polymer-supported Ph3P (1.2 eq.) and water (2 mL). The reaction mixture was stirred at 60° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was concentrated under reduced pressure, the residue triturated in EtOH and the solid filtered off. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 01: tR=0.31 min; [M+H]+=185.01.
Reaction SMILES: N[C:2]1C([N+]([O-])=O)=CC=C[C:3]=1OCC1OC1.C(N)(C)(C)C.[C:21]([NH:25][CH2:26][CH:27]([OH:40])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-])=O)[C:31]=1[NH2:39])([CH3:24])([CH3:23])[CH3:22]>C(O)C>[CH3:2][C:3]1[NH:39][C:31]2[C:30]([O:29][CH2:28][CH:27]([OH:40])[CH2:26][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:35][CH:34]=[CH:33][C:32]=2[N:36]=1
Reactant: CC(C)(C)NCC(O)COc1cccc([N+](=O)[O-])c1N
Reactant: Nc1c(OCC2CO2)cccc1[N+](=O)[O-]
Solvent: CC(C)(C)N
Solvent: CCO
Product: Cc1nc2cccc(OCC(O)CNC(C)(C)C)c2[nH]1

Procedure:
10.5 g. of the above 1-(2-amino-3-nitrophenoxy)-2,3-epoxy-propane were stirred for 30 hours at ambient temperature with 35 g. tert.-butylamine and 100 ml. ethanol. Subsequently, the reaction mixture was evaporated to dryness, the residue was dissolved in 200 ml. 2N hydrochloric acid, a small amount of undissolved material was filtered off with suction and the hydrochloric acid solution was shaken out several times with chlorofrom. 100 ml. 10N aqueous sodium hydroxide solution were then added to the aqueous acidic solution and the mixture extracted several times with ether. The ethereal extracts were dried over anhydrous sodium sulfate and then evaporated to about 100 ml., the base thereby separating out as a fine crystalline slurry by the use of ice cooling. There were obtained 10.5 g. 1-tert.-butylamino-2-hydroxy-3-(2-amino-3-nitrophenoxy)-propane; m.p. 75° - 77°C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)[CH:10]=2)[NH:5][CH:4]=1)#[N:2].[H-].[Na+].I[CH3:34]>CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:30])[C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)=[CH:20][CH:21]=3)[CH:10]=2)[N:5]([CH3:34])[CH:4]=1)#[N:2]
Reactant: CI
Reactant: COc1ccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(=O)NCCc3ccc4c(c3)c(C#N)cn4C)cc2)cn1
Reaction time: 3 h
Yield: 64.5 %

Procedure:
A solution of 0.250 g (0.631 mmol) N-(2-[3-Cyano-indol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide (reference example 1p) in 5 mL DMF is added to a cooled (0° C.) solution of 0.0328 g (0.820 mmol) sodium hydride (60% dispersion in mineral oil) in 2 mL DMF. After ten minutes 0.043 mL (0.69 mmol) iodomethane is added, and the cooling bath removed. After 3 hours, the reaction is quenched with water, concentrated, and the resulting residue flash chromatographed (2:2:1 CH2Cl2:EtOAc:hexanes) to provide 0.167 g of the product as a white solid in 65% yield. 1H NMR (CDCl3) δ 3.09 (2H, t, J=7 Hz), 3.80 (2H, m), 3.86 (3H, s), 3.99 (3H, s), 6.17 (1H, m, br), 6.83 (1H, d, J=8 Hz), 7.29 (1H, s), 7.37 (1H, d, J=8 Hz), 7.55-7.58 (3H, m), 7.64 (1H, s), 7.76-7.82 (3 H, m), 8.40 (1H, d, J=2 Hz). MS (ion spray) m/z 411 (M+H)+.