Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1)[CH2:7]2.[OH-].[Na+]>CO>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH:6]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[CH2:5]2
Reactant: COC(=O)c1ccc(OCCCC2Cc3c(c(OC)c(OC)c(OC)c3OC)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCOc1ccc(C(=O)O)cc1)C2
Yield: 92.5 %

Procedure:
To a solution of methyl 4-[3-(4,5,6,7-tetramethoxyindan-2-yl)propoxy]benzoate (7.35 g) in methanol (74 ml) was dropwise added aqueous sodium hydroxide (3N, 8.57 ml), which was heated under reflux for 6 hr. The reaction mixture was concentrated in vacuo, made acidic with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was recrystallized from hexane-ethyl acetate to yield the entitled compound (6.58 g) as crystals.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](O)=[CH:14][CH:15]=1.[OH-:17].[Ba+2:18].[OH-]>C1(C)C=CC=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11]([O-:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11]([O-:17])=[CH:12][CH:13]=[CH:14][CH:15]=1.[Ba+2:18]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: [OH-]
Agent: [Ba+2]
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1ccccc1[O-]

Procedure:
The barium nonylphenate is prepared by contacting nonylphenol (0.02 mole) and barium hydroxide (0.01 mole of Ba(OH)2) in the presence of 100 cc. of toluene. The mixture is agitated in the hot (60°-80° C.) until the barium hydroxide has entirely disappeared. About half the solvent is evaporated in vacuum so as to carry over all of the water formed and the concentrated solution is then made up to 100 cc. by means of fresh toluene. In this way there is obtained a solution of anhydrous barium nonylphenate in toluene of a concentration of about 1/10 M.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH2:31][CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=O)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:31][CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OCCN(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of (S)-benzyl 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (2.50 g, 7.80 mmol) in anhydrous DMF (20 mL) cooled to 0° C. in an ice bath was added a 60% dispersion of sodium hydride in mineral oil (0.47 g, 11.7 mmol). The mixture was allowed to warm to ambient temperature and stirred for 1 hour. 2-tert-Butoxyethyl methanesulfonate (2.3 g, 11.7 mmol) was added and the mixture was stirred at 0° C. in an ice bath, then allowed to slowly warm to ambient temperature and stirred for 18 hours. The mixture was partitioned between water (50 mL) and ethyl acetate (100 mL). The layers were separated and washed with aqueous 1N HCl, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 40M; 20% ethyl acetate/hexane) to afford (S)-benzyl 3-(tert-butoxycarbonyl(2-tert-butoxyethyl)amino)pyrrolidine-1-carboxylate (2.87 g, 88%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Li]CCCC.[C:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C1COCC1>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][C:25]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)([OH:28])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(C#N)c2)CC1
Temperature: -15 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
A solution of 3-Bromobenzonitrile (0.48 g, 2.64 mmol) in THF (20 mL) was stirred under nitrogen at −78° C. To this was added dropwise a solution of 2.0M nBuLi in hexanes (1.38 mL, 2.72 mmol). The solution was allowed to warm to −15° C. over 1.5 hours. The solution was recooled to −78° C. and a solution of N-Boc-4-piperidone (0.53 g, 2.64 mmol) in THF (5 mL) was added dropwise. The reaction mixture was allowed to warm to −10° C. and stirred at this temperature for three hours. The reaction was quenched with ½ saturated ammonium chloride solution (30 mL) and stirred 15 minutes. The THF was removed by evaporation and the residue extracted with methylene chloride (3×50 mL). The organic extracts were combined, dried over sodium sulfate, evaporated to give an orange oil which was purified by flash chromatography 3:5:2 methylene chloride: heptane: ethyl acetate to give the title compound (0.30 g) as a clear oil. 1H NMR [(CDCl3]: δ 7.82 (s, 1H), 7.72 (d, 1H), 7.58 (d, 1H), 7.55-7.42 (m, 1H), 4.20-3.95 (m, 2H), 3.35-3.10 (m, 2H), 2.08-1.83 (m, 2H), 1.80-1.66 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:25]=[C:24]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH3:35]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:22]1[CH:23]=[C:24]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:25]=[CH:20][C:21]=1[CH3:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)c2ccccc2)cc1I
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)c2ccccc2)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-iodo-1-methyl-4-(phenylsulfonyl)benzene (Intermediate 114), the title compound was obtained as a brown sticky solid in quantitative yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([CH:7]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:8]1=O)=O.O.[NH2:23][NH2:24].C(O)(=O)C>C(O)C>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]1[C:7]2[CH2:14][C:10]3[S:11][CH:12]=[CH:13][C:9]=3[C:8]=2[NH:24][N:23]=1
Reactant: NN
Reactant: COc1ccc(C(=O)C2Cc3sccc3C2=O)c(OC)c1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(-c2n[nH]c3c2Cc2sccc2-3)c(OC)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
5-(2,4-Dimethoxy-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.12 g, 3.69 mmol), hydrazine monohydrate (0.7 mL, 22 mmol), glacial acetic acid (0.6 mL) and ethanol (10 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(2,4-Dimethoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (2.5 g, 3.1 mmol) as yellow solid in 85% yield.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:8]=2[O:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([S:17]([N:20](COC)[C:21]3[N:22]=[N:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:18])=[C:12]([F:30])[CH:11]=2)=[CH:5][N:4](C2CCCCO2)[N:3]=1.NC1C(C2C=C(Cl)C=CC=2OC2C(Cl)=CC(S(/N=C3/N(COC)N=CC=C/3)(=O)=O)=C(F)C=2)=CN(C2CCCCO2)N=1>>[NH2:1][C:2]1[C:6]([C:7]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:8]=2[O:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([S:17]([NH:20][C:21]3[N:22]=[N:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:18])=[C:12]([F:30])[CH:11]=2)=[CH:5][NH:4][N:3]=1
Reactant: COCN(c1cccnn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2cn(C3CCCCO3)nc2N)cc1F
Agent: COCn1nccc/c1=N\S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2cn(C3CCCCO3)nc2N)cc1F
Product: Nc1n[nH]cc1-c1cc(Cl)ccc1Oc1cc(F)c(S(=O)(=O)Nc2cccnn2)cc1Cl

Procedure:
The title compound was prepared according to the procedure in Example 1036 using 4-{2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-chlorophenoxy}-5-chloro-2-fluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzenesulfonamide and 4-{2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-chlorophenoxy}-5-chloro-2-fluoro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]benzenesulfonamide (Preparation 891).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=1[CH:10]2[CH2:18][CH:19](OCC)[O:20]CC>O1CCCC1.Cl>[CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=1[CH:10]2[CH2:18][CH:19]=[O:20]
Reactant: CCOC(CC1C2=C(CCCC2)c2c(C)cc(C)c(OC)c21)OCC
Agent: Cl
Solvent: C1CCOC1
Product: COc1c(C)cc(C)c2c1C(CC=O)C1=C2CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
A tetrahydrofuran solution containing 1.45 g of 5,7-dimethyl-8-methoxy-9-(2,2-diethoxyethyl)-1,2,3,4-tetrahydro-9H-fluorene in 10 ml of tetrahydrofuran and 10 ml of 15% hydrochloric acid were stirred at room temperature for 3 hours. The reaction mixture was extracted with dichloromethane and the extract was washed with saturated aqueous sodium chloride solution and saturated sodium bicarbonate solution and then dried with magnesium sulfate. The solvent was distilled off to obtain 1.20 g of 5,7-dimethyl-8-methoxy-9-formylmethyl-1,2,3,4-tetrahydro-9H-fluorene.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.C(Cl)Cl.[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([CH2:19][C:20]([C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c[nH]c(C(=O)Cc2ccccc2)c1
Reaction time: 3 h
Yield: 5 %

Procedure:
Under nitrogen, methyl pyrrole-3-carboxylate (920 mg., 7 mmoles) was dissolved in 25 ml. of methylene chloride. Phenylacetyl chloride (930 mg., 6 mmoles) was added and dissolved. Finally, stannic chloride (1.2 ml., 12 mmoles) was added. The reaction mixture was stirred for 3 hours, water (15 ml.) added dropwise, diluted with 50 ml. of ether, the organic phase separated, washed with 20 ml. of water and evaporated to dryness to yield methyl 5-phenylacetylpyrrole-3-carboxylate (semisolid, Rf 0.3 on silica gel thin layer chromatography with ethyl acetate-1/hexane-5/5% acetic acid as eluant). The entire batch was employed without weight determination in the next step.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]2[N:25]([C:28](=[O:50])[CH:29]([NH:36][C:37](=[O:49])[CH:38]([N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH3:41])[CH3:39])[CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:26][CH2:27][CH:12]12)=O)C1C=CC=CC=1>CO.[Pd]>[C:45]([O:44][C:42](=[O:43])[N:40]([CH:38]([C:37](=[O:49])[NH:36][CH:29]([CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[C:28](=[O:50])[N:25]1[CH2:26][CH2:27][CH:12]2[NH:11][CH2:15][CH:14]([C:16](=[O:24])[NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]12)[CH3:39])[CH3:41])([CH3:46])([CH3:47])[CH3:48]
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C(=O)NC(C(=O)N1CCC2NCC(C(=O)Nc3ccccc3)C21)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 41 (440 mg, 0.64 mmol) and 10% palladium-on-carbon (88 mg) in MeOH (15 mL) was shaken at 48 psi under a H2 atmosphere. After 2 h, the mixture was filtered through a 0.45 μM filtering disc, washed with MeOH and concentrated to afford 42 (352 mg) as a white foam that was used without further purification. Mass spectrum, m/z [556.6] (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:19])[CH:25]=3)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=c1[nH]c2ccc(Br)cc2n1Cc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccc(-c3cccc(Cl)c3)cc2n1Cc1ccccc1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 16 %

Procedure:
A mixture of 1-benzyl-6-bromo-1,3-dihydro-benzoimidazol-2-one (0.75 g, 2.5 mmol), 3-chloro-phenyl boronic acid (0.4 g, 2.6 mmol), tetrakis(triphenylphosphine)-palladium (0) (0.23 g, 0.2 mmol), and potassium carbonate (0.72 g, 5.2 mmol) in toluene (15 mL) and H2O (8 mL) was subject to a blanket of nitrogen for 15 minutes at 50° C. and then heated to 85° C. for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate (100 mL) was added. The organic layer was washed twice with aqueous ammonium chloride (30 mL) and once with brine (30 mL), dried over magnesium sulfate and concentrated. After removal of the solvent, the residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 1-benzyl-6-(3-chloro-phenyl)-1,3-dihydro-benzoimidazol-2-one as a white solid (0.134 g, 16%): mp 168-169° C.; 1H-NMR (DMSO-d6) δ 11.0 (s, 1H), 7.66 (t, 1H, J=2.05 Hz), 7.58-7.5 (m, 1H), 7.45 (t, 2H, J=8.18 Hz), 7.37-7.22 (m, 7H), 7.08 (d, 1H, J=8.18 Hz), 5.1 (s, 2H);MS (ES) m/z 333([M−H]−, 100%); Anal. Calc. For C20H15ClN2O: C, 71.75, H, 4.52, N, 8.37. Found: C, 70.27, H. 4.56, N, 8.0.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:7][CH:6]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccc(O)nc1)c1ccccc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccccc2)cn1)c1ccccc1
Yield: 67.2 %

Procedure:
A solution of N-(6-hydroxy-pyridin-3-yl)-benzamide (0.64 g, 3.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate and filtered over a short pad of silica. Evaporation of the solvent in vacuo yielded the title compound (0.70 g, 68% yield) as a thick oil.
Reaction SMILES: C([SiH](CC)CC)C.[C:8]([N:11]1[C:17]2[CH:18]=[C:19]([C:22](=O)[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])[CH3:9]>FC(F)(F)C(O)=O>[C:8]([N:11]1[C:17]2[CH:18]=[C:19](/[CH:22]=[CH:23]/[CH2:24][N:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])[CH3:9]
Reactant: CC(=O)N1CCCCc2ccc(C(=O)CCN(C)C)cc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCCCc2ccc(/C=C/CN(C)C)cc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Triethyl silane (22.2 ml, 139 mmol) was added under a nitrogen atmosphere to a solution of 1-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-3-(dimethylamino)-1-propanone (5.00 g, 17.3 mmol) obtained in Reference Example 8 in trifluoroacetic acid, and then the mixture was stirred at room temperature for 5 days. After the solvent was distilled away under reduced pressure, ether was added to the residues which were then extracted with water. The aqueous layer was made basic with 8 N aqueous sodium hydroxide and then extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The resultant residues were purified by alumina column chromatography (developing solvent; hexane:ethyl acetate=1:1), whereby the title compound (2.74 g) was obtained as oily matter.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]1([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[O:20])[N:18]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:27][C:28]([F:44])([F:43])[C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])[N:30]=1>>[C:8]1([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:37](=[O:38])[C:36]4[CH:40]=[CH:41][CH:42]=[C:34]([C:31]5[N:30]=[C:29]([C:28]([F:44])([F:43])[F:27])[O:33][N:32]=5)[CH:35]=4)[CH2:23][CH2:22]3)=[O:20])[N:18]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1csc(-c2ccccc2)n1)N1CCNCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(C(=O)c2csc(-c3ccccc3)n2)CC1
Yield: 37 %

Procedure:
This compound was synthesized from (2-phenylthiazol-4-yl)(piperazin-1-yl)methanone TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (145 mg, yield 37%). 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.16-8.14 (m, 1H), 8.10 (s, 1H), 7.96 (m, 2H), 7.74-7.72 (m, 2H), 7.52 (m, 3H), 3.89-3.69 (m, 6H), 3.48 (s, 2H). MS (ESI) m/z: Calculated for C24H18F3N5O3S: 513.11. found: 514.3 (M+H)+
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:7][CH:8]([OH:29])[CH2:9][NH:10][C:11]([C:13]1[N:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5][CH3:6])[CH3:3].C(N(CC)CC)C.[C:37]([Cl:43])(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>C(Cl)Cl>[ClH:43].[CH2:2]([N:4]([CH2:7][CH:8]([OH:29])[CH2:9][NH:10][C:11]([C:13]1[N:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:15]2[C:20]([C:21]=1[O:22][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5][CH3:6])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCN(CC)CC(O)CNC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CC(O)CNC(=O)c1c(OC(=O)C(C)(C)C)c2ccccc2n1-c1ccccc1
Reaction time: 3 h

Procedure:
12.6 g of 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-hydroxy-1-phenylindole hydrochloride (0.03 mole) are mixed with 150 ml of methylene chloride, 4.2 ml of triethylamine (0.03 mole) and 3.9 ml of pivaloyl chloride (0.03 mole) and the reaction mixture allowed to stand for 3 h at room temperature. The mixture is subsequently washed with a saturated sodium chloride solution, dried over sodium sulfate and filtered. The solution is then evaporated, the residue dissolved in methylene chloride and purified by means of low pressure chromatography over silica gel acid. As the elution agent, first methylene chloride and subsequently methylene chloride containing 10% methanol are used. The 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-pivaloyloxy-1-phenylindole hydrochloride obtained as the residue after the evaporation of the eluate is then recrystallized from isopropanol. Melting point: 157°-159°.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CCN(C(=O)OC(C)(C)C)CC4)c4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(C4CCNCC4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
In a 10 ml round-bottomed flask, 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (46 mg, 0.069 mmol) was dissolved in dichloromethane (0.4 ml) and trifluoroacetic acid (0.22 ml, 2.86 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was suspended in dichloromethane (0.4 ml) and ethylenediamine (0.28 ml, 4.15 mmol) was added. The light yellow suspension was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The suspension was filtered and washed with hot water and ethyl acetate then dried under high vacuum to provide 27 mg (85%) of 2-(6-fluoro-1-piperidin-4-yl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow powder. MS: (M+H)+=436; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.08 (s, 1H), 8.47 (dd, J=8.9, 5.5 Hz, 1H), 8.39 (s, 1H), 7.96 (s, 1H), 7.77-7.85 (m, 1H), 7.10-7.22 (m, 1H), 4.70-4.88 (m, 1H), 3.13 (d, J=12.1 Hz, 2H), 2.67-2.81 (m, 2H), 2.01-2.20 (m, 2H), 1.88-2.01 (m, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10](Br)[CH:11]=1)=[O:5])[CH3:2].[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:25][O:24][CH3:23])=[CH:28][CH:29]=2)[CH:11]=1)=[O:5])[CH3:2]
Reactant: COCOc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cc(Br)nc2c1c(C)nn2C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(-c2ccc(OCOC)cc2)nc2c1c(C)nn2C1CCCCO1
Temperature: 85 °C
Reaction time: 1 h
Yield: 107.1 %

Procedure:
To a degassed mixture of 1.68 g 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester, 1.00 g 4-(methoxymethoxy)-phenylboronic acid and 0.70 g potassium carbonate in DME/water (v/v=2/1, 24 mL) at r.t. and under Ar-atmosphere 70 mg palladium(0) bis(tri-tert-butylphosphine) was added and the mixture was stirred at 85° C. for 1 h. To the mixture water and ethyl acetate were added, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. 2.08 g (100%) of the title compound were obtained.