Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][C:11](OCC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>>[O:12]=[CH:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a dry, cooled (−78° C.) solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate from Step A (1.00 g, 3.41 mmol) was added a solution of DiBAl—H (6.82 mL, 6.82 mmol, 1 M in CH2Cl2) slowly over 30 min. After an additional 30 min of stirring at −78° C., the reaction was quenched by the rapid addition of saturated aqueous Rochelle's salt (32 mL). The cooling bath was then removed and the reaction was allowed to rapidly stir until a noticeable decrease in the amount of emulsion was observed. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×30 mL). Combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of EtOAc:hexanes 5:95 to 40:60, to give the title compound. MS: m/z=150 (M−CO2C4H7).
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:54]1[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=1)CCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:54]2[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(-c2ccncc2)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Yield: 84.9 %

Procedure:
To a solution containing the product from Example 92D (0.50 g, 0.70 mmol) in N,N-dimethylformamide (7.0 mL) were added lithium chloride (0.30 g, 7.08 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.150 g, 0.214 mmol), and 4-tributylstannylpyridine (0.776 g, 2.11 mmol), and the mixture was heated to 100° C. for 18 hours. The reaction was filtered, diluted with ethyl acetate and washed with water, and brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in acetonitrile and washed twice with hexanes, and the acetonitrile layer was evaporated to give the title compound (0.422 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:32]=[CH:31][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1>>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]([C:21]2[CH:31]=[CH:32][C:18]([NH:1][C:2]3[N:7]=[C:6]([C:8]4[N:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]5=[N:10][CH:9]=4)[CH:5]=[CH:4][N:3]=3)=[CH:19][CH:20]=2)=[O:23])=[CH:25][CH:26]=1
Reactant: Cc1ccc(C(=O)c2ccc(Br)cc2)cc1
Reactant: Nc1nccc(-c2cnc3ccccn23)n1
Product: Cc1ccc(C(=O)c2ccc(Nc3nccc(-c4cnc5ccccn45)n3)cc2)cc1
Yield: 17 %

Procedure:
The title compound was prepared from 2-amino-4-(imidazo[1,2-a]pyridin-3-yl)pyrimidine and 4-bromo4′-methylbenzophenone following the general method of Example 2. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 98:2, as the eluent affording 52 mg (17% yield) of the title compound as a yellow solid: mp 238.9-239.2° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.15-10.13 (m, 2 H), 8.64 (s, 1 H), 8.50 (d, J=5.3 Hz, 1 H), 7.96 (d, J=8.5 Hz, 2 H), 7.79-7.74 (m, 3 H), 7.63 (d, J=7.8 Hz, 2 H), 7.53-7.49 (m, 2 H), 7.35 (d, J=7.7 Hz, 2 H), 7.16 (t, J=6.8 Hz, 1 H), 2.40 (s, 3 H); 13C NMR (400 MHz, DMSO-d6) δ 194.4, 159.4, 157.7, 157.4, 148.4, 145.1, 142.7, 139.4, 135.5, 131.5, 130.1, 129.9, 129.8, 129.3, 127.5, 121.3, 118.2, 117.8, 114.2, 108.6, 21.5; MS (TSP) m/z 406 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:27])[NH:14][C@@H:15]2[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16]2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:27])[NH:14][C@@H:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)N[C@@H]2CCN(Cc3ccccc3)C2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)N[C@@H]2CCNC2)C1
Reaction time: 8 h

Procedure:
To a solution of [(R)-1-((R)-1-benzyl-pyrrolidin-3-ylcarbamoyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester in ethanol under an inert atmosphere of argon is added palladium hydroxide on carbon. The reaction mixture is purged with nitrogen and placed under an atmosphere of hydrogen overnight. The mixture is filtered and the catalyst washed with ethanol. The organic portions are combined and concentrated in vacuo. The resulting brown oil is purified by column chromatography (Isolute™ Si, 2% MeOH in DCM) yield the title compound. MS (ES+) m/e 389.25 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1.C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1>C1COCC1>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:8]2[NH:9][C:15]1=[O:16]
Reactant: CNc1ncccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2cccnc21
Yield: 82.6 %

Procedure:
A solution of N2-methylpyridine-2,3-diamine (7 g) and CDI (13.82 g) in THF (100 mL) was refluxed for 5 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-100% EtOAc in hexane) to give 3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (7 g) as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][C@H:10]([NH:12]C(=O)OCC1C=CC=CC=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[NH2:12][C@H:10]([CH3:11])[CH2:9][N:8]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCN(C[C@@H](C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCN(C[C@@H](C)N)C(=O)OC(C)(C)C
Yield: 94.9 %

Procedure:
A suspension of 300 mg of (R)-benzyl 1-{tert-butoxycarbonyl(butyl)amino}propan-2-ylcarbamate and 30 mg of 10% palladium-carbon in 10 mL of methanol was vigorously stirred at room temperature for 16 hours in a hydrogen gas atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 180 mg of the title compound as a colorless oil (95%).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][N:8]2[C:16]([O:17][CH3:18])=[N:15][C:14]3[C:9]2=[N:10][C:11]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:12][C:13]=3[NH2:19])[CH2:4][CH2:3][CH2:2]1.F[C:26](F)(F)C(O)=O.C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.BrCCCBr.N1CCCC1>>[CH2:21]([O:20][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[C:16]([O:17][CH3:18])[N:8]2[CH2:7][CH2:6][CH2:5][N:1]2[CH2:2][CH2:26][CH2:3][CH2:4]2)=[C:13]([NH2:19])[N:12]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCC3)c2n1
Agent: BrCCCBr
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: C1CCNC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 20 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1,3-dibromopropane and pyrrolidine.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[H-].[Na+].[CH3:22][O:23][C:24](=[O:40])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][C:26]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39]>CN(C=O)C>[CH:2]1([CH2:7][CH2:8][N:9]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]([O:23][CH3:22])=[O:40])=[C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])[CH:27]=2)[S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:1]1
Reactant: Cc1ccc(S(=O)(=O)NCCC2CCCCC2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(CCC2CCCCC2)S(=O)(=O)c2ccc(C)cc2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.7 %

Procedure:
To a solution of N-2-cyclohexylethyl-p-toluenesulfonamide (300 mg) in DMF (5 mL) was added NaH (56 mg of a 60% dispersion in mineral oil). After gas evolution subsided, 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester (example 1178D, 266 mg) was added. After stirring at ambient temperature for 1.5 h, the reaction was quenched by addition of water (10 mL), and diluted with 50% EtOAc/hexane (50 mL). The organic solution was washed with water (10 mL), brine (2×10 mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexane to give the title compound as a colorless oil (250 mg, 70%).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH2:26][CH3:27])[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH3:25])[CH:16]=3)=[CH:9][CH:8]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[CH2:26]([N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:24][CH3:25])[CH:16]=2)[C:21]([C:22]#[N:23])=[C:13]1[C:10]1[CH:9]=[CH:8][C:7]([N:3]2[CH2:4][CH2:5][N:6]([CH3:29])[S:2]2(=[O:1])=[O:28])=[CH:12][CH:11]=1)[CH3:27]
Reactant: CCn1c(-c2ccc(N3CCNS3(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1c(-c2ccc(N3CCN(C)S3(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[4-(1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (34 mg, 0.086 mmol) in anhydrous DMF (1.0 mL) is added potassium carbonate (25 mg, 0.18 mmol) and iodomethane (20.4 mg, 0.144 mmol). The mixture is stirred at room temperature for 2 h and then diluted with water (6.0 mL) to give a precipitate. The precipitate is filtered, washed with water and dried to give 1-ethyl-6-methoxy-2-[4-(5-methyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-indole-3-carbonitrile, compound 726, as a white solid (35 mg, 98% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:32]=[CH:31][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=5)[N:17]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[F:52][C:53]1([F:59])[CH2:55][CH:54]1[C:56](O)=[O:57]>CN(C=O)C>[F:52][C:53]1([F:59])[CH2:55][CH:54]1[C:56]([NH:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:16]=[C:15]2[C:13]1[NH:12][C:11]2[CH:31]=[CH:32][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:9][C:10]=2[N:14]=1)=[O:57]
Reactant: CC1CCN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(N)cc45)nc3c2)CC1
Reactant: O=C(O)C1CC1(F)F
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1CCN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(NC(=O)C6CC6(F)F)cc45)nc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.4 %

Procedure:
3-(5-(4-Methylpiperidin-1-yl)-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (50 mg, 0.116 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (HOBt) (23.54 mg, 0.174 mmol), EDC (33.4 mg, 0.174 mmol) and sodium bicarbonate (9.76 mg, 0.116 mmol) was added to a solution of 2,2-difluorocyclopropanecarboxylic acid (14.18 mg, 0.116 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (35 mg). 1H NMR: (400 MHz, CD3OD): δ 8.49 (s, 1H), 7.75 (m, 1H), 7.66 (d, 1H, J=8.8 Hz), 7.54 (bs, 1H), 7.06 (m, 2H), 5.84 (dd, 1H, J=2.8 and 9.2 Hz), 3.96 (m, 1H), 3.80 (m, 1H), 3.58 (m, 2H), 2.69 (m, 4H), 2.11 (m, 3H), 1.82 (m, 4H), 1.70 (m, 2H), 1.49 (m, 1H), 1.41 (m, 2H), 0.99 (d, 3H, J=6.0 Hz); ESI-MS [M+H]+: 535.2.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6]O.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])=O.[Na+].[Na+].[OH:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])[C:22]=1[C:23](OC)=[O:24]>O>[F:34][C:33]([F:36])([F:35])[CH2:32][O:31][C:27]1[C:22]2[C:23]([OH:24])=[N:6][O:20][C:21]=2[CH:30]=[CH:29][CH:28]=1
Reactant: NO
Reactant: COC(=O)c1c(O)cccc1OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Solvent: O
Product: Oc1noc2cccc(OCC(F)(F)F)c12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of hydroxylamine sulfate (120 g, 732 mmol) in water (360 mL) was added potassium carbonate (121 g, 875 mmol) at 0° C. After 30 min of stirring, sodium sulfite (3.74 g, 29.7 mmol) and a methanolic solution of methyl 2-hydroxyl-6-(2,2,2-trifluoroethoxy)benzoate (36.4 g, 146 mmol, EXAMPLE 1, step 1, in 360 mL of methanol) were added to the mixture. Then the mixture was warmed to 50° C. and stirred for 30 h. After cooling to room temperature, reaction mixture was partially concentrated to approx. ⅔ volume and acidified with 2N hydrochloric acid. Product was extracted three times with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the desired product as a crystalline solid. Crude product (36.3 g) was used for the next step without further purification.
Reaction SMILES: C(Br)C1C=CC=CC=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:14][CH:15]=1.C(N(CC)CC)C.[H][H]>C(O)(C)C>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]=2)=[N:14][CH:15]=1
Reactant: [H][H]
Reactant: Cc1ccc(-c2ccncc2)nc1
Agent: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccc(C2=CCNCC2)nc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 40.1 %

Procedure:
Benzyl bromide in an amount of 10.5 g was added to a solution of 10 g of 5-methyl-2,4′-bipyridine in 70 mL of isopropyl alcohol, and stirred for 5 hours at 50° C. To the resulting reaction solution, 1.0 g of 2% palladium-S carbon and 6.0 g of triethylamine were added. This admixture was put in an autoclave, the autoclave's atmosphere was replaced twice with nitrogen gas under a nitrogen pressure of 196 kPa, and then hydrogen gas was blown into the autoclave over 3 hours at 80° C. under a hydrogen pressure of 196 kPa until the absorption of hydrogen gas in a volume of 4,200 mL was completed. After the replacement with nitrogen, the catalyst was filtered out and the resulting filtrate was concentrated under a reduced pressure of 1.33 kPa until the quantity thereof was reduced to 18.0 g. Further thereto, 50 mL of water and 10 g of a 25% aqueous solution of sodium hydroxide were added. The resulting solution was extracted with three 200 mL portions of ethyl acetate, and the organic layer was concentrated. The thus obtained solid was adsorbed to NH2-modified silica gel (produced by Biotage Japan, Ltd.), and eluted with ethyl acetate. The fraction obtained was concentrated, and the crystals thus deposited were dried to give 4.1 g of the intended compound as light yellow crystals. Yield rate: 40%, EI-MS: (m/z) 174 (M+), melting point: 78-80° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)[CH3:18].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:17]([C:19]1[CH:24]=[C:23]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:18]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CCc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1
Yield: 49.4 %

Procedure:
A microwave tube was charged with 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (152 mg, 0.54 mmol), 3-ethylphenylboronic acid (89 mg, 0.59 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (35 mg, 0.042 mmol), and K2CO3 (186 mg, 1.34 mmol). Dioxane (4 ml) and water (1 ml) were added, and the tube was microwaved at 150° C. for 45 min. The reaction mixture was filtered through a plug of celite. The filtrate was collected and partitioned between EtOAc/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a dark brown solid. The crude product was purified by silica gel chromatography using 20-50% EtOAc in hexanes as eluant provided 82 mg (50%) of 1-[2-(3-ethyl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow solid. MP 199-200.1° C., M+H=308.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH3:8].[Sn](Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>Cl>[Br:1][C:2]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH3:8]
Reactant: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2Br)cc1OC
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Product: COc1ccc(CCN(C)CCOc2ccc(N)cc2Br)cc1OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A portion (1.25 g. 2.73 mmol) of the 1-(2-bromo-4-nitrophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane produced in (3) above was slowly added to cooled conc. hydrochloric acid (50 ml), followed by adding of tin(II) chloride (2.1 g), stirring at 50° C. for 1 h and subsequent cooling. The reaction mixture was added to ice water and neutralized with an aqueous solution of potassium carbonate, followed by extraction with chloroform and drying with magnesium sulfate; subsequent concentration gave the end compound 1-(2-bromo-4-aminophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (1 g).
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.O>[CH:3]([S:4][C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:9]=1)=[CH2:2]
Reactant: COc1ccc(-c2nc(SCCBr)sc2-c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1

Procedure:
0.8 g of 2-(2-bromoethylthio)-4,5-bis-(p-methoxyphenyl)-thiazole are dissolved in 20 ml of toluene. 2 ml of a 30% strength solution of tetrabutylammonium hydroxide in water are added and the mixture is heated under reflux for 2 hours while stirring vigorously. The mixture is then allowed to cool, the organic phase is separated off, washed twice with 10 ml of water each time, dried over sodium sulphate and concentrated to dryness by evaporation. The crude product is purified by chromatography over a silica gel column with toluene/ethyl acetate (10:1) as eluant. The fractions that according to the thin layer chromatogram contain 2-vinylthio-4,5-bis-(p-methoxyphenyl)-thiazole are concentrated by evaporation and dried to constant weight. 2-Vinylthio-4,5-bis-(p-methoxyphenyl)-thiazole is obtained in the form of a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH2:32]([C:34]1[S:35][C:36]([CH3:53])=[C:37](/[CH:39]=[CH:40]/[C:41]2[C:42]([OH:52])=[N:43][N:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:45]=2)[N:38]=1)[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:32]([C:34]1[S:35][C:36]([CH3:53])=[C:37](/[CH:39]=[CH:40]/[C:41]2[C:42]([O:52][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:43][N:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:45]=2)[N:38]=1)[CH3:33]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)c(C)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(CC)sc4C)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 28.4 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.72 g), 4-[(E)-2-(2-ethyl-5-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol hydrochloride (1.39 g), potassium carbonate (1.11 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, tetrahydrofuran-hexane (1:5, v/v) to give ethyl {4-[4-({4-[({4-[(E)-2-(2-ethyl-5-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.80 g, yield 28%) as crystals. Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:27][NH:28][C@@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:37]=2)[NH:32][C:31]([CH3:45])([CH3:44])[CH2:30]1)[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(C(C)(C)C)(C)C.C(Cl)Cl.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>O>[CH3:44][C:31]1([CH3:45])[CH2:30][C@H:29]([NH:28][CH2:27][C@@H:9]([OH:8])[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:37]=2)[NH:32]1
Reactant: CC(C)(C)Cc1ccc2c(c1)[C@@H](NC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C)CC(C)(C)N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)Cc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C)CC(C)(C)N2
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (2S,3R)-3-(tert-butyldimethylsilyloxy)-4-((S)-2,2-dimethyl-6-neopentyl-1,2,3,4-tetrahydroquinolin-4-ylamino)-1-(3-fluorophenyl)butan-2-ylcarbamate (0.231 g, 0.360 mmol) in DCM (1.20 ml, 0.360 mmol) was added tetrabutylammonium fluoride (1.44 ml, 1.44 mmol). The resulting solution was stirred overnight. The mixture was transferred to a sep. funnel containing EtOAc and H2O. The aqueous layer was washed 4× with EtOAc. The proganic layers were combined, dried over MgSO4, filtered and concentrated. The crude mixture was purified by the MPLC. MS m/z: 528 (M+1).