Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[C:7]2/[C:8](=[O:22])[CH:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:10](=[O:12])[CH2:11]/2)=[CH:2]1>C(O)C.[Pd]>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH:7]2[CH2:11][C:10](=[O:12])[CH:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:8]2=[O:22])=[CH:2]1
Reactant: Cc1cc(C)c(C2C(=O)C/C(=C\c3ccoc3)C2=O)c(C)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(C2C(=O)CC(Cc3ccoc3)C2=O)c(C)c1
Reaction time: 5 h

Procedure:
To a solution of 4-[1-Furan-3-yl-meth-(E)-ylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (167 mg) in ethanol (5 ml) is added 5% palladium on charcoal (15 mg) and the resulting suspension stirred under an atmosphere of hydrogen (3 bar) for 5 hours. The reaction is filtered through a pad of Celite, washed with methanol and the filtrate purified by automated flash chromatography to give 4-furan-3-ylmethyl-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione.
Reaction SMILES: [Mg].II.[CH2:4]([O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[B:18](OC)([O:21]C)[O:19]C.S(=O)(=O)(O)O>C(OC1C=CC(Br)=CC=1)CCCCC.C1COCC1>[CH2:4]([O:10][C:11]1[CH:16]=[CH:15][C:14]([B:18]([OH:21])[OH:19])=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COB(OC)OC
Reactant: CCCCCCOc1ccc(Br)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
In an apparatus which had been baked out and blanketed with argon, magnesium turnings (1.89 g; 78 mmol) were treated with a crystal of iodine and covered with dried THF. A few drops of 4-hexyloxybromobenzene were then added to the solution without stirring. The Grignard reaction began very quickly and, while stirring, the 4-hexyloxybromobenzene (total amount: 20 g; 78 mmol) was then added dropwise at such a rate that the mixture boiled gently. During this addition, the mixture was diluted with a little THF (total amount: about 100 ml). The mixture was refluxed for 3 hours (only a few flakes of magnesium remaining in the solution) and subsequently allowed to cool. The Grignard solution was transferred to a 250 ml dropping funnel in a countercurrent of protective gas and added dropwise to a solution of trimethyl borate (8.9 g; 9.6 ml; 86 mmol) in 50 ml of dry THF while stirring at −70° C., resulting in formation of a precipitate. The reaction mixture was allowed to warm to RT overnight and was then introduced while stirring into a mixture of 100 g of ice and 3 ml of concentrated sulfuric acid. The organic phase was separated off, the aqueous phase was extracted 3 times with 100 ml each time of chloroform and the combined organic phases were evaporated. The crude product was subsequently recrystallized from hexane. Product: colorless, wax-like solid (11.28 g; 66%); melting point: 84-87° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(O)cc2)cs1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Yield: 53.2 %

Procedure:
2-({4-[2-(4-Hydroxyphenoxy)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (600 mg) obtained in Example 50-2 and 4-chlorobenzylbromide (312 mg) were dissolved in acetone (10 mL), potassium carbonate (210 mg) was added, and the mixture was refluxed for 6 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (420 mg) as a colorless oil.
Reaction SMILES: [CH:1]1([C@@H:7]2[CH2:12][NH:11][CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:28][C:29]1[C:30]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.CO>[CH:1]1([C@@H:7]2[CH2:12][N:11]([CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[C:30]=3[N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CNC[C@H]1C1CCCCC1
Reactant: O=Cc1cccc(F)c1N1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(Cc2cccc(F)c2N2CCOCC2)C[C@H]1C1CCCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
A solution of 3-((R)-2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylic acid (50.0 mg, 0.13 mmol, 1.0 equiv) and 3-fluoro-2-morpholinobenzaldehyde (108.8 mg, 0.52 mmol, 4.0 equiv) in acetic acid (0.2 mL) and methanol (0.5 mL) was stirred at room temperature for 60 minutes. Then sodium triacetoxyborohydride (110.2 mg, 0.52 mmol, 4.0 equiv) was added to the mixture and the resulting mixture was stirred at 75° C. for 3 hours. The solvent was removed by Genevac and the residue was dissolved in EtOAc (6 mL). The organic phase was washed by brine (3 mL), dried over Na2SO4 and concentrated. The residue was purified by HPLC (0.1% NH4OH) to afford the product (9 mg, 12%). MS: 577.2 [M−H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:50][CH2:51][CH2:52][C:53]1[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:50][CH2:51][CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: NCCc1cccnc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCCc4cccnc4)cc3)cn2)cc1
Yield: 103.7 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (60.0 mg, 0.0909 mmol) obtained in Step A in Example 1-D-19 and 3-(2-aminoethyl)pyridine (21.4 μl, 0.182 mmol) instead of 3-(aminomethyl)pyridine, amidation was carried out in the same manner as Step B in Example 1-D-19, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-pyridin-3-yl-ethyl)-benzamide as a brown solid (72.0 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-279) as a yellow powder (40.4 mg, 85%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([Cl:10])[C:7]([N+:11]([O-])=O)=[C:6]([Cl:14])[N:5]=2)[CH2:3][CH2:2]1>[Ni].C(O)C>[CH:1]1([C:4]2[N:5]=[C:6]([Cl:14])[C:7]([NH2:11])=[C:8]([Cl:10])[N:9]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1c(Cl)nc(C2CC2)nc1Cl
Agent: [Ni]
Solvent: CCO
Product: Nc1c(Cl)nc(C2CC2)nc1Cl
Yield: 67.2 %

Procedure:
70 g of 2-cyclopropyl-4,6-dichloro-5-nitropyrimidine are hydrated in the presence of 8.2 g Raney nickel in 700 ml ethanol at 100 bar for 6 hours at room temperature. The reaction product is first extracted with methylenechloride, then the solution is concentrated, and the residue dissolved in cyclohexane and recrystallized. 41 g of 2-cyclopropyl-4,6-dichloro-5-amino-pyrimidine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]3C(=O)[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=O)=[N:19][N:18]=[C:17]2[CH2:33][N:34]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:15]=1)C(C1C=CC=CC=1)=O.O.NN.C1(=O)NC(=O)C2=CC=CC=C12>C(O)C>[Cl:1][C:2]1[CH:15]=[CH:6][C:5]2[N:16]3[C:17]([CH2:33][NH2:34])=[N:18][N:19]=[C:20]3[CH2:21][N:22]=[C:23]([C:24]3[CH:25]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Solvent: CCO
Solvent: O
Product: NCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.33 h

Procedure:
A stirred mixture of 5-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (1.81 g, 0.003 mole) and absolute ethanol (30 ml) is treated with hydrazine hydrate (0.437 ml, 0.009 mole) and kept in an oil bath at 72°-76°C for two hours and 20 minutes. During this period the phthalimide dissolves and a second solid forms. The mixture is cooled in an ice bath and filtered. The solid is washed with ethanol and methylene chloride. The filtrate is concentrated in vacuo. This residue is mixed with cold water and extracted with chloroform. The extract is washed (brine), dried over anhydrous sodium sulfate and concentrated in vacuo to give 8-chloro-1-(aminomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine as a crude oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)[CH2:15][CH2:14]2)=[O:12])=[C:4]([O:30][CH3:31])[CH:3]=1.[Br-].[CH:33]1([Zn+])[CH2:36][CH2:35][CH2:34]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:7]([CH:33]2[CH2:36][CH2:35][CH2:34]2)=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)[CH2:15][CH2:14]2)=[O:12])=[C:4]([O:30][CH3:31])[CH:3]=1
Reactant: [Zn+]C1CCC1
Reactant: COc1cc(Cl)c(I)cc1NCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(Cl)c(C2CCC2)cc1NCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 65 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
A mixture of tert-butyl 3-(4-(2-(4-chloro-5-iodo-2-methoxyphenylamino)acetyl)piperazin-1-yl)azetidine-1-carboxylate (697 mg, 1.24 mmol), cyclobutylzinc bromide (4.46 mL, 2.23 mmol, 0.5 M in THF), Pd(OAc)2 (56 mg, 0.248 mmol), and S-Phos (102 mg, 0.248 mmol) in THF (15 mL) was stirred at 65° C. under argon for 16 h. The mixture was allowed to cool to RT, quenched with aqueous NH4Cl solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (methanol/dichloromethane=1:30) to afford the desired product (596 mg, 98% yield) as a brown oil. ESI-MS m/z: 493.5[M+H]+.
Reaction SMILES: [CH2:1]([C:7]1[N:8]=[C:9]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[S:10][C:11]=1[CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[C:18]([CH3:28])[CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[OH-].[Li+].Cl>C(O)C.O>[CH2:1]([C:7]1[N:8]=[C:9]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[S:10][C:11]=1[CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:18]([CH3:28])[CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1nc(-c2ccc(C)cc2)sc1CCC(=O)c1ccc(CCC(=O)OC)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCc1nc(-c2ccc(C)cc2)sc1CCC(=O)c1ccc(CCC(=O)O)c(C)c1
Yield: 86.9 %

Procedure:
The obtained methyl 3-[4-[3-[4-hexyl-2-(4-methylphenyl)thiazol-5-yl]propionyl]-2-methylphenyl]propionate (45 mg, 0.0915 mmol) was suspended in ethanol (2 mL) and water (1 mL). Lithium hydroxide monohydrate (12 mg, 0.275 mmol) was added to the suspension. The mixture was refluxed for 1 hour. 1N hydrochloric acid (5 mL) and ice-cooled water (2 mL) were added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure. The obtained residue was recrystallized with hexane and ethyl acetate to give the desired compound (38 mg) as while crystalline product (yield 87%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:27](=[O:36])[NH:28][C:29]2[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=2)[CH2:12][C:13]2[S:17][C:16]([C:18]([NH:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24])=[O:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[CH:39]=[C:38]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>COCCOC.C(O)C.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[O:37]1[C:38]2=[CH:39][CH:40]=[CH:45][C:44]2=[CH:43][CH:42]=[C:41]1[N:28]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:27]([CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH2:12][C:13]1[S:17][C:16]([C:18]([NH:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24])=[O:19])=[CH:15][CH:14]=1)=[O:36]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC(C)(C)c1ccc(C(Cc2ccc(C(=O)NCCS(=O)(=O)O)s2)C(=O)Nc2ccc(I)cc2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1ccc(C(Cc2ccc(C(=O)NCCS(=O)(=O)O)s2)C(=O)N(c2ccccc2)c2ccc3cccc-3o2)cc1
Temperature: 125 °C
Yield: 11.9 %

Procedure:
To 2-({5-[2-(4-tert-Butyl-phenyl)-2-(4-iodo-phenylcarbamoyl)-ethyl]-thiophene-2-carbonyl}-amino)-ethanesulfonic acid (100 mg, 0.16 mmol) in 2 ml 1,2-dimethoxyethane, 1 ml ethanol, and 0.5 ml water was added benzofuran-2-boronic acid (76 mg, 0.47 mmol), sodium carbonate (83 mg, 0.78 mmol), and dichlorobis(tri-o-tolylphosphine)palladium(II) (12 mg, 0.016 mmol). The resulting mixture was heated to 125° C. in microwave for 6 minutes. Chromatography of the reaction mixture (20% to 80% acetonitrile in water) obtained 2-({5-[2-(4-Benzofuran-2-yl-phenylcarbamoyl)-2-(4-tert-butyl-phenyl)-ethyl]-thiophene-2-carbonyl}-amino)-ethanesulfonic acid as a white solid (12 mg, 12%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22](Br)[S:21]2)=[O:10])[CH:6]([CH3:8])[CH3:7].[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:28])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22]([C:33]1[CH:34]=[CH:35][C:30]([NH2:29])=[CH:31][CH:32]=1)[S:21]2)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1)C(C)C
Reactant: Nc1ccc(B(O)O)cc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(-c3ccc(N)cc3)sc2n1)C(C)C

Procedure:
Compound A25 was synthesized from 12b (0.318 mmol) and 4-aminophenylboronic acid (0.477 mmol), following the procedure as described for compound A1, to give compound A25 as a white solid in 29%. MS (ESI, EI+) m/z=485.15 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Cl[C:44]1[CH:52]=[CH:51][C:47]([C:48]([NH2:50])=[O:49])=[CH:46][N:45]=1>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[CH:52]=[CH:51][C:47]([C:48](=[O:49])[NH2:50])=[CH:46][N:45]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: NC(=O)c1ccc(Cl)nc1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3ccc(C(N)=O)cn3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 6-chloronicotinamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].ClC(OC(Cl)C)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:28])[N:7]([CH:9]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)C1CNCC1c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (1.30 g, 3.20 mmol) in toluene (30 ml) at RT, was added 1-chloroethyl chloroformate (0.53 ml, 4.80 mmol). The reaction mixture was stirred at 90° C. overnight and concentrated under vacuo. The residue was dissolved in MeOH (30 ml) and the reaction mixture was heated at 80° C. for 2 hours. The solvent was evaporated and the crude product was directly used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1.[CH2:23]([CH2:30][CH2:31][CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>C(O)C>[CH2:34]([N:33]([CH2:22][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:12]2)=[CH:7][CH:6]=1)[CH2:32][CH2:31][CH2:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=c1cc(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Reactant: c1ccc(CNCCCCc2cccnc2)cc1
Solvent: CCO
Product: O=c1cc(-c2ccccc2)oc2cc(OCC(O)CN(CCCCc3cccnc3)Cc3ccccc3)ccc12
Temperature: 60 °C
Yield: 29.3 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)flavone (15 g, 51.0 mmol) and N-(3-nicotinylpropyl)benzylamine (22.5 g, 100 mmol) in ethanol (150 ml) was heated at 60° C. for 3 hours. The ethanol was then evaporated and the residue was washed with cyclohexane (three times) to remove the excess amine. The remaining residue was then extracted with ethyl acetate (twice), and the extracts were evaporated to give a red syrup. Purification of the red syrup by flash column chromatography eluting with EtOAc--MeOH (20:1) gave 8.0 g of a yellow syrup, 30% yield, which is stored in the refrigerator and used for the further reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2
Reactant: NCc1ccc2ncccc2c1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc4ncccc4c3)c2CC1)C(F)(F)F

Procedure:
Use a method similar to the General Procedure 5-2, using 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.2 g, 0.35 mmol) and 6-aminomethyl-quinoline (0.2 g, 1.06 mmol) with tris(dibenzylideneacetone)dipalladium(0) (32.0 mg, 0.04 mmol), BINAP (44.0 mg, 0.07 mmol) and cesium carbonate (0.2 g, 0.71 mmol) at 90° C. for 17 h, to obtain 7-chloro-6-[(quinolin-6-yl-methyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][O:13][C:14]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17].[NH4+].[Cl-]>CCOCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]([OH:17])([C:15]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:14]=2[O:13][CH3:12])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[O:10][CH3:11])=[C:3]([O:10][CH3:11])[CH:4]=1
Reactant: COC(=O)c1ccc(OC)cc1OC
Reactant: COc1ccc(Br)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(C(O)(c2ccc(OC)cc2OC)c2ccc(OC)cc2OC)c(OC)c1
Reaction time: 0.17 h

Procedure:
Add (4.23 g, 19.47 mmol) 1-bromo-2,4-dimethoxybenzene to an appropriately sized round bottom flask. Attach a rubber septum to seal the flask. Insert a needle into the septum as a vent and flush the round bottom flask with nitrogen for about 10 minutes. Add anhydrous ether (80 mL), followed by the drop wise addition of n-butyllithium in hexane (1.6M, 12.2 mL). Stir the cloudy mixture for 10 minutes and keep the round bottom flask on ice. Dissolve (2.20 g, 9.74 mmol) of methyl 2,4-dimethoxybenzoate in about 20 ml of anhydrous ether (if needed, more than about 20 ml can be used), and then add this drop wise to the reaction mixture. After the addition is complete, stir the reaction mixture for about 3 minutes longer. Pour the reaction mixture into a separatory funnel containing 5% NH4Cl (aq) (50 mL) and shake until a color change is observed (pale orange). The layers are allowed to separated, and dry the top ether layer with about 5 g anhydrous Na2SO4, filter, and the volatiles were removed in a rotary evaporator to dryness at 35-40° C. under 400 mbar. Place the crude oil of hexamethoxy red (yellow-orange in color) into the freezer. Yield is about 3.1 g.
Reaction SMILES: [F:1][CH:2]([F:33])[CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[C:14]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])[S:15][C:16]=2[NH:17]C(=O)OC(C)(C)C)=[O:11])[CH:6]=[N:5]1.Cl>O1CCOCC1>[NH2:17][C:16]1[S:15][C:14]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[N:13][C:12]=1[C:10]([NH:9][C:7]1[CH:6]=[N:5][N:4]([CH2:3][CH:2]([F:1])[F:33])[CH:8]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(CC(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(CC(F)F)c1

Procedure:
tert-butyl 4-(1-(2,2-difluoroethyl)-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate was stirred with 4.0M HCl in dioxane overnight. The reaction was concentrated and the residue was basified with sat. sodium bicarbonate. The mixture was extracted with ethyl acetate (3×), concentrated and purified on reverse phase HPLC to afford the title compound 384. 1H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 8.10 (s, 1H), 7.74 (s, 1H), 7.62-7.39 (m, 3H), 7.26 (dd, J=14.3, 5.9 Hz, 2H), 6.32 (tt, J=54.9, 3.7 Hz, 1H), 4.58 (td, J=15.1, 3.8 Hz, 2H). MS (ESI) m/z: 386.3 [M+H+].