Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([O:30]CC)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: CCOC(=O)c1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)COC)c2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Yield: 99.1 %

Procedure:
Ethyl 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylate (4.36 g, 9.2 mmol) synthesized in Example (17d) was dissolved in ethanol (100 mL), and a 4N aqueous sodium hydroxide solution (23 mL, 92 mmol) was added, followed by heating to reflux for 1 hour under nitrogen atmosphere. To the reaction solution, 2N hydrochloric acid (45 mL) was added to neutralize it, and the solvent was distilled off under reduced pressure. 1N hydrochloric acid was used to make the solution acidic, and extraction was carried out with ethyl acetate (300 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to afford the desired product (4.06 g, yield 99%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[C@H:9]([CH2:21][OH:22])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[OH:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(N=NC(NC(C)C)=O)=O)(C)C>ClCCl>[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[O:34][C:21](=[O:22])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:23]
Reactant: Oc1ccc2ccccc2c1
Reactant: CN(Cc1ccccc1)[C@H](CO)CCCNC(=O)OC(C)(C)C
Agent: CC(C)NC(=O)N=NC(=O)NC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1
Yield: 37.3 %

Procedure:
A μιξτυρε Oφ Nα-benzyl-Nδ-Boc-Nα-methylornithinol (168 mg), dichloromethane (10 ml), 2-naphthol (91 mg), triphenylphosphine (165 mg), and N,N′-diisopropylazodicarboxamide (124 μl) was stirred for 12 hrs at 25° C., under nitrogen. The reaction mixture was poured into dichloromethane and washed successively with saturated sodium bicarbonate and brine. The organic phase was then dried over anhydrous sodium sulfate and concentrated in vacuo. Further purification by flash chromatography gave the titled product (90 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ1.51 (s, 9H), 1.68 (m, 2H), 1.75 (m, 2H), 2.39 (s, 3H), 3.20 (m, 2H), 3.82 (d, J=13.3, 1H), 3.93 (d, J=13.2, 1H), 4.11 (dd, J=9.6; 3.6, 1H), 4.29 (dd, J=10.2; 8.4, 1H), 7.22 (m, 2H), 7.29 (t, J=7.8, 1H), 7.39 (m, 5H), 7.50 (t, J=8.0, 1H), 7.79 (m, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([N+:15]([O-])=O)=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:2]>CO.[Pd]>[CH2:18]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([NH2:15])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:19]
Reactant: CCN(CC)c1ccc(-c2ncc([N+](=O)[O-])s2)cc1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)c1ccc(-c2ncc(N)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a solution of N,N-diethyl-4-(5-nitrothiazol-2-yl)aniline (0.73 g, 2.64 mmol) in MeOH (30 mL) was added Pd/C (73 mg). The reaction mixture was stirred at rt under H2 overnight, then filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=5:1) to give the title compound as a white solid (0.45 g, 69%).
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([N:19]([CH3:39])[C@H:20]([C:36]([OH:38])=O)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH3:47][O:48][C:49](=[O:53])[C@@H:50]([CH3:52])[NH2:51]>CC(C)=O.C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[CH3:47][O:48][C:49](=[O:53])[C@@H:50]([CH3:52])[NH:51][C:36](=[O:38])[C@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[N:19]([C:17]([O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:18])[CH3:39]
Reactant: CN(C(=O)OCc1ccccc1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: COC(=O)[C@@H](C)N
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(C)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of isobutyl chloroformate (2.00 g.) in acetone (10 ml.) was added dropwise to a solution of N-benzyloxycarbonyl-N-methyl-O-benzyl-L-tyrosine (6.0 g.) and triethylamine (1.45 g.) in acetone (60 ml.) with stirring and cooling to -10° C. A solution of D-alanine methyl ester (2.22 g.) and triethylamine (1.45 g.) in chloroform (30 ml.) was then added. Stirring was continued for one hour at -10° C., then overnight at room temperature. The mixture was stripped of solvents. Water and ethyl acetate were added to the residue. The ethyl acetate layer was washed with water, saturated aqueous sodium bicarbonate, water again, aqueous citric acid, water again and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and stripped of ethyl acetate, affording (N-benzyloxycarbonyl-N-methyl-O-benzyl-L-tyrosyl)-D-alanine methyl ester (97% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[C:11]([CH3:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([CH3:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 11 h
Yield: 86.4 %

Procedure:
A mixture of 0.70 g (3.07 mmol) of 4-benzyloxy-2-methylbenzyl alcohol, 2.67 g (30.7 mmol) of manganese dioxide, 0.5 ml of methanol and 20 ml of chloroform was stirred at room temperature for 11 hours. Then insoluble matters were filtered off and the filter-rate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 0.60 g of 4-benzyloxy-2-methylbenzaldehyde.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=2)CC1.[H-].[Na+].CI.Cl.[O:18]1CCC[CH2:19]1>>[CH3:19][O:18][CH2:1][CH2:4][CH2:5][C:6]1[S:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(CCC2CC2)s1
Reactant: C1CCOC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCCCc1ccc(C=O)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a solution of 5-(3-hydroxypropyl)thiophene-2-carbaldehyde (Example 58.1; 70 mg, 0.41 mmol) in 1 mL anhydrous tetrahydrofuran under argon at room temperature was added hexanes-rinsed sodium hydride (17 mg of 60% dispersion in oil, 0.45 mmol) as a slurry in 1 mL anhydrous tetrahydrofuran. The resulting suspension was stirred for 15 minutes at room temperature. Methyl iodide (35 μL, 0.57 mmol) was added and the resulting mixture stirred for 2 h at room temperature. The reaction mixture was poured into 30 mL of 0.2 N hydrochloric acid. Organics were extracted with ether (2×30 mL), washed with 5% sodium bisulfite solution, dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (8-12% ethyl acetate in hexanes) to give 5-(3-methoxypropyl)thiophene-2-carbaldehyde (17 mg, 23%) as an oil. Used without further characterization.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:28](I)=[CH:27][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:30])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH:38]1([CH:41]=[O:42])[CH2:40][CH2:39]1>O1CCCC1>[C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:41]([CH:38]4[CH2:40][CH2:39]4)[OH:42])=[CH:27][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:30])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: O=CC1CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C(O)C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To a mixture of 4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-iodobenzamide (0.20 g, 0.36 mmol) in anhydrous tetrahydrofuran (5 mL) was added isopropylmagnesium chloride lithium chloride complex (1.3 M solution in tetrahydrofuran, 0.69 mL, 0.90 mmol) at −40° C. After 1 hour at −40° C., additional isopropylmagnesium chloride lithium chloride complex (1.3 M solution in tetrahydrofuran, 0.28 mL, 0.36 mmol) was added, the reaction mixture warmed to 0° C., and stirred for 1 hour. Cyclopropanecarboxaldehyde (excess) was then added, the reaction mixture was allowed to warm to ambient temperature, and stirred for 16 hours. After quenched with 1 N hydrochloric acid (3 mL), the mixture was diluted with ethyl acetate (50 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by reverse-phase preparative HPLC to afford the title compound as a colorless solid (0.015 g, 8%): 1H NMR (300 MHz, DMSO-d6) δ 11.69 (br s, 1H), 7.73 (d, J=8.7 Hz, 1H), 6.91 (d, J=12.7 Hz, 1H), 5.14 (d, J=4.5 Hz, 1H), 4.61 (dd, J=5.7, 4.9 Hz, 1H), 4.02-3.90 (m, 4H), 3.66 (d, J=9.3 Hz, 1H), 3.56 (d, J=9.3 Hz, 1H), 2.19-2.06 (m, 2H), 2.03-1.95 (m, 3H), 1.76-1.57 (m, 12H), 1.18-1.05 (m, 1H), 0.40-0.25 (m, 4H); MS (ES−) m/z 491.2 (M−1).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].Cl.Cl.[O:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1.[Cl-].[Na+].O>[F:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:27][CH:24]2[CH2:23][CH2:22][N:21]([CH:18]3[CH2:19][CH2:20][O:15][CH2:16][CH2:17]3)[CH2:26][CH2:25]2)[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])c(F)c1
Reactant: NC1CCN(C2CCOCC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(F)c([N+](=O)[O-])c(NC2CCN(C3CCOCC3)CC2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
A mixture of 1,3-difluoro-5-methyl-2-nitrobenzene (1 g), 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine, dihydrochloride (1.63 g), sodium bicarbonate (1.94 g) and tetrabutyl ammonium iodide (100 mg) in NMP (15 ml) was slowly heated at about 50° C. for 3 hours. After cooling to about 25° C., the reaction mixture was added to ethyl acetate (15 ml) and saturated brine (15 ml). The layers were separated and the aqueous extracted with ethyl acetate (15 ml). The combined ethyl acetate layers were then washed with saturated brine (4×4 ml), dried with 2 g anhydrous sodium sulphate then concentrated under vacuum. The residue was heated with acetonitrile (4 ml) to about 60° C. to give a solution, then cooled to 0 to 5° C. and stirred for 1 hour. The solid was filtered, washed with chilled acetonitrile (2 ml), then dried at 40-45° C. under high vacuum to give the title compound as an orange solid (0.83 g).
Reaction SMILES: [K].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([SH:12])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>CN1CCCC1=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([S:12][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1cc(S)cc(OC)c1
Agent: [K]
Solvent: CN1CCCC1=O
Product: COc1cc(OC)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
0.30 g (0.00144 mol) of 3,5-dimethoxythiophenol potassium salt was dissolved in 5 ml of 1-methyl-2-pyrrolidone, treated with 0.21 g (0.00144 mol) of 1-fluoro-4-nitrobenzene and a spatula tip of Cu powder and stirred at 160° C. for about 3 hrs. Thereafter, the solvent was removed by distillation, the residue was partitioned in water/ethyl acetate and the organic phase was washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:7. There was obtained 0.255 g (60%) of 1,3-dimethoxy-5-(4-nitrophenylsulphanyl)-benzene as yellow crystals; m.p.: 63-65° C.
Reaction SMILES: [S:1](=[O:36])(=[O:35])([O:3][CH2:4][C@@H:5]1[C@@H:9]([O:10][Si](C(C)(C)C)(C)C)[CH2:8][C@H:7]([N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[C:22]([NH:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:21]=3[CH:20]=[CH:19]2)[O:6]1)[NH2:2].F>C1COCC1.N1C=CC=CC=1.N1C=CC=CC=1.CCOC(C)=O>[S:1](=[O:36])(=[O:35])([O:3][CH2:4][C@@H:5]1[C@@H:9]([OH:10])[CH2:8][C@H:7]([N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[C:22]([NH:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:21]=3[CH:20]=[CH:19]2)[O:6]1)[NH2:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCc4ccccc4)nccc32)O[C@@H]1COS(N)(=O)=O
Agent: F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)OC[C@H]1O[C@@H](n2ccc3c(NCc4ccccc4)nccc32)C[C@@H]1O
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of ((2R,3S,5R)-5-[4-(benzylamino)-1H-pyrrolo[3,2-c]pyridin-1-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydrofuran-2-yl)methyl sulfamate (0.0300 g, 0.0563 mmol) in THF/pyridine (1 mL, 1:1) was added hydrofluoric acid in pyridine (3 drops) and stirred overnight. The reaction was diluted with EtOAc (5 mL) and quenched with saturated aq NaHCO3 (10 mL). The aq layer was extracted with EtOAc (3×10 mL) and the combined organics were dried (Na2SO4), filtered, and concentrated. The crude material was purified by preparative plate chromatography (10% MeOH/EtOAc) to give the final compound (0.00590 g, 25%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[C:4]([C:14]2[C:15](=[O:33])[NH:16][C:17](=[O:32])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][C:24]([N+:28]([O-])=O)=[CH:25][CH:26]=3)[N:21]([CH3:31])[CH:20]=2)=[CH:3]1>CN(C)C=O.[Ni]>[CH3:31][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=2)[C:19]([C:18]2[C:17](=[O:32])[NH:16][C:15](=[O:33])[C:14]=2[C:4]2[C:5]3[C:10](=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:20]1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Agent: [Ni]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(C)c4cc(N)ccc34)C(=O)NC2=O)c2ccc(N)cc21
Reaction time: 20 h
Yield: 82.6 %

Procedure:
3,4-Bis-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (50 mg, 0.11 mmole), as prepared in Example 2 g, was dissolved in N,N-dimethylformamide (10 mL), a catalytic amount of activated Raney Nickel was added and the reaction was shaken on a Parr Hydro-genator at 45 psi. for 20 hr. The reaction mixture was filtered through a bed of celite with ethyl acetate and concentrated. The product was purified by recrystallization from acetone and hexane to give 3,4-bis-(1-methyl-6-amino-1H-indol-3-yl)-pyrrole-2,5-dione (35 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][C:9](=O)[NH:10][C:5]2=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C1Cc2nc(Cl)ccc2N1
Solvent: C1CCOC1
Product: Clc1ccc2c(n1)CCN2
Temperature: 60 °C
Reaction time: 3 h

Procedure:
5-Chloro-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (78 mg, 0.46 mmol) was dissolved in THF (1.5 mL). BH3 (1M in THF, 0.92 mL, 0.92 mmol) was added and the mixture was stirred at 60° C. for 3 h. The mixture was cooled to room temperature, diluted with THF and quenched with 1N HCl. The mixture was treated with 2N NaOH until basic and was extracted with ether. The organic extracts were dried, filtered and evaporated to afford 20a.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.CN(C)C1C=CC=CC=1.[CH3:18][O:19][C:20](=[O:26])[CH2:21][CH2:22][C:23](Cl)=[O:24]>O1CCCC1>[Br:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:23](=[O:24])[CH2:22][CH2:21][C:20]([O:19][CH3:18])=[O:26])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: COC(=O)CCC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Yield: 70 %

Procedure:
The 2-amino-5-bromopyrazine (commercially available, 0.687 g, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL). Then N,N-dimethylaniline (500 μL, 1.0 eq.) and methyl-4-chloro-4-oxo-butanoate (535 μL, 1.1 eq.) was successively added. The mixture was refluxed for 12 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer were dried on magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate A2 (70%). 1H NMR (400 MHz, DMSO-d6) δ 11.02 (bs, 1H), 9.12 (s, 1H), 8.62 (s, 1H), 3.60 (s, 3H), 2.74 (t, 2H), 2.62 (t, 2H) ppm. LC-MS (Method A): RT 1.28, 290 (M+H+)
Reaction SMILES: [C:1]12[CH2:7][C:4](=[CH:5][CH:6]=1)[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]2=1>[Pd]>[CH:4]12[CH2:7][CH:1]([CH2:6][CH2:5]1)[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]2=1
Reactant: C1=C2CC(=C1)c1ccccc12
Agent: [Pd]
Product: c1ccc2c(c1)C1CCC2C1
Reaction time: 3 h
Yield: 80.2 %

Procedure:
4 g of a catalyst containing 10% of palladium on charcoal are added to a solution of 40 g of benzonorbornadiene in 400 cm3 of nitrogen-degassed methanol. Nitrogen is again bubbled into this mixture and the heterogeneous solution is stirred for three hours at a gauge pressure of hydrogen of 2 bars. The mixture is then filtered, concentrated under reduced pressure and benzonorbornene is purified by distillation; its boiling point at 22.5 millibars is 86° C. 33 g of a product whose nuclear magnetic resonance spectrum corresponds to the expected structure are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:18])[CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(C(C)C)C(C)C)C>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:18])[CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(CC)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCC(CC)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-ethylbutanamide (225 mg, 0.686 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (412 mg, 2.06 mmol), and N-ethyl-N-isopropylpropan-2-amine (239 μL, 1.37 mmol) in n-BuOH (5 mL) was purged under N2 and stirred at 160° C. in a sealed tube for 16 hours. The solvent was then removed in vacuo, and the liquid residue was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+; C-18) on Biotage SP4 unit eluting with a gradient of 15-90% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(2-ethylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (201 mg, 58% yield) as a solid. LCMS (APCI+) m/z 508, 510 (M+H)+, Retention time=4.15 minutes (Method 2).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>ClCCl.CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[O:9]
Reactant: Cc1ccccc1N
Reactant: Cc1cc[nH]c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)c1[nH]ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
2.0 g (15.98 mmol) of 3-methyl-1H-pyrrole-2-carboxylic acid were dissolved in 50 mL of dichloromethane. 5.60 mL (63.9 mmol) of oxalyl chloride were added, followed by 5 drops of DMF. The reaction mixture was stirred at room temperature for 2 hours and then the solvents were evaporated. The black oil residue was dissolved in 50 mL of dichloromethane and 6.85 g (63.9 mmol) of o-toluidine were added dropwise. The reaction was stirred at room temperature for 1 hour and then the solvent was evaporated. The crude product was purified by flash chromatography (dichloromethane to dichloromethane/methanol 95:5) and then triturated in diisopropylether to give 2.97 g (87% yield) of the title compound as a brown solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[CH:30]=4)[O:25][CH:24]=3)[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1>>[CH3:35][O:34][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:36][CH3:37])[O:25][CH:24]=[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][N:16]1[CH2:15][CH2:14][N:13]([C:9]3[CH:8]=[C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])[CH:12]=[CH:11][CH:10]=3)[CH2:18][CH2:17]1)[C:32]2=[O:33]
Reactant: COC(=O)Cl
Reactant: COc1cc2occ(CCCCN3CCN(c4cccc(N)c4)CC3)c(=O)c2cc1OC
Product: COC(=O)Nc1cccc(N2CCN(CCCCc3coc4cc(OC)c(OC)cc4c3=O)CC2)c1

Procedure:
In a similar manner to Example 13, but using methyl chloroformate and 3-{4-[4-(3-aminophenyl)-piperazin-1-yl]-butyl}-6,7-dimethoxychromen-4-one obtained in Example 12, methyl (3-{4-[4-(6,7-dimethoxy-4-oxo-4H-chromen-3-yl)-butyl]-piperazin-1-yl}-phenyl)-carbamate is obtained.
Reaction SMILES: ClC1C=CC2SC=C([CH2:9][N:10]3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.CN>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:10][CH3:9])=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Agent: CN
Product: CNC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 41 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with methylamine, the title compound was obtained as a colorless solid in 41% yield: mp 225-227° C.; 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.07-7.01 (m, 2H), 5.66 (br s, 1H), 4.46 (s, 2H), 4.08 (t, J=9.0 Hz, 2H), 3.45 (t, J=9.0 Hz, 2H), 2.94 (d, J=3.0 Hz, 3H), 2.60 (s, 3H); MS (ES+) m/z 349.2 (M+1).