Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[CH2:13][CH2:12]2)[C:5]([F:26])=[CH:4][N:3]=1.CCOC(C)=O.C(O)C>CO.[OH-].[OH-].[Pd+2]>[BrH:1].[NH2:8][C:7]1[CH:2]=[N:3][CH:4]=[C:5]([F:26])[C:6]=1[N:11]1[CH2:12][CH2:13][CH:14]([C:17]([N:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)=[O:18])[CH2:15][CH2:16]1
Reactant: CN1CCN(C(=O)C2CCN(c3c(F)cnc(Br)c3[N+](=O)[O-])CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: Br
Product: CN1CCN(C(=O)C2CCN(c3c(N)cncc3F)CC2)CC1
Reaction time: 6 h
Yield: 83.5 %

Procedure:
[1-(2-Bromo-5-fluoro-3-nitro-4-pyridyl)-4-piperidyl]-(4-methylpiperazin-1-yl)methanone 16 (20.24 g, 47.04 mmol) was dissolved/suspended in MeOH (389 mL)/EtOAc (78 mL) and Pd(OH)2 (1.651 g, 2.352 mmol) was added. The resulting mixture was degassed by vacuum/nitrogen cycles (×5) and the atmosphere was exchanged by vacuum/hydrogen cycles (×5). The reaction mixture was stirred vigorously under a hydrogen atmosphere (balloon) for 6 hrs. Additional Pd(OH)2 (4.95 g) was added and the reaction mixture was stirred overnight under hydrogen. The mixture was filtered through celite, washing through with methanol. The filtrate was concentrated in vacuo to leave an orange gum. Approx. 150 mL of ethanol was added and the mixture rotated on buchii for 10 mins, a yellow precipitate had formed during this time. The suspension was sonicated for 5 mins and the solid was then collected by filtration, washed with minimal ethanol and dried by suction for 1 h to afford product as a pale yellow solid. A second crop of product was obtained by concentrating the filtrate in vacuo. The residue was then slurried in minimal ethanol and sonicated for 5 mins then solid collected by filtration, dried by suction to leave second crop of product as a yellow solid. Both crops of product were combined to afford product as a yellow solid (15.8 g, 79%). MS (ES+) 322.2.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C@H:31]2[CH2:35][CH2:34][C@H:33]([C:36]3[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=3)[O:32]2)[CH:8]=[C:9]([O:15][CH2:16][C:17]#[C:18][CH2:19][N:20]2C(=O)C3=CC=CC=C3C2=O)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3].O.NN>C(O)C>[NH2:20][CH2:19][C:18]#[C:17][CH2:16][O:15][C:9]1[CH:8]=[C:7]([C@H:31]2[CH2:35][CH2:34][C@H:33]([C:36]3[CH:37]=[C:38]([O:46][CH3:47])[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=3)[O:32]2)[CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCOc1c(OCC#CCN2C(=O)c3ccccc3C2=O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(C)(=O)=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCOc1c(OCC#CCN)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(C)(=O)=O
Yield: 50 %

Procedure:
To a solution of trans-2-[3-methylsulfonyl-5-(4-phthalimido-but-2-ynyloxy)-4-propyloxyphenyl]-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran. (244, whole amount obtained from the previous step) in ethanol (5.0 mL) was added hydrazine hydrate (136 mL, 2.8 mmol). The resulting solution was refluxed overnight. The ethanol was removed in vacuo and the residue was diluted with methylene chloride (25 mL) and water (25 mL). The layers were separated and the water layer was extracted with methylene chloride (25 mL). The combined organic extracts were dried and concentrated in vacuo. The residue was purified using PLC (eluent, 5% methanol in methylene chloride) to obtain 75 mg (50% overall from 242) of trans-2-[3-(4-amino-but-2-ynyloxy) -5-methylsulfonyl-4-propyloxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (244). 1H-NMR (CDCl3) δ7.55 (1H, d, J=2.0 Hz), 7.37 (1H, d, J=2.0 Hz), 6.59 (2H, s), 5.16-5.28 (2H, m), 4.79 (2H, s), 4.12 (2H, t, J=6.6 Hz), 3.87 (6H, s), 3.81 (3H, s), 3.44 (2H, s), 3.23 (3H, s), 2.43-2.50 (2H, m), 1.83-2.03 (4H, m), 1.57 (2H, brs), 1.04 (3H, t, J=6.6 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:44][C@H:45]1[CH2:50][N:49]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54](B3OC(C)(C)C(C)(C)O3)[CH:53]=2)[CH2:48][CH2:47][N:46]1C(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:3]=[C:2]([C:54]5[CH:55]=[CH:56][CH:57]=[C:52]([CH2:51][N:49]6[CH2:48][CH2:47][NH:46][C@@H:45]([CH3:44])[CH2:50]6)[CH:53]=5)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=4)=[O:13])[CH:15]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(Br)c2)c1
Reactant: C[C@H]1CN(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-{[3-Bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.033 g, 0.05 mmol), 1,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (0.0316 g, 0.076 mmol), potassium carbonate (0.021 g, 0.15 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.0029 g, 0.0025 mmol) were combined in dioxane (1.5 mL) and water (0.5 mL). The mixture was microwaved at 150° C. for 30 min. The reaction mixture was then diluted with EtOAc and washed with H2O. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. This was taken up in 10% TFA/CH2Cl2 and stirred at room temperature for 3 h. The solvents were pumped off and the crude product was purified using a Gilson HPLC with a TFA system. The purified compound was taken up in EtOAc, washed with 2.5 N NaOH, with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound a white solid. LC-MS m/z 759.2 (M+H)+, 1.35 min (ret time); mp 110-112° C. Analytical HPLC shows 100% purity, (ret time 9.95 min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[CH:4][N:3]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1.N1C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([C:22]3[CH:23]=[CH:24][S:20][CH:21]=3)[CH:18]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccsc1
Reactant: Nc1ncc(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(=O)n(-c3ccsc3)c2)c(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 51.3 %

Procedure:
In a reaction vessel, 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (50 mg, 0.197 mmol), thiophene-3-boronic acid (50 mg, 0.393 mmol), and copper acetate (4 mg, 0.0197 mmol) were suspended in N,N-dimethylformamide (3 ml). Pyridine (31 mg, 0.393 mmol) was added thereto, followed by stirring at room temperature for 14.5 hours in the air. After the reaction was terminated, the mixture was concentrated and suspended in dimethylsulfoxide. Subsequently, the insoluble matters were removed by filtration and the resulting filtrate was purified by HPLC, to give the title compound (34 mg, 51%) as a pale yellow solid.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])[CH3:3].[K+].[OH:7][C:8]1[CH:27]=[CH:26][C:11]([C:12]([O:14][CH2:15][O:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[O:13])=[CH:10][CH:9]=1.[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl>CN(C=O)C>[O:32]1[CH2:31][CH:30]1[CH2:28][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][O:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:3][CH:2]3[O:4][CH2:5]3)=[CH:20][CH:19]=2)=[O:13])=[CH:26][CH:27]=1
Reactant: ClCC1CO1
Reactant: O=C(OCOC(=O)c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCOC(=O)c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Yield: 51 %

Procedure:
Potassium tert.butoxide (1.347 g, 12.00 mmol) is added to a solution of methylene di(p-hydroxybenzoate) prepared as described in Example 4(o) (1,728 g, 6.00 mmol) in DMF (75 ml), under a dry N2 atmosphere. Epichlorohydrin (2.22 g, 24.00 mmol) is added and after 24 hours at 20° C. the solvent is removed under reduced pressure. The residue is dissolved by adding dichloromethane (75 ml) and water (30 ml) and adjusting the pH to neutral using hydrochloric acid (1 M). After separating the phases the dichloromethane layer is washed with water (3×30 ml). The organic phase is dried (MgSO4) and the solvent removed under reduced pressure to give 1.22 g (51%) product as a colourless oil. 1H NMR (60 MHz, CDCl3): δ2.8 (4H, m, 2×epoxy--CH2), 3.3 (2H, m, 2×epoxy--CH), 4.05 (2H, dd, J=22, 11 Hz, 2×O--CH--H), 4.12 (2H, dd, J=22, 11 Hz, 2×O--CH--H), 6.14 (2H, s, O--CH2 --O), 6.9 (4H, m, 2×Ar), 7.9 (4H, m, 2×Ar).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]O.S(Cl)(Cl)=O>CCOCC>[OH:1][C:2]1[CH:10]=[C:9]([N:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: CN(C)c1ccc(C(=O)O)c(O)c1
Reactant: CO
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N(C)C)cc1O
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of 2-hydroxy-4-(N,N-dimethylamino)benzoic acid (9.05 g, 50 mmol) and MeOH (100 mL) at 0° C. was added thionyl chloride (5.34 mL, 75 mmol) dropwise. The reaction was warmed to room temperature and refluxed for 14 hours. After cooling, ether was added to the mixture and the reaction was carefully quenched with satd NaHCO3. The mixture was diluted with ether (200 mL) and partitioned. The organic layer was dried over MgSO4 and the crude product was adsorbed onto silica gel. The crude product was chromatographed on silica gel (5% CH2Cl2/hexane to 25% CH2Cl2/hexane) and triturated with ether/hexane to give the desired product as a white solid (7.1 g, 73%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:46])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:47])[C:3]=1[C:48]([O:50][CH3:51])=[O:49])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:44])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C:35](=[N:39][OH:40])[C@@H:34]([O:41][CH3:42])[C@H:33]([CH3:43])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:45].[N:52]1C=CC=[CH:54][CH:53]=1>CO>[NH2:52][CH2:53][CH2:54][O:40]/[N:39]=[C:35]1\[C@@H:36]([O:37][CH3:38])[C@@H:31]([NH:30][C:14]2[C:13](=[O:44])[C:12]3[CH:11]=[C:10]4[C:19]([C:20](=[O:27])[C@@:21]5([O:25][CH3:26])[C@@:8]([OH:46])([C:9]4=[O:45])[C:7]4[C:2]([OH:1])=[C:3]([C:48]([O:50][CH3:51])=[O:49])[C:4]([CH3:47])=[CH:5][C:6]=4[CH2:23][C@H:22]5[OH:24])=[C:18]([OH:28])[C:17]=3[C:16](=[O:29])[CH:15]=2)[O:32][C@@H:33]([CH3:43])[C@@H:34]\1[O:41][CH3:42]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)C(=NO)[C@H]1OC)C4=O
Reactant: c1ccncc1
Solvent: CO
Product: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)/C(=N/OCCN)[C@H]1OC)C4=O
Reaction time: 6 h
Yield: 33 %

Procedure:
To a solution of the ketone from Step A of the preparation of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,5R,6S)-4-(hydroxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate [Isomer A](Example 48) (50 mg, 0.072 mmol) in methanol (1 mL) was added 2-(aminooxy)-1-ethanaminum dihydrochloride (10.7 mg, 0.072 mmol) and pyridine (0.1 mL) at room temperature. The mixture was stirred under nitrogen for 6 h. The reaction mixture was quenched with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR)-methyl 11-((2S,3R,5R,6S,Z)-4-(2-aminoethoxyimino)-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-1,6,8,14a-tetrahydroxy-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (18 mg, 33%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H), 7.00 (br s, 1H), 6.53 (s, 1H), 5.93 (s, 1H), 4.98 (d, J=1.5 Hz, 1H), 4.95 (d, J=6.0 Hz, 1H), 4.87 (br s, 1H), 4.29-4.26 (m, 3H), 3.83 (s, 3H), 3.74-3.70 (m, 2H), 3.61-3.54 (m, 2H), 3.58 (s, 3H), 3.47 (s, 3H), 3.40 (s, 3H), 3.34 (d, J=19.5 Hz, 1H), 3.11-3.06 (m, 2H), 2.40 (s, 3H), 1.37 (d, J=6.0 Hz, 3H), 1.24 (t, J=7.0 Hz, 2H); MS (ESI+) m/z 754 (M+H); HPLC 95.6% (AUC), tR 10.86 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1B(O)O>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: Cc1cc(Cl)ncc1N
Product: COc1ccc(F)c(-c2cc(C)c(N)cn2)c1
Yield: 76 %

Procedure:
Obtained (1.225 g, yield 76%) following the procedure described in Intermediate 27, starting with 6-chloro-4-methylpyridin-3-amine (7.01 mmol, 1.000 g), 2-fluoro-5-methoxyphenylboronic acid (7.01 mmol, 1.191 g).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([C:27]3[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=3)=[O:26])[CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[CH3:11][C:12]1[C:13]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([N:5]4[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]4(=[O:10])=[O:9])=[CH:29][CH:28]=3)=[O:26])[CH2:23][CH2:24]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C(C)C)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 14.9 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (300 mg) described in Preparation Example 6 and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (421 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 4, the title compound (68 mg) was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H]4CCCNC4)C(F)=CN=3)=CNC2=NC=1.C(N(C(C)C)CC)(C)C.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([S:60]([CH3:59])(=[O:62])=[O:61])[CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.04 g, 0.11 mmol) in CH2Cl2 (1.4 mL) and DMF (0.30 mL) was added N,N-diisopropyl-N-ethylamine (0.30 mL, 1.70 mmol) followed by methanesulfonyl chloride (0.02 g. 0.20 mmol). The reaction mixture was allowed to stir at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 389.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[C:13](Cl)[CH:14]=[CH:15][C:16]=3[O:19][CH3:20])[N:11]([CH2:22][CH2:23][F:24])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:19][CH3:20])[N:11]([CH2:22][CH2:23][F:24])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCc2c1c1c(OC)ccc(Cl)c1n2CCF
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)C1CCCc2c1c1c(OC)cccc1n2CCF
Reaction time: 18 h
Yield: 87.7 %

Procedure:
8-chloro-9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (15) (5.3 g, 15.0 mmol) was dissolved in methanol (180 mL) and triethylamine (1.8 g, 18.0 mmol, 2.5 mL) and 10% Pd/C (2 g in methanol (20 mL)) were added. The mixture was placed on the Parr hydrogenator and shaken for 18 h under a hydrogen atmosphere. The reaction was filtered through a pad of celite, washed with methanol and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with 10% aqueous potassium carbonate (200 mL), dried over magnesium sulfate and concentrated in vacuo to give 4.2 g (88%) of 9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (16) as a light brown solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 14.3, 20.6, 21.8, 27.6, 40.3, 43.3 (d, JCF=23 Hz), 54.9, 60.1, 82.0 (d, JCF=165 Hz), 99.8, 102.1, 107.3, 117.2, 121.8, 134.9, 137.6, 153.8, and 176.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[CH3:25][OH:26].[NH3:27]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:25]([NH2:27])=[O:26])[CH:14]=[C:13]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: N
Reactant: CO
Reactant: C[C@H](Nc1cc(N)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Solvent: ClCCl
Product: C[C@H](Nc1cc(NC(N)=O)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,4,6-triamine was dissolved in 2 ml of methylene chloride, and 49 mg of N,N′-carbonyldiimidazole was added thereto, and the mixture was stirred at room temperature overnight. A saturated ammonia methanol solution was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 23 mg of the objective compound as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[CH:9]=[C:10]([C:17]([OH:19])=[O:18])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[O:7])=[CH:4][CH:3]=1.CCOCC.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:7][C:6]([C:31]1[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=1)([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=1)[C:8]1[CH:9]=[C:10]([C:17]([OH:19])=[O:18])[C:11](=[CH:15][CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(C(=O)O)c(C(=O)O)c1
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1C(=O)O

Procedure:
To a solution of 2.00 g of 4-(4-chlorobenzoyl) phthalic acid in 63 ml of tetrahydrofuran was dropwise added 50 ml of ether solution (0.59M) of 4-chlorophenylmagnesium bromide at room temperature in 20 minutes. The reaction mixture was refluxed under heating for 3 hours, cooled with ice, hydrolyzed with 10% hydrochloric acid and shaken with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with chloroform and methanol (2:1) to give crude 4-[hydroxybis (4-chlorophenyl) methyl]phthalic acid. This intermediate was provided for the following reaction without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=1)(=[O:3])[CH3:2].[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1.O>C(Cl)Cl.CN(C)C1C=CN=CC=1.Cl>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=1)[C:15]([CH:12]1[CH2:14][CH2:13]1)=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CC(=O)Nc1cccc(I)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)N(C(=O)C1CC1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
In analogy to Example 13ap), from N-benzyl-5-bromo-isatin (G.Tacconi et al., J. Prakt. Chem. 315, 339 (1973)) there is obtained the corresponding N-benzyl-5-bromo-isatin oxime as a yellow solid. Yield: 94%. Mass spectrum: peaks inter alia at 330 (M+, 17%); 285 (14%), 91 (100%). 13ar) 1.36 g of N-acetyl-3-iodo-aniline are dissolved in 25 ml of methylene chloride and treated with 61 mg of 4-dimethylamino-pyridine. A solution of 5.25 ml of cyclopropanecarbonyl chloride in 7 ml of methylene chloride is added dropwise to this solution. The mixture is stirred at room temperature overnight, then poured into 100 ml of water and made weakly acid with a few drops of dil. hydrochloric acid. Extraction with ethyl acetate and chromatography on silica gel with ethyl acetate gives 1.85 g of cyclopropanecarboxylic acid acetyl-(3-iodo-phenyl)-amide as a yellowish oil which solidifies in time. Yield: 92%. Mass spectrum: peaks inter alia at 329 (M+, 8%); 287 (58%), 69 (100%).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27].C(=O)([O-])O.[Na+]>C1COCC1>[C:26]([N:16]1[CH2:17][CH2:18][N:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a stirred suspension of 1 (2 tert-butylphenyl)piperazine dihydrochloride (29 mg, 0.1 mmol) and triethylamine (0.021 mL, 0.3 mmol) in THF (1.0 mL) was added acetyl chloride (23 mg, 0.3 mmol) at rt. After stirring for 2 h at room temperature, saturated sodium hydrogen carbonate solution (1.5 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (2 mL). The organic layer was separated by phase separation filter kit and the filtrate was evaporated under reduced pressure. The resulting residue was dissolved in DMSO (1 mL) and the solution was purified by preparative HPLC. The eluted fraction was evaporated by air blowing at 60° C. to give a title compound (20.5 mg, 79%). LC/MS (ESI+) m/z 261 [M+H], purity 100%.