Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[CH:23][C:22]([C:40]3[NH:44][N:43]=[N:42][N:41]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:54][CH2:55][OH:56].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=3)=[CH:23][C:22]([C:40]3[N:41]=[N:42][N:43]([CH2:54][CH2:55][OH:56])[N:44]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: OCCBr
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(-c3nnn[nH]3)cc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(-c3nnn(CCO)n3)cc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 50 °C
Reaction time: 2 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(tetrazol-5-yl)pyridin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (120 mg), potassium carbonate (51 mg) and excess of 2-bromoethanol are dissolved in N,N-dimethylformamide (3 ml), and the mixture is stirred at 50° C. for 2 hours. Water and ethyl acetate are added to the reaction solution and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=2:1→1:1) to give (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[2-(2-hydroxyethyl)-2H-tetrazole-5-yl]pyridin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (119 mg). MS (m/z): 695 [M+H]+
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH2:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:32][CH:33]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, off-white solid (89 mg, 73%), MS (ISP) m/z=487.4 [(M+H)+], mp 190° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-isobutyl-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[C:17]2=[O:18])=[C:4]([F:20])[CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 34.8 %

Procedure:
2-(4-Chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (3 g) was dissolved in dimethylformamide (100 ml), and anhydrous potassium carbonate (0.8 g) was added thereto. To the resultant mixture was added methyl bromoacetate (1.8 g), and the mixture was heated at 70°-80° C. for 3 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ether, and the extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography to give 1.3 g of 2-(4-chloro-2-fluoro-5-methoxycarbonylmethoxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (Compound No. 1). M.P., 98°-99.5° C.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.N1CCCCC1.[CH3:37][O:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[ClH:11].[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:42]2[CH2:43][CH2:44][CH:39]([O:38][CH3:37])[CH2:40][CH2:41]2)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1
Reactant: COC1CCNCC1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Solvent: C1CCNCC1
Product: COc1cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCC(OC)CC2)cc(OC)c1
Product: Cl

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-chloro-pentan-1-one and piperidine with 4-methoxypiperidine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-(4-methoxypiperidin-1-yl)pentan-1-one hydrochloride, m.p. 195-196° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1>CCOC(C)=O>[Cl:14][C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[N:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Clc1nccc(-c2cccnc2Cl)n1
Reactant: NCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Clc1ncccc1-c1ccnc(NCCCN2CCOCC2)n1
Temperature: 80 °C

Procedure:
To 2-chloro-4-(2-chloropyridin-3-yl)pyrimidine (100 mg, 0.44 mmol) and potassium carbonate (122 mg, 0.88 mmol) was added DMSO (1.0 mL) and 3-morpholinopropan-1-amine (77 mg, 0.53 mmol). The resulting mixture was heated for 15 hours at 80° C. The cooled reaction was diluted with EtOAc and extracted with water. The organic layer was dried over sodium sulfate, filtered and concentrated to yield the desired product as a yellow oil. MS m/z=334 [M+H]+. Calc'd for C16H20ClN5O: 333.84.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]([C:23]1[N:28]=[N:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([F:36])[CH:30]=2)=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:16]([C:23]1[N:28]=[N:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[C:31]([F:36])[CH:30]=2)=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc(-c2ccc(Cc3ccccc3)nn2)cc1F
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(-c4ccc(Cc5ccccc5)nn4)cc3F)c2cc1OC
Temperature: 180 °C

Procedure:
A mixture of 4-Chloro-6,7-dimethoxy-quinoline (0.19 g, 0.85 mmol), 4-(6-benzyl-pyridazin-3-yl)-2-fluoro-phenol (Step 3, 0.2 g, 0.71 mmol) and DMAP (0.1 g, 0.85 mmol) in 6 mL of toluene was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 2 h. The mixture was cooled to RT and diluted with 60 mL of EtOAc. The solution was washed with 20 mL of brine 2×, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (50% to 100% EtOAc in hexanes) to provide title compound as a white solid. MS (ESI pos. ion) m/z: 487.3 (M+H). Calc'd Exact Mass for C28H22FN3O3: 467.49.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[N:10]2)=[CH:5][CH:4]=1.ClC1C(CC(OCC)=O)=CC2C(=CC(OC)=CC=2)N=1.ClC1C(CC(OCC)=O)=CC2C(=CC=CC=2OC)N=1>CCOC(C)=O.CCO.[Pd]>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cc1cnc2cc(OC)ccc2c1
Agent: [Pd]
Agent: CCOC(=O)Cc1cc2c(OC)cccc2nc1Cl
Agent: CCOC(=O)Cc1cc2ccc(OC)cc2nc1Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)Cc1cnc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35 %

Procedure:
Ethyl 2-(7-methoxyquinolin-3-yl)acetate. To a solution of a crude mixture of ethyl 2-(2-chloro-7-methoxyquinolin-3-yl)acetate and ethyl 2-(2-chloro-5-methoxyquinolin-3-yl)acetate in EtOAc (200 mL) and EtOH (200 mL) was added 10% Pd/C (50 mg, 0.47 mmol). The reaction mixture was placed under an atmosphere of hydrogen and stirred at ambient temperature for 3 days. The crude reaction mixture was filtered through silica and concentrated to afford a brown oil. Purification by FCC (SiO2, 0-5%, MeOH/DCM) yielded the title compound as a light brown solid (6.0 g, 35% over 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 7.20 (dd, J=9.0, 2.3 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 3.76 (s, 2H), 1.26 (t, J=6.8 Hz, 3H). [M+H]=246.2.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([CH2:17][OH:18])=[CH:9][O:8]1)[CH3:5])[CH3:2].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(OCC)(=O)C>ClCCl>[C:25]([O:18][CH2:17][C:10]1[C@H:11]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@H:12]2[C@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[O:8][CH:9]=1)(=[O:27])[CH3:26]
Reactant: CCOC(C)O[C@@H]1OC=C(CO)[C@H]2CC[C@@H](C)[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(C)O[C@@H]1OC=C(COC(C)=O)[C@H]2CC[C@@H](C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
(1S, 4aS, 7R, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-4-(hydroxymethyl)-7-methylcyclopenta[c]pyran (100 mg, 0.00039 mol) obtained in Example 25 was dissolved in 5 mι of dichloromethane, and 0.15 mι (0.0016 mol) of pyridine and 0.1 mι (0.0012 mol) of acetic anhydride were added. Furthermore, 5 mg of N, N-dimethylaminopyridine was added, the reaction mixture was stirred at room temperature for 5 hours. Then, the reaction mixture was poured into 30 mι of ethyl acetate, and the organic layer was washed with water (30 mι), 2N hydrochloric acid solution (30 mι), saturated sodium bicarbonate solution (30 mι) and saturated sodium chloride solution (30 mι), was dried by adding magnesium sulfate, was filtered, and then concentrated under a reduced pressure. The residual matter was purified by chromatography using silica gel, and the fraction obtained from hexane:ether=6:4 eluent was concentrated. A colorless oily substance was thus obtained, i.e., (1S, 4aS, 7R, 7aR)-4-(acetoxymethyl)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[c]pyran (71 mg, yield=61.0%). This (1S, 4aS, 7R, 7aR)-4-(acetoxymethyl)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-7-methylcyclopenta[ c]pyran had the following physicochemical properties:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].C(N(CC)CC)C.N1C=CC=N1>C1C=CC=CC=1>[C:8]([N:3]1[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N:4]1)(=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)Cl
Reactant: Cc1cc(C)[nH]n1
Agent: c1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC(=O)n1nc(C)cc1C
Temperature: 10 °C
Reaction time: 4 h

Procedure:
N-acrylyl-3,5-dimethyl pyrazole was prepared by reacting 3,5-dimethylpyrazole with acrylyl chloride in the presence of triethylamine. 19.2 grams (0.2 mole) of 3,5-dimethylpyrazole and 20.2 grams (0.2 mole) of triethylamine were dissolved in 125 milliliters of benzene and the solution put into a dropping funnel. The acrylyl chloride, 18.1 grams (0.2 mole) was dissolved in 25 milliliters of benzene and this solution put into a flask equipped for stirring and cooled to 10°C. The pyrazole solution was then added to the acrylyl chloride solution over a period of 45 minutes with constant stirring. Temperature of the reaction mix was held at 8° to 15°C. throughout the addition. Following the addition, the reaction mix was allowed to warm to room temperature and let stand for 4 hours. The mix was then filtered to remove triethylamine-hydrochloric acid salt which was formed in the reaction. The filtrate was heated to evaporate off volatiles, leaving 24.5 grams of an amber-colored liquid residue. The residue was then cooled to about 0°C. and 12.1 grams of a white crystalline precipitate was filtered out. After standing 16 hours at about 0°C., 2.5 more grams of crystalline solid was filtered out. The solids were combined and twice recrystallized from a solution of 18 milliliters of methanol and 2 milliliters of water to yield 9.4 grams of a crystalline solid having a melting point of 36°-37°C. The nuclear magnetic resonance (NMR) spectra of the solid conformed with that of the expected product.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:14][CH3:15])=[CH:6][C:7]([N:10]([O:12][CH3:13])[CH3:11])=[N:8][CH:9]=1.[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>N1C=CC=CC=1>[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH2:3][C:4]2[C:5]([NH:14][CH3:15])=[CH:6][C:7]([N:10]([O:12][CH3:13])[CH3:11])=[N:8][CH:9]=2)=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]
Reactant: CNc1cc(N(C)OC)ncc1CCl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Product: CNc1cc(N(C)OC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of the above 5-(chloromethyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine HCl (3.5 g, 16.3 mmol) and 4-fluoro-3-nitroaniline (41.5 mL, 0.3 mol) in pyridine (150 mL) was stirred at 50° C. for 8 h. The reaction mixture was concentrated in vacuo to afford a crude product which was washed with H2O and dried to give 5-((4-fluoro-3-nitrophenylamino)methyl)-N2-methoxy-N2,N4-dimethylpyridine-2,4-diamine (3.3 g, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.83 (m, 1 H), 7.62 (s, 1 H), 7.30 (t, J=9.2 Hz, 1 H), 7.20 (m, 1 H), 6.98 (m, 1 H), 6.81 (s, 1 H), 5.98 (s, 1 H), 4.14 (s, 2 H), 3.69 (s, 3 H), 3.30 (s, 3H), 2.89 (d, J=4.8 Hz, 3 H); MS (ESI) m/z: 336.2 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:19]1[CH:20]=[CH:21][C:22](=O)[NH:23][CH:24]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11].I[CH3:27].[C:28](=[O:31])([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:19]1[CH:20]=[CH:21][C:28](=[O:31])[N:23]([CH3:22])[CH:24]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:27])[CH:17]=1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CI
Reactant: O=C(CC(c1ccc(=O)[nH]c1)c1ccccc1Cl)c1ccc(=O)[nH]c1
Agent: [K+]
Product: Cn1cc(C(=O)CC(c2ccc(=O)n(C)c2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 161, step 1, 5,5′-[1-(2-chlorophenyl)-3-oxopropane-1,3-diyl]dipyridin-2(1H)-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=383.1 [M+H]+.
Reaction SMILES: [CH2:1]([Br:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([N:12]1[C:16]2[C:17](=[O:26])[C:18]3[C:23]([C:24](=[O:25])[C:15]=2[N:14]=[C:13]1[CH3:27])=[CH:22][CH:21]=[CH:20][CH:19]=3)([CH3:11])[CH3:10]>C(#N)C>[Br-:8].[CH2:1]([N:14]1[C:15]2[C:24](=[O:25])[C:23]3[C:18]([C:17](=[O:26])[C:16]=2[N+:12]([CH:9]([CH3:10])[CH3:11])=[C:13]1[CH3:27])=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc2c(n1C(C)C)C(=O)c1ccccc1C2=O
Solvent: CC#N
Product: Cc1n(Cc2ccccc2)c2c([n+]1C(C)C)C(=O)c1ccccc1C2=O
Product: [Br-]

Procedure:
Benzyl bromide (1.9 ml) was added to a solution of 1-isopropyl-2-methyl-4,9-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazole (0.8 g) in acetonitrile (20 ml) and the mixture was stirred under reflux for 6 hours. After cooling, the resulting precipitate was collected by filtration and washed with ethyl acetate. The obtained solid was recrystallized from methanol to give 1-benzyl-3-isopropyl-2-methyl-4,9-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazol-3-ium bromide (0.47 g) as a yellow powder.
Reaction SMILES: O[CH2:2][C@@H:3]1[O:8][C:7](=[O:9])[C@H:6]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]([CH3:20])([CH3:19])[CH2:4]1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl>[CH3:19][C:5]1([CH3:20])[C@H:6]2[N:10]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[CH2:2][C@H:3]([O:8][C:7]2=[O:9])[CH2:4]1
Reactant: CC(N[C@H]1C(=O)O[C@@H](CO)CC1(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1ccccc1)N1C[C@H]2CC(C)(C)[C@@H]1C(=O)O2
Reaction time: 46 h
Yield: 30 %

Procedure:
To a solution of (3R,6R)-6-hydroxymethyl-4,4-dimethyl-3-(1-phenyl-ethylamino)-tetrahydro-pyran-2-one (compound of formula XXXIV, 1.42 g, 5.14 mmol) in 45 ml of methylene chloride was added triethylamine (1.1 ml, 7.9 mmol) and p-toluenesulfonyl chloride (1.2 g, 6.2 mmol) at about 0° C. The mixture was warmed to a temperature of about 20° C. to about 25° C. and was stirred for about 46 hours. The mixture was washed twice with water, and the aqueous layers were extracted with methylene chloride. The combined organic layers were dried over MgSO4, filtered and concentrated. Purification of the residue by filtration through a pad of silica gel eluting first with hexane followed by 20% ethyl acetate in hexane afforded 0.4 g of (1R,4R)-8,8-dimethyl-5-(1-phenyl-ethyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXV) as a colorless solid after recrystallization from methanol-water.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][C:8]([OH:10])=[C:7]([C:11]3[C:19](=O)[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=3)[C:5]=2[CH:6]=1.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][C:8]([OH:10])=[C:7]([C:11]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]=3[N:22]=[O:23])[C:5]=2[CH:6]=1
Reactant: O=C1C(c2c(O)[nH]c3ccccc23)=Nc2ccccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=Nc1c(-c2c(O)[nH]c3ccccc23)[nH]c2ccccc12
Yield: 90 %

Procedure:
Indirubin-3′-oxime was synthesized by reaction of indirubin with hydroxylamine hydrochloride in a pyridine solution (Farbwerke vorm. Meister Lucius & Brüning in Hoechst a.M., Patentschrift des Reichspatentamtes Nr. 283726 (1913)). 13C-NMR-spectroscopy revealed the location of the hydroxyimino residue in 3′-Position (δ(C2)=171.05 ppm; δ(C3′)=145.42 ppm; DMSO-d6, RT).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>CN(C=O)C.O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[C:27]([F:28])([F:29])[F:30])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To 4-hydroxy-N-(t-butoxycarbonyl)piperidine (10.0 g) in DMF was added NaH (2.2 g) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours. 4-Flouro-3-trifluoromethyl-1-nitrobenzene (5.3 mL) was added and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with aqueous NaHCO3 and aqueous HCl, dried over sodium sulfate, concentrated and purified on silica gel column (hexane/ethyl acetate, gradient) to afford a compound of formula (C), 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-1-nitrobenzene in 80% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([NH:9][CH:10]=[C:11]([C:17](=[O:28])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([Cl:26])[C:19]=2F)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.NC1C=C(NC=C(C(=O)C2C=C(F)C(F)=C(Cl)C=2F)C(OCC)=O)C(F)=CN=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([N:9]2[C:19]3[C:18](=[CH:23][C:22]([F:24])=[C:21]([F:25])[C:20]=3[Cl:26])[C:17](=[O:28])[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10]2)[CH:3]=1
Reactant: CCOC(=O)C(=CNc1cc(N)c(F)cn1)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)C(=CNc1cc(N)ncc1F)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cc(N)c(F)cn2)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To 150 mg of the mixture of ethyl 3-(4-amino-5-fluoropyridine-2-yl)amino-2-(3-chloro-2,4,5-trifluoro-benzoyl)acrylate and ethyl 3-(2-amino-5-fluoropyridine-4-yl)amino-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate were added 230 mg of anhydrous potassium carbonate and 450 mg of N,N-dimethylformamide, and the mixture was stirred at 100° C. for 20 minutes and allowed to cool. The solution was separated by adding 20 ml of chloroform and 100 ml of distilled water, and the chloroform layer was washed with 100 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 3.2 g; eluent: chloroform:methanol, 100:1), and the fraction containing the main product was concentrated under reduced pressure to obtain 35 mg of the title compound as a yellow solid residue.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:77][CH:78]1[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:77][CH:78]5[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]5)=[O:28])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 29.4 %

Procedure:
To a mixture of 0.0649 g (0.141 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.0309 g (0.229 mmole) of 1-hydroxybenzotriazole, 0.0825 g (0.229 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1113 g (0.862 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.021 g (0.211 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0231 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-215) as a white solid.