Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]([C:25](=[O:28])[CH2:26][CH3:27])[N:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17]CC)=[O:16].O>C1COCC1>[OH:22][C:20]1[C:14]([C:15]([OH:17])=[O:16])=[N:13][N:12]([CH3:11])[C:25](=[O:28])[C:26]=1[CH3:27]
Reactant: CCOC(=O)C(=NN(C)C(=O)CC)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(O)c(C(=O)O)nn(C)c1=O
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
To a solution of LiHMDS (331 mL, 331 mmol, 1 M solution in THF) in THF (430 mL) at −78° C. was added a solution of diethyl 2-(2-methyl-2-propionylhydrazono)malonate (21.40 g, 82.86 mmol) prepared by the procedure described in Example 168 (step B) in THF (10 mL). The resulting mixture was slowly warmed to −40° C. over 1 hour and stirred for 1.5 hours at −40° C. To the −40° C. reaction mixture was added water (500 mL). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the THF. The resulting aqueous mixture was quenched with 6 N aqueous HCl at 0° C., and acidified to pH 1 to 2. The resulting mixture was stirred for 16 hours at room temperature. The precipitates were filtered off and triturated with CH2Cl2 to afford 7.21 g (47%) of the desired product. The filtrate was extracted with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was triturated with CH2Cl2 to afford 3.56 g (23%) of additional desired product. The aqueous layer was extracted again with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was triturated with CH2Cl2 to afford 1.32 g (9%) of additional desired product. A total of 12.09 g (79%) of the desired product was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.[CH2:20]([Mg]Br)[CH3:21]>O1CCCC1.CCOCC>[CH2:20]([C:2]1([OH:1])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:4][CH2:3]1)[CH3:21]
Reactant: O=C1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC1(O)CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a vigorous stirring solution of benzyl (4-oxocyclohexyl)methylcarbamate (1 g) in tetrahydrofuran (20 mL) at −78° C. was slowly added 1 M ethylmagnesium bromide (11.48 ml, 11.48 mmol) in ether. After completion of the addition, the mixture was stirred at −78° C. for 2 hours and was warmed to 0° C., and stirred in an ice bath for 30 minutes. The reaction was quenched with a cold NH4Cl aqueous solution. The precipitates were filtered off and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane and loaded onto Analogix purification system, and was eluted with 0-50% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:11][N:10]([CH2:22][C:23]([F:26])([F:25])[F:24])[C:9]1=[O:27])(C)(C)C.[ClH:29]>CCOC(C)=O>[ClH:29].[NH2:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])[CH2:11][N:10]([CH2:22][C:23]([F:26])([F:24])[F:25])[C:9]1=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1C[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl[(3S,5S)-5-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]carbamate (1.50 g, 3.67 mmol) in EtOAc (30 mL) at 0° C. was saturated with HCl (g) and aged for 30 min. The resulting mixture was concentrated in vacuo to give the title compound. MS: m/z=309.0 (M+1); 1H NMR (500 MHz, CD3OD) δ 7.29-7.17 (m, 3H), 4.36-4.25 (m, 2H), 4.12 (dq, 1H, J=15.1, 9.3 Hz), 3.84 (m, 1H), 3.75 (ddd, 1H, J=12.0, 5.4, 1.7 Hz), 3.64 (t, 1H, J=11.6 Hz), 2.46 (m, 1H), 2.37 (q, 1H, J=12.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1ccc(F)cc1

Procedure:
In close analogy to the procedure described above, 2-(4-fluoro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1>>[CH:11]1([C:17]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:18])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C1CC=CCC1
Product: O=C(O)c1ccc(NC(=O)C2CC=CCC2)cc1

Procedure:
4-(3-Cyclohexene-1-carbonylamino)-benzoic acid was prepared as described in Example 3 from 12 g (0.0875 mol) of p-aminobenzoic acid and 13.9 g (0.0963 mol) of 3-cyclohexene-1-carboxylic acid chloride.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:35]([CH:32]1[CH2:34][CH2:33]1)(=[O:37])=[O:36]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)C1CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. cyclopropansulfonyl chloride (10 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 24 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropansulfonamide (percentage yield: 96%), was obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.[OH-].[Na+].Cl[C:8]([CH2:10][CH2:11][O:12][C:13](=[O:16])[CH:14]=[CH2:15])=[O:9]>O.C(Cl)Cl>[CH3:1][CH:2]1[CH2:4][N:3]1[C:8](=[O:9])[CH2:10][CH2:11][O:12][C:13](=[O:16])[CH:14]=[CH2:15]
Reactant: CC1CN1
Reactant: C=CC(=O)OCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)OCCC(=O)N1CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a stirred 0° C. solution of 2-methylaziridine (5.1 g, about 80 mmol, 90% pure, available from Aldrich) and NaOH (3.6 g, 90 mmol) in a mixture of 50 mL of water and 25 mL of methylene chloride was added dropwise a solution of acrylic acid-2-chlorocarbonylethyl ester (11.6 g, 59 mmol) in 25 mL of methylene chloride. When the addition was complete, the reaction flask was removed from the ice bath and the reaction mixture was allowed to warm to room temperature and was stirred overnight. The phases were then separated and the methylene chloride phase was washed once with 25 mL of water, dried over K2CO3, filtered, and solvent removed at reduced pressure to leave 8.1 g of acrylic acid-3-(2-methylaziridin-1yl)-3-oxopropyl ester as a colorless oil. NMR and IR spectral analyses confirmed the structure of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]4)[C:15]([N:17]4[CH2:22][C:21](=[O:23])[N:20]([CH3:24])[C@H:19]5[CH2:25][CH2:26][CH2:27][C@H:18]45)=[N:16][C:12]=3[CH:11]=[C:10]([C:36](=[N:38][OH:39])[NH2:37])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:40][OH:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]4)[C:15]([N:17]4[CH2:22][C:21](=[O:23])[N:20]([CH3:24])[C@H:19]5[CH2:25][CH2:26][CH2:27][C@H:18]45)=[N:16][C:12]=3[CH:11]=[C:10]([C:36]3[NH:37][C:40](=[O:41])[O:39][N:38]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CO
Reactant: CN1C(=O)CN(c2nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)[C@H]2CCC[C@@H]21
Solvent: ClCCl
Product: CN1C(=O)CN(c2nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)[C@H]2CCC[C@@H]21

Procedure:
(4aS,7aS)-4-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl]-1-methyloctahydro-2H-cyclopenta[b]pyrazin-2-one was prepared in analogy to Example 3.1, Step 3 using 4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-4-methyl-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (197 mg, 0.357 mmol) as starting material and 0-20% methanol in DCM as eluant for chromatography. MS ESI calc'd. for C29H33ClN8O3 [M+H]+ 577. found 577. 1H NMR (500 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.98 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.49 (t, J=2.0 Hz, 1H), 8.04 (s, 1H), 4.31-4.28 (m, 1H), 3.88-3.84 (m, 2H), 3.69-3.61 (m, 3H), 2.88 (s, 3H), 2.34-2.24 (m, 1H), 2.31-2.04 (m, 1H), 1.89-1.75 (m, 2H), 1.70-1.61 (m, 1H), 1.47-1.33 (m, 3H), 1.25-1.20 (m, 2H), 1.08-0.98 (m, 1H), 0.85-0.82 (m, 1H), 0.73-0.60 (m, 5H), 0.62-0.33 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:15]N(C=O)C>CO>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:15])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CN(C)C=O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(Br)n1

Procedure:
A mixture of 6-bromo-2-pyridinecarboxylic acid (0.3 g, 1.5 mmol), thionyl chloride (0.27 ml, 3.7 mmol) and DMF (catalytic amount) in methanol (10 ml) was heated to reflux for 2 hrs under nitrogen atmosphere. The reaction mixture was concentrated to dryness to provide methyl 6-bromo-2-pyridinecarboxylate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][NH:13][CH3:14]>CO>[CH3:12][N:13]([CH3:14])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNC
Reactant: ClCCCOc1cccnc1
Solvent: CO
Product: CN(C)CCCOc1cccnc1
Temperature: 100 °C
Yield: 92.9 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (2.00 g, 11.65 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of dimethylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and the mixture was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated to give 1.95 g (92.9%) of an oil.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[N:10][OH:11])[CH:2]=[CH2:3].[CH3:12][N:13]=[C:14]=[O:15]>CC(C)=O.C(N(CC)CC)C>[CH2:1]([N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[N:10][O:11][C:14](=[O:15])[NH:13][CH3:12])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)CSC1=NO
Reactant: CN=C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CCN1C(=O)CSC1=NOC(=O)NC
Reaction time: 8 h

Procedure:
To a solution of (1.7 g) 3-allyl-2-oximino-4-thiazolidinone in 20 ml of acetone was added 1.0 ml methylisocyanate and 1 drop of triethylamine. The mixture was placed in a pressure bottle and left standing overnight at ambient temperature. The solution was concentrated to a solid residue. Recrystallized from ethyl acetate. Weight 1.7 g. m.p. 108°-110°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.C(N(CC)CC)C.[C:23]([O:27][C:28](=[O:31])[NH:29][NH2:30])([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:30][NH:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:14]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=O)CCCCCCCCC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCCC(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.81 g (50 mmol) of sebacic acid monomethyl ester is dissolved in tetrahydrofuran and successively mixed with 8.32 ml (60 mmol) of triethylamine and 5.28 ml (55 mmol) of chloroformic acid ethyl ester [ethyl chloroformate] at -5° C. After 15 minutes 6.61 g (50 mmol) of tert-butylcarbazate in tetrahydrofuran is instilled at this temperature and then stirred at room temperature for 2 hours. The precipitate is suctioned off, the filtrate is concentrated by evaporation and taken up in ethyl acetate. The organic phase is successively washed with NaHCO3 solution, citric acid and water and dried on Na2SO4. The oil obtained after concentration by evaporation of the ethyl acetate is chromatographed on silica gel in diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)[N:6]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)=[O:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:40]([C:39]4[CH:38]=[CH:37][C:36]([C:34]([NH:33][C:30]5[CH:29]=[CH:28][C:27]([N:24]6[CH2:23][CH2:22][O:21][CH2:26][CH2:25]6)=[CH:32][CH:31]=5)=[O:35])=[CH:43][CH:42]=4)[NH:18][C:11]=3[CH:10]=2)[N:6]=1
Reactant: Cc1nc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cs1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Product: Cc1nc(COc2ccc3nc(-c4ccc(C(=O)Nc5ccc(N6CCOCC6)cc5)cc4)[nH]c3c2)cs1

Procedure:
Compound 622 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methylthiazol-4-yl)methoxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C29H27N5O3S: 526.18; found: 526.06.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][C:22]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([CH3:33])=[CH:20][CH:21]=3)=[O:31])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1ccc(-c2ocnc2C(=O)O)cc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccc(C)cc3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-p-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.08 min; [M+H]+=391.12.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1)([O-:3])=[O:2].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.FC(F)(F)C(O)=O>CC#N>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7]1
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Reactant: C1=COCCC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc([N+](=O)[O-])n(C2CCCCO2)n1
Yield: 0 %

Procedure:
A mixture of methyl 5-nitro-1H-pyrazole-3-carboxylate (7.5 g, 43.8 mmol), 3,4-dihydro-2H-pyran (8 mL, 87.7 mmol) and trifluoroacetic acid (65 μL, 0.9 mmol) in anhydrous MeCN (100 mL) was refluxed for 16 hrs. The solvent was evaporated and the residue was resuspended in CH2Cl2 (50 mL) and washed with H2O and brine. After drying with Na2SO4, solvent evaporation and silica gel column chromatography (PE-EtOAc, 9:1) methyl 1-(tetrahydro-2H-pyran-2-yl)-5-nitro-1H-pyrazole-3-carboxylate (3.71 mg, 33%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[C:17](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][N:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])/[CH:19]=[CH:18]/[C:17]2[C:13]([CH3:12])=[N:14][O:15][C:16]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: Cc1noc(-c2ccccc2)c1/C=C/C(=O)O
Reactant: COC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(=O)/C=C/c2c(C)noc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A mixture of methyl 4-aminobenzoate (0.30 g), (E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (0.35 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.27 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and (E)-N-(4-methoxycarbonylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenamide (0.51 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 174–175° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([NH:13][CH2:14][CH2:15][O:16][C:17](OC3C=CC=CC=3)=[O:18])[N:10]=[C:9]([CH2:26][CH2:27][CH3:28])[N:8]=2)[CH2:3][CH2:2]1.[NH3:29]>ClCCl>[NH2:29][C:17]([O:16][CH2:15][CH2:14][NH:13][C:11]1[N:12]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:8]=[C:9]([CH2:26][CH2:27][CH3:28])[N:10]=1)=[O:18]
Reactant: N
Reactant: CCCc1nc(NCCOC(=O)Oc2ccccc2)nc(N2CCOCC2)n1
Solvent: ClCCl
Product: CCCc1nc(NCCOC(N)=O)nc(N2CCOCC2)n1
Reaction time: 7 h
Yield: 97.4 %

Procedure:
19.4 g (0.05 mole) of 2-morpholino-4-[[2-[(phenoxycarbonyl)oxy]ethyl]amino]-6-propyl-1,3,5-triazine, dissolved in 100 ml of anhydrous dichloromethane are introduced into one liter of liquid ammonia. Stirring is continued for 7 hours at a temperature of between -35° C. and -45° C. The ammonia is then evaporated and the organic phase is washed successively with an aqueous solution of sodium bicarbonate and with water. It is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue obtained crystallizes in a 50:50 mixture (v/v) of ethyl acetate-hexane. 15.1 g of 2-[[2-[(aminocarbonyl)oxy]ethyl]amino]-4-morpholino-6-propyl-1,3,5-triazine are obtained.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1c2n(c3c(-c4ccc(F)cc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, white solid (66 mg, 79%), MS (ISP) m/z=334.5 [(M+H)+], mp 278° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]3)[N:5]=[C:4]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[C:28](Cl)([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].C([O-])(O)=O.[Na+]>CCOC(C)=O>[C:24]([C:4]1[CH:3]=[C:2]([C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29])[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:11][CH2:10]3)[N:5]=1)([CH3:26])([CH3:27])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-n3nc(C(C)(C)C)cc3N)ccc2C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(-n3nc(C(C)(C)C)cc3C(=O)OCC(Cl)(Cl)Cl)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
To a stirring solution of t-butyl 6-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (see WO 2006/071940A2, 0.075 g, 0.20 mmol) and Troc-Cl (0.028 ml, 0.21 mmol) in EtOAc (2 ml) was added sat'd. NaHCO3 (0.82 ml, 0.61 mmol). The resulting biphasic solution was stirred at RT overnight. The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were washed with brine (1×), dried (MgSO4) and concentrated in vacuo to give crude t-butyl 6-(3-t-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.110 g, 100% yield). 1H NMR (DMSO-d6) δ 9.93 (brs, 1H), 7.29-7.24 (m, 2H), 6.83-6.80 (m, 1H), 6.27 (s, 1H), 4.85 (s, 2H), 4.52 (brs, 2H), 3.57-3.53 (m, 2H), 2.82-2.79 (m, 2H), 1.44 (s, 9H), 1.27 (s, 9H); MS (ESI) m/z: 545.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:23]1([N:29]=[C:30]=[S:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:30](=[S:31])[NH:29][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: S=C=Nc1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=S)Nc2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.131 g, 0.44 mmol) in dichloromethane (5 mL) was added phenyl isothiocyanate (58 μL, 0.48 mmol). The reaction mixture was shaken at room temperature for 2 hours. The solvent was then removed under reduced pressure to give 3-(4-methoxybenzyl)-N-phenyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carbothioamide as a solid residue (LCMS [M+H]: 430), which was used for next step without further purification.