Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].O>CN(C=O)C>[C:17]1([CH2:16][CH2:15][CH2:14][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[C:8]2=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C1NCCc2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(Br)cc2CCN1CCCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline (2.82 g, 12.5 mmol) in DMF (80 ml) is added 1-bromo-3-phenylpropane (2.89 ml, 18.75 mmol), KI (200 mg, 1.25 mmol) and NaH (600 mg, 25 mmol). The reaction mixture is stirred for 3 hours and subsequently poured into H2O (300 ml). The resulting emulsion is extracted with EtOAc (2×150 mL) and the organic phase washed with 2N HCl (1×200 mL), H2O (1×200 mL), saturated NaHCO3 solution (1×200 mL), saturated NaCl solution (2×200 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 9:1 hexane/EtOAc) to give 2-(3-phenylpropyl)-6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH:21]1[C:26]([CH:27]=O)=[CH:25][C:24]2[O:29][CH2:30][O:31][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]([Cl:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[C:7]2[NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:27][C:26]2[CH:21]=[CH:22][C:23]3[O:31][CH2:30][O:29][C:24]=3[CH:25]=2)[CH2:18][CH2:19]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)cc(Br)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1cc(NC2CCN(Cc3ccc4c(c3)OCO4)CC2)c2cc(Cl)cc(Br)c2o1

Procedure:
8-bromo-6-chloro-4-(piperidin-4-ylamino)-chromen-2-one and piperonal were allowed to react under reductive alkylation conditions for 44 hours at room temperature, then treated with 1 M K2CO3, extracted with CH2Cl2, filtered through silica gel (5 g SepPak), rinsed with 95:5 CH2Cl2:MeOH, and concentrated. Purification by silica gel preparatory plate (0.25 mm×20 cm×20 cm) developed with 95:5 CH2Cl2:MeOH to give the title compound as a white solid (6 mg). 1H NMR (300 MHz, ppm, DMSO-d6) δ 1.6 (m, 2H), 1.9 (m, 2H), 2.1 (m, 2H), 2.8 (m, 2H), 3.4-3.5 (m, 3H), 5.33 (s, 1H), 5.99 (s, 2H), 6.77 (m, 1H), 6.85 (m, 2H), 7.38 (m, 1H), 8.05 (d, J=2 Hz, 1H), 8.36 (d, J=2 Hz, 1H). MS(ESI) 493 (M+H), 491 (M−H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:25][O:24][C:17]1[CH:16]=[C:15]([N:11]2[CH2:12][CH2:13][CH:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:9][CH2:10]2)[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 89.8 %

Procedure:
To a solution of 1-methyl-4-(piperidin-4-yl)piperazine (4.2 g, 22.91 mmol) in anhydrous DMF (40 mL) was added 4-fluoro-2-methoxy-1-nitrobenzene (3.92 g, 22.91 mmol) and potassium carbonate (3.80 g, 27.5 mmol). This suspension was heated at 70° C. overnight. After cooling, the reaction mixture was concentrated, and the residue partitioned between ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated. The residue was separated by flash chromatography (0-15% 2% ammonium hydroxide MeOH solution in dichloromethane) to give 6.88 g of the title compound. Yield: 90%. MS (DCI) m/z 335 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 1.58-1.68 (m, 2H), 1.93-1.99 (m, J=11.53 Hz, 2H), 2.29 (s, 3H), 2.44-2.51 (m, 4H), 2.62 (s, 4H), 2.92-3.02 (m, 2H), 3.90-3.98 (m, 7H), 6.31 (d, J=2.37 Hz, 1H), 6.42 (dd, J=9.32, 2.54 Hz, 1H), 7.99 (d, J=9.49 Hz, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C[Si]([N:15]=[C:16]=[O:17])(C)C>C(O)(C)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:16]([NH2:15])=[O:17])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N=C=O
Reactant: C1CC2(CCN1)OCCO2
Solvent: CC(C)O
Product: NC(=O)N1CCC2(CC1)OCCO2
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a stirred solution of 1,4-dioxa-8-azaspiro[4,5]-decane (1.1 g, 7.67 mmol) in isopropanol (20 mL) at rt was added trimethylsilylisocyanate (1.5 mL, 10.6 mmol) and the resulting solution stirred overnight before the volatiles were removed in vacuo to give 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid amide (1.47 g, quant.); 1H-NMR (300 MHz, d6-DMSO) 5.96 (2H, s), 3.88 (4H, s), 3.33 (4H, t), 1.51 (4H, t).
Reaction SMILES: [F:1][C:2]1([F:54])[CH2:7][O:6][C:5]([NH:8]C(C2C=CC(OC)=CC=2)(C2C=CC=C(OC)C=2)C2C=CC=CC=2)=[N:4][C@@:3]1([C:33]1[N:38]=[C:37]([NH:39][C:40]([C:42]2[C:47]([Cl:48])=[CH:46][C:45]([C:49]([F:52])([F:51])[F:50])=[CH:44][N:43]=2)=[O:41])[CH:36]=[CH:35][C:34]=1[F:53])[CH3:32].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>ClCCl>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:54])([F:1])[C@:3]([C:33]2[N:38]=[C:37]([NH:39][C:40]([C:42]3[C:47]([Cl:48])=[CH:46][C:45]([C:49]([F:52])([F:50])[F:51])=[CH:44][N:43]=3)=[O:41])[CH:36]=[CH:35][C:34]=2[F:53])([CH3:32])[N:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3nc(NC(=O)c4ncc(C(F)(F)F)cc4Cl)ccc3F)C(F)(F)CO2)(c2ccccc2)c2cccc(OC)c2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(c2nc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)N=C(N)OCC1(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((R)-5,5-difluoro-2-{[(4-methoxy-phenyl)-(3-methoxy-phenyl)-phenyl-methyl]-amino}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide (80 mg, 0.104 mmol) was dissolved in dichloromethane (0.1039 ml), TFA (80.0 μl, 1.04 mmol) was added and the reaction mixture was stirred at rt for 18 hours. The reaction mixture was poured onto a mixture of ice ethyl acetate and NH4OH (w=25%). The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed over silica gel (column 4 g, dichloromethane/methanol 95:5+0.5% ammonia) to give the title compound: 32 mg (65.9% yield).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([N:11]([CH2:17][CH2:18]OS(C)(=O)=O)[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])(=[O:10])=[O:9].[Cl-:24].[Li+]>CC(C)=O>[CH3:7][S:8]([N:11]([CH2:17][CH2:18][Cl:24])[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])(=[O:10])=[O:9]
Reactant: [Cl-]
Reactant: CS(=O)(=O)NN(CCOS(C)(=O)=O)S(C)(=O)=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)NN(CCCl)S(C)(=O)=O
Yield: 20 %

Procedure:
A three-step process with a total yield less than 10% has been previously reported published in the following patents and journal articles: U.S. Pat. No. 5,637,619 (Jun. 10, 1997 for VNP40101M); U.S. Pat. No. 4,684,747 (Aug. 4, 1987 for intermediate VNP4090CE); WO97/02029 (Jan. 23, 1997); Journal of Medicinal Chemistry, 1990, 33(8): 2259-2264; Journal of Medicinal Chemistry, 1996, 39(3): 796-801, as illustrated in FIG. 1. 2-Hydroxyethylhydrazine (HEH) was used a starting material and reacted with methanesulfonyl chloride to obtain 1,2-bis(methylsulfonyl)-1-[2-(methylsulfonyloxy)ethyl]hydrazine (BMH) at −20° C. for 18 hours, using pyridine as base. The crude intermediate BMH was treated with lithium chloride in acetone under reflux for 3 days to afford 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (VNP4090CE). After purification by flash column chromatography, an approximately 20% yield was reached for the two steps. VNP4090CE was condensed with methyl isocyanate at room temperature using triethylamine (TEA) as a base. After crystallization from ethanol, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylcarbamoyl)hydrazine (VNP40101M) with an approximately 42% yield. The total yield of this process was less than 10%. It is noted that the process used methyl isocyanate, which is extremely dangerous for manufacturing in scaleup kilogram amounts. For this reason, the present inventors investigated the synthesis and have developed new methods to prepare VNP40101M.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[N:18]=[N:17][C:16]=2[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][C:10]=1[O:33][CH3:34])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:29]([C:16]1[N:17]=[N:18][C:19]([O:21][CH:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:33][CH3:34])[CH:11]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 4-(4-benzyloxy-3-methoxy-phenyl)-3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazine (1.0 mmol, 462 mg) in methanol/ethyl acetate (10 mL, 1/1) was added 10% palladium on activated carbon (70 mg). The mixture was repeatedly de-gassed under vacuum, filled with hydrogen for 3 times. Then hydrogen balloons were attached to the reaction, which was stirred at room temperature for 2 hours. TLC/LCMS monitored to completion. The mixture was then filtered through celite, the celite cake was washed with 1/1 methanol/ethyl acetate for 3 times, and the organic layers were combined and condensed under reduced pressure to give 4-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-methoxy-phenol as a white powder (327 mg), which was used directly in the next step.
Reaction SMILES: [CH2:1]([NH:8][CH:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=1>>[CH2:1]([N:8]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)[CH:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: O=CNCc1ccccc1
Product: Cc1cc(C)cc(N(C=O)Cc2ccccc2)c1
Yield: 99.2 %

Procedure:
Using general procedure A, N-benzylformamide (170 mg, 1.26 mmol) was coupled with 5-iodo-m-xylene (150 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 3:1; 15 mL fractions). Fractions 7-13 provided 247 mg (99% yield) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 7.39−7.22 (m, 5H), 6.91 (s, 1H), 6.75 (s, 2H), 5.00 (s, 2H), 2.30 (s, 6H).
Reaction SMILES: CO.S(=O)(=O)(O)O.[CH:8]([O:13][CH3:14])([O:11]C)OC.[C:15]([C:23]1C(=O)[O:25][C:26]([CH3:30])=[CH:27][C:28]=1[OH:29])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH3:14][O:13][C:8]([C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH3:30])[O:25][C:15]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:11]
Reactant: Cc1cc(O)c(C(=O)c2ccccc2)c(=O)o1
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)oc(C)cc1=O
Yield: 75.8 %

Procedure:
A flask fitted with a reflux condenser and calcium chloride drying tube is charged with 70 ml dry methanol, 7.3 gms of 96% sulfuric acid and 10.15 gms of trimethyl orthoformate. 3-Benzoyl-4-hydroxy-6-methyl-2-pyrone (22 gms) is then added in small portions and the resulting reaction mixture is refluxed for 24 hours. The mixture is cooled and poured into water. Extraction with methylene chloride yields 17.7 gms of crude 3-methoxycarbonyl-6-methyl-2-phenyl-4-pyrone. mp (from methylene chloride/ether=101-2.5
Reaction SMILES: [CH3:1][C:2]1[S:26][C:5]2=[N:6][C:7]([CH3:25])=[C:8]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([O:20]C)=[O:19])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:4]2[CH:3]=1.[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[S:26][C:5]2=[N:6][C:7]([CH3:25])=[C:8]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([OH:20])=[O:19])[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:4]2[CH:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc(C)cc2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc(C)cc2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a solution of methyl 2-(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.135 g; 0.367 mmol) in methanol (8 mL) and ethanol (4 mL) was added a 5% sodium hydroxide solution (10.5 mL; 13.125 mmol). The reaction mixture was heated under reflux for 4.5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.107 g (82%) of the title compound as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][CH:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:22](=[O:23])[CH:16]([CH3:15])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Nc1ccc(F)cc1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccc(F)cc1

Procedure:
Prepared according to general Procedure A using 4-fluoroaniline (18 g, 162 mmol), pyridine (13 mL, 162 mmol) and diethyl methylmalonate (28 mL, 162 mmol). After purification ethyl 3-(4-fluorophenylamino)-2-methyl-3-oxopropanoate was obtained. Mass Spectrum (ESI) m/e=240.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]2[CH2:11][C:12]2[O:16][C:15]([C:17](OCC)=[O:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:28][CH3:29].[NH3:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]2[CH2:11][C:12]2[O:16][C:15]([C:17]([NH2:30])=[O:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: N
Reactant: CCOC(=O)c1ccc(Cn2c(-c3ccccc3)cc3cc(OC)c(Cl)cc32)o1
Product: COc1cc2cc(-c3ccccc3)n(Cc3ccc(C(N)=O)o3)c2cc1Cl
Temperature: 25 °C
Reaction time: 44 h

Procedure:
A suspension of ethyl 5-(6-chloro-5-methoxy-2-phenylindol-1-ylmethyl)furan-2-carboxylate (258 mg) in ammonia (Ca. 7 mol/L methanol solution, 12.4 mL) was stirred at room temperature for 44 hours. The reaction mixture was filtered, washed with methanol, and then concentrated under reduced pressure to obtain the title compound (138 mg). 1H-NMR (CDCl3) δ ppm: 3.95 (3H, s), 5.23 (2H, s), 6.10 (1H, d, J=3.5 Hz), 6.50-6.55 (1H, m), 7.03 (1H, d, J=3.5 Hz), 7.15 (1H, s), 7.35-7.55 (6H, m).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]2[C:9]=1[S:10][C:11]1[C:12]([CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])=[C:13]([O:26][CH3:27])[CH:14]=[C:15]([CH2:24][NH2:25])[C:16]=1[NH:17]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1(=[O:46])[O:45][C:43](=[O:44])[CH2:42][CH2:41][CH2:40]1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[CH2:32]([O:31][C:29]([CH2:28][C:12]1[C:11]2[S:10][C:9]3[C:18](=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[C:8]=3[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[N:17]([C:39](=[O:46])[CH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])[C:16]=2[C:15]([CH2:24][NH2:25])=[CH:14][C:13]=1[O:26][CH3:27])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCCC(=O)O1
Reactant: COc1cc(CN)c2c(c1CC(=O)OCc1ccccc1)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(CN)c2c(c1CC(=O)OCc1ccccc1)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2C(=O)CCCC(=O)O
Temperature: 0 °C
Yield: 71.1 %

Procedure:
A mixture of 360 mg (0.67 mmol) of benzyl (6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-phenothiazin-4-yl)-acetate, 91.7 mg (0.80 mmol) of glutaric anhydride and 63.7 mg (0.80 mmol) of pyridine in 5 ml of toluene was treated with 10 mg of N,N-dimethylaminopyridine. The mixture was heated to 110° under argon for 48 hours and then poured into ice-water, whereupon the mixture was acidified with 1N hydrochloric acid and exhaustively extracted with methylene chloride. The organic phase was dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel with chloroform/methanol (9:1), whereupon 310 mg (71%) of 5-(4-benzyloxycarbonylmethyl-6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-phenothiazin-10yl)-5-oxo-pentanoic acid were obtained as a white solid of m.p. 65°-68°.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7](I)[CH3:8].Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[CH2:20][NH:21][CH2:22][CH2:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.CN(C)C=O>O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[CH2:20][N:21]([CH2:7][CH3:8])[CH2:22][CH2:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(C2=CCCNC2)c1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCC=C(c2cccc(OC)c2)C1
Reaction time: 16 h

Procedure:
9.8 g of sodium carbonate and 2.6 ml of ethyl iodide were added to a suspension of 7 g of 3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine hydrochloride and 70 ml of dimethylformamide and the mixture was stirred for 16 hours and was diluted with water. The mixture was extracted with ethyl acetate and the organic extract was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-1-1 cyclohexane-chloroform-triethylamine mixture to obtain 5.3 g of 3-(3-methoxyphenyl)-1-ethyl-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][NH:28][CH2:29][C:30]([OH:32])=[O:31])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>CO>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][N:28]([C:34](=[O:36])[CH3:35])[CH2:29][C:30]([OH:32])=[O:31])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CNC[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N(CC(=O)O)C[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O

Procedure:
In 4 ml of methanol was dissolved 60 mg of ethyl ester of N-[trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]glycine obtained in Example 40. To the solution were added 0.2 ml of acetic anhydride and 0.2 ml of triethylamine. The mixture was heated for one hour under reflux while stirring. The reaction mixture was concentrated under reduced pressure, which was subjected to extraction with ethyl acetate. The organic layer was washed with an aqueous solution of potassium hydrogensulfate, an aqueous solution of sodium hydrogencarbonate and water, which was then dried, followed by distilling off the solvent. The residue was dissolved in 4 ml of methanol, to which was added 2 ml of a 5% aqueous solution of potassium carbonate. The mixture was stirred for 30 minutes at 60° C. The reaction mixture was concentrated under reduced pressure, to which was added 1N hydrochloric acid to acidify the solution, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, then the solvent was distilled off under reduced pressure. From the residue, 45 mg of N-[trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]-N-acetyl glycine was obtained as crystals, m.p. 143°-145° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[C:18]([CH2:20][C:21](OCC)=[O:22])#[N:19].N1CCCCC1>C1(C)C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:20]([C:18]#[N:19])[C:21](=[O:22])[NH:1]2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc(C(=O)c2ccccc2)c(N)c1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc2c(-c3ccccc3)c(C#N)c(=O)[nH]c2c1
Temperature: 300 °C
Yield: 28.8 %

Procedure:
A solution of (2-amino-4-methoxy-phenyl)-phenyl-methanone (400 mg, 1.76 mmol) and ethyl 2-cyanoacetate (239 mg, 225 μl) in toluene (6 ml) containing catalytic amounts of piperidine (15.0 mg, 17.4 μl) was pumped at a flow rate of 0.42 ml min−1 (residence time 40 min) through a steel reactor coil (volume=17 ml) that was heated to 300° C. The reaction mixture was evaporated to dryness and the remaining solid was triturated with CH2Cl2/heptane 2:1 for 3 h. The solid was filtrated off and washed two times with CH2Cl2/heptane 1:1 to give the title compound (140 mg, 29%) as off-white solid. MS (ESI): 277.4 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Brc1ccccn1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccccn4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-bromopyridine [CAS 109-04-6; commercially available] (237 mg, 1.5 mmol) according to general procedure II. Obtained as a yellow solid (345 mg, 80%). MS (ISP) 433.2 [(M+H)+]; mp 158-159° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[S:14][C:15]([C:18](O)=O)=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:35][C:36]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:37]=1[C:38]([NH2:40])=[O:39]>N1C=CC=CC=1.CN(C=O)C>[C:38]([C:37]1[C:36]2[N:35]=[C:18]([C:15]3[S:14][C:13]([C@H:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:17][CH:16]=3)[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)(=[O:39])[NH2:40]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1ccc(C(=O)O)s1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 16B (2.4 g) in pyridine (20 mL) and DMF (20 mL) was added CDI (1.6 g), and the mixture was stirred at 40° C. for 1 hour. 2,3-Diaminobenzamide dihydrochloride (1.8 g) was added, and the mixture stirred at ambient temperature overnight and concentrated. The concentrate was stirred in of acetic acid (20 mL) at 80° C. for 4 hours and concentrated. The concentrate was partitioned between ethyl acetate and saturated sodium bicarbonate solution, and the extract was washed with water and concentrated. The concentrate was purified by flash chromatography on silica gel with 40-80% ethyl acetate in hexane.