Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:15]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+]([O-])([O-])=O.[C:34]1([NH:40][C:41]([NH2:43])=[NH2+:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C)C=O.O>[NH:40]([C:41]1[N:43]=[C:16]([C:15]2[C:14]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[N:13][N:12]3[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:8][CH:9]=[CH:10][C:11]=23)[CH:17]=[CH:18][N:42]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Reactant: NC(=[NH2+])Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3ccccc3)n2)cc1
Temperature: 140 °C

Procedure:
To a solution of (2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (100 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was added N-phenylguanidinium nitrate (252 mg, 1.27 mmol) and potassium carbonate (175 mg, 1.27 mmol). The suspension was heated at 140° C. (bath temperature) for 21 hours. The mixture was cooled to room temperature, ether was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes-ethyl acetate) provided 3-(2-anilino-4-pyrimidinyl)-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine which was recrystallized from ether/hexanes (90 mg, 76%) to give a white crystalline solid. 1H NMR (CDCl3): δ 8.15 (d, 1 H), 7.69–7.59 (m, 5 H), 7.32–7.27 (m, 3 H), 7.18–7.13 (m, 3 H), 7.02 (t, 1 H), 6.49 (d, 1 H), 6.06–6.01 (m, 2 H), 4.01 (m, 1 H), 2.20–2.10 (m, 2 H), 1.86–1.64 (m, 6 H); 13C NMR (CDCl3): δ 163.20 (d, JCF=246.6 Hz), 161.55, 160.11, 156.76, 152.27, 142.72, 141.15, 139.74, 131.47 (d, JCF=8.3 Hz), 129.72 (d, JCF=3.4 Hz), 128.82, 128.66, 122.28, 119.52, 115.60 (d, JCF=21.3 Hz), 110.83, 106.91, 105.15, 90.34, 53.86, 33.32, 24.05; MS m/z 465 (M+1).
Reaction SMILES: [CH:1]([O:4][CH:5]([O:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH3:11])([CH3:10])[C:7](=[O:9])[CH3:8])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH3:24][C@@H:25]([CH2:28][CH:29]=[CH2:30])[CH:26]=[O:27].O>CCOCC.C1COCC1>[CH:13]([O:12][CH:5]([O:4][CH:1]([CH3:2])[CH3:3])[C:6]([CH3:11])([CH3:10])[C:7](=[O:9])[CH2:8][C@@H:26]([OH:27])[C@@H:25]([CH3:24])[CH2:28][CH:29]=[CH2:30])([CH3:15])[CH3:14]
Reactant: CC(=O)C(C)(C)C(OC(C)C)OC(C)C
Reactant: C=CC[C@H](C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C=CC[C@H](C)[C@H](O)CC(=O)C(C)(C)C(OC(C)C)OC(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,1-diisopropoxy-2,2,-dimethyl-3-butanone (3.08 g) in 15 mL of ether is added slowly to a solution of lithium diisopropylamide (15.7 mmol) in 20 mL of ether cooled to −78° C., the mixture is stirred for 30 minutes, warmed to −40° C. and stirred for 30 minutes, then recooled to −78° C. A solution of bis(1,2:5,6-di-O-isopropylidene-α-D-glucofuranos-3-O-yl)cyclopentadienyltitanium chloride (17.4 mmol) in 180 mL of ether is added dropwise over 40 minutes, and the reaction is stirred for an additional 30 minutes at −78° C., warmed to −30° C. and kept for 45 minutes, then recooled to −78° C. A solution of (2S)-2-methyl-4-pentenal (16.36 mmol) in 30 mL of ether is added over 10 minutes and the mixture is stirred for 2 hours at −78° C. A 5 M solution of water in THF (28 mL) is added, the mixture is stirred for 1 hour and then filtered through Celite. The filtrate is washed with sat. aq. NaCl, and the brine layer is back extracted with ether. The organic phases are combined, dried with Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[H-].[Na+].Br[CH:22]([CH3:28])[C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24].O>CN(C=O)C>[CH:25]1([C:23](=[O:24])[CH:22]([N:6]2[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]2=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH3:28])[CH2:27][CH2:26]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Reactant: CC(Br)C(=O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(I)cn2C(C)C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of N-(5-iodopyridin-2-yl)-4-methylbenzenesulfonamide (33.1 g) in DMF (400 mL) was added sodium hydride (60% oil dispersion, 3.89 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Then 2-bromo-1-cyclopropylpropan-1-one (23.5 g) was added to the obtained mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting solid was suspended in diisopropyl ether, the suspension was stirred for 1 hr, and the solid was collected by filtration. The obtained solid was dissolved in ethyl acetate (1100 mL) at 70° C., and hexane (400 mL) was dropwise added at 60° C. The mixture was allowed to cool to room temperature overnight. The resulting precipitate was collected by filtration, washed with hexane/ethyl acetate (1/1) 3 times, and dried to give the title compound (30.5 g) as a white solid.
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[F:37][C:38]1[CH:46]=[C:45]2[C:41]([C:42]([CH:47]=O)=[CH:43][NH:44]2)=[CH:40][CH:39]=1.N1CCCCC1>C1(C)C=CC=CC=1.O>[F:37][C:38]1[CH:46]=[C:45]2[C:41]([C:42]([CH:47]=[C:15]3[C:14]4[N:10]([C:11]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:12][N:13]=4)[C:9]4[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=4[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[O:28])[C:16]3=[O:17])=[CH:43][NH:44]2)=[CH:40][CH:39]=1
Reactant: O=Cc1c[nH]c2cc(F)ccc12
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4cc(F)ccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of N-isopropyl-N-(6-methoxy-pyridin-3-yl)-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 11) (150 mg, 0.311 mmol) and 6-fluoro-1H-indole-3-carbaldehyde (61 mg, 0.373 mmol) in toluene (20 mL) was added piperidine (100 μL). The reaction vessel was equipped with a Dean-Stark trap that contained toluene and 4A molecular sieves and was heated at reflux for 24 hours. The solution was cooled to room temperature and was diluted with water. The aqueous solution was washed with EtOAc (3×) and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (10% EtOAc in hexanes to 100% EtOAc) to yield 158 mg of 2-[4-(6-fluoro-1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. MS 628.3 (M+1), 626.2 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:5].C(OCC)(OCC)O[CH2:17][CH3:18].N1C=CC=C[CH:26]=1>C(O)C.S(=O)(=O)(O)O>[CH2:17]([O:5]/[C:4](/[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[CH3:1])=[CH:6]/[C:7]([O:9][CH2:10][CH3:26])=[O:8])[CH3:18]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)CC(=O)c1ccccc1C
Reactant: c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)/C=C(/OCC)c1ccccc1C
Yield: 75 %

Procedure:
19.2 g (100 mmol) of methyl 2-methylbenzoylacetate and 17.7 g of triethyl orthoformate in 40 ml of ethanol plus 0.4 ml of concentrated sulfuric acid are refluxed for 16 hours. After cooling, 2 ml of pyridine are added and the mixture is then concentrated. The residue is taken up in methyl t-butyl ether and extracted 2×with water. The organic phase is dried over sodium sulfate and concentrated. The crude product contains in addition to the title compound about 15% of the corresponding (E) methyl ester (Compound No. 1.47). Distillation results in 16.5 g (75%) of the title compound as colorless oil. 1H-NMR (CDCl3): δ=1.05 (3H, t); 1.37 (3H, t); 2.25 (3H, s); 3.97 (2H, q); 3.99 (2H, q); 5.32 (1H, s); 7.1-7.3 (4H, m) ppm.
Reaction SMILES: C([Li])(C)(C)C.I[C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][C:14]2=O.CC[O:24]CC>CCCCCC>[N:8]1[CH:9]=[CH:10][N:11]=[CH:12][C:7]=1[C:15]1([OH:24])[CH:16]2[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]2)[CH2:14]1
Reactant: Ic1cnccn1
Reactant: CCOCC
Reactant: O=C1CC2CCN1CC2
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Product: OC1(c2cnccn2)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyllithium (11.43 ml of a 1.4M solution in hexane, 16 mmol) was added dropwise to a rapidly stirred solution of 2-iodopyrazine (Hirschberg et al. J. Org. Chem., (1961), 26, 1907: 1.65 g, 8.0 mmol) in ether (60 ml). at -35° C. After 0.25 h a solution of quinuclidinone (1 g, 8.0 mmol) in ether (20 ml) was added dropwise and the reaction mixture warmed to room temperature and stirred for 2 h. Quenching with water (25 ml) was followed by extracting with dichloromethane (4×75 ml) and drying (Na2SO4). The residue remaining after evaporation of the solvents under reduced pressure was purified by chromatography on alumina (Grade II-III), using dichloromethane/methanol (93:7) as eluant, to give 3-(2-pyrazinyl)-1-azabicyclo[2.2.2]octan-3-ol as a red solid (0.5 g). The product was further purified by recrystallisation from ethyl acetate, m.p. 187°-190° C. (dec); (Found C, 64.24; H, 7.34; N, 20.68. C11H15N3O requires C, 64.39; H, 7.32: N, 20.49%); δ (360 MHz, CDCl3) 1.20-1.40 (1H m, CH of CH2); 1.50-1.70 (2H, m, CH2); 2.10-2.25 (1H, m, CH of CH2): 2.34 (1H, b rs, CH); 2.70-2.80 (2H, m, CH2 --N); 2.88-3.00 (3H, m, CH2 --N and CH of CH2 --N); 3.85 (1H, dd, J=1.5 and 16 Hz, CH of CH2 --N); 4.85 (1H, br s, OH); 8.54 (1H, d, J=2 Hz, pyrazine-H); 8.65 (1H, d, J=2 Hz, pyrazine-H); 8.89 (1H, d, J=2 Hz, pyrazine-H).
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[C:13]1([C:18]2[C:27]([CH:28]=[O:29])=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=[C:24]3[C:19]=2[C:20](=[O:35])[CH2:21][C:22]([CH3:34])([CH3:33])[O:23]3)[CH2:17][CH2:16][CH2:15][CH:14]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:13]1([C:18]2[C:27]([CH:28]([OH:29])[C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=3)=[C:26]([CH:30]([CH3:31])[CH3:32])[CH:25]=[C:24]3[C:19]=2[C:20](=[O:35])[CH2:21][C:22]([CH3:33])([CH3:34])[O:23]3)[CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Reactant: CC(C)c1cc2c(c(C3=CCCC3)c1C=O)C(=O)CC(C)(C)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(C3=CCCC3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 0.75 h

Procedure:
At −78° C., 780 μl (391 μmol) of a freshly prepared 0.5 M solution of bromo[4-(trifluoromethyl)phenyl]magnesium in tetrahydrofuran are slowly added dropwise to a solution of 94 mg (301 μmol) of 5-cyclopent-1-en-1-yl-7-isopropyl-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 34A) in 2.3 ml of tetrahydrofuran. The mixture is then allowed to thaw slowly to −20° C. and stirred at this temperature for 45 min. 10% strength sodium bicarbonate solution is then added, the mixture is extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. The organic phases are dried over magnesium sulfate, the solvent is removed under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 20:1→10:1) and then by preparative HPLC (method 1).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:9][C:10]([C:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N+:13]=1[O-:20])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(C(C)C)CC)(C)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[C:5]([O:9][C:10]([C:12]1([C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[NH+:13]1[O-:20])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(N)c(C(=O)OC(C)(C)C)[n+]1[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=CC=C(N)C(C(=O)OC(C)(C)C)(C(=O)c2ccccc2)[NH+]1[O-]
Temperature: 10 °C
Reaction time: 0.67 h
Yield: 96.9 %

Procedure:
4 mL of a chloroform solution containing 0.45 g (2 mmol) of 2-t-butoxycarbonyl amino-6-methylpyridine-N-oxide and 0.26 g (2 mmol) of diisopropylethylamine was prepared, and was adjusted to 10° C. 0.29 g (2 mmol) of benzoyl chloride was added dropwise to the solution over 10 minutes at 10° C. After stirring further for 40 minutes at 10° C., 5 mL of water was added thereto, followed by liquid separation. The chloroform layer obtained by liquid separation was washed twice with 5 mL of water, and then dried with magnesium sulfate, followed by filtration. The resulting solution was concentrated under reduced pressure and dried to obtain 0.64 g of 2-t-butoxycarbonyl-2-benzoyl amino-6-methylpyridine-N-oxide (yield: 97%) in the form of yellow-brown amorphous which was the target product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C[N:13]([CH:15]1[CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].[C:20](OCC)(=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:13]([CH3:14])[CH:15]1[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19]1
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CN(C)C1CCNC1
Product: CN1CCC(N(C)c2ccc([N+](=O)[O-])cc2Cl)C1
Reaction time: 24 h

Procedure:
3-Chloro-4-fluoronitrobenzene (1.0 g) and N,N-dimethyl-3-aminopyrrolidine (1.72 g) are combined and stirred for approximately 24 hours. The mixture is then diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure ethyl acetate followed by pure methanol is used as the eluants) to provide the desired product as a yellow oil.
Reaction SMILES: C[C:2]([CH3:5])([O-])C.[K+].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][C:11]=12.O>O1CCCC1>[CH3:11][N:7]1[CH:8]=[CH:9][N:10]=[C:2]1/[CH:5]=[CH:16]/[C:13]1[CH:14]=[CH:15][N:10]2[CH:9]=[CH:8][N:7]=[C:11]2[CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccn2ccnc2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccnc1/C=C/c1ccn2ccnc2c1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-triphenylphosphonium-1-methyl-1H-imidazole chloride (656 mg, 1.6 mmol, 1 equiv) in tetrahydrofuran (5 ml) at room temperature was added dropwise a solution of potassium tert-butoxide in tetrahydrofuran (1M, 3.3 ml, 3.3 mmol, 2 equiv). This brightly orange mixture was stirred thus for 2 hours and then a solution of imidazo[1,2-a]pyridine-7-carbaldehyde (245 mg, 1.7 mmol, 1 equiv) in tetrahydrofuran (8 ml) was added and the lightly coloured mixture was stirred at room temperature overnight. To the reaction was added water and the mixture was extracted with ethyl acetate. The organic liquors were washed with water and brine and then dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (0-20% methanol/ethyl acetate) furnishing 7-[(E)-2-(1-methyl-1H-imidazol-2-yl)-vinyl]-imidazo[1,2-a]pyridine (87 mg). MS:
Reaction SMILES: [N:1]#[N:2].Cl.C[O:5][C:6](=[O:29])[C@H:7]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])[NH:8][S:9]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(O[CH2:33][CH3:34])C.CO[CH2:37][CH2:38][NH2:39]>C(O)(=O)C>[N:1]#[N:2].[C:6]([OH:29])(=[O:5])[CH3:7].[C:12]1([S:9]([NH:8][C@H:7]([C:6]([NH:39][CH2:38][CH2:37][CH2:33][CH3:34])=[O:29])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:10])=[O:11])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2ccccc12
Reactant: COCCN
Reactant: CCOCC
Agent: Cl
Agent: N#N
Solvent: CC(=O)O
Product: CCCCNC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2ccccc12
Reaction time: 48 h
Yield: 77 %

Procedure:
A 1.0 gram amount of N2 -(1-naphthalenesulfonyl)-L-arginine methyl ester hydrochloride was dissolved in 2 ml of methoxyethylamine with vigorous agitation. After the resulting solution was allowed to stand at room temperature for 2 days, the methoxyethylamine was removed in vacuo and the residual syrup was washed well with 5 ml of water to obtain a powdery product. And then this powder was dissolved in minimum volume of acetic acid. To this solution ethyl ether was added to precipitate the viscous oily product. Reprecipitation from ethanol-ethyl ether gave N2 -(1-naphthalenesulfonyl)-N-butyl-L-argininamide acetate in a powder form in 77% yield.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:41][CH2:42][CH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>CN(C)C=O>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:41][CH2:42][CH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CCCOC3CCCCO3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.5 g) in dimethylformamide (20 ml) are added potassium carbonate (0.6 g), potassium iodide (0.72 g) and 2-(3-bromopropyloxy)-3,4,5,6-tetrahydro-2H-pyrane (0.97 g) and the mixture is stirred at room temperature overnight. The reaction solution is concentrated and to the resulting residue is added water. The mixture is extracted three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=50:1) to give 5-{N-methyl-N-[3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl]amino}-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.3 g) as colorless amorphous.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:13][C@@H:14]([NH2:30])[CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:31]1([C:37]([Cl:39])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl.O>[CH:7]1([CH2:13][C@@H:14]([NH:30][C:37]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:38])[CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:20][CH2:21]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[ClH:39]
Reactant: COc1ccccc1C1CCN(C[C@H](N)CC2CCCCC2)CC1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1C1CCN(C[C@@H](CC2CCCCC2)NC(=O)C2CCCCC2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 0.076 g of potassium carbonate (0.54 mmol) in 1 ml. of water was added a solution of 0.18 g of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidin-1-yl]-ethyl}-amine (0.54 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0° C. and 0.076 mL of cyclohexanecarboxylic acid chloride (0.54 mmol) was added. The reaction was allowed to stir overnight at 0° C., and was then diluted with 5 mL of water and 20 mL of dichloromethane and the phases separated. The aqueous phase was extracted with three additional portions of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride.hydrate salt of the title compound with isopropanolic HCl to yield 0.177 g (68%) of white solid; mp=100–103° C.; MS (+) ESI m/z=441 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16](=[O:33])[NH:17][C:18]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([NH:17][C:18]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)NCCCCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
45 mg of (6-{[(6-oxo-5,6-dihydro-phenanthridin-2-ylcarbamoyl)-methyl]-amino}-hexyl)-carbamic acid tert-butyl ester (0.097 mmol) were dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at room temperature overnight, evaporated, taken up with diethyl ether, filtered and the collected solid was dried under vacuum to afford 30 mg (65% yield) of the title compound as a light-yellow solid.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].C([O-])(=O)C.[NH4+:10].[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH:26](Br)[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)(=O)C>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:10]=[C:1]([CH3:2])[O:4][C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)C(Br)c1ccncc1
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(-c2ccc(OCc3ccccc3)cc2)c(-c2ccncc2)o1
Yield: 41 %

Procedure:
To a mixture of sodium acetate (323 mg, 2.38 mmol) and ammonium acetate (304 mg, 3.95 mmol) in acetic acid (10 mL) was added 1-(4-(benzyloxy)phenyl)-2-bromo-2-(pyridin-4-yl)ethanone (302 mg, 0.79 mmol). The resulting mixture was then refluxed for 48 h. After removal of the solvent under vacuum, the residue was dissolved in ethyl acetate and the solution was washed with satd NaHCO3. The organic phase was dried and concentrated in vacuum to give an oil, which was purified via silica gel chromatography (1:3 EtOAc/n-hexane) to provide 111 mg (41%) of the title compound. 1H NMR (400 MHz, CDCl3) δ: 2.58 (s, 3H), 5.15 (s, 2H), 7.01 (d, 2H), 7.39 (m, 7H), 7.56 (d, 2H), 8.57 (d, 2H). MS m/z: 343 [M+1]+.