Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]>O1CCOCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][N:27]([CH2:2][CH2:1][S:3]([CH3:6])(=[O:5])=[O:4])[CH2:26][CH2:25]3)[CH2:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: C=CS(C)(=O)=O
Reactant: COc1cc(C2=CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COc1cc(C2=CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
A solution of methyl vinyl sulfone (201 mg, 1.89 mmol) and 1-{4-[3-(methyloxy)-4-nitrophenyl]-3-cyclohexen-1-yl}piperazine (200 mg, 0.63 mmol) was stirred in dioxane (6 mL) under N2. The reaction was then heated to 95° C. and stirred for approximately 3 h. The reaction was then cooled to rt and concentrated under vacuum. The residue was taken up in DCM and aqueous (saturated) NaHCO3. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step G (222 mg, 0.52 mmol, 83%) as a light yellow solid. MS (ESI): 424 [M+H]+.
Reaction SMILES: [Na].CO[C:4]1[N:5]=[N:6][C:7]([S:10]([C:13]2[N:14](S(C3C=CC=CC=3)(=O)=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:12])=[O:11])=[CH:8][CH:9]=1.[CH3:31][OH:32]>>[CH3:31][O:32][N:5]1[CH:4]=[CH:9][CH:8]=[C:7]([S:10]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:11])=[O:12])[NH:6]1
Reactant: CO
Reactant: COc1ccc(S(=O)(=O)c2cc3ccccc3n2S(=O)(=O)c2ccccc2)nn1
Agent: [Na]
Product: CON1C=CC=C(S(=O)(=O)c2cc3ccccc3[nH]2)N1
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a solution of sodium metal (18.6 mmol, 428 mg) dissolved in methanol (8 mL) was added a solution of 3-methoxy-6-(N-phenylsulfonylindole-2-sulfonyl)-pyridazine (1.86 mmol, 850 mg) and the reaction was stirred for 10 minutes. The reaction mixture was quenched with H2O (10 mL) and CHCl3 (25 mL). The CHCl3 layer was collected, dried, filtered, and the filtrate was evaporated to obtain 2-methoxy-6-(indole-2-sulfonyl)-pyridazine (82%, 440 mg).
Reaction SMILES: Cl[CH:2]([CH3:13])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH:2]([CH3:13])[CH2:3][CH2:4][C:5](=[O:6])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(Cl)CCC(=O)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C(C)CCC(=O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-phenyl-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 407.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.P(OC)(OC)(O[CH3:14])=O>C(Cl)Cl>[CH3:14][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([OH:1])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: Oc1ccc2c(c1)NCC2
Reactant: COP(=O)(OC)OC
Solvent: ClCCl
Product: CN1CCc2ccc(O)cc21
Reaction time: 0.17 h
Yield: 107.5 %

Procedure:
To 37.78 g (0.286 mol) of 6-hydroxyindoline 5 in a 100 ml round-bottom flask fitted with a magnetic stirrer, thermometer and condenser connected to a source of nitrogen was added 13.38 ml (16.02 g, 0.114 mol) of trimethyl phosphate. It was then placed in an oil bath and heating was commenced. The bath temperature reached 105° in 10 min. Then the reaction mixture became homogeneous and shortly thereafter an exotherm occurred. The flask was removed periodically from the oil bath to keep the internal temperature below 150°. The reaction was heated at 140°-150° for 2 hr. Thin layer chromatography on silica gel plates eluted with 50% Ethyl acetate/hexane or 4% methanol/methylene chloride showed that starting material was still present and 3 ml (3.59 g, 25.6 mmol) more of trimethyl phosphate was added. Heating was continued at 155° for 1.5 hr. The reaction mixture was allowed to cool and then dissolved in 100 ml of saturated sodium carbonate solution and 100 ml of methylene chloride with warming in portions. The aqueous phase was separated and washed with 2×100 ml of methylene chloride. The organic phases were combined, washed with 200 ml of half-saturated brine, dried over sodium sulfate and concentrated in vacuo to leave 28.6 g (67%) of dark tar. This was dissolved in methylene chloride and filtered through 300 ml of silica gel in methylene chloride. A total of 800 ml of methylene chloride eluate and then 400 ml of ethyl acetate was collected. Concentration and collection of the residue from hexane gave 18.29 g (43%) of crude product 7 as a brown solid which was used for the preparation of 9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.[CH3:16][CH:17]1[NH:22][C:21]([NH2:23])=[N:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:16][CH:17]1[CH2:18][CH2:19][N:20]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:23]=[C:21]2[NH:22]1
Reactant: CC1CCN=C(N)N1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1CCn2c(nc(-c3ccncc3)cc2=O)N1
Yield: 51.3 %

Procedure:
A mixture of 6 g (31.0 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate, 4.6 g (31.0 mmol) of 6-methyl-1,4,5,6-tetrahydro-pyrimidin-2-ylamine hydrochloride (prepared according to J. Org. Chem., 20, 1955, 829-838) and 6.44 g (46.0 mmol) of potassium carbonate in 50 ml of ethanol was heated at reflux temperature during 18 h. The reaction mixture was cooled and the solvent removed by evaporation. The residue obtained was treated with water and the precipitate recovered by filtration to give 3.85 g (51%) of product. Mp.: 245-247° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (1.009), imidazole (680 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (5 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml), and the solid precipitate was filtered, air-dried and recrystallized from acetone-isopropyl ether to give 4-(4-chlorophenyl)-2-(1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole as pale yellow prisms (662 mg, 61%). Melting point 113-114° C.
Reaction SMILES: Cl.C(OC([NH:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@:14]1([C:25]([OH:27])=[O:26])[CH2:21][C:18]2([CH2:20][CH2:19]2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:22]([OH:24])=[O:23])=[O:12])=O)(C)(C)C.[OH-].[Na+]>CC(C)=O.O>[NH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@:14]1([C:25]([OH:27])=[O:26])[CH2:21][C:18]2([CH2:19][CH2:20]2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:22]([OH:24])=[O:23])=[O:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H](N)C(=O)N[C@@]1(C(=O)O)CC2(CC2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 50 °C
Yield: 59.3 %

Procedure:
Add concentrated hydrochloric acid (36.94 mL, 430.11 mmol) to a solution of (1S,2S,5R,6S)-2-[[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]spiro[bicyclo[3.1.0]hexane-4,1′-cyclopropane]-2,6-dicarboxylic acid (82.24 g, 215.06 mmol) in acetone (822.4 mL), and stir the mixture at 50° C. After 1.5 hours cool the mixture to 0° C. and add 50% sodium hydroxide in water to pH=3.6-3.8. Stir the solid obtained for 1 hour, filter and wash with water. Dry under vacuum for 48 hours to yield the title compound as a white solid (36 g, 127.53 mmol). MS (m/z): 283 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[N:14][CH:13]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)Cl>[Br:22][C:15]1[C:16]([C:18]([O:20][CH3:21])=[O:19])=[N:17][C:12]([NH:11][C@@H:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][C@@H:2]2[OH:1])=[CH:13][N:14]=1
Reactant: COC(=O)c1cncc(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a solution of methyl 6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate (1.0 g, 3.5 mmol) in CH2Cl2 (35 mL) was added N-bromsuccinimide (0.69 g, 3.86 mmol). Stir at t for 2 hr. Wash the reaction with sat. aq. NaHCO3. The organic extract was dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 20% ethyl acetate/hexanes) to afford 380 mg (30%) of methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate as a solid: 1H NMR (CDCl3) δ 3.01-3.06, 3.24-3.29, 4.00, 4.75-4.78, 5.45-5.46, 7.25-7.32, 7.94; MS (ESI+) for C15H14BrN3O3 m/z 386 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:18]1[CH2:19][CH2:20][N:15]([C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]=2)[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(N2CCOCC2)CC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl-4-oxo-1-piperidine carboxylate (8.0 g, 40 mmol) and morpholine (3.6 g, 42 mmol) in benzene (16 mL) was added p-toluenesulfonic acid (40 mg) and the resulting solution was refluxed using a Dean-Stark trap for 24 h. After cooling to rt, the solution was concentrated under vacuum to afford the title compound a as a thick reddish-orange oil which was used without any further purification (11.1 g, ˜quant). 1H NMR (400 MHz, CDCl3): δ 7.36 (s, 1 H), 3.94 (br s, 2 H), 3.74 (m, 4 H), 3.54 (m, 2 H), 2.80 (m, 4 H), 2.16 (br s, 2 H), 1.47 (s, 9 H).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[Na+].[I-:13].O>CN(C=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([I:13])=[N:3][CH:4]=1
Reactant: [I-]
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cnc1I
Temperature: 97.5 °C

Procedure:
To a stirred mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.5 mmol) in anhydrous DMF (20 mL) was added NaI (12.0 g, 80 mmol) was added in one portion and the resulting mixture was heated at 95-100° C. for 2 days. The reaction mixture was cooled to room temperature and poured into water. It was then extracted with EtOAc and the combined extracts were washed with aqueous 10% Na2S2O3. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide 5-Chloro-2-iodo-3-nitro-pyridine. Mass spectrum m/z: 285.2 (M+H).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-])=O.[F-:15].[K+]>>[F:15][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: [F-]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [K+]
Product: O=C1OC(=O)c2cc(F)ccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 59.6 %

Procedure:
Into a reaction vessel were placed 290 grams (1.5 mol) 4-nitrophthalic anhydride and 91 grams (1.57 mol) of anhydrous potassium fluoride. The reaction vessel was closed and shaken to mix the reactants and was then attached to a distilling head, receiver, and nitrogen inlet. The mixture was heated, under a nitrogen blanket beginning at 100°C. while the temperature was raised to 230°C. over a 25 minute period and kept at a temperature of 230°-250°C. for about 4 hours. After 2 hours, the nitrogen line was replaced by a vacuum line and the system evacuated to about 160 mm. This resulted in the collection over the next 2 hours of 148.5 grams (60% yield) 4-fluorophthalic anhydride, which upon analysis indicated the material to be greater than 97% pure (melting point 72°-76°C.).
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2cc[nH]c21
Product: Clc1ccnc2[nH]ccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine 7-oxide was added slowly to 200 mL POCl3 and the resulting mixture stirred at 80° C. overnight. The excess POCl3 was then removed in vacuo and the residue treated with 500 mL H2O and basified with saturated K2CO3 (aq), prior to extraction with EtOAc (2×300 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-Chloro-1H-pyrrolo[2,3-b]pyridine (12.9 g, 76%). MS (ES+): 153 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=2)=[CH:9][CH:8]=1.Cl.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][NH2:33]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=3)=[CH:9][CH:8]=2)[N:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[F:25])[N:33]=1)=[O:23]
Reactant: CCOc1cccc(-c2ccc(C=CC(=O)C(=O)OC)cc2)c1
Reactant: NNc1ccccc1F
Agent: Cl
Solvent: CC(=O)O
Product: CCOc1cccc(-c2ccc(C3CC(C(=O)OC)=NN3c3ccccc3F)cc2)c1
Temperature: 125 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
4-(3′-Ethoxy-biphenyl-4-yl)-2-oxo-3-butenoic acid methyl ester (190.0 mg, 0.61 mmol) prepared in Step 3 of Preparation 18 and 2-fluorophenylhydrazine hydrochloride (110.0 mg, 0.67 mmol) were added to acetic acid (3.0 mL). The reaction mixture was stirred at 125° C. for 1 hour and then concentrated under reduced pressure. Ethyl acetate was added to the reaction mixture, which was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 250.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].[C:12]([CH2:14][C:15](O)=[O:16])#[N:13].P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:12]([CH2:14][C:15]([NH:4][C:3]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:16])#[N:13]
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: N#CCC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cccc([N+](=O)[O-])c1NC(=O)CC#N
Temperature: 60 °C
Yield: 66.3 %

Procedure:
To a solution of 2-methyl-6-nitroaniline (25 g, 164.3 mmol) in benzene (200 ml) were added cyanoacetic acid (14.5 g, 170.46 mmol) and PCl5 (35 g, 168 mmol). The reaction mixture was heated at 60° C. for 7 h. After cooling to rt, the reaction mixture was filtered and the solid was washed with benzene and water. The solid was dried under reduced pressure to afford the title acetamide (24 g, 109 mmol) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=O)[CH:8]=2)[NH:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C1Cc2cc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)ccc2N1
Yield: 29 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 29% of theory; LC (method 5): tR=0.98 min; Mass spectrum (ESI+): m/z=333 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][CH2:10][CH:9]1[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][C@H:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[CH3:18]>>[CH2:1]([N:8]1[CH2:11][CH2:10][CH:9]1[C:12]([NH:16][C@H:17]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)[CH3:18])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCN1Cc1ccccc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2CCN2Cc2ccccc2)cc1
Yield: 53.2 %

Procedure:
The title compound (D76) (98 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 1-benzylazetidine-2-carboxylic acid (100 mg, available from Apollo#OR7040) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (113 mg). Reaction time: 1 h
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1Br)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19](Br)=[C:18]([N+:23]([O-])=O)[CH:17]=2)[CH:10]=1)=[O:8])([O-])=O.[H][H].N>[Pd].C(O)(C)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:23])[CH:17]=2)[CH:10]=1)=[O:8]
Reactant: [H][H]
Reactant: O=C(c1cccc(C(=O)c2ccc(Br)c([N+](=O)[O-])c2)c1)c1ccc(Br)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: N
Solvent: CC(C)O
Product: Nc1cccc(C(=O)c2cccc(C(=O)c3cccc(N)c3)c2)c1
Yield: 30 %

Procedure:
To a sealed glass reaction vessel equipped with a thermometer, stirrer and reflux condenser, 10.7 g (0.02 mole) of 1,3-bis(3-nitro-4-bromobenzoyl)benzene, 0.43 g of a 5% palladium/activated carbon catalyst (a product of M. E. Chemcat Co.) and 50 ml of isopropyl alcohol were charged. Hydrogen was introduced with stirring at 30°~35° C. Absorbed hydrogen was 2.20 l (0.098 mole) over 9 hours. Successively, 3.6 g (0.06 mole) of a 28% aqueous ammonia solution was added and introduction of hydrogen was continued at 30°~35° C. for 6 hours and additionally at 60° C. for 4 hours with stirring. Further absorbed hydrogen was 0.401 g (0.018 mole). The catalyst was removed by filtration at the same temperature, 4.5 g of a 36% aqueous hydrochloric acid solution was added to the filtrate, and the mixture was allowed to cool. The precipitated crystal of 1,3-bis(3-aminobenzoyl)benzene hydrochloride were filtered, dissolved in 200 ml of water, and neutralized with a 28% aqueous ammonia solution. The precipitated crystals were filtered, washed and dried to obtain 1.9 g of 1,3-bis(3-aminobenzoyl)benzene. The yield was 30%.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[C:17]([C:36]2[O:40][N:39]=[C:38]([C:41]3[CH:46]=[CH:45][C:44]([CH2:47][N:48](C)[C:49](=O)OC(C)(C)C)=[CH:43][C:42]=3[F:57])[CH:37]=2)=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]3[CH2:35][CH2:34][O:33][CH2:32]3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=O)(C)(C)C>ClCCl>[F:57][C:42]1[CH:43]=[C:44]([CH2:47][NH:48][CH3:49])[CH:45]=[CH:46][C:41]=1[C:38]1[CH:37]=[C:36]([C:17]2[C:16]([NH2:15])=[N:21][CH:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH:31]4[CH2:35][CH2:34][O:33][CH2:32]4)(=[O:29])=[O:30])=[CH:24][CH:23]=3)[N:18]=2)[O:40][N:39]=1
Reactant: CN(Cc1ccc(-c2cc(-c3nc(-c4ccc(S(=O)(=O)C5CCOC5)cc4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)c(F)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2cc(-c3nc(-c4ccc(S(=O)(=O)C5CCOC5)cc4)cnc3N)on2)c(F)c1
Reaction time: 2 h
Yield: 54 %

Procedure:
TFA (281.6 mg, 190.3 μL, 2.470 mmol) was added to a solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(4-tetrahydrofuran-3-ylsulfonylphenyl)pyrazin-2-yl]isoxazol-3-yl]-3-fluoro-phenyl]methyl]-N-methyl-carbamate (100 mg, 0.1235 mmol) in dichloromethane (2.069 mL) at room temperature and the resulting solution stirred for 2 h. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were collected and lypholised to give the product as a yellow solid (34.0 mg, 44% yield); 1H NMR (400.0 MHz, DMSO) d 2.13-2.19 (m, 2H), 2.63 (m, 3H), 3.66 (m, 1H), 3.76 (m, 1H), 3.85 (m, 1H), 4.04 (m, 1H), 4.21-4.28 (m, 3H), 7.27 (m, 2H), 7.52 (m, 1H), 7.60-7.65 (m, 2H), 8.00 (m, 2H), 8.12 (t, 1H), 8.36 (m, 2H) and 8.94 (m, 3H) ppm; MS (ES+) 510.2
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:14](=[O:15])[C@H:13]3[CH2:16][CH2:17][CH2:18][C@H:12]3[NH:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[CH:5][CH:4]=1.[C:25]1(=[O:39])[N:29]([CH2:30][C:31](Cl)=[O:32])[C:28](=[O:34])[C:27]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:26]12.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:14](=[O:15])[C@H:13]3[CH2:16][CH2:17][CH2:18][C@H:12]3[N:11]([C:31](=[O:32])[CH2:30][N:29]3[C:28](=[O:34])[C:27]4=[CH:35][CH:36]=[CH:37][CH:38]=[C:26]4[C:25]3=[O:39])[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[CH:5][CH:4]=1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccc(Cl)cc2)C(=O)[C@H]2CCC[C@H]21
Yield: 14.8 %

Procedure:
(3aR*,10aS*)-9-(4-Chlorobenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one hydrochloride (426 mg, 1.2 mmol) and phthalimidoacetyl chloride (389 mg, 1.7 mmol) were suspended in toluene (4 mL). The suspension was refluxed for 16 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with chloroform. The extract solution was washed with water and a saturated aqueous solution of sodium hydrogencarbonate, which was dried and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was crystallized from ethanol-hexane to give 91 mg (yield 15%) of the titled compound, m.p. 205°-206° C.