Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)=[O:28])[CH:21]=3)=[CH:16][CH:17]=2)[C:12]([Cl:42])=[CH:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:2]1([NH:1][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[C:12]([Cl:42])=[CH:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(c3)c(Cl)cn4C(=O)Nc3ccccc3)ccn2)CC1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2ccc3c(c2)c(Cl)cn3C(=O)Nc2ccccc2)ccn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
After dissolving 260 mg of tert-butyl 4-{[(4-{[1-(anilinocarbonyl)-3-chloro-1H-5-indolyl]oxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylate in 5 ml of trifluoroacetic acid, the solution was stirred at room temperature for 5 minutes. Sodium bicarnobate water and 5N aqueous sodium hydroxide were added, and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 200 mg of N1-phenyl-3-chloro-5-[(2-{[(4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide as a faint yellow solid. After adding 0.5 ml of formaldehyde (37% in water), 170 mg of sodium triacetoxyborohydride, 50 mg of acetic acid and 5 ml of tetrahydrofuran to the solid, the mixture was stirred at room temperature for 10 minutes. Sodium bicarnobate water and 5N aqueous sodium hydroxide were added, extraction was performed with ethyl acetate, and the extract was washed once with brine. The obtained ethyl acetate solution was passed through a glass filter coated with NH type silica gel. The silica gel was washed with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain 210 mg of a faint yellow oil. The oil was solidified from a hexane and ethyl acetate mixed solvent to obtain 90 mg of a powder.
Reaction SMILES: [FH:1].ClC(O[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=O>>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[F:1]
Reactant: F
Reactant: Cc1cccc(C)c1OC(=O)Cl
Product: Cc1cccc(C)c1F
Temperature: 130 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
1.1 kg of anhydrous hydrogen fluoride were placed in a 3 l autoclave and the autoclave was sealed and heated to 130° C. At this temperature, 1 kg of 2,6-dimethylphenyl chloroformate was pumped in over a period of 3 hours, the pressure of the gases formed being released at 40 bar. Finally, the mixture was stirred for 1 hour at 130° C. The reaction mixture was then cooled and excess hydrogen fluoride was distilled off at 100 mbar. Further working-up of the reaction mixture was carried out as described in Example 9. 2,6-Dimethylfluorobenzene was obtained in a yield of 58.3%.
Reaction SMILES: Cl.[Si:2]([O:19][CH2:20][C:21]1[C:22]([O:32][CH3:33])=[N:23][C:24]([CH:27](OC)[O:28]C)=[CH:25][CH:26]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>O1CCCC1>[Si:2]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[N:23][C:22]=1[O:32][CH3:33])([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1nc(C(OC)OC)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C=O)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
1 M hydrochloric acid (40 mL) was added to a solution of 3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-(dimethoxymethyl)-2-methoxypyridine (5.47 g) in tetrahydrofuran (40 mL), and the mixture was stirred at 60° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→1:1) to give 5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methoxypyridine-2-carbaldehyde (3.2 g, 73%) as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[N:4]=1)=[CH2:2].[Br:13][C:14]1[C:15]2[N:16]([C:20](=[O:23])[NH:21][N:22]=2)[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1.C(Cl)Cl>[N:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:1][CH2:2][N:21]1[C:20](=[O:23])[N:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Br:13])[C:15]2=[N:22]1
Reactant: O=c1[nH]nc2c(Br)cccn12
Reactant: C=Cc1ccc2ncccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O=c1n(CCc2ccc3ncccc3n2)nc2c(Br)cccn12
Temperature: 160 °C
Yield: 61.7 %

Procedure:
2-Vinyl-1,5-naphthyridine (10-2) (109 mg, 0.70 mmol) and triazolopyridinone 1-5 (150 mg, 0.70 mmol) were placed in a microwave vial and dissolved in NMP (1 mL). To the mixture was added catalytic powdered KOH (7.9 mg, 0.14 mmol), and the vial was capped and heated at 160° C. under microwave irradiation for 20 min. After cooling, the mixture was diluted with CH2Cl2 (100 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography (40 g cartridge), eluting with 20-100% EtOAc/hexanes, then 1-10% EtOH/EtOAc. The fractions containing the desired product (10-3) were pooled, and after solvent removal in vacuo, 160 mg (62%) of a fluffy yellow solid were obtained. LC/MS: m/z (M+H)=370.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=1[C:16]#[N:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=2[C:16]#[N:17])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 130 °C
Yield: 95.9 %

Procedure:
A mixture of 4-chloro-3-(trifluoromethyl)phenol (1 g, 5.09 mmol), 2-fluoro-5-formylbenzonitrile (0.759 g, 5.09 mmol) and K2CO3 (0.844 g, 6.11 mmol) in DMF (10 mL) was heated with a microwave condition at 130° C. for 4 h. The solution was diluted with EA and washed with water twice, dried over Na2SO4 and concentrated in vacuo to afford the title compound (1.59 g, 96% yield) as a yellow solid. LCMS: rt=3.54 min, [M+H+]=326
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[CH3:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:15]=1[NH2:16]>CO.C(O)(=O)C>[CH3:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:15]=1[N:16]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:16][C:15]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=2[CH3:13])[CH3:11])[N:5]=1)[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1ccc(N)c(C)c1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=Nc1ccc(C)cc1C)c1cccc(C(C)=Nc2ccc(C)cc2C)n1
Reaction time: 72 h

Procedure:
Chemicals 2,6-Diacetylpyridine (2.0 g, 12.3 mmol) and 2,4-dimethylaniline (8.9 g, 73.7 mmol) were dissolved in a round-bottom flask with a stirring bar, to which 50 ml of anhydrous methanol were added. Three drops of glacial acetic acid were added, and the flask was sealed. After stirring the solution for three days, 3.79 g (84%) of a yellow solid were collected and identified as the desired ligand for catalyst 5. H NMR (CDCl3) δ8.39 (d,2), 7.85 (t, 1), 7.05 (s, 2), 7.00 (d, 2), 6.60 (d, 2).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.Cl.C(N=C=NCCCN(C)C)C.C1C=C2N=NN(O)C2=CC=1.N.[NH2:41][CH2:42][C:43]1[C:44]([OH:51])=[N:45][C:46]([CH3:50])=[CH:47][C:48]=1[CH3:49]>O.ClCCl.C(N(CC)CC)C>[OH:51][C:44]1[C:43]([CH2:42][NH:41][C:15]([C:3]2[CH:4]=[N:5][N:6]([CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:2]=2[CH3:1])=[O:17])=[C:48]([CH3:49])[CH:47]=[C:46]([CH3:50])[N:45]=1
Reactant: Cc1c(C(=O)O)cnn1CCc1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2cnn(CCc3ccccc3)c2C)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
A mixture of 5-methyl-1-phenethyl-1H-pyrazole-4-carboxylic acid (60 mg, 0.27 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (95 mg, 0.5 mmol), N-hydroxybenzotrizole (67 mg, 0.5 mmol), triethylamine (0.1 mL) and dichloromethane (5 mL) were stirred at 25° C. for 0.5 hours. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (50 mg, 0.33 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 ml) was added and the mixture was extracted with dichloromethane (10 mL t 3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-5-methyl-1-phenethyl-1H-pyrazole-4-carboxamide as a white solid (30 mg, 31%). LRMS (M++) m/z: calcd 364.19. found 364. 1H NMR (300 MHz, d6-DMSO): δ 11.47 (s, 1H), 8.08 (s, 1H), 7.57 (t, J=5.1 Hz, 1H), 7.30-7.15 (m, 5H), 5.85 (s, 1H), 4.23-4.18 (m, 4H), 3.06 (t, J=7.2 Hz, 2H), 2.31 (s, 3H), 2.15 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.CN(C1C=CC=CN=1)C>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:19](=[O:21])[CH3:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a stirred solution of N-benzhydryl-azetidin-3-ol (3.56 g, 14.9 mmol.) in dichloromethane (60 mL) was added acetic anhydride (2.1 mL, 22.4 mmol.), triethylamine (3.1 mL, 22.4 mmol.) and dimethylaminopyridine (ca. 10 mg). The mixture was stirred for 3 hours then diluted with ethyl acetate (200 mL) and washed with saturated aqueous ammonium chloride solution (100 mL), 1N aqueous sodium hydroxide (100 mL) and brine (100 mL), dried (MgSO4) and evaporated to leave N-benzhydryl-3-acetoxy-azetidine (4.2 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][NH:23][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:21][CH2:20]1
Reactant: NCC1CC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCC1CC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(cyclopropylmethyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.2 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.23 mmol of cyclopropylmethylamine. LC/MS [9.79 min; 412 (M+1)]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][NH:29][C@@H:30]2[CH2:35][CH2:34][C@H:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][CH2:31]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].C=O.[CH3:42]C(O)=O.[BH3-]C#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][N:29]([CH:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][CH2:31]2)[CH3:42])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)N2CCCC2CN[C@H]2CC[C@@H](C(=O)OC)CC2)ccc1NC(=O)Nc1ccccc1C
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCC(N(C)CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
To a stirred solution of methyl cis-4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methylamino]cyclohexanecarboxylate (300 mg, 0.55 mmol), HCHO (300 ml), and AcOH (66 mg, 1.1 mmol) in MeOH (10.0 ml) was added NaBH3CN (70 mg, 1.1 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. After concentrated in vacuo, water was added and extracted with CH2Cl2. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by TLC with MeOH—CH2Cl2 (3:97, v/v) as eluent to give methyl 4-[N-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethyl]-N-methylamino]cyclohexanecarboxylate (160 mg, 52%) as an amorphous solid. 1H-NMR (CDCl3) δ 1.30–2.20 (m, 12H), 2.27–2.37 (m, 6H), 2.50 –2.60 (m, 1H), 3.30–3.80 (m, 5H), 3.55 (s, 2H), 3.66–3.73 (m, 6H), 4.10–4.20 (m, 1H), 6.60–7.55 (m, 7H), 8.03 (m, 1H), 8.15 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[NH:4][C:5]([NH:7][CH2:8][CH2:9][CH2:10][NH:11]C(=O)[O-])=S.NC1NC2C=CC=CC=2N=1>>[NH:4]1[C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[N:1]=[C:5]1[NH:7][CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: Nc1ccccc1NC(=S)NCCCNC(=O)[O-]
Agent: Nc1nc2ccccc2[nH]1
Product: NCCCNc1nc2ccccc2[nH]1

Procedure:
3-{[(2-aminoanilino)carbothioyl]amino}propylcarbamate (ESI-MS; [M+H+]: 325.15), which was then converted with HgO/cat. S into the corresponding aminobenzimidazole (6.4 g; ESI-MS; [M+H+]: 291.15). After removal of the Boc group using TFA, the crude product obtained was boiled in CH3OH with addition of active carbon, filtered, evaporated and crystallized from CH3OH/methyl t-butyl ether; 6 g of beige solid; ESI-MS; [M+H+]: 191.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][O:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21](S)[C:20](=[O:26])[CH:19]4C)[N:9]=2)=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][O:12][C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20](=[O:26])[CH2:19]4)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1C(=O)N(S)c2ccc(CN3N=C(c4ccc(Cl)cc4)COC3=O)cc21
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1Cc2cc(CN3N=C(c4ccc(Cl)cc4)COC3=O)ccc2N1
Reaction time: 6 h

Procedure:
Powdered Zn (157.3 mmoles) is added to a solution of the compound obtained in Step F (15.73 mmoles) in glacial acetic acid (150 ml). The reaction mixture is stirred for 6 hours and then filtered. The filtrate is evaporated to dryness and then taken up in water (200 ml) and DCM (400 ml). The phases are separated and the aqueous phase is extracted with DCM; the organic phases are combined. The organic phase obtained is washed with water and then with saturated NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue obtained is recrystallised from ethanol to yield the title product.
Reaction SMILES: C(O)(=O)C.O[CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[O:20]=[C:21]([CH:28]1[CH2:31][CH:30]([C:32]([O:34][CH2:35][CH2:36][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])=[O:33])[CH2:29]1)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[CH:18]1[C:19]2[CH:6]([CH:22]([C:21](=[O:20])[CH:28]3[CH2:31][CH:30]([C:32]([O:34][CH2:35][CH2:36][C:37]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[O:38])=[O:33])[CH2:29]3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(=O)C1CC(C(=O)OCCC(=O)c2ccccc2)C1
Reactant: OC1c2ccccc2Oc2ccccc21
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)C1CC(C(=O)OCCC(=O)c2ccccc2)C1)C1c2ccccc2Oc2ccccc21
Reaction time: 168 h

Procedure:
Acetic acid (20 ml) was added to a stirred suspension of 9-hydroxyxanthene (3.96 g, 20 mmol) and ethyl 3-oxo-3-[3-(phenacylmethyloxycarbonyl) cyclobutyl]propanate (6.0 g, 18 mmol) in ethanol (20 ml) at room temperature. A clear solution formed and was allowed to stand for 7 days at room temperature.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][CH2:17][C@@H:18]2[O:23][C:22]3[C:24]([CH:29]=[CH:30][CH3:31])=[C:25]([NH2:28])[CH:26]=[CH:27][C:21]=3[O:20][CH2:19]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][CH2:17][CH:18]2[O:23][C:22]3[C:24]([CH:29]=[CH:30][CH3:31])=[C:25]([NH:28][C:2]([O:4][CH3:5])=[O:3])[CH:26]=[CH:27][C:21]=3[O:20][CH2:19]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CC=Cc1c(N)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC=Cc1c(NC(=O)OC)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.6 %

Procedure:
Methyl chloroformate (2.93 mL, 37.9 mmole) was added to a solution of {(2R)-7-amino-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methyl-benzenesulfonate (2.35 g, 6.30 mmole) in ethyl acetate (125 mL), followed by the addition of N,N-diisopropylethylamine (5.50 mL, 31.6 mmole) dropwise over a period of 20 minutes. The solution was stirred under nitrogen at room temperature over a period of 10 hours. This solution was then washed with 2N aqueous HCl, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. Filtration, evaporation in vacuum and column chromatography on silica gel with 0.2% methanol/methylene chloride gave the (R)-enantiomer of the title compound as a white foam (1.90 g, 70%). 1H (CDCl3) doublet, 7.8 δ (2 H); doublet, 7.3 δ (3 H); doublet, 6.7 δ (1 H); broad singlet, 6.6 δ (1 H); multiplet, 6.1 δ (2 H); multiplet, 4.4 δ (1 H); multiplet 4.2 δ (3 H); multiplet, 4.0 δ (1 H); singlet, 3.7 δ (3 H); singlet, 2.4 δ (3 H); doublet, 1.9 δ (3 H).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[CH2:16][CH2:15][O:14][C:11]=3[CH:12]=2)[CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:23])([CH3:3])[CH3:2].O1CCOCC1.[Mn]([O-])(=O)(=O)=O.[K+].C=O>O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[CH2:16][CH2:15][O:14][C:11]=3[CH:12]=2)[C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:6][C:5]1=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCC3
Agent: O=[Mn](=O)(=O)[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1c(=O)nc(-c2ccccc2)c2cc3c(cc21)OCC3

Procedure:
To a stirred solution of 3.2 g. of 1-isopropyl-3,4,6,7-tetrahydro-4-phenyl-furo[3,2-g]quinazolin-2(1H)-one in 150 ml. of dioxane cooled to 8°±5°C. is added dropwise a solution of 2.0 g. of potassium permanganate in 130 ml. of water. After the addition is completed 1.5 ml. of formalin solution is added. The resulting precipitated solids are removed by filtration and the filtrate concentrated in vacuo to give an oil of 1-isopropyl-6,7-dihydro-4-phenyl-furo[3,2-g]quinazolin-2(1H)-one.
Reaction SMILES: C(#N)C.F[C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([C:9](=[O:24])[C:10]([C:21]([OH:23])=[O:22])=[CH:11][N:12]2[C@@H:17]2[CH2:19][C@@H:18]2[F:20])=[CH:7][CH:6]=1.Cl.C(N(CC)CC)C.C(O)(=O)C(O)=O.[NH:39]1[CH2:43][CH2:42][C@@H:41]([C:44]2([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:46][CH2:45]2)[CH2:40]1>C(N(CC)CC)C>[C:50]([O:49][C:48]([NH:47][C:44]1([C@@H:41]2[CH2:42][CH2:43][N:39]([C:5]3[C:14]([O:15][CH3:16])=[C:13]4[C:8]([C:9](=[O:24])[C:10]([C:21]([OH:23])=[O:22])=[CH:11][N:12]4[C@@H:17]4[CH2:19][C@@H:18]4[F:20])=[CH:7][CH:6]=3)[CH2:40]2)[CH2:45][CH2:46]1)=[O:54])([CH3:53])([CH3:51])[CH3:52]
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1c(N2CC[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
An acetonitrile solution (45 mL) containing 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3 g), triethylamine hydrochloride (2.8 g), and boron trifluoride-tetrahydrofuran complex (2.84 g) was stirred at room temperature for 30 minutes. tert-Butyl {1-[(3R)-pyrrolidin-3-yl]cyclopropyl}carbamate oxalic acid salt (3.54 g) and triethylamine (5.71 mL) were further added to reaction mixture, followed by stirring for 10 hours at the same temperature. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 12 hours, and the solvent was evaporated under reduced pressure. 80% Hydrated methanol (20 mL) was added to the residue, and the pH of the product was adjusted to 7 by use of 5N aqueous sodium hydroxide solution, followed by stirring at 60° C. for 30 minutes and at room temperature for 16 hours. The thus-produced crystals were recovered through filtration and dried, to thereby yield 4.79 g of the title compound (yield: 94%).
Reaction SMILES: C([O:5][C:6](=[O:52])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17](=[O:51])[NH:18][CH:19]1[C:25](=[O:26])[N:24]([C:27]([CH:37]([CH3:39])[CH3:38])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](=[O:30])[NH2:29])[C:23]2[CH:40]=[CH:41][CH:42]=[CH:43][C:22]=2[N:21]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:20]1=[O:50])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]([C:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:28](=[O:30])[NH2:29])[N:24]1[C:25](=[O:26])[CH:19]([NH:18][C:17]([C:9]2[N:8]([CH2:7][C:6]([OH:52])=[O:5])[C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:51])[C:20](=[O:50])[N:21]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:22]2[CH:43]=[CH:42][CH:41]=[CH:40][C:23]1=2)([CH3:39])[CH3:38]
Reactant: CC(C)C(C(N)=O)(c1ccccc1)N1C(=O)C(NC(=O)c2cc3ccccc3n2CC(=O)OC(C)(C)C)C(=O)N(c2ccccc2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(C(N)=O)(c1ccccc1)N1C(=O)C(NC(=O)c2cc3ccccc3n2CC(=O)O)C(=O)N(c2ccccc2)c2ccccc21
Yield: 75.5 %

Procedure:
To a solution of {2-[1-(Isopropyl-phenyl-carbamoylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-indol-1-yl}-acetic acid tert-butyl ester (0.072 g) in dichloromethane (4 ml) at ambient temperature was added trifluoroacetic acid (1.5 ml) gradually with stirring. After the reaction was stirred 30 minutes, the dichloromethane and trifluoroacetic acid were evaporated under reduced pressure to afford a clear glass. The glass was purified by preparative RP-HPLC on a C-18 column with a gradient elution of 45-55% acetonitrile in water with 0.1% trifluoroacetic acid buffer over a 30 minute period at a rate of 100 ml/min. Fractions containing the desired material were combined, frozen and lyophilized to afford the title compound (0.050 g) as a white powder. 1H NMR (300 MHz, CDCl3): d 1.07 (d, J=4.4 Hz, 3H), 1.10 (d, J=4.4 Hz, 3H), 4.23 (d, J=16.6 Hz, 1H), 4.40 (d, J=16.6 Hz, 1H), 5.01 (m, 1H), 5.06 (s, 2H), 5.44 (d, J=7.1 Hz, 1H), 7.03 (dd, J=1.2, 8.1 Hz, 1H), 7.17-7.52 (m, 17H), 7.67 (d,J=8.1 Hz, 1H), 7.74 (d,J=7.1 Hz, 1H); MS (ES): m/z=644.2 (MH+);TLC (CH2Cl2 /CH3OH(19:1)): Rf =0.15; RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 45-55% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 ml/min): tr =22 min (to =3 min).