Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]([Cl:8])=[O:7])(=O)C.Cl.Cl.[NH2:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[C:21]([N:24]=[C:25]([NH2:31])[NH:26][CH2:27][CH2:28][O:29][CH3:30])[S:22][CH:23]=2)[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>ClCCl>[ClH:8].[NH2:31][C:25](=[N:24][C:21]1[S:22][CH:23]=[C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][NH:11][C:6](=[O:7])[CH2:5][OH:4])[CH:14]=2)[N:20]=1)[NH:26][CH2:27][CH2:28][O:29][CH3:30]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COCCNC(N)=Nc1nc(-c2cccc(CN)c2)cs1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNC(N)=Nc1nc(-c2cccc(CNC(=O)CO)c2)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.6 %

Procedure:
A solution of acetoxyacetyl chloride (1.08 g) in dichloromethane (10 ml) was added slowly to a suspension of 4-(3-aminomethylphenyl)-2-[[(amino)(2-methoxyethyl-amino)methylene]amino] thiazole dihydrochloride (2.5 g) and triethylamine (1.60 g) in dichloromethane (40 ml) with cooling on an ice bath. The mixture was stirred at room temperature for 1 day. The solvent was removed under reduced pressure. The residue was suspended in water (100 ml). The mixture was alkalified with an aqueous potassium carbonate solution and then extracted with a mixture of ethyl acetate (250 ml) and tetrahydrofuran (50 ml). The extract was dried with magnesium sulfate and then was evaporated in vacuo. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (20:1). The solvent was removed under reduced pressure. The residue was dissolved in methanolic ammonia (50 ml). The mixture was stirred with cooling on an ice-water bath for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in ethanol (50 ml) and 4N- dioxane solution of hydrogen chloride (10 ml) was added to the mixture. The mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration. Recrystallization from ethanol afforded 2-[[(amino)(2-methoxyethylamino)methylene]amino]-4-(3-hydroxyacetamidomethylphenyl)thiazole hydrochloride (0.57 g).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[NH:10]=[C:11]=[NH:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Br:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]([NH2:12])=[NH:10])=[CH:5][CH:4]=1
Reactant: Nc1ccc(Br)cc1
Reactant: N=C=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(N)Nc1ccc(Br)cc1
Yield: 76.3 %

Procedure:
Hydrochloric acid (1.503 mL, 9.07 mmol) was added to 4-bromoaniline (2 g, 11.63 mmol) and carbodiimide (0.538 g, 12.79 mmol) in ethanol (10 mL) heated to reflux for 90 min. The solvent was removed under reduced pressure and potassium carbonate (0.964 g, 6.98 mmol) in water (10.00 mL) was added. Crystals were filtered off and washed with several portions of DCM to give the title compound (1.9 g, 60%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:23]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:24][O:25][C:26](=[O:32])[CH:27]([CH:29]1[CH2:31][CH2:30]1)O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH3:24][O:25][C:26](=[O:32])[CH:27]([CH:29]1[CH2:31][CH2:30]1)[O:22][C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)[CH:23]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:10]=3
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Reactant: COC(=O)C(O)C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1COCCO1
Product: COC(=O)C(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
A mixture of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 (0.20 g, 0.64 mmol), cyclopropyl-hydroxy-acetic acid methyl ester (0.253 g, 1.28 mmol), triphenylphopshine (0.205 g, 1.28 mmol) and DIAD (252 μL, 1.28 mmol) in dioxane (6 mL) was stirred at RT for 18 h then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in TBME) to give Cyclopropyl-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-acetic acid methyl ester (0.068 g, 25%). LCMS: RT=3.43 min, [M+H]+=424.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH:13]([OH:15])[CH:12]([OH:16])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:19]=[C:20](F)[CH:21]=[CH:22][CH:23]=1>CS(C)=O>[Cl:17][C:18]1[CH:23]=[C:22]([CH:21]=[CH:20][CH:19]=1)[O:15][C@H:13]1[CH2:14][N:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:11][C@H:12]1[OH:16]
Reactant: OC1CN(Cc2ccccc2)CC1O
Reactant: Fc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O[C@@H]1CN(Cc2ccccc2)C[C@@H]1Oc1cccc(Cl)c1
Temperature: 95 °C

Procedure:
A slurry of 1.2 g. (50 mmoles) of sodium hydride (2.1 g. of 57% oil dispersion, washed with ether to remove the oil) in 25 ml. of dimethyl sulfoxide was stirred while 9.6 g. (50 mmoles) of 1-benzyl-3,4-dihydroxypyrrolidine, cis isomer, in 25 ml. of dimethyl sulfoxide was added. The mixture was stirred at ambient temperature for one hr., then 50 ml. of dimethyl sulfoxide was added and the temperature was raised to 95° C. for 0.5 hr. Mechanical stirring of the thick slurry was necessary while 13 g. (100 mmoles) of m-chlorofluorobenzene was added. During the heating period of 1 hr. at 95° C., all precipitate dissolved. The reaction mixture was concentrated by vacuum distillation of the dimethyl sulfoxide and excess m-chlorofluorobenzene. The residue was poured into water and extracted with hot cyclohexane. The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated to give 7.5 g. (49%) of off-white crystals, m.p. 86°-87.5° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:6][C:5]=1[O:20][CH3:21].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH:28]=1.Cl>CN(C)C=O.O>[CH3:21][O:20][C:5]1[CH:6]=[C:7]([CH2:10][CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])[CH:8]=[CH:9][C:4]=1[O:3][CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH:28]=1
Reactant: COc1cc(CCCC2OC(=O)NC2=O)ccc1O
Reactant: ClCc1coc(/C=C/c2ccccc2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1coc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
Sodium hydride (60% in oil, 0.32 g) was added, at 0° C., to a solution of 5-[3-(4-hydroxy-3-methoxyphenyl]propyl]-2,4-oxazolidinedione (1.0 g) in N,N-dimethylformamide (DMF) (20 ml). The mixture was stirred for one hour at room temperature. To the reaction mixture was then added 4-chloromethyl-2-[(E)-styryl]oxazole (0.87 g), which was stirred for 3.5 hours at 90° C. The reaction mixture was poured into water, which was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure to yield 5-[3-[3-methoxy-4-[2-[(E)-styryl]-4-oxazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione (1.1 g, 66%). The product was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.178-179° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[OH:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([OH:22])=[CH:16][C:17]=3[OH:21])[O:12][C:11]=2[C:23]([O-])=[O:24])=[CH:8][CH:7]=1>CO>[OH:5][C:6]1[CH:27]=[CH:26][C:9]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([OH:22])=[CH:16][C:17]=3[OH:21])[O:12][C:11]=2[C:23]([NH:4][CH2:3][CH2:1][OH:2])=[O:24])=[CH:8][CH:7]=1
Reactant: O=C([O-])c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Reactant: NCCO
Solvent: CO
Product: O=C(NCCO)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.1 %

Procedure:
Ethanolamine (100 mg), was added to a solution of 4',5,7-trihydroxyisoflavonecarboxylate (100 mg) in 2 ml methanol, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced presure, the residue was purified by silica gel column chromatography (chloroform:methanol=95:5), and the solid thus obtained was recrystallized from a methanol/diethyl ether mixed solvent, giving 40 mg of 4',5,7-trihydroxy-N-(2-hydroxyethyl)-2-isoflavonecarboxamide.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: OC1CCNC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCC(O)C1
Yield: 6.5 %

Procedure:
In the manner described in Example 28 (1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea (225 mg, 0.427 mmol) from Example 27B was reacted with pyrrolidin-3-ol (0.103 mL, 1.281 mmol) to yield 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[3-(3-hydroxy-pyrrolidin-1-yl)-propoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea (16 mg, 4%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.28 (s, 1H), 8.52 (s, 1H), 7.55 (d, 2H), 7.35 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.70 (brs, 1H), 4.25 (m, 3H), 3.95 (s, 3H), 2.80-2.30 (m, 6H), 1.95 (m, 2H), 1.55 (m, 2H), 1.30 (s, 9H); LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].Br[CH2:25][C:26]([O:28][CH2:29]C)=[O:27]>>[CH3:29][O:28][C:26](=[O:27])[CH2:25][O:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([F:20])[C:13]=1[CH:10]([C:9](=[O:21])[NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:23][CH:22]=1)[O:11][CH3:12]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(O)cccc1F
Reactant: CCOC(=O)CBr
Product: COC(=O)COc1cccc(F)c1C(OC)C(=O)NCc1ccc(C#N)cc1

Procedure:
In analogy to example 16.4 (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-6-hydroxy-phenyl)-2-methoxy-acetamide (example 80.4) was reacted with ethyl bromoacetate to give (RS)-{2-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-3-fluoro-phenoxy}-acetic acid methyl ester. Yellow oil. MS 387.2 ([M+H]+)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[O:55])[C@H:13]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[N:47]C(OC(C)(C)C)=O)[NH:39]C(OC(C)(C)C)=O)[N:14]([C:16](=[O:33])[C@H:17]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:18]C(OC(C)(C)C)=O)[CH3:15].[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59]>>[F:56][C:57]([F:62])([F:61])[C:58]([OH:60])=[O:59].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[O:55])[C@H:13]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:47])[N:14]([C:16](=[O:33])[C@H:17]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:18])[CH3:15]
Reactant: CN(C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)Nc1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)[C@@H](N)Cc1ccccc1)[C@@H](CCCNC(=N)N)C(=O)Nc1ccc2ccccc2c1

Procedure:
Boc-Phenylalanyl-Nω,Nω′-bis-Boc-Nα-methylarginine β-naphthylamide was treated with trifluoroacetic acid (Procedure E), followed by HPLC purification (Method A) to afford a white solid (45 mg): 1H NMR (400 MHz, D2O) δ1.70 (m, 2H), 1.92 (m, 1H), 2.15 (m, 1H), 2.82 (s, 3H), 3.42 (m, 4H), 4.83 (HOD with proton hidden), 5.19 (m, 1H), 7.18 (m, 2H), 7.31 (m, 1H), 7.68 (m, 4H), 8.15 (m, 4H), and 8.20 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:4]([CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])=[C:4]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27]
Reactant: CCOC(=O)C(O)c1c(C)c(F)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)c1c(C)c(F)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 4 h
Yield: 70.3 %

Procedure:
A solution of ethyl 2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (˜1.54 g, 3.76 mmol) in DCM (60 mL) was treated with Dess-Martin periodinane (1.91 g, 4.51 mmol) at 23° C. After 4 h, the orange reaction was slowly added to 10% Na2S2O3 (28 mL) at 23° C. After 5 min of stirring, the reaction was diluted with H2O (40 mL) and extracted with DCM (3×20 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was dissolved in benzene. The solution was wet-loaded onto a 40 g “gold” ISCO silica gel column and purified by flash chromatography (hexane→ethyl acetate/hexanes 1:4) giving the desired product (1.08 g, 70% yield over 2 steps from ethyl 2-tert-butoxy-2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate). 1H NMR (400 MHz, CDCl3) δ 8.16-8.08 (m, 2H), 7.76-7.68 (m, 2H), 4.41 (q, J=7.1 Hz, 2H), 2.39 (d, JHF=3.2 Hz, 3H), 1.40 (t, J=7.1 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−122.3 (app. s, 1F), −73.3 (s, 3F).
Reaction SMILES: Br[CH:2]([CH:6]([CH2:9]Br)[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[CH:11]([NH2:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[C:18]1([CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:24]2[CH2:9][CH:6]([CH2:7][CH3:8])[CH:2]2[C:3]([OH:5])=[O:4])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCC(CBr)C(Br)C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCC1CN(C(c2ccccc2)c2ccccc2)C1C(=O)O

Procedure:
19.5 g of 2A and 29 g of benzhydrylamine in acetonitrile were stirred and refluxed for 48 hours. The resulting mixture was cooled, filtered free of insoluble amine salt and the filtrate evaporated to dryness. The residue, which was a complex mixture of product, was partially purified using a column of silica gel and petroleum ether/ethyl acetate as the eluent. The first fast-running products to emerge were collected and evaporated to dryness, leaving the benzyl ester of 1-diphenylmethyl-2-carboxy-3-ethylazetidine (2B) as the major component (65% by NMR) of the crude residual mixture.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27]OS(C)(=O)=O)[CH:17]=2)=[CH:3]1.[Na].[SH:36][C:37]1[N:41]([CH3:42])[N:40]=[N:39][N:38]=1.O>CS(C)=O>[CH3:1][N:2]1[C:10]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][S:36][C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH:17]=2)=[CH:3]1
Reactant: Cn1nnnc1S
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: Cn1nnnc1SCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 55 °C
Yield: 46.1 %

Procedure:
100 mg of the product of Example 58 in 10 ml of DMSO were treated with 120 mg of 5-mercapto-1-methyltetrazole sodium salt. The solution was heated at 55° C. for 6 hours, then cooled and poured into water. The aqueous phase was extracted with ethyl acetate. The ethyl acetate extracts were dried and concentrated. Chromatography on silica gel with dichloromethane/ethyl acetate (4:1) gave 48 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(1-methyl-5-tetrazolylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 95°-97° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([C:15]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:16]=1[OH:17])[CH2:13][CH3:14]>OS(C(F)(F)F)(=O)=O>[OH:17][C:16]1[CH:18]=[CH:19][C:20]([C:9](=[O:11])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:21]([OH:22])[C:15]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1c(O)cccc1O
Reactant: O=C(O)CCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Product: CCCc1c(O)ccc(C(=O)CCc2ccccc2)c1O

Procedure:
Using the procedure in Example 51, step 1, 3-phenylpropionic acid and 2-(n-propyl)resorcinol were condensed in triflic acid to form 1,3-dihydroxy-4-(3-phenylpropionyl)-2-(n-propyl)benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][C:12](=[N:14][OH:15])[NH2:13].C(NC(C)C)(C)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][C:12](=[N:14][O:15][C:38]([CH:35]1[CH2:37][CH2:36]1)=[O:39])[NH2:13]
Reactant: NC(CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Cl)cccc21)=NO
Reactant: O=C(Cl)C1CC1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: NC(CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Cl)cccc21)=NOC(=O)C1CC1
Yield: 54.8 %

Procedure:
A stirred solution of 2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-hydroxyacetimidamide (0.40 g, 1.0 mmol), diisopropylamine (0.16 g, 1.6 mmol) and cyclopropane carbonyl chloride (0.16 g, 1.6 mmol) in dichloromethane (20 mL) was stirred for 16 h at ambient temperature. The colorless solid that precipitated from the solution was filtered, washed with water (5 mL) and diethyl ether (5 mL) to afford 2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-[(cyclopropylcarbonyl)oxy]ethanimidamide as a colorless solid (0.25 g, 53%): 1H NMR (300 MHz, DMSO-d6) δ7.31 (dd, J=8.0, 8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 2H), 6.64 (br s, 2H), 6.54 (s, 1H), 6.47 (s, 1H), 5.88 (s, 2H), 4.77 (ABq, 2H), 4.43 (ABq, 2H), 1.75-1.67 (m, 1H), 0.86-0.73 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ176.9, 171.9, 156.5, 153.6, 148.9, 144.8, 141.9, 130.8, 130.0, 128.6, 117.4, 108.8, 104.4, 101.8, 104.5, 101.8, 104.4, 101.8, 93.0, 77.5, 58.4, 11.7, 8.45, 8.42; MS (ES+) m/z 456.1 (M+1), 478.1 (M+23).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[CH2:14]=O.CO.[BH4-].[Na+]>O>[CH3:14][N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
In a dried reaction flask, (R)-tert-butyl pyrrolidin-3-ylcarbamate (5.774 g, 31.0 mmol) and formaldehyde solution (37%, 6.82 mL) were dissolved into methanol (124 mL) under a nitrogen protection. The mixture was stirred at room temperature for 1 hr. Sodium borohydride (3.518 g, 93.0 mmol) was added in portion under an ice bath. The mixture was stirred at room temperature for 3 hr. Water was added and the solution was concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to produce a white solid (3.685 g) in 59.4% yield.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:31]([O:33]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:37][NH2:38]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:37][NH:38][C:31](=[O:33])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][C:24]([CH:27]([CH3:28])[CH3:29])=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(C)C)cc1)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(CN(C)C)cc2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of ethyl 2-(4-((dimethylamino)methyl)phenyl)-3-(4-isopropylphenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (210 mg) in 85% hydrazine monohydrate (1 mL) and methanol (10 mL) was stirred at 23° C. for overnight. Methanol was removed under reduced pressure. The crude was purified by flash chromatography to give the title compound (72 mg, yield 37%). LC-MS (ESI) m/z: 439 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.18 (d, 3H), 1.19 (d, 3H), 2.26 (s, 6H), 2.79-2.83 (m, 1H), 3.51 (d, 2H), 4.27 (d, J=8.0 Hz, 1H), 4.73 (d, J=8.0 Hz, 1H), 6.98-7.00 (m, 2H), 7.05-7.07 (m, 2H), 7.18-7.22 (m, 3H), 7.25-7.27 (m, 2H), 7.54-7.56 (m, 1H), 7.56-7.59 (m, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)=[CH:10][CH:11]=1.[CH3:19][S:20]SC.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:19][S:20][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)=[CH:10][CH:11]=1
Reactant: Brc1cccc(-c2ccc(Br)s2)c1
Reactant: CSSC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc(-c2cccc(Br)c2)s1
Reaction time: 0.17 h

Procedure:
5M solution of n-butyllithium (2.2 mL; 5.5. mM) was slowly added to a solution of 2-bromo-5(3'-bromophenyl)thiophene (1.59 g; 5 mM) in 10 mL of tetrahydrofuran at -78° under nitrogen. The mixture was stirred 10 mins. and dimethyldisulfide (1.35 mL; 15 mM) was added slowly. This mixture was stirred overnight at R.T. after which 5 mL of sat'd. ammonium chloride and 15 mL of ethyl acetate were added. The organic phase was separated, washed with 2×5 mL of sat'd. sodium chloride, and dried over anhyd. magnesium sulfate. Solvent removal and purification on silica gel with hexane as solvent gave 2-methylthio-5-(3'-bromophenyl)thiophene as a colorless oil boiling at 142°-5°/0.5 mm.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:19]([C:21]1[CH:41]=[CH:40][C:24]2[N:25]([CH3:39])[C:26]([CH2:28][NH:29][C:30]3[CH:35]=[CH:34][C:33]([C:36](=[NH:38])[NH2:37])=[CH:32][CH:31]=3)=[N:27][C:23]=2[CH:22]=1)=[O:20].Cl[C:50]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:51].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH3:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][O:52][C:50](/[N:38]=[C:36](\[NH2:37])/[C:33]1[CH:32]=[CH:31][C:30]([NH:29][CH2:28][C:26]2[N:25]([CH3:39])[C:24]3[CH:40]=[CH:41][C:21]([C:19]([N:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=4)[CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:20])=[CH:22][C:23]=3[N:27]=2)=[CH:35][CH:34]=1)=[O:51]
Reactant: CCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1

Procedure:
55 g of 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide tosylate was dissolved in 437 ml of acetone and 273 ml of water. 16.4 g of hexyl chloroformate and 34 g of potassium carbonate was added to it at a temperature of about 15° C. After the end of the reaction, the precipitated product is filtered off and washed with acetone/water. Dissolved the obtained solid in 270 ml of acetone under heating and then filtered. The title product was crystallized by the addition of 220 ml of water. The isolated substance is dried under reduced pressure at 45° C.