Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:17]([CH2:18][C:19]([OH:21])=O)=[CH:16][N:15]=[CH:14]1.[OH:22][N:23]1[C:28](=O)C2C=CC=CC=2N=N1.Cl.[CH3:35]N(C)CCCN=C=NCC.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[CH3:35][O:22][N:23]([CH3:28])[C:19](=[O:21])[CH2:18][C:17]1[N:13]([CH2:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=2)[CH:14]=[N:15][CH:16]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1cncn1Cc1ccc2ccccc2c1
Reactant: O=c1c2ccccc2nnn1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cncn1Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2-naphthylmethyl)-1H-imidazol-5-ylacetic acid hydrochloride (prepared in Example 4, 0.819 mg, 2.70 mmol) in dimethylformamide (15 ml) was added sequentially N, O-dimethylhydroxylamine hydrochloride (293 mg, 3.0 mmol), 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HOOBT, 489 mg, 3.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 575 mg, 3.0 mmol) and triethylamine (1.67 ml, 12.0 mmol) and the resulting mixture stirred at room temperature for 18 h. Saturated aq. sodium bicarbonate (30 ml) and water (30 ml) were added and the mixture was extracted with methylene chloride (2×50 ml). The combined organic extracts were washed with brine (50 ml) and the solvent evaporated in vacuo. The residue was purified by flash chromatography (2-4% methanol/methylene chloride gradient elution) to provide the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([O:5]C1C(F)=C(F)C(F)=C(F)C=1F)=O.[NH2:19][C:20]1[N:24]([CH2:25][CH3:26])[N:23]=[C:22]([CH2:27][C:28]([OH:30])=O)[CH:21]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33]C=1.N1CCCC1>CN(C=O)C>[CH2:25]([N:24]1[C:20]([NH:19][C:3](=[O:5])[C:2]([F:1])([F:17])[F:18])=[CH:21][C:22]([CH2:27][C:28](=[O:30])[N:31]2[CH2:33][CH2:34][CH2:35][CH2:36]2)=[N:23]1)[CH3:26]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: c1ccncc1
Reactant: CCn1nc(CC(=O)O)cc1N
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CCn1nc(CC(=O)N2CCCC2)cc1NC(=O)C(F)(F)F
Reaction time: 0.25 h
Yield: 44.3 %

Procedure:
Pentafluorophenyl trifluoroacetate (497 mg, 1.773 mmol) was added dropwise to a stirred solution of (5-amino-1-ethyl-1H-pyrazol-3-yl) acetic acid (150 mg, 0.887 mmol) and pyridine (0.143 mL, 1.773 mmol) in DMF (3 mL). The reaction mixture was stirred for 15 min and pyrrolidine (0.220 mL, 2.66 mmol) was added. The reaction mixture was stirred at 65° C. for 40 min. The mixture was cooled and quenched with water (5 mL) and extracted with EtOAc (3×). The extract was dried over Na2SO4, filtered and concentrated. The residue was purified using RP-HPLC to give product (125 mg). MS: (M+H)+=318.8. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.32 (t, J=7.2 Hz, 3H), 1.87-2.06 (m, 4H), 3.46 (t, J=6.8 Hz, 2H), 3.53 (t, J=6.8 Hz, 2H), 3.66 (s, 2H), 4.07 (q, J=7.2 Hz, 2H), 5.30 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Cl.[CH:14]([N:17]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:19][CH2:20]Cl)([CH3:16])[CH3:15]>>[CH:14]([N:17]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:19][CH2:20][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[C:5](=[O:12])[C:6]1=[O:11])([CH3:16])[CH3:15]
Reactant: CC(C)N(CCCCl)C(C)C
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Product: Cc1ccc2c(c1)C(=O)C(=O)N2CCCN(C(C)C)C(C)C

Procedure:
By using 5-methylisatin and 3-diisopropylaminopropyl chloride hydrochloride, a method analogous to that described in Reference Example 1 was carried out to obtain 1-(3-diisopropylaminopropyl)-5-methylisatin having a melting point of 87°-89° C. (yeld: 53.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]=3[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][O:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-(4-chlorophenyl)-1-methoxybutan-2-yl)-1H-indol-4-amine (30 mg) and 4-methylmorpholine (46 mg) in DCM (3 mL) was added methanesulfonyl chloride (16 mg) dropwise. Then the mixture was stirred at room temperature overnight. The solution was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by chromatography on silica gel (20-30% ethyl acetate in hexane) to afford the title compound as a white solid. LC/MS m/z=407.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:8]=[C:7](N)[CH:6]=1)[CH3:2].N(OCCC(C)C)=O.C(I)[I:29]>C(#N)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:8]=[C:7]([I:29])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C

Procedure:
3-Amino-5-(5-methyl-pyridin-2-yl)-benzoic acid ethyl ester (3.7 g, 14.45 mmol) was added to 50 mL of acetonitrile, and the mixture was stirred at room temperature. Isoamyl nitrite (9.7 mL, 72.27 mmol) was slowly added, followed by methylene iodide (7.0 mL, 86.7 mmol). The reaction mixture was slowly heated to 60° C. for 30 minutes, then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic phase was separated, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by liquid chromatography (30% to 100% methylene chloride/hexanes) to give 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid ethyl ester, MS (M+H)=368.
Reaction SMILES: [NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:13].[CH2:20]([N:22]([CH2:36][CH3:37])[C:23](=[O:35])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH3:21]>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:12])=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:23]([N:22]([CH2:36][CH3:37])[CH2:20][CH3:21])=[O:35])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C:3]1=[O:13]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1(c2ccccc2)C(=O)Nc2cc(Cl)c(Cl)cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3)c3cc(Cl)c(Cl)cc32)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.293 g of 3-amino-5,6-dichloro-1,3-dihydro-3-phenylindol-2-one and 0.290 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a DCM/AcOEt mixture (85/15; v/v) as the eluent gives the expected product after crystallization from a DCM/iso ether mixture. m=0.26 g. M.p.=119°-121° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.C(OCC)C>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:1])=[C:3]2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:25][CH:24]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)c2ccccc2n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Ethyl 3-methyl-1H-indole-2-carboxylate (480 mg, 2.362 mmol) was dissolved in anhydrous DMF (5 mL), followed by the addition of granular potassium carbonate (408 mg, 2.95 mmol) and p-chlorobenzylchloride (0.38 mL, 2.95 mmol). The reaction was allowed to stir at 60° C. for 24 h, after which time the solution was diluted with a 1:1 solution of ethyl acetate:diethyl ether. The organic phase was washed with 10% aqueous sodium carbonate, dried with magnesium sulfate, and concentrated in vacuo. Purification was accomplished via silica gel flash chromatography (60 g silica, 10% EtOAc/hexanes) to give the title compound as a white powder. (Yield: 510 mg, 1.60 mmol, 66%) 1H NMR (400 MHz, CDCl3) 7.71, 7.34-7.15, 6.95, 5.73, 4.34, 2.63, 1.36
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4](O)=[O:5].Cl.[N:15]([O-])=O.[Na+].S(=O)=O>O>[N+:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:15][NH:1]2)([O-:13])=[O:12]
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: O=S=O
Agent: [Na+]
Solvent: O
Product: O=c1[nH][nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g (27.5 mmol) 2-amino-6-nitro-benzoic acid are combined with 22.2 ml (225.3 mmol) concentrated HCl and 45 ml (30.0 mmol) 5% aqueous sodium nitrite solution and stirred for 1 h at ambient temperature. Then the suspension is diluted with 150 ml dist. H2O and added dropwise to 350 ml destilliertes water which has been saturated with sulphur dioxide. Sulphur dioxide is piped through the reaction mixture for a further 30 min. Then the reaction mixture is refluxed for 30 min and then left to cool slowly to 20° C. The resulting precipitate is filtered off.
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=O.[CH:7]1[CH:15]=[CH:14][C:13]2[C:9](=[N:10][O:11][N+]=2[O-])[CH:8]=1.C(NCC)C>O1CCCC1>[CH3:5][C:4]1([CH3:6])[N+:1]([O-:3])=[C:13]2[CH:14]=[CH:15][CH:7]=[CH:8][C:9]2=[N+:10]1[O-:11]
Reactant: CC(C)[N+](=O)[O-]
Reactant: [O-][n+]1onc2ccccc21
Solvent: C1CCOC1
Solvent: CCNCC
Product: CC1(C)[N+]([O-])=c2ccccc2=[N+]1[O-]
Reaction time: 8 h

Procedure:
To a mixture containing 2-nitropropane (10.7 g., 0.12 moles), benzofuroxan (13.6 g., 0.10 moles) and tetrahydrofuran (50 ml.) is added dropwise diethylamine (8.7 g., 0.12 mole). The reaction temperature rises during addition. Upon completion of addition, the reaction mixture is allowed to sit overnight at room temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1[C:21]([C:26](O)=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:21]3[C:20]([F:19])=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncccc1F
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncccc3F)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=383.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:30]=[C:29]3[C:17]([C:18](=[O:32])[C:19]4[N:28]3[C:27](=[O:31])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=4)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[N:11]1([C:14]2[CH:30]=[C:29]3[C:17]([C:18](=[O:32])[C:19]4[N:28]3[C:27](=[O:31])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=4)=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)-n2c(nc4ccccc4c2=O)C3=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C1c2ccc(N3CCNCC3)cc2-n2c1nc1ccccc1c2=O
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
To a solution of 9-(4-t-butyloxycarbonylpiperazinyl)indolo[2,1-b]quinazoline-6,12-dione (Example 52, 40 mg, 925 μmol) in 1 mL of methylene chloride was added 1 mL of trifluoroacetic acid (TFA). After 30 min, saturated sodium bicarbonate was added. The aqueous layer was separated and extracted with 3×50 mL of chloroform, dried over anhydrous sodium sulfate, filtered and solvent removed in vacuo to give 37 mg of crude product. Silica gel chromatorgraphy using (95:5) methylene chloride:methanol as eluent gave 24 mg (77%) of the title compound: mp 214° C. (dec); 1H NMR(DMSO-d6) δ 2.5 (s, 4H), 3.5 (s, 4H), 6.88-6.94 (dd, 1H), 7.62-7.66 (d, 1H), 7.68-7.75 (m, 1H), 7.90-7.94 (m, 2H), 7.95-7.98 (m, 1H), 8.26-8.31 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH2:17])=[CH:7][N:6]=1)[CH2:10]2
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1cnc(O[C@H]2CN3CCC2CC3)nc1
Product: Nc1ccccc1-c1cnc(O[C@H]2CN3CCC2CC3)nc1

Procedure:
The product of Example 19A (280 mg, 1.0 mmol) was coupled with 3-aminophenylboronic acid (Lancaster, 276 mg, 2.0 mmol) according to the procedure of Example 1B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.1) as a solid (230 mg, yield, 77%). 1H NMR (300 MHz, MeOH-d4) δ 1.48-1.62 (m, 1H), 1.65-1.90 (m, 2H), 2.01-2.15 (m, 1H), 2.21-2.29 (m, 1H), 2.74-3.04 (m, 5H), 3.36-3.47 (m, 1H), 5.12-5.20 (m, 1H), 6.75 (ddd, J=8.2, 2.1, 1.0 Hz, 1H), 6.89 (ddd, J=7.4, 1.7, 1.0 Hz, 1H), 6.93 (t, J=1.8 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 8.74 (s, 2H) ppm. MS (DCl/NH3) m/z 297 (M+H)+.
Reaction SMILES: NC(N)=O.C(=O)([O-])N.[NH2:9][C:10]1[CH:11]=[C:12]([CH:16]([OH:35])[CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]4)[CH2:20][CH2:19]2)[CH:13]=[CH:14][CH:15]=1.[C:36]([C:39]1C=C(N2CCC2=O)C=C[CH:44]=1)(=[O:38])C.CC1C=CC2C(=CC=CC=2N2CCN(CCC3C=C(C=CC=3)N)CC2)N=1>>[OH:35][CH:16]([C:12]1[CH:11]=[C:10]([N:9]2[CH2:44][CH2:39][C:36]2=[O:38])[CH:15]=[CH:14][CH:13]=1)[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]3)[CH2:20][CH2:19]1
Reactant: Cc1ccc2c(N3CCN(CC(O)c4cccc(N)c4)CC3)cccc2n1
Reactant: CC(=O)c1cccc(N2CCC2=O)c1
Agent: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Agent: NC(=O)[O-]
Agent: NC(N)=O
Product: Cc1ccc2c(N3CCN(CC(O)c4cccc(N5CCC5=O)c4)CC3)cccc2n1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield according to the general procedure for the synthesis of cyclic amide, urea and carbamate derivatives of 1-(3-aminophenyl)2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethanol (Method H) starting from 1-(3-acetylphenyl)-2-azetidinone (D10) and 2-methyl-5(1l-piperazinyl)quinoline (D3).
Reaction SMILES: C([O-])(=O)C.[P:5]([O:9]P(O)(O)=O)([OH:8])([OH:7])=[O:6].[C@@H:14]1([N:23]2[C:32]3[N:31]=[CH:30][N:29]=[C:27]([OH:28])[C:26]=3[N:25]=[CH:24]2)[O:22][C@H:19]([CH2:20]O)[C@@H:17]([OH:18])[C@H:15]1[OH:16]>>[C@@H:14]1([N:23]2[C:32]3[N:31]=[CH:30][N:29]=[C:27]([OH:28])[C:26]=3[N:25]=[CH:24]2)[O:22][C@H:19]([CH2:20][O:9][P:5]([OH:7])([OH:8])=[O:6])[C@@H:17]([OH:18])[C@H:15]1[OH:16]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: O=P(O)(O)OP(=O)(O)O
Agent: CC(=O)[O-]
Product: O=P(O)(O)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 24 h

Procedure:
Cells of Escherichia coli JM109 introduced with each of the aforementioned mutant EB-AP genes were added at a density of 100 mg/dl in terms of dry cell weight to a solution in an acetate buffer (pH 4.0) containing 12 g/dl of pyrophosphoric acid and 6 g/dl of inosine, and reaction was performed at 30° C. for 24 hours while pH was maintained at 4.0. The results of measurement of the produced amount of 5′-inosinic acid are shown in Table 4. The produced inosinic acid consisted only of 5′-inosinic acid, and 2′-inosinic acid and 3′-inosinic acid byproducts were not observed at all.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=[N:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40]C1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:48]([N:51](C(C)C)[CH2:52]C)(C)C.CN(CC1CCCN1)C.ClCl>O1CCCC1.CO>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:41]1[CH2:36][CH2:37][CH2:38][C:39]1([CH3:40])[N:51]([CH3:52])[CH3:48])=[O:6])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)CC1CCCN1
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCCC2(C)N(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 50 %

Procedure:
Prepared analogously to Example 1g from (1S)-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and rac-2-(dimethylaminomethyl)pyrrolidine in tetrahydrofuran. Yield: 50%; Rf value: 0.32 (Reversed phase RP 8: methanol/5% sodium chloride solution=6:4); C24H27Cl2N5O2 (488.416); mass spectrum: (M+H)+=488/490/492 (chlorine isotope) and (M−H)−=486/488/490 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C@@H:10]([CH3:13])[CH2:11][OH:12].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C@@H:10]([CH3:13])[CH2:11][OH:12])=[C:2]([NH:1][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH:7]=1
Reactant: C[C@@H](CO)Nc1ccc(Br)cc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(Br)ccc2N[C@@H](C)CO)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 113.6 %

Procedure:
A 1-L, round bottomed flask fitted with a nitrogen inlet, magnetic stir bar, and thermocouple was charged with (S)-2-(2-amino-4-bromophenylamino)propane-1-ol (47.55 g, 194 mmol), and pyridine (475 mL). The mixture was cooled to 0° C. and p-toluene sulfonyl chloride (37.0 g, 194 mmol) was added in portions of 12.6 and 24.4 g. The internal temperature rose from 1.5 to 15.6° C. following each addition. The reaction mixture stirred at 0° C. for 1.5 h and was then warmed to room temperature. The pyridine was removed under reduced pressure, and the residue was diluted with ethyl acetate (300 mL) and washed with water (100 mL). The combined organic phases were washed with half saturated brine (100 mL) and concentrated under reduced pressure. The residue was dissolved in toluene (250 mL), and the solution concentrated under reduced pressure (in order to remove some residual pyridine). The crude product was purified by column chromatography on silica gel (eluting with 1:1 hexanes-ethyl acetate). The product-containing fractions were combined and concentrated under reduced pressure. Toluene (250 mL) was added, and the mixture was concentrated under reduced pressure to removed trace pyridine. The material was dried under vacuum (ca 17 Torr) to afford (S)-N-(5-bromo-2-(1-hydroxypropan-2-ylamino)phenyl)-4-methylbenzenesulfonamide (88 g, 110%) as a viscous yellow oil that contains 11 wt % toluene. MS (ESI, pos. ion) m/z 399 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COC1(c2ccc(F)c(F)c2)CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(c2ccc(F)c(F)c2)CCNC1
Yield: 63.8 %

Procedure:
Preparation according to Preparation 15. Tert-butyl-3-(3,4-difluorophenyl)-3-methoxypyrrolidin-1-carboxylate (2.65 g, 8.46 mmol), methylene chloride (20 mL) and trifluoroacetic acid (5 mL). Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) gave the title compound (1.15 g, 63%). MS m/z (rel. intensity, 70 eV) 198 (46), 183 (79), 171 (bp), 141 (53), 113 (41).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Oc1ccccc1
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Product: CCCCOC(=O)c1nc(Oc2ccccc2)c2ccccc2c1O
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 1.399 g of 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (5 mmol) and 2.86 g of phenol was heated at 145° C. to 150° C. for 24 h. After cooling to ambient temperature the mixture was suspended in 50 ml of aqueous 2N NaOH and the mixture was extracted with 4×25 ml of ethyl acetate. The combined organic phases were washed with 3×25 ml of aqueous 2N NaOH, 50 ml of brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with hexanes:ethyl acetate (9:1) and (95:5). 0.650 g of the title compound were obtained; 1H NMR (CDCl3): δ=11.52 (s, 1H), 8.32 to 8.39 (m, 2 H), 7.72 to 7.86 (m, 2 H), 7.13 to 7.42 (m, 5 H), 4.31 (t, 2 H), 1.69 (m, 2 H), 1.37 (m, 2 H), 0.93 (t, 3 H).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:10](O)[CH3:11])[CH:6]=[CH:7][C:8]=1[Cl:9]>CC(O)=O>[Br:1][CH:10]([C:5]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=1)[CH3:11]
Reactant: Br
Reactant: CC(O)c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Product: CC(Br)c1ccc(Cl)c(Cl)c1

Procedure:
This compound is prepared by the procedure described in Preparation 3.4 from 25 ml of a 33% solution of HBr in AcOH and 5 g of 3,4-dichloro-1-(1-hydroxyethyl)benzene. 6.4 g of the expected product are obtained.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][CH3:25])=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24][CH3:25])=[CH:14][C:13]2=[O:26])[C:3]([OH:27])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2SC)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Temperature: 23 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2-methylsulfanyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (250 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 12 mL) was added lithium hydroxide (0.080 g, 0.003 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2-methylsulfanyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (200 mg, 83%) as a semi-solid.