Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9]O.S(Cl)([Cl:13])=O>CN(C)C=O>[CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][Cl:13]
Reactant: O=c1cc(CO)occ1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=c1cc(CCl)occ1O
Temperature: 10 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
50 g(351.8 mmol) of kojic acid was dissolved in 250 ml of N,N-dimethylformamide. The resulting solution was cooled in an ice bath of 10° C. and 30 ml(411.3 mmol) of thionyl chloride was added dropwise thereto. The mixture was stirred at room temperature for 2 hours and 2000 ml of ice water was added. The precipitate was filtered and dissolved into 1000 ml of ethyl acetate. The reaction product was dried over magnesium sulfate, decolored with active charcoal and filtered. The filtrate was concentrated and hexane was added to give crystals, which were then dried under vacuum to give 37.5 g(66.83%) of the desired chlorokojic acid as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Cl[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:22]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[S:29](=[O:32])(=[O:31])[CH2:30][C:21]=3[C:20]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])=[N:19]2)[CH2:13]1.[Na+].[I-]>C(#N)C.C(Cl)Cl>[N:35]1([C:33]([C:20]2[C:21]3[CH2:30][S:29](=[O:32])(=[O:31])[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:22]=3[N:18]([CH:14]3[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][CH2:10][N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])[CH2:13]3)[N:19]=2)=[O:34])[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: O=C(c1nn(C2CCCN(CCCl)C2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1CCCN1CCN1CCCC(n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)C1
Yield: 9.9 %

Procedure:
A solution of 2-pyrrolidone (35 mg; 0.42 mmol; 2 eq.) with NaH (10 mg; 0.42 mmol; 2 eq.) in ACN at 0° C. is added to a solution of enantiomer B of 1-[1-(2-chloroethyl)piperidin-3-yl]-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (100 mg; 0.21 mmol; 1 eq.) and NaI (31 mg; 0.21 mmol; 1 eq.) in ACN (2 mL). Reaction mixture is heated to 60° C. for 18 h after which DCM is added and organic phase is washed with water and brine. It is dried over MgSO4 then purified by MD-Autoprep to give 11 mg (9%) of the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.05 (d, J=7.7 Hz, 1H), 8.00-7.82 (m, 2H), 7.81-7.67 (m, 1H), 4.89-4.64 (m, 3H), 4.00-3.83 (m, 2H), 3.83-3.56 (m, 8H), 3.22-3.12 (m, 1H), 2.99-2.82 (m, 1H), 2.67-2.34 (m, 4H), 2.29-2.15 (m, 2H), 2.15-1.54 (m, 8H). MS (ESI+): 528.5. HPLC (max plot) 97.6%; Rt 1.86 min.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.CCN(C(C)C)C(C)C.N1C=CC=CC=1.[C:29](Cl)([Cl:31])=[O:30]>ClCCl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([C:29]([Cl:31])=[O:30])[CH2:8][C:7]=2[CH:13]=1
Reactant: O=C(Cl)Cl
Reactant: Brc1ccc2c(c1)CNCCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(Cl)N1CCOc2ccc(Br)cc2C1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (3.0 g, 11.34 mmol) was suspended in dichloromethane (30 mL) followed by addition of DIPEA (3 mL, 34 mmol) and pyridine (4 mL, 49 mmol) and the resulting partially heterogeneous mixture was added portionwise over 5 minutes to a 0° C. cooled solution of phosgene (20 W % in toluene, 15 mL, 28 mmol) in dichloromethane (15 mL). The resulting mixture was then allowed to slowly warm to room temperature over 30 minutes then concentrated. The residue was partitioned with ethyl acetate and water and the organic phase washed twice with 1M aqueous hydrochloric acid then brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carbonyl chloride (3.35 g) as a pale yellow oil. MS (EI) for C10H9BrClNO2: 292 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([OH:16])=[CH:8][CH:7]=1.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:37]CO.[C:40]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([O:16][CH2:40][CH2:21][C:22]2[S:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)=[N:24][C:23]=2[CH3:37])=[CH:8][CH:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Reactant: CCOC(Cc1ccc(O)c2c1CCCC2)C(=O)OC
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCCC2)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid methyl ester (example 2 c]) was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol [PCT Int. Appl. (2001), WO 01/00603 A1] in tetrahydrofuran in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 1 e], to yield [rac]-2-ethoxy-3-(4-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid as colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([NH2:15])[CH:5]=1)(=[O:3])[CH3:2].[F:16][C:17]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>N1C=CC=CC=1>[C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([NH:15][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:17]=2[F:16])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(N)c1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(NC(=O)c2ccc(F)cc2F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
A mixture of 4'-acetyl-2'-aminomethanesulfonanilide (1.6 g) and 2,4-difluorobenzoyl chloride (1.5 g) in pyridine (15 ml) was stirred at 0° C. for 3 hours. The mixture was evaporated and the residue was stirred with 5% sodium hydroxide (40 ml) for 1 hour at room temperature. The mixture was washed with toluene, and the aqueous layer was acidified with hydrochloric acid. The precipitates obtained were recrystallized from a mixture of acetone and ethyl acetate (1:1) to give pale brown needles of N-(5-acetyl-2-methanesulfonamidophenyl)-2,4-difluorobenzamide (1.3 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[N+:9]([C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>CN(C=O)C>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=1)=[O:20]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 9 h

Procedure:
To a stirred slurry of 12.45 g (0.11mole) of creatinine in 100 ml of dry DMF is added 16.41 g (0.1 mole) of m-nitrophenyl isocyanate (previously recrystallized from benzene-pentane). After nine hours, ice water is gradually added until crystallization occurres. A large excess of ice water precipitates the product as gummy crystals which then crystallize. The crude product is allowed to air dry for several days. Recrystallization from THF-H2O followed by THF gives pure product, 1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-m-nitrophenyl urea; m.p. 182°-188° C. sl. dec.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.Cl.[CH3:11][CH:12]([C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)[CH2:13][O:14][N+:15]([O-:17])=[O:16]>>[CH3:11][CH:12]([C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH:25][C:7]([C@@H:5]2[CH2:4][S:3][C:2](=[O:1])[NH:6]2)=[O:9])[CH2:20][CH2:19]1)[CH2:13][O:14][N+:15]([O-:17])=[O:16]
Reactant: O=C1N[C@H](C(=O)O)CS1
Reactant: CC(CO[N+](=O)[O-])[C@H]1CC[C@H](CN)CC1
Agent: Cl
Product: CC(CO[N+](=O)[O-])[C@H]1CC[C@H](CNC(=O)[C@@H]2CSC(=O)N2)CC1

Procedure:
91 mg of the desired-compound were obtained as a colorless oil using similar procedures to those in Example 3 by using 76.9 mg of (4R)-2-oxo-4-thiazolidinecarboxylic acid and 110 mg of trans-4-(1-methyl-2-nitroxyethyl)cyclohexylmethylamine hydrochloride.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][C@H:3]1[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.Cl[C:18]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>O1CCCC1>[CH3:9][O:8][C:6]([C@@H:3]1[CH2:4][CH2:5][N:2]1[C:18]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1)=[O:7]
Reactant: COC(=O)[C@@H]1CCN1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CC[C@H]2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
(S)-methyl azetidine-2-carboxylate hydrochloride (1 g, 6.60 mmol) was diluted with Tetrahydrofuran (Volume: 20 ml) and treated with TRIETHYLAMINE (0.919 ml, 6.60 mmol). The reaction mixture was stirred vigorously and sonicated periodically, until a fine suspension resulted. This was stirred for 1 h and filtered through a small plug of celite. The plug was washed well with THF (20 mL) and the combined filtrate and washes were treated with methyl 6-chloro-5-nitronicotinate (0.714 g, 3.30 mmol). The reaction mixture was concentrated in vacuo and heated briefly (5 min) to 80° C. LCMS showed complete conversion. The reaction mixture was diluted with DCM (10 mL) and purified using flash column chromatography on silica gel (80 g SiO2, 20-30% ethyl acetate in hexanes) to afford the title compound (S)-methyl 6-(2-(methoxycarbonyl)azetidin-1-yl)-5-nitronicotinate (0.90 g, 3.05 mmol, 92% yield) as a yellow oil. [M+H] calc'd for C12H13N3O6, 295; found, 295.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22](O)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: OCCc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCCc2ccccc2)c1

Procedure:
Mitsunobu reaction of phenol 58 with phenethyl alcohol gave 2-(3-(3-phenethoxyphenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.360 g, 30%): 1H NMR (400 MHz, CDCl3) δ 7.77-7.81 (m, 2H), 7.66-7.71 (m, 2H), 7.22-7.34 (m, 6H), 6.71-6.78 (m, 2H), 6.65 (dd, J=7.2, 2.0 Hz, 1H), 3.87 (t, J=6.8, 2H), 3.74 (t, J=7.2 Hz, 2H), 2.88 (t, J=6.4 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 1.98-2.06 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(N[SiH2:14][NH:15][C:16]([CH3:19])(C)C)(C)(C)C>>[F:1][C:2]1([F:8])[CH2:7][CH2:6][CH2:5][N:4]([SiH2:14][N:15]2[CH2:16][CH2:19][CH2:7][C:2]([F:8])([F:1])[CH2:3]2)[CH2:3]1
Reactant: FC1(F)CCCNC1
Reactant: CC(C)(C)N[SiH2]NC(C)(C)C
Product: FC1(F)CCCN([SiH2]N2CCCC(F)(F)C2)C1
Reaction time: 0.5 h

Procedure:
A quantity of 0.1 mol 3,3-difluoropiperidine and 0.1 mol bis(t-butylamino)silane were mixed and stirred in a flask under the protection of nitrogen. Every 4 hours, the mixture was pumped with vacuum of 100 torr for 30 minutes. After 48 hours, the end-product bis(3,3-difluoropiperidino)silane was obtained by vacuum distillation at 118° C. / 10 torr.
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]([NH:12][CH2:13][CH2:14][CH3:15])(Cl)[CH:6]=[N:7][C:8]=1[C:9]#[N:10])#[N:2].[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22][SH:23])=[CH:18][CH:17]=1.N1C=CC=CC=1.O>CC(C)=O>[C:9]([C:8]1[C:3]([C:1]#[N:2])=[N:4][C:5]([NH:12][CH2:13][CH2:14][CH3:15])=[C:6]([S:23][CH2:22][C:19]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[N:7]=1)#[N:10]
Reactant: SCc1ccccc1
Reactant: CCCNC1(Cl)C=NC(C#N)=C(C#N)N1
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCCNc1nc(C#N)c(C#N)nc1SCc1ccccc1
Yield: 30.4 %

Procedure:
2,3-Dicyano-6-n-propylamino-6-chloropyrazine (1.11 g; 0.005 mole) and 0.87 g (0.007 mole) of benzylthiol were dissolved in 50 ml of acetone. The solution was cooled to 0° to 5° C. With stirring, a solution prepared from 0.40 g (0.005 mole) of pyridine and 20 ml of water was added dropwise over the period of 30 minutes. The mixture was further stirred at 20° to 30° C. for 1 hour, and concentrated under reduced pressure to remove acetone. The residue was extracted with 100 ml of chloform. The extract was washed twice with 50 ml of water, dried over anhydrous calcium chloride, and concentrated under reduced pressure to afford a yellowish solid. Recrystallization of the solid from ethanol afforded 0.47 g (yield 30%) of 2,3-dicyano-5-n-propylamino-6-(benzylthio)pyrazine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](I)[CH3:18].C1CCCCC1.C(OCC)(=O)C>CS(C)=O>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:17][CH3:18])[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NC1CC=CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCN(C(=O)OC(C)(C)C)C1CC=CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of cyclohex-3-enyl-carbamic acid tert-butyl ester (Kampferer, P.; Vasella, A. Helvetica Chimica Acta 2004, 87, 2764-2789) (4.34 g, 22 mmol) in 20 ml of DMSO was added sodium hydride (880 mg, 60% dispersion, 22 mmol) and after one hour of stirring ethyl iodide (1.78 ml, 22 mmol). After further stirring for 2 hours at room temperature the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and brine and extracted three times with ethyl acetate. The organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and after chromatography (silica, cyclohexane/ethyl acetate=12/1) the title compound (Rf=0.30, 2.88 g, 58% yield) was obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]3([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH2:17][O:16]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH3:26]>CO>[NH2:26][CH2:17][C:15]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([OH:16])[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:25][CH2:24][C:5]1=2
Reactant: Cc1ccc2c(c1)c1c(n2CC2(c3cccnc3)CO2)CCN(C)C1
Reactant: N
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2CC(O)(CN)c2cccnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,8-Dimethyl-5-((2-(pyridin-3-yl)oxiran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.3 mmol) was dissolved in MeOH (2 mL) and aq. ammonia (2 mL) and the reaction mixture was allowed to stir at RT for 24 h. The progress of reaction was monitored by LCMS. The volatiles were removed under reduced pressure to obtain a crude oily product that was purified by reverse phase HPLC to afford 7 mg of 1-amino-3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol as TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.65 (m, 2H), 8.43 (dd, 1H), 7.75 (m, 1H), 7.18 (d, 1H), 6.88 (m, 2H), 4.67 (d, 1H), 4.55 (m, 2H), 4.29 (t, 1H), 3.90 (m, 2H), 3.69 (m, 1H), 3.5 (m, 2H), 3.1 (m, 1H), 3.11 (s, 3H), 2.34 (s, 3H). Separation by chiral HPLC provides enantiomers II-264a-b.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][C:13]([OH:15])=O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[O:28]=[C:29]1[N:35]2[CH2:36][CH2:37][C@H:34]2[C:33]2=[C:38]([C:41]([NH:43][NH2:44])=[O:42])[N:39]=[CH:40][N:32]2[C:31]2[CH:45]=[CH:46][S:47][C:30]1=2>CN(C)C=O>[O:11]=[C:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7](=[O:8])[N:9]1[CH2:12][C:13]([NH:44][NH:43][C:41]([C:38]1[N:39]=[CH:40][N:32]2[C:31]3[CH:45]=[CH:46][S:47][C:30]=3[C:29](=[O:28])[N:35]3[CH2:36][CH2:37][C@H:34]3[C:33]=12)=[O:42])=[O:15]
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Reactant: NNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)NNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.1 %

Procedure:
A solution of 5.8 g (19 mmol) of N-phthaloylglycine in 30 ml of dimethylformamide was treated at room temperature with 3.2 g (19.75 mmol) of 1,1'-carbonyldiimidazole and the mixture was subsequently heated to 50°. After 30 minutes the mixture was cooled to room temperature, 5.6 g (19.63 mmol) of (S)-8-oxo-11,11 a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno-[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide were added thereto and the mixture was stirred at room temperature for 12 hours. The suspension obtained was filtered and the colour-less powder obtained was washed with ethanol and diethyl ether. There were obtained 8.7 g (96%) of (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl)-8-oxo-11,11a-dihydro-8H,10H-azeto [1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide of m.p. >260°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[CH2:30]([O:29][C:27]([CH2:26][CH2:25][CH2:24][CH2:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:28])[CH3:31]
Reactant: CCOC(=O)CCCCBr
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCn1c(C(=O)OCc2ccccc2)cc2ccccc21
Reaction time: 0.5 h

Procedure:
Benzyl indole-2-carboxylate (10 g) was dissolved in DMF (100 ml). Sodium hydride (60% oil, 1.8 g) was added under ice-cooling, and the mixture was stirred for 30 minutes. Ethyl 5-bromopentanoate (6.7 ml) was further added and the mixture was stirred for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and hexane as an eluent to give 12.44 g of benzyl 1-(4-ethoxycarbonylbutyl)indole-2-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:19][C:20]1[CH:21]=[C:22]([CH:45]=[CH:46][C:47]=1[NH2:48])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:34]2[CH2:38][CH2:37][C:36]3([CH2:42][CH2:41][N:40]([CH2:43][CH3:44])[CH2:39]3)[CH2:35]2)=[CH:28][CH:27]=1)=[O:24]>CC(N(C)C)=O>[CH2:43]([N:40]1[CH2:41][CH2:42][C:36]2([CH2:35][N:34]([CH2:33][CH2:32][C:29]3[CH:30]=[CH:31][C:26]([NH:25][C:23]([C:22]4[CH:45]=[CH:46][C:47]5[NH:48][C:4]([C:3]6[CH:6]=[C:7]([C:10]7[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=7)[CH:8]=[CH:9][C:2]=6[OH:1])=[N:19][C:20]=5[CH:21]=4)=[O:24])=[CH:27][CH:28]=3)[CH2:38][CH2:37]2)[CH2:39]1)[CH3:44].[CH2:43]([N:40]1[CH2:41][CH2:42][C:36]2([CH2:35][N:34]([CH2:33][CH2:32][C:29]3[CH:30]=[CH:31][C:26]([NH:25][C:23]([C:22]4[CH:45]=[CH:46][C:47]5[NH:48][C:4]([C:3]6[CH:6]=[C:7]([C:10]7[C:11]([OH:16])=[N:12][CH:13]=[CH:14][CH:15]=7)[CH:8]=[CH:9][C:2]=6[OH:1])=[N:19][C:20]=5[CH:21]=4)=[O:24])=[CH:27][CH:28]=3)[CH2:38][CH2:37]2)[CH2:39]1)[CH3:44]
Reactant: CCN1CCC2(CCN(CCc3ccc(NC(=O)c4ccc(N)c(N)c4)cc3)C2)C1
Reactant: COc1ncccc1-c1ccc(O)c(C=O)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CCN1CCC2(CCN(CCc3ccc(NC(=O)c4ccc5[nH]c(-c6cc(-c7cccnc7O)ccc6O)nc5c4)cc3)C2)C1
Product: CCN1CCC2(CCN(CCc3ccc(NC(=O)c4ccc5[nH]c(-c6cc(-c7cccnc7OC)ccc6O)nc5c4)cc3)C2)C1
Temperature: 95 °C

Procedure:
A mixture of 2-Hydroxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (20 mg) and 3,4-Diamino-N-{4-[2-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenyl}-benzamide HCl salt (60 mg) in dimethylacetamide (1.5 ml) was heated at 95° C. for 3 h then cooled and purified by RP-HPLC (0.1% TFA) to afford (A) 2-[2-Hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-1H-benzoimidazole-5-carboxylic acid {4-[2-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenyl}-amide (10 mg) LCMS MH+ 617.5 as well as (B) 2-[2-Hydroxy-5-(2-hydroxy-pyridin-3-yl)-phenyl]-1H-benzoimidazole-5-carboxylic acid {4-[2-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenyl}-amide (10 mg) LCMS MH+ 603.7.
Reaction SMILES: C(O)(=O)C.C(N(CC1C=CC=CC=1)CCN)C1C=CC=CC=1.[N+:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]CCCCCCCCCC)([O-:25])=[O:24].C=O>C(O)C.C(OCC)(=O)C>[N+:23]([CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([O-:25])=[O:24]
Reactant: CCCCCCCCCCCCCCCCCC[N+](=O)[O-]
Agent: C=O
Agent: NCCN(Cc1ccccc1)Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Acetic acid (1.5 mL) was added to a solution of N,N-dibenzylethylene diamine (3.0 g, 12.5 mmol) in ethanol (25 mL) and the solution was stirred at 60° C. for 10 min A white solid formed which dissolved on heating to 80° C. Compound 3 (1.73 g, 6.25 mmol) was added and the stirring was continued at 80° C. for an additional 10 min. Paraformaldehyde (2.5. g, 88 mmol) was added to this solution in small portions over a period of 30 min and the suspension was stirred for 5 h at 80° C. Solvents were removed and the residue was treated with water. The pasty solid obtained was dissolved in ethyl acetate, washed with water and dried (Na2SO4). The oil obtained was purified by silica gel chromatography. (hexane/ethyl acetate, 9/1, 7/3). UV visible fractions were collected and evaporated to give 4 as an oil. Yield: 3.2 g (64%).
Reaction SMILES: CP(C)C.O1CCCC1.[N:10]([CH2:13][CH2:14][O:15][C:16]([C@:18]1([F:38])[C@@H:23]2[C@H:19]1[CH2:20][C@@H:21]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C@@:22]2([NH2:27])[C:24]([OH:26])=[O:25])=[O:17])=[N+]=[N-]>O1CCCC1.O>[NH2:10][CH2:13][CH2:14][O:15][C:16]([C@:18]1([F:38])[C@@H:23]2[C@H:19]1[CH2:20][C@@H:21]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C@@:22]2([NH2:27])[C:24]([OH:26])=[O:25])=[O:17]
Reactant: [N-]=[N+]=NCCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: NCCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Reaction time: 13 h
Yield: 35.4 %

Procedure:
20 μL of a 1M trimethylphosphine/tetrahydrofuran solution was added to 6 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-azidoethyl) ester dissolved in a mixture of 0.15 mL of tetrahydrofuran and 0.02 mL of water at room temperature, and the mixture was stirred for 13 hours. After the solvent was distilled under reduced pressure, the residue was purified by reverse phase column chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.), eluent: water to a 50% aqueous solution of acetonitrile), and the obtained solids were further washed with tetrahydrofuran, thereby yielding 2 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-aminoethyl) ester.