Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[NH:10][C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([OH:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[NH2:41][C@@H:42]([CH3:61])[C:43]([N:45]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:46][CH:47]([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])=[O:44]>ClCCl>[CH2:54]([N:45]([CH2:46][CH:47]([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])[C:43](=[O:44])[C@@H:42]([NH:41][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][C:9]([NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:19])=[O:18])[CH3:61])[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1
Reactant: O=C(NCc1ccccc1)Nc1ccsc1C(=O)O
Reactant: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)N)OCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)NC(=O)c1sccc1NC(=O)NCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a solution of 3-(3-benzylureido)thiophene-2-carboxylic acid (Compound V-1) 49.7 mg (0.18 mmol) and N-hydroxybenzotriazol 6.1 mg (0.045 mmol) in dichloromethane 1 ml, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 43.1 mg (0.225 mmol) was added and the mixture was stirred at room temperature for 0.5 hr. A solution of (S)-2-amino-N-benzyl-N-(2,2-diethoxyethyl)propanamide (Compound VI-1) 44.2 mg (0.15 mmol) in dichloromethane 1 ml was added to the reaction mixture and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was washed with sat. NaHCO3 aq. 1 ml, water 1 ml and brine 1 ml. The organic phase was filtered on celite 1 g and magnesium sulfate 150 mg. The mother solution was concentrated in vacuo and the residue was purified with PTLC (development solvent: chloroform:methanol=98:2) to obtain the titled compound 44.7 mg (54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:13]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:15])=[O:14].[C:36]1(C)C=CC=C[CH:37]=1>>[CH2:36]([O:15][C:13](=[O:14])[CH2:16][C:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=2[O:10][CH:9]=1)[CH3:37]
Reactant: COc1cccc2c1OCC2=O
Reactant: Cc1ccccc1
Reactant: O=C(O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)Cc1coc2c(OC)cccc12

Procedure:
A mixture of 7-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, the reaction mixture was concentrated and loaded over silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, ethyl(7-methoxy-1-benzofuran-3-yl)acetate was obtained as a white oil. Yield: 1.9 g (81%); 235 (M+H).
Reaction SMILES: [CH:1]1([C:6]([O:8]C)=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:1]1([CH2:6][OH:8])[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: BrCCCCCCOC1CCCCO1
Reactant: COC(=O)C1CC=CC1
Product: OCC1(CCCCCCOC2CCCCO2)CC=CC1

Procedure:
The above procedure was repeated except that methyl cyclopent-3-ene carboxylate (prepared as described by A. H. Schmid and A. W. Wolkoff, J. Org. Chem. 32, 254 (1967)) was used with the 6-tetrahydropyranyloxyhexyl bromide of part D of this example and 1-(6-tetrahydropyranyloxyhexyl)-1-hydroxymethylcyclopent-3-ene was obtained as an oil (IR 3400, 3010 cm-1, nmr τ 4.4, 5.4, 6.35, 7.8, 8.5).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)=[N:4][N:3]=1.[C:22](=[N:24]S(Cl)(=O)=O)=[O:23].O>CCOCC>[CH3:16][C:13]([C:11]1[CH:12]=[C:7]([C:5]2[S:6][C:2]([NH:1][C:22]([NH2:24])=[O:23])=[N:3][N:4]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[OH:17])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2nnc(N)s2)cc(C(C)(C)C)c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1cc(-c2nnc(NC(N)=O)s2)cc(C(C)(C)C)c1O
Yield: 53.8 %

Procedure:
A suspension of 4-(5-amino-1,3,4-thiadiazol-2-yl)-2,6-bis(1,1-dimethylethyl)-phenol (1.0 g, 0.0032 mole) in ether (5 ml) is added to a 0° C. solution of N-carbonylsulfamyl chloride (0.46 g, 0.0032 mole) in ether (5 ml). The resulting mixture is stirred 15 minutes before water (10 ml) is added. The mixture is diluted with ether and washed with 2M HCl and saturated aqueous NaCl. Extract with aqueous 1M NaOH (3×). The combined aqueous layers are made acidic with aqueous 2M HCl. The resulting precipitate is filtered and washed with water to provide 0.6 g (1.2 g theor., 53%) of N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl]-urea after drying in vacuo at 50° C; mp >270° C.
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:33])N(C)[C:14](=[O:31])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:17]=2)=[CH:3]1.[OH-:34].[K+]>CCO.O>[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])[O:33][C:14](=[O:31])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:17]=2)=[CH:3]1
Reactant: CN1C(=O)C(c2cccc(OCCN3CCOCC3)c2)=C(c2cn(C)c3ccccc23)C1=O
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cn1cc(C2=C(c3cccc(OCCN4CCOCC4)c3)C(=O)OC2=O)c2ccccc21
Temperature: 25 °C

Procedure:
3-(1-Methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)phenyl]-1-methylpyrrole-2,5-dione (0.22 g, 0.5 mmol) was dissolved in EtOH (10 mL) and a solution of KOH (1.5 g) in H2O (2.5 mL) was added. After the reaction mixture was refluxed for 3 h, it was cooled to room temperature, followed by evaporation of EtOH. The residue was acidified with aq. HCl to pH=4.5. The product was extracted with EtOAc and the EtOAc layer was dried over sodium sulfate and concentrated to give 3-(1-methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)phenyl]furan-2,5-dione which was in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].II.C(OC)=[O:11].Cl.[CH3:15][CH2:16][CH2:17]CCC>C(OCC)C.C(OCC)(=O)C>[CH2:7]=[CH:6][CH2:5][CH2:4][CH:3]([OH:11])[CH2:2][CH2:15][CH:16]=[CH2:17]
Reactant: CCCCCC
Reactant: C=CCCCCBr
Reactant: COC=O
Agent: Cl
Agent: II
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=CCCC(O)CCC=C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A 300 ml-capacity three neck flask containing a stirring bar and Mg (8 g, 16.3 mmol) and connected to a condenser was sufficiently dried. Then, a nitrogen atmosphere was established in the flask, and diethyl ether (24.5 ml) and I2 were introduced into the flask. When a solution of 1-bromo-3-butene (7) (22 ml, 16.3 mmol) in diethyl ether (24.5 ml) was slowly added to the brown suspension thus obtained, a reaction started, and a color of I2 disappeared. After generation of a Grignard reagent, HCOOMe (9.78 ml, 16.3 mmol) was slowly dropped into the flask, and the mixture thus obtained was stirred for 30 minutes. Subsequently, when generation of alcohol was recognized by thin-layer chromatography (hexane:ethyl acetate=10:1), diluted hydrochloric acid was added to the mixture to stop the reaction. After cooling the mixture, an organic layer was separated and extracted with ethyl acetate. This organic layer was dehydrated over Na2SO4 and filtered. The solvent was distilled off, and the organic layer was purified by flash chromatography on silica gel (hexane:ethyl acetate=10:1). Thus, 1,8-nonadiene-5-ol (8) (11.613 g, 8.3 mmol, yield: 51%) was obtained as an intended compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+].O>CN1CCN(C)C1=O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[N+:12]=[N-:13]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: N#Cc1ccc(CN=[N+]=[N-])cc1
Yield: 96.7 %

Procedure:
50 g of 4-bromomethylbenzonitrile is dissolved in 350 ml of 1,3-dimethyl-2-imidazolidinone and stirred at 25° for 2 hours with 32.5 g of sodium azide. The mixture is subsequently combined with 500 ml of water under ice cooling, extracted twice with dichloromethane, washed with water, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, thus obtaining 39 g of 4-azidomethylbenzonitrile as a colorless liquid.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH:6]([CH3:11])[CH2:7][C:8]([OH:10])=O)[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[N:40]=[C:39]([NH:41][NH2:42])[CH2:38][N:37]=[C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])[C:35]=2[CH:50]=1>O1CCCC1>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[N:40]=[C:39]([NH:41][NH:42][C:8](=[O:10])[CH2:7][CH:6]([N:5]3[C:1](=[O:17])[C:2]4=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]4[C:4]3=[O:12])[CH3:11])[CH2:38][N:37]=[C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])[C:35]=2[CH:50]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reactant: CC(CC(=O)O)N1C(=O)c2ccccc2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(CC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)N1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 20, 3-phthalimidobutyric acid and carbonyldiimidazol are reacted in tetrahydrofuran. To this mixture is added 7-chloro-2-hydrazino-5-(o-fluorophenyl)-3H-1,4-benzodiazepine to give 3-phthalimidobutyric acid 2-[7-chloro-5-(o-fluorophenyl)-3H-1,4-benzodiazepin-2yl]hydrazide which is warmed with acetic acid to give N-[2-[8-chloro-6-(o-fluorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepin-1-yl]propyl]phthalimide
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1([C:13]([OH:15])=O)[CH2:12][CH2:11]1.[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[C:32]([C:34]2[CH:35]=[C:36]([NH:41][C:42]3[N:47]=[C:46]([CH:48]([F:50])[F:49])[CH:45]=[CH:44][N:43]=3)[CH:37]=[C:38]([CH3:40])[CH:39]=2)[CH:31]=[N:30]1>ClCCl>[F:50][CH:48]([F:49])[C:46]1[CH:45]=[CH:44][N:43]=[C:42]([NH:41][C:36]2[CH:35]=[C:34]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][CH2:27][NH:26][C:13]([CH:10]4[CH2:12][CH2:11]4)=[O:15])[CH:33]=3)[CH:39]=[C:38]([CH3:40])[CH:37]=2)[N:47]=1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CCN)c2)c1
Reactant: O=C(O)C1CC1
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CCNC(=O)C3CC3)c2)c1
Reaction time: 0.17 h

Procedure:
Dichloromethane (1 mL) and N,N-diisopropylethylamine (0.087 mL, 0.50 mmol) were added to a vial containing cyclopropanecarboxylic acid (17.2 mg, 0.2 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.025 g, 0.15 mmol). The reaction mixture was stirred for 10 minutes and N-(3-(1-(2-amino ethyl)-1H-pyrazol-4-yl)-5-methylphenyl)-4-(difluoromethyl)pyrimidin-2-amine hydrochloride (38 mg, 0.10 mmol) was added. The reaction mixture was stirred for two hours and then concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile/water with 0.1% TFA modifier) to afford N-(2-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)ethyl)cyclopropanecarboxamide. MS ESI calc'd. for C21H23F2N6O [M+H]+ 413. found 413. 1H NMR (600 MHz, DMSO): δ 9.78 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.76 (s, 1H), 7.29 (s, 1H), 7.01 (d, J=4.9 Hz, 1H), 7.00 (s, 1H), 6.80 (t, J=54.5 Hz, 1H), 4.13 (t, J=6.2 Hz, 2H), 3.44 (q, J=6.0 Hz, 2H), 2.25 (s, 3H), 1.47-1.45 (m, 1H), 0.61-0.59 (m, 4H).
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH3:11])=[O:9].[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1.O>CN(C)C=O>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:8](=[O:9])[O:10][CH3:11])=[C:25]([CH3:30])[CH:24]=1
Reactant: Cc1cc(OCc2nc3ccccc3s2)ccc1N
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1C
Reaction time: 2 h
Yield: 54 %

Procedure:
82.5 ml of pyridine and 18.9 ml of methyl chloroformate were added to a solution of 55.0 g of 4-(benzothiazol-2-ylmethoxy)-2-methylaniline [prepared as described in step (b) above] in 400 ml of dimethylformamide cooled in an ice-water bath and the resulting mixture was stirred at the same temperature for 2 hours. At the end of this time, the reaction mixture was poured into water resulting in the precipitation of a crystalline solid which was washed with water and then further washed with diethyl ether to give a crude crystalline solid. This was recrystallised from a 4:1 by volume mixture of tetrachloromethane and acetone to give 36.2 g (yield 54%) of the title compound as a solid having a melting point of 147° to 149° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].Cl>O1CCCC1.C(OCC)(=O)C.CCCCCC>[C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:21]=[O:22])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 22.84 g (95.0 mmol) of 3-bromobiphenyl in 280 ml of dry tetrahydrofuran was added 61 ml (99.8 mmol) of n-butyllithium (1.64 mol/liter, n-hexane solution) at −70 ° C. under an atmosphere of nitrogen. The mixture was stirred at the same temperature for 1 hour, and to this was added dropwise 36.55 g (0.50 mol) of N,N-dimethylformamide. The resultant mixture was stirred overnight, while being slowly warmed to room temperature. To the reaction solution was added 400 ml of about 5% aqueous hydrochloric acid, and the mixture was stirred for 2 hours at room temperature. The mixture was extracted with tert-butyl methyl ether, and the organic layer was washed with an about 5% aqueous solution of sodium bicarbonate and water, then dried and concentrated. The residue was subjected to silica gel column chromatography (eluted with n-hexane, then n-hexane:ethyl acetate=15:1) to obtain 13.95 g (76.56 mmol) of 3-phenylbenzaldehyde.
Reaction SMILES: [Br:1]Br.[Br-:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH2:13][P+:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[Br-:1].[Br:3][C:10]1[C:5]([OH:4])=[C:6]([CH2:13][P+:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=1
Reactant: BrBr
Reactant: COc1ccc(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Solvent: CO
Product: COc1cc(Br)c(O)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 2 h
Yield: 76 %

Procedure:
In the course of 1.5 hours, at 5°, 16 g of bromine are added dropwise to a solution of 50 g of [(2-hydroxy-5-methoxy-phenyl)methyl]-triphenyl-phosphonium bromide in 11 of methanol. The solution is then concentrated in vacuo at 20° to 130 ml, 250 ml of ethyl acetate are added thereto in the course of 2 hours, the resulting yellow suspension is stirred for 2 hours at 0°, and the slightly yellow crystals are filtered off with suction and recrystallised from methanol. [(3-Bromo-2-hydroxy-5-methoxy-phenyl)-methyl]-triphenyl-phosphonium bromide is thus obtained in the form of colourless crystals [m.p.: 259°; IR (KBr): 2875, 1585, 1565, 1415, 1325, 1200, 1165, 1150 cm-1 ; 1H-NMR (360 MHz), DMSO-d6); 3.43 (s, 3H, OCH3), 5.03 (d, 2H, CH2P+), 6.42 (dd, 1H), 7.08 (dd, 1H, 7.61 to 7.80 (m, 12H), 7.92 (m, 3H), 9.00 (br, s, 1H, OH) ppm]; yield 76% of the theoretical yield
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:25]1[CH2:28][C:27]([CH2:31][NH2:32])([CH2:29][NH2:30])[CH2:26]1>>[NH2:30][CH2:29][C:27]1([CH2:31][NH:32][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:28][O:25][CH2:26]1
Reactant: NCC1(CN)COC1
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(NCC3(CN)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (s, 1 H), 7.86-7.75 (m, 3 H), 7.59-7.51 (m, 3 H), 7.67 (t, J=3.6 Hz, 1 H), 7.57 (d, J=2.1 Hz, 1 H), 6.22 (s, 1 H), 5.45 (d, J=16.4 Hz, 1 H), 5.10 (brs, 1 H), 4.76 (brs, 1 H), 4.60 (m, 4 H), 3.94 (d, 2 H), 4.52 (s, 2 H), 3.47 (s, 2 H), 2.46 (s, 3 H).
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:27][S:28]([O:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:42](=[NH:44])[NH2:43])[CH:38]=2)[CH:33]=1)(=[O:30])=[O:29]>N1C=CC=CC=1>[CH3:27][S:28]([OH:31])(=[O:30])=[O:29].[O:1]([CH2:8][C:9]([O:11][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:42](=[NH:43])[NH2:44])[CH:38]=2)[CH:33]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Product: N=C(N)c1ccc2cc(OC(=O)COc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a solution of 1.1 g of phenoxyacetic acid in 50 ml of pyridine, was added 2.2 g of DCC. The mixture was stirred at room temperature for 30 minutes, then admixed with 2.0 g of 6-amidino-2-naphthol methanesulfonate, and again stirred overnight at room temperature. The insolubles were removed by filtration, 500 ml of ethyl ether was added to the mother liquor and thoroughly stirred to precipitate a solid substance which was collected by filtration and recrystallized three times from methanol to obtain 0.3 g of 6-amidino-2-naphthyl phenoxyacetate methanesulfonate.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH:3]=1.[BH4-].[Na+].CC[O:13][CH2:14][CH3:15]>>[CH2:14]([O:13][CH:7]1[CH2:6][CH:5]2[O:8][C:2]1([CH3:1])[CH2:3][CH2:4]2)[C:15]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CC1=CCC(=O)CC1
Reactant: CCOCC
Agent: [BH4-]
Agent: [Na+]
Product: CC12CCC(CC1OCc1ccccc1)O2

Procedure:
By procedures similar to those described in Embodiment 3, (+)-2-exo-hydroxy-1-methyl-7-oxabicyclo[2.2.1]heptane was prepared by treatment of 4-methyl-3-cyclohexen-1-one with sodium borohydride followed by epoxidation-cyclization and ether formation to yield the desired product, b.p. 100°-101° C. (0.2 mm).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16](O)=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][C:36]1[C:41]([NH2:42])=[CH:40][CH:39]=[CH:38][C:37]=1[OH:43]>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[NH:35][C:36]3[C:37]([OH:43])=[CH:38][CH:39]=[CH:40][C:41]=3[N:42]=2)[N:8]([C:6]([C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:31][CH:30]=2)=[O:7])[CH2:12]1
Reactant: Nc1cccc(O)c1N
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](c2nc3cccc(O)c3[nH]2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 2,3-diaminophenol, the title compound was obtained in 91% purity by HPLC. MS(ESI+): m/z=441.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>ClCCl>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH:3]=2)[NH:7]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)CC(=O)N2
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: -30 °C
Yield: 90 %

Procedure:
A stirred solution of 5-amino-1,3-dihydro-indol-2-one (2 g, 13.5 mmol, prepared according to U.S. Pat. No. 6,114,371) in 30 ml of dichloromethane was added with tirethylamine (1.9 ml). The solution was cooled down to −30° C. in an acetone-dry ice bath and added with methanesulfonyl chloride (1 ml, 13.5 mmol) dropwise. Upon the completion of the addition, the resulting mixture was heated at 45° C. for 1 hour until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-methanesulfonamide (2.7 g, 90%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N+:9]([O-])=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[CH:12]=2.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:28]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=[O:28])[C:11]2[CH:12]=[C:13]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[N:14]=[CH:15][C:16]=2[CH:17]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(Nc1cc2c[n+]([O-])c(-c3ccccc3Cl)cc2cn1)C1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2c(=O)[nH]c(-c3ccccc3Cl)cc2cn1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
To a slurry of 3-(2-chlorophenyl)-7-(cyclopropanecarboxamido)-2,6-naphthyridine 2-oxide (50 mg, 0.1 mmol) in tetrahydrofuran (0.5 mL) at 0° C. was added trifluoroacetic anhydride (0.04 mL, 0.29 mmol) dropwise over 2 minutes. The mixture was allowed to warm to room temperature and stir for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as a yellow solid (10 mg, 20%). 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 10.33 (s, 1H), 9.51 (s, 1H), 8.86 (s, 1H), 8.54 (s, 1H), 7.62-7.52 (m, 1H), 7.53-7.38 (m, 3H), 2.08 (m, 1H), 0.88 (m, 4H). LCMS (Method E): RT=3.759 min, M+H+=340.0.