Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25](Br)=[O:26].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][NH2:35]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:24][C:25]([NH:35][CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)=[O:26])=[CH:21][CH:22]=1
Reactant: O=C(Br)CBr
Reactant: NCc1ccccn1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Cl)cc1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccc(Cl)cc1)N(CC(=O)NCc1ccccn1)CC2

Procedure:
prepared by reaction of 1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [CH:1]12[CH2:25][CH2:24][CH:4]([C:5]([C:7]3[N:12]=[C:11]4[N:13]([CH3:23])[C:14](=[O:22])[N:15]([CH2:16][CH:17]5[CH2:19][C:18]5(F)F)[C:10]4=[CH:9][CH:8]=3)=[CH:6]1)[CH2:3][NH:2]2.[O:26]1[CH:30]=[CH:29][C:28]([C:31]([OH:33])=O)=[N:27]1.[CH3:34]CN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1>[CH3:34][C:17]([CH3:18])([CH3:19])[CH2:16][N:15]1[C:10]2[C:11](=[N:12][C:7]([C:5]3[CH:4]4[CH2:24][CH2:25][CH:1]([CH:6]=3)[N:2]([C:31]([C:28]3[CH:29]=[CH:30][O:26][N:27]=3)=[O:33])[CH2:3]4)=[CH:8][CH:9]=2)[N:13]([CH3:23])[C:14]1=[O:22]
Reactant: O=C(O)c1ccon1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CCC3CN4)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4C(=O)c3ccon3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(2-Azabicyclo[2.2.2]oct-5-en-5-yl)-1-[(2,2-difluorocyclopropyl)-methyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (6-3, 40 mg, 0.12 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 21 mg, 0.18 mmol, 1.5 equiv), DIPEA (64 μL, 0.36 mmol, 3.0 equiv) and HATU (69 mg, 0.18 mmol, 1.5 equiv) were added to anhydrous 1,4-dioxane (12 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 2-7 as a white solid. MS m/z (M+H): calculated=442.1685; observed=442.1682. 1H NMR δ (ppm)(CHCl3-d): 8.41 (1H, dd, J=27.39, 1.68 Hz), 7.26-7.21 (1H, m), 7.18 (1H, dd, J=8.10, 1.54 Hz), 6.99 (1H, ddd, J=22.62, 6.35, 2.02 Hz), 6.70 (1H, dd, J=12.85, 1.68 Hz), 5.56-5.52 (0.4H, m), 5.41 (0.6H, m), 4.24-4.16 (1H, m), 3.95 (0.4H, dd, J=11.04, 2.28 Hz), 3.90-3.84 (1H, m), 3.75 (1H, dd, J=15.06, 7.88 Hz), 3.62 (0.6H, dd, J=12.35, 2.29 Hz), 3.58-3.52 (0.4H, m), 3.48 (3H, d, J=3.78 Hz), 3.36 (0.6H, d, J=12.38 Hz), 2.22-2.11 (1H, m), 2.05-1.9 (1H, m), 1.91-1.80 (1H, m), 1.61-1.46 (3H, m), 1.29-1.24 (1H, m). (Mixture of rotamers at RT)
Reaction SMILES: [N:1]1([CH:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[C:11]([CH3:18])=[N:10]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].[NH2:27]OS(O)(=O)=O>O>[NH2:27][N:13]1[C:14]2[C:9](=[CH:8][C:7]([CH:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=2)[N:10]=[C:11]([CH3:18])[C:12]1=[O:17]
Reactant: NOS(=O)(=O)O
Reactant: Cc1nc2cc(C(c3ccccc3)n3ccnc3)ccc2[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cc(C(c3ccccc3)n3ccnc3)ccc2n(N)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
A mixture of 5 parts of 6-[(1H-imidazol-1-yl)phenylmethyl]-3-methyl-2(1H)-quinoxalinone, 3.3 parts of sodium hydroxide and 30 parts of water was stirred for 1 hour at room temperature. 5 Parts of hydroxylamine-O-sulfonic acid were added and the reaction mixture was stirred for 4 hours at 20° C. The product was extracted with dichloromethane (3×65 parts). The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off and dried, yielding 2 parts (38.2%) of 1-amino-6-[(1H-imidazol-1-yl)phenylmethyl]-3-methyl-2(1H)-quinoxalinone; mp. 192.8° C. (comp. 85).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH:5]=O.[C:22]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH2:22])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Temperature: 100 °C
Yield: 79.5 %

Procedure:
To a stirred solution of 3-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (2.8 g, 8.2 mmol) in 1,4-dioxane (30 mL) were added K2CO3 (1.68 g, 12.24 mmol) and methyl triphenyl phosphonium bromide (4.37 g, 12.24 mmol) at ambient temperature. Then the resultant reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as a white solid (1.94 g, 70%): mp 141-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.70 (m, 2H), 7.41 (m, 1H), 7.21 (m, 2H), 6.71 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.23 (d, J=10.8 Hz, 1H), 4.92 (s, 2H); ESIMS m/z 298.10 ([M−H]−)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[Li]CCCC.[CH2:17]1[O:20][CH:18]1[CH3:19]>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[CH2:17][CH:18]([OH:20])[CH3:19]
Reactant: CC1CO1
Reactant: FC(F)(F)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)Cc1c(Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-3-(trifluoromethyl)benzene (1.0 g, 5.5 mmol) in THF (10.0 mL) was added 2.5 M of n-BuLi in hexane (2.2 mL) at −78° C. and stirred for 1 h. Propylene oxide (370 mg, 6.4 mmol) was added to the reaction mixture at −78° C. and slowly warmed to rt. The reaction mixture was stirred for an additional 30 min. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a yellow oil. The material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to yield the desired product as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ=1.33 (d, J=6.1 Hz, 3H), 1.40 (d, J=6.3 Hz, 1H), 3.08-3.22 (m, 2H), 4.21-4.33 (m, 1H), 7.29-7.34 (m, 1H), 7.58-7.64 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22]CC[C@H:19]([NH:23][C:24](=O)OC(C)(C)C)[CH2:18]4)[CH:14]=[CH:13][CH:12]=3)=[N:9][N:8](C3CCCCO3)[C:5]2=[CH:6][N:7]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[C:15]([N:17]5[CH2:22][CH2:24][NH:23][CH2:19][CH2:18]5)[N:16]=4)=[N:9][NH:8][C:5]3=[CH:6][N:7]=2)[CH2:40][C:39]1=[O:44]
Reactant: CN1CCNCC1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(Br)cc34)n2)C1
Product: CN1CCN(c2cc3c(-c4cccc(N5CCNCC5)n4)n[nH]c3cn2)CC1=O
Yield: 28 %

Procedure:
Following the procedure of Example 224, tert-butyl (3S)-1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate and 1-methylpiperazin-2-one were reacted and deprotected by the procedure of Example 229. The mixture was purified by lyophilization from water and trituration of the crude product with cold methanol. The solid material was collected by filtration to afford 52 mg (28%) of 223 over two steps. ESI MS m/z 393.2 (M+1). 1H NMR (400 MHz, DMSO) δ 13.55 (s, 1H), 9.07 (s, 2H), 8.81 (s, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.52 (d, J=7.5 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 3.95 (s, 2H), 3.88 (m, 6H), 3.48-3.44 (m, 2H), 3.31 (s, 4H), 2.91 (s, 3H)
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl.[NH:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1>C(#N)C>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:18]2[CH2:21][CH:20]([OH:22])[CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OC1CNC1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Temperature: 60 °C
Yield: 71.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with acetonitrile (50 mL), 5-fluoro-2-nitropyridine (1.2 g, 7.9 mmol), K2CO3 (2.1 g, 15.8 mmol), and azetidin-3-ol hydrochloride (1.3 g, 11.9 mmol). The mixture was heated at 60° C. for 1 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 20:1) to afford 147a (1.1 g, 73%) as a yellow solid. MS-ESI: [M+H]+ 196.0.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].I[CH2:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].O>CN(C)C=O>[S:1]([CH2:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]#[N:3]
Reactant: O=C1N[C@H](CI)[C@@H]1N1C(=O)c2ccccc2C1=O
Reactant: N#C[S-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CSC[C@H]1NC(=O)[C@H]1N1C(=O)c2ccccc2C1=O
Reaction time: 2 h

Procedure:
1.5 g of potassium thiocyanate were added at 75° C. with stirring to a mixture of 1.78 g of the product of Step A in 5 ml of dimethylformamide and the mixture was stirred for 31/2 hours and was poured into water. The mixture was vacuum filtered and the product was washed with water and dried. The product was empasted with hot isopropyl ether, vacuum filtered and dried to obtain 1.25 g of racemate of cis 4-thiocyanatomethyl-3-phthalimido-2-oxo-azetidine.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:20])[CH2:15][S:16][C:17](=O)[CH3:18])([CH3:3])[CH3:2].CO.[OH-].[Na+].BrCC[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40][CH2:39]1>C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:20])[CH2:15][S:16][CH2:17][CH2:18][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:40][CH2:39]1)([CH3:3])[CH3:2]
Reactant: CC(=O)SCC(=O)Nc1c(C(C)C)cccc1C(C)C
Reactant: BrCCCCCCCCCCCCN1CCN(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CSCCCCCCCCCCCCN1CCN(c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a mixture of 1.47 g of N-(2,6-diisopropylphenyl)-2-(acetylthio)acetamide and 12 ml of methanol was added dropwise 1.7 ml of a 30% aqueous sodium hydroxide solution at 0° C. in an argon atmosphere. After stirring for 30 minutes, a mixture of 2.05 g of 1-bromo-12-(4-phenylpiperazinyl)dodecane synthesized in (1) above and 14 ml of methanol was added thereto, followed by stirring at 60° C. for 1 hour and then at room temperature for 16 hours. To the reaction mixture was added 100 ml of ethyl acetate, and the mixture was washed successively with water and a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography using a 1:2 mixture of ethyl acetate and hexane as a developing solvent. The resulting crystals were recrystallized from isopropyl alcohol-water to yield 1.66 g of the title compound as white powder (m.p.=76.5° -77.5° C.).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:10]1[C:4]2[C:3]3[C:11](=[O:12])[NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[O:20][C:2]=3[S:6][C:5]=2[CH2:7][CH2:8][CH2:9]1
Reactant: O=C(Nc1ccccc1O)c1c(Br)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1Nc2ccccc2Oc2sc3c(c21)CCCC3
Temperature: 140 °C
Reaction time: 4 h
Yield: 51.4 %

Procedure:
To a solution of 2-bromo-4,5,6,7-tetrahydro-N-(2-hydroxyphenyl)-benzo[b]thiophene-3-carboxamide (5.3 g) in dimethyl sulfoxide (50 ml) was added potassium carbonate (4.2 g) and the mixture was stirred at 140° C. for 4 hours. The completion of the reaction was confirmed by thin layer chromatography. The mixture was cooled to room temperature and the reaction mixture was poured into water (300 ml). After neutraliation with hydrochloric acid, the mixture was extracted twice with chloroform and washed with saturated brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one (2.1 g).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.O[CH2:13][C:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>Br.O>[N:16]1[CH:15]=[C:14]([CH2:13][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=3[N:3]=2)[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: OCc1cnc2ccccn12
Reactant: Cc1ccc2nc(S)[nH]c2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2[nH]c(SCc3cnc4ccccn34)nc2c1
Temperature: 25 °C

Procedure:
A mixture of 903 mg (5.5 mmole) of 2-mercapto-5-methylbenzimidazole and 805 mg (5.4 mmole) of 3-hydroxymethylimidazo[1,2-a]pyridine (prepared as in Example 1) was dissolved in 10 ml of 48% aqueous hydrobromic acid and 10 ml of acetic acid and heated to reflux. After being cooled to room temperature, the mixture was poured into water and made alkaline with potassium carbonate. The oil that separated was extracted into dichloromethane, washed with water, dried over magnesium sulfate, filtered, and concentrated to an oil that crystallized on standing. The solid was collected by filtration, washed with diethyl ether, and air dried to yield the title compound as 610 mg of analytically pure solid. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].Br[CH:15]1[CH2:20][CH2:19][O:18][C:16]1=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>O>[F:6][C:7]1[CH:8]=[C:9]([NH:10][CH:15]2[CH2:20][CH2:19][O:18][C:16]2=[O:17])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1OCCC1Br
Reactant: Nc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OCCC1Nc1cccc(F)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A dimethylformamide solution (20 ml) of 1.93 ml of 3-fluoroaniline, 4.60 ml of α-bromo-γ-butyrolactone and 4.24 g of sodium carbonate was heated with stirring at 80° C. for 15 hours. The reaction liquid was cooled to room temperature, diluted with water and extracted with ether. The ether extract was dried over anhydrous magnesium sulfate, and thereafter the solvent was distilled off to provide 4.64 g of crude 3-[(3-fluorophenyl)amino]-dihydrofuran-2(3H)-one as a pale yellow, oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:53](O)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:53]([O:23][C:22]([C:21]1[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]2[C:19]([C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=2)=[O:24])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: OCc1ccccc1
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)OCc2ccccc2)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
To a mixture of 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (190 mg), triphenylphosphine (130 mg), benzyl alcohol (52 μl) and THF (6.0 ml) was added diethyl azodicarboxylate (86 μl) at 0° C. with stirring, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, the residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-3/2) to give 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid benzyl ester as a colorless powder.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:35](O)[CH2:36][OH:37].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([N:5]([CH2:35][CH2:36][OH:37])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: OCCO
Reactant: CCCCNS(=O)(=O)c1ccc(C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCN(CCO)S(=O)(=O)c1ccc(C)cc1

Procedure:
Dissolve N-butyl-4-methyl-benzenesulfonamide (10 mmol) in tetrahydrofuran (50 mL) and add triphenylphosphine (10 mmol). Treat this with ethylene glycol (10 mmol) followed by addition of diethyl azodicarboxylate (10 mmol). Stir the reaction at 25° C. for 18 hours. Concentrate the reaction under vacuum. Purify the residue by flash chromatography (silica gel, toluene/ethyl acetate) to provide N-butyl-N-(2-hydroxy-ethyl)-4-methyl-benzenesulfonamide.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:28]=[C:27]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[C:26]([Cl:39])=[C:25]3[C:20]=2[CH2:21][CH2:22][CH2:23][O:24]3)[O:7][C@@H:6]1[CH2:40][O:41]C(=O)C)(=O)C.C[O-].[Na+].CC(O)=O>CO>[Cl:39][C:26]1[C:27]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][CH:35]=2)=[CH:28][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:40][OH:41])[O:7]2)=[C:20]2[C:25]=1[O:24][CH2:23][CH2:22][CH2:21]2
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(C4CC4)cc3)c(Cl)c3c2CCCO3)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@H]1O[C@@H](c2cc(Cc3ccc(C4CC4)cc3)c(Cl)c3c2CCCO3)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a suspension of acetate 180 (152 mg, 0.24 mmol) in MeOH (5 mL) was added NaOMe (25 wt % in MeOH, 0.05 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Glacial AcOH was added to the mixture to acidify the mixture. The mixture was concentrated under reduced pressure. The residue was purified by prep HPLC (reverse phase) to provide the compound E155 (37 mg, 34%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([OH:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:1]([CH:3]1[CH2:7][CH:6]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Reactant: CCOC(=O)C1CC(O)CC1CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CCOC(=O)C1CC(OCc2ccc(OC)cc2)CC1CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a mixture of ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (37.78 g, 203 mmol, Preparation #P.1) in DCM (100 mL) and cyclohexane (200 mL) at about 0° C. was added 4-methoxybenzyl 2,2,2-trichloroacetimidate (93.58 g, 331 mmol) followed by dropwise addition of trifluoromethanesulfonic acid (1.6 mL, 18.0 mmol) over about 35 min. The reaction mixture was stirred at about 0° C. for about 30 min. The ice bath was removed and the reaction mixture was stirred at ambient temperature for about 16 h. The suspension was poured into ice-water (500 mL) and stirred for about 30 min. The solid was removed by filtration while washing with DCM (100 mL). The layers in the filtrate were separated and the aqueous layer was extracted with DCM (3×200 mL). The combined organic layers were washed with water (200 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified using silica gel chromatography eluting with a gradient of 0-100% DCM:EtOAc (95:5) in DCM to give ethyl 2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate (39.80 g, 64%): LC/MS (Table 1, Method b) Rt=2.90 min; MS m/z: 307 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][NH:9][C:10]([C:12]1[CH:49]=[CH:48][C:15]([O:16][C:17]2[C:22]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])=[CH:21][CH:20]=[C:19]([O:37][C:38]3[CH:43]=[CH:42][C:41]([C:44](=[NH:47])[NH:45][OH:46])=[CH:40][CH:39]=3)[N:18]=2)=[CH:14][CH:13]=1)=[NH:11].[C:50](O)(=[O:52])[CH3:51]>>[C:1]([N:9]([OH:8])[C:10]([C:12]1[CH:49]=[CH:48][C:15]([O:16][C:17]2[C:22]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])=[CH:21][CH:20]=[C:19]([O:37][C:38]3[CH:43]=[CH:42][C:41]([C:44](=[NH:47])[N:45]([OH:46])[C:50](=[O:52])[CH3:51])=[CH:40][CH:39]=3)[N:18]=2)=[CH:14][CH:13]=1)=[NH:11])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: N=C(NO)c1ccc(Oc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)c(Oc3ccc(C(=N)NO)cc3)n2)cc1
Product: CC(=O)N(O)C(=N)c1ccc(Oc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)c(Oc3ccc(C(=N)N(O)C(C)=O)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
Acetic anhydride (0.12 ml, 1.25 mmol) was added dropwise to a solution of 2,6-bis-(4-(N-hydroxycarbamimidoyl)-phenoxy)-3-(2-naphthyl-sulphonamido)-pyridine (0.35 g, 0.59 mmol) in 5 ml of acetic acid at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to afford 0.3 g (51.0%) of the crude product which was used for the next step without further purification. M+=LCMS (+ve mode) 668.1+1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[O:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[CH:23][C:6]1=2
Reactant: OC1CCOCC1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(OC3CCOCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and tetrahydropyran-4-ol.