Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13]([CH:16]=[CH:17][CH2:18]Cl)[CH2:14][S:15][C@H:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:38].[Na+].[C:40]([NH2:48])(=[O:47])[C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>CC(C)=O.CN(C)C=O>[I-:38].[CH:1](=[N:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13]([CH:16]=[CH:17][CH2:18][N+:44]3[CH:45]=[CH:46][C:41]([C:40](=[O:47])[NH2:48])=[CH:42][CH:43]=3)[CH2:14][S:15][C@H:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccncc1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C=CCCl)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1cc[n+](CC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N=Cc4ccccc4)[C@H]3SC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a chilled mixture of the 3-chloropropenylcephem XVII (Z isomer) (16.4 g) in acetone (5 ml), was added dropwise a solution of sodium iodide (6.3 g, 42 mmole) in acetone (30 ml) over 10 minutes under nitrogen atmosphere, and the mixture was stirred at room temperature. The reaction was monitored by the ratio of uv absorption [E1 cm1% (255 nm)/E1 cm1% (320 nm)]. When the ratio reached below 1.30 (after 45 minutes), the mixture was diluted with carbon tetrachloride (400 ml), and allowed to stand at room temperature. When the ratio came to below 1.10 (after 3 hours), the mixture was concentrated to a half its volume. The concentrate was treated with a small amount of charcoal and diatomaceous earth, and filtered. The filter cake was washed with a 1:1 mixture (100 ml) of methylene chloride and carbon tetrachloride. To the combined solution of the filtrate and washings, was added a solution of isonicotinamide (3.5 g, 28.7 mmole) in dimethylformamide (20 ml) and the mixture was concentrated under reduced pressure. The concentration was allowed to stand at room temperature for 1.5 hours and washed with isopropyl ether (100 ml×3). The residual brown semi-solid was dissolved in methylene chloride (50 ml) and the solution was added dropwise, with stirring, to ethyl acetate (1.5 L). The resulting precipitate was collected by filtration and washed with ethyl acetate (200 ml). After drying over phosphorous pentoxide in vacuo, 17 g of the title compound XXI-H (E isomer) was obtained. Yellow amorphous powder. M.p. 150°-155° C. (dec.). Estimated purity 80% by nmr.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[CH3:33][N:34]=[C:35]=[O:36]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:35]([NH:34][CH3:33])=[O:36])[CH2:28][CH2:27]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: CN=C=O
Reactant: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Solvent: ClCCl
Product: CNC(=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 47 h
Yield: 84.8 %

Procedure:
1-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-[(4-piperidinyl)acetyl]piperazine (Preparative Example 10) (500 mg, 0.9 mmoles) was dissolved in anhydrous dichloromethane (5 ml) and methyl isocyanate (220.3 mg, 3.6 mmoles) was added. The mixture was stirred under argon at 25° C. for 47 h. Additional methyl isocyanate (110.15 mg, 1.8 mmoles) was added and the reaction was stirred for a total of 144 h. The solution was heated at 74° C. for 5 h and the stirred at 25° C. for an additional 24 h. The solution was chromatographed on silica gel using 2% (10% conc. NH4OH in methanol)dichloromethane as the eluant to give 438.9 mg of the title compound (Yield: 79%).
Reaction SMILES: [C:1]([BH3-])#N.[Na+].C1COCC1.[CH:10]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:49]([NH:51][S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:54])=[O:53])=[O:50])=[CH:21][C:22]=3[N:23]3[CH2:29][C:28]([C:30]([N:32]4[CH2:39][C:38]56[CH2:40][NH:41][CH2:42][C:34]5([CH2:35][O:36][CH2:37]6)[CH2:33]4)=[O:31])=[CH:27][C:26]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:25]=4[C:24]=23)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C=O>CO>[CH:10]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:49]([NH:51][S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:53])=[O:54])=[O:50])=[CH:21][C:22]=3[N:23]3[CH2:29][C:28]([C:30]([N:32]4[CH2:39][C:38]56[CH2:40][N:41]([CH3:1])[CH2:42][C:34]5([CH2:35][O:36][CH2:37]6)[CH2:33]4)=[O:31])=[CH:27][C:26]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:25]=4[C:24]=23)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)C=C(C(=O)N1CC34CNCC3(COC4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)N1CC34COCC3(CN(C)C4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
A 1M solution of sodium cyanoborohydride in THF (0.15 mL, 0.15 mmol) was added to a solution of 13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-(3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-ylcarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (Example 22) (10 mg, 0.015 mmol) and formaldehyde (37 wt. % in water) (0.01 mL, 0.1 mmol) in MeOH (1 mL) and the mixture was stirred at rt for 16 h. The reaction was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC (H2O-MeOH with 0.1% TFA buffer) to yield 13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-((10-methyl-3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (7.9 mg, 9.4 μmol, 63% yield) as a bright yellow solid. LCMS: m/e 685 (M+H)+. LCMS retention time: 1.92 min. (Column: SunFire C18 5u 4.6×50 mm. Solvent A=90% Water/10% Acetonitrile/0.1% TFA. Solvent B=10% Water/90% Acetonitrile/0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=4 mL/min.) 1H NMR (400 MHz, MeOD) δ ppm 8.09 (br s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.54 (br d, J=8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.14 (dd, J=8.5, 2.5 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 7.07 (s, 1H), 5.22 (br d, J=14.8 Hz, 1H), 4.13-3.12 (m, 10H), 4.23 (br d, J=14.8 Hz, 1H), 3.90 (s, 3H), 2.97-2.76 (m, 5H), 2.15-1.67 (m, 6H), 1.52-1.07 (m, 8H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.[CH2:17]=[C:18]([CH3:20])[CH3:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:18]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C#N)cc1
Temperature: 0 °C

Procedure:
In 612 ml of methylene chloride were suspended 45.0 g of 4-cyanobenzoic acid and 3.1 ml of conc. sulfuric acid. To the suspension was added, while stirring at 0° C., 310 ml of isobutene. The mixture was stirred for 13 days. The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, which was subjected to extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. Resulting precipitate was collected by filtration and washed with hexane. The filtrate and the washing were combined, which was concentrated under reduced pressure. The concentrate was purified by means of a silica gel chromatography (hexane/ethyl acetate=10/1), followed by crystallization from methylene chloride/petroleum ether to afford 43.1 g of the titled compound as a white crystalline product.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH:19]=[CH:18][C:5]=1[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)([O-])=O.CCN(C(C)C)C(C)C>[Pt].C1COCC1>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][C:20]1[CH:21]=[C:4]([NH2:1])[C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][CH:9]=2)=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(C(F)(F)F)cc1
Agent: [Pt]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
To a 50 mL round-bottomed flask were added a stir bar, 2-nitro-4-(quinolin-2-ylmethoxy)-N-(4-(trifluoromethyl)benzyl)aniline (310 mg, 0.69 mmol), THF (6.9 mL), and DIPEA (60 μL, 0.3 mmol) followed by 5% platinum on carbon (15 mg, 0.08 mmol). The reaction vessel was evacuated and then placed under one atmosphere of hydrogen for 16 h. The mixture was then flushed with N2 and filtered through a pad of Celite. The Celite was then rinsed with additional THF (25 mL). The resulting solution was concentrated to dryness to afford the title compound which was used without further purification. MS (ESI): mass calcd. for C24H20F3N3O, 423.16; m/z found, 424.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26]>C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Product: CS(=O)(=O)Nc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cn1

Procedure:
100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide was reacted with methanesulfonamide and 108 μL of 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine via Procedure F. The crude reaction was concentrated to dryness and purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonamido)nicotinamide. MS (Q1) 403 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl:34][CH2:35][C:36]([NH:38]O)=[NH:37]>C(OCC)(=O)C.CN(C=O)C>[Cl:34][CH2:35][C:36]1[N:38]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[O:7][N:37]=1
Reactant: N=C(CCl)NO
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2nc(CCl)no2)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
DMF (10 ml) was added to a mixture of 3-fluorobenzoic acid (710 mg, 5.07 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (972 mg, 5.07 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (685 mg, 5.07 mmol) and 2-chloro-N-hydroxy-acetamidine (500 mg, 4.61 mmol) at room temperature and then stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. DMF (14 ml) was added to the residue and the resulting solution was heated at 135° C. for 3.5 h to effect cyclization to oxadiazole. After cooling the reaction mixture was washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. 3-Chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole (383 mg, 35% yield over 2 steps, yellow oil) was obtained by flash chromatography on silica gel, using 5% ethyl acetate in hexane. 1H NMR (CDCl3), δ (ppm): 7.96 (d, 1H), 7.86 (m, 1H), 7.54 (m, 1H), 7.33 (m, 1H), 4.68 (s, 2H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[N:10][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=12.[F:24][C:25]1([F:34])[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.N1C2C(=NC=CC=2)N(O)N=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[F:24][C:25]1([F:34])[CH2:30][CH2:29][CH:28]([C:31]([N:6]2[CH2:5][CH2:4][N:3]([C:8]3[N:9]=[N:10][C:11]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:12]4[CH:17]=[CH:16][N:15]=[CH:14][C:13]=34)[C@H:2]([CH3:1])[CH2:7]2)=[O:32])[CH2:27][CH2:26]1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2ccncc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@@H]1CN(C(=O)C2CCC(F)(F)CC2)CCN1c1nnc(-c2ccccc2)c2ccncc12

Procedure:
(R)-4-(2-methylpiperazin-1-yl)-1-phenylpyrido[3,4-d]pyridazine 16 (150 mg, 491 μmol), 4,4-difluorocyclohexanecarboxylic acid (88.7 mg, 540 μmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (113 mg, 589 μmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (80.2 mg, 589 μmol), sodium bicarbonate (82.5 mg, 982 μmol) were stirred in DMF (3 ml) for one hour. The reaction was then taken up in ethyl acetate (30 ml) and washed with aqueous K2CO3 (10%), water, and brine. The organic phase was dried (MgSO4) and evaporated to give an orange oil. Chromatography of the residue over silica with a gradient of hexane to 100% ethyl acetate gave (R)-(4,4-difluorocyclohexyl)(3-methyl-4-(1-phenylpyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone 17 as a yellow solid. LC/MS m/z=452 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([F:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:12]2)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:22][C:11]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH:9]2[NH:8][CH:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(F)(c1ccccn1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(c2ccccn2)CC2CCC(C1)N2
Reaction time: 2 h
Yield: 84.9 %

Procedure:
3-Fluoro-3-pyridin-2-yl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (PA Isomer 1) (0.056 g) was dissolved in DCM (1 mL) and TFA (5 mL). The solution was stirred for 2 hours then the solvent was removed by evaporation under vacuum. The residue was loaded onto an SCX-2 cartridge and washed with DCM, methanol and then eluted with ammonia (2 M in methanol). The solvent was removed by evaporation under vacuum to afford the title compound as a white solid (0.032 g). LCMS m/z 207 [M+H]+. R.T.=0.37 min (Analytical Method 3).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[N:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[C:36]([NH2:41])[CH:35]=2)=[O:30])[CH3:27].N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl.CN(C)C=O>[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[N:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[C:36]([NH:41][C:11]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)=[N:17][CH:16]=[CH:15][CH:14]=1)=[O:13])[CH:35]=2)=[O:30])[CH3:27]
Reactant: CCOC(=O)c1cnc2cc(N)ccc2c1
Reactant: O=C(O)c1cccnc1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc2cc(NC(=O)c3cccnc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reaction time: 2 h
Yield: 122.5 %

Procedure:
2-(4-Trifluoromethyl-phenyl)-nicotinic acid (534 mg, 2.0 mmol) was suspended in 10 ml of dichloromethane, and oxalyl chloride (0.7 ml, 8.0 mmol) was added followed by a drop of dimethylformamide. After 2 h at room temperature, the volatiles were removed under vacuum, and to the residue was added 10 ml of chloroform, 7-amino-quinoline-3-carboxylic acid ethyl ester (216 mg, 1.0 mmol), pyridine (0.2 ml, 2.5 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol). After heating at reflux overnight, the reaction mixture was diluted with 50 ml of dichloromethane, washed with 35 ml of 2N NaOH, water, dried (magnesium sulfate) filtered, and concentrated under vacuum to afford 570 mg of a brown gum. This material was purified by silica gel chromatography eluting with 50 to 80% ethyl acetate in hexanes to provide 189 mg of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)=[O:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:44]=[CH:45][C:40]([CH:38]=[O:39])=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1ccc(B(O)O)cc1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C=O)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 obtained in Example 128-(4) and 4-formylphenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-formylphenyl)-2-thienylmethyl)benzene as a colorless solid. APCI-Mass m/Z 660/662 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-formylphenyl)-2-thienylmethyl)benzene was treated in a manner similar to Example 130-(2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)benzene as colorless crystals. APCI-Mass m/Z 682/684 (M+NH4). (3) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl) benzene was treated in a manner similar to Example 120-(3) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-difluoromethylphenyl)-2-thienylmethyl)benzene as colorless powder. APCI-Mass m/Z 514/516 (M+NH4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22](O)(=[O:28])/[CH:23]=[CH:24]/[CH:25]=[CH:26]/[CH3:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.CO>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:22](=[O:28])/[CH:23]=[CH:24]/[CH:25]=[CH:26]/[CH3:27])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: C/C=C/C=C/C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: C/C=C/C=C/C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 16.8 %

Procedure:
Preparation of example 90 from the title compound of Example 7 (hydrochloride) (41 mg, 0.131 mmol), (2E,4E)-hexa-2,4-dienoic acid (18 mg, 0.157 mmol), triethylamine (0.055 mL, 0.393 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (60 mg, 0.157 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 2:1 hexane:acetone), also in an analogous manner, after a final trituration with methanol afforded the title compound (8 mg, 0.022 mmol) as a yellow powder in 16% yield.
Reaction SMILES: CC([N:5]([C:11](=[O:17])[NH:12][O:13][CH2:14][CH2:15][Cl:16])[CH2:6][CH2:7][C:8](Cl)=[O:9])CC.O=S(Cl)Cl.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23].N1C=CC=CC=1.C(=O)=O.CC(C)=O>C(Cl)(Cl)Cl>[CH3:23][CH:22]([NH:26][C:8](=[O:9])[CH2:7][CH2:6][NH:5][C:11](=[O:17])[NH:12][O:13][CH2:14][CH2:15][Cl:16])[CH2:24][CH3:25]
Reactant: CCC(C)N(CCC(=O)Cl)C(=O)NOCCCl
Reactant: CCC(C)N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC(C)NC(=O)CCNC(=O)NOCCCl
Reaction time: 16 h
Yield: 58 %

Procedure:
A solution of N-(1-methylpropyl)-β-chloroethoxycarbamyl-β-alaninyl chloride [prepared from 9.8 g (0.05 mol) of 7 and 10 mL of SOCl2 as described earlier]in 20 ML of CHCl3 was added to a solution of 4 g (0.055 mol) of sec-butylamine and 4.4 g (0.055 mol) of pyridine in 50 mL of CHCl3 at dry ice-acetone temperature. After 16 h the reaction mixture was worked up as described earlier to give 7.05 g (58%) of 51: mp 97°-98° C.; 1H NMR (CDCl3) δ 0.89 (t, 3, CH2CH3), 1.12 (d, 3, CHCH3), 1.45 (m, 2, CH2CH3) 2.40 (t, 2, CH2CO) , 3.46 (m, 2, NCH2) , 3.65 (t, 2, CH2Cl), 3.92 (m, 1, NHCH--) and 4.29 (t, 2, --CH2OCO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10](O)[CH2:11][CH3:12]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10][CH2:11][CH3:12]
Reactant: CCC(O)c1c(F)cccc1OC
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(F)cccc1OC
Reaction time: 10 h
Yield: 79.6 %

Procedure:
500 mg of palladium-on-charcoal (10%) were added to a solution of 15 g (81.4 mmol) of 1-(2-fluoro-6-methoxy-phenyl)-propan-1-ol in 200 ml of ethanol and the mixture was hydrogenated at room temperature for 10 hours. The catalyst was filtered off over Dicalite and the filtrate was concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 1:2). There were obtained 10.9 g (73%) of 1-fluoro-3-methoxy-2-propyl-benzene as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1([CH3:10])[N+:8]([O-:9])=[CH:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].C([C@H](N)C(O)=O)CC([NH:15][C@H](C(NCC(O)=O)=O)CSSC[C@H](NC(CC[C@H](N)C(O)=O)=O)C(NCC(O)=O)=O)=O.C(OOC(C)(C)C)(C)(C)C>P([O-])([O-])([O-])=O>[NH2:15][C:7]1[CH2:6][CH2:5][C:4]([C:1](=[O:3])[NH2:2])([CH3:10])[N+:8]=1[O-:9]
Reactant: CC1(C(N)=O)CCC=[N+]1[O-]
Reactant: N[C@@H](CCC(=O)N[C@@H](CSSC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O)C(=O)NCC(=O)O)C(=O)O
Agent: CC(C)(C)OOC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Product: CC1(C(N)=O)CCC(N)=[N+]1[O-]
Reaction time: 0.08 h

Procedure:
Trapping of GS. and t-BuO. radicals. 50 μL 0.1 M phosphate buffer solution containing 30 mM AMPO and 100 mM GSSG or (CH3)3CO—OC(CH3)3. The mixture was then transferred to 50 μL capillary tube and the radicals were generated by UV photolysis. EPR spectrum of the adduct was recorded over a 5 min time period.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[N:10]1[CH:11]=[CH:12][N:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][C:14]=12.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:20][CH2:19][C:16]2[CH:17]=[CH:18][N:13]3[CH:12]=[CH:11][N:10]=[C:14]3[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccn2ccnc2c1
Reactant: O=C(O)c1ccc(Br)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)s1
Reaction time: 8 h

Procedure:
A solution of 5-bromothiophene-2-carboxylic acid (1.279 g, 6.18 mmol), imidazo[1,2-a]pyridin-7-ylmethanamine (1 g, 6.79 mmol), 1-hydroxybenzotriazole hydrate (1.041 g, 6.79 mmol) and N-methylmorpholine (1.698 ml, 15.44 mmol) in dimethylformamide (20 ml) at room temperature was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.131 g, 11.12 mmol). The mixture was stirred overnight and poured into a gently stirred round-bottom flask containing water (100 ml) and ethyl acetate (30 ml). The resulting bilayer suspension was stirred for several minutes, filtered and washed with water then minimal ethyl acetate to give the title compound after drying.