Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1)=[O:2].[H-].C([Al+]CC(C)C)C(C)C.O>C(Cl)Cl.C1(C)C=CC=CC=1>[OH:2][CH2:1][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1
Reactant: O=CCCc1cn(-c2cccnc2)c2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OCCCc1cn(-c2cccnc2)c2ccccc12
Temperature: 25 °C

Procedure:
A solution of 1.0 g of 3-(2-formylethyl)-N-(3-pyridyl)indole in 15 ml of methylene chloride under nitrogen is cooled to -20° and 4.6 ml of 1.75M diisobutylaluminum hydride in toluene is added dropwise. The reaction is allowed to warm to room temperature for 2 hours and 20 ml of water is added with vigorous stirring. The reaction mixture is filtered through celite which is further washed with methylene chloride. The organic phase is separated, dried over potassium carbonate and evaporated to yield 3-(3-hydroxypropyl)-N-(3-pyridyl)indole as an oil; IR (CH2Cl2) 3480 cm-1.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.C([O-])([O-])=O.[K+].[K+].[CH2:35]([O:37][C:38](=[S:48])[CH2:39][CH2:40][CH2:41][CH2:42][CH:43](Br)[CH2:44][CH2:45][CH3:46])[CH3:36]>O>[CH2:35]([O:37][C:38](=[S:48])[CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([S:3][C:1](=[O:4])[CH3:2])[CH2:44][CH2:45][CH3:46])[CH3:36]
Reactant: CCCC(Br)CCCCC(=S)OCC
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [K+]
Solvent: O
Product: CCCC(CCCCC(=S)OCC)SC(C)=O
Reaction time: 10 h
Yield: 94 %

Procedure:
8.6 grams (0.113 mole) of thioacetic acid in 20 ml of water-free ethanol were neutralized to phenolphthalein with 81 ml of 10% ethanolic potash solution (0.113 mole potassium hydroxide) and 29.7 grams (0.1 mole) of 6-bromo-8-methylthiooctanoic acid ethyl ester added. The mixture was heated at reflux for 6 hours in a nitrogen atmosphere and allowed to stand for 10 hours at room temperature. The precipitated potassium bromide was filtered off, the filtrate concentrated in a vacuum, the residue taken up in 300 ml of diethyl ether and filtered, the filtrate was washed twice, each time with 100 ml of water, dried with sodium sulfate and concentrated in a vacuum. There were obtained 26 grams (89% of theory) of crude 6-acetylthio-8-methylthiooctanoic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[S:12])[NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[Ca+2]>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:12][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C)OC(=O)NCC(N)=S
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CCOC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
To a solution of 10 g of the above-obtained (tert-butoxycarbonylamino)acetothioamide in 150 ml of ethanol were added 7.3 ml of ethyl bromopyruvate and 2.7 g of calcium carbonate, and the mixture was stirred at room temperature for 6 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in chloroform. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a small amount of water, and then dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and isopropyl ether was added to the residue. The crystals precipitated were collected by filtration, and dried under reduced pressure to give 11.2 g (yield 74%) of ethyl 2-(tert-butoxycarbonylamino)methylthiazole-4-carboxylate.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:32][C@@H:33]([C@H:35]4[CH2:39][NH:38][C:37](=[O:40])[CH2:36]4)[CH3:34])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][N:16]=[C:15]([C:19]5[CH:20]=[N:21][N:22](COCC[Si](C)(C)C)[CH:23]=5)[CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH:21]1[CH:20]=[C:19]([C:15]2[CH:14]=[C:13]([C:11]3[N:10]=[C:9]([O:32][C@@H:33]([C@H:35]4[CH2:39][NH:38][C:37](=[O:40])[CH2:36]4)[CH3:34])[C:8]4[N:4]([CH:1]5[CH2:3][CH2:2]5)[CH:5]=[N:6][C:7]=4[CH:12]=3)[CH:18]=[CH:17][N:16]=2)[CH:23]=[N:22]1
Reactant: C[C@@H](Oc1nc(-c2ccnc(-c3cnn(COCC[Si](C)(C)C)c3)c2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1nc(-c2ccnc(-c3cn[nH]c3)c2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1

Procedure:
the crude material (R)-4-((R)-1-((3-cyclopropyl-6-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: was treated with TFA at rt for 30 minute. LC-MS showed reaction was complete. Reaction mixture was stripped off and purified by HPLC to afford title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[Cl:16][C:17]1[CH:18]=[N+:19]([O-:37])[CH:20]=[C:21]([Cl:36])[C:22]=1[CH2:23][C@@H:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)O.CCN=C=NCCCN(C)C.Cl.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][C@H:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[CH2:23][C:22]2[C:21]([Cl:36])=[CH:20][N+:19]([O-:37])=[CH:18][C:17]=2[Cl:16])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(CC2OCCO2)cc1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CC3OCCO3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
To a solution of 4-((1,3-dioxolan-2-yl)methyl)benzoic acid (362 mg, 1.05 mmol) in DCM (9 mL) was added (1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol (200 mg, 0.96 mmol) followed by DMAP (58 mg, 0.48 mmol) and EDC.HCl (396 mg, 1.9 mmol). The mixture was allowed to stir a room temperature for 18 hours and then water (20 mL) and DCM (20 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography, eluting with 30-100% EtOAc in DCM, to afford the title compound as an off-white solid (497 mg, 97%).
Reaction SMILES: [H][H].[CH3:3][O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]=[N+]=[N-])=[C:8]([F:16])[CH:7]=1>CO>[CH3:3][O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[C:8]([F:16])[CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])c(F)c1
Solvent: CO
Product: COC(=O)c1ccc(CN)c(F)c1
Yield: 83 %

Procedure:
Hydrogen was passed through a degassed solution of 4-azidomethyl-3-fluorobenzoic acid methyl ester from Example E3.3 (2.11 g, 10 mmol) in methanol containing 10% palladium on carbon for 2 h. The reaction mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to give a colourless oil identified as the title compound (1.51 g, 83%).
Reaction SMILES: C([O:5][C:6]([C:8]1([O:12]/[N:13]=[C:14](/[C:45]2[N:46]=[C:47]([NH:50]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:48][CH:49]=2)\[C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:28])=[C:22]([CH2:25]I)[CH2:23][S:24][C@H:19]23)=[O:16])[CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.[NH2:70][C:71]1[S:72][C:73]2[CH:78]=[CH:77][N:76]=[CH:75][C:74]=2[N:79]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>CS(C)=O.CCOCC.C(O)=O.Cl.O>[NH2:50][C:47]1[S:48][CH:49]=[C:45](/[C:14](=[N:13]/[O:12][C:8]2([C:6]([OH:5])=[O:7])[CH2:11][CH2:10][CH2:9]2)/[C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[C:21]([C:27]([O-:29])=[O:28])=[C:22]([CH2:25][N+:76]4[CH:77]=[CH:78][C:73]5[S:72][C:71]([NH2:70])=[N:79][C:74]=5[CH:75]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:46]=1
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CI)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Reactant: Nc1nc2cnccc2s1
Agent: Cl
Solvent: CCOCC
Solvent: COc1ccccc1
Solvent: O
Product: Nc1nc(/C(=N/OC2(C(=O)O)CCC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccc5sc(N)nc5c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of benzhydryl 7-[(Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)-acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIe'] (643 mg, 0.6 mmole) and 2-aminothiazolo[4,5-c]pyridine (100 mg, 0.67 mmole) in 3 ml of dry DMSO was stirred at room temperature for an hour. The reaction mixture was diluted with ether (50 ml) to separate a precipitate, which was triturated with ether (50 ml). The resulting precipitate was dissolved in 30 ml of methylene chloride. After filtration, the filtrate was evaporated and the residue was triturated with isopropyl ether to give 622 mg of the crude blocked quaternary salt as a brown powder. A mixture of the crude solid (450 mg, 0.37 mmole), anisole (0.5 ml), trifluoroacetic acid (5 ml), and water (0.3 ml) was stirred at room temperature for 1.25 hours and concentrated under reduced pressure. The residue was triturated with isopropyl ether (70 ml), and the precipitate was isolated by filtration to give 330 mg of crude final product as a yellow powder, which was dissolved in a mixture of 85% formic acid (1 ml) and concentrated hydrochloric acid (0.05 ml). The solution was allowed to stand at room temperature for 20 minutes and adsorbed on a column of HP-20 resin (40 ml). It was eluted with water (150 ml), 30% aqueous methanol (150 ml) and 50% aqueous methanol (300 ml). Fractions containig the desired product were combined, concentrated and lyophilized to give 167 mg of powder, which was found to be a mixture of the Δ2 and Δ3 isomers by NMR and HPLC. It was further purified by column chromatography using the packing of the PrepPAK-500/C18 (Waters) (20 ml) and the eluate with water (400 ml) was collected in 10 ml fractions, which were monitored by HPLC. The desired fractions were combined, concentrated and lyophilized to afford 58 mg (20%) of Ik as a pale yellow amorphous powder. Mp >150° C. (dec.). Estimated purity 80% (by HPLC).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[ClH:11]>O>[Cl:11][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: Cl
Reactant: O=[N+]([O-])c1ccc(O)nc1
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Cl)c1
Temperature: 52.5 °C

Procedure:
A 5 L flask with mechanical stirrer, thermocouple, and addition funnel was charged with 2-hydroxy-5-nitropyridine (200 g) and concentrated HCl (890 mL). The mixture was warmed to 50-55° C. and a solution of KClO3 (61.3 g, 0.5 mol) in water (850 mL) was added dropwise over 75 minutes maintaining the reaction temperature at 55-59° C. Following complete addition, the reaction mixture was cooled in an ice-water bath to an internal temperature of <6° C. and then filtered. The filter cake was washed with cold water (700 mL) and dried under vacuum at 50° C. for 12 hours to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 7.43 (d, J=3 Hz, 1H), 7.59 (d, J=3 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:11]([CH3:13])([CH3:12])[C:10](=[O:14])[NH:9][C:8]2=[O:15])=[CH:4][CH:3]=1.BrC1C=CC(CN2CC(=O)NC2=O)=CC=1.[CH:33]1([N:36]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41](B4OC(C)(C)C(C)(C)O4)[CH:42]=3)[C:37]2=[O:54])[CH2:35][CH2:34]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH:33]1([N:36]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([C:2]4[CH:17]=[CH:16][C:5]([CH2:6][N:7]5[C:11]([CH3:13])([CH3:12])[C:10](=[O:14])[NH:9][C:8]5=[O:15])=[CH:4][CH:3]=4)[CH:42]=3)[C:37]2=[O:54])[CH2:35][CH2:34]1
Reactant: CC1(C)C(=O)NC(=O)N1Cc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)C(=O)NC(=O)N1Cc1ccc(-c2ccc3c(c2)CN(C2CC2)C3=O)cc1
Yield: 54.7 %

Procedure:
1-(4-bromobenzyl)-5,5-dimethylimidazolidine-2,4-dione (8B4) (0.168 mmol, 50 mg) (prepared according to the method described for intermediate (1B4), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (1A5) (0.1 mmol, 53.0 mg), tris(dibenzylidineacetone)dipalladium (0.008 mmol, 8.1 mg), tricyclohexylphosphine (0.02 mmol, 5.7 mg) and potassium phosphate (0.27 mmol, 60.7 mg) were suspended in dioxane (3 ml) and water (1 ml) and heated to 130° C. in the microwave for 15 min. The reaction mixture was quenched with water (6 ml) and DCM (9 ml) and the organic layer separated using a hydrophobic fritted tube. The organic phase was concentrated and the residue purified on silica eluting with 0-100% EtOAc/heptane to give 1-(4-(2-cyclopropyl-1-oxoisoindolin-5-yl)benzyl)-5,5-dimethylimidazolidine-2,4-dione (8I1) 21.3 mg (53%); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, 1H) 7.54 (d, 1H) 7.57 (m, 3H) 7.43 (d, 2H) 7.33 (bs, 1H) 4.56 (s, 2H) 4.37 (s, 2H) 3.94 (m, 1H) 1.34 (s, 6H) 0.95-0.88 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:5]2[C:15](=[O:31])[N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=O)[C:4]2=[CH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:5]2[C:15](=[O:31])[N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=[S:41])[C:4]2=[CH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1cc2c(c(-c3ccncc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Solvent: Cc1ccccc1
Product: Cn1cc2c(c(-c3ccncc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=S
Temperature: 110 °C
Reaction time: 12 h
Yield: 39.1 %

Procedure:
To a mixture of 5-methyl-7-(4-pyridyl)-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (50 mg, 0.12 mmol) and Lawesson's reagent (25 mg, 0.06 mmol) in toluene (5 ml) was stirred at 110° C. for 12 hours. The solution was concentrated and the residue was purified by preparative thin-layer chromatography (EA:MeOH=5:1) to give the title compound as a yellow solid (10 mg, 19%).
Reaction SMILES: [C:1]1([C@H:7]([CH3:16])[CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:18]([C@@H:20]1[C@@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][N:22]([C@H:31]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[C:32]([O:34]CC2C=CC=CC=2)=[O:33])[CH2:21]1)=O>>[C:1]1([C@H:7]([CH3:16])[CH2:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:18][C@@H:20]3[C@@H:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:23][N:22]([C@H:31]([CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[C:32]([OH:34])=[O:33])[CH2:21]3)[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Reactant: C[C@H](CCC1CCNCC1)c1ccccc1
Agent: Cl
Product: C[C@H](CCC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1)c1ccccc1
Yield: 53.6 %

Procedure:
The title compound was prepared from 30 mg (0.13 mmol) of 4-(3-(R)-phenylbutyl)piperidine.HCl and 50 mg (0.13 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) using procedures analogous to those described in EXAMPLE 1, Steps J and H. 36 mg (54%) of the title compound was obtained: 1H NMR (500 MHz, CD3OD) δ 0.94-1.84 (23H). 2.06-2.14 (m, 1H). 2.36-2.42 (m, 1H). 2.57-2.60 (2H). 2.74-3.02 (3H). 3.10-3.12 (m, 1H). 3.30-3.60 (7H). 7.10-7.13 (3H). 7.21-7.29 (3H), 7.34-7.39 (4H); ESI-MS 517 (M+H).
Reaction SMILES: FC1C(O)=C(F)C(F)=C(F)C=1F.[NH:13]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C@H:14]([C:19]([NH:21][CH2:22][C:23]([OH:25])=O)=[O:20])[CH2:15][C:16](=[O:18])[NH2:17].[NH2:36][C@H:37]([C:39]([NH:41][C@H:42]([C:52]([NH:54][C@H:55]([C:64]([NH:66][C@H:67]([C:77]([NH:79][C@H:80]([C:83]([NH:85][C@H:86]([C:88]([O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:89])[CH3:87])=[O:84])[CH2:81][OH:82])=[O:78])[CH2:68][CH2:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:65])[CH2:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:53])[CH2:43][CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:40])[CH3:38].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:13]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C@H:14]([C:19]([NH:21][CH2:22][C:23]([NH:36][C@H:37]([C:39]([NH:41][C@H:42]([C:52]([NH:54][C@H:55]([C:64]([NH:66][C@H:67]([C:77]([NH:79][C@H:80]([C:83]([NH:85][C@H:86]([C:88]([O:90][C:91]([CH3:92])([CH3:93])[CH3:94])=[O:89])[CH3:87])=[O:84])[CH2:81][OH:82])=[O:78])[CH2:68][CH2:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:65])[CH2:56][C:57](=[O:63])[O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:53])[CH2:43][CH2:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:40])[CH3:38])=[O:25])=[O:20])[CH2:15][C:16](=[O:18])[NH2:17]
Reactant: C[C@H](N)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
2.45 g. (13.3 mmoles) of pentafluorophenol, 1.31 g. (4.02 mmoles) of Z-Asn-Gly-OH (see Example 1) and 5.4 g. (4.02 mmoles) of H-27-32-OtBu are dissolved in 24 ml. of dry DMF, thereafter the solution is cooled to 0°C, and 0.915 g. (4.43 mmoles) of DCC are added to it. The reaction mixture is stirred at 0°C for 0.5 hours and at room temperature for 2.5 hours. The separated DCU is filtered off, and the filtrate is evaporated to dryness. The solid residue is triturated with ethyl acetate, filtered, and washed with hot ethyl acetate. 4.12 g. (89 %) of Z-25-32-OtBu are obtained. M.p.: 200°-201°C; Rf3 = 0.6; [α]D = -13.9° (c = 1, in DMF).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][N:16]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:30])C=CC=CC=1>ClCCl>[CH3:22][S:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)=[O:30]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(S(C)=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-methylsulfanyl-pyridine (70 mg, 0.22 mmol) in dichloromethane (2.1 mL) was added 2-benzenesulfonyl-3-phenyl-oxaziridine (58.5 mg, 0.22 mmol) and the reaction mixture was stirred overnight at room temperature. The mixture was then evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate 8:2 to 1:3) afforded the title compound (70 mg, 95%) as a white solid. MS: m/e=329.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[CH:11](=O)/[CH:12]=[CH:13]/[CH3:14].[NH4+].[OH-]>Cl>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:9][CH3:10])[N:6]=[C:13]([CH3:14])[CH:12]=[CH:11]2
Reactant: COc1cc(N)ccc1F
Reactant: C/C=C/C=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc2nc(C)ccc2cc1F
Yield: 97.1 %

Procedure:
To 4-fluoro-3-methoxyaniline (4.0 g, 28 mmol) refluxing in 6N HCl (50 mL) was added dropwise (E)-but-2-enal (4.0 g, 57 mmol). The reaction was heated to reflux for 2 hours then cooled and neutralized with NH4OH. The organic phase was extracted with DCM. The combined organic phases dried over MgSO4, filtered and concentrated under reduced pressure to provide 6-fluoro-7-methoxy-2-methylquinoline (5.2 g, 96% yield) as a dark brown paste.
Reaction SMILES: N1C=CC=C1.COC(O)[C:9]([F:12])([F:11])[F:10].Cl.[CH:15]1[CH:19]=[C:18]([CH2:20][C:21]2[NH:25][CH:24]=[CH:23][CH:22]=2)[NH:17][CH:16]=1>O1CCCC1>[NH:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:20]([C:18]1[NH:17][CH:16]=[CH:15][CH:19]=1)[C:9]([F:12])([F:11])[F:10]
Reactant: c1c[nH]c(Cc2ccc[nH]2)c1
Reactant: COC(O)C(F)(F)F
Agent: Cl
Solvent: c1cc[nH]c1
Solvent: C1CCOC1
Product: FC(F)(F)C(c1ccc[nH]1)c1ccc[nH]1
Yield: 80 %

Procedure:
Pyrrole (150 mmol) and trifluoroacetaldehyde methyl hemiacetal (75 mmol) in tetrahydrofuran are heated at reflux with catalytic amounts of hydrochloric acid for 2 hours under an inert atmosphere. GC analysis of the reaction mixture indicated the presence of the desired dipyrromethane in greater than 80% yield. Neutralization of the acid followed by work up and chromatography gave the pure bis(pyrrol-2-yl)-trifluoromethylmethane 3 (R3 =CF3)). MS:m/z=214. This preparation has been disclosed in Wijesekera U.S. patent application Ser. No. 08/143,261 filed on Oct. 26, 1993.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)C[Mg]Br.[Cl:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][N:18]2[C:23](=[O:24])[CH:22]=[CH:21][C:20]([CH:25]=[O:26])=[CH:19]2)=[CH:15][CH:14]=1>C1COCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]2[CH:19]=[C:20]([CH:25]([OH:26])[C:10]3[CH:9]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH:21]=[CH:22][C:23]2=[O:24])=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(=O)n(Cc2ccc(Cl)cc2)c1
Reactant: COc1cccc(C[Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64 %

Procedure:
According to Scheme 7 Method B: A solution of 3-methoxybenzylmagnesium bromide (1.2 eq, 1.00 mmol, 1.00 mL) was added dropwise to a solution of 1-(4-chlorobenzyl)-1,6-dihydro-6-oxopyridine-3-carbaldehyde (1 eq, 1.21 mmol, 0.30 g, Example 10 Step 1) in THF (15 mL) at −78° C. under a nitrogen atmosphere. The reaction mixture was stirred for 14 hours at room temperature. The resulting mixture was poured onto ice and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and evaporated. Purification by flash chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/AcOEt 80/20 to 70/30) afford 1-(4-chlorobenzyl)-5-(hydroxy(3-methoxyphenyl)methyl)pyridin-2(1H)-one (0.64 mmol, 0.28 g, 64%) as a yellow semi-solid.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2F)ccn1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccccc2F)ccn1)NO
Reaction time: 22 h

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (30 mg, 0.07 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:7) to furnish III as a white wax (15 mg, 79%).