Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.Cl.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1/[CH:8]=[N:19]/[NH:18][C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1cnccc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1ccc(N/N=C/c2cnccc2Br)cc1
Temperature: 50 °C

Procedure:
To a solution of 4-bromopyridine-3-carbaldehyde (2.50 g, 13.4 mmol) in ethanol (25 mL) and water (5 mL) was added 4-fluorophenyhydrazine hydrochloride (2.38 g, 14.6 mmol) (mixture turned a deep red) followed by sodium acetate (3.7 g, 27 mmol) in 5 mL of water (mixture turned a bright yellow). The mixture was warmed at 50° C. for 30 minutes to afford an orange precipitate. The mixture was cooled and diluted with water (50 mL) and the solid was collected by filtration. The filter cake was washed with water and dried to afford N-[1-(4-bromopyridin-3-yl)-meth-(E)-ylidene]-N′-(4-fluorophenyl)-hydrazine.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH:20]=[CH2:21].Cl(O)(=O)(=O)=O.[I:27]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>O.O1CCCC1>[I:27][CH2:21][CH:20]1[O:18][C:4]2[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[C:11]([C:2](=[O:1])[C:3]=2[CH2:19]1)=[CH:10][CH:9]=[CH:8][N:7]=3
Reactant: C=CCc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: O=c1c2c(n(-c3ccccc3)c3ncccc13)OC(CI)C2

Procedure:
To a solution of 4.0 g. (0.014 moles) of 4-hydroxy-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(1H)-one in 380 ml. of tetrahydrofuran, there is added, dropwise, with stirring at 3°-5° C., 4.0 g. of 70% perchloric acid in 11.5 ml. of water, followed by the slow addition of 10.2 g. of N-iodo-succinimide over a period of 45 minutes. The reaction is stirred at room temperature for three hours, treated with a saturated solution of sodium sulfite, and extracted with 2×250 ml. of ether. The organic layer is dried over magnesium sulfate, filtered and concentrated to a solid residue. The crude products are separated on a 60G silica gel column with methanol:chloroform (5:95). The desired fraction is recrystallized from ethyl acetate to yield the title compound, m.p. 178°-180° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][N:7]=[C:8]([C:12]1([O:17][CH2:16][CH2:15][O:14]1)[CH3:13])[C:9]([OH:11])=O.[NH2:18][CH:19]1[C:37](=[O:38])[N:21]2[C:22]([C:34]([OH:36])=[O:35])=[C:23]([CH2:26][S:27][C:28]3[S:29][C:30]([CH3:33])=[N:31][N:32]=3)[CH2:24][S:25][C@H:20]12.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(Cl)Cl.C(N(CC)CC)C.CN(C)C=O>[CH3:5][O:6][N:7]=[C:8]([C:12]1([O:17][CH2:16][CH2:15][O:14]1)[CH3:13])[C:9]([NH:18][CH:19]1[C:37](=[O:38])[N:21]2[C:22]([C:34]([OH:36])=[O:35])=[C:23]([CH2:26][S:27][C:28]3[S:29][C:30]([CH3:33])=[N:31][N:32]=3)[CH2:24][S:25][C@H:20]12)=[O:11]
Reactant: CON=C(C(=O)O)C1(C)OCCO1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)C1(C)OCCO1
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
Thionyl chloride (1.52 g.) was added to a solution of dry N,N-dimethylformamide (0.92 g.) in dry ethyl acetate (16 ml.) under ice-cooling, and stirred at the same temperature for 30 minutes. 2-Methoxyimino-3,3-ethylenedioxybutyric acid (syn isomer, 2.3 g.) was added to the solution and stirred under ice-cooling for an hour. The solution was added dropwise to a stirred solution of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (3.44 g.) and triethylamine (4.9 ml.) in dry methylene chloride (70 ml.) over 30 minutes and stirred at -20° to -30° C. for 1.5 hours. After adding an aqueous solution of sodium bicarbonate to the resultant solution, the aqueous layer was separated and washed with ethyl acetate. A mixed solvent (100 ml.) of ethyl acetate and methanol (4:1) was added to the aqueous solution, adjusted to pH 2.5 with 20% sulfuric acid under ice-cooling and filtered. The ethyl acetate layer was separated from the filtrate. The aqueous layer was extracted with ethyl acetate (50 ml.) twice. The ethyl acetate layer and the extract were combined, washed with water and saturated aqueous sodium chloride in turn, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diisopropyl ether and the precipitates was collected by filtration to give 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.2 g.), yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[CH:10][C:3]=12.C1C(=O)N([I:19])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[C:10]([I:19])[C:3]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc2c(Br)ccnc2[nH]1
Solvent: ClCCl
Product: Cc1[nH]c2nccc(Br)c2c1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a mixture of 4-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (D24) (1.65 g, 7.82 mmol) in DCM (70 mL) was added NIS (1.935 g, 8.60 mmol) at 0° C. and the mixture was stirred for 1.5 hour at 0° C. The mixture was evaporated in vacuo. DCM (ca. 20 mL) was added to the residue. The formed precipitate was filtered, rinsed with DCM to give the title compound (2.45 g). LCMS (A): m/z (M+H)+ 337/339, C8H6BrIN2 requires 336/338 (acidic).
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(CC(O)=O)=O>C(O)C.CO.O>[Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Agent: CC(=O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.5 %

Procedure:
2-Bromo-5,6-dichloro-1-(2,3-di-O-acetyl-5deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (7.70 g, 16.52 mmol) was dissolved in ethanol (100 mL) and methanol (100 mL). A solution of sodium carbonate (1.75 g, 16.52 mmol) in water (30 mL) was added to the diacetate solution. The resulting mixture was stirred at rt for 17 h. The reaction mixture was concentrated, dissolved in ethyl acetate (125 mL) and extracted with water (3×50 mL). The ethyl acetate layer was dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column with 1:30 methanol:CH—2Cl2. The resulting product was further purified on a silica gel column with 1:2 ethyl acetate: hexanes, followed by 1:1 ethyl acetate:hexanes to give the title compound (3.00 g, 7.85 mmol, 48%); MS (El): m/z (rel. intensity) 405 (0.05, M++Na); 1H NMR (DMSO-d6) δ8.00 (s, 1H, Ar—H), 7.87 (s, 1H, Ar—H), 5.87 (d, 1H, OH, J=6.7 Hz), 5.53 (d, 1H, OH, J=6.2 Hz), 5.29 (d, 1H, CH, J=5.1 Hz), 4.52 (m, 1H, CH), 4.01 (m, 1H, CH), 3.91 (m, 1H, CH), 1.42 (d, 3H, CH3, J=6.5 Hz).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:14]([O:16]CC)=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[N:25]1[NH:26][N:27]=[N:28][C:29]=1[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33].C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1>C(O)C.[Pd].CN(C=O)C>[N:28]1[NH:27][N:26]=[N:25][C:29]=1[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:14]([OH:16])=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:33]
Reactant: O=C(O)c1ccccc1-c1nn[nH]n1
Reactant: CCCCCCC(C(=O)OCC)n1cnc2c([N+](=O)[O-])cccc21
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCCCC(C(=O)O)n1cnc2c(NC(=O)c3ccccc3-c3nn[nH]n3)cccc21
Reaction time: 4 h
Yield: 9.6 %

Procedure:
Ethyl 2-(4-nitro-1H-benzimidazol-1-yl)octanoate (4.44 moles, 1.48 g.) was hydrogenated over 0.6 g of 5% Pd/C in 100 ml ethanol. The catalyst was filtered over celite. The solution was concentrated. The residue was dissolved in 25 ml DMF and added to a stirred mixture of 2-(2H-tetrazol-5-yl)benzoic acid (4.21 mmoles, 0.80 g), dicyclohexylcarbodiimide (4.31 mmoles, 0.89 g.), and hydroxybenzotriazole (4.44 mmoles, 0.60 g) in 50 mi DMF. The reaction was stirred for 4 hours. The solid was removed by filtration. The reaction was concentrated. The residue was dissolved in ethyl acetate, and washed with water. The pH was adjusted to 8.0 using 5N NaOH. The aqueous layer was acidified to pH 2.5 using 2N HCL, and then extracted with ethyl acetate. The organic phase was separated, washed with water, dried and concentrated. The product was purified over silica gel eluted with 2% EtOH in ethyl acetate with 1% acetic acid to yield 0.18 g of 2-[4-[2-(2H-tetrazol-5-yl)benzamido]-1H-benzimidazol-1-yl]octanoic acid. (MS)
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1)#[N:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].CN(C)C=O>O.C(=O)([O-])[O-].[Na+].[Na+]>[NH:19]1[C:1]([C:3]2[CH:18]=[CH:17][C:6]3[C:7](=[O:16])[NH:8][C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[S:11][C:5]=3[CH:4]=2)=[N:2][N:21]=[N:20]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1NC2=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2Sc2cc(-c3nnn[nH]3)ccc21

Procedure:
Heat a mixture of 800 mg. of 3-cyano-10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepine, 293 mg. of sodium azide and 265 mg. of ammonium chloride in 25 ml. of dimethylformamide at 130°-135° C. for 6 hours. Dilute the mixture with water and excess sodium carbonate. Extract with ethyl acetate. Acidify the aqueous phase and separate the precipitate by filtration to obtain the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.[NH:73]1[CH2:77][CH2:76][CH2:75][CH2:74]1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C1(C)C=CC=CC=1>[N:73]1([C:2]2[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=2)[CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)=[CH:14][C:9]=3[N:8]=[C:7]2[CH2:27][C:28]2([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:77][CH2:76][CH2:75][CH2:74]1
Reactant: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)CCCC1
Reactant: C1CCNC1
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(N3CCCC3)c2)CCCC1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a 5 mL microwave vial were added methyl 1-{[1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]methyl}cyclopentanecarboxylate (50.5 mg, 0.08 mmol), RuPhos (4.1 mgs, 0.008 mmol), RuPhos pre-catalyst (7.1 mg, 0.009 mmol), pyrrolidine (15 μL, 0.17 mmol) and toluene (1.5 mL). The vial was flushed with N2, NaOt-Bu was added (16.2 mg, 0.17 mmol) then capped and placed in a heating block at 100° C. After 6 h the mixture was cooled to RT, transferred to a round-bottomed flask and concentrated to dryness. The resulting residue was purified using FCC to provide 21 mg of the title compound. MS (ESI): mass calcd. for C36H38N4O3, 574.71; m/z found 575.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([CH2:22][C:23]([OH:25])=[O:24])([CH2:18][C:19]([OH:21])=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Na]>C(O)CCC>[CH3:1][O:2][C:3]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([CH2:22][C:23]([OH:25])=[O:24])([CH2:18][C:19]([OH:21])=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(=O)c1ccccc1C2(CC(=O)O)CC(=O)O
Agent: [Na]
Solvent: CCCCO
Product: COc1cccc2c1Cc1ccccc1C2(CC(=O)O)CC(=O)O

Procedure:
4-Methoxy-10-oxo-9,10-dihydroanthracene-9,9-diacetic acid, whose preparation is described in Example 2, (5.2 g.) in n-butanol (300 ml.) is heated under reflux and sodium (10 g.) is gradually added in small pieces to the boiling solution. When all the sodium has dissolved, the solution is allowed to cool and is then extracted three times with water. The aqueous extracts are combined, washed with ether and acidified with concentrated hydrochloric acid. The resulting precipitate is extracted into ether, the ether is washed with water, dried (MgSO4) and evaporated to give a solid which is recrystallised from ethyl acetate-petroleum ether (b.p. 60°-80°C.) to give 4-methoxy-9,10-dihydroanthracene-9,9-diacetic acid m.p. 150°-153°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[CH2:10][C:11]([F:14])([F:13])[F:12].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([OH:15])[CH2:10][C:11]([F:13])([F:14])[F:12]
Reactant: O=C(Cc1ccccc1Br)CC(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(Cc1ccccc1Br)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-bromophenyl)-4,4,4-trifluorobutan-2-one (7.0 g, 24.9 mmol) in MeOH (150 ml) was added NaBH4 (1.23 g, 32.3 mmol) at 0° C. and stirred for 1 h at RT. Then the reaction mixture was quenched with MeOH and concentrated under reduced pressure to afford crude compound. The title compound was purified by separation methods A, E and H. (Yield 1.6 g of Enantiomer-1 and 1.4 g-Enantiomer-2). The enantiomer-1 showed up at tr=5.67 min and enantiomer-2 showed up at tr=9.57 min with Chiralcel OD-H (4.6×250 mm) 5μ, hexane:2-PrOH:TFA (90:10:0.1), 1 ml/min.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1.[CH3:18][N:19]1CCCC1=O>O>[C:18]([C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([S:11]([NH2:14])(=[O:13])=[O:12])=[C:4]([CH:15]([CH3:17])[CH3:16])[CH:3]=1)#[N:19]
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1Br
Reactant: CN1CCCC1=O
Solvent: O
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1C#N

Procedure:
A one-liter flask containing 92 parts of 4-bromo-2,5-diisopropylbenzenesulfonamide, 30 parts of cuprous cyanide, and 250 parts N-methylpyrrolidone is heated at 190°-200° for 2 hours. The reaction mixture is cooled to 100° and is then poured into 1000 parts water. The precipitated material is filtered. It is heated for 2 hours near reflux with 1000 parts water and 30 parts sodium cyanide. The reaction is cooled and the precipitate filtered to obtain 60 parts 4-cyano-2,5-diisopropylbenzenesulfonamide. The solid can be recrystallized from methanol, and then exhibits a m.p. of 200°-202°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:15](=O)[C:16]([N:18]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[C:24][C:25]3[S:29][CH:28]=[N:27][CH:26]=3)=[O:17])[CH:9]2C(O)=O)=[CH:4][C:3]=1[O:35][CH3:36].C([O-])(=O)C.[Na+].CCOCC.CCCCCCC>C(OC(=O)C)(=O)C.O>[C:30]([N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[C:24]([C:25]3[S:29][CH:28]=[N:27][CH:26]=3)=[C:9]3[C:10]4[CH:11]=[C:2]([Br:1])[C:3]([O:35][CH3:36])=[CH:4][C:5]=4[CH2:6][CH2:7][N:8]3[C:15]=2[C:16]1=[O:17])([CH3:31])([CH3:33])[CH3:32]
Reactant: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCCC#Cc1cncs1)C(C)(C)C)CC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 105 °C
Reaction time: 0.75 h
Yield: 43.3 %

Procedure:
A mixture of 220 mg of 17h and 150 mg of sodium acetate in 15 ml of acetic anhydride was stirred at 105° C. for 45 min. The reaction mixture was cooled, diluted with 60 ml of water and stirred at ambient temperature for 1 hr to destroy excess anhydride. The aqueous material was then neutralized by careful addition of cold con. aq. NH4OH. The product was extracted with ethyl acetate. The extract was washed with water, dried, concentrated and the material isolated was chromatographed over silica gel using a gradient of heptane/ethyl acetate as eluent. The material isolated was treated with ether/heptane, to give 85 mg of 17i as white crystals. MS-ESI: [M+1] 514.11 and 516.11.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=O)[CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH3:2].[NH2:20][C@H:21]([C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:24])[CH3:22].C([BH3-])#N.[Na+]>>[CH2:1]([O:3][C:4]([CH:5]([NH:20][C@H:21]([C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:24])[CH3:22])[CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=O)CCc1ccc2ccccc2c1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)C(CCc1ccc2ccccc2c1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in Example 26, ethyl-2-oxo-4-(2-naphthyl)-butyrate and L-alanyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-[1-ethoxycarbonyl-3-(2-naphthyl)propyl]-L-alanyl-L-proline. The mass spectrum shows a molecular ion at 426 and a peak at 408 (M-18, H2O). The nmr spectrum is consistent with the proposed structure. The elemental analysis indicates a hemihydrate.
Reaction SMILES: COC1C(C(O)[C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=CC=C(OC)N=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[C:24]([O:30][CH3:31])[CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]([OH:27])[C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: COc1cc(F)ccc1C=O
Reactant: COc1ccc(C(O)C#Cc2ccccc2)c(OC)n1
Product: COc1cc(F)ccc1C(O)C#Cc1ccccc1
Yield: 96 %

Procedure:
Following the procedure used to prepare 1-(2,6-dimethoxy-pyridin-3-yl)-3-phenyl-prop-2-yn-1-ol, 4-fluoro-2-methoxy-benzaldehyde was reacted to give the title compound (1.60 g, 96%) as a colourless oil. LCMS (Method A): RT=4.30 min, [M+Na]+=279.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH2:8]P(=O)(OCC)OCC)=[O:7])[CH3:4].[N+:17]([C:20]1[CH:33]=[CH:32][C:23]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=O)=[CH:22][CH:21]=1)([O-:19])=[O:18]>COCCOC>[C:26]1([C:24]([C:23]2[CH:32]=[CH:33][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)=[CH:8][C:6]([O:5][CH2:3][CH3:4])=[O:7])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 1.5 h

Procedure:
To a stirred suspension of sodium hydride, derived from 10.56 g. of a 50% suspension in mineral oil, in 400 ml. of 1,2-dimethoxyethane was added 51.6 g. of diethyl ethoxycarbonylmethylphosphonate, during 1 hour. When gas evolution ceased, a solution of 47.7 g. of 4-nitrobenzophenone in 400 ml. of 1,2-dimethoxyethane was added, dropwise, during 1.5 hours. Stirring was continued overnight and then the solvent was removed by evaporation in vacuo. The residue was partitioned between ethyl acetate and water. The layers were separated, and the water layer was extracted with fresh ethyl acetate. The combined ethyl acetate solutions were evaporated in vacuo to give the title compound as an oil, which slowly solidified.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34]/[C:35](=[CH:39]\[CH:40]1[C:45]([CH3:47])([CH3:46])[CH2:44][CH2:43][CH:42]=[C:41]1[CH3:48])/[C:36](=O)[CH3:37]>>[CH3:37][C:36](/[C:35](/[CH3:34])=[CH:39]/[CH:40]1[C:45]([CH3:47])([CH3:46])[CH2:44][CH2:43][CH:42]=[C:41]1[CH3:48])=[CH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)/C(C)=C/C1C(C)=CCCC1(C)C
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(=CCc1ccccc1)/C(C)=C/C1C(C)=CCCC1(C)C
Yield: 19.5 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (2.80 g, 6.26 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 3.9 mL, 6.26 mmol, 1.0 equiv.) and (E)-3-methyl-4-(2,6,6-trimethylcyclohex-2-enyl)but-3-en-2-one (1.94 g, 9.39 mmol, 1.5 equiv.), 0.36 g (20%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 995:5).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][NH2:19])[O:15][C:14]1=[O:20])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][NH:19][C:21](=[O:23])[CH3:22])[O:15][C:14]1=[O:20])[CH3:2]
Reactant: CCc1ccc2nc(C)[nH]c2c1N1CC(CN)OC1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1ccc2nc(C)[nH]c2c1N1CC(CNC(C)=O)OC1=O
Reaction time: 2 h

Procedure:
A mixture of (±)-3-(5'-1-Ethyl-2-methylbenzimidazolyl)-5-(aminomethyl)oxazolidin-2-one (XL, EXAMPLE 71, 0.100 g) in pyridine (2 ml) and acetic anhydride (1 ml) is stirred under nitrogen for 2 hrs. The mixture is then concentrated under reduced pressure to give the title compound, no further purification is necessary by analysis, mp 217°-218°, NMR (CDCl3 /DMF-d7, 300 MHz) 7.74, 7.52, 4.80, 4.27, 3.93, 3.58, 2.61 and 1.38 δ; CMR (DMF-d7, 75.47 MHz) 13.06, 14.67, 22.2, 38.65, 42.2, 72.01, 101.7, 109.34, 109.96, 114.57, 132.5, 134.2, 143.3, 153.5, 155.7 and 171.7 δ.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)=O)(C)(C)C>>[C:1]1([C:7]2[O:11][C:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:32][C@H:28]4[CH2:29][CH2:30][CH2:31][NH:27]4)=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(Cc2ccc(-c3ccccc3)o2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Product: c1ccc(-c2ccc(Cc3ccc(OC[C@H]4CCCN4)cc3)o2)cc1
Yield: 60 %

Procedure:
The title compound (80 mg, 50%) was prepared from the product of step 4 (0.1 g, 0.4 mmol) and (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.17 g, 0.48 mmol) using the procedure of Example 154, step 3; 1HNMR (400 MHz, CD3OD) δ 7.58 (d, J=8 Hz, 2H), 7.32 (t, J=6 Hz, 2H), 7.26 (d, J=8 Hz, 2H), 7.19 (t, J=8 Hz, 1H), 7.17 (d, J=3.6 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 6.63 (d, J=3.2 Hz, 1H), 6.09 (d, J=3.2 Hz, 1H), 4.32 (dd, J=7.2, 3.6 Hz, 1H), 4.08 (t, J=9.4 Hz, 1H), 4.01 (m, 1H), 3.98 (s, 2H), 3.35 (m, 2H), 2.25 (m, 1H), 2.11 (m, 2H), 1.98 (m, 1H); LC/MS (ESI+) m/z: 91%; 334 (M+1, 100).
Reaction SMILES: FC1C=C(C2C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=2)C=CC=1F.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C:34]1[CH:35]=[C:36]([C:45]([O:47]C)=[O:46])[C:37](=[O:44])[N:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[N:39]=1>>[C:45]([C:36]1[C:37](=[O:44])[N:38]([CH2:40][CH:41]([CH3:42])[CH3:43])[N:39]=[C:34]([C:28]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=2[F:26])[CH:35]=1)([OH:47])=[O:46]
Reactant: COC(=O)c1cc(-c2ccc(F)cc2F)nn(CC(C)C)c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(C(=O)O)c1=O

Procedure:
Following the procedure of Example 1 (7), 6-(2,4-difluorophenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as slightly yellow needles (yield: 92.7%).