Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])/[C:5](=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[C:13]([O:23][CH3:24])[CH:12]=1)/[CH2:6][CH2:7][CH:8]=O)[CH3:2].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)(=O)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])/[C:5](=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[C:13]([O:23][CH3:24])[CH:12]=1)/[CH2:6][CH2:7][CH2:8][NH:31][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([F:26])[CH:28]=1)[CH3:2]
Reactant: NCc1cccc(F)c1
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCNCc1cccc(F)c1

Procedure:
To a methylene chloride (2.0 mL) solution of (E)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-5-oxo-valeric acid ethyl ester (142 mg), 3-fluorobenzylamine (141 μL), acetic acid (1.0 mL) and sodium triacetoxy borohydride (105 mg) were added one by one. After agitating reaction solution at room temperature overnight, a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, an elution solvent: ethyl acetate->ethyl acetate:ethanol=10:1), and 81 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[C:9](Br)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[CH3:10][C:9]([C:5]1[S:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: O=C(O)c1cccs1
Reactant: CC(C)(C)Br
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of 5.0 g (39.02 mmol) of thiophene-2-carboxylic acid (Aldrich Chemical Co.) in 100 mL of methylene chloride stirred at 0° C. was added 11 g (82.5 mmol) of AICl3 and 5.8 g (43.0 mmol) of t-butyl bromide. The solution was stirred at room temperature for 18 hours then poured into 100 mL of ice water, and the mixture was extracted with ether. The extracts were washed with brine and dried over MgSO4, then concentrated to give 3.33 g of the title product. MS (M+H)+ : 202. NMR (CDCl3) δ:1.42 (s, 9H), 6.89 (d, 1H, J=4 Hz), 7.72 (d, 1H, J=4 Hz).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=[O:23])([O-])[O-].[Na+].[Na+].OO.Cl.S([O-])([O-])=O.[Na+].[Na+]>O.C(#N)C.C1CCCCC1>[CH:20]1([O:23][N:13]2[C:14]([CH3:17])([CH3:16])[CH2:15][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][C:12]2([CH3:19])[CH3:18])[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: OO
Solvent: C1CCCCC1
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 6.48 g (24.8 mmol) of 4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 1/100th of a solution of 0.270 g of anhydrous sodium carbonate diluted with water to a mass of 100 g (0.00270 g, 0.0254 mmol), and 37 ml of acetonitrile is heated to 80° C. A solution of 3.68 g (54 mmol) of 50% aqueous hydrogen peroxide is added to the reaction mixture over 1.75 hours while the temperature is brought to and maintained at reflux. After the peroxide is added, the reaction mixture is heated at 80° C. for 5 hours, then kept at room temperature overnight. A total of 0.60 g (5.9 mmol) of concentrated hydrochloric acid in 8 ml of water is added to the reaction mixture in portions. After the addition of 25 ml of cyclohexane to the reaction mixture, the temperature is brought to reflux (62° C.). A solution of 0.134 g (0.496 mmol) of ferric chloride hexahydrate in 2.5 ml of water is added to the reaction mixture. A solution of 6.96 g (102 mmol) of 50% aqueous peroxide is added dropwise over 3.25 hours to the reaction mixture while the temperature is maintained at 62° C. After the peroxide is added, the reaction mixture is stirred at reflux for 2 hours. Upon cooling, residual peroxide is decomposed by the addition of aqueous sodium sulfite solution. Work-up with ethyl acetate and purification by flash chromatography afford 3.06 g (34% overall yield) of the title compound. GC assay is 92%.
Reaction SMILES: COC([C:5]1([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:9][CH2:8][C:7]([CH2:15][O:16][CH2:17][O:18][CH3:19])([CH2:10][O:11][CH2:12][O:13][CH3:14])[C:6]1=[O:20])=O.C(N(CC)CC)C.Cl.C(N(CC)CC)C.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C)C(=O)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH:5]2[C:6](=[O:20])[C:7]([CH2:10][O:11][CH2:12][O:13][CH3:14])([CH2:15][O:16][CH2:17][O:18][CH3:19])[CH2:8][CH2:9]2)=[CH:27][CH:26]=1
Reactant: COCOCC1(COCOC)CCC(Cc2ccc(Cl)cc2)(C(=O)OC)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCOCC1(COCOC)CCC(Cc2ccc(Cl)cc2)C1=O
Temperature: 130 °C
Reaction time: 8 h

Procedure:
In 1-(4-chlorobenzyl)-3,3-bis((methoxymethoxy)methyl)-2-oxocyclopentane carboxylic acid methyl ester (2.0 g, 0.00482 mol), N,N-dimethylacetamide (2 mL), triethylamine (0.20 mL, 0.00482×0.3 mol), and triethylamine hydrochloride (0.995 g, 0.0482×1.5 mol) were added and stirred at 130° C. for 8 hours. In the reaction liquid, ethyl acetate and saturated sodium bicarbonate water were added, and the mixture was partitioned. After extracting the aqueous layer using ethyl acetate, the organic layer was dried using anhydrous sodium sulfate and concentrated. Thereafter, the dried and concentrated product was purified using a silica gel column, and a target product was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:3]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].[Cl-].[NH4+]>O1CCCC1>[CH:22]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:3]=1)=[O:23]
Reactant: Cc1ccc(-c2cc(Br)ccn2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C=O)ccn2)cc1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-bromo-2-(4-methylphenyl)pyridine (3.2 g) in 30 ml of tetrahydrofuran was cooled to -70° C., and 1.6M n-butyl lithium (8.1 ml) was added. The solution was stirred for 15 minutes at -70° C., and then dimethylformamide (1.3 ml) added. The mixture was allowed to warm slowly to room temperature over a period of 2 hours, and aqueous saturated ammonium chloride solution added. The mixture was partitioned between methylene chloride and water, the organic layer separated and dried over sodium sulfate, the solvent evaporated under reduced pressure, and the residue flash-chromatographed on silica gel, eluting with 20% ethyl acetate in heptane, to yield 0.81 g of 4-formyl-2-(4-methylphenyl)pyridine, m.p. 66° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13])#[N:2].[SH2:14]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13])(=[S:14])[NH2:2]
Reactant: S
Reactant: N#Cc1cccc2c1CCCC2=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1cccc2c1CCCC2=O

Procedure:
Analogously to Example 29a), 10.6 g (62 mmol) of 5-cyano-l-tetralone in 200 ml of pyridine and 8.6 ml of triethylamine are treated with hydrogen sulfide and worked up. There is thus obtained the title compound in the form of yellow crystals, m.p. 200°-205°.
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](O)=[C:6](N)[CH:5]=1)([O-])=O.COC1C=CC=CC=1[NH2:19]>>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]([NH2:19])=[CH:4][CH:9]=1)([O-:12])=[O:11]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Reactant: COc1ccccc1N
Product: Nc1ccc([N+](=O)[O-])cc1

Procedure:
If, in Example 10, the 4,6-dinitro-2-amino-phenol is replaced by 12.3 parts of 2-methoxy aniline and the 4-nitro aniline by 30.9 parts of 4-amino-4'-nitro-diphenylamine-2'-sulphonic acid, one obtains a dyestuff which dyes leathers from different tanning processes in shades which are much more yellow.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:7].[CH3:12][C:13]1([CH3:25])[CH2:19][NH:18][C:17](=O)[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[O:14]1>>[Cl:7][C:17]1[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[O:14][C:13]([CH3:25])([CH3:12])[CH2:19][N:18]=1
Reactant: CC1(C)CNC(=O)c2ccccc2O1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CN=C(Cl)c2ccccc2O1
Temperature: 25 °C
Yield: 112.8 %

Procedure:
After adding phosphorous oxychloride (5 mL) and phosphorous pentachloride (0.65 g, 3.13 mmol) to 2,2-dimethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.60 g, 3.13 mmol) (refer to the aforementioned Non-Patent Document 3 for a description of the synthesis method) at room temperature, the mixture was refluxed while heating for 5.5 hours. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure and the residue was poured over crushed ice. The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layer was washed twice with “saturated aqueous sodium bicarbonate solution (30 mL)+H2O (20 mL) and then with brine (30 mL) followed by drying with magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure to obtain 0.74 g of 5-chloro-2,2-dimethyl-2,3-dihydro-benzo[f][1,4]oxazepine in the form of a brown oily substance. This substance was used in the next reaction without purifying further.
Reaction SMILES: [CH:1]([C:4]1[NH:14][C:7]2=[CH:8][N:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]2[C:5]=1[CH:15]=[O:16])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:17]([N:14]1[C:7]2=[CH:8][N:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]2[C:5]([CH:15]=[O:16])=[C:4]1[CH:1]([CH3:3])[CH3:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc2c(C=O)c(C(C)C)[nH]c2cn1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (Compound 6, 110 mg, 0.50 mmol), benzyl bromide (0.18 ml, 1.50 mmol), and K2CO3 (208 mg, 1.50 mmol) in DMF (2.5 ml) was stirred at room temperature for 4 h. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (50% EtOAc-hexanes) to yield the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:56]1[CH2:61][CH2:60][S:59](=[O:63])(=[O:62])[CH2:58][CH2:57]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:56]4[CH2:61][CH2:60][S:59](=[O:63])(=[O:62])[CH2:58][CH2:57]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and thiomorpholine-S,S-dioxide (0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (80 mg, 87%) which was obtained as a white solid. MS: m/e=462.1 [M+H]+.
Reaction SMILES: C(O)(=O)CC.[BH4-].[Na+].[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:18][CH2:17][C:16](=[N:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][NH:14]1)=[O:12])[CH3:9].S(=O)(=O)(O)O.O.O.[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37]>C(OCC)(=O)C.C(O)C>[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37].[CH2:21]([O:20][NH:19][C@H:16]1[CH2:15][NH:14][C@H:13]([C:11]([O:10][CH2:8][CH3:9])=[O:12])[CH2:18][CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCC(=NOCc2ccccc2)CN1
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: 45 °C

Procedure:
Propanoic acid (34.9 ml, 466.2 mmol, 6 eq) was added to a suspension of sodium borohydride (5.75 g, 155.4 mmol, 2 eq) in ethyl acetate (160 ml) and held until the reaction was deemed to be complete. The resulting solution was added to a solution of (S)-5-Benzyloxyimino-piperidine-2-carboxylic acid ethyl ester in ethyl acetate (120 ml total volume) and sulfuric acid (20.7 ml, 388.5 mmol, 5 eq) at −20° C. and held until reaction was deemed to be complete. The reaction was quenched by the addition of water (240 ml), then neutralized with aqueous ammonia solution. The organic layer was washed with water and concentrated in vacuo to 80 ml. The solution was warmed to 45° C. and held at this temperature. Ethanol (80 ml, 95%) at 40° C. was added, followed by a freshly prepared solution of oxalic acid dihydrate (9.8 g, 77.7 mmol) in ethanol (40 ml). The mixture was cooled and the product was isolated by filtration. The solid was washed with an ethyl acetate/ethanol mixture, then with ethyl acetate. The solid was dried to give ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) as a single isomer (16.4 g, 44.5 mmol, 57.3%).
Reaction SMILES: C[O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:31]=[CH:32][C:7]=1[CH2:6]2)=[O:4].O.[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C.Cl>[F:39][C:36]1[CH:37]=[CH:38][C:33]([N:30]2[C:8]3[CH:9]=[C:10]4[C@:5]([C:3]([OH:4])=[O:2])([CH2:6][C:7]=3[CH:32]=[N:31]2)[CH2:14][N:13]([S:15]([C:18]2[CH:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH2:12][CH2:11]4)=[CH:34][CH:35]=1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Yield: 102.6 %

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid methyl ester (0.3 g) in tetrahydrofuran (10 mL) and water (10 mL) was treated with lithium hydroxide monohydrate (0.11 g) at 60° C. for 16 hours. The cooled mixture was diluted with ethyl acetate and 1.0 M aqueous hydrochloric acid solution. The aqueous phase was washed with ethyl acetate, the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the title compound as a foam (0.3 g). LCMS (Method G): 540.4 (M+H)+, Retention time 3.16 minutes.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]([CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH3:9])[C:5]([O-:7])=[O:6].[Na+].[CH2:18](Br)[C:19]#C.Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O1CCCC1>[O:3]=[C:4]([CH:8]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[C:9]#[C:18][CH3:19])[C:5]([OH:7])=[O:6]
Reactant: C#CCBr
Reactant: CC(C(=O)C(=O)[O-])c1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC#CC(C(=O)C(=O)O)c1ccc(Cl)cc1
Yield: 66 %

Procedure:
A 3N aqueous solution (1.0 ml) of sodium hydroxide and 5.0 ml of tetrahydrofuran were added to 0.57 g (2.4 mmoles) of sodium 2-oxo-3-(p-chlorophenyl)butanoate, and the mixture was stirred until a completely uniform solution formed. Then, 0.20 ml (2.7 mmoles) of propargyl bromide and 24 ml of triethylbenzylammonium chloride were added, and the mixture reacted at room temperature for 12 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ether. The ether layer was dried over magnesium sulfate. The drying reagent was separated by filtration, and the solvent was evaporated. The resulting oily product was purified to give the desired 2-oxo-3-(p-chlorophenyl)-hexynoic acid in a yield of 66 %.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C(#N)C>[Br:11][C:3]1[CH:4]=[CH:5][C:6]([N:8]([CH3:10])[CH3:9])=[N:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)c1cccc(F)n1
Solvent: CC#N
Product: CN(C)c1ccc(Br)c(F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 190 %

Procedure:
To a solution of Intermediate (6-fluoro-pyridin-2-yl)-dimethyl-amine (12.4 g, 88.4 mmol) in acetonitrile (400 mL) at 0° C. was added a solution of N-bromosuccinimide (7.87 g, 44.2 mmol) in acetonitrile (95 mL) dropwise over 15 min. The resulting solution was stirred at 0° C. for 1 hour. Another portion of N-bromosuccinimide (7.87 g, 44.2 mmol) in acetonitrile (95 mL) was subsequently added at 0° C. dropwise over 15 min. The solution was slowly warmed to room temperature and stirred overnight. The solution was concentrated in vacuo and diluted with dichloromethane (500 mL). This was washed with water (300 mL) and the aqueous layer back extracted with dichloromethane (3×200 mL), before drying over MgSO4, filtering, and concentrating in vacuo. The material was passed through a silica pad, eluting with 0-10% ethyl acetate in heptanes. The organics were concentrated in vacuo to afford desired material (18.4 g, 95% yield) that solidified upon standing. 1H NMR (CDCl3, 400 MHz) 5=7.48-7.67 (m, 1 H) 6.21 (dd, J=8.59, 1.56 Hz, 1 H) 3.05 (s, 6 H); MS (FID)=218.0 (M)+.
Reaction SMILES: C1C2C(COC([NH:18][C:19]([CH3:71])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:33]([O:65][CH3:66])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:63][CH3:64])[C@@H:43]([CH3:62])[C:44]([NH:46][C@@H:47]([CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>ClCCl>[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:33]([O:65][CH3:66])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:63][CH3:64])[C@@H:43]([CH3:62])[C:44]([NH:46][C@@H:47]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])([CH3:71])[NH2:18]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a stirring mixture of #122 (600 mg, 0.611 mmol, 1.00 eq.) in 15 mL of dichloromethane, diethylamine (5 mL, 50 mmol, 80 eq.) was added. The reaction was allowed to stir at room temperature for 3 hours. Reaction was concentrated in vacuo and mixture was purified by Silica Chromatography (Gradient: 0%-40% methanol in dichloromethane) producing #123 (0.46 g, 99%) as a solid. LC-MS (Protocol Q1): m/z 760.3 [M+H+] retention time=0.83 minutes. 1H NMR (400 MHz, CD3OD), δ 7.14-7.30 (m), 4.70-4.78 (m), 4.56-4.64 (m), 4.05-4.19 (m), 3.87 (dd), 3.79-3.84 (m), 3.72-3.77 (m), 3.62-3.70 (m), 3.46-3.56 (m), 3.37-3.45 (m), 3.33-3.36 (m), 3.16-3.24 (m), 3.09-3.11 (m), 2.98-3.05 (m), 2.95 (d), 2.91 (d), 2.87 (d), 2.83 (d),2.73-2.79 (m), 2.40-2.51 (m), 2.29-2.39 (m), 2.16-2.28 (m), 2.04-2.15 (m), 2.01 (s), 1.73-1.96 (m), 1.50-1.68 (m), 1.47-1.49 (m), 1.46 (s), 1.43 (s), 1.38 (s), 1.35 (d), 1.23-1.32 (m), 1.17-1.22 (m), 1.15 (d), 1.04-1.11 (m), 0.94-1.03 (m), 0.82-0.91 (m).
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@:3]12[O:29][CH3:30].N1C=CC=CC=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>C(Cl)Cl>[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43]([NH:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@:3]12[O:29][CH3:30])=[O:44]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2NC(=O)Cc1cccs1
Reaction time: 0.5 h

Procedure:
A solution of the major isomer of p-nitrobenzyl 7-amino-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate (53 mg., 0.12 mMol) in anhydrous CH2Cl2 (1 ml.) is cooled in an ice-bath and treated with pyridine (10.7 μl, 0.13 mMol) and 2-thienylacetyl chloride (17.8 μl., 0.13 mMol). The resulting solution is stirred in the cold for 30 mins., and then diluted with CH2Cl2, washed with H2O (3x) and brine, dried with MgSO4, filtered, and evaporated in vacuo. Crystallization of the residual yellow oil (66 mg.) from CH2Cl2 - hexane affords p-nitrobenzyl 7-(2-thienylacetamido)-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate as off-white crystals: mp 148°-151° C.; ir (neat) 3.04, 5.57, 5.74, 5.91, 6.54, 7.40, 8.1, 11.67, and 13.5μ; nmr (CDCl3) δ 2.05 (s, 3, COCH3), 3.23 (s, 3, OCH3), 3.38 (s, 2, SCH2), 3.82 (s, 2, thienyl-CH2), 4.75, 5.10 (ABq, 2, J=13Hz, CH2OAc), 5.32 (d, 1, J=9Hz, H7), 5.35 (s, 2, CH2Ar), 6.82 (d, 1, J=9Hz, NH), 6.95 (m, 2, thienyl-H), 7.23 (m, 1, thienyl-H), and 7.53, 8.17 (ABq, 4, J=9Hz, ArH); mass spectrum m/e 561 (M+), 381, 365, 321, and 200.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][CH:26]=[CH:27][C:28]=2[CH3:29])[O:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[S:25][CH:26]=[CH:27][C:28]=4[CH3:29])[O:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1ccsc1-c1nc(CCl)co1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Product: Cc1ccsc1-c1nc(COc2ccc(CCCCn3ccnc3)cc2)co1
Yield: 87 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was allowed to react with 4-chloromethyl-2-(3-methyl-2-thienyl)oxazole to give 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(3-methyl-2-thienyl)oxazole. The yield was 87%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 88-89° C.