Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC2C3N(C=C(C4N(C(C)C)N=C(C)N=4)N=3)CCOC=2C=1.[Br:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([F:34])[CH:27]=1.[NH2:35][OH:36]>>[Br:25][C:26]1[CH:33]=[CH:32][C:29]([C:30](=[NH:31])[NH:35][OH:36])=[C:28]([F:34])[CH:27]=1
Reactant: NO
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Product: N=C(NO)c1ccc(Br)cc1F

Procedure:
Scheme 10 shows the synthesis of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine III from 4-bromo-2-fluorobenzonitrile 11. Addition of hydroxylamine to the nitrile of 11 gave 4-bromo-2-fluoro-N-hydroxybenzimidamide 24. Michael addition of 24 to ethyl propiolate gave ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25. Heating 25 in a high-boiling solvent such as toluene, xylene, ethylbenzene, or diphenyl oxide gave cyclized imidazole, ethyl 2-(4-bromo-2-fluorophenyl)-1H-imidazole-4-carboxylate 26, along with by-product pyrimidine, 2-(4-bromo-2-fluorophenyl)pyrimidin-4-ol. Alternatively, 25 can be cyclized to 26 with catalytic Lewis acids such as Cu(I) or Cu(II) salts. Alkylation of 26 with a 2-hydroxyethylation reagent, such as 1,3-dioxolan-2-one, in a base, such as N-methylimidazole or cesium carbonate, gave ethyl 2-(4-bromo-2-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazole-4-carboxylate 27. Ring-cyclization of 27 with an aqueous basic reagent, such as potassium hydroxide, lithium hydroxide, and methyl tributylammonium hydrochloride, gave 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid 28. Addition of acetamidine to 28 with triphenylphosphine gave 9-bromo-N-(1-iminoethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide 29. Ring-cyclization of 29 with isopropylhydrazine hydrochloride 4 in acetic acid gave 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine III.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(NCC)C.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Solvent: CCNCC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Fmoc-Leu-Leu-OBzl (2-MeO-4-OC12OC22) (1.02 g) was dissolved in chloroform (10 mL), and diethylamine (1.94 mL, 18.7 mmol) was added dropwise under ice-cooling. The mixture was warmed to room temperature, acetonitrile (5 mL) was added, and the mixture was stirred for 2.5 hr. Diethylamine (970 μL, 9.35 mmol) was added, and the mixture was further stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was precipitated with acetonitrile (10 mL) to give Leu-Leu-OBzl (2-MeO-4-OC12OC22) as wet crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]([C:10](=[O:12])[NH2:11])([F:9])[F:8])C.C(O)C.[O-]CC.[Na+].Cl>C(O)C.O1CCOCC1>[F:8][C:7]1([F:9])[CH2:6][CH2:5][C:4](=[O:3])[NH:11][C:10]1=[O:12]
Reactant: CCOC(=O)CCC(F)(F)C(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C1CCC(F)(F)C(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
4-carbamoyl-4,4-difluoro butyric acid ethyl ester (18 g) synthesized in Section (2) was dissolved in ethanol (100 mL) and a 1.0 N sodium ethoxide ethanol solution (105 mL) was slowly added thereto. After stirring for 3 hours at room temperature, the mixture was adjusted to a pH of 3 to 4 by addition of 3.0 N hydrochloric acid in dioxane, and the resulting NaCl was removed by filtration. The highly viscous oil was slurried with diethyl ether (100 mL). The resulting white solid was filtered and dried to give 11.4 g of the title compound.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14]>>[CH2:9]([OH:10])[C@@H:7]([OH:8])[CH:5]([OH:6])[C@H:3]([OH:4])[CH2:2][OH:1].[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)C(O)[C@H](O)CO

Procedure:
Production of D-lyxose, which is a rare sugar, from D-glucose was carried out. By using yeast Candida famata R28, D-arabitol was produced from D-glucose with a yield of 50%. This reaction was carried out by a fermentation method. The produced D-arabitol was converted into D-xylulose by an acetic acid bacterium Acetobacter aceti IFO 3281 with a yield of almost 100%. This could be isomerized to D-lyxose by using L-ribose isomerase. The product was purified and crystallized by ion exchange chromatography and the like, and it was confirmed to be D-lyxose by an instrumental analysis.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][CH2:20][CH2:19]4)=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].N#N.[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42]>C1COCC1.C(O)C>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21][CH2:20][CH2:19]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1CCCc2ccccc21
Agent: N#N
Agent: O=C(O)/C=C/C(=O)O
Agent: [Al+3]
Solvent: CCO
Solvent: C1CCOC1
Product: Fc1ccc2c(C3CCN(CCN4CCCc5ccccc54)CC3)noc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(1,2,3,4-tetrahydroquinolin-1-yl)ethanone (5.5 g, 14 mmol) in THF (50 ml) was charged with lithium aluminum hydride (17 ml, 17 mmol, 1M in ether) dropwise under N2 at room temperature. The mixture was stirred for 8 hours at room temperature. At the end of this period the excess of hydride was quenched with ice chips and 3 ml of 20% NaOH. The mixture was diluted with EtOAc (150 ml) and stirred for 1 hour. The EtOAc was dried with MgSO4 and filtered. The solvent was removed to dryness. The residue was purified by flash chromatography over a silica gel column (SiO2, 55 g; eluted with 1-3% CH3OH: DCM). The product thus obtained weighed 1.83 g. This material was dissolved into hot ethanol and was treated with a solution of fumaric acid (700 mg) in ethanol. The crystals were collected and weighed 1.85 g, m.p. 192°-193° C. ANALYSIS: Calculated for C23H26FN3O.C4H4O4 : 65.44%C 6.10%H 8.48%N Found: 65.20%C 6.19%H 8.32%N
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[C:34]([C:39]([OH:41])=O)=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.[CH3:42][NH:43][CH3:44].O1CCCC1>CN1CCCC1=O>[CH3:42][N:43]([CH3:44])[C:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[CH:29]=[CH:28][C:27]([C:25]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:26])=[CH:32][CH:31]=1)=[O:41]
Reactant: O=C(O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: CNC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-carboxylic acid of Example 65 (92 mg, 0.17 mmol) in 1-methyl-2-pyrrolidinone (4.5 mL) was added a 2.0 M solution of dimethylamine in tetrahydrofuran (0.42 mL, 0.848 mmol) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,tetramethyluronium hexafluorophosphate (71 mg, 0.187 mmol) and the reaction mixture stirred at room temperature under nitrogen for 2 hours. The reaction mixture was then partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a white foam. Purification by flash chromatography using a solvent gradient of 1 to 7% methanol in dichloromethane gave a colorless glass that was crystallized from ethyl acetate/hexane to afford the title compound 0.082 g, 85%) as a white solid, m.p. 206-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2-methylphenol (101 mg, 0.71 mmol) was dissolved in tetrahydrofuran (2.1 mL) and the solution was treated with sodium hydride (60% dispersed in mineral oil, 31 mg, 0.78 mmol). After stirring for 30 minutes at 22° C., 2-chloro-5-nitropyridine (101 mg, 0.64 mmol) was added and the reaction mixture was heated to reflux for 1 hour. The solution was cooled to ambient temperature, quenched with saturation aqueous NH4Cl and concentrated in vacuo. The residue was redissolved in ethyl acetate then washed 2× with saturated NaHCO3, saturated NaCl, dried over anhydrous Na2SO4 and concentrated in vacuo.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:18][O:19][P:20]([O-:23])[O:21][CH3:22]>>[CH3:18][O:19][P:20]([O:21][CH3:22])([C:2]([OH:1])([CH2:8][C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:23]
Reactant: COP([O-])OC
Reactant: CCOC(=O)C(=O)Cc1cnc2ccccn12
Product: CCOC(=O)C(O)(Cc1cnc2ccccn12)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of ethyl 2-oxo-3-(imidazo[1,2-a]pyridin-3-yl)propanoate (2.32 g; 0.01 mole) in 5.5 g (0.05 mole) of dimethylphosphite is stirred at ambient temperature for 3 days. The excess dimethylphosphite is removed under high vacuum on a rotary evaporator at a bath temperature of about 55° to give the crude product. This is purified by flash chromatography on silica gel to afford ethyl 2-dimethoxyphosphinyl-2-hydroxy-3-(imidazo[1,2-a]pyridin-3-yl)propanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([C:29]([NH2:32])([CH3:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:32][C:29]([CH3:31])([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:33])[F:34])[CH:24]=3)[CH3:30])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)O)c1=O
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)NC(C)(C)c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 0.17 h

Procedure:
1.98 g (6.74 mmol) of [3-(4-chlorophenyl)-4-allyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 218A and 1.51 g (7.42 mmol) of 1-methyl-1-[(3-trifluoromethyl)phenyl]-ethylamine from Example 1A are placed in 50 ml of DMF and treated with 1.09 g (8.09 mmol) of HOBt. After 10 mins' stirring, 1.68 g (8.76 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at RT. For the workup, the reaction mixture is stirred with 500 ml of water. Next, the resulting precipitate is suction-filtered, washed with water and dried under high vacuum. 2.41 g (75% of theory) of the target compound are thus obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl.[C:24]1([S:30][CH3:31])[CH:29]=[CH:28][CH:27]=CC=1>N1C=CC=CC=1>[F:11][C:2]([F:1])([F:12])[C:3]([NH:5][CH:6]([CH3:7])[C:8]([C:24]1[S:30][CH:31]=[C:28]([CH3:27])[CH:29]=1)=[O:10])=[O:4]
Reactant: C[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: CSc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: c1ccncc1
Product: Cc1csc(C(=O)C(C)NC(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a stirred mixture of N-(trifluoroacetyl)-L-alanine (5.05 g, 27.3 mmol) and pyridine (0.3 mL) was added oxalyl chloride (7.62 g, 60 mmol) at 0° C. under a nitrogen atmosphere. The reaction mixture was then allowed to warm to room temperature and stirred for an additional 2 hrs. The reaction mixture was then concentrated under reduced pressure to provide an oil that was combined with 8 mL of thioanisole. The resulting solution was then added a solution of AlCl3 (76 mmol, about 2.8 eq. relative to the N-(trifluoroacetyl)-L-alanine, about 10 g) in thioanisole (7 mL) at 0° C. The resulting reaction mixture was then allowed to warm to room temperature and stirred for about 14 hrs. After stirring, the reaction mixture was poured into cold 1 N aqueous hydrochloric acid (200 mL) and the resulting mixture extracted with ethyl acetate (200 mL), the ethyl acetate dried (Na2SO4), and the ethyl acetate removed under reduced pressure to provide a residue that was purified by flash chromatography using a silica gel column eluted with ethyl acetate/hexane in a ratio of 1:9 to provide S (−)-2-[N-(trifluoroacetyl)amino]-1-(4-methylthiophenyl)-1-propanone (B) (35% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[C:5]([CH3:16])[NH:4][N:3]=1.[H-].[Na+].Cl[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:12])([CH3:13])[C:9]([CH3:15])([CH3:14])[O:8]2)=[C:5]([CH3:16])[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nn(COCC[Si](C)(C)C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reaction time: 1.5 h
Yield: 86 %

Procedure:
A stirred suspension of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.15 g, 0.68 mmol) in THF (5 mL) was treated with NaH (0.032 g, 60% dispersion in oil, 0.81 mmol) at r.t. After 5 minutes [2-(chloromethoxy)ethyl]-trimethylsilane (0.14 mL, 0.81 mmol) was added and the reaction mixture stirred for 1.5 h. The reaction mixture was quenched with water (5 mL), diluted with EtOAc (20 mL) and the organic fraction separated. The organic fraction was dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-40% EtOAc/hexanes) gave the title compound (0.206 g, 86%) as a clear oil. δH (CDCl3) 5.35 (2H, s), 3.60 (2H, m), 2.50 (3H, s), 2.35 (3H, s), 1.35 (12H, s), 0.90 (2H, m), 0.00 (9H, s). LCMS (ES+) 353.0 (M+H)+.
Reaction SMILES: C([Li])CCC.C1C2CC3C(=CC=CC=3)C=2C=CC=1.Cl[CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26].[CH2:27]([CH:34]1[C:46]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>CCCCCC.O1CCCC1.O>[CH2:20]([C:34]1([CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=2[C:41]2[C:46]1=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26]
Reactant: COCCOCCCl
Reactant: COCCOCCC1c2ccccc2-c2ccccc21
Agent: [Li]CCCC
Agent: c1ccc2c(c1)Cc1ccccc1-2
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COCCOCCC1(CCOCCOC)c2ccccc2-c2ccccc21
Temperature: 22 °C
Reaction time: 1 h

Procedure:
7.05 g of butyllithium dissolved in 44 ml of hexane was slowly added in 5 minutes into 18.28 g of fluorene dissolved in 150 ml of anhydrous tetrahydrofuran at -50° C. under nitrogen protection. The mixture was stirred at -30~15° C. for 1 hour before it was cooled again to -40~-50° C. Then, 15.23 g of 1-chloro-2-(2-methoxyethoxy)-ethane was added in 5 minutes. The mixture was subsequently stirred for 2 hours while the temperature was gradually increased to 22° C. The main product in the solution was 9-(3,6-dioxaheptyl)-fluorene as detected by GC-MS. This solution was then cooled to -50° C., and 7.1 g of butyllithium dissolved in 44 ml of hexane was slowly added in 5 minutes under nitrogen protection. The mixture was stirred at -30 to -15° C. for 1 hour before it was cooled again to 40 to -50° C. Then, 15.30 g of 1-chloro-2-(2-methoxyethoxy)-ethane was added during 5 minutes. The mixture was subsequently stirred for 5 hours at 22° C., dispersed in water, and extracted with ether. The etheral solution was washed with water and brine, dried with magnesium sulfate, and evaporated. The residue was distilled to collect 37.1 g (91%) of colorless liquid at 160° C./0.08 mm Hg. MS (m/z): 370 (M+), 219, 191, 178, 89, 59.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH2:10]>[Hg]>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:10][CH2:9][C:8]([N:7]([CH3:12])[CH3:6])=[O:11])[CH3:2]
Reactant: CCNCC
Reactant: C=CC(=O)N(C)C
Agent: [Hg]
Product: CCN(CC)CCC(=O)N(C)C

Procedure:
In accordance with this example, anhydrous diethylamine (44 grams) and N,N-dimethylacrylamide (60 grams) were heated at reflux temperature (about 56°-60° C.) for 48 hours. After this period of time, the reaction mixture was subjected to distillation to separate unreacted amine and amide followed by recovery of product in 86 per cent yield at 70° C. and 2 mm. mercury pressure. The liquid product (purity = about 95 per cent) is designated herein as Amine Catalyst V, and has the formula, (C2H5)2N-CH2CH2C(0)N(CH3)2. The structure of this novel product was confirmed by infrared functional analysis and purity by gas-liquid chromatographic analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=1.S(Cl)(Cl)(=O)=O.[CH3:18]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:18])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Cl)cc1F
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)Cc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(4-Chloro-2-fluorophenyl)acetic acid (25.0 g, 133 mmol) was dissolved in MeOH (133 mL). Sulfuryl dichloride (9.67 mL, 133 mmol) was then added, and the reaction was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated in vacuo to give the title compound which was used without further purification. MS (m/z)=203 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10]C(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].[OH-].[Na+].C1(CC(O)=O)C=CC=CC=1.CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.CN(C)C1C=CC(C=O)=CC=1.CO>P([O-])([O-])([O-])=O.C(O)(=O)C>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=C(O)Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Temperature: 28 °C
Reaction time: 0.17 h

Procedure:
An amount of penicillin acylase enzyme, either free or immobilized on the carrier, sufficient to contain about 50 I.U. of activity, was suspended in 60 ml of 7.5-pH phosphate buffer. The mixture was maintained at 28° C. in a vessel connected to a pH controller which electrometrically determined the pH and metered in sufficient 0.8 N sodium hydroxide solution to maintain the pH at approximately 8.0. A solution containing 5 g of penicillin G potassium salt in phosphate buffer, also at 28° C., was added to the vessel, and the rate of formation of phenylacetic acid by the enzyme-catalyzed hydrolysis of the penicillin G was determined from the rate of addition of sodium hydroxide solution to maintain the pH. The liquid in the vessel was sampled upon addition of the penicillin G salt and after 10 and 30 minutes. These samples (0.5 ml) were immediately mixed with 3 ml of a solution of 1 ml of 0.05 M sodium hydroxide, 2 ml of 20% acetic acid and 0.5% (weight-volume) p-dimethylaminobenzaldehyde/methanol, and were allowed to stand for 10 minutes. The amount of 6-aminopenicillanic acid formed was determined by spectrophotometrically measuring the light absorption of the mixture at a wave length of 415 nm.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[O:10][C:6]=2[C:5]([O:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:4][CH:3]=1.[CH2:23]([N:25]([CH2:31][CH3:32])[C:26](=[O:30])/[CH:27]=[CH:28]/[CH3:29])[CH3:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([C:9]1[O:10][C:6]2[C:5]([O:14][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[CH:4][CH:3]=[C:2](/[C:28](/[CH3:29])=[CH:27]/[C:26]([N:25]([CH2:31][CH3:32])[CH2:23][CH3:24])=[O:30])[C:7]=2[CH:8]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1cc2c(Br)ccc(OC(C)c3ccccc3)c2o1
Reactant: C/C=C/C(=O)N(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OC(C)c2ccccc2)c2oc(C(C)=O)cc12
Temperature: 84 °C
Yield: 43.6 %

Procedure:
1-[4-Bromo-7-(1-phenylethoxy)benzofuran-2-yl]ethanone (compound 3) (1.0 g, 2.79 mmol) and (E)-N,N-diethyl-2-butenamide (0.47 g, 3.35 mmol) were dissolved in triethylamine (10 ml), and the inside of the system was replaced by nitrogen gas. Palladium acetate (0.031 g, 0.14 mmol) and tri-o-tolylphosphine (0.085 g, 0.28 mmol) were added and the mixture was stirred with heating at 78-90° C. for 16 hr. After confirmation of the completion of the reaction by TLC, 5% HCl aqueous solution was added and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, dried over MgSO4, and the solvent was evaporated to give a brown oil. Purification by silica gel column chromatography (hexane:acetone=5:1) was performed to give (E)-3-[2-acetyl-7-(1-phenylethoxy)benzofuran-4-yl]-N,N-diethyl-2-butenamide (0.51 g, yield 43.6%) as a pale-yellow crystal.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:21][CH2:22]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Reactant: ICC1CCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CC4CCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and iodomethylcyclopentane.