Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]([C:13]([C:12]2[C:11]([Cl:10])=[N:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CNC(=O)c1ccc[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.7 %

Procedure:
To a mixture of 1H-pyrrole-2-carboxylic acid methylamide (430 mg, 3.5 mmol) and 2-chloronicotinoyl chloride (0.6 g, 3.4 mmol) in benzene (15 mL) at 0° C. was added a dropwise solution of tin (IV) chloride (1.6 g) in benzene (5 mL). The mixture was allowed to warm up slowly to room temperature and stirred for 4 hours. The reaction was diluted with ethyl acetate, washed with water, brine, dried and concentrated to give 320 mg (35%) of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid methylamide.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)(=O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([NH:8][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCNCc2ccccc2)CC1
Reaction time: 48 h
Yield: 43 %

Procedure:
Benzylamine (345 μl, 3.22 mmol, 1.1 eq) was added to a solution of tert-butyl 4-(2-(methyl-sulfonyloxy)ethyl)piperidine-1-carboxylate (0.9 g, 2.93 mmol, 1 eq) and triethylamine (0.8 ml, 5.86 mmol, 2 eq) in toluene (50 ml), and refluxing was carried out for 48 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated and the residue was taken up in ethyl acetate (100 ml), washed with water (30 ml) and sat. NaCl solution (40 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, ethyl acetate), a yellow solid was obtained. Yield: 43% (400 mg, 1.25 mmol).
Reaction SMILES: NC[CH2:3][N:4](CCN)[CH2:5]CN.[CH3:11][C:12]1([CH3:32])[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][N:20]([CH:26](N)[CH3:27])[CH2:19][CH2:18][N:17]([CH3:29])[CH2:16][C:15]([CH3:31])([CH3:30])[S:14][S:13]1>>[CH3:3][N:4]([CH2:27][CH2:26][N:20]1[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:12]([CH3:32])([CH3:11])[S:13][S:14][C:15]([CH3:31])([CH3:30])[CH2:16][N:17]([CH3:29])[CH2:18][CH2:19]1)[CH3:5]
Reactant: NCCN(CCN)CCN
Reactant: CC(N)N1CCN(C)CC(C)(C)SSC(C)(C)CN(C)CC1
Product: CN(C)CCN1CCN(C)CC(C)(C)SSC(C)(C)CN(C)CC1

Procedure:
1H NMR (300 MHz,in CDCl3): δ2.71 (t,J=6 Hz,4H,-N-CH2 -CH2 -N(CH3)-), 2.64 (s,4H,-N-CH2 -C(CH3)2-S-), 2.62 (t,J=6 Hz,4H,-N-CH2 -CH2 -N(CH3)-), 2.52 (m,2H,-CH2 -CH2 -N(CH3)2), 2.46 (m,2H,-CH2 -CH2 -N(CH3 (2), 2.37 (s,6H,-CH2 -N(CH3)-CH2 -), 2.25 (s,6H,-CH2 -CH2 -N(CH3)2) and 1.28 (s,12H,-S-C(CH3)2 -) ppm. 13C NMR (75 MHz, in CDCl3): δ74.8, 67.7, 57.6, 57.2, 53.9, 51.7, 51.3, 45.9, 45.1 and 26.9 ppm. MS (El; m/z): 376(4,M+), 377(2,M+ +1), 378(0.6,M+ +2), 318(1,M+ -((CH3)2N-CH2 ·)), 262 (3), 255 (1), 246(1), 187 (7), 156(9), 144(8), 133(9), 130(16), 113 (17), 101(27), 99(21), 98(12), 72(32), 71(28), 70(42), 58(100), 56(13), 55(13), 43(31), and 42(38).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[C:6](C(O)=O)[N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1.F[C:18](F)(F)[C:19](O)=O.C[N:25](C)C=O>CS(C)=O.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O>[Cl:2][C:3]1([NH:25][CH2:18][CH3:19])[CH:7]=[CH:6][N:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:4]1
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Cl)nn1-c1cccnc1
Agent: [Pd+2]
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CS(C)=O
Product: CCNC1(Cl)C=CN(c2cccnc2)N1
Temperature: 100 °C

Procedure:
3-Chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride (1.00 g, 2.50 mmol) was dissolved in a mixture of dimethylsulfoxide (0.625 mL) and N,N-dimethylformamide (11.9 ml). Trifluoroacetic acid (1.93 ml, 25.0 mmol) was added followed by the addition of palladium(II) trifluoroacetate (0.332 g, 1.00 mmol). The reaction was heated at 100° C. overnight, at which time LCMS indicated that a reaction had occurred but no desired product had been formed.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH2:15][C:14](=[O:16])[N:13]3[C:9](=[N:10][C:11]4[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:12]=43)[CH2:8]2)=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C=CC(C2CC(=O)N3C(=[N:37]C4C=CC(Cl)=CC=43)C2)=CC=1.N>O1CCOCC1.O>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:8][C:9]2[NH:10][C:11]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:12]=3[N:13]=2)[CH2:15][C:14]([NH2:37])=[O:16])=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3cc(Cl)ccc3n21
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)Cc2nc3ccc(Cl)cc3n21
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(-c2ccccc2)cc1

Procedure:
The 1:1-mixture of 3-(biphenyl-4-yl)-7-chloro-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one and 3-(biphenyl-4-yl)-8-chloro-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (200 mg) was dissolved in 1,4-dioxane (3 ml) at reflux temperature. A 25% solution of ammonia in water (1 ml) was added to give a light red solution. Refluxing was continued for 2 h while addition of 25% ammonia solution in 1 ml portions was repeated every half an hour (3 times). Then all volatiles were removed at the water aspirator and the residue was triturated with acetone to leave 3-(biphenyl-4-yl)-4-(5-chloro-2-benzimidazolyl)butyramide (165 mg) as light yellowish solid.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][S:11]/[C:10]/2=[N:14]\[C:15]([N:17]2[CH:21]=[CH:20][N+](C)=[CH:18]2)=[O:16])=[CH:5][CH:4]=1.[CH3:23]NCC#C.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][S:11]/[C:10]/2=[N:14]\[C:15](=[O:16])[N:17]([CH3:18])[CH2:21][C:20]#[CH:23])=[CH:7][CH:8]=1
Reactant: C#CCNC
Reactant: C[n+]1ccn(C(=O)/N=C2\SCCN2c2ccc(Cl)cc2)c1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN(C)C(=O)/N=C1\SCCN1c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
1-({[(2Z)-3-(4-Chlorophenyl)-1,3-thiazolidin-2-ylidene]amino}carbonyl)-3-methyl-1H-imidazol-3-ium iodide (97 mg, 0.216 mmol, Example 25B), N-methylprop-2-yn-1-amine (0.020 mL, 0.238 mmol) and diisopropylethylamine (0.041 mL, 0.238 mmol) were heated in acetonitrile at 65° C. After 1 hour, the mixture was concentrated and the residue was purified by chromatography over silica using dichloromethane:methanol 95:5 as eluant to provide the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:14]1[CH:29]=[CH:28][C:17]([C:18]([NH:20][C:21]2[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:1]([NH:27][C:22]1[C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:28]=[CH:29][C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])=[CH:15][CH:16]=2)=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2ccccc2)cc1
Yield: 53.7 %

Procedure:
Using the procedure described in Example 93, Part A, benzoyl chloride (0.80 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (0.75 mmol) yielded 150 mg (54%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15](Cl)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:18][C@@H:19]1[CH2:24][N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH3:33])=[CH:28][CH:27]=2)[CH2:22][C@H:21]([CH3:34])[N:20]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([N:32]([CH3:33])[C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:23]4[CH2:24][C@H:19]([CH3:18])[N:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:21]([CH3:34])[CH2:22]4)=[CH:31][CH:30]=3)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CNc1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)N(C)c1ccc(CN2C[C@@H](C)N(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid chloride from step 1 was taken up in DCM (3 mL) and added to a solution of 1,1-dimethylethyl (2R,6S)-2,6-dimethyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D9) (0.23 g, 0.693 mmol) in DCM (2 mL). Triethylamine (0.193 mL, 1.386 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was re-extracted with DCM (×2) and the combined organics were dried and concentrated. The crude product was purified by column chromatography. Elution with 0-50% EtOAc/petroleum yielded the title compound as a white foam (0.331 g). δH (CDCl3, 400 MHz) 7.89 (2H, m), 7.36 (1H, m), 7.26 (1H, m), 7.19 (2H, m), 7.10 (2H, t), 6.99 (2H, m), 4.00 (2H, m), 3.53 (3H, s), 3.34 (2H, s), 2.58 (3H, s), 2.44 (2H, d), 2.05 (2H, m), 1.44 (9H, s), 1.18 (6H, d). MS (ES): MH+ 547.3.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[F:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][C:27]2[O:31][C:30]([C:32]#[CH:33])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.[CH:36](=[O:38])[CH3:37]>C1COCC1>[F:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][C:27]2[O:31][C:30]([C:32]#[C:33][CH:36]([OH:38])[CH3:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1
Reactant: C#Cc1ccc(Oc2ccc(F)cc2)o1
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)C#Cc1ccc(Oc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
Lithium diisopropylamide was generated by the addition of n-butyl lithium (14.2 mL, 35,4 mmol, 2.5M in hexanes) to a stirred -78° C. THF (100 mL) solution as of diisopropylamine (3.58 g, 35.4 mmol) followed by warming to -5° C. (ice/methanol) and stirring for 0.5 hours. To this stirred solution was added the 2-[5-(4-fluorophenoxy)-2-furyl]-ethyne (6.5 g, 32.2 mmol) prepared in step 3 as a THF solution via syringe. The reaction was stirred 0.5 hours and acetaldehyde (3.11 g, 70.8 mmol) was added via syringe, the ice bath was removed, and the reaction warmed to room temperature. Water was added and most of the THF removed in vacuo. The resulting mixture was partitioned between water and ethyl acetate. The combined ethyl acetate layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (30% ether/hexanes) to give 6.39 g (73%) of 4-[5-(4-fluorophenoxy)-2-furyl]-3-butyne-2-ol as a slightly yellow solid. mp(ether/hexanes) 56°-57.5° C. 1H NMR (300 MHz, CDCl3) δ 1.54 (d, 3H, J=7 Hz), 1.88 (d, 1H, J=6 Hz), 4.75 (m, 1H), 5.47 (d, 1H, J=4 Hz), 6.53 (d, 1H, J=4 Hz), 7.04 (m, 4H). MS (DCI/NH3) m/e 247 (M+H)+, 229.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCCC1>[CH:18]1([NH:17][C:16]([NH:15][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
The half-ester of the formula (V) may be converted into an "activated" ester prior to reaction with the 7-(α-aminoarylacetamido)-Δ3 -cephem derivative, using the preferred reagent N-hydroxy-succinimide in the presence of a dehydrating agent such as dicyclohexylcarbodiimide. The "activated" ester product of the formula: ##STR10## is then conveniently reacted with the Δ3 -cephem derivative in the reaction solution in which it is formed, without any prior isolation being necessary. In a typical procedure, a solution of the half-ester, N-hydrogen-succinimide and a dehydrating agent in a reaction-inert organic solvent, e.g., tetrahydrofuran, is stirred for several hours at room temperature, after which the solid N,N'-dicyclohexylurea formed in the reaction is removed, preferably by means of filtration. To the solution containing the "activated" ester, there is then added a solution of the Δ3 -cephem derivative, and the reaction equilibrium generally shifts substantially to completion in the presence of a tertiary amine or inorganic base, as hereinbefore exemplified and preferably with stirring during a period from about 1 to about 12 hours at room temperature. The solvent may then be removed, e.g., by means of evaporation in vacuo, and the residue dissolved in water, with the aqueous solution then being acidified to a low pH value and subsequently extracted with a water-immiscible organic solvent, e.g., ethyl acetate. The resultant organic phase is then subjected to a procedure similar to that described in method (1) for the isolation and purification of the product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][N:3]1[CH2:5][C:6]([O:8]CC)=O.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.B(F)(F)F.[CH3:24][CH2:25][O:26]CC.C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[C:25]([N:3]1[CH:2]([CH3:1])[CH2:4][N:17]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[C:6](=[O:8])[CH2:5]1)(=[O:26])[CH3:24]
Reactant: CCOC(=O)CN1CC1C
Reactant: NCc1ccc(F)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (2-methylaziridin-1-yl)acetate (4.0 g, 28 mmol), 4-fluorobenzylamine (5.3 g, 42 mmol), and boron trifluoride etherate (0.5 mL) was heated in a sealed stainless steel vessel inside a Teflon liner at 95° C. for 60 h (Bull. Chem. Soc. Jpn. 1986, 59: 321). The resulting mixture was dissolved in dichloromethane (50 mL), cooled to 0° C., and treated with a mixture of triethylamine (13 mL, 95 mmol) and acetic anhydride (6.7 mL, 71 mmol). The reaction mixture was stirred at room temperature overnight, and extracted successively with saturated aqueous solution of sodium bicarbonate, dilute aqueous HCl, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a mixture of 7-10 % methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the title piperazinone.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCS[C@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 48 h
Yield: 55.1 %

Procedure:
A solution of 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranose (2.0 g, 6.5 mmol) and 1-bromohexadecane (2.0 g, 6.5 mmol) in dichloromethane (40 ml) containing triethylamine (1 ml) is kept under nitrogen for 2 days at room temperature. The reaction is worked up in the usual manner to give a syrup which is put on a silica gel column and eluted with 2-5% ethyl acetate in chloroform. The desired fractions are pooled and concentrated to dryness. Crystallization from aqueous ethanol gives hexadecyl 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranoside (1.9 g, 55%), m.p. 49°-50°, [α]D +9° (c, 1.5, chloroform).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C@@H:16]([C:18]2([C:21]([O:23]CC)=[O:22])[CH2:20][CH2:19]2)[C@H:15]([OH:26])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(OC)(O[CH3:31])(=O)=O.O>O1CCCC1>[CH2:3]([O:10][C:11]([N:13]1[CH2:14][C@H:15]([O:26][CH3:31])[C@@H:16]([C:18]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]2)[CH2:17]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)CC1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1(C(=O)O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (0.149 g, 3.73 mmol) was suspended in anhydrous tetrahydrofuran (20 ml) to which, after cooling to 0° C., was subsequently added dropwise a dry tetrahydrofuran (20 ml) solution of 1-benzyloxycarbonyl-3-(S)-hydroxy-4-(R)-(1-ethoxycarbonylcyclopropyl)pyrrolidine (0.98 g, 2.92 mmol) over a period of 5 minutes. After 15 minutes of stirring in an ice bath, dimethyl sulfate (0.441 ml, 4.66 mmol) was added dropwise to the reaction solution which was cooled in the ice bath. The reaction solution was stirred at room temperature for 4 hours and then mixed with water (0.5 ml), followed by evaporating tetrahydrofuran under reduced pressure. The thus obtained residue was dissolved in ethanol (40 ml), and a 1 M sodium hydroxide aqueous solution (8.76 ml) was added dropwise to the resulting solution at room temperature. The reaction solution was heated under reflux for 2 hours and then ethanol was evaporated under reduced pressure. The resulting residue was cooled in an ice bath, acidified by adding dropwise a 1 M hydrochloric acid aqueous solution (15 ml) and then extracted with ethyl acetate (50 ml×3). All of the organic layers were combined, washed with a 1 N hydrochloric acid aqueous solution (50 ml) and saturated brine (50 ml) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 0.935 g (quantitative) of the title compound as a colorless amorphous substance.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[F:15][C:16]([F:33])([F:32])[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26](=O)[C:27](OC)=[O:28].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:32][C:16]([F:15])([F:33])[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[C:26]1[C:27](=[O:28])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(C(F)(F)F)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccc(C(F)(F)F)cc45)C(=O)NC3=O)c21
Temperature: 50 °C
Yield: 34.9 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (208 mg, 1.1 mmol) and methyl 2-(5-trifluoromethyl-1H-indol-3-yl)oxoacetate (300 mg, 1.1 mmol) in DMF (5.4 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (1.1 mL, 1.1 mmol) at 4° C. under N2. The reaction was stirred for 20 min at this temperature, and additional KOtBu (2.2 mL, 2.2 mmol) was added. The resulting dark red solution was heated up to 50° C. over night. The mixture was cooled to room temperature and quenched with 1 N HCl (9 mL) and poured into EtOAc (300 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (150 mL), and brine (3×150 mL). The solution was dried (MgSO4), filtered, and concentrated to a red solid. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (157 mg, 35%) as a red solid, mp 270–280° C. dec. 1H NMR (DMSO-d6) δ 12.24 (s, 1H), 11.26 (s, 1H), 8.11 (s, 1H), 7.63 (m, 1H), 7.55 (m, 1H), 7.27 (m, 2H), 6.92 (m, 2H), 6.65 (s, 1H), 6.49 (s, 1H), 3.73 (s, 3H). MS (ESI): m/z=411 [C22H14F3N3O2+H]+
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][C:16]#[N:17]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[C:15](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)/[C:16]#[N:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc(F)cc2)cc1OC
Yield: 72.5 %

Procedure:
4-Fluorobenzaldehyde (620 mg) and 3,4-dimethoxybenzyl cyanide (880 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (1.02 g, yield: 72%).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[OH-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.O>[C:31]([O:30][C:28]([N:20]([CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:19][CH2:18][CH2:17][O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)c1oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)O)oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c12
Yield: 96.5 %

Procedure:
4-[3-(tert-Butoxycarbonyl-pyridin-3-ylmethyl-amino)-propoxy]-3-methyl-benzofuran-2-carboxylic acid ethyl ester (634 mg), the first intermediate of Example 87, was stirred with lithium hydroxide (113 mg) in tetrahydrofuran (2.7 ml) and water (2.7 ml) at 50° C. overnight. 2N HCl (1.35 ml) and ethyl acetate were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was obtained as a colorless foam (575 mg, 97%). The foam was used as a starting material in the next step without further purification. ESI-MS: m/z 441 (MH+); 1H-NMR δ: 1.51 (9H, s), 2.05-2.11 (2H, m), 2.74 (3H, s), 3.44 (2H, m), 4.02 (2H, t, J=5.4 Hz), 4,51 (2H, s), 6.51 (1H, d, J=7.6 Hz), 7.14 (1H, d, J=8.3 Hz), 7.23-7.34 (2H, m), 7.79 (1H, br), 8.51 (1H, dd, J=1.3, 5.0 Hz), 8.59 (1H, m).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Cl.[C:21](=[O:24])([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:24][C:21]1[CH:6]=[C:5]([CH:4]=[CH:3][CH:2]=1)[C:10]#[N:1]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c1

Procedure:
A solution of 0.65 g (5.4 mmol) 3-hydroxybenzoinitirle, 1.5 g (5.3 mmol) of 3-(2-quinolinylmethyloxy)benzyl chloride, and 0.75 g (5.4 mmol) of potassium carbonate in 15 ml of DMF is heated at 60° C. overnight. The reaction mixture is poured into water. The precipitated product is collected on a filter and purified by dry column chromatography to give 3-[3-(2-quinolinylmethyloxy)benzyloxy]benzonitrile. (M.P. 86°-87° C.)