Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH3:14].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([CH3:14])[CH:9]=1
Reactant: Cc1cc(F)ccc1Br
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccc(F)cc1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
n-Butyllithium (1.6 M in hexane, 109 mL, 0.175 mol) was added dropwise to a −78° C. solution of 1-bromo-4-fluoro-2-methylbenzene (30 g, 0.16 mol) in THF (500 mL) under N2. After complete addition, the reaction mixture was stirred for 1 h at −78° C. The bright yellow solution was quickly cannulated to another flask containing a pre-cooled (−78° C.) solution of diethyl oxalate (27.8 g, 0.19 mol) in THF (400 mL). After stirring for another 30 min at −78° C., the reaction mixture was quenched by the addition of saturated NH4Cl solution (800 mL). The aqueous layer was extracted with EtOAc (3×400 mL) and the combined organics were dried (Na2SO4), concentrated in vacuo and purified via silica gel chromatography to provide ethyl 2-(4-fluoro-2-methylphenyl)-2-oxoacetate (22.0 g, yield, 66% yield). 1H NMR (400 MHz, CDCl3): δ 7.73 (dd, J=9.2, 5.6 Hz, 1 H), 7.02-6.96 (m, 2 H), 4.40 (m, 2 H), 2.60 (s, 3 H), 1.29 (t, J=6.8 Hz, 3 H). MS (ESI) m/z: 233.0 [M+Na]+
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.Cl>C1COCC1.C(Cl)Cl>[F:1][C:2]1[C:10]2[CH:9]=[C:8]([B:16]([OH:21])[OH:17])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cccc2sccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: OB(O)c1cc2c(F)cccc2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 4-fluorobenzo[b]thiophene (80.4 mg, 0.528 mmol) in anhydrous THF (1 mL) was added n-butyllithium (0.363 mL, 0.581 mmol) dropwise. The reaction mixture was stirred at −78° C. for 60 minutes. A solution of triisopropyl borate (0.146 mL, 0.634 mmol) was added. The reaction mixture was stirred at −78° C. for 30 minutes and was then allowed to warm to room temperature over a 2 hour period. TLC showed completion of reaction. 1N HCl (100 mL) and DCM (50 mL) were added to the reaction mixture. The aqueous and organic layers were separated. The aqueous layer was concentrated to 50 mL, yielding a solid precipitate that was filtered and dried to give the title compound as off-white, needle-shaped crystals. The product was used without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:14]#[C:15]Br>ClCCl>[C:15]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)#[N:14]
Reactant: N#CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a cold (0° C.) solution of 1-Boc-piperazine (25 g, 0.13 mol) in dry dichloromethane (500 mL) was added TEA (52 mL, 0.40 mol) followed by a solution of cyanogen bromide (28.5 g, 0.27 mol) in anhydrous DCM (250 mL) over a period of 30 min. The reaction mixture was stirred at RT for 16 hours, then washed with a 10% aq. solution of sodium bicarbonate, water, brine and dried. The solvent was removed under vacuum and the residue was purified by flash chromatography (CHCl3/MeOH 95/5) to give 15 g (57%) of The title compound as a solid. TLC-CHCl3/MeOH (9/1): Rf=0.7.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]34[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]3)[NH:13][CH2:12]4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]34[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]3)[N:13]([CH2:19][C:20]3[CH:27]=[CH:26][C:23]([CH3:24])=[CH:22][CH:21]=3)[CH2:12]4)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Cc1ccc(C=O)cc1
Reactant: c1cc2[nH]ncc2cc1NC12CCC(CC1)NC2
Product: Cc1ccc(CN2CC3(Nc4ccc5[nH]ncc5c4)CCC2CC3)cc1

Procedure:
Reaction of Intermediate 26 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[O:9][C:8]1=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:19]([NH:21][C@H:22]([C:27](O)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20]>>[CH2:1]([C@@H:7]1[C:8](=[O:18])[O:9][C@H:10]1[CH2:11][CH:12]([O:17][C:27](=[O:28])[C@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:21][CH:19]=[O:20])[CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Reactant: CC(C)C[C@H](NC=O)C(=O)O
Product: C=CCCC(C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(C)C)NC=O

Procedure:
by esterifying (S)-3-hexyl-(S)-4-[(R)-2-hydroxy-5-hexenyl)-2-oxetanone with N-formyl-L-leucine there was obtained
Reaction SMILES: [C:1]1([P:7]([O:15][C:16]2[C@H:17]([CH3:40])[C@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].N1C=CN=C1.CO>CN(C)C=O>[Si:41]([O:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[C:16]([O:15][P:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[C@H:17]([CH3:40])[C@@H:18]12)[CH3:37])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of p-nitrobenzyl(1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (5.00 g, 8.41 mmol) in dimethylformamide (250 ml) were added t-butyldimethylsilyl chloride (2.54 g, 16.8 mmol) and imidazole (1.14 g, 16.8 mmol) in an ice bath, and the reaction mixture was stirred in the ice bath for 7 hours. After checking the completion of the reaction, methanol was added thereto and the resulting mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-(diphenylphosphoryloxy)-1-methylcarbapen-2-em-3-carboxylate (5.27 g, yield 88%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][C:12]2=[N:11][C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:30]Br>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH:18]=[C:19]([Br:30])[C:12]2=[N:11][C:10]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCC2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC=C2Br
Reaction time: 1 h
Yield: 43 %

Procedure:
A mixture intermediate 14, ethyl 3-benzyloxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate, (1.00 g, 3.05 mmol) and sodium acetate (1.50 g) in acetic acid (20 ml) was heated at 120° C. and then treated with a solution of bromine (1.5 g, 9.2 mmol) in acetic acid (5 ml). After 1 h at 120° C., the reaction mixture was cooled and concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.531 g (43% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.34 (3H, t, J=7.1 Hz, CH3), 2.60 (2H, m, CH2), 4.28 (2H, t, J=7.3 Hz, CH2), 4.38 (2H, q, J=7.1 Hz, OCH2), 5.34 (2H, s, OCH2), 7.05 (1H, t, J=4.8 Hz, CH), 7.3–7.52 (5H, m, aromatics).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][CH2:11][CH2:12][NH:13][CH3:14])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(O)C>[CH3:14][N:13]([CH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:15]=[CH:16][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=1)[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=2)[N:20]=1
Reactant: CNCCCOc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CN(CCCOc1ccc([N+](=O)[O-])cc1)Cc1ccc2cc([N+](=O)[O-])ccc2n1

Procedure:
N-[3-(4-Nitrophenoxy)propyl]methylamine hydrochloride (3.08 g, 12.49 mmol), 2-(chloromethyl)-6-nitroquinoline (2.78 g, 12.49 mmol), and potassium carbonate (3.45 g, 25.0 mmol) were stirred in 2:1 acetonitrile/ethanol (120 mL) at reflux for 18 hours. The mixture was concentrated and the residue was partitioned between 10% aqueous K2CO3 and 4:1 dichloromethane/isopropanol. The organic phase was dried, decolorized and concentrated to afford crude product which was purified by column chromatography (1:2 hexane/ethyl acetate). Yield: 2.63 g (53%) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[NH:9][N:8]=2)[CH:2]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:29][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:27][CH:26]=1>N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:9]([S:30]([C:28]3[S:29][C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)=[CH:26][CH:27]=3)(=[O:31])=[O:32])[N:8]=2)[CH:2]=1
Reactant: Oc1ccccc1C1CC(c2cccnc2)=NN1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc(-c2ccccn2)s1)N1N=C(c2cccnc2)CC1c1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To 2-(3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (29.85 mg, 0.1149 mmol) placed in a sealed tube was added a solution of 5-pyridin-2-ylthiophene-2-sulfonyl chloride (29.85 mg, 0.1045 mmol) in pyridine (0.5 mL). The reaction mixture was shaken at rt for 18 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (2.0 mL) and extracted with DCM. The organic solutions were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by RP-HPLC to give 2-{3-pyridin-3-yl-1-[(5-pyridin-2-yl-2-thienyl)sulfonyl]-4,5-dihydro-1H-pyrazol-5-yl}phenol (I-126) (14.50 mg, 30.0%). 1H NMR (300 MHz, d6-DMSO) δ: 9.77 (s, 1H), 8.87 (bd, 1H), 8.64 (dd, 1H), 8.56 (bd, 1H), 8.12 (dt, 1H), 8.03 (d, 1H), 7.87-7.92 (m, 2H), 7.72 (d, 1H), 7.48 (dd, 1H), 7.35-7.40 (m, 2H), 7.11-7.17 (m, 1H), 6.81-6.85 (m, 2H), 5.24 (dd, 1H), 3.74 (dd, 1H), and 3.20 (dd, 1H). LCMS: (FA) ES+ 463.0, ES-460.9.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)=[C:12]=S>>[C:5]1([CH:2]2[CH2:3][O:4][C:12]([NH:11][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[N:24]=[CH:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:27][CH:26]=5)[N:21]=4)=[CH:18][CH:19]=3)=[N:1]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccccc1
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(NC4=NC(c5ccccc5)CO4)cc3)n2)cc1

Procedure:
The title compound was prepared with 2-amino-2-phenylethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as a white solid (0.14 g, 30%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([NH:8][CH:9]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](OC)=[O:11])=[O:7])[CH3:4].C(O)C.[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH:31]=[CH2:32]>C1C=CC=CC=1>[CH2:3]([O:5][C:6]([N:8]1[CH2:32][CH:31]([C:30]([O:34][CH2:35][CH3:36])=[O:33])[C:10](=[O:11])[CH:9]1[CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)NC(C(=O)OC)C(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OCC)C(C(c2ccccc2)c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
To a suspension of 80% sodium hydride (2.48 g, 83 mmol) in benzene (50 ml) was slowly added a solution of methyl 2- ethoxycarbonylamino- 3,3-diphenylpropanoate (Example 1b, 27.0 g, 83 mmol) in benzene (200 ml) and the mixture then heated at reflux for 1 h. Ethanol (1.0 ml) followed by ethyl acrylate (8.95 ml, 83 mmol) were added and the reaction heated at reflux for 2 h, the solvent was then distilled off and the residue allowed to cool to room temperature. A solution of the residue in water was added to a concentrated sulphuric acid/ice mixture and the product extracted into ethyl acetate. The organic phase was washed with saturated brine and dried (MgSO4). The residue was chromatographed on silica gel in dichloromethane/methanol (97:3) to give 1,4-bis(ethoxycarbonyl)-2-(diphenylmethyl)-pyrrolidin-3-one, m/z (CI+) 396(MH). A solution of this oil in 1.0M oxalic acid was heated at reflux for 8 h, cooled and the product extracted into chloroform. After separation the chloroform was removed in vacuo and the residue chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluant to give 2-(diphenylmethyl)-1-ethoxycarbonylpyrrolidin-3 -one. 1H NMR (250 MHz, CDCl3) δ7.14-7.52 (10H, m), 4.80 (1H, br s), 4.68 (1H, vbr s), 4.18 (2H, br q), 3.94 (1H, vbs), 3.06 (1H, m), 2.34 (1H, m), 1.76 (1H, m), 1.22 (3H, t, J=7.0 Hz). m/z (CI+) 324(MH).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:18])[C:15]([F:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Cl:18][C:14]1[C:15]([F:17])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(F)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCc2cc(F)c(Cl)cc21
Reaction time: 3.5 h
Yield: 197.8 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (160 mg, 0.22 mmol) in methanol (3 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3.5 hours at 25 C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 93 mg of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.11 (m, 1H), 6.85 (m, 1H), 3.05-2.95 (m, 3H), 2.95-2.80 (m, 3H), 2.68 (m, 1H), 2.38 (bm, 1H), 1.31 (m, 3H). MS calculated for C11H13ClFN+H: 214, observed: 214.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9]>C(Cl)(Cl)Cl>[CH2:6]([O:5][C:1]([CH2:2][CH2:3][N:13]1[CH2:14][CH2:15][N:10]([CH:8]=[O:9])[CH2:11][CH2:12]1)=[O:4])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: O=CN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCN1CCN(C=O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.6 %

Procedure:
Ethyl acrylate (326 g) and chloroform (2 liters) are added to 1-formylpiperazine (320 g) and the mixture is stirred at room temperature for 3 days. The solvent is evaporated under reduced pressure to yield crude 4-ethoxycarbonylethyl-1-formylpiperazine (580 g) as an orange oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:14].[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>CN(C=O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:13]([C:3]2[C:4](=[O:12])[NH:5][C:6]3[C:11]([C:2]=2[NH:41][CH2:40][C:39]2[CH:42]=[CH:43][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:14])=[CH:18][CH:19]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2c(Cl)c3ccccc3[nH]c2=O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(CNc2c(C(=O)N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)c(=O)[nH]c3ccccc23)cc1
Temperature: 100 °C
Yield: 70.5 %

Procedure:
4-chloro-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (Example 74b) (4.25 g, 9.18 mmol) was dissolved in DMF (20 mL), and 4-methoxybenzylamine (2.68 mL, 20.6 mmol) was added. The reaction was heated at 100° C. for 1.5 hours, then cooled to room temperature and poured into ice water (300 mL). The resultant precipitate was collected by filtration and further chromatographed on silica gel (0% to 20% MeOH in dichloromethane) to give crude N,N-bis(4-methoxybenzyl)-4-(4-methoxybenzylamino)-2-oxo-1,2-dihydroquinoline-3-carboxamide (3.65 g, 71%), which was used without further purification. MS 564 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12])=[C:6]([CH:16]=[CH2:17])[CH:5]=1)[CH3:3].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:1][CH:2]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12])=[C:6]([CH:16]=[CH2:17])[CH:5]=2)[CH3:3])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: C=Cc1cc(C(C)N)ccc1NS(=O)(=O)C=C
Product: C=Cc1cc(C(C)NC(=O)Nc2ccc(C(C)(C)C)cc2)ccc1NS(=O)(=O)C=C
Reaction time: 5 h
Yield: 200 %

Procedure:
Ethenesulfonic acid [4-(1-amino-ethyl)-2-vinyl-phenyl]-amide (15.6 mg, 0.04 mmol), 4-tert-butyl phenylisocyanate (1.2 eq, 0.053 mmol, 9.45 μl), and TEA (1.2 eq, 0.12 mmol, 16.73 μl) were added in MC. The reaction mixture was stirred for 5 hrs. The reaction mixture was extracted with methylene chloride. A combined organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified with column chromatography (n-Hx:EA=3:1->2:1) to yield title compound (34.2 mg, 40%).
Reaction SMILES: Cl.[CH3:2][N:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH:16]([CH3:18])[CH3:17])[NH:14][C:13](=[O:19])[C:12]=2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH3:4].CC([O:32][CH2:33][C@H:34]1[O:39][C@H:38](Br)[C@H:37]([O:41]C(C)=O)[C@@H:36]([O:45]C(C)=O)[C@@H:35]1[O:49]C(C)=O)=O.[OH-].[Na+]>ClCCl>[CH:16]([N:15]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([N:3]([CH3:2])[CH3:4])=[CH:6][CH:7]=2)=[C:12]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:13]([O:19][C@@H:38]2[O:39][C@H:34]([CH2:33][OH:32])[C@@H:35]([OH:49])[C@H:36]([OH:45])[C@H:37]2[OH:41])=[N:14]1)([CH3:17])[CH3:18]
Reactant: COc1ccc(Cc2c(-c3ccc(N(C)C)cc3)n(C(C)C)[nH]c2=O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(C(C)C)c2-c2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
To a suspension of 5-[4-(N,N-dimethylamino)phenyl]-1-isopropyl-4-(4-methoxyphenyl)methyl-3H-pyrazole-3-on hydrochloride (0.051 g), acetobromo-α-D-glucose (0.16 g) and benzyl(n-tributyl)ammonium chloride (0.12 g) in dichloromethane (3 mL) was added sodium hydroxide (2 mol/L, 0.19 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent:ethyl acetate). The obtained semi purified 1-isopropyl-4-(4-methoxyphenylmethyl)-5-[4-(N,N-dimethyl-amino)phenyl]-3-(2,3,4,6-tetraacetyl-β-D-glucopyranosyloxy)-1H-pyrazoel was dissolved in methanol, and sodium methoxide (28% methanol solution, 0.02 mL) was added to the solution. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELLPAC C18UG80, 5μM, 20×50 mm, flowrate 30 mL/min linear gradient, water/methanol=90/10-10/90) to give the title compound (0.040 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[O:15][C:14]([P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:12]=3)[N:7]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:6]=2[C:5]([CH2:28][CH2:29][CH2:30][CH2:31]O)=[CH:4][C:3]=1[F:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[NH2:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[O:15][C:14]([P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:12]=3)[N:7]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:6]=2[C:5]([CH2:28][CH2:29][CH2:30][CH2:31][Br:54])=[CH:4][C:3]=1[F:33]
Reactant: BrC(Br)(Br)Br
Reactant: CCOP(=O)(OCC)c1ccc(-c2nc3c(N)c(F)cc(CCCCO)c3n2CC(C)C)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc(-c2nc3c(N)c(F)cc(CCCCBr)c3n2CC(C)C)o1

Procedure:
To a cold (0° C.) solution of 1.0 mmol of 4-amino-7-(4-hydroxybutyl)-5-fluoro-1-isobutyl-2-(2-diethylphosphono-5-furanyl)benzimidazole in 20 mL of CH2Cl2 was added 3.0 mmol of PPh3 and 3.0 mmol of CBr4. After 40 min. at rt solvent was removed and the residue was subjected to chromatography to give 4-amino-7-(4-bromobutyl)-5-fluoro-1-isobutyl-2-(2-diethylphosphono-5-furanyl)benzimidazole. CCl4 gave the corresponding chloro compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[OH:13])([OH:3])=[O:2].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1F)([O-:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=1)([OH:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COc1ccc(CC(=O)O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CC(=O)O)c(Oc2cccc([N+](=O)[O-])c2)c1

Procedure:
A solution of 2-carboxymethyl-5-methoxyphenol (34.1 g, 0.187 mol), 2-nitrofluorobenzene (19.7 mL, 0.187 mol), and K2CO3 (65 g, 0.467 mol) in DMF (200 mL) was heated to 110° C. for 18 h. The solution was diluted with water (200 mL) and extracted with ethyl acetate. The ethyl acetate layer was concentrated to give the crude title compound which was used as is for the next step (57 g).