Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.CS(C)=O.[CH2:11]([C:13]1[C:14]([C:25]2[CH:26]=[CH:27][C:28]3[N:29]([CH:31]=[C:32]([CH2:34][OH:35])[N:33]=3)[CH:30]=2)=[N:15][C:16]([O:23][CH3:24])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])[CH3:12].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:11]([C:13]1[C:14]([C:25]2[CH:26]=[CH:27][C:28]3[N:29]([CH:31]=[C:32]([CH:34]=[O:35])[N:33]=3)[CH:30]=2)=[N:15][C:16]([O:23][CH3:24])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])[CH3:12]
Reactant: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2nc(CO)cn2c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2nc(C=O)cn2c1
Temperature: 0 °C
Yield: 78.8 %

Procedure:
To SO3-pyr complex (0.320 g, 2.01 mmol) was added pyridine (0.16 mL, 2.02 mmol) and DMSO (0.36 mL, 5.07 mmol). Slurry was stirred at room temperature 10 min before DCM (2.0 mL) was added and mixture was cooled to 0° C. Then solution of methyl 5-ethyl-6-(2-(hydroxymethyl)imidazo[1,2-a]pyridin-6-yl)-2-methoxynicotinate (0.346 g, 1.01 mmol), Hunig's base (0.60 mL, 3.44 mmol) and DMSO (0.36 mL, 5.07 mmol) in DCM (4.0 mL) was added dropwise. Reaction mixture was stirred at 0° C. 30 min and LC/MS showed complete consumption of starting material. DCM was removed under reduced pressure and residue was treated with H2O (10 mL). Solid which was formed was collected by filtration affording methyl 5-ethyl-6-(2-formylimidazo[1,2-a]pyridin-6-yl)-2-methoxynicotinate (0.270 g) in 79% yield.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.Cl>ClCCl>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:13][CH:12]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Oc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.5 %

Procedure:
Diphenyl oxide (52.2 g), 100 ml of dichloromethane, and 42.8 g of aluminum trichloride are added to a flask equipped with a mechanical stirrer, an addition funnel and a reflux condenser with a drying tube. 4-Methoxybenzoyl chloride (anisoyl chloride, 50 g) is added over 30 minutes. The mixture is stirred at ambient temperature for 2 days and then poured into 200 ml of 4M HCl. The organic layer is washed with 1M NaCl, dried with MgSO4, and evaporated. After bulb-to-bulb distillation at 215° C. using 0.3 mm Hg pressure, product is recrystallized from dry ethanol to give 69.1 g (78 percent yield) of the title compound, with a melting point of 118° C.-119° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:7][O:8][C:4]=2[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17]>>[F:1][C:2]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:5]2[C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Cc1noc2cc(F)ccc12
Product: COC(=O)Cc1noc2cc(F)c([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl 6-fluoro-1,2-benzisoxazole-3-acetate (6.0 g, 28.7 mmol) is added portionwise to nitric acid (90%, 60 mL) at 0° C. The reaction mixture is stirred at 0° C. for 30 minutes and poured into an ice/water mixture. The aqueous mixture is extracted with methylene chloride. The organic extracts are combined, washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow oil. Flash column chromatography of the oil using silica gel and ether/petroleum ether solutions gives the title product as a pale yellow solid which is identified by 1HNMR spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>CO.[Pd]>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)cc(C(=O)O)c1N
Reaction time: 17 h
Yield: 79.1 %

Procedure:
A pressure flask capable of withstanding 150 psi. was added 2-amino-5-fluoro-3-nitrobenzoic acid (1.2 g, 6.0 mmol) dissolved in methanol (40 mL) and 10% palladium on carbon (150 mg). The reaction was placed in a Parr apparatus and the flask flushed three times with hydrogen leaving an internal pressure of 65 psi. The reaction was continued for 17 hours while maintaining a pressure of 65 psi. The reaction was filtered through celite, washed with methanol and the filtrate evaporated to dryness to give 2,3-diamino-5-fluorobenzoic acid (808 mg, 79%) as a dark brown solid.: m.p. 181°-191° (dec); 1H NMR (400 MHz, DMSO-d6 δ 6.43 (dd, 1H), 6.71 (dd, 1H); 13C NMR (100 MHz, DMSO-d6) δ 102.4, 102.7, 104.6, 104.8, 109.3, 109.4, 137.0, 138.5, 138.6, 152.5, 154.8, 170.1.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:22])/[C:13](/I)=[CH:14]\[CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:43]1[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[C:45]([C:53]([F:56])([F:55])[F:54])[CH:44]=1.[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:22])/[C:13](/[C:43]1[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:50])=[O:51])=[C:45]([C:53]([F:55])([F:56])[F:54])[CH:44]=1)=[CH:14]/[CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)/C(I)=C\CC1CCCC1
Reactant: CS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/CC1CCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
A mixture of zinc dust (0.65 g, 10 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (2 mL) under argon was treated with 1,2-dibromoethane (140 mg, 0.75 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (82 mg, 0.75 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-4-cyclopentyl-2-iodo-but-2-enoic acid methyl ester (prepared in Example 21, 1.03 g, 3.5 mmol) in dry tetrahydrofuran (1.5 mL) over 3 min. After the addition, the reaction mixture was stirred for 1 h at 40-45° C. and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (3 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) and triphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (10 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromo-1-methanesulfonyl-2-trifluoromethyl-benzene (prepared in Example 12, 0.76 g, 2.5 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 25° C. for 15 h. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution (50 mL), and the organic compound was extracted into ethyl acetate (2×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 2/1 hexanes/ethyl acetate) afforded (E)-4-cyclopentyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-but-2-enoic acid methyl ester (0.85 g, 87%) as a viscous oil: EI-HRMS m/e calcd for C18H21F3O4S (M+) 390.1113, found 390.1113.
Reaction SMILES: C1(CO)CC1.C[O-].[Na+].[CH3:9][N:10]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]1=[O:29].[Br:30][C:31]1[CH:36]=[C:35]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH:34]=[CH:33][C:32]=1[O:42][CH2:43][CH:44]1[CH2:46][CH2:45]1>>[Br:30][C:31]1[CH:36]=[C:35]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH:34]=[CH:33][C:32]=1[O:42][CH2:43][CH:44]1[CH2:46][CH2:45]1.[CH:44]1([CH2:43][O:42][C:32]2[CH:31]=[CH:36][C:35]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])=[CH:34][C:33]=2[C:18]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11](=[O:29])[N:10]([CH3:9])[CH:19]=2)[CH2:45][CH2:46]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1=O)CCCC2
Agent: CCS(=O)(=O)c1ccc(OCC2CC2)c(Br)c1
Agent: C[O-]
Agent: OCC1CC1
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3c2CCCC3)c1

Procedure:
2-bromo-1-(cyclopropylmethoxy)-4-(ethanesulfonyl)benzene was prepared in a similar manner as Example 79, step 3 except that the alkoxide of cyclopropylmethanol was substituted for sodium methoxide. The title compound of Example 163, step 3 and 2-bromo-1-(cyclopropylmethoxy)-4-(ethanesulfonyl)benzene were reacted in a similar manner as in Example 89, step 2 to give the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 7.83 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.56 (d, J=2.4 Hz, 1H), 7.43 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 4.02-3.90 (m, 2H), 3.43 (s, 3H), 3.29-3.23 (m, 2H), 2.49-2.44 (m, 4H), 1.61-1.50 (m, 4H), 1.15-1.08 (m, 5H), 0.53-0.51 (m, 2H), 0.29-0.27 (m, 2H). LCMS: 402.0 (M+H)+
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]([OH:10])=O)(=[O:4])[CH:2]=[CH2:3].S(Cl)([Cl:13])=O>C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][C:8]([Cl:13])=[O:10])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C=CC(=O)OCCC(=O)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Carboxyethyl acrylate (1 eq.) is dissolved in CH2Cl2 and the solution is cooled in an ice bath. Thionyl chloride (1 eq.) is added dropwise and the mixture is allowed to warm to room temperature and stir for 4 hours. The solvent is removed under reduced pressure and the desired product is isolated by vacuum distillation.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[N:20][CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:19]=[N:20][CH:21]=1
Reactant: Cc1cncc(B(O)O)c1
Reactant: O=C(O)c1cccc2ccc(Cl)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cncc(-c2ccc3cccc(C(=O)O)c3n2)c1
Temperature: 125 °C
Yield: 72.1 %

Procedure:
A mixture of 2-chloroquinoline-8-carboxylic acid (0.600 g, 2.8 mmol), 5-methylpyridin-3-ylboronic acid (0.410 g, 3.0 mmol), K3PO4 (1.1 g, 5.2 mmol), and Pd(dppf)Cl2.CH2Cl2 (0.10 g, 0.122 mmol) in DMF (3 mL) and water (1 mL) was microwave heated (125° C.×1 Hour). The mixture was filtered over celite and the celite cake was washed with ethyl acetate (30 mL). The filtrate was combined with 60 mL aqueous saturated NaHCO3 solution and the mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated. The crude material was purified by flash chromatography (a gradient of 0 to 100% ethyl acetate in pentane) to obtain 2-(5-methylpyridin-3-yl)quinoline-8-carboxylic acid (0.535 g, 2.02 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=1[O:38][CH3:39])=[O:14])(C)(C)C>C(Cl)Cl>[C:13](/[C:15](/[CH3:40])=[CH:16]/[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][C:29]=1[O:38][CH3:39])([OH:14])=[O:12]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(/C=C(\C)C(=O)OC(C)(C)C)cc23)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(/C=C(\C)C(=O)O)cc23)c(OC)c1
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Trifluoroacetic acid (50 ml) was added to a solution of methyl E-4-[5-[2-(t-butoxycarbonyl)-1-propenyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoate (6.4 g) in a small volume of methylene chloride (10 ml) cooled in an ice-bath. After 1.5 hr, the solution was evaporated (at approximately room temperature), and the residue was crystallized from methanol to give methyl E-4-[5-(2-carboxy-1-propenyl)-1-methylindol-3-ylmethyl]-3-methoxybenzoate (4.2 g, 75%) as a white powder: mp 182°-183°; partial NMR (250 MHz, DMSO-d6): 2.03(s, 3H, CCH3), 3.75(s, 3H), 3.83(s, 3H), 3.90(s, 3H), 4.06(s, 2H, ArCH2Ar').
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:23][S:22][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[S:21][CH:20]=[CH:19][CH:18]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:24]([O-:26])=[O:25])=[O:3].[Na+].C[Si](C)(C)Cl.[SiH3]NC(=O)C(F)(F)F.[C:41]1([CH2:47][C:48](Cl)=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:41]1([CH2:47][C:48]([CH:16]([C:17]2[S:21][CH:20]=[CH:19][CH:18]=2)[C:14]([NH:13][CH:10]2[C:11](=[O:12])[N:8]3[C:7]([C:24]([OH:26])=[O:25])=[C:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[CH2:23][S:22][C@H:9]23)=[O:15])=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: O=C(Cl)Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C(N[SiH3])C(F)(F)F
Agent: [Na+]
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)Cc3ccccc3)c3cccs3)[C@H]2SC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium cephalothin (3.36 g.) in anhydrous alcohol-free chloroform (20 ml.) is silylated by the addition of trimethylchlorosilane (2.2 ml.). After stirring for 30 minutes, monosilyltrifluoroacetamide (5.0 ml.) and phenylacetyl chloride (4.0 ml.) are added and the mixture is then heated to 45° C. for 2 days under a condenser fitted with a drying tube. The volatiles are evaporated to afford a residue which is dissolved in 100 ml. of ethyl acetate and washed three times with water. The ethyl acetate layer is dried over magnesium sulfate, filtered and the solution evaporated in vacuo to a residue. The residue is triturated with chloroform, any insolubles are removed by filtration and the product precipitated from the filtrate with hexane. This procedure is followed two more times. The 7-(phenylacetyl-2-thienylacetyl)amino-3-acetoxymethyl-3-cephem-4-carboxylic acid is obtained in a solvent-free form by freeze drying from a solution in benzene.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])([O-])=O.[K+].[K+].[Na+].[Cl-].[O-]S([O-])(=O)=O.[Mg+2].[Cl-].[Cl-].[Ca+2].P([O-])([O-])([O-])=O.[C:36](O)(=[O:46])[C:37]1[CH:45]=[CH:44][C:42]([OH:43])=[C:39]([O:40][CH3:41])[CH:38]=1.[OH-].[Na+].Cl>O>[O:46]=[CH:36][C:37]1[CH:45]=[CH:44][C:42]([OH:43])=[C:39]([O:40][CH3:41])[CH:38]=1
Reactant: COc1cc(C(=O)O)ccc1O
Agent: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])O
Solvent: O
Product: COc1cc(C=O)ccc1O
Temperature: 30 °C
Reaction time: 24 h

Procedure:
A culture of Micromucor isabellinus (Zyl 849) grown on yeast malt agar was used to inoculate a 500 mL starter culture flask containing 100 mL medium (15 g glucose; 5 g (NH4)2SO4; 2 g K2HPO4; 0.2 g NaCl; 0.2 g MgSO4; 0.015 g CaCl2, trace element solution, 1 mL; vitamins solution 10 mL; made up to 1 liter with pH 6.0 phosphate buffer (0.2M)) containing 2 g/L vanillic acid which was incubated at 30° C. with shaking at 200 rpm for 24 hours. This starter culture was added to 5 liters of the same medium in a fermenter with the medium components made up to 1 liter with deionised water and vanillic acid added to a concentration of 1.5 gL-−1, immediately prior to inoculation. The fermenter contents were stirred at 30° C. for 18 hours with the pH of the medium being maintained at pH 5.2 by the addition of 5M sodium hydroxide solution. After this time the medium pH was gradually reduced to 3.7 over 45 minutes by the addition of 5M HCl and temperature was maintained at 30° C. Dissolved oxygen concentration was maintained at 70% of saturation throughout the process. Assay was by hplc as described above. Prior to the pH being allowed to drop at the 18 hour stage, the amount of vanillic acid in the system was measured at 1.48 gL-−1; vanillin was detected in solution at 0.02 gL-l. As the reaction proceeded various amounts of vanillic acid or glucose were added as follows: 19.25 hours, 50 g glucose; 20.25 hours, 3 g vanillic acid; 21.5 hours, 4 g vanillic acid; 23 hours, 4 g vanillic acid. Substrate and product concentrations were measured as being: 19.25 hours, vanillic acid 1.5 gL-−1, vanillin 0.1 gL-−1;: 20.25 hours, vanillic acid 1.16 gL-−1, vanillin 0.36 gL-−1;: 21.5 hours, vanillic acid 1.07 gL-−1, vanillin 0.74 gL-−1;: 23 hours, vanillic acid 1.06 gL−1, vanillin 1.22 gL-−1;: 26 hours, vanillic acid 0.83 gL-−1, vanillin 1.96 gL-−1.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[C:12](=[N:25][NH2:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:12](=[N:25][NH:26][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1cccc2cnccc12
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(C(=NNc2cccc3cnccc23)c2ccccc2)cc1
Temperature: 85 °C
Yield: 86.3 %

Procedure:
To a suspension of 5-bromoisoquinoline (200 mg, 0.96 mmol), benzhydrylidene-hydrazine (189 mg, 0.96 mmol), palladium diacetate (2.2 mg, 0.0096 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 6 mg, 0.0096 mmol) in dry toluene (1 mL), sodium tert-butoxide (130 mg, 1.34 mmol) was added and the mixture was heated at 85° C. for 4 hours. The mixture, cooled to room temperature, was filtered over celite and the pad was washed with diethylether. The solvent was evaporated under vacuum and the residue was purified by flash chromatography with hexane/ethylacetate 7/3 as eluant, affording 268 mg of the title compound (86% yield).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:20]1[CH2:48][O:47][C:22]2([CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([Sn](CCCC)(CCCC)CCCC)=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[O:21]1>C1(C)C(C)=CC=CC=1>[CH2:20]1[CH2:48][O:47][C:22]2([CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([C:2]4[N:3]=[C:4]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]5)[C:5]5[C:10]([CH:11]=4)=[CH:9][CH:8]=[CH:7][CH:6]=5)=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[O:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(N4CCC5(CC4)OCCO5)cc3)cc3ccccc23)CC1
Yield: 51.6 %

Procedure:
3-Bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.72 g) and 4-(4,4-ethylenedioxypiperidin-1-yl)phenyltributylstannum (3.12 g) were reacted in the presence of tetrakistriphenylphosphine dichloride (0.5 g) in xylene (50 ml) at 140° C. for 5 hr. The reaction solution was concentrated, and ethyl acetate and an aqueous saturated solution of sodium bicarbonate were added to the resulting residue, for partitioning. The resulting organic layer was washed with water and brine, dried over magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 1.27 g of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:22][CH2:23][C:24]([NH:27][S:28]([C:31]1[S:35][C:34](Cl)=[N:33][CH:32]=1)(=[O:30])=[O:29])([CH3:26])[CH3:25]>>[OH:22][CH2:23][C:24]([NH:27][S:28]([C:31]1[S:35][C:34]([C:21]#[C:20][C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:16][CH2:15]4)=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[N:33][CH:32]=1)(=[O:30])=[O:29])([CH3:26])[CH3:25]
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 2-chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (68 mg, 0.25 mmol) (example B.14) according to general procedure II. Obtained as a yellow solid (60 mg, 45%). MS (ISP) 528.0 [(M+H)+]; mp 204-207° C.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]([OH:24])[CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2].[C:28](OCC)(=O)C.CCCCCC>>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH:19]([O:24][CH3:28])[CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCC(O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCC(OC)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from (±)-2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(1-hydroxypentyl)pyridine (Example 95) according to the procedures described in Example 98. 1H NMR (300 MHz, CDCl3): δ 7.10 (m, 4 H), 4.32 (m, 2 H), 3.92 (m, 1 H), 3.76 (septet, J=7.0 Hz, 1 H), 3.42 (septet, J=6.6 Hz, 1 H), 3.12 (s, 3 H), 1.87 (m, 1 H), 1.52 (m, 2 H), 1.19 (m, 16 H), 0.821 (t, J=7.4 Hz, 3 H). FAB-MS: calcd for (C24H34NFO2) 387, found 388 (M+H). Anal. Calcd for C24H34NO2F: C, 74.38; H, 8.84; N, 3.61; F, 4.90. Found: C, 74.38; H, 8.82; N, 3.45; F, 4.90. mp 121-123° C. Rf=0.5 (20% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][N:11]([CH3:31])[C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[C:27]3[C:22](=[CH:23][C:24]([N:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=3)[C:20](=[O:21])[O:19]2)=[CH:14][CH:13]=1>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][C:6]([CH:18]([C:27]2[CH:26]=[CH:25][C:24]([N:28]([CH3:29])[CH3:30])=[CH:23][C:22]=2[C:20]([OH:21])=[O:19])[C:15]2[CH:14]=[CH:13][C:12]([N:11]([CH3:10])[CH3:31])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Reactant: CN(C)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2)c2ccc(N(C)C)cc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in part A above, but substituting 18.2 g of anhydrous stannic chloride for the anhydrous zinc chloride, 70.0 ml of N,N-dimethylaniline and 14.9 g of 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide prepared as described in Example 1, part A above were interacted to obtain 15.0 g of 2-[4,4'-bis(dimethylamino)-benzhydryl]-5-dimethylaminobenzoic acid which melted at 208°-212° C.