Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH:5]=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1cncc(-c2ccc(C(F)(F)F)cc2)c1)c1ccccc1
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 11.35 g (40.96 mmol) of N-(5-bromopyridin-3-yl)benzamide, 11.67 g (61.43 mmol) of [4-(trifluoromethyl)phenyl]boronic acid and 8.68 g (81.91 mmol) of sodium carbonate were dissolved in 68 ml of 1,2-dimethoxyethane, 21 ml of water and 151 ml of DMF. The mixture was flushed with argon, 237 mg (0.21 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography (cyclohexane/ethyl acetate 1:1). Yield: 10.6 g (76% of theory)
Reaction SMILES: [CH2:1]([Sn:11](Cl)([CH2:19][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[F-:30].[K+].C1C=CC=CC=1>O>[CH2:1]([Sn:11]([F:30])([CH2:19][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C[Sn](Cl)(CC(C)(C)c1ccccc1)c1ccc(F)cc1)c1ccccc1
Reactant: [F-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C[Sn](F)(CC(C)(C)c1ccccc1)c1ccc(F)cc1)c1ccccc1
Yield: 79.5 %

Procedure:
A mixture consisting of the crude dineophyl-parafluorophenyltin chloride (50 g) and potassium fluoride (5.8 g, 0.1 mol) was heated for 2 hours in the presence of benzene (120 g) and water (23 g). The aqueous layer of the reaction mixture was removed, and the organic layer was washed with water, filtered and concentrated under reduced pressure. The residue thus obtained was crystallized from petroleum ether to give 38.5 g of dineophyl-parafluorophenyltin fluoride as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=O.[CH2:7]([NH2:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:7]([NH:13][C:4](=[O:6])[CH2:3][CH2:2][NH2:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCCC(=O)O
Reactant: CCCCCCN
Product: CCCCCCNC(=O)CCN

Procedure:
As above using β-alanine in place of glycine and n-hexylamine in place of n-heptylamine.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=1.[H][H]>[Pd].C(O)C>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:14]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][NH:12][C:9]3=[CH:10][N:11]=2)[CH:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1c[nH]c2cnc(-n3cnnc3)cc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1c[nH]c2cnc(-n3cnnc3)cc12
Yield: 80.1 %

Procedure:
Ethyl 3-(5-(1,2,4-triazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)prop-2-enoate (0.4 g, 1.4 mmol) was hydrogenated over palladium on carbon (10%, 0.25 g) in ethanol (50 mL) at 45 psi of hydrogen for 6 hours. The catalyst was removed by filtration and the solvent evaporated in vacuo to give the title compound (0.32 g, 80%) as a colourless solid. mp 215°-218° C. 1H NMR (360 MHz, CDCl3 : d4 -MeOH 9:1) δ 1.23 (3H, t, J=7.1Hz), 2.72 (2H, t, J=7.4Hz), 3.12 (2H, t, J=7.4Hz), 4.13 (2H, q, J=7.1Hz), 7.36 (1H, s), 7.61 (1H, s), 8.60 (1H, s) and 8.89 (2H, s).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:19]=[CH:18][C:12]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C([O-])([O-])=O.[K+].[K+].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH2:32]([O:31][C:29]([N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[C:12]1[CH:18]=[CH:19][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:20])[F:21])=[CH:10][CH:11]=1)=[O:30])[CH3:33]
Reactant: CS(=O)(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N(c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)S(C)(=O)=O
Reaction time: 16 h

Procedure:
To 6.7 g (20 mmole) 4'-(hexafluoro-2-hydroxy-2-propyl)-methanesulfonanilide (prepared as in Example 1) in 100 ml acetonitrile, add 4.1 g (30 mmole) K2CO3 and 2.2 g (20 mmole) ethyl chloroformate. Stir 16 hours, filter and concentrate. Partition the residue between Et2O and 5% Na2CO3. Dry, concentrate and recrystallize first from Et2O-hexane and then from toluene to give the product; m.p. 108°-112° C.
Reaction SMILES: [C:1]1([NH:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][OH:11]>CCO>[OH:11][N:10]=[C:8]([NH2:9])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: N#CNc1ccccc1
Solvent: CCO
Product: NC(=NO)Nc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-phenylcyanamide was dissolved in EtOH (7 mL) and treated with H2NOH (1.5 eq of a 50% aq solution). The mixture was stirred at room temperature for 12 hours then reduced to dryness to afford 2-hydroxy-1-phenylguanidine (5) as a clear yellow oil, which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25]([O:27][C:28](=[O:38])[CH:29](Br)[CH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:26].O>CN(C)C=O.C(OCC)(=O)C>[CH2:25]([O:27][C:28](=[O:38])[CH:29]([N:12]1[C:11]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:10]=2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:26]
Reactant: CCOC(=O)C(Br)C1CCCCCC1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)[nH]c2cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C1CCCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 2.2 g (8.31 mmol) 2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 1, intermediate a) in 22 ml N,N-dimethyl formamide was added 3.2 g (9.89 mmol) cesium carbonate and 2.6 g (9.89 mmol) bromo-cycloheptyl-acetic acid ethyl ester. The reaction mixture was stirred at 100° C. for 1 hour. Then, 3.2 g (9.89 mmol) cesium carbonate and 2.6 g (9.89 mmol) bromo-cycloheptyl-acetic acid ethyl ester were added. Stirring was continued at 100° C. for another 6 hours. Another 3.2 g (9.89 mmol) cesium carbonate and 2.6 g (9.89 mmol) bromo-cycloheptyl-acetic acid ethyl ester were added and the reaction mixture was stirred at 100° C. for 18 hours. The reaction mixture was poured on 200 ml water and 200 ml ethyl acetate and the layers were separated. The aqueous layer was extracted a second time with 200 ml ethyl acetate. The organic layers were washed with 200 ml brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40). Light yellow solid (63%). MS (Turbo Spray): m/z=447.2 [M+H].
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:24]([O:26][C:27]([CH3:29])=[CH2:28])=[O:25]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:24](=[O:25])[O:26][C:27]([CH3:29])=[CH2:28])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Reactant: C=C(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)OC(=O)Nc1cc(C(C)(C)C)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
To a solution of Example B1 (10.00 g, 46.4 mmol, 1.00 eq) and pyridine (7.58 ml, 92.9 mmol, 2.00 eq) in CH2Cl2 (225 ml) at 0° C. was added isopropenyl chloroformate (5.33 ml, 4.8.8 mol, 1.05 eq). After 45 min at 0° C., the completed reaction was washed with 3M HCl (2×), satd. NaHCO3 (1×), and brine (1×), dried (MgSO4), filtered and evaporated to afford crude product (14.9 g) as an oil that solidified on the pump. The crude material obtained was upgraded by triturating in warm (60° C.) hexanes (70 ml) for 20-30 min until a powdery precipitate was obtained. After cooling to RT, the solids were collected by filtration, rinsing forward with hexanes. The cake was washed with more hexanes and then dried on the filter to afford prop-1-en-2-yl 3-t-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (10.79 g, 78% yield) as a tan powder which was used as is in the next reaction. MS (ESI) m/z: 300.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Yield: 76.5 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (100 mg, 0.353 mmol) and tert-Butyl 1-piperazinecarboxylate (65.8 mg, 0.353 mmol) were combined and purified as per Preparation Hb to give tert-butyl 4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (116.9 mg, 76% yield). LC-MS (M+H)+=433.3.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]([O:12]C)=O)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH2:14]([CH2:16][NH2:17])[OH:15].C>CO.C(O)C>[OH:15][CH2:14][CH2:16][NH:17][C:10](=[O:12])[CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: COC(=O)Cn1ccnc1[N+](=O)[O-]
Reactant: NCCO
Solvent: CO
Solvent: CCO
Product: O=C(Cn1ccnc1[N+](=O)[O-])NCCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.6 %

Procedure:
A mixture of 2.50 g (13.5 mmol) of methyl 2-nitroimidazole-1-acetate and 3.0 ml (50.0 mmol) of ethanolamine in 15.0 ml methanol was stirred 20 hr at room temperature. The mixture was diluted with 45 ml ethanol and heated on a stream bath to effect solution. The hot solution was decolorized with charcoal, filtered and evaporated to dryness. The residue was recrystallized from a solution of 150 ml ethyl acetate and 10 ml of methanol to afford 1.81 g (62.4%) of SR-2508 as a white powder, mp 164.5-165.0° C., that was homogeneous by thin layer chromatography on silica gel with 10% methanol in ethyl acetate (Rf 0.16). The solubility of SR-2508 in 0.9% saline solution was approximately 200 mg/ml.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]([CH3:16])([CH3:15])[C:13]#[N:14]>CO.[Ni]>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:11])[C:3]([C:12]([CH3:15])([CH3:16])[C:13]#[N:14])=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)(C#N)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: [Ni]
Solvent: CO
Product: CC(C)(C#N)c1c(Cl)cc(N)cc1Cl
Yield: 113.1 %

Procedure:
A mixture of intermediate (2) (0.066 mole) in CH3OH (200 ml) was hydrogenated at RT under a 3 bar pressure for 1 hour with Raney Nickel (15 g) as a catalyst. After uptake of H2, the catalyst was filtered through celite, washed with CH3OH and the filtrate was evaporated, yielding 17.1 g of 4-amino-2,6-dichloro-α,α-dimethylbenzeneacetonitrile (intermediate 3).
Reaction SMILES: F[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.CS(C)=O>O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:2]2[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=Cc1ncccc1F
Reactant: O=S([O-])c1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ncccc1S(=O)(=O)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
A mixture of 3-fluoropyridine-2-carbaldehyde (0.70 g), 4-fluorobenzenesulfinic acid sodium salt (1.1 g) and dimethyl sulfoxide (7.0 mL) was stirred at 100° C. for 18 hours. The mixture was cooled to room temperature, diluted with water (20 mL), and the resulting precipitate was removed by filtration. The filtrate was extracted with ethyl acetate, and the combined organic extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as a pale yellow oil (0.67 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[C:30]2[CH:42]=[N:43][N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:29]=2[C:28]1=[O:53]>>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:3]1[C:4]([N+:14]([O-:16])=[O:15])=[C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][C:2]=1[C:31]1[C:30]2[CH:42]=[N:43][N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:50])([CH3:52])[CH3:51])[C:29]=2[C:28](=[O:53])[N:27]([CH3:26])[CH:32]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2cnn(COCC[Si](C)(C)C)c2c1=O
Reactant: COC(=O)CNc1ccc(Br)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Product: COC(=O)CNc1ccc(-c2cn(C)c(=O)c3c2cnn3COCC[Si](C)(C)C)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using methyl {[4-bromo-3-(2,4-difluorophenoxy)-2-nitrophenyl]amino}acetate and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one as the starting materials. LCMS calculated for C28H32F2N5O7Si (M+H)+: m/z=616.2. found: 616.2.
Reaction SMILES: [N:1]([O-:3])=O.[K+].[F:5][C:6]([F:20])([F:19])[C:7](=[O:18])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].C(O)(C)(C)C.C(O)(=O)C>O>[F:5][C:6]([F:19])([F:20])[C:7](=[O:18])[C:8](=[N:1][OH:3])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: O=N[O-]
Reactant: Cc1ccccc1CCCC(=O)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: Cc1ccccc1CCC(=NO)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
A solution of potassium nitrite (22.2 g, 0.26 mol) in water (total volume=7.4 mL) was added in one portion to a stirred solution of 1,1,1-trifluoro-5-(2-methylphenyl)-2-pentanone (20 g, 0.087 mol), tert-butanol (25 mL) and acetic acid (25 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2.5 hr. Another solution of potassium nitrite (7.5 g, 0.088 mol) in water (2.5 mL) then was added. After stirring for 1.5 hr, the reaction mixture was poured into water. The resulting mixtutre was extracted with diethyl ether (3x). The combined ether extracts were washed with water and then washed with a saturated aqueous solution of NaHCO3. Thereafter, the organic extract was dried (MgSO4) and concentrated under reduced pressure to give the title compound (22.1 g, 98% yield) as a yellow crystalline mass. This product was used for the reaction described in the following example. A sample of the product, recrystallized for hexane, had mp 80°-81° C.; nmr (CDCl3) δ 2.35 (s, 3H), 2.8 (s, 4H), 7.1 (s, 4H); ir (CHCl3) 3540, 3340, 1730, 1165-1 ; Anal Calcd for C12H12F3NO2 : C, 55.60% H, 4.67%; Found: C, 55.41% H, 4.60%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])(=O)C.[K+].[F:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1>CC(N(C)C)=O.O.[OH-].[Pd+2].[OH-]>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:5]2[S:1][CH:2]=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: c1cscn1
Reactant: Fc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Fc1ccc(-c2cncs2)cc1
Temperature: 145 °C
Reaction time: 16 h
Yield: 21.3 %

Procedure:
To a sealed tube containing a solution of thiazole (2 g, 23.53 mmol) in DMA (10 mL) was added potassium acetate (6.9 g, 70.58 mmol), 1-fluoro-4-iodobenzene (15.6 g, 70.58 mmol), and palladium hydroxide\C (0.53 g, 2.35 mmol) under nitrogen. The reaction mixture was heated to 145° C. and stirred for 16 h. The reaction mixture was cooled to room temperature and diluted with water (200 mL), filtered through Celite® reagent, and extracted with ethyl acetate (300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (100-200μ silica gel, eluting with 10% EtOAc and hexane) to afford 5-(4-fluorophenyl)thiazole (0.9 g, 22%). 1H NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 8.01 (s, 1H), 7.55 (t, 2H), 7.11 (t, 2H).
Reaction SMILES: [I:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]([CH3:18])[CH:10](O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>ClC1C=CC=CC=1Cl>[I:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH3:18])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(NC(=O)c1ccc(I)cc1)C(O)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1cc2ccccc2c(-c2ccc(I)cc2)n1
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of amide 3c, 8.54 g, 22.4 mmol) and P2O5 (40 g) in o-dichlorobenzene (140 mL) was refluxed for overnight, then cooled to room temperature. It was cooled to 0° C. by application of an external ice-water bath. To this cooled mixture was cautiously added 200 mL of H2O. After the vigorous reaction had subsided, the dark solution was washed with toluene (2×40 mL). The aqueous layer was cooled to 0° C. and made to pH >11 with 50% aqueous NaOH. The resulting mixture was extracted with toluene (4×50 mL). The organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from benzene, thereby affording a white solid (6.1 g, 79%). mp 146.5-147.4° C. 1H NMR (CDCl3) d 2.72 (s, 3 H, CH3), 7.38-7.51 (m, 4 H, aromatic) 7.61 (t, J=6.9 Hz, 1 H, aromatic), 7.75 (d, J=8.1 Hz, 1 H, aromatic), 7.84 (d, J=8.1 Hz, 1 H, aromatic), 7.94 (d, J=8.7 Hz, 1 H, aromatic). 13C NMR (CDCl3) d 24.34 (q, CH3), 94.58 (s, =CI--, aromatic), 118.20 (d, aromatic), 124.56 (s, aromatic), 126.31 (d, aromatic), 126.42 (d, aromatic), 126.94 (d, aromatic), 129.96 (d, aromatic), 131.68 (d, aromatic), 137.41 (d, aromatic), 137.51 (s, aromatic), 139.12 (s, aromatic), 150.88 (s, aromatic), 158.97 (s, =CCH3 --, aromatic). Anal. Calcd for C16H12IN: C, 55.67; H, 3.50; N, 4.06. Found: C, 55.63; H, 3.55; N, 4.07.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13](=[CH2:17])[C:14]([OH:16])=[O:15].[C:18]1([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N+]=[N-])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C>C(#N)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13](=[CH2:17])[C:14]([O:16][CH:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: C=C(ON1C(=O)c2ccccc2C1=O)C(=O)O
Solvent: CC#N
Solvent: CC(=O)O
Product: C=C(ON1C(=O)c2ccccc2C1=O)C(=O)OC(c1ccccc1)c1ccccc1
Yield: 99.1 %

Procedure:
2-[(1,3-Dioxo-2H-isoindol-2-yl)oxy]-2-propenoic acid (1.54 g, 4.8 mmole) was dissolved in 25 ml of acetonitrile and a solution of diphenyldiazomethane (1.17 g, 5.94 mmole/50 ml acetonitrile) was added dropwise. After approximately 1.1 equivalents of diphenyldiazomethane had been added, tlc showed no starting material remaining. The excess diphenyldiazomethane was decomposed with the addition of a small amount of acetic acid. The reaction solution was concentrated to a residue, dissolved in ethyl acetate, washed consecutively with 1N sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated to a solid. After trituration with hexane, 1.9 g of the title compound was obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]([C@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:28]1([S:34][C@@H:10]2[O:9][C@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:23]2[O:24][C:25](=[O:27])[CH3:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Reactant: Sc1ccccc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.8 %

Procedure:
To a solution of galactose pentaacetate (5.00 g, 12.8 mmol) in 125 mL of CH2Cl2 is added thiophenol (1.49 mL, 14.1 mmol) and boron trifluoride diethyl ether complex (4.73 mL, 38.4 mmol). The reaction mixture is stirred at room temperature for 5 h and then poured into 200 mL of ice water. The organic layer is washed with saturated NaHCO3 (200 ml), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (35% EtOAc/hexane) to give 5.4 g (96%) of 1-deoxy-1-(phenylthio)-2,3,4,6-tetra-O-acetyl-β-D-galactopyranose 39: Rf 0.22 (35% EtOAc/hexane); 1H NMR (CDCl3, 270 MHz) δ 7.35-7.65 (m, 5 H, ArH), 5.50 (br d, J=3.3 Hz, 1 H, H-4), 5.32 (t, J=9.8 Hz, 1 H, H-2), 5.13 (dd, J=9.8, 3.3 Hz, 1 H, H-3), 4.80 (d, J=9.8 Hz, 1 H, H-1), 4.13-4.32 (m, 2 H, H-6, H-6'), 4.02 (br t, J=6.5 Hz, 1 H, H-5), 2.02-2.23 (4s, 12 H, OAc).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([OH:22])=[O:21])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.Br[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>CN(C)C=O>[C:28]([O:30][CH:31]([O:21][C:20](=[O:22])[CH2:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:8]([C:6](=[O:7])[C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[CH3:23])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:29])[CH3:27]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)OC(OC(C)=O)c1ccccc1)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 81 %

Procedure:
180 g (0.503 mol) of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetic acid were dissolved in 900 ml of dimethylformamide, 35 g of triturated, anhydrous potassium carbonate were added and stirring was continued for 45 minutes at 50°C. 128 g (0.558 mol) of benzyl bromoacetate were then added and the mixture was stirred for 3 hours at 50°C. After evaporating the dimethylformamide under vacuum, the residue was dissolved in chloroform, washed several times with water, dried over sodium sulphate and then separated by chromatography on alumina. The eluate was concentrated by evaporation and the residue recrystallised from alcohol. The [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxy]-benzyl acetate which formed melted at 93°-94°C and the yield was 81% of the theoretical. This benzyl ester was converted as described in Example 1 or 2 into the free acid.