Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[OH:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:30][C:31]#[N:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CCOc1ccc(Cl)cc1C1c2ccccc2CCN1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of (±)-1-(5-chloro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (1.9 g, 5.00 mmol, 1.00 eq.) and chloroacetonitrile (0.34 mL, 5.19 mmol, 1.04 eq.) in DMSO (1.5 mL) was added to a suspension of potassium carbonate (980 mg, 7.09 mmol, 1.42 eq.) in DMSO (1.5 mL) (exothermic). The mixture was heated up to 80° C. and stirred at that temperature for 1 hour. The reaction mixture was poured onto ice. After the ice melted, the mixture was filtered and the filter cake was rinsed with water. The resulting yellow gum was dried under hv The product was used without further purification.
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:18])[O:13][C:14]=2[CH2:15][CH2:16][CH3:17])[CH:5]=1.[C:20]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[CH3:21].[Li]>>[C:24]([O:23][C:20](=[O:22])[CH2:21][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:18])[O:13][C:14]=2[CH2:15][CH2:16][CH3:17])[CH:5]=1)=[O:19])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCCc1oc(C)nc1-c1cccc(C(=O)OC)c1
Agent: [Li]
Product: CCCc1oc(C)nc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
3-(2-Methyl-5-propyl-oxazol-4-yl)-benzoic acid methyl ester (0.47 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-[3-(2-methyl-5-propyl-oxazol-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (0.58 g) as a light-brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][C:8]2[C:9]([CH3:27])=[C:10]([CH3:26])[C:11](OS(C(F)(F)F)(=O)=O)=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[CH2:30](C([Sn])=C(CCCC)CCCC)[CH2:31]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][C:8]2[C:9]([CH3:27])=[C:10]([CH3:26])[C:11]([CH:30]=[CH2:31])=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(C)c1OS(=O)(=O)C(F)(F)F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1c(C(=O)OC)cc(Cc2ccc(OC)cc2)c(C)c1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution of methyl 5-(4-methoxybenzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (0.34 g) in DMF (7.00 mL) were added tributylvinyltin (0.37 g), trans-dichlorobis(triphenylphosphine)palladium(II) (0.03 g) and lithium chloride (0.25 g), and the mixture was stirred at 90° C. for 2 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.20 g).
Reaction SMILES: [OH:1][CH:2]([CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O-:14])=[O:13])=[CH:7][CH:6]=1.[ClH:20]>>[ClH:20].[OH:1][CH:2]([CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1
Reactant: CC(C)NCC(O)COc1ccc(CC(=O)[O-])cc1
Agent: Cl
Product: CC(C)NCC(O)COc1ccc(CC(=O)O)cc1

Procedure:
4-[2-hydroxy-3-[(1-methylethyl)amino]-propoxy]phenylacetate (563 mg, 2.00 mmol) in 6 M hydrochloric acid (15 ml) was heated at 100° C. for 4 h. The reaction mixture was concentrated (rotavapor) and the residue was taken up in water and lyophilised. 1H and 13C NMR spectra were in accordance with the structure and MALDI mass spectrometry gave a M+H at 268 as expected.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]([O:6]C)=O>C(CC=O)CC=O>[CH:3]1([CH:4]=[O:6])[CH2:2][CH2:1][CH:3]([CH:4]=[O:6])[CH2:2][CH2:1]1
Reactant: CCCC(=O)OC
Agent: O=CCCCC=O
Product: O=CC1CCC(C=O)CC1

Procedure:
The procedure according to Example 17 was repeated, but using the same amount of the polymer obtained from Example 10 instead of the polymer obtained from Example 1; 1,4-cyclohexane dicarboxaldehyde (1.4 g) as a cross-linker instead of glutaric dialdehyde, and methyl 3-methylpropionate (25 ml) as a solvent, to obtain a negative pattern with a resolution of 0.15 μm (FIG. 3).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](O)=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1>>[Cl:3][C:12]1[C:11]2[C:16](=[CH:17][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[N:15]=[CH:14][CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)ccnc2c1
Product: COc1ccc2c(Cl)ccnc2c1
Temperature: 25 °C

Procedure:
To a solution of POCl3 (11 mL, excess), 7-methoxyquinolin-4-ol (1.87 g, 10.67 mmol) was added and heated from RT to 90° C. The mixture was allowed to cool to RT, concentrated in-vacuo and cooled in an ice bath during the slow adjustment to pH 7 by alternating ice and 1N NaOH. The solid was filtered and rinsed with water. The title compound was isolated as a tan solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH2:15][O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH:8]1[CH2:9][CH2:10][C:11]2([C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH2:15][O:14]2)[CH2:12][CH2:13]1
Reactant: c1ccc(CN2CCC3(CC2)OCc2cccnc23)cc1
Agent: [Pd]
Solvent: CCO
Product: c1cnc2c(c1)COC21CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
A solution of 0.39 g (1.4 mmol) 1′-benzyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine] in 14 ml ethanol was purged with argon prior to adding 0.15 g (10 mol %) palladium on activated charcoal. The flask was evacuated, refilled with hydrogen gas and stirred at room temperature under an atmosphere of hydrogen for 16 h. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated to dryness to give the title compound (0.24 g, 91%) as an amorphous solid.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:13]3[N:14]=[CH:15][CH:16]=[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:12]3=[N:11][C:10]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=1)#[N:2].[NH4+].[Cl-].[N-:31]=[N+:32]=[N-:33].[Na+]>>[NH:31]1[C:1]([C:3]2[N:8]=[CH:7][C:6]([C:9]3[N:13]4[N:14]=[CH:15][CH:16]=[C:17]([N:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)[C:12]4=[N:11][C:10]=3[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][CH:4]=2)=[N:2][N:33]=[N:32]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C#N)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CCOC(=O)c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(-c2nnn[nH]2)nc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Compound 32a (378 mg, 1.00 mmol), NH4Cl (80.2 mg, 1.50 mmol), and NaN3 (97.5 mg, 1.50 mmol) were placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry DMF (4 mL) was added and then the reaction was stirred at 110° C. for 1 h. The reaction was cooled to rt and poured into water (25 mL). The pH of the mixture was adjusted with 2 M HCl to pH 2 and then the precipitate was isolated by filtration. The solid was dried under reduced pressure to afford compound 32b. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (s, 1H), 8.29-8.40 (m, 2H), 8.23 (d, J=5.6 Hz, 1H), 6.50 (d, J=5.6 Hz, 1H), 4.23 (q, J=6.8 Hz, 2H), 4.01-4.11 (m, 4H), 3.77-3.86 (m, 4H), 1.16 (t, J=7.0 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C19H19N9O3: 422.2 (M+H). Found: 422.2.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CO
Product: N#Cc1ccc(CCCN)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a 10 g (30 mmols) portion of 4-(3-phthalimidopropyl)benzonitrile were added 1.89 ml (39 mmols) of hydrazine hydrate and 130 ml of methanol, and the mixture was refluxed for 3 hours, cooled to room temperature and then concentrated. The residue was dissolved in 200 ml of 1 mol dm-3NaOH, followed by extraction with ether. The extract was dried over K2CO3 and concentrated, giving 4.32 g (yield 90%) of 4-(3-aminopropyl)benzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][CH3:11].BrBr>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)#[C:10][CH3:11]
Reactant: CC
Reactant: O=Cc1ccc(Br)cc1
Agent: BrBr
Product: CC#Cc1ccc(Br)cc1

Procedure:
A solution of 1 g of 1-(1-propynyl)-4-bromo-benzene (produced from 4-bromobenzaldehyde by Wittig reaction, bromination of the resulting ethane and bromine elimination analogously to Example 1e) is reacted with 700 mg of tetrakis(triphenylphosphine)palladium (0) and 1.53 g of 4-(4-pentylphenyl)-2,3-difluoro-benzeneboric acid as described under a). Chromatography on silica gel with 3% ethyl acetate in petroleum ether and fractional crystallization from ethyl acetate gives 0.84 g of 1-(4-pentylphenyl)-2,3-difluoro-4-[4-(1-propynyl)-phenyl]benzene, m.p. 102.9° C.; cl.p. (N-I) 198.9° C.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].N12CCCC1=NCCC2.[Cl:14][C:15]1[CH:23]=[C:22]([F:24])[C:21]([C:25]2[C:29]([Br:30])=[C:28]([C:31]([F:34])([F:33])[F:32])[N:27]([CH3:35])[C:26]=2[Br:36])=[CH:20][C:16]=1[C:17](O)=[O:18].O>CN(C=O)C>[Cl:14][C:15]1[CH:23]=[C:22]([F:24])[C:21]([C:25]2[C:29]([Br:30])=[C:28]([C:31]([F:33])([F:34])[F:32])[N:27]([CH3:35])[C:26]=2[Br:36])=[CH:20][C:16]=1[C:17]([O:4][CH:1]([CH3:3])[CH3:2])=[O:18]
Reactant: CC(C)O
Reactant: Cn1c(Br)c(-c2cc(C(=O)O)c(Cl)cc2F)c(Br)c1C(F)(F)F
Agent: C1CN=C2CCCN2C1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)c1cc(-c2c(Br)c(C(F)(F)F)n(C)c2Br)c(F)cc1Cl
Temperature: 40 °C
Yield: 47.9 %

Procedure:
Isopropanol (0.2 g; 3.2 mmoles), 1,5-diazabicyclo -[4.3.0]non-5-ene (0.21 g; 1.6 mmoles) are added to a mixture of 2-chloro-5-(2,4-dibromo-1-methyl-5-trifluorometh-ylpyrrol-3-yl)-4-fluorobenzoic acid (0.8 g; 1.6 mmoles) and N,N′-carbonyldiimidazole (0.77 g; 1.6 mmoles) in DMF (4 ml) heated to 40° C. for 1.5 hours, and the mixture is heated to 40° C. for 2 hours. The reaction mixture is poured into water (10 ml), extracted with ethyl ether (3×20 ml), the ether phase is washed with a saturated solution of sodium chloride, anhydrified on sodium sulfate and concentrated in a rotavapor. The raw product obtained (0.8 g) is chromatographed on silica gel, eluating with n-hexane/ethyl acetate 90:10. 0.4 g of product are obtained in the form of a colourless oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH:22]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccccc1)c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.4 %

Procedure:
To a solution of ethyl 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetate (50 mg, 0.13 mmol) in DMF (2.0 mL) was added sodium hydride (60 wt % oil 6.19 mg, 0.15 mmol) at 0° C., and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added benzyl bromide (0.018 mL, 0.15 mmol) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give ethyl 2-(2-(1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)-3-phenylpropanoate (15.9 mg, 0.033 mmol, 25.8%) as a colorless oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]([Si](C)(C)C)([F:22])[F:21].[CH:27]([C:29]1[O:30][C:31]2[C:38]([Br:39])=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]=1[CH3:34])=[O:28].Cl>C1COCC1.O>[F:19][C:20]([F:22])([F:21])[CH:27]([C:29]1[O:30][C:31]2[C:38]([Br:39])=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]=1[CH3:34])[OH:28]
Reactant: Cc1c(C=O)oc2c(Br)cccc12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(O)C(F)(F)F)oc2c(Br)cccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
14 mg of tetrabutylammonium fluoride and 1.22 ml of trifluoromethyltrimethylsilane, dropwise, are added to a solution, cooled to 0° C. with an ice bath, of 1.58 g (6.6 mmol) of 2-formyl-3-methyl-7-bromobenzofuran in 60 ml of THF. The solution is left stirring for 30 min at 0° C. and then for 1 h at room temperature and a solution of 6 ml of THF and of 3 ml of hydrochloric acid (3M) is added. Stirring is continued for 2 h at room temperature, 100 ml of water are added and extraction is carried out with ethyl acetate (3×60 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. 198 g (Yield: 97%) of 2-(2,2,2-trifluoro-1-hydroxyethyl)-3-methyl-7-bromobenzofuran are obtained--M.p.: 93° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:14][C:13]([C:15](=[O:55])[CH:16]([O:53][CH3:54])[C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][N:26](C(C5C=CC(OC)=CC=5)(C5C=CC(OC)=CC=5)C5C=CC(OC)=CC=5)[CH:27]=4)=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:56][CH3:57].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>CO.O>[NH:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([CH:16]([O:53][CH3:54])[C:15]([C:13]3[O:14][C:10]([C:5]4[CH:4]=[C:3]([O:56][CH3:57])[C:2]([Br:1])=[C:7]([O:8][CH3:9])[CH:6]=4)=[CH:11][CH:12]=3)=[O:55])=[CH:18][CH:19]=2)[CH:27]=[N:26]1
Reactant: COc1ccc(C(c2ccc(OC)cc2)(c2ccc(OC)cc2)n2cc(-c3ccc(C(OC)C(=O)c4ccc(-c5cc(OC)c(Br)c(OC)c5)o4)cc3)cn2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4cn[nH]c4)cc3)o2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
To a suspension of 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(1-(tris(4-methoxyphenyl)methyl)-1H-pyrazol-4-yl)phenyl)ethanone (0.10 g, 0.12 mmol) in MeOH—H2O (22 mL, 10:1) was added pyridinium para-toluenesulfonate (0.046 g, 0.16 mmol). After stirring for 18 hrs at room temperature, saturated aqueous NaHCO3 was added and the volatiles were removed in vacuo. The residue was diluted with a small amount of H2O then extracted with EtOAc. The combined organics were washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (50-100% EtOAc-hexanes) provided 2-(4-(1H-pyrazol-4-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanone as a yellow foam (0.010 g, 17% yield). MS: m/z 497.0 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[O:13][CH:11]1[CH2:12][NH:8][CH:9]([CH2:22][O:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:10]1
Reactant: COC(=O)c1ccc(OCC2CC(Oc3ccc(F)cc3F)CN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCC2CC(Oc3ccc(F)cc3F)CN2)cc1
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinylmethoxy]benzoate (529 mg, 1.15 mmol) in CH2Cl2 (5 ml) was added TFA (5 ml). The mixture was stirred overnight. The mixture was concentrated in vacuo and the residue was made basic by the addition of sat. NaHCO3. The mixture was extracted with CHCl3 (2×100 ml). The extracts were dried over K2CO3 and evaporated to give methyl 4-[4-(2,4-difluorophenoxy)-2-pyrrolidinylmethoxy]benzoate (385 mg, 92%) as a yellow oil. 1H-NMR (CDCl3) δ1.89-1.95 (m, 1 H), 2.28-2.35 (m, 1 H), 3.09 (dd, J=12.5, 4.9 Hz, 1 H), 3.33 (d, J=12.5 Hz, 1 H), 3.60 (m, 1 H), 3.86 (s, 3 H), 4.10 (d, J=5.6 Hz, 2 H), 4.84 (m, 1 H), 6.73-6.89 (m, 3 H), 6.91 (d, J=8.5 Hz, 2 H), 7.96 (d, J=8.5 Hz, 2 H).
Reaction SMILES: S1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:3][CH2:2]1.O[O:17][S:18]([O-:20])=O.[K+]>CO.O>[O:17]=[S:18]1(=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)SCCC2n1ccnc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=S1(=O)CCC(n2ccnc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-thiochroman-4-yl-1H-imidazole, which can be prepared as described in Example 16, (130 mg, 0.60 mmol) in methanol (3 mL) at 0° C. is added dropwise a solution of Oxone® (excess) in water (3 mL). The reaction mixture is stirred overnight at room temperature. The reaction is then concentrated an the resulting residue is purified by silica gel flash chromatography (0:1 to 1:19 methanol-dichloromethane), to afford 1-(1,1-dioxo-thiochroman-4-yl)-1H-imidazole; MS: (ESI) m/z 249.1 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 2.83-3.13 (m, 2 H), 3.42-3.65 (m, 1 H), 3.64-3.82 (m, 1 H), 6.18 (t, J=7.1 Hz, 1 H), 7.14 (d, J=7.6 Hz, 1 H), 7.49-7.78 (m, 4 H), 8.02 (d, J=8.0 Hz, 1 H), 9.06 (s, 1 H).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([CH3:8])=[N:5][CH:4]=1.[C-:9]#[N:10].[Na+].O>CN(C=O)C>[CH3:8][C:6]1[O:7][C:3]([CH2:2][C:9]#[N:10])=[CH:4][N:5]=1
Reactant: Cc1ncc(CBr)o1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc(CC#N)o1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 5-(bromomethyl)-2-methyl-oxazole CAS [82190-68-9] (15 g, 85 mmol) in DMF (150 mL) was treated with NaCN (10.4 g, 213 mmol) at room temperature and the mixture stirred at 70° C. for 1 h. After this time the mixture was poured onto ice-cooled water (300 mL) and extracted with CH2Cl2 (5×200 mL). The combined organic extracts were then washed with brine, dried with Na2SO4 for 30 min, and the mixture concentrated to afford crude 2-methyl-5-oxazoleacetonitrile product CAS [1159511-94-0] (10 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B(O)O)=[C:4]([O:12][C@H:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])[CH:3]=1.[CH2:18]([O:21][C:22]1([CH3:55])[CH2:27][CH2:26][N:25]([C:28]2[N:33]3[CH:34]=[C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39](Br)[CH:38]=4)[N:36]=[C:32]3[CH:31]=[C:30]([CH3:44])[C:29]=2[C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[CH2:24][CH2:23]1)[CH:19]=[CH2:20].C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=CC(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:18]([O:21][C:22]1([CH3:55])[CH2:23][CH2:24][N:25]([C:28]2[N:33]3[CH:34]=[C:35]([C:37]4[CH:38]=[C:39]([C:5]5[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=5[O:12][C@H:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])[CH:40]=[CH:41][CH:42]=4)[N:36]=[C:32]3[CH:31]=[C:30]([CH3:44])[C:29]=2[C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[CH2:26][CH2:27]1)[CH:19]=[CH2:20]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(C)c(C)cc1B(O)O
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)c(C)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 77 %

Procedure:
Prepared in 77% yield from (S)-(4,5-dimethyl-2-(pent-4-en-2-yloxy)phenyl)boronic acid and (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=11.5 Hz, 2H), 7.92-7.87 (m, 1H), 7.58-7.52 (m, 1H), 7.43 (s, 1H), 7.32 (s, 1H), 7.22 (s, 1H), 6.81 (s, 1H), 6.11-5.99 (m, 2H), 5.82-5.68 (m, 1H), 5.48-5.38 (m, 1H), 5.10-4.94 (m, 3H), 4.27-4.19 (m, 1H), 4.07-3.92 (m, J=5.0 Hz, 3H), 3.87-3.76 (m, 1H), 3.69 (s, 3H), 3.06-2.97 (m, 1H), 2.79-2.68 (m, 1H), 2.47 (s, 3H), 2.42-2.34 (m, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 2.25-2.18 (m, 1H), 2.02-1.95 (m, 2H), 1.86-1.75 (m, 2H), 1.29 (s, 3H), 1.27 (s, 9H), 1.16 (d, J=6.3 Hz, 3H); LCMS (ESI, M+1): 694.35.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19](O)=[O:20])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:22]([O:26][C:27](=[O:35])[CH2:28][CH:29]([NH2:34])[CH:30]([OH:33])[CH2:31][F:32])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:22]([O:26][C:27](=[O:35])[CH2:28][CH:29]([NH:34][C:19]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:13]1[C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1)=[O:12])=[O:20])[CH:30]([OH:33])[CH2:31][F:32])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)c1nccc2ccccc12
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)c1nccc2ccccc12)C(O)CF
Temperature: 0 °C
Yield: 91.6 %

Procedure:
A stirred mixture of (S)-1-(isoquinoline-1-carbonyl)-2-piperidinecarboxylic acid (278 mg, 0.98 mmol), 3-amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (213 mg, 1.03 mmol), HOBt (145 mg, 1.07 mmol), DMAP (137 mg, 1.12 mmol) and anhydrous THF (25 ml) was cooled to 0° C. then EDC (206 mg, 1.07 mmol) was added. The mixture was allowed to warm to room temperature during 16 hrs then concentrated under reduced pressure. The residue was purified by flash chromatography (5% methanol in DCM) to afford the title compound as a white foam (425 mg, 92%): 1H NMR (400 MHz, CDCl3) δ 1.20-3.30 (17H, m), 3.95-4.18 (2H, m), 4.29-4.64 (4H, m), 4.86-5.01 (1H, m), 7.65-8.00 (4H, m), 8.10-9.00 (3H, m); 19F (376 MHz, CDCl3) δ −229.39, −229.41, −229.57, −229.60, −229.64, −229.69, −230.41, −231.08.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=[O:8])[N:3]=[CH:2]1.[Na].[CH3:11]O>>[NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH3:11])=[O:8])[N:3]=[CH:2]1
Reactant: CO
Reactant: O=C(O)Cc1c[nH]cn1
Agent: [Na]
Product: COC(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-Imidazoleacetic acid, sodium salt, hydrate (compound ix, where R2 is H) (3.0 g, 18.1 mmol) in MeOH (50 ml) was cooled to about 0° C. and anhydrous HCl gas was bubbled into the mixture for about 15 minutes while maintaining reaction temperature below about 5° C. The reaction was stirred for about ½ hour at room temperature and then solvents were removed under reduced pressure to yield an oil which solidifies on standing. Mass spec 141.0 MH+, NMR (300 MHZ, DMSO-d6, 30° C.), 9.0–9.2 (1H, s), 7.4–7.6 (1H, s), 3.85–3.95 (2H, 3), 3.6–3.7 (3H, s).