Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][CH2:5][CH:6]([C:19]([F:22])([F:21])[F:20])[C:7]([N:9]1[C@H:13]([C:14]([O:16]C)=[O:15])[C@@H:12]([CH3:18])[O:11][CH2:10]1)=[O:8])(=O)C.[OH-].[Na+]>>[SH:4][CH2:5][CH:6]([C:19]([F:22])([F:21])[F:20])[C:7]([N:9]1[C@H:13]([C:14]([OH:16])=[O:15])[C@@H:12]([CH3:18])[O:11][CH2:10]1)=[O:8]
Reactant: COC(=O)[C@@H]1[C@@H](C)OCN1C(=O)C(CSC(C)=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: C[C@H]1OCN(C(=O)C(CS)C(F)(F)F)[C@@H]1C(=O)O

Procedure:
The product from part (c) is treated with sodium hydroxide according to the procedure of Example 1(c) to yield (4S-trans)-3-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-5-methyl-4-oxazolidinecarboxylic acid. This diastereoisomeric mixture can then be separated into the individual isomers.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10](=[O:12])[CH3:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Br-:13].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>O1CCCC1>[Br:13][CH2:11][C:10]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][N:4]=1)=[O:12]
Reactant: [Br-]
Reactant: COc1cnc(C(C)=O)c(Cl)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: COc1cnc(C(=O)CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To 0.90 g of 1-(3-chloro-5-methoxypyridin-2-yl)ethanone in 10 ml of tetrahydrofuran, 1.82 g of trimethylphenylammonium tribromide was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the precipitated solid was filtered off, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 0.57 g of the desired product as pale yellow crystals.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH2:9][OH:10])=[C:6]([CH3:8])[N:7]=1)[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[S:4][C:5]([CH:9]=[O:10])=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C)c(CO)s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCc1nc(C)c(C=O)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.2 %

Procedure:
Manganese dioxide (9.50 g, 109.3 mmol) was added to a solution of 2-ethyl-4-methylthiazole-5-methanol (Example 30; 0.86 g, 5.5 mmol) in dichloromethane (200 mL). The mixture was allowed to stir at room temperature for 72 h and then was filtered through Celite®. The filter cake was washed with dichloromethane (200 mL) and the combined filtrates were concentrated to give 2-ethyl-4-methylthiazole-5-carboxaldehyde (0.48 g, 57% yield) as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14](OC)=[O:15])[CH:9]=1>C(OCC)C>[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][OH:15])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cc(Cl)ccn1
Reaction time: 8 h

Procedure:
To a slurry of lithium aluminum hydride (0.45 g, 11.9 mmol) in anhydrous diethyl ether (40 mL) at 0° C., a solution of methyl 4-chloro-pyridine-2-carboxylate (2.0 g, 11.7 mmol) in diethyl ether (30 mL) was added. The resulting mixture was stirred at room temp. overnight, and quenched with successive addition of water (0.45 mL), 15% aqueous NaOH (0.45 mL), and water (1.35 mL). The resultant slurry was stirred at room temp. for 30 min., and filtered through a small plug of Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide 4-chloro-2-hydroxymethylpyridine.
Reaction SMILES: [CH2:1]([CH:4]([C:8]([CH3:10])=[CH2:9])[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)Cl>[CH2:1]([CH:4]([C:8]1([CH3:10])[O:19][CH2:9]1)[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(C(=C)C)C(C)=O
Solvent: ClCCl
Product: C=CCC(C(C)=O)C1(C)CO1
Reaction time: 3 h
Yield: 23.3 %

Procedure:
To a solution of 3-allyl-4-methyl-pent-4-en-2-one (20.0 g) in methylene chloride (100 ml) was added dropwise a solution of m-chloroperbenzoic acid (29 g) in methylene chloride (300 ml) at 0° to 5° C. The reaction mixture was stirred at 0° to 5° C. for 3 hours and then at 20° C. overnight. The reaction solution was progressively washed with an aqueous sodium hydrogen carbonate solution, aqueous sodium sulfite solution, aqueous sodium hydrogen carbonate solution and then with an aqueous sodium chloride solution. After removing the solvent by evaporation, the residue was distilled to obtain 7.2 g of the unreacted material and 5.2 g of the objective 3-allyl-4-methyl-4,5-epoxy-pentan-2-one.
Reaction SMILES: [Cl:1][C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:14][Mg]Cl.[NH4+].[Cl-].Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([C:4](=[O:5])[CH3:14])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: CON(C)C(=O)c1cccnc1Cl
Reactant: C[Mg]Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)c1cccnc1Cl
Reaction time: 2 h

Procedure:
2-Chloro-N-methoxy-N-methyl-nicotinamide (3.90 g, 19.4 mmol, 1.0 equiv) is dissolved in THF (200 mL) under nitrogen and the mixture is cooled in an ice bath. Methylmagnesium chloride (17.0 ml, 48.6 mmol, 2.5 equiv) is added within 2 minutes. After 15 min a grey precipitate is formed. Stirring is continued for 2 h, the mixture is cooled in an ice bath and sat. NH4Cl (150 mL) is added. The solution is acidified with 1N HCl solution (60 mL) followed by addition of sat. NaHCO3 solution (30 mL). The organic layer is separated and concentrated in vacuo. The residue is combined with the remaining water layer and extracted with diethyl ether (200 mL). The combined etheral layers are washed twice with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. This provides 2.57 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5]([Br:13])=[CH:4][CH:3]=1.Br[CH2:15][C:16]([NH2:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH2:15][C:16](=[O:17])[NH2:18])[C:5]([Br:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc(Br)c1O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)ccc(Br)c1OCC(N)=O
Temperature: 60 °C
Yield: 62.5 %

Procedure:
A mixture of methyl 6-amino-3-bromo-2-hydroxybenzoate (prepared according to Wang et al, Bioorg Med Chem Lett, 2007, 17, 2817, 7.55 g), bromoacetamide (4.55 g) and potassium carbonate (10.0 g) in DMF (70 mL) was heated to 60° C. for 17 hours. After cooling, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and water and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give an orange solid which was triturated with ether to give methyl 6-amino-3-bromo-2-carbamoylmethoxybenzoate (5.81 g) as a sandy coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][CH2:63][C:64]1[CH:65]=[CH:66][C:67]2[C:71]([CH2:74][F:75])([CH2:72][F:73])[O:70][B:69]([OH:76])[C:68]=2[CH:77]=1>CN(C=O)C>[F:75][CH2:74][C:71]1([CH2:72][F:73])[O:70][B:69]([OH:76])[C:68]2[CH:77]=[C:64]([CH2:63][NH:62][C:18](=[O:20])[C:17]3[CH:21]=[CH:22][C:14]([C:11]4[CH2:10][C:9]([C:4]5[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=5)([C:24]([F:27])([F:25])[F:26])[O:13][N:12]=4)=[CH:15][C:16]=3[CH3:23])[CH:65]=[CH:66][C:67]1=2
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC2(CF)CF
Reaction time: 0.17 h
Yield: 33.2 %

Procedure:
A solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-benzoic acid (100 mg, 0.24 mmol) and DIPEA (124 mg, 0.88 mmol) in DMF (5 mL) was stirred at rt for 5 min and then HATU (183 mg, 0.48 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (126 mg, 0.44 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified by prep-TLC to provide the final title product (50 mg, 33%). 1H NMR (400 MHz, CDCl3): δ 7.47 (m, 9H), 4.61 (m, 6H), 4.07 (d, 1H), 3.78 (d, 1H), 2.41 (s, 3H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)O1.Br[C:24]1[N:28]2[N:29]=[C:30]([C:33]([O:35]C)=[O:34])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1>O1CCOCC1.C([O-])(O)=O.[Na+].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]>[F:21][C:18]([F:19])([F:20])[C:16]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[C:9]([C:24]2[N:28]3[N:29]=[C:30]([C:33]([OH:35])=[O:34])[CH:31]=[CH:32][C:27]3=[N:26][CH:25]=2)[CH:17]=1
Reactant: COC(=O)c1ccc2ncc(Br)n2n1
Reactant: CC1(C)OB(c2cc(C(F)(F)F)cc3[nH]ncc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: O=C(O)c1ccc2ncc(-c3cc(C(F)(F)F)cc4[nH]ncc34)n2n1
Temperature: 140 °C

Procedure:
To a 10 mL vial was added a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-indazole (0.066 g, 0.211 mmol), methyl 3-bromoimidazo[1,2-b]pyridazine-6-carboxylate (0.054 g, 0.211 mmol) and PdCl2(dppf) (7.74 mg, 10.57 μmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (1 mL). The resulting orange suspension was heated at 140° C. for 30 minutes in a microwave reactor. The major peak by LCMS was the decarboxylated product. The reaction mixture was extracted into EtOAc and the water layer was separated and acidified with concentrated HCl to pH 2. The water layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give an oil, which was used without further purification (36 mg).
Reaction SMILES: BrBr.[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6](C(N)=O)[CH:5]=1.Cl.Cl.Cl.COC(C1C=C(N2CCN([C@@H]3CN[C@H](C(N4CCSC4)=O)C3)CC2)C2C(=CC=CC=2)[N:25]=1)=O>[OH-].[K+].O1CCCC1>[NH2:25][C:6]1[CH:5]=[C:4]([Cl:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: COC(=O)c1cc(N2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)c2ccccc2n1
Reactant: NC(=O)c1cc(Cl)c2ccccc2n1
Agent: BrBr
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1cc(Cl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (2.32 mL) was dissolved in 5% aqueous potassium hydroxide solution (190 mL), and a solution of 4-chloroquinoline-2-carboxamide [product of Example 262 (1), 9.80 g] in tetrahydrofuran (190 mL) was dropwise added thereto. The mixture was stirred at room temperature for 30 min, and the mixture was stirred at 80° C. for 1 hr with heating. The reaction mixture was filtrated and the filtrate was added to water. The mixture was extracted with chloroform, and the extract was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 2-amino-4-chloroquinoline (1.98 g) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]1[O:13][CH2:12][CH2:11][O:5]1
Reactant: O=Cc1cc(F)ccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(Br)c(C2OCCO2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of 2.0 g (9.9 mmol) 2-bromo-5-fluorobenzaldehyde in 20 ml toluene were added 0.722 ml (13.0 mmol) ethane-1,2-diol and 5 mg (0.03 mmol) toluene-4-sulfonic acid monohydrate. The reaction mixture was heated in a rotary evaporator at 60° C. and 200 mbar during 4 h. After evaporation of the solvent and flash chromatography 2.32 g (95%) of the title compound were obtained as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4](Cl)[CH2:5][S:6][CH2:7][C:8]([OH:10])=[O:9].[N-:13]=[N+:14]=[N-:15].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:13]=[N+:14]=[N-:15])[CH2:5][S:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: COC(=O)C(Cl)CSCC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(CSCC(=O)O)N=[N+]=[N-]
Yield: 88.3 %

Procedure:
1.00 gram (4.70 mmoles) of the 2-chloro-3-carboxymethylmercapto-propionic acid methyl ester produced in Example 9 was stirred with 0.46 gram (7.08 mmoles) of sodium azide and 0.10 gram of Aliquat 336 in 2 ml of water for 15 hours at 50° C. After working up according to Example 2 there were obtained 0.91 gram (88% of theory) of 2-azido-3-carboxymethylmercapto-propionic acid methyl ester as an analytically pure material.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2C(=O)O[C:15](C)([CH3:19])[O:14][C:13]2=[O:21])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(O)C>[CH2:15]([O:14][C:13](=[O:21])[CH2:12][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:9]#[C:10][CH3:11])[CH3:19]
Reactant: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Solvent: c1ccncc1
Solvent: CCO
Product: CC#CC(CC(=O)OCC)c1ccc(O)cc1
Temperature: 90 °C
Yield: 94.7 %

Procedure:
Phenol 1.2 (1.2 g, 4 mmol) was dissolved in pyridine (3 mL) and ethanol (1 mL). The mixture was heated to 90° C. for 16 h and then concentrated to an oil which was purified by column chromatography (elution with 1-3% MeOH in dichloromethane). Phenol 16 (0.88 g, 91%) was obtained as an oil. 1H NMR(500 MHz)(acetone-d6) δ 8.24 (s, 1H); 7.21 (d, 2H, J=9.5 Hz); 6.78 (d, 2H, J=9.0 Hz); 4.06 (m, 2H); 3.98 (m, 1H); 2.68-2.59 (m, 2H); 1.78 (d, 3H, J=2.5 Hz); 1.75 (t, 3H, J=7.0 Hz). MS ESI (pos.) m/e: 233.1 (M+H); 255.1 (M+Na).
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]=[C:9]1[S:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:15]=2)[NH:10]1>ClCCl>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[NH:10][C:9](=[O:8])[S:13][N:12]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nsc(=O)[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2nsc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
At 0° C., 0.8 ml of TFA was added to a solution of 129 mg (purity 70%, 0.44 mmol) of tert-butyl [4-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)phenyl]carbamate in 4 ml of dichloromethane, and the mixture was stirred at RT for 40 min Subsequently, the reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 54 mg (purity 90%, 57% of theory)
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[N:21]=[C:20]2[NH:22][N:23]=[CH:24][C:19]2=[C:18]([N:25]2[CH2:31][CH:30]3[O:32][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[N:17]=1.[CH3:33][O:34][CH2:35][CH:36](O)[CH2:37][O:38][CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:15][C:16]1[N:21]=[C:20]2[N:22]([CH:36]([CH2:37][O:38][CH3:39])[CH2:35][O:34][CH3:33])[N:23]=[CH:24][C:19]2=[C:18]([N:25]2[CH2:31][CH:30]3[O:32][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[N:17]=1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Reactant: COCC(O)COC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Yield: 126 %

Procedure:
Diisopropyl azodicarboxylate (1.1 mL, 5.4 mmol) was added in drops to a suspension of 3-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.1 g, 4.1 mmol), 1,3-dimethoxypropan-2-ol (0.65 g, 5.4 mmol), and triphenylphosphine (1.4 g, 5.4 mmol) in tetrahydrofuran (33 mL). When this Mitsunobu reaction was deemed to be complete by LC/MS analysis, the mixture was adsorbed onto flash silica gel and purified by automated flash chromatography (methanol/chloroform) to provide 3-(6-chloro-1-(1,3-dimethoxypropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane as an amber glass (1.9 g, >100%) contaminated with triphenylphosphine oxide. MS (ES+): 368.2, 370.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C@:3]([CH3:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C@H:4]([OH:11])[C:5]#[C:6][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C@:3]([CH3:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C@H:4]([OH:11])[C:5]#[CH:6]
Reactant: CCCC[C@@](C)(OC)[C@H](O)C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#C[C@@H](O)[C@@](C)(CCCC)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
Dissolve (3R,4R)-4-methoxy-4-methyl-1-trimethylsilyl-1-octyn-3-ol (40 mg, 0.17 mmol) in tetrahydrofuran (1 mL) and place under an argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (1.4 mL of a 1M solution in tetrahydrofuran, 1.4 mmol). Stir for 1 hour at room temperature and partition between methylene chloride and water. Separate the organic phase, wash with saturated aqueous sodium chloride and dry (MgSO4). Evaporate the solvent in vacuo to give the title compound as a thick clear oil (21 mg, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16](Br)[CH:15]=2)[C:7]=1[F:23])[CH3:2].[C:25]1(C)C=CC=C[CH:26]=1.C(C([Sn])=C(CCCC)CCCC)CCC>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.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:15]=[C:16]([CH:25]=[CH2:26])[CH:17]=[C:18]([C:20]#[N:21])[CH:19]=2)[C:7]=1[F:23])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2cc(Br)cc(C#N)c2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Solvent: CCOC(C)=O
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CC(=O)OCC)c2F)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
A 2-necked flask was equipped with a reflux condenser and charged with 117c (1.14 g, 2.78 mmol) and tetrakis(triphenylphosphine)palladium (308 mg, 0.28 mmol). Anhydrous toluene (15 mL) and tributylvinyltin (0.85 mL, 2.91 mmol) were added, and the reaction was heated to reflux under nitrogen for 16 h. The solution was cooled to RT and EtOAc (50 mL) was added. The mixture was washed with H2O (25 mL) and brine (25 mL), and dried over anhydrous MgSO4. The solvents were evaporated, and the resulting oil purified by flash chromatography over silica gel(0% to 25% EtOAc/hexanes) to provide 770 mg (78%) of [4-chloro-3-(3-cyano-5-vinyl-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (118).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]#[N:25])[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccnc1Cl
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1cccnc1N1CCC(S(=O)(=O)c2cccc(Cl)c2)CC1
Yield: 66.2 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-3-cyanopyridine (108 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (91 mg), a yellow solid, in 62% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13](O)=[O:14])[N:12]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:34]2[N:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=N1.CN1CCOCC1.NC1C=NC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH:10]=[C:11]([C:13]([NH:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:14])[N:12]=1
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Nc1cccnc1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic acid (403 mg, 1.2 mmol) was dissolved in dichloromethane (5 mL) and treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (459 mg, 1.56 mmol) and N-methylmorpholine (NMM) (182 mg, 1.8 mmol). The mixture was stirred under argon for 15 minutes before 3-aminopyridine (349 mg, 3.6 mmol) was added. Stirring at rt was continued overnight. The reaction mixture was then adsorbed onto silica gel and chromatographed (2-3% MeOH in CH2Cl2) to afford 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(3-pyridinyl)-1H-imidazole-4-carboxamide (266 mg, 54% yield): LC-MS m/z 409.3, retention time 2.43 min (method 1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Cl:33])[C:17]=1[NH:18][C:19]1[C:28]2[C:23](=[C:24]([OH:31])[C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[O:22][C:21](=[O:32])[CH:20]=1>>[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Cl:33])[C:17]=1[NH:18][C:19]1[C:28]2[C:23](=[C:24]([O:31][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[O:22][C:21](=[O:32])[CH:20]=1
Reactant: CCOC(=O)CCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: CCOC(=O)CCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from ethyl 5-bromopentanoate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 4.03 (q, 2H), 3.98 (t, 2H), 3.91 (s, 3H), 2.36 (t, 2H), 1.80-1.60 (m, 4H), 1.15 (t, 3H); MS (ESI): 480.9.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[C:5]([NH2:8])=[N:6][N:7]=1.C(N(CC)CC)C.S(O[CH2:37][CH2:38][O:39][CH2:40][CH2:41]OS(C1C=CC(C)=CC=1)(=O)=O)(C1C=CC(C)=CC=1)(=O)=O.C(OCC)(=O)C>CN(C=O)C>[F:18][C:13]1[CH:12]=[C:11]([NH:10][N:9]=[C:4]2[C:3]([CH2:2][N:1]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:7][N:6]=[C:5]2[NH2:8])[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: NCC1=NN=C(N)C1=NNc1ccc(F)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC1=NN=C(CN2CCOCC2)C1=NNc1ccc(F)c(F)c1
Temperature: 87 °C
Yield: 14.3 %

Procedure:
The mixture of 5-aminomethyl-4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (125 mg, 0.5 mmole) and triethylamine (152 mg, 1.5 mmole) in 5 mL of dry DMF was heated to 87° C. To this solution was added slowly di(2-tosyloxyethyl)ether (311 mg, 0.75 mmole) in 1 mL of DMF. The reaction mixture was heated at 87° C. for 1.5 hours, and then worked up by the addition of saline and ethyl acetate. The crude material was purified by preparative TLC (CH2Cl2:CH3OH=16:1) to yield 23 mg of the title compound as a yellow powder. MS (m/z, ES+): 323 (M+1, 100%); 1H NMR (ppm, 300 MHz, CDCl3) δ 7.52 (m, 2H), 7.24 (m, 1H), 6.25 (br s, 2H), 3.95 (s, 2H), 3.74 (m, 4H), 2.64 (m, 4H).