Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[CH:12][CH:11]=3)[CH:8]=[CH:9][C:2]=12.[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][CH3:17])=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=3)[CH:8]=[CH:9][C:2]=12
Reactant: O=[N+]([O-])[O-]
Reactant: CNc1ccc(-c2ccc3nonc3c2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CNc1ccc(-c2ccc3nonc3c2)cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
140 mg (0.62 mmol) (4-benzo[1,2,5]oxadiazol-5-yl-phenyl)-methyl-amine are stirred at 0° C. in 2 mL concentrated sulfuric acid, then treated with 66 mg (1.05 eq.) potassium nitrate and stirred an additional 4 hours. The reaction mixture is poured onto ice, the precipitate filtered off, thoroughly washed with water and dried under high vacuum. The crude product is column chromatographed with ethyl acetate/petroleum ether 1:2 to yield after evaporation of the product-containing fraction the desired product as an orange solid. MS(ES−): 269 (M−1).
Reaction SMILES: C(Br)C1C=CC=CC=1.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]>>[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][N:31]([CH2:10][C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([O:16][CH3:17])=[O:15])[C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: COC(=O)c1cccc(CBr)c1
Agent: BrCc1ccccc1
Product: COC(=O)c1cccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)c1
Yield: 64 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with methyl 3-(bromomethyl)benzoate to react with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one, the title compound was obtained as a white solid in 64% yield: mp 122-124° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.99-7.93 (m, 2H), 7.52-7.40 (m, 2H), 4.53 (s, 2H), 4.11-4.05 (m, 2H), 3.96 (s, 3H), 3.49-3.43 (m, 2H), 2.59 (s, 3H), 2.49 (s, 3H); MS (ES+) m/z 374.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:11]([O:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCBr
Reactant: Oc1cc(F)cc(F)c1
Product: CCCCCCCCCCOc1cc(F)cc(F)c1

Procedure:
Quantities: 3,5-difluorophenol (5.0 g, 0.038 mol), 1-bromodecane (8.84 g, 0.04 mol).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]3([F:29])[C:23]([F:24])=[C:22]([O:25][CH2:26][CH3:27])[CH:21]=[CH:20][CH:19]3[CH3:28])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3([F:29])[C:23]([F:24])=[C:22]([O:25][CH2:26][CH3:27])[CH:21]=[CH:20][CH:19]3[CH3:28])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2ccc(C=CC3(F)C(F)=C(OCC)C=CC3C)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2ccc(CCC3(F)C(F)=C(OCC)C=CC3C)cc2)cc1
Yield: 81.9 %

Procedure:
0.36 g of Pd/C was added to 7.29 g of the compound (20) having been dissolved in 100 mL of toluene and 100 mL of Solmix, and under a hydrogen atmosphere, the mixture was stirred at room temperature until hydrogen was not absorbed. Pd/C was removed by filtration, and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallization to obtain 6.00 g of 2-(2-(4-(4-propylphenyl)phenyl) ethyl)-2,3-difluoro-4-ethoxytoluene (Compound 1-3-3-22) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([Sn](C)(C)C)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[C:17]1[S:18][C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=1.C(OCC)(=O)C>C1COCC1>[CH2:22]([C:19]1[S:18][C:17]([C:9]2[O:8][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[CH:10]=2)=[CH:21][CH:20]=1)[CH3:23]
Reactant: COc1cccc2oc([Sn](C)(C)C)cc12
Reactant: CCc1ccc(Br)s1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1ccc(-c2cc3c(OC)cccc3o2)s1
Yield: 41.8 %

Procedure:
To a solution of 4-methoxy-2-(trimethylstannyl)benzo(b)furan (3.00 g) and 2-bromo-5-ethylthiophene (1.84 g) in THF (25 ml) was added bistriphenylphosphinepalladium dichloride (224 mg), and the mixture was stirred with refluxing overnight. After cooling, ethyl acetate was added to the reaction mixture and the mixture was filtered through celite. The filtrate was washed with water and saturated brine, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.04 g) as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]>C1(C)C=CC=CC=1>[N:1]1([CH2:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of piperidine (25 ml) and 3-(bromomethyl)benzoic acid, methyl ester (20 g) in toluene (600 ml) was stirred at room temperature for 4 h. The white preciptiate was removed by filtration and the filtrate was distilled to give the title compound as a colourless oil (17.56 g) b.p. 110° (10-1 mm). TLC silica; ether; Rf 0.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:19]=[C:13]2[C:14](=[O:18])[NH:15][CH2:16][CH:17]=[C:12]2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]#[CH:28]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:28][C:27]#[CH:26])[CH:6]=[CH:5][C:4]=1[C:10]1[N:19]=[C:13]2[C:14](=[O:18])[NH:15][CH2:16][CH:17]=[C:12]2[N:11]=1
Reactant: C#CCBr
Reactant: COc1cc(O)ccc1C1=NC2=CCNC(=O)C2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCOc1ccc(C2=NC3=CCNC(=O)C3=N2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1 g of 2-(2-methoxy-4-hydroxy-phenyl)-5H-imidazo[4,5-c]pyridin-4-one was suspended in 30 1.41 g of potassium carbonate were added, and the mixture was stirred at room temperature. After 15 minutes and again after one hour, 0.9 ml of propargyl bromide was added, and the mixture was then stirred for another 1.25 hours. The solvent was substantially evaporated in vacuo, and the residue was stirred with methylene chloride. After the precipitate had been filtered off and washed with water, the product contained in the organic phase was purified on a silica gel column (eluant: methylene chloride/ethanol 1:0 to 1:0.03). The product crystallized with half a mol of ethanol. Yield: 0.07 g (7% of theory). Melting point: 178°-180° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:18])=[O:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:3])=[O:2].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>>[CH2:20]([O:21][C:22]([C:24]1[CH2:28][CH2:27][CH2:26][C:25]=1[NH:18][C:16](=[O:17])[NH:15][C:12]1[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:23])[CH3:19]
Reactant: CCOC(=O)c1cc(NC(N)=O)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C1CCCC1=O
Product: CCOC(=O)C1=C(NC(=O)Nc2ccc([N+](=O)[O-])c(C(=O)OCC)c2)CCC1

Procedure:
using ethyl 2-nitro-5-ureidobenzoate and ethyl cyclopentanone-2-carboxylate there is obtained ethyl 5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-2-nitrobenzoate, m.p. 152°-155° C.,
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12.[C:14]1([CH2:20]O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]2[NH:11][CH:12]=[CH:13][C:3]=12
Reactant: O=C(O)c1cnc2[nH]ccc2c1Cl
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cnc2[nH]ccc2c1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
To a suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-Carboxylic acid (343 mg) in N,N-dimethylformamide (4 ml) was added phenylmethanol (375 μl) 4-dimethylaminopyridine (428 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (676 mg). After stirring at ambient temperature for 3 days, the reaction mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel with chloroform to give benzyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (200 mg) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][C:10]=1[OH:20].[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23]O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:16]2[O:18][CH2:23][C:22]([CH3:26])([CH3:25])[N:21]=2)[CH3:19])=[CH:11][C:10]=1[OH:20]
Reactant: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)c(O)c1
Reactant: CC(C)(N)CO
Solvent: Cc1ccccc1C
Product: CC(C1=NC(C)(C)CO1)c1ccc(-c2ccc(F)cc2F)c(O)c1

Procedure:
A solution of 2-(2',4'-difluoro-2-hydroxy-4-biphenylyl) propionic acid (1 g.) and 2-amino-2-methylpropan-1-ol (1 ml.) in xylene (20 ml.) was stirred under reflux for 3 days. The solvent was distilled and the solid residue was recrystallised from aqueous methanol to give 2-[1-(2',4'-difluoro-2-hydroxy-4-biphenylyl)ethyl]-4,4-dimethyl-2-oxazoline, m.p. 188°-194° C. (decomposes).
Reaction SMILES: [ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:35]=[CH:34][C:10]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH2:17][N:16]2CC2C=CC=CC=2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4]>[OH-].[OH-].[Pd+2].CO>[ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][N:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:18][CH2:17][NH:16]2)=[O:12])=[CH:34][CH:35]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)NCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(=O)NCC2CN(c3ccccc3)CCN2)cc1

Procedure:
To methanol (400 mL) add 4-[(methylsulfonyl)amino]-N-[[4-phenyl-1-(phenylmethyl)piperazin-2-yl]methyl]benzamide hydrochloride (40 g, 77 mmol) and Pd(OH)2 (2.0 g). When the addition is complete, place the reaction mixture on a Parr hydrogenator at 50 p.s.i. of H2 and shake. Monitor the progress of the reaction by thin-layer chromatography. Upon completion of the reaction, remove the catalyst by suction filtration through celite. Wash the pad with methanol. Remove the solvent in vacuo to obtain a residue. Recrystallize from methanol to provide the title compound.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[NH:15][C:14]2[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][O:20][C:16]1[C:14]2[NH:15][C:11]([CH2:10][CH2:9][NH:7][CH3:6])=[N:12][C:13]=2[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc2nc(CCN(C)C(=O)OC(C)(C)C)[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCc1nc2cccc(OC)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
A solution of 1.5 g of [2-(7-methoxy-1H-benzoimidazol-2-yl)-ethyl]-methyl-carbamic acid tert.-butyl ester in 10 mL DCM was treated with 0.39 mL of TFA and stirred overnight at rt. The reaction mixture was concentrated in vacuo, redissolved in DCM and treated with diluted NaOH. After separation of the 2 phases the water phase was lyophilized to yield 380 mg of [2-(7-methoxy-1H-benzoimidazol-2-yl)-ethyl]-methyl-amine as beige solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:2][O:3][C:4](=[O:11])[C@@H:5](/[N:6]=[CH:17]/[C:16]1[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=1)[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)/N=C/c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
L-Leucine methyl ester hydrochloride (3.65 g) was dissolved in methanol (35 mL) and 4-fluoro-benzaldehyde (2.65 mL) and Na2CO3 (4.0 g) were added. The mixture was stirred at ambient temperature for 3 days. After that, the mixture was filtrated, evaporated to dryness. The residue was dissolved in TBME. The precipitate was filtrated off. The TBME solution was evaporated to dryness to yield the title compound as a colorless oil (4.66 g; 92%). MS (ESI): m/z=252.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(O)(=O)CC.[N+:21]([O-])([OH:23])=[O:22]>>[N+:21]([C:8]1[CH:9]=[N:10][C:11]2[C:6]([C:7]=1[OH:13])=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:12]=2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2cc(C(F)(F)F)ccc12
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2cc(C(F)(F)F)ccc2c1O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(trifluoromethyl)-4-quinolinol (22.7 g, 0.106 mol) and propionic acid (106 mL) was heated to 120° C. Nitric acid (10 mL of 70%) was added dropwise and heating was continued for an additional 2 hours. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration then washed with water and diethyl ether to provide 13.3 g of 3-nitro-7-(trifluoromethyl)-4-quinolinol as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=O)[C:14]#[C:15][CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][NH:19][NH2:20]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]([CH3:16])[N:19]([CH3:18])[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: CNN
Solvent: CO
Product: Cc1cc(C2CCN(C(=O)OC(C)(C)C)C2)nn1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 88.7 %

Procedure:
To a stirred solution of 3-(1-oxo-but-2-ynyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.8 g, 3.4 mmol) in MeOH (20 mL) was added methyl-hydrazine (5 g, 44 mmol). The mixture was stirred at room temperature for 10 hours. The reaction mixture was quenched with water (50 mL) and extracted with CH2Cl2 (50 mL×3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (PE/EA=1:1) to afford 3-(1,5-dimethyl-1H-pyrazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (800 mg, 88%) as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1)[CH3:2]>[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=CCCCCC(=O)O)cc1
Agent: [Pd]
Product: CCOc1ccc(CCCCCCC(=O)O)cc1
Yield: 96.7 %

Procedure:
This compound was synthesized from 7-(p-ethoxyphenyl)-6-heptenoic acid (1.24 g, 5 mmol) and Pd/C (125 mg) by a hydrogenation reaction. Crystallization (petroleum ether) afforded the product (1.21 g, 97%) as white crystals (mp 65-66° C.). IR: 3400-2500, 1715 cm-1 ; 1H-NMR: 1.32 (m, 7H), 1.55 (m, 5H), 2.30 (t, 2H), 2.50 (t, 2H), 3.95 (q, 2H), 6.90 (q, 2H), 10.20 (bs, 1H). Anal. Calcd. for C15H22O3 : C, 71.97, H, 8.86%; Found: C, 71.91, H, 8.87%.
Reaction SMILES: [CH3:1][Mg]I.[F:4][C:5]([F:22])([F:21])[C:6]1[N:11]=[C:10]([N:12]2[CH2:16][C@@H:15]3[C:17](=[O:20])[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)[CH:9]=[CH:8][CH:7]=1>CCOCC>[CH3:1][C@:17]1([OH:20])[C@@H:15]2[C@@H:14]([CH2:13][N:12]([C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:5]([F:4])([F:21])[F:22])[N:11]=3)[CH2:16]2)[CH2:19][CH2:18]1
Reactant: C[Mg]I
Reactant: O=C1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@H]12
Solvent: CCOCC
Product: C[C@@]1(O)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reaction time: 1 h

Procedure:
Methylmagnesium iodide in ether (0.302 mL, 0.907 mmol) was added to (3aR,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]hexahydrocyclopenta[c]pyrrol-4(1H)-one (70 mg, 0.259 mmol) from Example 32 in ether (0.1 mL) at 25° C., and the reaction mixture was stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The combined organic washes were purified by silica gel chromatography using 0-30% ethyl acetate/hexane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.46 (t, J=7.9, 1H), 6.93 (d, J=7.2, 1H), 6.50 (d, J=8.6, 1H), 5.92 (s, 1H), 4.03 (dd, J=11.1, 3.7, 1H), 3.69 (t, J=9.4, 1H), 3.61-3.50 (m, 1H), 3.43 (dd, J=10.0, 5.7, 1H), 2.83-2.69 (m, 1H), 2.46 (td, J=9.0, 3.9, 1H), 2.14-2.02 (m, 1H), 1.90 (dq, J=11.6, 8.4, 1H), 1.79-1.62 (m, 2H), 1.42 (s, 3H); MS (ESI+) m/z 287 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)(Cl)Cl>[CH3:21][O:20][C:19]1[C:6]2[C:5]3[CH:22]=[CH:23][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:3][C:4]=3[CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:8][C:7]=2[CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1-c1ccc(N)cc1C(c1ccccc1)O2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1cccc2c1-c1ccc(NS(C)(=O)=O)cc1C(c1ccccc1)O2
Yield: 79 %

Procedure:
The solution of Example 5F (200 mg. 0.66 mmole), pyridine (300 mg) and methanesulfonyl chloride (227 mg., 2.00 mmole) in chloroform (3 mL) was stirred for 1 hour, washed with aqueous HCl (1M), dried (Na2SO4), filtered and concentrated under reduced pressure. Toluene was added and then concentrated. Heptane was added and concentrated under reduces pressure to provide the titled compound (199 mg. 80%). 1H NMR (300 MHz, CDCl3) δ 2.95 (s, 3H), 3.94 (s, 3H), 6.00 (s, 1H), 6.30 (s, 1H), 6.61 (d, J=2 Hz, 1H), 6.62 (dd, J=10 Hz, 2 Hz, 1H), 6.69 (dd, J=9 Hz, 1 Hz, 1H), 7.15 (t, J=9 Hz, 1H), 7.25 (dd, J=9 Hz, 2 Hz, 1H), 7.32-7.39 (m, 5H), 8.45 (d, J=9 Hz, 1H); MS (APCI) m/e 382 (M+H), 399 (M+NH4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1([CH2:25]O)[CH2:24][CH2:23]1.CO>ClCCl>[CH:22]1([CH2:25][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH2:24][CH2:23]1
Reactant: OCC1CC1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: ClCCl
Solvent: CO
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCC1CC1
Yield: 83 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using cyclopropanemethanol (28 μL, 0.34 mmol) as the coupling partner. Chromatography (1: 1 methanol:dichloromethane) through SiO2 yielded 49 mg (83%) of the titled compound as a white solid. ESI-MS m/z 346 (MH+), 344 (M−H−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:7][C:6]2[CH:10]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[C:6]([CH:10]=1)[C:7]([O:9][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-2-hydroxybenzoic acid (2.03 g, 11.8 mmol), benzyl bromide (2.79 ml, 23.5 mmol) and potassium carbonate (4.87 g, 35.3 mmol) in DMF (20 ml) was stirred at room temperature overnight then heated at 60° C. for 1 hour. Cooled, diluted with water (150 ml) and extracted with ethyl acetate (×3). The organics were washed with water (×2) and brine, dried (MgSO4), and concentrated in vacuo to yield the crude title compound as a yellow oil which was used immediately without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[O:9][CH2:10][CH2:11][C:4]=12.C(=O)([O-])O.[Na+].[Br:19]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:19][C:8]1[C:3]([Si:2]([CH3:13])([CH3:12])[CH3:1])=[C:4]2[CH2:11][CH2:10][O:9][C:5]2=[N:6][CH:7]=1
Reactant: BrBr
Reactant: C[Si](C)(C)c1ccnc2c1CCO2
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)c1c(Br)cnc2c1CCO2
Reaction time: 9 h
Yield: 79.9 %

Procedure:
To a solution of 4-(trimethylsilyl)-2,3-dihydrofuro[2,3-b]pyridine (463 mg, 2.40 mmol) in dichloromethane (10 mL) were added sodium hydrogen carbonate (504 mg, 6.00 mmol) and bromine (959 mg, 6.00 mmol) at room temperature, and the mixture was stirred for 9 hr. An aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→30/70) to give the title compound (522 mg, yield 80%).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][C@H:5]1[O:8][C:7](=[O:9])[CH2:6]1.[OH-:19].[Na+]>C1COCC1.O>[OH:8][C@H:5]([CH2:4][CH:3]([O:2][CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][C:7]([OH:19])=[O:9]
Reactant: [OH-]
Reactant: CCCCCCCCCC(C[C@@H]1CC(=O)O1)OC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCC(C[C@@H](O)CC(=O)O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(ref. Gu, et al. Nature 459, 731-735 (2009)). To a solution of 6 (92.0 mg, 0.359 mmol, 1.0 equiv) in THF (1.5 mL) was added a solution of NaOH (15.7 mg, 0.394 mmol, 1.1 equiv) in water (1.5 mL). The reaction mixture was stirred at rt for 1 h. During this time, its appearance changed from turbid to clear (t=about 0.5 h). The solution was quenched by addition of 1 M HCl (1 mL) and extracted with ether (2×5 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried (Na2SO4) and concentrated in vacuo to afford a pale yellow oil. Purification of the crude product by chromatography on SiO2 (1:1 EtOAc/hexanes containing 0.5% AcOH) provided (3R)-1 (94.4 mg, 96%) as a colorless oil: ATR/IR 2920, 2851, 1709, 1413, 1187, 1079, 736 cm−1; 1H NMR (CDCl3) 4.35-4.20 (m, 1H), 3.55-3.45 (m, 1H), 3.38, 3.37 (2s, 3H), 2.56-2.50 (m, 2H), 1.80-1.35 (m, 3H), 1.35-1.25 (m, 14H), 0.90 (t, 3H, J=6.9 Hz); 13C NMR (CDCl3) 176.4, 175.7, 68.1, 65.4, 56.7, 56.0, 41.6, 41.5, 39.7, 39.1, 32.9, 32.8, 31.9, 29.8, 29.6, 29.5, 29.3, 25.2, 24.5, 22.7, 14.1.
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]=[CH:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCc1c(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-hexenyl)pyridine (Example 19) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.14 (m, 4 H), 4.33 (s, 2 H), 3.41 (sept, J=6.6 Hz, 1 H), 3.23 (sept, J=6.6 Hz, 1 H), 2.26 (m, 2 H) 1.33 (d, J=6.6 Hz, 6 H), 1.30 (d, J=6.6 Hz, 6 H), 1.26 (m, 1 H), 1.14 (m, 7 H), 0.82 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C24H34FNO) 371, found 372 (M+H). mp 93-95° C. Rf=0.4 (20% ethyl acetate/hexane).