Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Br[CH2:12][CH2:13][C:14]#[N:15].[H-].[Na+]>CN(C=O)C>[C:14]([CH2:13][CH2:12][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])#[N:15]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: N#CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCn1cnc2c(N)ncnc21
Yield: 75 %

Procedure:
As shown in Scheme 4, alkylation of adenine 10 with 3-bromopropionitrile in the presence of NaH in DMF gave N9-(cyanoethyl)adenine 15 in 75% yield. Reaction of 15 with methyl iodoacetate and lithium 2,2,6,6-tetramethylpiperidine (Li TMP) in THF afforded a mixture of N7-alkylated product 16 (60% yield) and N9-isomer 17 (20% yield). Reduction of the ester group in 16 with NaBH4 in wet THF13 gave N7-(hydroxyethyl)adenine 18 in 55% yield. Conversion of 18 to phosphonate 19 (60% yield) was accomplished by use of diethyl (p-toluenesulfonyloxymethane)phosphonate and sodium tert-butoxide in DMF.14 Treatment of compound 19 with Me3SiBr15 then afforded phosphonic acid 20 in 45% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:10]([C@@H:20]([OH:22])[CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C@@H:10]([C@@H:20]([O:22][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)[CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C[C@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(C(F)(F)F)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a stirred solution of 250 mg (0.79 mmol) of (S)-1-[(3R,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol in DMF (10 mL) was added NaH (57 mg, 1.18 mmol). The reaction mixture was stirred at RT for 30 minutes, and then at 50° C. for 20 minutes. A solution of 2-chloro-5-trifluoromethyl-pyridine (172 mg, 0.95 mmol) in DMF (2 mL) was added dropwise and stirring was continued 3 hours at 50° C. The reaction mixture was concentrated under vacuo. Extraction with EtOAc/H2O, followed by column chromatography (SiO2, EtOAc/H, 1:4) yielded 350 mg (96%) of the title compound as a colorless oil. ES-MS m/e: 461.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH:10]([C:13]#[N:14])[C:11]#[N:12])[CH:3]=1.[NH2:15][NH2:16]>COCCOCCOC>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[C:11]([NH2:12])=[N:15][NH:16][C:13]=2[NH2:14])[CH:3]=1
Reactant: CSc1nc(Cl)cc(C(C#N)C#N)n1
Reactant: NN
Solvent: COCCOCCOC
Product: CSc1nc(Cl)cc(-c2c(N)n[nH]c2N)n1
Temperature: 150 °C

Procedure:
2-(6-Chloro-2-(methylthio)pyrimidin-4-yl)malononitrile (2b) (500 mg, 2.23 mmoles) was dissolved in 15 mL of diethylene glycol dimethyl ether along with of hydrazine [68.4 μL, 69.8 mg; 2.18 mmoles) and the reaction mixture sealed in a microwave vessel. The reaction was heated at 150° C. for 10 minutes (300 Watt) and then allowed to cool down. The solvent was removed under reduced pressure and the crude suspended in acetone, warmed to almost reflux and stirred. Then continued stirring while allowing to cool down to rt. The precipitate was isolated via suction filtration and washed with more acetone and air-dried. The product (3b) was obtained as a mustard colored powder (240 mg, 42% yield) and was used in the next step without further purification. LC/MS (M+1) 257, 259.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:19])[C:15](O)([CH3:17])[CH3:16])[N:10]=[CH:9][N:8]=1)[C:2]#[C:3][CH2:4][CH3:5].CCN(S(F)(F)[F:26])CC.O>C(Cl)(Cl)Cl>[F:26][C:15]([CH3:17])([CH3:16])[CH:14]([CH3:19])[O:13][C:11]1[CH:12]=[C:7]([O:6][CH2:1][C:2]#[C:3][CH2:4][CH3:5])[N:8]=[CH:9][N:10]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC#CCOc1cc(OC(C)C(C)(C)O)ncn1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC#CCOc1cc(OC(C)C(C)(C)F)ncn1
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
First, 0.31 g of 4-(2-pentynyloxy)-6-(2-hydroxy-1,2-dimethylpropyloxy)pyrimidine was dissolved in 3 ml of chloroform, to which 0.5 ml of a solution containing 0.24 g of DAST in chloroform was added dropwise at 0° C., followed by stirring for 10 minutes. The reaction mixture was then poured into water, which was extracted three times with chloroform. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.16 g of 4-(2-fluoro-1,2-dimethylpropyloxy)-6-(2-pentynyloxy)pyrimidine (the present compound (17)).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2.CS(O)(=O)=O.[OH-].[Na+]>ClCCl>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:1][CH2:10][CH2:9]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1NCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
NaN3 (6.2 g, 94.78 mmol) was added to a solution of 5-bromo-1-indanone (10 g, 47.39 mmol) in 40 mL mixture of methane sulphonic acid and dichloromethane (1:1) in portion wise at 0° C.-5° C. The resulting mixture was stirred for 8 h at room temperature. The reaction mixture was cooled to 0° C. in ice bath, neutralized with 5% aq. NaOH solution, and the aqueous layer with extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with water and brine solution, dried over sodium sulphate, filtered and concentrated under vacuum. The residue was purified by silica gel flash column chromatography by eluting with 30% ethyl acetate in hexane to afford title compound (6.4 g, 60%) as solid. 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J=8.4 Hz, 1H), 7.5 (d, J=8.4 Hz, 1H), 7.4 (s, 1H), 6.1 (bs, 1H), 3.6 (t, J=6.8 Hz, 2H), 3.0 (t, J=6.4 Hz, 2H).
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][N:4]([CH2:13][CH2:14][CH2:15][N:16]2C(=O)C4C(=CC=CC=4)C2=O)[CH:3]3[CH2:2]1.O.NN.[ClH:30]>C(O)C>[ClH:30].[ClH:30].[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][N:4]([CH2:13][CH2:14][CH2:15][NH2:16])[CH:3]3[CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCc2cccc3c2C1CC3
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCN1CCc2cccc3c2C1CC3
Reaction time: 8 h
Yield: 64 %

Procedure:
A solution of 2-[3-(2,2a,4,5-Tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propyl]-isoindole1,3-dione (2 g, 5.78 mmol) and hydrazine hydrate (2.9 g, 57.8 mol) in ethanol (60 mL) was refluxed for 1 h. The reaction mixture was cooled down and treated with an additional amount of ethanol (30 mL) and concentrated HCl (7 mL). Then the reaction mixture was refluxed for 4 h and left overnight in a refrigerator. The precipitate was filtered off, and the solvent was evaporated. The residue was redissolved in water (15 ml) and made alkaline with 25% ammonia. Then, was extracted with CH2Cl2 (3×120 mL), the organic layer was dried over Na2SO4, and evaporated to dryness. The crude was dissolved in ethylacetate. A 2.8 M solution of hydrogen chloride in ethanol was then added. The precipitate formed was collected by filtration to give the desired product (0.80 g, 64% yield) as a beige solid.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.O[C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]>>[CH:1]1([CH2:4][O:5][C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: OCC1CC1
Product: COC(=O)c1cc(OCC2CC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D14 (first part of synthesis) from cyclopropylmethanol and methyl 3-hydroxy-5-(2-oxopyrrolidin-1-yl)-benzoate (D41).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[C:10](Cl)(=[O:12])[CH3:11]>>[C:10]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4])(=[O:12])[CH3:11]
Reactant: CCCCC(O)C(=O)O
Reactant: CC(=O)Cl
Product: CCCCC(OC(C)=O)C(=O)O

Procedure:
The compound obtained in step A is treated with acetyl chloride according to the process described in example 90 B.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([C@H:18]([CH:20]2[S:25][CH2:24][CH2:23][CH2:22][S:21]2)[OH:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:26]([CH3:28])[CH3:27])[S:14]2)[C@H:10]1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([C@@H:18]([O:19][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:20]2[S:25][CH2:24][CH2:23][CH2:22][S:21]2)[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:26]([CH3:28])[CH3:27])[S:14]2)[C@H:10]1[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@@H](O)C3SCCCS3)O[C@@H]2S1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]([C@@H](OCc3ccccc3)C3SCCCS3)O[C@@H]2S1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A solution of 96 (3.3 g, 6 mmol) in DMF (40 mL) was treated with sodium hydride (830 mg, 24 mmol, 70% mineral oil dispersed) for 30 min at room temperature, followed by the addition of (bromomethyl)benzene (2.1 g, 12 mmol). After additional 1 hour at room temperature, the reaction was quenched by water (100 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layer was washed with brine (5×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 10%-30% ethyl acetate in petroleum ether to afford 97 as a brown syrup (2.8 g, 73%); (ES, m/z) [M+H]+ 637.1; 1H NMR (300 MHz, CDCl3) δ 7.24-7.41 (m, 15H), 6.32-6.34 (d, J=6.3 Hz, 1H), 4.65-4.82 (m, 5H), 4.37-4.39 (m, 3H), 4.05-4.25 (m, 3H), 3.76-3.89 (m, 1H), 3.02 (s, 6H), 2.77-2.92 (m, 4H), 1.64-1.68 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[Na].[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18]Cl)=[C:13]([CH3:20])[CH:12]=1>C(O)C>[CH3:20][C:13]1[CH:12]=[C:11]([CH3:10])[CH:16]=[C:15]([CH3:17])[C:14]=1[CH2:18][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: [O-][n+]1ccccc1S
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: [Na]
Solvent: CCO
Product: Cc1cc(C)c(CSc2cccc[n+]2[O-])c(C)c1
Yield: 88.7 %

Procedure:
A mixture of 17 gms (0.05 mole) 2-mercaptopyridine N-oxide, sodium salt (40% aqueous solution) and 8.5 gms (0.05 mole) α2 chloroisodurene in 50 ml of ethanol is brought to reflux for 15 minutes. The volatiles are removed and the residue extracted with 150 ml of boiling chloroform, filtered and dried over sodium sulfate. Evaporation and trituration of the residue with a few drops of acetone induce crystallization. A yield of 11.5 gms of 2-(2,4,6-trimethylphenylmethylthio)pyridine N-oxide is obtained. Melting point 137° - 138° C. Structure confirmed by IR and NMR.
Reaction SMILES: [CH2:1](O)[CH2:2][CH3:3].[F:5][C:6]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:7]=1[O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11]>S(=O)(=O)(O)O.ClC(Cl)C>[F:5][C:6]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:7]=1[O:8][CH:9]([CH3:13])[C:10]([O:12][CH2:1][CH2:2][CH3:3])=[O:11]
Reactant: CC(Oc1ccc(O)cc1F)C(=O)O
Reactant: CCCO
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: CCCOC(=O)C(C)Oc1ccc(O)cc1F
Reaction time: 6.5 h
Yield: 35.5 %

Procedure:
(ii) n-Propanol (35 ml) and concentrated sulfuric acid (6 drops) were added to a solution of crude 2-(2-fluoro-4-hydroxyphenoxy)propionic acid (8.6 g) in dichloroethane (13 ml). The mixture was heated under reflux with stirring for a period of 6.5 hours, cooled, and the solvent was evaporated under reduced pressure. The residue was treated with water and the aqueous mixture was extracted with dichloromethane. The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to give an oil (5.7 g; 54.8%). The oil was purified by vacuum distillation to give n-propyl 2-(2-fluoro-4-hydroxyphenoxy)propionate (3.7 g; 35.5%); bp 210°-220° C. at 0.1 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11].C1N2CN3CN(C2)CN1C3.[C:22](=O)(O)[O-:23].[Na+]>FC(F)(F)C(O)=O>[OH:11][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:8]=2[C:9]([CH:22]=[O:23])=[CH:10][C:2]=1[CH3:1]
Reactant: O=C([O-])O
Reactant: Cc1ccc2c(c1O)CCC2
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C=O)c2c(c1O)CCC2
Temperature: 87.5 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To a clear solution of 5-Methyl-indan-4-ol (6 gm, 0.0405 mole) in 30 ml Trifluoroacetic acid, Hexamine (5.7 gm, 0.0405 mole) was added at 25-28° C. The reaction mixture was heated and stirred at 85-90° C. for 6 hours. The cooled reaction mixture was poured into saturated Sodium bicarbonate solution and extracted with Ethylacetate (2×200 ml). The organic layer was dried over Sodium sulphate and distilled under vacuum to give a crude product which was purified by column chromatography using Ethyl acetate:Hexane (10:90) as mobile phase The collected fractions were distilled to give 5.4 gm of desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[F:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:16](/[C:15]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH3:11])[CH:14]=2)\[C:17]#[N:18])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc(F)c(F)c2)cc1OC
Yield: 86.4 %

Procedure:
3,4-Difluorobenzaldehyde (426 mg) and 3,4-dimethoxybenzyl cyanide (532 mg) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (780 mg, yield: 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][S:15][C:16](SC)=[N:17][C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:18]([N:17]=[C:16]([S:15][CH3:14])[NH:13][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])#[N:19]
Reactant: NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CSC(=NC#N)SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSC(=NC#N)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A mixture of 2.02 g (10.0 mmol) of 2-nitrobenzene-sulfonamide, 1.46 g (10.0 mmol) of dimethyl N-cyanodithioiminocarbonate and 1.38 g (10.0 mmol) of powdered, anydrous K2CO3 in 16 ml of acetone was heated at reflux for 20 hours. The reaction mixture was filtered and the solid collected was washed several times with acetone. The filtrate was evaporated and the orange oily residue was triturated with ether to afford a solid. The solid was collected by filtration, washed with ether and suspended in 10 ml of IN HCl. After stirring for 1 hour the solid was collected by filtration, washed with water and dried to yield 1.65 g (55 percent) of the desired product as a cream colored solid, mp 122° C. (decomposition). IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]([CH3:21])[C:10]=1[CH3:22])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[C:13]([CH2:16][C:17]([F:20])([F:18])[F:19])=[CH:12][N:11]([CH3:21])[C:10]=1[CH3:22]
Reactant: [H][H]
Reactant: Cc1c(OCc2ccccc2)c(=O)c(CC(F)(F)F)cn1C
Agent: [Pd]
Solvent: CO
Product: Cc1c(O)c(=O)c(CC(F)(F)F)cn1C
Yield: 69 %

Procedure:
A clear solution of 3-benzyloxy-1,2-dimethyl-5-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (1.1 g, 3.53 mmol) in methanol (32 mL) was debenzylated using Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W, 0.17 g) as catalyst in a hydrogen atmosphere at a pressure of 50 psi for 30 min. The reaction mixture was diluted with methanol (30 mL), and sonicated for 10 min. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The volume of the filtrate was reduced to about 20 mL by evaporation under reduced pressure. HPLC analysis (HPLC Method 1, Example 24) of the filtrate indicated the presence of about 42% (peak percent area) of the starting material. Another 150 mg of Pd/C was added, and the mixture was subjected to the debenzylation reaction condition for a further 20 min, and worked up as described above. The catalyst was filtered off, and the filtrate was evaporated to dryness to afford 3-hydroxy-1,2-dimethyl-5-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as a solid product (0.54 g, 69% yield, HPLC Method 1 (Example 24), RT=9.9 min, HPLC purity (peak percent area): 99.3% at λ=280 nm). 1H NMR (DMSO-d5) δ ppm: 7.70 (s, 1H), 3.65 (s, 3H), 3.39 (q, J=11.5 Hz, 2H), 2.26 (s, 3H). MS-ESI (m/z) 222.2 ([M+1]+, 100%), 202.2, 182.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[NH2:19])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[C:22]([O-])([O-])=O.[Cs+].[Cs+].CI>CS(C)=O>[C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:22])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[NH2:19])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Cn1cc(C(N)=O)c2cc(O)ccc21
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CI
Product: COc1ccc2c(c1)c(C(N)=O)cn2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (3-carbamoyl-5-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (50 mg, 0.172 mmol) in DMSO (1.7 mL) was added Cs2CO3 (336 mg, 1.03 mmol). The mixture was stirred at RT for 5 min, followed by addition of methyl iodide (0.048 mL, 0.774 mmol), and stirring was continued at RT for 3 days. The reaction mixture was partitioned between water and CH2Cl2, the layers were separated and the aqueous phase was extracted twice with CH2Cl2. The combined organics were washed twice with brine, dried (phase separator) and concentrated in vacuo to afford the title compound as a yellow solid: MS (LC/MS): 305 [M+H]+, 327 [M+Na]+, 609 [2M+H]+; tR (HPLC conditions c): 4.31 min. The material thus obtained was used in the next reaction step without further purification.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C@@H:10]([CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH2:9]1)C1C=CC=CC=1.[C:29]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O-:36])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[F:19][C:15]1[CH:14]=[C:13]([C@@H:11]2[C@@H:10]([CH2:20][OH:21])[CH2:9][N:8]([C:34](=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][C:29]([O:38][CH2:39][CH3:40])=[O:37])[CH2:12]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1cccc(F)c1
Reactant: CCOC(=O)CCCCC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)CCCCC(=O)N1C[C@H](CO)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C

Procedure:
A 240 mg portion of [(3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-yl]methanol obtained by eliminating benzyl from (3R,4S)-1-benzyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-fluorophenyl)pyrrolidine in the same manner as in Reference Example 17 was dissolved in 2.4 ml of dichloromethane, mixed with 235 mg of monoethyl adipate, 229 mg of WSC and 199 mg of HOBt and stirred at room temperature for 3Hours. The reaction solution was washed with water and dried with anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. By purifying the residue by a silica gel column chromatography (chloroform-methanol), 320 mg of ethyl 6-[(3S,4R)-3-(3-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-1-yl]-6-oxohexanoate was obtained as a pale yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:16][CH:17]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:30])[N:7]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34](C)[CH:33]=1>>[C:18]([N:15]1[CH2:14][CH2:13][CH:12]([C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[CH:5][C:6](=[O:30])[N:7]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[CH:11]=2)[CH2:17][CH2:16]1)([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N1CC=C(c2cc(Br)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Reactant: Cc1cc(F)ccc1B(O)O
Product: CC(C)(C)N1CCC(c2cc(-c3ccc(F)cc3)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
The title compound was prepared from 5-bromo-7-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,6-dichlorophenyl)quinolin-2(1H)-one (INTERMEDIATE ABA5) and using 4-fluoro-2-methylphenylboronic acid as described in EXAMPLE ABA11. 1H NMR (CD3OD, 500 MHz): δ 1.252 (s, 9H), 1.734 (bs, 2H), 1.955 (bs, 2H), 2.384 (s, 3H), 2.865 (bs, 4H), 3.497 (m, 2H), 6.451 (s, 1H), 6.685 (d, J=8.5 Hz, 1H), 7.190 (m, 2H), 7.265 (m, 1H), 7.332 (d, J=8.2 Hz, 1H), 7.618 (t, J=8.2H, 1H), 7.720 (m, 2H), 7.962 (d, J=10.7 Hz, 1H. Mass spectrum (ESI): 537.2 (M+1).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[C:11]1([CH2:13][CH2:12]1)[C:10]2=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[C:11]1([CH2:13][CH2:12]1)[C:10]2=[CH2:1]
Reactant: [Li]CCCC
Reactant: CC1(C)Oc2ccc(Br)cc2C(=O)C12CC2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2OC(C)(C)C12CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of methyl(triphenyl)phosphonium bromide (20.8 g, 58.2 mmol) in tetrahydrofuran (168 ml) was added n-butyllithium (2.69 M solution in hexane, 21.6 ml, 58.2 mmol) under dry ice-acetone bath cooling and argon atmosphere. The mixture was stirred for 1 hour at 0° C. To the mixture was added 6-bromo-2,2-dimethyl-4H-spiro[chromene-3,1′-cyclopropan]-4-one (8.18 g, 29 mmol). The mixture was stirred for 1 hour at 0° C. The reaction was quenched by adding water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=20:1-10:1) to afford 6-bromo-2,2-dimethyl-4-methylene-4H-spiro[chromene-3,1′-cyclopropane] (7.69 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][F:11])[C:5]([CH:8]=C)=[N:6][CH:7]=1.I([O-])(=O)(=O)=[O:13].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][F:11])[C:5]([CH:8]=[O:13])=[N:6][CH:7]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ncc(Cl)cc1CF
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ncc(Cl)cc1CF
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
To a solution of 5-chloro-3-(fluoromethyl)-2-vinylpyridine (65 mg, 0.38 mmol) in THF (2.3 mL) and water (3.5 mL) was added a solution of osmium tetroxide (2.5 wt % in 2-methyl-2-propanol, 80 μl, 0.038 mmol, Aldrich). After 5 min, sodium meta-periodate (122 mg, 0.568 mmol, Aldrich) was added in one portion and the reaction mixture was allowed to stir for 1 h. The reaction mixture was partitioned between brine and EtOAc. The organic phase was separated and dried over MgSO4. The filtrate was absorbed onto a plug of silica gel and purified by chromatography, eluting with a gradient of 5% to 45% EtOAc in hexane, to provide the title compound as grey solid (55 mg).