Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:14][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(C)=O)ccc1OCc1ccccc1
Temperature: 85 °C
Yield: 100 %

Procedure:
Methyl 5-acetylsalicylate (100 g, 0.515 mol) was dissolved in acetonitrile (1 L) in a 2 L flask under reflux conditions and a nitrogen atmosphere. Potassium carbonate (213.5 g, 1.545 mol) was added portion-wise over 15 min. Benzyl bromide (67.4 mL, 0.566 mol) was added using a dropping funnel over 15 min. The reaction was heated to 85° C. for 9 h, and then filtered and rinsed with acetonitrile (100 mL). The solution was concentrated to about 300 mL volume under reduced pressure and partitioned between water (1 L) and ethyl acetate (1 L). The organic layer was washed with saturated sodium chloride (250 mL), dried using magnesium sulfate (75 g), and then filtered and rinsed with ethyl acetate (100 mL). The organic layer was concentrated to give 2-benzyloxy-5-acetylbenzoic acid methyl ester as a solid (100% yield).
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.Cl>CN(C)C=O>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:24]
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: Clc1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccccc2Cl)c1=O
Reaction time: 8 h
Yield: 44.3 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles) and 2-chlorobenzyl bromide (300 mg, 1.5 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (193 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s, 1 H), 10.13 (br. s, 1 H), 7.45-7.50 (m, 1 H), 7.26-7.32 (m, 2 H), 7.05-7.09 (m, 1 H), 5.05 (s, 2 H), 4.65 (t, J=11.87 Hz, 1 H), 4.13 (d, J=5.56 Hz, 2 H), 2.20-2.30 (m, 2 H), 1.79 (d, J=13.14 Hz, 2 H), 1.59-1.69 (m, 3 H), 1.28 (q, J=12.97 Hz, 2 H), 1.06-1.16 (m, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[C:26]([NH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[C:26]([NH:29][C:30]1[CH:35]=[C:34]([C:16]2[C:6]3[N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:8]=[N:9][C:5]=3[CH:4]=[C:3]([C:1]#[N:2])[CH:17]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Yield: 36.3 %

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 3-acetamidophenylboronic acid (90 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and the crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (98:2). The eluent from this column was evaporated under reduced pressure and the crude product was purified further by prep LCMS, then recrystallised from dichloromethane/diethyl ether to give the product as a white solid (64 mg, 36%) m/z, 353.0 (M+H)+.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][CH:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[K+]>C(OCC)C.O>[Cl:14][C:15]1[N:20]=[C:19]([N:6]([CH2:7][CH:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: O=C1OCCC1CNC1CCCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: O=C1OCCC1CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of 1.67 g (0.009 mole) of 3-cyclopentylaminomethyl-dihydro-furan-2-one in 25 mL of ethyl ether was added 15 mL of ice-water followed by 1.68 g (0.0087 mole) of 2,4-dichloro-5-nitro-pyrimidine. A solution of 1.36 g (0.014 mole) of potassium bicarbonate in 5 mL of water was added over 20 minutes. The mixture was stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure to remove the ethyl ether and the mixture then filtered, washing with water and then water-acetonitrile. The solid was purified by recrystallization from hexanes-ethyl acetate (1:1) to give 2.2 g of (rac)-3-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-dihydro-furan-2-one (IV-49).
Reaction SMILES: C(OC(=O)[O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH:17]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)[C:18]2[NH:22][C:21](=[O:23])[N:20]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:19]=2)[C:10]=1[F:39])C.[OH-].[Na+].C(O)(=O)C>O>[F:39][C:10]1[C:9]([O:8][CH2:7][CH2:6][OH:5])=[CH:14][C:13]([O:15][CH3:16])=[CH:12][C:11]=1[CH:17]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=1)[C:18]1[NH:22][C:21](=[O:23])[N:20]([C:24]2[N:25]=[CH:26][CH:27]=[CH:28][N:29]=2)[N:19]=1
Reactant: CCOC(=O)OCCOc1cc(OC)cc(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
After the atmosphere in the reaction vessel had been replaced with nitrogen, the suspension containing carbonic acid 2-{3-[(4-cyanophenylamino)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester ethyl ester obtained in Example 65 was added at a bath temperature of 15° C., and rinsing in with methanol (2407 mL) and tetrahydrofuran (826 mL). 5 N aqueous sodium hydroxide solution (1599 mL, 7.995 mol) was added dropwise to the mixture at the bath temperature of 15° C., then the bath temperature was set at 20° C., and the reaction suspension was stirred for 16 hours. Thereafter, the bath temperature was set at 15° C., and acetic acid (2288 mL) was added dropwise to the solution obtained. Then, the bath temperature was set at 22° C., and water (3750 mL) was added dropwise. Seed crystals of the captioned compound (374 mg, 0.836 mmol) were added to the mixture which was then stirred for 20 minutes. Then, water (3754 mL) was added dropwise, and the bath temperature was cooled to 0° C. over a period of about 2 hours. Stirring was maintained for 16 hours at the bath temperature of 0° C. The precipitate was filtered, washed with water (2250 mL), and dried under reduced pressure at 40 to 50° C. to obtain the captioned compound (660 g, net weight 631.6 g) as a pale yellow white powder.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CN(C)C=O.C(O)(=O)C>[C:1]1([CH:7]([O:14][C:15]([C@@H:17]2[N:22]3[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@H:21]3[S:20][CH2:19][CH:18]2[OH:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1SCC(O)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
In the same manner as that described under (a), 111 g of 3-hydroxy-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (crude product) in a mixture of 640 ml of dimethylformamide and 160 ml of glacial acetic acid are reduced with 4.5 g of sodium borohydride and worked up. The title compound having the properties mentioned under (a) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19]>>[F:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:18]([CH3:20])[CH3:19])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(F)cc2[nH]ncc12
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(F)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 1 (step a) from methyl 6-fluoro-1H-indazole-4-carboxylate (0.500 g, 2.58 mmol), sodium hydride (0.129 g, 3.22 mmol), and 2-iodopropane (0.386 mL, 3.86 mmol). The product was collected as a yellow solid (0.32 g, 52%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (d, J=6.57 Hz, 6H) 3.96 (s, 3H) 5.04 (quin, J=6.57 Hz, 1H) 7.61 (dd, J=9.60, 2.27 Hz, 1H) 8.03 (dt, J=8.46, 1.20 Hz, 1H) 8.41 (s, 1H).
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](/[C:23](/[CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24]\[C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H][H]>CO>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]([NH2:27])=[O:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(/C(=C\C(N)=O)C4CCCC4)c3)ncnc21
Solvent: CO
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC(N)=O)C4CCCC4)c3)ncnc21
Temperature: 30 °C
Reaction time: 21 h

Procedure:
A solution of (4-{1-[(1Z)-3-amino-1-cyclopentyl-3-oxoprop-1-en-1-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate, (10, 500 mg) in methanol (MeOH, 8.0 mL) in a pressure glass tube was treated with the catalyst Ru(COD) (SL-A153-1) (CF3CO2)2 (6.6 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 50 bar pressure. The reaction mixture was stirred at 30° C. under this hydrogen pressure for 21 h. When HPLC analysis showed that the substrate was completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 98% ee (99% of the second peak, (R)-11; 1% of the first peak, (S)-11) by chiral HPLC analysis. The reaction mixture was then filtered through a thin silica gel pad and the pad was washed with methanol (5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (470 mg) was analyzed by chiral HPLC analysis and result showed a 98.0% of enantiomeric excess favoring the second peak (99.0% of the second peak, (R)-11; 1.0% of the first peak, (S)-11).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:12][CH:13]([CH2:18][C:19]([O:21]C)=[O:20])[C:14]([O:16]C)=[O:15].CO>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:18](\[CH:13]([CH3:12])[C:14]([OH:16])=[O:15])/[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1
Reactant: COC(=O)CC(C)C(=O)OC
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C(=O)O)/C(=C\c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (60% in paraffin oil, 31g, 686 mmol) in toluene (150 mL) was added a solution of 4-fluorobenzaldehyde (30 g, 214 mmol) and dimethyl methylsuccinate (58 g, 312 mmol) in toluene (150 mL) over 1 hour at 0° C. under nitrogen. The reaction was initiated by addition of a drop of methanol at room temperature and was stirred at room temperature for 2 hours. The reaction was quenched by slow addition of 2.0 N aqueous NaOH (300 mL) at 0° C. The resulting mixture was stirred at 110° C. for 4 hours. The mixture was then cooled to room temperature and the aqueous layer was diluted with water (300 mL) and washed with Et2O (2×300 mL). The aqueous phase was cooled in an ice-water bath. Addition of concentrated HCl was followed by extraction with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (50 mL) followed by brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ethyl acetate-hexanes to give 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid. The procedure above was repeated using a separate amount of 4-fluorobenzaldehyde (30 g, 214 mmol). The products of the two reactions were combined to provide 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid as a pale yellow solid (28g, 27.5% overall). MS cald. for C12H12FO4 [(M+H)+]: 239, obsd. 239.2.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH2:10]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)/[CH:11]=[C:12](/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])\[CH3:13]>O1CCCC1>[CH2:10]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:26])=[CH:28][CH:29]=1)/[CH:11]=[C:12](/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])\[CH3:13]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)Nc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32.4 %

Procedure:
Sodium hydride(0.74 g) and 3-aminopyridine(0.87 g) were stirred in tetrahydrofuran(30 ml) for 1 hour while being cooled with ice. 4-geranyloxybenzoic acid(2.54 g) and N,N'-carbonyldiimidazole(1.65 g) was stirred in tetrahydrofuran(10 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. After being stirred for 20 minutes at room temperature, the reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.05 g of the aimed compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:25][N:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([F:31])([F:30])[F:29]>C(OCC)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([C:27]([C:28]([F:29])([F:31])[F:30])([NH:26][CH3:25])[C:32]([F:35])([F:34])[F:33])[S:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: CN=C(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CNC(c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)s1)(C(F)(F)F)C(F)(F)F
Reaction time: 3 h

Procedure:
A solution of 2,3-bis(4-fluorophenyl)thiophene (5.4 g, 20 mmole) in 150 ml diethyl ether/30 ml toluene was cooled to 10° and treated with 1.6M n-butyl lithium (15 ml, 1.2 equiv.). The reaction mixture was heated at reflux for 1.5 hours, cooled to 0° and treated dropwise with a solution of N-methyl hexafluoroacetone imine (4.3 g, 1.2 equiv.) in 10 ml diethyl ether. The reaction mixture was stirred for 3 hours at 0° and then quenched with water.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:22])[C:28]=4[Cl:29])=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: COc1ccc(-c2nc3cc(-c4cccc(Cl)c4Cl)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.15 mmol) and 2,3-dichlorophenylboronic acid (329 mg, 1.72 mmol) the subtitle compound was obtained (288 mg, 60%). MS 415 m/z (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:8]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:9][CH:10]=1)=[O:4].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=2)[C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:10]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C=CC(=O)O)c(-c2cccc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCC(=O)O)c(-c2cccc(C(F)(F)F)c2)c1
Yield: 92.6 %

Procedure:
The compound of step 1 (400 mg, 1.14 mmol) and Palladium (10%) on charcoal (23 mg) were suspended in methanol (30 ml). The mixture was hydrogenated for 3 h at 4 bar hydrogen pressure, subsequently filtered over Celite and evaporated to dryness to yield the title compound (372 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=2)[CH2:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:34][CH:35]=2)[CH2:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH:19]=2)=[O:17])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(Cc2cccc(C(=O)c3c[nH]c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc(CC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)c2)c2ccccc21
Temperature: 20 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
A mixture of 3-[3-[2,2-bis(4-isobutylphenyl)ethyl]-benzoyl]indole (442 mg), ethyl 4-bromobutyrate (185 mg) and potassium carbonate (360 mg) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 4 hours. Ethyl 4-bromobutyrate (185 mg) and potassium carbonate (120 mg) were added, and resulting mixture was stirred at 20° C. for 16 hours. The reaction mixture was poured into a mixture of ethyl acetate and 1N-hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of hexane and ethyl acetate (10:1) to give ethyl 4-[3-[3-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl]indol-1-yl]butyrate (480 mg) as an oil.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:39]=[CH:38][C:30]([C:31]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:34]([NH:33][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([C:20]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:39][CH:38]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 51.2 %

Procedure:
A solution of 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-N-tert-butyl-benzamide (1.0 g, 1.83 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 10 mL, 10 mmol) was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford N-tert-butyl-4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-benzamide (380 mg, 51.1%) as a white solid: LC/MS m/e calcd for C25H28FN3O [M+H]+ 406.52, observed 406.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2=[O:15])#[CH:2].[F:16][C:17]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CCN(CC)CC.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.[Cu]I>[F:16][C:17]1[CH:27]=[C:26]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[O:9][C:8]([CH3:13])([CH3:14])[CH2:7][C:6]3=[O:15])[CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C#Cc1ccc2c(c1)C(=O)CC(C)(C)O2
Reactant: CCOC(=O)c1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CC(C)(C)O3)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A solution of 6-ethynyl-2,2-dimethylchroman-4-one (Compound 262, 314.0 mg, 1.57 mmol) and ethyl 2-fluoro-4-iodobenzoate (440.0 mg, 1.50 mmol) in 10.0 mL Et3N was purged with argon for 15 minutes. To this solution was added bis(triphenylphosphine)-palladium(II) chloride (275.0 mg, 0.39 mmol) and copper(I) iodide (75.0 mg, 0.39 mmol). After sparging for an additional 10 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was filtered through a pad of Celite using an Et2O wash. Concentration of the filtrate under reduced pressure, followed by column chromatography (3-5% EtOAc-hexanes) of the residual solid afforded 400.0 mg (69%) the title compound as an orange solid. 1H NMR (300 MHz, CDCl3) δ: 8.05 (1H, d, J=2.1 Hz), 7.90 (1H, d, J=7.8 Hz), 7.60 (1H, dd, J=2.2 8.5 Hz), 7.29 (1H, dd, J=1.5, 8.2 Hz), 7.25 (1H, d, J=11.4 Hz), 6.93 (1H, d, J=8.5 Hz), 4.39 (2H, q, J=7.1 Hz), 2.75 (2H, s), 1.48 (6H, s), 1.40 (3H, t, J=7.1 Hz).