Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Sc1cccc(Br)c1

Procedure:
10 g (52.9 mmol) of 3-bromothiophenol are placed in the presence of 9.4 ml (63.5 mmol) of ethyl bromoisobutyrate and 8 g (57.9 mmol) of K2CO3 in 100 ml of EtOH. This mixture is stirred at reflux for 4 h and then dry concentrated. The residue is taken up in water. After extraction in AcOEt and then drying on MgSO4, the organic phases are dry concentrated. The oil obtained is purified by flash chromatography on silica (petroleum ether:AcOEt 90:10) and 11a is isolated in the form of clear oil (16.8 g, quantitative yield). TLC silica gel 60 F 254 Merck, petroleum ether:AcOEt 90:10, Rf=0.72.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[CH:13][NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:7](=[O:12])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.C(OC([N:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH:13]=[C:6]2[C:5]3[C:10](=[CH:11][C:2]([C:31]4[NH:30][CH:34]=[CH:33][CH:32]=4)=[CH:3][CH:4]=3)[CH2:9][NH:8][C:7]2=[O:12])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COc1ccc(NC=C2C(=O)NCc3cc(Br)ccc32)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(NC=C2C(=O)NCc3cc(-c4ccc[nH]4)ccc32)cc1
Temperature: 180 °C
Yield: 37.1 %

Procedure:
To a suspension of 7-bromo-4-[(4-methoxy-phenylamino)-methylene]-1,4-dihydro-2H-isoquinolin-3-one (36 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL) is add 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (25.3 mg, 0.12 mmol), 2 M aqueous solution of cesium carbonate (300 μL) and tetrakis(triphenylphosphine)-palladium (0) (30 mg). The reaction mixture is heated in a microwave at 180° C. for 5 min. The reaction mixture is then filtered and the filtrate is purified by Prep. HPLC. The pure fractions were combined and concentrated to yield the title compound (12.8 mg).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[C:3]([S:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>ClCCl>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([S:7]([C:3]2[CH:2]=[C:1]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=[CH:5][CH:4]=2)=[O:34])[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: COc1cc(Sc2cccc(-c3ccccc3)c2)cc(OC)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(S(=O)c2cccc(-c3ccccc3)c2)cc(OC)c1OC
Yield: 87 %

Procedure:
At 0° C., to a solution of 500 mg (1.42 mmol) of compound (4a) and 5 mL of dichloromethane was added very slowly 1 equiv. of m-CPBA over 3 h. Sulfoxide formation was monitored by thin-layer chromatography. Purification was performed with a flash chromatographic column, and an amorphous powder of (4c) was obtained (87% yield). 1H NMR (500 MHz, CDCl3) δ 7.92 (br, 1H), 7.71 (d, 2H), 7.62-7.60 (m, 3H), 7.58-7.40 (m, 4H), 6.94 (s, 2H), 3.79 (s, 3H), 3.74 (s, 6H). MS (ESI) m/z 369.1 (M+H)+.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>C1(C)C=CC=CC=1.ClCCl>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Yield: 709.4 %

Procedure:
19.4 grams of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 49 grams of powdered KOH and 4.8 grams of hexadecyl bromide were stirred in 500 ml toluene (500 ml) were stirred and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 100 ml and the reaction mixture was cooled to room temperature. The cooled reaction mixture was dissolved in 500 ml dichloromethane, washed twice with 200 ml water, and the solvent was removed under reduced pressure. The obtained residue was dissolved in 500 ml of a 90:10:5 (v/v) mixture of methanol:water:concentrated H2SO4, and the resulting solution was refluxed for 30 minutes, cooled to room temperature, and extracted with 500 ml dichloromethane. The extract was washed twice with 100 ml water, 100 ml aqueous 5% sodium carbonate, and again with 100 ml water, until neutral. The solvent was removed under reduced pressure and the crude product was recrystallized from hexane at 4° C., yielding 35.3 grams of pure 1-hexadecyl-sn-glycerol. The yield was 76%.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[F:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[CH2:8][Mg]Br.[Cl-].[NH4+]>C(OCC)C>[F:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[CH2:8][C:2]([CH3:4])([OH:3])[CH3:1]
Reactant: Fc1ccc(C[Mg]Br)c(F)c1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc(F)cc1F

Procedure:
11.0 mL acetone, diluted with 50 mL diethyl ether, is added dropwise to a solution of 500 mL of 0.25 molar 2,4-difluorobenzylmagnesium bromide in diethyl ether within 20 minutes. Then the mixture is refluxed for 1.5 hours and then hydrolyzed with 10% ammonium chloride solution. The ether phase is separated off, washed with water, dried with sodium sulfate, and evaporated down. The fractional distillation of the residue yields the alcohol as a colorless liquid (boiling point: 70° C.-73° C./2 mmbar). Yield: 20.0 g (86%).
Reaction SMILES: C([S:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=3)[CH:15]=2)[CH2:10]1)(=[O:7])=[O:6])CCC.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C)C=O>[CH2:17]([CH:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[N:22]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:23]=3)[CH:13]=2)[CH:9]1[N:8]=[S:5](=[O:7])=[O:6])[CH2:9][CH2:10][CH3:11]
Reactant: BrCc1ccccc1
Reactant: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1Cc2cc(-c3ccc(=O)n(Cc4ccccc4)n3)ccc2C1N=S(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 183.5 %

Procedure:
To 1.0 g of 2-n-butylsulfonylamino-5-[pyridazin-3(2H)-on-6-yl]indane dissolved in 30 ml of dimethylformamide were added 828 mg of potassium carbonate and 547 mg of benzyl bromide, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and crude crystals precipitated were collected by filtration, dried and then recrystallized from ethanol to obtain 1.15 g of 2-n-butyl sulfonylamino-5-[2-benzylpyridazin-3(2H)-on-6-yl]indane. This compound had the same physical property values as those of the compound obtained in Example 85.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[Cl:12]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:12])=[O:6]
Reactant: ClCCl
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1c(Br)cccc1C(=O)Cl
Reaction time: 0.05 h

Procedure:
3-Bromo-2-methylbenzoic acid (2000 mg) was added to dichloromethane (50 mL) and N,N-dimethylformamide (1 mL). Oxalyl chloride (649 mg) was added and the solution was stirred for three minutes. The mixture was washed with 1 M aqueous HCl three times, washed with brine, and dried on anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum to yield the product.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH:21]([CH3:23])[CH3:22])=[C:9]([CH2:18][CH:19]=O)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:4].[Br-].[CH3:28][C:29]1[CH:54]=[CH:53][C:32]([CH2:33][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:31][CH:30]=1>C(OCC)(=O)C.CCCCCC>[CH:24]([C:6]1[C:5]([CH2:3][OH:4])=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]([CH2:18][CH2:19][CH2:28][C:29]2[CH:54]=[CH:53][C:32]([CH3:33])=[CH:31][CH:30]=2)=[C:8]([CH:21]([CH3:22])[CH3:23])[N:7]=1)([CH3:26])[CH3:25]
Reactant: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(CCCc2c(C(C)C)nc(C(C)C)c(CO)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from methyl-2,6-diisopropyl-4-(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and 4-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. 1H NMR (300 MHz, CDCl3): δ 7.08 (m, 4 H), 7.01 (d, J=8 Hz, 2 H), 6.85 (d, J=8 Hz, 2 H), 4.30 (s, 2 H), 3.39 (sept, J=6.6 Hz, 1 H), 3.13 (sept, J=6.6 Hz, 1 H), 2.41 (t, J=7 Hz, 2 H), 2.31 (s, 3 H), 2.27 (m, 2 H), 1.58 (m, 2 H), 1.31 (d, J=6.6 Hz, 6 H), 1.26 (d, J=6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C28H34FNO) 419, found 420 (M+H). Anal. Calcd for C28H34FNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.33; H, 8.28; N, 3.22. mp 79-80° C. Rf=0.4 (20% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl>[C:13]([C:3]1[C:4]([CH3:12])([CH3:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]=1[CH3:1])(=[O:15])[CH3:14]
Reactant: CC1=CC(C)(C)c2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)C1=C(C)c2ccccc2C1(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 20 g 1,3,3-trimethylindene (see e.g. J. Am. Chem. Soc. 76, 5430 (1954) ) 13 g acetyl chloride and 55 ml 1,2-dichloroethane in a nitrogen atmosphere was dosed with stirring 21.5 g aluminum trichloride over a period of one and a half hour and at a temperature of 20-25° C. After an additional stirring period of 30 minutes at 20° C. the mixture was poured on ice and stirred for another hour. The organic layer was washed with subsequently 5%-sodium carbonate solution, saturated sodium chloride solution and concentrated by means of a rotatory evaporator. Vacuum distillation of the residue yielded a 15.3 g of a fraction boiling up to 145° C. at 3 mm Hg. Recrystallization from methanol yielded 10 g 2-acetyl-1,3,3-trimethylindene of 99.8% purity, mp 104.5-105.0° C.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH2:19])(=[O:18])=[O:17].CN(C=O)C.S([O-])(O)(=O)=O.[Na+].O>>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](/[N:19]=[CH:3]/[N:4]([CH3:6])[CH3:5])(=[O:18])=[O:17]
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1ccccc1Br
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)/C=N/S(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.6 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (14.6 mL, 104 mmol) was added to a solution of 2-bromobenzene-1-sulfonamide (20.4 g, 86.4 mmol) in DMF (56 mL, 720 mmol) and the resulting solution was stirred at room temperature for 90 minutes. A solution of sodium hydrogen sulfate (1.7 g, 14 mmol) in water (170 mL, 9.4 mol) was cooled at 0° C. and then added to the reaction mixture. The precipitate was filtered, washed with water, and dried to yield the title compound (24.3 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](Cl)=[O:29])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[OH:12][C:3]1[C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[CH:26]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(Cl)c1cccc(-c2ccncc2)c1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)c2cccc(-c3ccncc3)c2)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-4-yl)benzoic acid (1.5 g, 7.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum giving 1.5 g of crude 3-(pyridin-4-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (950 g, 5.8 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) was added crude 3-(pyridin-4-yl)benzoyl chloride (1.5 g, 7 mmol) portion wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 2-hydroxy-3-(3-(pyridin-4-yl)benzamido)benzoate as a yellow solid (1.8 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([Cl:28])=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[C:23]([Cl:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=2[CH3:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)c(B(O)O)cc1Cl
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Product: COc1cc(C)c(-c2ccnc(OCc3ccccc3)c2[N+](=O)[O-])cc1Cl
Yield: 47 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (774 mg, 2.81 mmol) and 2-methyl-5-chloro-4-methoxyphenylboronic acid (prepared as described in Speicher, A.; Kolz, J.; Sambanje, R. P. Synthesis, 2002, 17, 2503) (620 mg, 3.09 mmol) were treated substantially as described in Part A of Example 19a to give 1.15 g (47%) of 2-benzyloxy-4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridine: 1H NMR (400 MHz, CDCl3) δ ppm 8.26 (d, J=5.1 Hz, 1 H), 7.45–7.42 (m, 2H), 7.39–7.30 (m, 3H), 7.13 (s, 1H), 6.82 (d, J=5.1 Hz, 1 H), 6.79 (s, 1 H), 5.54 (s, 2 H), 3.90 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:10](Cl)=[O:11])(=[O:6])=[O:5].[CH2:24]([OH:28])[CH2:25][CH2:26][CH3:27].N>O>[CH2:24]([O:28][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:7]([S:4](=[O:5])(=[O:6])[N:3]([CH3:23])[CH3:2])[CH:8]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2S(=O)(=O)N(C)C)CC1
Reactant: CCCCO
Agent: Cl
Agent: N
Solvent: O
Product: CCCCOC(=O)c1ccc(N2CCN(C)CC2)c(S(=O)(=O)N(C)C)c1

Procedure:
40 Grams of 3-dimethylsulfamoyl-4-(4-methylpiperazine-1-yl)-benzoylchloride-hydrochloride (0.1 mole) were heated under reflux for 2 hours with 0.4 l of n-butanol. Subsequently the n-butanol was eliminated in vacuo, the residue was dissolved in 0.5 l of water, and the pH value of the filtered solution was adjusted to 8.5 by means of 2N ammonia. The crystalline precipitate was suction-filtered, washed with water, then dried in vacuo at 40° C. and finally dissolved and reprecipitated from a mixture of acetic ester and diisopropylether.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([F:25])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[N:30]2[N:34]=[C:35]([CH:37]=O)[N:36]=[C:29]2[N:28]=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([F:25])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:37][C:35]3[N:36]=[C:29]4[N:28]=[C:27]([CH3:26])[CH:32]=[C:31]([CH3:33])[N:30]4[N:34]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Product: CCOc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc1F

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-[2-(4-ethoxy-3-fluoro-phenyl)-ethyl]-dihydro-pyran-2,4-dione from Step 1 to 5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31).
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@@H:53]1[O:65][C@H:64]([CH2:66][O:67][C:68](=[O:70])[CH3:69])[C@@H:59]([O:60][C:61](=[O:63])[CH3:62])[C@H:54]1[O:55][C:56](=[O:58])[CH3:57])(=O)C.C(=O)(O)[O-].[Na+]>COCCOC.C(OCC)(=O)C>[C:56]([O:55][C@@H:54]1[C@H:59]([O:60][C:61](=[O:63])[CH3:62])[C@@H:64]([CH2:66][O:67][C:68](=[O:70])[CH3:69])[O:65][C@H:53]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:58])[CH3:57]
Reactant: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 55 °C

Procedure:
To a suspension of ethyl 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 63) (40.0 g, 0.103 moles) in anhydrous 1,2-dimethoxyethane (240 ml) under an atmosphere of nitrogen was added 4-methylmorpholine (11.5 g, 12.5 ml, 0.114 moles) and the resultant mixture was heated to 45° C. with stirring. To this mixture was then added trimethylsilyl trifluoromethanesulphonate (27.5 g, 22.4 ml, 0.124 moles) over a period of 10 minutes. The resultant orange solution was then heated to 55° C., and a solution of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (36.1 g, 0.113 moles) in 1,2-dimethoxyethane (100 ml plus 20 ml to rinse through) was added over a period of 10 minutes. The reaction was then stirred at 57–60° C. for 2 hours after which time the mixture was cooled to ambient temperature. The reaction mixture was then cautiously added to a mixture of saturated aqueous sodium bicarbonate solution (400 ml) and ethyl acetate (400 ml) with vigorous stirring. The layers were separated and the aqueous phase was extracted with ethyl acetate (400 ml). The combined organic phases were dried over anhydrous magnesium sulphate and were then concentrated in vacuo to give the crude product as an orange foam (74.9 g) that could be used as such for the next step. This crude product can be purified using flash chromatography on silica gel eluting with a gradient system of 10% v/v diethyl ether in dichloromethane changing to 25% v/v diethyl ether in dichloromethane to give the title compound as a colourless foam.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2Cl)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[OH:28]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:28][C:20]2[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=2[F:18])[CH:3]=1
Reactant: Clc1ccnc2cc(Br)sc12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A mixture of the bromide 41 (5.1 g, 20.5 mmol), potassium carbonate (5.65 g, 4 mmol) and 2-fluoro-4-nitrophenol (4.82 g, 30.7 mmol) was heated at 190° C. in diphenyl ether (25 ml) for 3 hrs. After cooling to room temperature it was diluted with DCM and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (eluent EtOAc:hexane, 3:1) to afford title compound 42 as a yellow solid (5.4 g, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.55 (d, J=5.28 Hz, 1H), 8.46 (dd, J=2.5 and 10.4 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.72 (t, J=8.4 Hz), 6.99 (d, J=5.47 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[OH-].[K+]>C1(C)C=CC=CC=1.O>[O:14]([C:5]1[N:4]=[CH:3][CH:2]=[CH:7][N:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccccc1
Reactant: Clc1cncnc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ncccn2)cc1
Temperature: 25 °C

Procedure:
A mixture of 5-chloropyrimidine (5.00 g, 0.0437 mol), phenol (5.38 g, 57.2 mmol), dibenzo-18-crown-6 (0.84 g, 0.0023 mol) and ground potassium hydroxide (5.92 g, 0.1055 mol) in toluene (75 ml) was heated at reflux for 3 hours with azeotropic removal of water. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between water and chloroform. The layers were separated and the aqueous phase was extracted with chloroform three times. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 2-phenoxypyrimidine as a white powder (95% pure, 4.56 g, 0.0265 mol): 1H NMR (CDCl3, 400 MHz) 8.57 (d, 2H), 7.43 (t, 2H), 7.26 (t, 1H), 7.20 (d 2H); TLC (n-heptane/ethyl acetate=1:1) Rf 0.42.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:15])[CH:21]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:12][CH2:13][CH3:14]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCCCn1ccc2cc(Br)ccc21
Product: CCCCn1ccc2cc(-c3cccc(Cl)c3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-butyl-1H-indole (Step 1 of Example 29) and 3-chlorophenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (APCI, [M+H]+) m/z 284. 1HNMR (400 MHz, DMSO-d6): δ 7.85 (s, 1H), 7.69 (s, 1H), 7.63 (d, 1H, J=8.36 Hz), 7.55 (d, 1H, J=8.55 Hz), 7.47-7.41 (m, 3H), 7.34 (d, 1H, J=7.94 Hz), 6.48 (d, 1H, J=3.05 Hz), 4.19 (t, 2H, J=7.01 Hz), 1.73 (p, 2H, J=7.16 Hz), 1.25 (h, 2H, J=7.46 Hz), and 0.88 ppm (t, 3H, J=7.31 Hz). Elemental Analysis for C18H18ClN: Calculated: C, 76.18; H, 6.39; N, 4.94. Found: C, 76.85; H, 6.23; N, 4.81.