Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]1([S:26][CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10]([C:23]3[CH:24]=[CH:25][C:20]([S:26][CH3:27])=[CH:21][CH:22]=3)[C:9]=2[CH:15]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CSc1ccccc1
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CSc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
A solution of 26.2 g (0.10 mol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example 1a) in 25 ml (0.21 mol) of thioanisole is added dropwise to a solution of 14.7 g (0.11 mol) of aluminium chloride in 15 ml (0.13 mol) of thioanisole at 35°-40° C. The reaction mixture is thereafter stirred for 30 minutes at 30° C. and for 2 hours at 80° C., and then after cooling, c. 50 ml of water and then concentrated hydrochloric acid and methylene chloride are added cautiously in sufficient amount to form a homogeneous two-phase mixture. The organic phase is separated, washed with water, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 6.7 g (18% ) of 5,7-di-tert-butyl-3-(4-methylthiophenyl)-3H-benzofuran-2-one, m.p. 125°-131° C. (compound (108), Table 1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:23]=[CH:22][S:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35](Cl)=[O:36]>C(Cl)Cl>[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35]([N:16]1[CH2:17][CH:18]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH2:15]1)=[O:36]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccsc3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)c(F)c1)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccsc2)C1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 0.023 g (0.071 mmol) of 3-(SR)-(4-phenylpiperidinylmethyl)-4-(RS)-(3-thienyl)pyrrolidine and 0.079 mL of Et3N in 2 mL of CH2Cl2 was added 0.059 g (0.28 mmol) of 3,4-difluorobenzoyl chloride and the reaction mixture was stilled for 0.5 h. The reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3 solution. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, acetone: hexanes, 1:3) to give 0.026 g of the title compound. 1H NMR (CDCl3) δ7.17-7.49 (m, 9H), 7.13 and 7.08 (s, 1H), 7.04 and 6.99 (d, 1H, J=4.6 Hz),4.08-4.15 (m, 2H); Mass Spectrum (CI) m/e=482 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.C(OC([NH:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)=O)(C)(C)C.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:54]4[CH:55]=[CH:56][CH:57]=[C:52]([CH2:51][NH2:50])[CH:53]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)NCc1cccnc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3cccc(CN)c3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.9 %

Procedure:
A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) and 3-(t-butyloxycarbonylaminomethyl)pyridine (516 mg, 2 mmoles) in DMSO (2 ml) was stirred at ambient temperature for 30 minutes. The mixture was poured into ethyl acetate (200 ml), and the precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt (500 mg), sodium bisulfite (50 mg) in HCOOH (5 ml) was stirred at 40°-50° C. for 80 minutes and evaporated to dryness under reduced pressure. The residual solid was dissolved in water (40 ml), and the mixture was neutralized with NaHCO3. Insoluble material was filtered off, and the filtrate was chromatographed on a reverse phase column (packing of PrepPAK-500/C18 cartridge, 100 ml), eluting with water, 5%, 10%, 20% and 30% aqueous CH3OH, successively. The fractions containing the desired compound were combined, evaporated and lyophilized to provide 10 mg (1.8%) of the title compound (I-1I) (E) as a tan powder.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:29]C1C=CC(C2CCC3C(=CC=C(OC4N=CC(N)=CC=4)C=3)O2)=CC=1>C(OCC)(=O)C.CCCCCCC>[F:29][C:4]1[CH:5]=[CH:6][C:1]([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)=[CH:2][CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1

Procedure:
N-{6-[2-(4-Fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methane sulfonamide was prepared as described for N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl] methane sulfonamide in Example 46 starting from 442 mg of 6-[2-(4-fluorophenyl)-chroman-6-yloxy]-pyridin-3-ylamine (Example 76). The product was passed through silica gel using ethyl acetate-heptane (10:3) as an eluant and then crystallised from diethyl ether. 1H NMR (400 MHz, CDCl3) δ: 8.09 (d, 1H, J 2.8 Hz), 7.72 (dd, 1H, J 8.9, 2.8 Hz), 7.40 (m, 2H), 7.08 (m, 2H), 6.92-6.87 (m, 4H), 6.74 (s, 1H), 5.03 (dd, 1H, J 10.4, 2.3 Hz), 3.01 (m, 1H), 3.00 (s, 3H), 2.80 (m, 1H), 2.19 (m, 1H), 2.07 (m, 1H).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].CCN(C(C)C)C(C)C.C1CN([P+](Cl)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:21]([N:23]([CH2:24][CH3:25])[C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[N:13][CH:14]=1)[CH3:22]
Reactant: CCNCC
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)nc1
Agent: Cl[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(Oc2ccc3c(c2)COB3O)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To the solution of 6-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinic acid (0.813 g, 3 mmol) in anhydrous DMF (70 mL) was added diethylamine (3.2 mL, 30 mmol) and DIPEA (1.6 mL, 9 mmol) under N2. The mixture was cooled with ice bath and a coupling agent PyCloP (Aldrich#26564, 1.4 g, 3.3 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min and at room temperature overnight, and then rotary evaporated. The residue was dissolved in EtOAc and washed with water, evaporated and purified by flash column chromatography over silica gel eluted with EtOAc to provide the title amide compound as a white solid (0.92 g, 2.82 mmol, yield 94%).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C[N:8]2[C:12]3[CH:13]=[C:14]([F:30])[C:15]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[N:23]([CH:27]4[CH2:29][CH2:28]4)[CH:22]=[CH:21]5)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:31][CH:32]2[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]2)=CC=1.C1CC=CCC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[CH:27]1([N:23]2[C:24]3[C:20](=[CH:19][C:18]([C:15]4[C:14]([F:30])=[CH:13][C:12]5[NH:8][C:9]([O:31][CH:32]6[CH2:33][CH2:34][CH:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:36][CH2:37]6)=[N:10][C:11]=5[C:16]=4[F:17])=[CH:26][CH:25]=3)[CH:21]=[CH:22]2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc5c(ccn5C5CC5)c4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCC=CC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc5c(ccn5C5CC5)c4)c(F)cc3[nH]2)CC1

Procedure:
To a solution of ethyl 4-{[1-(biphenyl-4-ylmethyl)-5-(1-cyclopropyl-1H-indol-5-yl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclohexane-carboxylate (0.080 g, 0.124 mmol) and Pd(OH)2 (0.023 g, 0.032 mmol) in 1.65 mL of EtOAc and 0.83 mL of EtOH was added 1,4-cyclohexadiene (0.300 mL, 3.19 mmol). The resulting black suspension was microwaved at 130° C. for 2 h, then filtered through a Celite™ pad, and washed with 100% EtOAc. The resulting filtrate was concentrated in vacuo. Purification of the resulting crude residue by preparative TLC (40% EtOAc/hexanes) afforded the title compound. LCMS: calculated for C27H27F2N3O3 479.52, observed m/e 480.1 (M+11)+ (Rt 2.58/4 min).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:12])=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
25.0 g (0.15 moles) of 4-(trifluoromethyl)phenol and 23.5 g (0.17 moles) of potassium carbonate were mixed in 80 ml of acetone in a 200 ml three-necked flask. The flask was equipped with a reflux condenser, a dropping funnel and a thermometer and was connected with a calcium chloride tube for shielding the flask against moisture of the outside. After the mixing, 21.4 g (0.17 moles) of dimethyl sulfate were added at a temperature of not higher than 30° C. in a dropwise manner to the mixture under stirring. After that, the reaction mixture was refluxed at reflux temperature of acetone for 5 hrs. After completing the reaction, the reaction liquid was cooled down to room temperature. The resulting precipitates (solid) were separated by filtration. The obtained filtrate was concentrated by an evaporator. To the resulting residue 100 ml of water and 100 ml of n-hexane were added, thereby extracting the target product into the n-hexane layer. To the resulting water layer 50 ml of n-hexane were added, thereby conducting an extraction again. The resulting two n-hexane layers were combined together, followed by washing with 80 ml of 2 mol/L sodium hydroxide aqueous solution. The resulting n-hexane layer was washed two times with 50 ml of water. The obtained n-hexane layer was dried with magnesium sulfate anhydride, followed by concentration by an evaporator and then by removal of hexane by distillation under reduced pressure, thereby obtaining 22.8 g (0.13 moles) of oily 4-(trifluoromethyl)anisole (isolation yield: 84.0%). This product was found to have the following properties.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]#[N:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:17][C:18]#[N:19]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:13]([CH2:17][C:18]#[N:19])[C:14]#[N:15])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(C#N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 11.8 %

Procedure:
To a 500 mL reaction flask was added 2.0 g (51.0 mmole) sodium hydride (60% dispersion in oil) and 20 mL hexanes. The hexanes were removed by pipette and replaced by 90 mL dry tetrahydrofuran (THF). The suspension was cooled to 0° C. and a solution of 10.0 g (46.4 mmole) 4-chlorophenylsulfonyl acetonitrile in 90 mL THF was added via addition funnel over 10 minutes maintaining the reaction temperature below 12° C. The resulting solution was removed from the cold bath and stirred at room temperature for 40 min. The solution was recooled to 0°C. and 3.4 mL (48.7 mmole) bromoacetonitrile in 5 mL THF was added dropwise via addition funnel. After 5 minutes, the reaction was removed from the cold bath and stirred at room temperature for two hours. The reaction was quenched with 1 mL of saturated ammonium chloride and concentrated to an oil which was transferred with 150 mL of dichloromethane to a separatory funnel containing 120 mL water. The organic layer was separated and washed once more with 120 mL water and once with 120 mL brine. The organic layer was then dried (Na2SO4), filtered, concentrated, and chromatographed through a bed of silica gel using 85:15 hexane:ethyl acetate. Isolation gave 1.4 g (12% yield) of the title compound as a yellow powder that was 96% pure by HPLC, m.p. 130-137° C.
Reaction SMILES: C12OC(CC1)CN(C1N=C(C3C=CC(N)=CC=3)N=C3N(C(COC)COC)N=CC=13)C2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH2:44]([OH:47])[CH2:45][OH:46].[CH3:48][O:49][CH2:50][CH:51]([N:55]1[C:59]2=[N:60][C:61]([C:72]3[CH:77]=[CH:76][C:75]([N:78]=[C:79]=[O:80])=[CH:74][CH:73]=3)=[N:62][C:63]([N:64]3[CH2:70][CH:69]4[O:71][CH:66]([CH2:67][CH2:68]4)[CH2:65]3)=[C:58]2[CH:57]=[N:56]1)[CH2:52][O:53][CH3:54]>ClCCl.C(N(CC)CC)C>[OH:46][CH2:45][CH2:44][O:47][C:79](=[O:80])[NH:78][C:75]1[CH:74]=[CH:73][C:72]([C:61]2[N:60]=[C:59]3[N:55]([CH:51]([CH2:50][O:49][CH3:48])[CH2:52][O:53][CH3:54])[N:56]=[CH:57][C:58]3=[C:63]([N:64]3[CH2:65][CH:66]4[O:71][CH:69]([CH2:68][CH2:67]4)[CH2:70]3)[N:62]=2)=[CH:77][CH:76]=1
Reactant: OCCO
Reactant: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N=C=O)cc3)nc21
Agent: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)OCCO)cc3)nc21
Reaction time: 3 h
Yield: 53 %

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1,3-dimethoxypropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (65 mg, 0.15 mmol) in dichloromethane (1.5 mL) was treated with triethylamine (0.2 mL), followed by a solution of triphosgene (23 mg, 0.08 mmol) in dichloromethane (1 mL). After the passage of 10 minutes, the appropriate nucleophile—in the case, ethylene glycol (84 μL, 1.5 mmol)—was added to the 3-(1-(1,3-dimethoxypropan-2-yl)-6-(4-isocyanatophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. After 3 hours, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 2-hydroxyethyl(4-{1-[2-methoxy-1-(methoxymethyl)ethyl]-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)carbamate (41 mg, 53%). MS (ES+): 513.2 (M+H)+
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17]Br>O1CCCC1.CN(C)C=O.CN(C)C=O>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:10]
Reactant: Fc1ccc(CBr)cc1F
Reactant: OCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCCCCCCCCOCc1ccc(F)c(F)c1
Yield: 46.2 %

Procedure:
A solution of 1,8-octanediol (300 mg, 2.05 mmol) in tetrahydrofuran/N,N-dimethylformamide 2:1 (3 mL) was added dropwise at 0° C. to a suspension of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.3 mmol) in N,N-dimethylformamide (1.5 mL), then after 2 h 3,4-difluorobenzyl bromide (445 mg, 2.15 mmol) was added. After 4 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded 8-(3,4-difluoro-benzyloxy)-octan-1-ol (258 mg, 46%). Colorless oil, m/e=273.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=O)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH2:19][NH2:20].CC(O)=O>CCO>[Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:19][NH2:20])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Product: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A mixture of (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone (0.720 g, 2.74 mmol), anhydrous hydrazine (0.430 mL, 13.7 mmol) and AcOH (0.025 mL, 0.44 mmol) in EtOH (40 mL) was heated at reflux for about 20 h. During this time, water was removed from the reaction mixture via the use of a Dean-Stark trap. The reaction mixture was cooled to ambient temperature, the volatiles were removed under reduced pressure and the residue was partitioned between water (29 mL) and EtOAc (30 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvent evaporated under reduced pressure. The crude material was purified by silica gel chromatography using a gradient of 10 to 50% EtOAc in heptane as the eluent to provide 5-chloro-4-(cyclohexyl(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine as an off-white solid (0.37 g, 48%); LC/MS (Table 2, Method o) Rt=2.22 min; MS m/z: 277 and 279 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+]>CC(C)=O>[N:15]([CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4])=[N+:16]=[N-:17]
Reactant: O=C(CBr)c1cccc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(=O)c1cccc2ccccc12

Procedure:
Combine 24.9 g (0.1 mol) of 2-bromo-1-(naphthalen-1-yl)ethanone and 24 g (0.37 mol) of sodium azide in 200 mL of 60% aqueous acetone. Heat the mixture at reflux for about 18 to 36 hr and follow the progress of the reaction by thin-layer chromatography on silica gel. At the completion of the reaction, distill off the acetone and add 25 mL of water. Extract the aqueous mixture with three 100 mL portions of diethyl ether. Dry the organic extracts over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].NC(OCC)=O.[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[C:17]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: CCOC(N)=O
Product: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
A number of different blocking agents can be used to block the amine group on the glutamic acid. These blocking agents include acyl-type protecting groups, urethan protecting groups, alkyl-type protecting groups, and arylidene-type protecting groups. Alternatively, rather than using blocking agents, the amine group can be protonated to block its functionality. Preferably, blocking of the glutamic acid is achieved by reacting it with carbobenzoxy chloride in an aqueous alkaline solution to form N-carbobenzoxy glutamic acid, which is commonly referred to as Z-glutamic acid. This reaction is inexpensive and provides about a 90% yield of Z-glutamic acid. Altematively, Z-glutamic acid can be obtained from Aldrich Chemical Company, 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233. Z-glutamic acid has the following structure: ##STR1##
Reaction SMILES: [ClH:1].[F:2][C:3]([F:29])([F:28])[C:4]1[CH:9]=[CH:8][C:7]([C@:10]23[CH2:15][C@H:14]2[CH2:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[CH:25]=[CH:24][C:23](=O)[NH:22][C:21]2=[O:27])[CH2:11]3)=[CH:6][CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>COCCOC>[ClH:1].[S:39]=[C:23]1[CH:24]=[CH:25][N:20]([CH2:19][CH2:18][CH2:17][CH2:16][N:12]2[CH2:13][C@H:14]3[C@:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:29])([F:28])[F:2])=[CH:5][CH:6]=4)([CH2:15]3)[CH2:11]2)[C:21](=[O:27])[NH:22]1
Reactant: O=c1ccn(CCCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Solvent: COCCOC
Product: O=c1[nH]c(=S)ccn1CCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Yield: 59.8 %

Procedure:
A solution of 1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2,4(1H,3H)-pyrimidinedione (E5, 110 mg, 0.3 mmol) and Lawesson's reagent (184 mg, 0.5 mmol) in DME (2 mL) was stirred at reflux for 2 hours. The solvent was evaporated under vacuum. The crude was re-dissolved in ethyl acetate and washed with water. The organic phase was dried (Na2SO4) filtered and evaporated; the crude was purified by flash chromatography with DCM-MeOH—NH4OH (98-2-0.2) to give the title compound as a yellow oil (80 mg, 63% yield).
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1B(O)O>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.O>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cc1ccc(C)c(B(O)O)c1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)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: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(C(=O)OCC)c(-c2cc(C)ccc2C)c1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
Diethyl bromoterephthalate (45.2 g, 150 mmol), K2CO3 (41.5 g, 300 mmol), 140 ml of toluene and 140 ml of H2O were placed in a reaction vessel and argon was passed in for 30 minutes. 2,5-dimethylbenzeneboronic acid (24.8 g, 165 mmol) (cf. B3) and Pd(PPh3)4 (0.7g, 0.6 mmol) were subsequently added under protective gas. The brownish mixture, which was turbid due to phase separation, was stirred vigorously under a blanket of protective gas at an internal temperature of 85° C. The reaction was complete after 24 hours (according to TLC). After phase separation, the organic phase was shaken with dilute HCl/H2O (until neutral). The aqueous phase was shaken with toluene and the organic phases were combined. After filtering off any palladium residues, the solution was evaporated. The product was obtained as a yellow oil in sufficient purity (greater than 97%). Yield: 48.7 g (99%).