Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]([O:16][C:17](C1C=CC=CC=1)(Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:10]1C=CC=C[CH:11]=1)[C:4]1C=CC=[CH:6][CH:5]=1.[CH:31]12[O:37][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36]2>C1COCC1.C(OCC)(=O)C.[Cu]Cl>[CH2:17]([O:16][C:3]1[CH:4]=[CH:5][CH:6]=[CH:11][C:10]=1[C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrC(OC(Br)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCC2OC2C1
Agent: Cl[Cu]
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O[C@@H]1CCCC[C@H]1c1ccccc1OCc1ccccc1
Temperature: -30 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A 1 L round bottom flask equipped with a mechanical stirrer, addition funnel, condenser, and nitrogen inlet is charged with 6.6 g (0.27 mol) of magnesium turnings and 25 ml of dry tetrahydrofuran. To this stirred mixture a solution of 50 g (0.27 mol) of bromophenyl benzylether in 50 ml of dry THF is added dropwise. The reaction needs to be heated (30°-40° C.) at first to initiate it but then the heating mantel is removed and the temperature maintained by the rate of addition. Once the addition is complete the reaction is held at 45°-50° C. for 2 hours, then 300 ml of dry THF is added. The solution is cooled to -30° C. and 1.2 g (0.012 mol) of copper (I) chloride is added. The resulting mixture is stirred for 10 minutes and then a solution of 26 g (0.265 mol) of cyclohexene oxide in 30 ml of THF is added dropwise over 1 hour. Upon completion of the addition the reaction is allowed to warm to 0° C. and stirred for 2 hours, then diluted with 300 ml of ethyl acetate and quenched by addition of 150 ml of saturated aqueous ammonium sulfate solution. The organic phase is separated and washed with another 75 ml of ammonium sulfate solution. The combined aqueous phases are extracted with 100 ml of ethyl acetate. The organic phases are combined, dried with magnesium sulfate, and evaporated under reduced pressure to yield 65 g of trans-2-(2'-benzyloxyphenyl)cyclohexanol as an amber oil, which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[C:27]3[O:29][CH2:30][O:31][C:24]=2[C:25]([F:33])=[C:26]3[F:32])[C:19]([F:34])=[CH:18][N:17]=1>>[CH3:13][O:12][C:10]([CH:8]1[CH2:7][C:6]2[CH:14]=[C:2]([NH:1][C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:28]=[C:27]5[O:29][CH2:30][O:31][C:24]=4[C:25]([F:33])=[C:26]5[F:32])[C:19]([F:34])=[CH:18][N:17]=3)[CH:3]=[CH:4][C:5]=2[O:9]1)=[O:11]
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Reactant: Fc1cnc(Cl)nc1Nc1cc2c(F)c(F)c1OCO2
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4cc5c(F)c(F)c4OCO5)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with 2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine gave (±)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.36 (bs, 1H), 9.93 (bs, 1H), 8.22 (d, 1H, J=4.8 Hz), 7.91 (bs, 1H), 7.38 (m, 3H), 7.15 9bd, 1H, J=8.7 Hz), 6.79 (d, 1H, J=6.0 Hz), 5.33 (dd, 1H, J=6.3 and 6.6 Hz), 3.69 (s, 3H), 3.50 (dd, 1H, J=10.5 and 10.8 Hz), 3.22 (dd, 1H, J=6.0 Hz); LCMS: purity: 100%; MS (m/e): 461 (MH+).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[N:14]=[CH:13][N:12]([CH2:16][CH3:17])[C:11]=2[CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[CH:8]=1)[CH3:6].[OH:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.ClC(Cl)C.C1CCCCC1>>[CH2:16]([N:12]1[C:11]2[CH:10]=[C:9]([C:18]([F:21])([F:19])[F:20])[CH:8]=[C:7]([CH:5]([O:25][CH2:26][C:27]3([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH3:6])[C:15]=2[N:14]=[CH:13]1)[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: CCn1cnc2c(C(C)OC(=N)C(Cl)(Cl)Cl)cc(C(F)(F)F)cc21
Solvent: CC(Cl)Cl
Solvent: C1CCCCC1
Product: CCn1cnc2c(C(C)OCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Temperature: 0 °C

Procedure:
(±)-(1-(1-Ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)ethyl 2,2,2-trichloroacetimidate (670 mg, 1.664 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (727 mg, 2.496 mmol) were combined in a dichloroethane/cyclohexane mixture (4:2, 6 mL) and cooled to 0° C. The reaction mixture was treated with tetrafluoroboric acid-diethyl ether complex (91 μL, 0.67 mmol), and subsequent processing including extractive work up and purification were carried out as described in example 8 to give 274 mg (30.7%) as white foam-like solid. 1H-NMR (500 MHz, CHLOROFORM-D) δ ppm 7.97 (s, 1 H), 7.54 (s, 1 H), 7.29-7.37 (m, 5 H), 7.16-7.24 (m, 1 H), 5.11 (q, J=6.4 Hz, 1 H), 4.20-4.29 (m, 2 H), 3.64-3.80 (m, J=13.1 Hz, 2 H), 3.29-3.37 (m, 2 H), 2.93-3.10 (m, 2 H), 2.09-2.22 (m, 2 H), 1.87-2.03 (m, 2 H), 1.56 (t, 3 H), 1.39-1.48 (m, 12 H). 532.40 (MH)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23](=[O:28])[CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23]([OH:28])([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)[CH2:24]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Brc1cncnc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cncnc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
n-Butyl lithium (2.5 M, 1.8 mL, 4.5 mmol) was added dropwise to a solution of 5-bromo-pyrimidine (0.668 g, 4.2 mmol) in THF (10 mL), under nitrogen at −78° C. and stirred for 1 hour. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.675 g, 3.0 mmol) in THF (5 mL) was added dropwise at −78° C. and the reaction mixture warmed to room temperature over 1 hour. Saturated aqueous ammonium chloride and ethyl acetate were added, the organics separated, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 10% methanol/ethyl acetate. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.14 g). LCMS m/z 306 [M+H]+. R.T.=2.89 min (Analytical Method 3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][N:15]([C:19]4[S:20][C:21]5[C:22](=[O:30])[NH:23][C:24]([CH3:29])([CH3:28])[CH2:25][C:26]=5[N:27]=4)[C:14]=3[CH:31]=2)[CH:3]=1.C(N(CC)CC)C>CO.[Pd]>[CH3:28][C:24]1([CH3:29])[NH:23][C:22](=[O:30])[C:21]2[S:20][C:19]([N:15]3[C:14]4[CH:31]=[C:10]([O:9][C:4]5[CH:3]=[CH:2][N:7]=[C:6]([CH3:8])[N:5]=5)[CH:11]=[CH:12][C:13]=4[O:18][CH2:17][CH2:16]3)=[N:27][C:26]=2[CH2:25]1
Reactant: Cc1nc(Cl)cc(Oc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)n1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nccc(Oc2ccc3c(c2)N(c2nc4c(s2)C(=O)NC(C)(C)C4)CCO3)n1
Reaction time: 24 h
Yield: 64.4 %

Procedure:
To a suspension of Example 394 (40 mg, 0.088 mmol) in MeOH (15 mL) was added triethylamine (0.040 mL, 0.263 mmol) and 5% Pd/C (10 mg, 25% wt). The reaction mixture was stirred under an atmosphere of hydrogen for 24 h, then the catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between DCM (50 mL) and water (50 mL); the organic phase was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo to give the title compound (24 mg, 65%) as an off-white solid. δH (CDCl3) 8.45 (1H, d, J 5.8 Hz), 7.97 (1H, d, J 2.6 Hz), 6.98 (1H, d, J 8.9 Hz), 6.84 (1H, dd, J 8.9 and 2.6 Hz), 6.63 (1H, d, J 5.8 Hz), 5.58 (1H, s), 4.41-4.26 (2H, m), 4.16-4.05 (2H, m), 2.84 (2H, s), 2.62 (3H, s), 1.37 (6H, s). LCMS (ES+) 424.0 (M+H)+, RT 2.75 minutes (Method 1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:35])[C@@H:10]([NH:22][C:23](=[O:34])[CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.[C:43]1([C:49](Cl)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)(Cl)Cl>[C:30]([O:29][C:27]([NH:26][CH2:25][CH2:24][C:23]([NH:22][C@H:10]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:49]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:35])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:34])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the crude product of tert-butyl (4S)-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-4-{[3-(tert-butoxycarbonylamino)propionyl]amino}-5-oxopentylcarbamate and triethylamine (1.52 g) in chloroform (100 ml) was added triphenylmethyl chloride (4.20 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl (4S)-4-{[3-(tert-butoxycarbonylamino)propionyl]amino}-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (7.20 g) as an oil.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[C:1]1([C:7]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:8]([CH3:9])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC=C(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1OC1(c1ccccc1)c1ccccc1
Yield: 98.8 %

Procedure:
A solution of 2.00 g (10.3 mmol) 1,1-diphenylpropene and 2.09 g (10.4 mmol) 85% m-chloroperbenzoic acid in 15 ml dichloromethane was stirred in the dark at room temperature for 4 hours. The mixture was partitioned between dichloromethane and saturated K2CO3 solution and the organic layer was washed with brine and dried over Na2SO4. This was concentrated to give 2.14 g (98%) of 2,2-diphenyl-3-methyloxirane as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([CH3:26])([CH3:25])[O:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]([S:23][CH3:24])[N:16]=2)[CH2:10]1)([CH3:6])([CH3:5])[CH3:4].[CH3:27][C:28](OC(C)=O)=[O:29].O.NN>CN(C=O)C>[NH2:22][C:21]1[C:20]2[CH:19]=[N:18][C:17]([S:23][CH3:24])=[N:16][C:15]=2[N:14]([C@H:11]2[CH2:12][CH2:13][C@H:9]([O:8][Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:26])[CH3:25])[CH2:10]2)[C:28](=[O:29])[CH:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1ncc(C#N)c(N[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)C2)n1
Agent: NN
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2c(N)cc(=O)n([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.7 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 303 mg, 7.59 mmol) was added in one portion, under argon atmosphere, to a mixture of 4-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-2-methylsulfanyl-pyrimidine-5-carbonitrile (658 mg, 1.81 mmol) in anhydrous DMF (10 mL) and the resulting mixture was stirred at RT for 30 min. Anhydrous Ac2O (2.56 mL, 27.1 mmol) was added dropwise, over a period of 35 min, and the reaction mixture was stirred for additional 10 min. The resulting mixture was quenched with NH4Cl (sat'd aq, 50 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was dissolved in MeOH (15 mL), and hydrazine hydrate (0.877 mL, 18.08 mmol) was added dropwise. The resulting mixture was heated at 85° C. in a microwave reactor for 50 min. The solvent was evaporated under reduced pressure and water was added to the residue. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (3×10 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH) to afford 800 mg of 5-amino-8-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:14]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COC(=O)c1cccc(O)c1
Product: COC(=O)c1cccc(OCc2ccc(F)cc2)c1

Procedure:
Reaction of methyl 3-hydroxybenzoate with p-fluorobenzyl chloride as described in the preparation of Intermediate 1A gave the title ester as white prisms: mp 58-59° C. (hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.94 (3H, s, OCH3), 5.1 (2H, s, OCH2), 7.09-7.69 (8H, m, aromatics). Anal. Calcd for C15H13FO3: C, 69.22; H, 5.03. Found: C, 69.08; H, 4.97.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH3:21]>CN(C=O)C.C(OCC)C.[I-].[K+]>[CH2:19]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH2:20][CH3:21]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCOc1ccc(C=O)cc1OC
Temperature: 65 °C
Reaction time: 5 h
Yield: 99.5 %

Procedure:
To a suspension of vanillin (2.00 g, 13.2 mmol), potassium carbonate (2.74 g, 19.8 mmol) and potassium iodide (60.0 mg, 0.361 mmol) in DMF (15 mL) was slowly added 1-bromopropane (1.56 mL, 17.2 mmol) via syringe. The reaction mixture was stirred at 65° C. for 5 hours. After cooling to room temperature, the mixture was diluted with diethyl ether (100 mL), and the organic phase was washed with water (2×50 mL). After drying over anhydrous MgSO4, filtration and evaporation of the filtrate in vacuo gave crude 4-(propyloxy)-3-methoxybenzaldehyde (2.55 g) which was used in the next step without further purification.
Reaction SMILES: C(O)(=O)C.[CH3:5][N:6]1[C:14]2[C:13](=[O:15])[NH:12][C:11]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)=[N:10][C:9]=2[C:8]([CH2:27][CH2:28][CH3:29])=[N:7]1.S(=O)(=O)(O)O.[N+:35]([O-])([OH:37])=[O:36]>>[CH3:5][N:6]1[C:14]2[C:13](=[O:15])[NH:12][C:11]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[C:19]([N+:35]([O-:37])=[O:36])[CH:18]=3)=[N:10][C:9]=2[C:8]([CH2:27][CH2:28][CH3:29])=[N:7]1
Reactant: O=[N+]([O-])O
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC(C)=O)cc3)nc12
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC(C)=O)c([N+](=O)[O-])c3)nc12
Temperature: 25 °C

Procedure:
Glacial acetic acid (1.93 ml, 0.0337 mol) was added to N-{4-[(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]-pyrimidin-5-yl)methyl]phenyl}acetamide (1.93 g, 0.0057 mol), followed by concentrated sulphuric acid (5.8 ml) and the mixture cooled in an ice-bath. Concentrated nitric acid (3.86 ml) was then added dropwise and once addition was complete, the reaction was stirred at room temperature for an hour.
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Cl:1][CH:2]([CH3:6])[C:3]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)=[O:4]
Reactant: CC(Cl)C(=O)Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(Cl)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-chloropropionyl chloride (49 ml) in dichloromethane (50 ml) was added to a mixture of anhydrous aluminium trichloride (55.5 g) in dichloromethane (120 ml). The mixture was stirred for 10 minutes at room temperature and then a solution of fluorobenzene (39.5 ml) in dichloromethane (30 ml) was added dropwise. The resulting mixture was stirred for one hour, allowed to stand for 16 hours and then poured on to an ice-hydrochloric acid mixture. The two phase mixture was vigorously stirred at room temperature for 11/2 hours, separated and the aqueous layer washed with dichloromethane (2×50 ml). The combined organic extracts were then washed with aqueous sodium hydroxide (3N, 2×100 ml), water (1×100 ml) and brine (1×100 ml), dried (MgSO4) and evaporated under reduced pressure to afford 2-chloro-1-(4-fluorophenyl)-1-propanone, 71.3 g.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][NH:10][CH2:9][CH:8]2[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][N:10]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:9][CH:8]2[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC1CNCC(=O)N1Cc1ccc(F)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1CN(C(=O)OCc2ccccc2)CC(=O)N1Cc1ccc(F)cc1

Procedure:
To a solution of ethyl [1-(4-fluorobenzyl)-6-oxo-piperazin-2-yl]acetate (3.7 g, 12.5 mmol) in dichloromethane (100 mL) was added benzyl chloroformate (2.2 mL, 15.1 mmol) and triethylamine (3.5 mL, 25.1 mmol), stirred over night. The reaction mixture was diluted with dichloromethane, washed with 1N HCl, water and brine, dried over sodium sulfate, filtered and concentrated to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.23-7.38 (m, 7H), 7.01 (t, J=8.6 Hz, 2H), 5.12-5.22 (m, 3H), 4.40-4.56 (m, 1H), 3.90-4.24 (m, 5H), 3.72-3.86 (m, 1H), 3.04-3.18 (m, 1H), 2.49-2.62 (m, 2H), 1.12-1.28 (m, 3H). ES MS (M+1)=429.24.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:15][O:16][CH2:17][CH3:18])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[C:25]([O:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[CH:45]=[CH:44][C:41]([CH2:42][N:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:6]=[C:7]2[CH2:15][O:16][CH2:17][CH3:18])=[CH:40][CH:39]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 93.4 %

Procedure:
A procedure similar to that described in Example 82(a) was repeated, except that 315 mg of ethyl 4-(1-hydroxy-1-methylethyl)-2-ethoxymethylimidazole-5-carboxylate [prepared as described in Preparation 44 (iii)], 145 mg of potassium t-butoxide and 510 mg of 4-[2-(t-butoxycarbonyl)phenyl]benzyl bromide were employed and the product was purified by column chromatography through silica gel using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to obtain 600 mg of the title compound as a syrup.
Reaction SMILES: [OH:1][C@H:2]([CH2:21][NH:22][C:23]([CH3:36])([CH3:35])[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH2:3][O:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)[CH3:6].[Cl-].[NH4+].[N-:39]=[N+:40]=[N-:41].[Na+].O>CN(C)C=O>[CH3:36][C:23]([NH:22][CH2:21][C@@H:2]([OH:1])[CH2:3][O:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[NH:41][N:40]=[N:39][N:20]=2)=[CH:17][CH:18]=1)[CH3:6])([CH3:35])[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1
Reactant: CC(OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1-c1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1-c1ccc(-c2nnn[nH]2)cc1
Temperature: 115 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
2′-[1-[(2R)-2-Hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy]ethyl]biphenyl-4-carbonitrile (500 mg) obtained in Step 2 was dissolved in N,N-dimethylformamide (6.0 ml), ammonium chloride (535 mg) and sodium azide (676 mg) were successively added and the mixture was stirred overnight at 115° C. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was dissolved in methanol, water was added and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound (280 mg).
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].[C:6]([NH2:10])([CH3:9])([CH3:8])[CH3:7]>O>[C:6]([NH:10][CH2:1][C@H:2]([OH:3])[CH2:4][OH:5])([CH3:9])([CH3:8])[CH3:7]
Reactant: OC[C@H]1CO1
Reactant: CC(C)(C)N
Solvent: O
Product: CC(C)(C)NC[C@H](O)CO
Temperature: 25 °C
Yield: 78 %

Procedure:
(S)-Glycidol was added dropwise, with stirring, to a mixture of 54.7 g of tert-butylamine and 25 mL of water, heated at reflux. The resulting mixture was heated at reflux for 12 h, and was thereafter allowed to cool to room temperature. The mixture was concentrated in vacuo and was treated with ether to effect crystallization. 28.6 g (78%) of crystalline product was thus obtained: 1H NMR (CDCl3) δ1.0 (s, C(CH3)3), 2.4-2.6 (m), 3.3-4.2 (m); 13C NMR (CDCl3) δ28.6 (3 CH3), 45.2 (CH2NH), 50.2 (C(CH3)3), 65.5 (CH2OH), 70.6 (CHOH).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.O>C(Cl)Cl>[C:1]1([S:7]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)(=[O:22])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(C1=NOCC1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(C1=NOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-(phenylsulfonyl)-4,5-dihydroisoxazole I-250a and I-250b were prepared by the oxidation of racemic 3-(phenylsulfinyl)-4,5-dihydroisoxazole I-249. 3-(Phenylsulfinyl)-4,5-dihydroisoxazole I-249 is dissolved in methylene chloride (0.03 M). m-Chloroperbenzoic acid (77% by weight, 2.95 equiv) are added in two portions and the reaction is allowed to stir at room temperature for 14 h after which it is transferred to a separatory funnel with excess water and methylene chloride. The organic layer is washed with saturated sodium bicarbonate (2×), dried over magnesium sulfate, and concentrated to provide crude solid that is recrystallized from methylene chloride/hexanes to provide the desired racemic 3-(phenylsulfonyl)-4,5-dihydroisoxazole I-250. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=371.7 m/z. Activity: C