Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:26]=[CH:25][C:6]2[N:7]=[C:8]([C:10]3[CH:24]=[CH:23][C:13]([CH2:14]P(=O)(OCC)OCC)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.[CH3:27]C(C)([O-])C.[K+].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O.CCCCCC.CCOCC>C1COCC1>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:14][C:13]2[CH:12]=[CH:11][C:10]([C:8]3[S:9][C:5]4[CH:4]=[C:3]([CH3:27])[CH:26]=[CH:25][C:6]=4[N:7]=3)=[CH:24][CH:23]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: COc1cccc(C=O)c1
Reactant: CC(C)(C)[O-]
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(OC)cc3s2)cc1)OCC
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(C=Cc2ccc(-c3nc4ccc(C)cc4s3)cc2)c1
Yield: 33.7 %

Procedure:
Prepared as described in the Alkene Formation section using diethyl 4-(6-methoxybenzothiazol-2-yl)benzylphosphonate (0.05 g, 0.133 mmol) in dry THF (5 ml), potassium t-butoxide (0.03 g, 0.266 mmol) and 3-methoxybenzaldehyde (0.018 g, 0.133 mmol) in dry THF (5 ml) to give the title compound (0.016 g, 34%) as a yellow solid after work-up and flash chromatography (4:1 Hexane/Et2O).
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CC#N>[Br-:22].[CH:24]1([CH2:23][N+:1]23[CH2:7][C:4]([C:8]([OH:9])([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)([CH2:5][CH2:6]2)[CH2:3][CH2:2]3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: BrCC1CCCCC1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CC3CCCCC3)(CC1)C2
Product: [Br-]
Yield: 13 %

Procedure:
Following the general procedure outlined in Example 1, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (33.0 mg, 0.118 mmol) and (bromomethyl)cyclohexane (0.03 mL, 0.21 mmol) in 2 CH3CN/3 CHCl3 (2.5 mL) were reacted to give the desired product (7 mg, 13%). EI-MS m/z 376 (M+) Rt (1.90 min).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([F:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][CH:14]([C:20]([CH3:22])=O)[C:15](OCC)=[O:16].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:22][C:20]1[C:14]([CH3:13])=[C:15]([OH:16])[C:10]2[C:8](=[C:7]([F:12])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=2)[N:9]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CC(C)(C)c1ccc(N)c(F)c1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Yield: 23.4 %

Procedure:
4-t-Butyl-2-fluoroaniline (4.79 g) prepared according to the above process and ethyl 2-methyl-acetoacetate (4.96 g) were refluxed in toluene (60 ml) in the presence of trifluoroboron etherate (0.3 ml) for 3 hr to obtain a reaction solution. The reaction solution thus obtained was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The reaction product was refluxed in diphenyl ether (80 ml) for one hr and was allowed to stand for cooling. The precipitated product was then collected by filtration under the reduced pressure to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-hydroxyquinoline (compound 1, 1.66 g). 1H-NMR data on this compound in deutro-DMSO (dimethyl sulfoxide) were as shown below.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:32])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[C:23][CH:24](O)[C:25]3[CH:30]=CC=CC=3)[CH:20]=2)[O:15][CH2:14][CH2:13]1.[CH2:33](N(CC)CC)[CH3:34]>C(Cl)Cl>[CH3:32][C:12]1([CH3:11])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[C:23][C:24]3[CH:25]=[CH:30][C:2]([CH:1]=[O:5])=[CH:34][CH:33]=3)[CH:20]=2)[O:15][CH2:14][CH2:13]1
Reactant: CCN(CC)CC
Reactant: CC1(C)CCOc2ccc(C#CC(O)c3ccccc3)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1(C)CCOc2ccc(C#Cc3ccc(C=O)cc3)cc21
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.396 g (11 mmol) of freshly distilled oxalyl chloride in 25 ml of methylene chloride is placed in a 4-necked flask equipped with a stirrer, a thermometer and two pressure-equalizing addition funnels fitted with drying tubes. The solution is cooled to -60° C. and then treated dropwise with a solution of 1.875 g (24 mmol) of dimethyl sulfoxide (distilled from calcium hydride) in 5 ml of methylene chloride over a five minute period. The reaction mixture is then stirred at -60° C. for an additional 10 minutes. A solution of 2.92 g (10 mmol) of 4-[(4,4-dimethylchroman-6-ylethynyl]benzyl alcohol in 10 ml of methylene chloride is then added to the reaction mixture over a period of 5 minutes. The mixture is stirred for a further 15 minutes and is then treated with 5.06 g (50 mmol) of triethylamine. The cooling bath is then removed and the mixture is allowed to warm to room temperature. Thirty ml of water is then added to the mixture and stirring is continued for a further 10 mintues. The organic layer is then separated and the aqueous layer is extracted with 20 ml of methylene chloride. The organic layers are then combined and washed successively with dilute HCl, water and dilute Na2CO3 solution and then dried (MgSO4). The solution is then filtered and concentrated in vacuo and the residue is purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[N:23](COCC[Si](C)(C)C)[C:22]5[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=5[N:20]=4)=[CH:14][CH:13]=3)[C:9](=[O:11])[NH:10][C:3]=12.[ClH:36]>CCO>[ClH:36].[ClH:36].[NH:20]1[C:21]2[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=2[N:23]=[C:19]1[O:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[NH:10][C:9]2=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(Oc2nc3ccccc3n2COCC[Si](C)(C)C)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A mixture of 7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.053 g) and 2N HCl in EtOH (5.0 mL) was stirred at 60° C. for 10 h. After cooling to room temperature, the solvent was removed. The residue was recrystallized from EtOH-AcOEt to give 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride (0.030 g)
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.O.NN>CO.[Ni]>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Yield: 81.2 %

Procedure:
A solution of compound 141 (0.12 g, 0.423 mmol) in dry methanol (5 mL) was treated with Ra—Ni (˜0.05 g), hydrazine hydrate (0.13 mL, 4.235 mmol) at room temperature. The resulting mixture was refluxed for 2 min, in pre-heated oil bath. The reaction was brought to room temperature, filtered through celite bed and washed with methanol (2 20 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 95:5) to obtain 3-(1,2,3,5,8,8a-Hexahydroindolizin-7-yl)-1H-indol-5-amine, (0.087 g, 81%) as a solid. mp 208-210° C.; 1H NMR (DMSO-d6) δ 1.33-1.48 (m, 1H), 1.67-1.79 (m, 2H), 1.94-2.13 (m, 2H), 2.16-2.26 (m, 2H), 2.58-2.65 (m, 1H), 2.85 (d, 1H, J=15.6 Hz), 3.08-3.17 (m, 1H), 3.59 (dd, 1H, J=4.5, 15.7 Hz), 4.49 (s, 2H), 6.01 (d, 1H, J=4.5 Hz), 6.48 (dd, 1H, J=1.8, 9.1 Hz), 7.01 (d, 1H, J=1.5 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.17 (d, 1H, J=2.7 Hz), 10.60 (s, 1H); ESI-MS (m/z, %) 254 (MH+, 62), 185 (100). A solution of the amine (0.053 g, 0.209 mmol) in dry ethanol (3 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.12 g, 0.418 mmol) at room temperature and the solution was stirred for 24 h. Solvent was evaporated, crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2 20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 5:95) to obtain compound 142 (0.06 g, 79%) as a solid. mp 122-124° C.; 1H NMR (DMSO-d6) δ 1.38-1.46 (m, 1H), 1.70-1.78 (m, 2H), 1.93-2.12 (m, 2H), 2.20-2.28 (m, 2H), 2.62-2.72 (m, 1H), 2.83 (d, 1H, J=15.9 Hz), 3.07-3.13 (m, 1H), 3.59 (dd, 1H, J=4.5, 16.0 Hz), 6.07 (d, 1H, J=3.9 Hz), 6.22 (brs, 2H), 6.66 (d, 1H, J=8.1 Hz), 7.09 (dd, 1H, J=3.9, 4.9 Hz), 7.22 (s, 1H), 7.30-7.32 (m, 2H), 7.58 (d, 1H, J=4.5 Hz), 7.71 (d, 1H, J=2.7 Hz), 10.92 (s, 1H); ESI-MS (m/z, %) 363 (MH+, 20), 294 (100), 182 (15), ESI-HRMS calculated for C21H23N4S (MH+), calculated: 363.1655; observed: 363.1637.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19](O)=[O:20])=[O:5].Cl.[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34][NH2:35]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:16])([CH3:17])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([NH:35][CH2:34][CH2:33][C:32]([F:37])([F:36])[F:31])=[O:20])=[O:5]
Reactant: NCCC(F)(F)F
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Agent: Cl
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NCCC(F)(F)F

Procedure:
The title compound was prepared from the product of Example 45A and commercially available 3,3,3-trifluoropropylamine hydrochloride by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz), 1.43 (s, 6H), 1.48 (s, 6H), 2.39-3.50 (m, 2H), 3.35-3.42 (m, 2H), 7.68-7.81 (m, 3H), 8.31 (t, J=5.4 Hz, 1H), 11.53 (br s, 1H). MS (ESI+) m/z 527 (M+H)+. Anal. calcd. for C22H21F7N2O3S: C, 50.19; H, 4.02; N, 5.32. Found: C, 50.30; H, 4.13; N, 5.00.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[CH:14][C:13]=2[C:17]=1[CH2:18][CH2:19][CH2:20][NH2:21].ClC1C(CCCN)=CC2OC=CC=2C=1.N1C=CC=CC=1>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[CH:14][C:13]=2[C:17]=1[CH2:18][CH2:19][CH2:20][NH:21][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCc1c(Cl)ccc2occc12
Agent: NCCCc1cc2occc2cc1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)NCCCc1c(Cl)ccc2occc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (1.95 ml) was added dropwise to a solution of 3-(5-chloro-benzofuran-4-yl)-propylamine mixture with 3-(5-chloro-benzofuran-6-yl)-propylamine (2.86 g) and pyridine (2.2 ml) in dry THF (70 ml) at 0° under nitrogen. The mixture was stirred at room temperature for 3 h, then evaporated to dryness in vacuo . The residue was purified by HPLC (CN-PK5-10530 column). Eluting with 5% isopropanol/heptane gave the title compound as a colourless solid (1.37 g) mp 82-83° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9](=O)[CH3:10].[Cl-].[NH4+:13].[C-:14]#[N:15].[Na+]>N>[NH2:13][C:9]([CH3:10])([CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[C:14]#[N:15]
Reactant: CC(=O)COC1CCCCO1
Reactant: [C-]#N
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Agent: [Na+]
Product: CC(N)(C#N)COC1CCCCO1
Yield: 88.2 %

Procedure:
A solution of 1-(tetrahydro-pyran-2-yloxy)-propan-2-one (126.6 g, 0.8 mol), ammonium chloride (65.8 g, 1.23 mol) and sodium cyanide (45.5 g, 0.92 mol) in a solution of aqueous ammonia (920 ml, 28%) is stirred vigorously at room temperature for 5 hours. The aqueous phase is extracted repeatedly with ethyl acetate. The collected organic extracts are dried and the solvent is evaporated under reduced pressure to give the 2-amino-2-methyl-3-(tetrahydro-pyran-2-yloxy)-propionitrile (130 g, 88.2%) as a liquid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([C:24]1[S:28][C:27]([CH2:29][NH:30][C:31](=[O:51])[C@H:32]([CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[NH:33][C:34]([O:36][CH3:37])=[O:35])=[CH:26][CH:25]=1)[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:71](O)[CH:72]([CH3:74])[CH3:73].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]([C:24]1[S:28][C:27]([CH2:29][NH:30][C:31](=[O:51])[C@H:32]([CH:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[NH:33][C:34]([O:36][CH3:37])=[O:35])=[CH:26][CH:25]=1)[N:11]([CH2:71][CH:72]([CH3:74])[CH3:73])[S:12]([C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)(=[O:13])=[O:14])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)CO
Reactant: COC(=O)N[C@H](C(=O)NCc1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)s1)C(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)NCc1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)s1)C(c1ccccc1)c1ccccc1

Procedure:
A solution of N-({5-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-{[(4-nitrophenyl)sulfonyl]amino}ethyl]thiophen-2-yl}methyl)-Nα-(methoxycarbonyl)-β-phenyl-L-phenyl alaninamide (60 mg, 0.080 mmol), Ph3P (105 mg, 0.398 mmol), isobutanol (0.037 mL, 0.398 mmol) and DIAD (0.077 mL, 0.398 mmol) in THF (0.4 mL) stirred at 40° C. under N2 atmosphere, for 18 hours. Ethyl acetate and water were added and the phases were separated. The organic phase was washed with brine, dried, and concentrated under reduce pressure. The concentrate was purified on silica gel using 5%-65% ethyl acetate in hexane to afford the title compound with impurities. MS: m/z=810.3 ((MH+)).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][C:13]([CH:32]=[CH2:33])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][C:13]([CH:32]=[CH2:33])=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3[nH]cnc23)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 111 %

Procedure:
N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-vinylpyridin-2-amine (76.3 mg, 0.172 mmol) was dissolved in DCM (2.9 mL) and trifluoroacetic acid (Aldrich, St. Louis, Mo., hplc grade, 0.60 mL, 7.8 mmol) was added via syringe. The reaction was stirred at room temperature for 35 minutes, concentrated, treated with MeOH, and filtered. The solid was washed with Et2O, but was not sufficiently (>95% by HPLC) pure. So, the solid and filtrate were combined, concentrated, treated with 2 N ammonia in MeOH, and concentrated again. The material was treated with Et2O, but this did not precipitate product. So, it was concentrated, treated with water, and filtered. The solid was washed with water, but was still not 95% pure. So, the solid was collected and purified on HPLC (10% to 100% MeCN/water over 30 minutes using a total flow rate of 100 mL/min) to afford N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-vinylpyridin-2-amine (68.6 mg). MS (ESI pos. ion) m/z 360 (M+H)+. 1H NMR (d6-DMSO) δ 12.70 (s, 1H), 9.98 (s, 1H), 8.65 (s, 1H), 8.55 (d, J=2.54 Hz, 1H), 8.40 (d, J=2.35 Hz, 1H), 8.19 (dd, J=8.8 Hz, 2.74 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.79 (dd, J=17.5 Hz, 10.9 Hz, 1H), 5.78 (d, J=16.4 Hz, 1H), 5.26 (d, J=11.0 Hz, 1H), 3.85 (s, 3H), 2.86 (s, 3H).
Reaction SMILES: NO.[CH3:3][C:4]([CH3:8])([CH3:7])[CH:5]=[O:6].C([Zn][CH2:12][CH3:13])C.[C:14](OC(=O)C)(=[O:16])[CH3:15]>CCCCCC.C1(C)C=CC=CC=1.ClC1C=CC=CC=1>[C:14]([O:6][CH:5]([CH2:12][CH3:13])[C:4]([CH3:8])([CH3:7])[CH3:3])(=[O:16])[CH3:15]
Reactant: CC[Zn]CC
Reactant: CC(C)(C)C=O
Reactant: CC(=O)OC(C)=O
Agent: NO
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: CCC(OC(C)=O)C(C)(C)C
Reaction time: 48 h
Yield: 73 %

Procedure:
A vial was charged with aminoalcohol 1 (0.0074 g, 0.026 mmol) prepared as in Example 1. To the vial was added 1.60 mL of a stock solution containing trimethylacetaldehyde (0.26 g), chlorobenzene internal standard (0.26 g), 1 M diethylzinc in hexane (6.0 mL), and toluene (3.0 mL). After 48 h, acetic anhydride (0.200 mL) was added. After an additional 72 h, a sample of the solution was analyzed by gas chromatography at 70° C. on a Cyclodex B stationary phase. The product 3-acetoxy-2,2-dimethylpentane was formed in 73% yield and 98% enantiomeric excess. The identity and yield of the product was established by comparison with an authentic sample prepared by treatment of racemic 2-methyl-3-pentanol with acetic anhydride.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:18][C:19]=3[CH3:20])=[CH:11][CH:10]=2)[N:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:36]=[O:37]>O>[CH3:1][C:2]1[C:6]([CH:36]=[O:37])=[C:5]([CH3:7])[N:4]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:18][C:19]=3[CH3:20])=[CH:11][CH:10]=2)[N:3]=1
Reactant: Cc1cc(C)n(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(C)c1C=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 55 %

Procedure:
A mixture of 4-[4-(3,5-dimethyl-1H-pyrazol-1-ylmethyl)phenoxymethyl]-5-methyl-2-phenyloxazole (1.62 g), phosphorus oxychloride (1.00 g), and N,N-dimethylformamide (20 ml) was stirred for 5 days at room temperature. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and with saturated aqueous sodium chloride solution, then dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and 3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-carbaldehyde (950 mg, yield: 55%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[N:7]=C2N[C:9](=O)[CH2:10][C:5]2=[CH:4][CH:3]=1.[CH3:12]C(C)([O-])C.[K+].CI.O.[CH3:21][N:22]([CH:24]=[O:25])[CH3:23]>>[Cl:1][C:2]1[N:7]=[C:21]2[N:22]([CH3:23])[C:24](=[O:25])[C:10]([CH3:9])([CH3:12])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1Cc2ccc(Cl)nc2N1
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CI
Solvent: O
Product: CN1C(=O)C(C)(C)c2ccc(Cl)nc21
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 0.25 g (1.5 mmol) 6-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (WO9910349 A1) was dissolved in 5 ml of DMF and cooled to 5° C. To this solution was added 4.5 ml (4.5 mmol) of potassium t-butoxide (1M solution in THF) followed by 0.37 ml (6.0 mmol) of methyl iodide. The reaction mixture was stirred at 5° C. for 1 hour. The reaction mixture was poured into 50 ml of water and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and evaporated to yield 0.25 g of 6-chloro-1,3,3-trimethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as a dark amorphous solid. TLC: Rf=0.8 (1:1 hexane/ethyl acetate). 1H NMR (CDCl3) δ 7.38 (d, 1H), 6.95 (d, 1H), 3.25 (s, 3H), 1.38 (s, 3H). Mass spectrum: m/e=211,213 (p+1, p+3).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]([C:13]1[C:22]([CH3:23])=[C:21]([OH:24])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:25])[CH:19]=2)[CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O>[CH3:9][O:10][C:11]([C:13]1[C:22]([CH3:23])=[C:21]([O:24][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:25])[CH:19]=2)[CH:14]=1)=[O:12]
Reactant: COC(=O)c1cc2ccc(F)cc2c(O)c1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)c1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Yield: 66.2 %

Procedure:
Benzyl bromide (10 mL, 82.51 mmol) was added to a mixture of 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid methyl ester (15.56 g, 66.43 mmol) and potassium carbonate (19.26 g, 136.6 mmol) in acetone (300 mL). The reaction mixture was heated at reflux for 3 hours. The acetone was removed in vacuo. The residue was diluted with water, and the resulting mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated. A concentrated solution of the crude product in 25% ethyl acetate in hexanes was loaded onto a Analogix SuperFlash™ column. Flash chromatography (25-50% ethyl acetate in hexanes) provided 14.27 g (66% yield) of 4-benzyloxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester as a slightly yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.34 (s, 1 H), 8.19 (dd, J=8.9, 5.9 Hz, 1 H), 7.64 (dd, J=10.7, 2.3 Hz, 1 H), 7.57 (d, J=6.6 Hz, 2 H), 7.36-7.54 (m, 4 H), 4.98 (s, 2 H), 3.89 (s, 3 H), 2.56 (s, 3 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[C:4]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:3]=1.[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].[C:22]1([CH3:34])[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>C(O)C>[CH3:14][O:13][CH2:12][CH2:11][O:10][C:4]1[N:3]=[C:2]([N:31]2[CH2:32][CH2:33][N:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:34])=[CH:23][CH:24]=3)[CH2:29][CH2:30]2)[N:7]=[C:6](/[CH:8]=[C:19]2/[C:18](=[O:20])[NH:17][C:16](=[O:21])[S:15]/2)[CH:5]=1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: COCCOc1cc(C=O)nc(Cl)n1
Solvent: CCO
Product: COCCOc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCN(c3ccc(C)cc3)CC2)n1
Temperature: 80 °C
Reaction time: 15.5 h
Yield: 104.5 %

Procedure:
Crude 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carbaldehyde (sad105-052, 41.9 mg) was dissolved in ethanol (1.5 mL) and was added to a 10 mL vial containing the thiazolidine-dione (21.3 mg, 0.18 mmol) and the 1-(p-tolyl)piperazine (39.3 mg, 0.18 mmol). The reaction mixture was shaken at 80° C. for 15.5 h. LC-MS showed a peak with the desired mass at 2.18 min (M+1=456). The solvent was concentrated under reduced pressure and the residue was dissolved in EtOAc (20 mL) and washed with saturated NaHCO3 (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 85.7 mg of brown oil. Purification by flash chromatography (SiO2,10 g, Hexanes/EtOAc 9:1 to 6:4 to 1:1) provided 11.5 mg (13.9% 2 steps, 83 mg theoretical) of pure (Z)-5-((6-(2-methoxyethoxy)-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione as a yellow solid.