Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[C:21]([Cl:38])=[CH:20][N:19]=1>>[Cl:38][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccc(OC)cc4-n4cccn4)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine in an analogous manner to example 730. Product was isolated as a tan solid (0.043 g, 39%). Mp 82-87° C. LCMS (m/e) 519 (M); 1H-NMR (DMSO, 400 MHz) δ 9.83 (s, 1H), 9.17 (s, 1H), 8.29 (s, 1H), 8.16-8.13 (d, 1H, J=8.59 Hz), 8.09 (s, 1H), 7.85 (s, 1H), 7.20 (s, 1H), 7.20-7.15 (br, 1H), 7.10-7.05 (br, 1H), 7.00-6.95 (q, 1H, J=7.08 Hz), 6.95-6.90 (br, 1H), 6.55 (s, 1H), 3.85 (s, 3H), 3.70-3.50 (br, 1H), 3.17-3.16 (d, 1H, J=5.30 Hz), 3.05-2.70 (m, 6H), 1.15-1.00 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@@H:17]([C:20]([O:22]CC)=[O:21])[CH2:16][C@@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[C:20]([C@@H:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])[C@@H:15]([NH:25][C:26]([C:28]2[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=2)=[O:27])[CH2:16]1)([OH:22])=[O:21]
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 12 h
Yield: 82 %

Procedure:
(1R*,2S*,4R*)-N1-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine (916 mg) was suspended in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (8 ml), and a 1N aqueous solution (3.3 ml) of sodium hydroxide was added at room temperature to stir the mixture for 12 hours at the same temperature. After adding 1N hydrochloric acid (3.3 ml), the solvent was distilled off under reduced pressure, and the residue was washed with water and ether to obtain the title compound (712 mg) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:12][C:10]([CH3:11])([CH3:13])[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][O:15]2)[CH:3]=1)=[O:14]
Reactant: CC(C)(C)C(=O)Nc1cccc(O)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 3-amino-phenol (60 g, 6.55 mol) in 2 N NaOH (1 l), cooled to 10° C., pivaloyl chloride (68 ml, 0.55 mol) in toluene (200 ml) is added within 1 h. After stirring for 15 h at 25° C., the mixture is cooled to 0° C. and acidified to pH 1 with conc. HCl. Extraction with EtOAc washing with water, 10% NaHCO3, water, and brine, followed by drying (Na2SO4), evaporation of volatiles, and crystallization (EtOAc/hexanes) gives N-(3-hydroxy-phenyl)-2,2-dimethyl-propionamide. N-(3-Hydroxy-phenyl)-2,2-dimethyl-propionamide (49 g, 0.254 mol) in dichloromethane (1 l) is treated with dihydropyrane (66 ml, 0.762 mol) and pyridinium p-toluenesulfonate (957 mg, 3.8 mmol). After stirring for 6 days at 25° C., the solvent is removed and the residue crystallized from EtOAc/hexanes to give 2,2-dimethyl-N-[3-(tetrahydro-pyran-2-yloxy)-phenyl]-propionamide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([N:18]=[C:19]2[NH:23][CH2:22][CH2:21][NH:20]2)=[C:13]([Cl:24])[CH:12]=1)(OC)=[O:8].C(OCC)(=O)C>O1CCCC1>[Cl:24][C:13]1[CH:12]=[C:11]([CH2:7][OH:8])[CH:16]=[C:15]([Cl:17])[C:14]=1[N:18]=[C:19]1[NH:20][CH2:21][CH2:22][NH:23]1
Reactant: COC(=O)c1cc(Cl)c(N=C2NCCN2)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc(Cl)c(N=C2NCCN2)c(Cl)c1
Yield: 48.7 %

Procedure:
Lithium aluminium hydride (300 mg, 7.9 mM) was added to a stirred suspension of 2-(4-carbomethoxy-2,6-dichlorophenylimino)imidazolidine (750 mg, 2.6 mM) in dry tetrahydrofuran (50 ml) with stirring. The mixture was then stirred at room temperature for several hours after which time ethyl acetate was carefully added. The solvent was then removed under vacuum and water was added to the residue. After basification with dilute sodium hydroxide the aqueous mixture was extracted several times with ethyl acetate. The extract (750 mg) was dried and evaporated to give a solid which was recrystallised from isopropanol to give a white solid (330 mg) mp 208°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](N(OC)C)=[O:10].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)Cc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1Cl)c1ccccc1
Reaction time: 5 h
Yield: 14.8 %

Procedure:
To a solution of 2-(2-chlorophenyl)-N-methoxy-N-methylacetamide (0.51 g, 2.4 mmol) in anhydrous THF (10 mL) cooled to −78° C., a solution of phenylmagnesium bromide (1 mol/L, 3.5 mL) in THF was added. The reaction mixture was stirred at this temperature for five hours. TLC (PE:EtOAc=10:1) indicated that 50% of the starting materials were consumed. H2O (10 mL) was added to quench the reaction, and the aqueous layer extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc=50:1) to afford Intermediate 10 as a colorless oil (80 mg, yield: 14.8%).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[C:20]([CH2:22][CH3:23])[C:19]([OH:24])=[CH:18][C:17]=3[O:25][CH3:26])[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]1[N:29]=[CH:30][NH:31][C:32]=1[CH:33]=O.CC1C=NC2N(N=C(C=O)N=2)C=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[C:20]([CH2:22][CH3:23])[C:19]([OH:24])=[CH:18][C:17]=3[O:25][CH3:26])[O:11][C:10](=[O:12])[C:9]([CH2:27][C:28]3[N:29]=[CH:30][NH:31][C:32]=3[CH3:33])=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c(OC)cc1O
Reactant: Cc1nc[nH]c1C=O
Agent: Cc1cnc2nc(C=O)nn2c1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc[nH]c3C)C(=O)O2)c(OC)cc1O

Procedure:
The title compound was prepared analogously to Example A(126), where 6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione was substituted in place of 6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl-dihydro-pyran-2,4-dione and 4-methyl-5-imidazol carboxaldehyde was substituted in place of 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of that example. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (t, J=7.5 Hz, 3H), 1.10-1.56 (m, 10H), 1.73-1.68 (m, 1H), 1.92 (s, 3H), 2.21-2.5 (m, 6H), 3.20-3.22 (m, 2H), 3.44 (s, 3H), 6.17 (s, 1H), 6.50 (s, 1H), 7.53 (s, 1H). Anal. Calcd. For C26H34N2O5.1H2O: C, 66.08; H, 7.68; N, 5.93. Found: C, 65.93; H, 7.66; N, 5.89. MS(ESI): 455.2 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[CH:11][CH3:12]>C1C=CC=CC=1>[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:11]([CH3:12])[CH3:10])([CH3:9])[CH3:8].[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: C=CC
Solvent: CC(C)c1ccccc1
Solvent: c1ccccc1
Product: CC(C)c1ccccc1C(C)C

Procedure:
In these experiments, cumene was manufactured by contacting 5.55 parts by weight benzene and 1 part by weight propylene in the batch slurry reactor using the procedure detailed above for Test Sequence for Cumene Manufacture in a Batch Test over catalyst comprising the 0.127 cm MCM-49 quadrulobal catalyst (Material 1) and the 250 to 297 micron catalyst prepared from it by crushing and sieving (Material 2). Cumene (isopropylbenzene, IPB) and diisopropylbenzene (DIPB) products were collected from each experiment and it was found that Material 2 again provided a 30% reduction in the DIPB/IPB ratio.
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[C@@H:12]([CH2:22][O:23]CC2C=CC=CC=2)[O:11][C@H:10]1[N:31]1[C:35]2[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=2[CH:33]=[CH:32]1)C1C=CC=CC=1.C(O)(=O)C.COC(O)C.[H][H]>[Pd].O>[C@@H:10]1([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[CH:33]=[CH:32]2)[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@@H:9]1[OH:8]
Reactant: [H][H]
Reactant: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd]
Agent: COC(C)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Yield: 80 %

Procedure:
A mixture of 2.5 g of 7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5 ml of acetic acid, 500 mg of 20% palladium on charcoal, and 95 ml of methoxyethanol is hydrogenated at 50°-55° C. and approximately 3 atmospheres until uptake of hydrogen ceases. The mixture is filtered, evaporated in vacuo, and coevaporated with xylenes to provide a red syrup which is dissolved in water and treated with Amberlite ion exchange resin (20 ml of wet IR-45). The resin is filtered and washed several times with boiling water. The combined filtrates are evaporated in vacuo to provide 992 mg of crude 7-β-D-arabinofuranosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine. Recrystallization of this material from water provides 800 mg of product, m.p. 117°-120° C. (after drying at 100° C. for one hour); [α]D25 =+16.2 (1.02% in H2O).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[C:10]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCCC(CC)CO
Reactant: O=C(O)c1ccccc1
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CCCCC(CC)COC(=O)c1ccccc1

Procedure:
In analogy to the procedure carried out in example 1, 12 mol of 2-ethylhexanol were reacted with 8 mol of benzoic acid and tetrabutyl titanate. Distillation (3 mbar, overhead temperature 134° C.) gives 2-ethylhexyl benzoate in a purity, determined by gas chromatography, of 99.7%.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[O:9][C:10]([CH3:13])([CH3:12])[O:11][CH:7]2[CH:6]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:5][C:4]1=[O:20].C(N(CC)CC)C.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].Cl>C(Cl)Cl>[Si:28]([O:1][CH2:2][CH:3]1[CH:8]2[O:9][C:10]([CH3:12])([CH3:13])[O:11][CH:7]2[CH:6]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:5][C:4]1=[O:20])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CCOC(C)OC1CC(=O)C(CO)C2OC(C)(C)OC12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(C)OC1CC(=O)C(CO[Si](C)(C)C(C)(C)C)C2OC(C)(C)OC12
Temperature: 0 °C
Reaction time: 13 h
Yield: 97.4 %

Procedure:
2-Hydroxymethyl-3,4-(dimethylmethylenedioxy)-5-(1-ethoxyethoxy)cyclohexanone (765 mg) was dissolved in 7 ml of dry methylene chloride, and 1.2 ml of triethylamine, 55.6 mg of N,N-dimethylaminopyridine and 520 mg of tert-butyldimethylsilyl chloride were added at 0° C., followed by stirring the mixture at 0° C. for 13 hours. The obtained reaction mixture was poured into 1N hydrochloric acid, and extracted with diethyl ether. The extract was washed with a saturated sodium hydrogen carbonate aqueous solution and then with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 1.04 g of 2-(tert-butyldimethylsilyloxymethyl)-3,4-(dimethylmethylenedioxy)-5-(1-ethoxyethoxy)cyclohexanone having the following properties.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH2:5][OH:6])[CH3:4].C1(C=CC(O)=CC=1)O.C[O-].[Na+].[C:19](OC)(=[O:23])[C:20]([CH3:22])=[CH2:21]>C1(C)C=CC=CC=1>[C:19]([O:1][CH2:2][C:3]([CH3:7])([CH3:4])[CH2:5][OH:6])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: CC(C)(CO)CO
Reactant: C=C(C)C(=O)OC
Agent: C[O-]
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCC(C)(C)CO
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
To a 2-L flask was charged neopentyl glycol (208.3 g, 2.0 moles), toluene (250 mL), hydroquinone (0.5 g) and sodium methoxide (25% in methanol, 8 g). The mixture was heated to 60-65° C. and methyl methacrylate (120 g, 1.2 moles) was added dropwise over 1 hour. The reaction was held at 70° C. for one hour under moderate vacuum to remove methanol and low boilers. Reaction was worked up by washing with 2×250 mL water and 1×100 mL saturated sodium chloride solution at 70° C. Toluene was evaporated and the resulting crude product (166 g) distilled to provide 3-hydroxy-2,2-dimethylpropyl methacrylate of 97% GC assay. To a 300 mL flask was charged 3-hydroxy-2,2-dimethylpropyl methacrylate (11.5 g, 0.064 moles), methylene chloride (20 g), DMAP (0.01 g), hydroquinone (0.05 g) and the mixture cooled to 0-5° C. To this was added dropwise diketene (5.4 g) at <3° C. Reaction allowed to warm to room temperature and stir overnight. Reaction cooled to 0-5° C. and additional diketene (2 g) added to complete reaction. Once reaction was complete, the dichloromethane was removed at 60° C. with house vacuum. Crude product distilled via Kugelrohr distillation to provide desired product of 92.6% assay with 1.6% starting material remaining (GC assay).
Reaction SMILES: S(Cl)(Cl)=O.Cl.[C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[NH2:18])=[CH:11][CH:10]=1)([OH:8])=[O:7].[CH3:21]O>>[C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[NH2:18])=[CH:11][CH:10]=1)([O:8][CH3:21])=[O:7]
Reactant: CC(C)(N)CCc1ccc(C(=O)O)cc1
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(CCC(C)(C)N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thionyl chloride (31 ml) was added dropwise to methanol (210 ml) at -70°. The solution was stirred for 10 mins and then 3-(4-carboxyphenyl)-1, 1-dimethylpropanamine hydrochloride (20 g) in methanol was added dropwise. The reaction mixture was allowed to warm to ambient temperature and then heated under reflux for 1 h. The solvent was evaporated, the residue partitioned between potassium carbonate and ether and the organic layer dried. Removal of the solvent gave the title compound, as an oil.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.CCN(C(C)C)C(C)C>CCO>[CH3:14][C@H:15]1[CH2:20][N:19]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
To a microwave vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (from Example 9, step 3) (47.8 mg, 0.164 mmol) and tert-butyl [(3S,5R)-5-methylpiperidin-3-yl]carbamate (33.7 mg, 0.157 mmol), EtOH (1.00 mL) was added, followed by DIPEA (41.5 mg, 0.321 mmol). The mixture was heated under microwave irradiation at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a yellow solid (44.5 mg, 75%). LCMS calc. for C18H27N4O5 (M+H)+: m/z=379.2. found 379.2.
Reaction SMILES: C(OC([N:11]1[C@H:20]([C:21](O)=O)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.C(OC([N:34]1[C@@H:43]([C:44]([OH:46])=O)CC2[C:36](=CC=CC=2)[CH2:35]1)=O)C1C=CC=CC=1>>[N:34]1([CH2:21][C@H:20]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][NH:11]2)[CH2:35][CH2:36][O:46][CH2:44][CH2:43]1
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1
Reactant: O=C(O)[C@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1
Product: c1ccc2c(c1)CN[C@@H](CN1CCOCC1)C2

Procedure:
The procedure is in accordance with the process of Preparation 1′, replacing the (3S)-2-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid used in Step A by (3R)-2-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10](O)[CH:11]=1)=[O:5])[CH3:2].P(Br)(Br)([Br:19])=O.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH3:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10]([Br:19])[CH:11]=1)=[O:5])[CH3:2]
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)c1cc(O)nc2[nH]nc(C)c12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Br)nc2[nH]nc(C)c12
Temperature: 110 °C
Reaction time: 5 h
Yield: 26.1 %

Procedure:
A mixture of 6-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (13.7 g) and phosphorous oxybromide (19.5 g) in toluene (300 mL) was stirred at 110° C. for 5 h, cooled to r.t., and added dropwise into an ice cold solution of potassium acetate (18.2 g) in water (300 mL). The mixture was extracted twice with ethyl acetate, the combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in a membrane pump vacuum. 6-Bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (4.6 g, 26% yield) was obtained. This material was dissolved in THF (60 mL), and 3,4-dihydro-2H-pyran (1.6 mL) and p-toluenesulfonic acid monohydrate (0.91 g) was added. The solution was stirred at r.t. for 48 h, then 3,4-dihydro-2H-pyran (1.6 mL) was added and the solution stirred again for 48 h. The mixture was poured into water and extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated in a membrane pump vacuum. The residue was purified by flash chromatography (silica, heptane/ethyl acetate gradient). 6-Bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (2.2 g, 38%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+].[CH3:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](OC)=[O:29].Cl>O1CCCC1.O>[CH3:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](=[O:29])[CH2:17][C:16]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:2]([CH3:1])[CH:3]=1)=[O:18]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Reactant: COCCOc1ccccc1C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1ccccc1C(=O)CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Temperature: 25 °C
Yield: 16.9 %

Procedure:
To a solution of 1-{3-methyl-4-[(phenylmethyl)oxy]phenyl}ethanone (0.81 g, 3.4 mmol) in tetrahydrofuran (11 mL) was added sodium hydride (0.27 g, 6.7 mmol) followed by methyl 2-{[2-(methyloxy)ethyl]oxy}benzoate (0.70 g, 3.4 mmol, Harkin, S. H.; Wells, N. S., GB Patent 2250511, 1992) and the resultant mixture was heated in a 60° C. oil bath for 12 h. The solution was allowed to cool to room temperature and was diluted with water then 1M aqueous hydrochloric acid. The mixture was extracted (3× ethyl acetate) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 5:1 hexanes/ethyl acetate) gave 0.24 g (17%) of 1-(2-{[2-(methyloxy)ethyl]oxy}phenyl)-3-{3-methyl-4-[(phenylmethyl)oxy]phenyl}propane-1,3-dione as a colorless oil. 1H NMR (400 MHz, CDCl3): 8.01 (dd, 1H), 7.89 (m, 2H), 7.34-7.45 (m, 7H), 7.08 (t, 1H), 6.97 (d, 1H), 6.92 (d, 1H), 5.17 (s, 2H), 4.24 (m, 2H), 3.85 (m, 2H), 3.42 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.O(C(C)(C)C)[Na].Br[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[ClH:37]>COCCOC>[ClH:37].[O:30]([CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: CC(C)(C)O[Na]
Agent: Cl
Solvent: COCCOC
Product: c1ccc(OCCOc2ccccc2N2CCNCC2)cc1
Temperature: 55 °C
Reaction time: 0.08 h

Procedure:
The product from Step 1 above (0.55 g, 2.0 mmol) was added to a stirred solution of NaO-t-Bu (0.55 g, 2.0 mmol) in DME (5 mL). After 5 min, β-bromophenetole (0.56 g, 2.8 mmol) was added, and the reaction was stirred at 55° C. for 15 h. 2 M HCl was added, and the reaction mixture was stirred for another 3 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between 2 M NaOH/CHCl3. The aqueous phase as extracted with CHCl3 (×3). The combined organic lasers were dried (MgSO4), concentrated, and the residue was purified by chromatography on silica gel using CHCl3/MeOH/NH4OH (90:10:0.4) as eluent to give the free base of the title compound. The free base was treated with HCl/ether, and the resulting hydrochloride salt was dried (80° C., 1 mmHg) to afford 0.254 g (35%) of the title compound as a light brown semi-solid material that solidified upon standing. Anal. (C18H22N2O2.HCl.H2O) H, N; C. calc, 61.27; found, 61.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[CH:11]1([C:16](O)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:16]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:9][CH3:10])[CH:5]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)C1CCCC1
Reactant: COc1ccccc1OC
Product: COc1ccc(C(=O)C2CCCC2)cc1OC
Temperature: 60 °C
Reaction time: 24 h
Yield: 116.1 %

Procedure:
To polyphosphoric acid (76 g) was added 1,2-dimethoxybenzene (7.9 g, 0.057 mol) followed by cyclopentanecarboxylic acid (9.8 g, 0.086 mol). The mixture was stirred at 60° C. during 24 hours then cooled down to −5° C. and quenched by the addition of 200 ml ice/water followed by 100 ml of ether. After stirring at room temperature for 3 hours, the two layers were separated and the aqueous phase extracted with three 100 ml portions of ether. The two ethereal phases were combined, washed with 50 ml of NaOH and 50 ml of brine and dried over MgSO4. Filtration and concentration gave 15.5 g of dark brown oil. This oil was purified by vacuum distillation (180-190° C., 0.03 mbar) through a short path to give 11.8 g (88%) of a white solid.