Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[CH:12](OC)([O:15][CH3:16])[O:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:14][O:13][CH:12]([O:15][CH3:16])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCC=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCCCCCCCC(OC)OC

Procedure:
Decanal dimethyl acetal was prepared by reacting 796 g decanal with 763.5 g trimethyl orthoformate in the presence of 1.97 g p-toluene sulfonic acid dissolved in 6.07 g methanol at a temperature of 45° C. for a period of time of 0.33 hours. The resulting product was washed with an aqueous 2.5% sodium bicarbonate solution, and then with water; dried over anhydrous sodium sulfate; filtered through CELITE®/sodium sulfate and distilled at 92–98° C. at 4.36–4.97 mm Hg. Then, into a 2 liter reaction flask equipped with stirrer, thermometer, heating mantle, addition funnel, vacuum apparatus, and reflux condenser the following ingredients were added at 17° C.:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([NH:12]C(=O)OC(C)(C)C)=[CH:7][C:6]=2[C:5]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:4]=2[N:3]=1.ClC1C=C(NC(=O)OC(C)(C)C)C=NC=1C#N>>[CH3:24][C:22]1[CH:21]=[CH:20][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:23]=1)[N:10]=[CH:9][C:8]([NH2:12])=[CH:7]3
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(NC(=O)OC(C)(C)C)cc12
Agent: CC(C)(C)OC(=O)Nc1cnc(C#N)c(Cl)c1
Product: Cc1ccc2c(c1)nc(N)c1ncc(N)cc12

Procedure:
8-methylbenzo[f][1,7]naphthyridine-2,5-diamine was prepared (as minor product) together with tert-butyl 5-amino-8-methylbenzo[f][1,7]naphthyridin-2-ylcarbamate (as major product) from tert-butyl 5-chloro-6-cyanopyridin-3-ylcarbamate (from the previous step) following the procedures described for Example 5/Step 2. 1H NMR (DMSO-d6): δ 10.11 (s, 1H), 9.02 (s, 1H), 8.82 (d, 1H), 8.06 (d, 1H), 7.34 (s, 1H), 7.15 (dd, 1H), 6.99 (s, 2H), 2.44 (s, 3H). LRMS [M+H]=225.1
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][CH2:11][CH2:12][CH:13]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:29]([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:29]([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:25](=[O:27])[C@H:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[NH2:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCC(N)C(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCC(N)C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 8 h

Procedure:
All the obtained oily t-butyloxycarbonyl-ε-carbobenzoxy-L-lysine and L-proline benzylester hydrochloride (4.3 g, 17.8 m mole) were dissolved in methylene dichloride and WSC (3.3 ml, 17.8 m mole) was added thereto while cooling to -15° C. The mixture was stirred overnight and the methylene dichloride solution was distilled under reduced pressure leaving a residue. The residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order, and dried with anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure to obtain an oily t-butyloxycarbonyl-ε-carbobenzoxy-L-lysyl-L-proline benzylester.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([B:18]3[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]3)[C:13]=2[CH3:27])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C1N=CN([C:33](N2C=NC=C2)=[O:34])C=1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[C:3]2[N:4]([C:33](=[O:34])[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([B:18]4[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:26])([CH3:25])[O:19]4)[C:13]=3[CH3:27])[C:9](=[O:10])[CH:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(NC(=O)Cc2ncccc2F)cccc1B1OC(C)(C)C(C)(C)O1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2c(F)cccn2c1=O
Temperature: 120 °C
Yield: 65 %

Procedure:
A mixture of 2-(3-fluoropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (9.01 g, 24.3 mmol) and CDI (15.78 g, 97 mmol) in toluene (97 mL) was heated at 120° C. for 7 h. The cooled mixture was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel (220 g), eluting with EtOAc-hexanes (gradient from 20-100%), to provide 5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as a yellow solid (6.26 g, 65% yield). Mass spectrum m/z 397 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.11 (dd, J=7.6, 0.8 Hz, 1H), 7.94 (dd, J=7.5, 1.3 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.23 (dd, J=7.8, 1.4 Hz, 1H), 6.85-6.76 (m, 1H), 6.35 (td, J=7.4, 5.0 Hz, 1H), 6.09 (s, 1H), 2.36 (s, 3H), 1.36 (s, 12H).
Reaction SMILES: [N:1]([CH:4]([CH3:28])[CH2:5][O:6][CH:7]1[CH2:27][CH2:26][C:10]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]4[CH2:24][CH2:23]4)=[C:16]([F:25])[CH:15]=3)[O:13][C:9]=2[CH2:8]1)=[N+]=[N-].C1C[O:32][CH2:31][CH2:30]1>[C].[Pd]>[CH:22]1([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]3[O:13][C:9]4[CH2:8][CH:7]([O:6][CH2:5][CH:4]([NH:1][C:31](=[O:32])[CH3:30])[CH3:28])[CH2:27][CH2:26][C:10]=4[N:11]=3)=[CH:15][C:16]=2[F:25])[CH2:24][CH2:23]1
Reactant: C1CCOC1
Reactant: CC(COC1CCc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2C1)N=[N+]=[N-]
Agent: [Pd]
Product: CC(=O)NC(C)COC1CCc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-(2-azidopropoxy)-2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,5,6,7-tetrahydro-1,3-benzoxazole (870 mg), 10% palladium-carbon (containing water (50%), 800 mg) and THF (10 mL) was stirred at room temperature for 10 min. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. To the obtained residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound (725 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:16]I.O>C1COCC1>[C:3]([O:7][C:8]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13][CH3:16])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 25.9 %

Procedure:
A suspension of 60% NaH (635.7 mg, 15.89 mmol) in THF (10 ml) was cooled to 0° C. To the mixture was added a solution of 2-t-butoxycarbonylamino-2-methyl-1-propanol (1.5398 g, 8.14 mmol) in THF (5 ml) dropwise, and stirred for 1.5 hours. To the mixture was added a solution of methyl iodide (0.50 ml, 8.03 mmol) in THF (5 ml) dropwise at 0° C., and stirred for 2.5 hours. The reaction mixture was added to water and extracted three times with ethyl acetate. The extract was dried over MgSO4, concentrated and purified by silica gel chromatography (hexane/ethyl acetate=5/1-0/1) to give the title compound (422 mg; 26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[N:7]([CH2:10][C:11]3[CH:22]=[CH:21][C:14]4[N:15]=[C:16](S(C)=O)[O:17][C:13]=4[CH:12]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.[CH:27]1([CH2:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH:27]1([CH2:33][NH:34][C:16]2[O:17][C:13]3[CH:12]=[C:11]([CH2:10][N:7]4[C:6]5[CH:23]=[C:24]([O:25][CH3:26])[C:3]([O:2][CH3:1])=[CH:4][C:5]=5[N:9]=[CH:8]4)[CH:22]=[CH:21][C:14]=3[N:15]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1cc2ncn(Cc3ccc4nc(S(C)=O)oc4c3)c2cc1OC
Reactant: NCC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc2ncn(Cc3ccc4nc(NCC5CCCCC5)oc4c3)c2cc1OC
Temperature: 90 °C
Yield: 29.4 %

Procedure:
A stirred mixture of 6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (60 mg, 0.162 mmol), cyclohexylmethylamine (36 mg, 0.323 mmol), and DIEA (63 mg, 0.485 mmol) in anhydrous DMA (2 mL) was heated at 90° C. for 15 h. After cooling to rt, the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc), CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford N-(cyclohexylmethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-amine (20 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.99 (t, J=5.7 Hz, 1H), 7.37 (s, 1H), 7.11-7.24 (m, 4H), 5.42 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H), 3.11 (t, J=6.2 Hz, 2H), 1.50-1.79 (m, 7H), 1.07-1.26 (m, 2H), 0.81-1.00 (m, 2H). LCMS (ESI) m/z 421 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]([C:50]([O:52]C(C)(C)C)=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:41][C@H:42]([C:50]([OH:52])=[O:51])[CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[O:37])=[CH:31][CH:32]=2)=[CH:39][CH:40]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@@H](Cc3ccccc3)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-Phe-OtBu HCl (52 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ12.22-12.98 (br.s, 1 H), 8.95 (s, 1 H), 8.10 (d, 1 H), 7.22 (m, 12 H), 7.10 (d, 2 H), 7.04 (t, 1 H), 6.96 (m, 2 H), 6.87 (m, 4 H), 4.45 (m, 1 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 3.06 (dd, 1 H), 2.91 (s, 3 H), 2.84 (dd, 1 H), 2.42 (t, 2 H), 2.39 (s, 3 H), 2.06 (m, 2 H), 1.68 (m, 2 H); MS (APCI+) m/z 706 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.Cl.NO.[N:38]1C=CC=CC=1.C(O)C>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]#[N:38])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:32][CH:33]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C#N)cc1
Yield: 67.1 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), hydroxylamine hydrochloride (0.14 g), pyridine (0.26 g) and ethanol (20 mL) was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Acetic anhydride (20 mL) was added to residue, and the mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbonitrile as colorless crystals (0.40 g, 68%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 158-159° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])(=O)C.[NH4+:17]>>[NH2:17]/[C:3](/[C:2]([F:12])([F:11])[F:1])=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CCOC(=O)/C=C(\N)C(F)(F)F
Temperature: 85 °C

Procedure:
To a stirred ethyl trifluoroacetoacetate (87.8 g, 0.48 mol) at 85° C., ammonium acetate (74 0 g, 0.96 mol) was added in portions over 1 hour such that efficient stirring of the mixture was maintained. The mixture was heated at 85° C. for an additional 4 hours. After this period, GC analysis of the reaction mixture showed that the all the ethyl trifluoroacetoacetate had been consumed and the yield of ethyl 3-amino-4,4,4-trifluorocrotonate was greater than 98%.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1.[C:15]1([C@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO.C(OC(C)C)(C)C>CN(C)C=O.C(O)C>[C:15]1([C@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)Cc1coc2cc(O)ccc12
Agent: C[C@@H](N)c1ccccc1
Solvent: CCO
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)C[C@@H]1COc2cc(O)ccc21
Temperature: 35 °C
Reaction time: 18 h
Yield: 57.9 %

Procedure:
To (6-hydroxy-1-benzofuran-3-yl)acetic acid (2.80 g) and dichloro[(+)-1,2-bis((2R,5R)-2,5-diisopropylphosphorano)benzene]ruthenium (II)-N,N-dimethylformamide complex (2.1 mg) were added (1R)-1-phenylethylamine (1.77 g) and deaerated methanol (28 mL), and the mixture was stirred at 35° C. for 18 hr under a hydrogen atmosphere (0.85 MPa). The mixture was allowed to cool to room temperature, and concentrated under reduced pressure. To the concentrated residue were added ethanol (14 mL) and N,N-dimethylformamide (7.7 mL), and the mixture was dissolved by heating to 70° C. While maintaining the same temperature, diisopropyl ether (28 mL) was added dropwise. The mixture was cooled to 5° C. and stirred for 1 hr, and the solid was collected by filtration, washed with diisopropyl ether-methanol (4:1, 6 mL), and dried at 50° C. under reduced pressure to give a crude resultant product (3.58 g). To the crude product (3.00 g) were added ethanol (15 mL) and N,N-dimethylformamide (6 mL), and the mixture was dissolved by heating to 60° C. While maintaining the same temperature, diisopropyl ether (39 mL) was added dropwise, and the mixture was cooled to 5° C. The mixture was stirred at the same temperature for 2 hr, and the solid was collected by filtration, washed with diisopropyl ether-methanol (4:1, 6 mL), and dried at 50° C. under reduced pressure to give the title compound (2.66 g). 99.7% de. (high performance liquid chromatography conditions) column: CHIRALPAK AD-H (manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:22][C:23]#[N:24])[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CO.CC(O)=O.O=[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:22][CH2:23][NH2:24])[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CC#N)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1(CCN)CCN(S(=O)(=O)c2ccccc2Cl)CC1

Procedure:
1-(2-Chloro-benzenesulfonyl)-4-cyanomethyl-piperidine-4-carboxylic acid ethyl ester (8.5 g) dissolved in MeOH/AcOH (1:1, 250 ml) was hydrogenated over PtO2 (2.6 g) for 4 h at atmospheric pressure until full conversion (control by thin layer chromatography). The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in AcOEt and washed with 1M aqueous NaOH then with brine. The organic layer was dried over magnesium sulphate, the solvent removed in vacuo to give the desired product, crude light yellow oil (7.09 g), as a mixture together with some already spirocyclised amide. MS (ESI): 375.1 MH+). The crude material was directly used as such in the subsequent ring closure reaction.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=[C:4]([N:22]=[N+:23]=[N-:24])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCn2cnc3c(N=[N+]=[N-])nc(N)nc32)CO1
Temperature: 105 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.47 g, 1.5 mmol) in dry N,N-dimethylformamide (5 ml), sodium azide (0.20 g, 3.0 mmol) was added and the mixture was stirred at 100-110° C. for 4 hours. The solvent was removed and the residue washed with water to leave 2-amino-6-azido-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine as a crystalline solid (0.36 g, 75%), m.p. decomposed at 200° C.; λmax (MeOH) 272 (ε 8,210) and 301 (ε 10,100) nm; νmax (KBr) 1670, 1625, and 1560 cm−1; δH (CDCl3-CD3OD) 1.44 (6H, s, C(CH3)2), 1.6-2.2 (3H, m, CH2CHCH2), 3.5-3.8 (2H, dd (ABX), J 7 Hz and J 11 Hz, 2×Hax), 3.85-4.15 (2H, dd (ABX), J 4 Hz and J 11 Hz, 2×Heq), 4.29 (2H, t, J 7 Hz, CH2N), and 7.93 (1H, s, 8-H) (Found: C, 48.96; H, 5.66; N, 35.15%; M+ 318.1553. C13H18N8O2 requires C, 49.05; H, 5.70; N, 35.20%; M+ 318.1546).
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[NH:9][C:8]=2[CH:7]=[C:6]([F:32])[CH:5]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[F:32][C:6]1[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)=[CH:15][CH:14]=3)[NH:9][C:8]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3nc4c(C(N)=O)cc(F)cc4[nH]3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cc(F)cc2[nH]c(-c3ccc(C4CCNCC4)cc3)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
A mixture of EXAMPLE 88C (0.26 g, 0.6 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL) and the mixture stirred at ambient temperature for 4 hours. The mixture was concentrated and purified by flash chromatography on silica gel using 0-10% methanol/dichloromethane/0.1% ammonium hydroxide, followed by HPLC on a C18 column using 0-100% acetonitrile/water/0.1% trifluoroacetic acid, to provide the title compound (0.131 g) as the trifluoroacetate salt. 1HNMR (DMSO-D6) δ 9.22 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 8.21 (d, J=8.3 Hz, 2H), 7.94 (s, 1H), 7.55-7.62 (m, 2H), 7.45 (t, J=7.7 Hz, 2H), 3.40 (s, 2H), 2.99-3.07 (m, 2H), 1.99 (s, 2H), 1.78-1.90 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](O)=[O:5].O>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(F)cc(F)cc1F
Solvent: C1CCOC1
Solvent: O
Product: OCc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a stirred solution of 4.1 grams (0.023 mole) of 2,4,6-trifluorobenzoic acid in 50 ml of anhydrous tetrahydrofuran, under a nitrogen atmosphere was added dropwise 4.0 grams (0.047 mole) of borane-tetrahydrofuran complex (as 46.6 ml of a 1.0 molar solution in tetrahydrofuran). The addition caused the reaction mixture to foam. Upon completion of addition the reaction mixture was stirred at ambient temperature for two hours, then was heated under reflux for one hour. The reaction mixture was cooled and 50 ml of water was cautiously added. The tetrahydrofuran was removed under reduced pressure and the residue washed into a separatory funnel with 100 ml of aqueous 2N sodium hydroxide. The mixture was extracted with three 100 ml portions of methylene chloride. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 3.2 grams of 2,4,6-trifluorophenylmethyl alcohol as an oil.
Reaction SMILES: Cl[C:2]([C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:4].[CH3:26][O-:27].[Na+]>CO>[CH3:25][O:24][C:18]1[CH:19]=[C:20]([O:22][CH3:23])[N:21]=[C:16]([C:2]([O:27][CH3:26])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:4])[N:17]=1
Reactant: COc1cc(OC)nc(C(Cl)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC)nc(C(OC)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Yield: 67.9 %

Procedure:
2-Chloro-2-(4,6-dimethoxypyrimidin-2-yl)-N-methanesulfonyl-2-phenylacetamide (0.7 g) was boiled under reflux with sodium methoxide (0.2 g) in methanol (30 ml) for 5 hours. The methanol was evaporated off under vacuum. The residue was treated with ether and the precipitated sodium salt was taken into water. The aqueous solution was washed with ether, fresh ether was added, and the whole was acidified with hydrochloric acid. A white solid crystallised from the ether layer. This was filtered off, washed with water and a little ether, and dried to give 0.47 g of the desired product, mp 155°-7° C.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH2:25]>>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH:25][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: NCCc1ccccn1
Product: O=c1[nH]c2ncccc2c2cc(NCCc3ccccn3)ccc12
Yield: 4.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 456 using 6 (162 mg, 0.70 mmol) and 2-(pyridin-2-yl)ethanamine (343 mg, 2.81 mmol) to provide 477 (10 mg, 5% yield) as a white powder. LC-MS (M+H=317, obsd.=317). 1H NMR (400 MHz, DMSO-D6) δ 11.52 (s, 1H), 8.73 (dd, J=6.6, 27.5, 2H), 8.44 (d, J=4.7, 1H), 8.15 (m, 1H), 8.00 (d, J=8.8, 1H), 7.63 (m, 2H), 7.19 (m, 2H), 6.97 (t, J=43.4, 1H), 3.71 (t, J=6.9, 2H), 3.25 (t, J=6.8, 2H).