Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:4].[CH3:17][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:16])[C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:17])=[O:11])=[CH:13][CH:14]=1)=[O:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(NC(=O)C(F)(F)F)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(=O)C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
step b To a solution of 120 (4.29 g, 18.40 mmol) in MeOH (50 mL) and toluene (75 mL) was added dropwise trimethylsilyldiazomethane (15.64 mL, 31.3 mmol) until the yellow color persisted. The resulting solution was stirred for 30 min then the reaction was quenched with several drops of HOAc until the yellow color disappeared. The solvents were evaporated to afford methyl 4-(2,2,2-trifluoro-acetylamino)-benzoate (122) which was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[IH:10].C([O-])(O)=O.[Na+]>>[I:10][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9]
Reactant: I
Reactant: Nc1ncnc(Cl)c1N
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ncnc(I)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
6-Chloropyrimidine-4,5-diamine (Intermediate 88) (90 mg) was added slowly to HI (57%, aq) (2 mL) at 0° C. The reaction mixture was allowed to stir at 0° C. for 30 minutes and then at ambient temperature for 24 hours. NaHCO3 (sat aq.) was added dropwise until the reaction mixture was pH 8. The product was extracted with EtOAc (3×15 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a grey solid (144 mg, 98%);
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.C(OC([N:30]1[C:34]([C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:33][CH:32]=[C:31]1B(O)O)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:1][C:2]1[C:21]([C:31]2[NH:30][C:34]([C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:33][CH:32]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Reactant: CN(C)C(=O)c1ccc(B(O)O)n1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN(C)C(=O)c1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2Cl)[nH]1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
6-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 48.3, 257 mg, 0.560 mmol), (1-(tert-butoxycarbonyl)-5-(dimethylcarbamoyl)-1H-pyrrol-2-yl)boronic acid (Stage 73.2, 200 mg, 0.709 mmol), Pd(Ph3P)4 (64.7 mg, 0.056 mmol), Na2CO3 (237 mg, 2.240 mmol), water (560 μL) and DME (2.240 mL) were added to a MW vial, which was sealed, evacuated/purged with argon and stirred at 80° C. for 16 h. The RM was diluted with MeOH (1 mL)/DCM (2 mL), treated with Si-Thiol (194 mg, 0.280 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane-DCM (4:1)/EtOAc, from 5% to 50% EtOAc) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=1.16 min, m/z=469.1 [M+H]+, m/z=513.0 [M+FA+H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.98-3.28 (m, 6H) 6.69-6.75 (m, 1H) 6.76-6.81 (m, 1H) 7.40 (d, J=9.17 Hz, 2H) 7.85-7.93 (m, 2H) 8.62 (d, J=2.32 Hz, 1H) 8.81 (d, J=2.32 Hz, 1H) 10.65 (s, 1H) 11.89 (br. s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=3)[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:30])[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[CH:40]1([Mg]Br)[CH2:42][CH2:41]1>C1COCC1.[NH4+].[Cl-]>[CH:40]1([C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH2:21][C:20]2[CH:37]=[CH:38][CH:39]=[C:18]([C:16]3[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:4])=[O:3])([CH3:7])[CH3:6])[CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)[CH:19]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[OH:30])[CH2:42][CH2:41]1
Reactant: Br[Mg]C1CC1
Reactant: CC(C)(c1cc(-c2cccc(COc3ccccc3C(=O)c3ccccc3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(c1cc(-c2cccc(COc3ccccc3C(O)(c3ccccc3)C3CC3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To solution of (2-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzyloxy}-phenyl)-phenyl-methanone (EXAMPLE 74) (1.0 eq) in THF (0.03M) was added CeCl3 (2.7 eq). The resulting mixture was stirred for 1 h, then cooled to −78° C. Cyclopropyl magnesium bromide (0.24M in THF; 4.8 eq) was added and the final mixture was allowed to warm-up to room temperature. After stirring for 1 h the mixture was poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 40 to 100% in 15 min) afforded the title compound as a foam.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]([CH3:10])[C:6]([O:8]C)=[O:7].P([O-])([O-])([O-])=O.Cl>C(Cl)Cl>[F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][C@H:5]([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: C[C@@H](Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 30 °C

Procedure:
Methyl 2-(2,3,4-trifluoroanilino)propionate (1.0 g) was suspended in a 0.1 M phosphate buffer solution (pH 6.5; 200 ml). After adding α-chymotrypsin (manufactured by Sigma; 0.2 g), the mixture was gently stirred. The mixture was further stirred for 16 hours while maintaining at 30° C. After adding methylene chloride, the liquid reaction mixture was filtered through celite to eliminate denatured protein and then separated. The organic layer was washed with a 5% aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. Next, the solvent was evaporated under reduced pressure to thereby give methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (0.43 g). The optical purity of this product was 98% ee. On the other hand, the all aqueous layers obtained by the separation were combined and adjusted to pH 2 with 10% hydrochloric acid followed by extraction with IPE. The organic layer was dried over anhydrous magnesium sulfate and evaporated. Thus, the title compound was obtained as a crude product (0.47 g). The optical purity of this product was 92% ee. Further, the crude product was recrystallized from a solvent mixture of isopropyl ether with hexane. Thus, the title compound of 100% ee was obtained. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 29.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.CN([CH2:18][C:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)C>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:14][CH2:13][N:12]([CH2:18][C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: COc1ccc(C2=CCNCC2)cc1
Solvent: CC(C)O
Product: COc1ccc(C2=CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Yield: 41 %

Procedure:
4-(4-Methoxyphenyl)-1,2,3,6-tetrahydropyridine (540 mg, 2.8 mmol) was reacted with 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.8 mmol) as in Example 4 to give the title compound (367 mg, 41%) as tan crystals, m.p. 202°-204° C. (iPrOH); (Found: C, 73.51; H, 6.74; N, 12.15. C20H21N3O.0.33 H2O.0.2 C3 H8O requires C, 73.34; H, 6.95; N, 12.45%); δH (DMSO-d6) 2.44 (2H, m, tetrahydropyridinyl CH2), 2.70 (2H, m, tetrahydropyridinyl CH2), 3.10 (2H, m, tetrahydropyridinyl CH2), 3.74 (3H, s, ArOCH3), 3.76 (2H, s, ArCH2N), 6.04 (1H, m, CH=CR), 6.90 (2H, d, J 8.6 Hz, ArH), 7.04 (1H, dd, J 7.7, 4.6 Hz, 5-H), 7.36 (2H, d, J 8.5 Hz, ArH), 7.40 (1H, s, 2-H), 8.06 (1H, d, J 7.7 Hz, 4-H), 8.20 (1H, d, J 4.6 Hz, 6-H), and 11.48 (1H, br s, NH); m/z (CI+, NH3) 320 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.Cl>C(OCCO)C>[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: O
Solvent: CCOCCO
Product: COc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
5.0 g (32 mmol) of 2-chloro-3-nitropyridine was dissolved in 2-ethoxyethanol (150 mL), and water (150 mL) was added thereto. To the mixed solution, 3.9 g (32 mmol) of 4-methoxyaniline and 6 N hydrochloric acid (1 mL) were added, and the mixture was heated to reflux for 12 hours while stirring. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and washed with saturated brine, and then the obtained organic layer was dried over anhydrous magnesium sulfate. The inorganic matter was separated by filtration, and then the solvent was distilled off under reduced pressure, to obtain 6.6 g (yield: 85%) of N-(4-methoxyphenyl)-3-nitropyridin-2-amine as orange-colored crystals.
Reaction SMILES: [OH:1][NH:2][CH:3]([CH:35]([CH3:37])[CH3:36])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[O:23])[CH:15]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].[C:38](O)(=[O:40])[CH3:39].C(OC(=O)C)(=O)C>C1COCC1>[C:38]([N:2]([OH:1])[CH:3]([CH:35]([CH3:37])[CH3:36])[CH2:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[O:23])[CH:15]=2)=[CH:12][CH:13]=1)(=[O:6])=[O:7])(=[O:40])[CH3:39]
Reactant: CC(=O)O
Reactant: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)NO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(O)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a suspension of N-[(4′-{[2-(hydroxyamino)-3-methylbutyl]sulfonyl}biphenyl-3-yl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 107 (0.100 g, 0.192 mmol) and acetic acid (2 mL) in THF (20 mL) was added acetic anhydride (0.018 mL, 0.192 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from EtOH-ethyl acetate-diethyl ether-hexane to give the title compound as a white powder (0.085 g, 79%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6]O.[C:8](#[N:11])C=C.[CH2:12](O)[CH3:13]>>[N:1]12[CH2:13][CH2:12][CH2:6][C@H:2]1[CH2:3][CH:4]([C:8]#[N:11])[CH2:5]2
Reactant: CCO
Reactant: OC[C@@H]1CCCN1
Reactant: C=CC#N
Product: N#CC1C[C@@H]2CCCN2C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In 13 ml of ethanol, 4.71 g of (S)-2-pyrrolidinemethanol was dissolved, followed by the addition of 4.6 ml of acrylonitrile. The resulting mixture was heated under reflux for 2 hours. After the solvent was evaporated, the residue was dissolved in 70 ml of toluene, followed by the addition of 13 ml of triethylamine under ice-cooling. To the resulting mixture, 4.3 ml of methanesulfonyl chloride was added dropwise, followed by stirring at 0° C. for 10 minutes and then at room temperature for 30 minutes. After the addition of 15.7 g of potassium tert-butoxide, the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the toluene layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated and the resulting residue was subjected to silica gel column chromatography, whereby 5.22 g of (5S)-1-azabicyclo[3.3.0]octane-3-carbonitrile was obtained as a diastereomer mixture from the fraction eluted with chloroform-methanol-29% aqueous ammonia (100:10:1).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[CH:12][C:11]=1[CH3:20])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=[O:25])[CH2:24][CH2:23][CH2:22]1>CCCCCC.[Li]CCCC.C1COCC1>[Si:5]([O:8][CH2:9][C:10]1[C:11]([CH3:20])=[CH:12][CH:13]=[C:14]([O:16][CH2:17][O:18][CH3:19])[C:15]=1[C:21]1([OH:25])[CH2:24][CH2:23][CH2:22]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: COCOc1ccc(C)c(CO[Si](C)(C)C(C)(C)C)c1
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C)c(CO[Si](C)(C)C(C)(C)C)c1C1(O)CCC1
Reaction time: 2 h
Yield: 13.7 %

Procedure:
To a solution of tert-butyl-[[5-(methoxymethoxy)-2-methyl-phenyl]methoxy]-dimethyl-silane (Intermediate 174, 0.3 g, 1 mmol) in hexane (5 ml), BuLi (1.6M in hexane, 0.9 ml, 1.4 mmoli) was added at room temperature. The reaction mixture was stirred for 2 h and then added dropwise at −30° C. to a suspension of CeCl3 (0.37 g, 1.5 mmoli) in dry THF (5 ml) that was previously stirred at room temperature overnight. After 45 min at −30° C., cyclobutanone (0.07 g, 1 mmoli) dissolved in THF (1 ml) was added. The reaction was stirred at the same temperature for and then quenched with ammonium chloride (20 ml) and extracted with Ethyl Acetate (2×20 ml). Combined organic layers were dried over Na2SO4 and evaporated under vacuum to afford a colorless oil that was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 75:25 as eluents affording the title compound (0.05 g) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3CC[C@@H]12
Yield: 56.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 4-trifluoromethylphenylboronic acid (148 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 137 mg (56%) of the title compound as a white solid. mp 86°-89°. FDMS: m/e=373 α[D]589 =+28.90 (c =1.04, chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Br:10].P([O-])(OCC)(SCC)=[S:12].Cl>C(O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[S:12])[NH2:7])=[CH:4][C:3]=1[Br:10]
Reactant: CCOP([O-])(=S)SCC
Reactant: N#Cc1ccc(N)c(Br)c1
Agent: Cl
Solvent: CCO
Product: NC(=S)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.6 %

Procedure:
A stirred solution of 4-amino-3-bromobenzonitile (6.92 g, 35.1 mmol) and diethyl dithiophosphate (17.7 mL 105 mmol, 3 eq.) in absolute ethanol (160 mL) at 0° C. was perfused with hydrogen chloride gas at a moderate rate for 30 minutes. The resulting reaction mixture was stirred at room temperature for 12 hours, and then solvent was removed via evaporation under reduced pressure. The residue was suspended in a saturated solution of sodium hydrogen carbonate (25 mL), and this aqueous mixture was extracted with ethyl acetate (3×25 mL). The organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure. The residue was chromatographed using silica gel (approximately 300 g) and elution with an acetone gradient in methylene chloride [1:50 to 1:20] to afford the title compound (1.02 g, 25%) as an amorphous yellow solid: 1H NMR (DMSO-d6) δ 9.41 (br s, NH), 9.13 (br s, NH), 8.11 (d, J=2.1 Hz, 1H), 7.78 (dd, J=2.1 and 8.6 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 6.03 (s, 2NH); TLC: RBf =0.15[1% diethyl ether in methylene chloride].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:18]3[CH2:24][CH:23]4[N:25](C)[CH:20]([CH2:21][CH2:22]4)[CH2:19]3)[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.BrC1C=CC2N(C3CC4N(C)C(CC4)C3)C3C(SC=2C=1)=CC=CC=3>>[CH:23]12[NH:25][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]([N:6]1[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][C:14]=3[S:13][C:12]3[C:7]1=[CH:8][CH:9]=[CH:10][C:11]=3[O:16][CH3:17])[CH2:24]2
Reactant: COc1cccc2c1Sc1cc(Br)ccc1N2C1CC2CCC(C1)N2C
Agent: CN1C2CCC1CC(N1c3ccccc3Sc3cc(Br)ccc31)C2
Product: COc1cccc2c1Sc1cc(Br)ccc1N2C1CC2CCC(C1)N2

Procedure:
Using an adaptation of the method described in Procedure 21, substituting 3-bromo-6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine, 3cc for 3-bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine, 3i, the title compound 10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-bromo-6-methoxy-10H-phenothiazine, 4cc was obtained a mixture of endo and exo isomers.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[C:15](=[CH2:16])[C@H:14]([CH2:17][OH:18])[C@@H:13]([OH:19])[C@@H:12]1[F:20].[C:21]([CH:24]([CH:26]([C:28]([O-:30])=O)[OH:27])[OH:25])([O-])=[O:22].[Na+].[K+]>C(Cl)Cl.C(O)(C)C.C(Cl)(Cl)Cl>[C@@H:11]1([N:6]2[C:7]3[N:8]=[CH:9][N:10]=[C:2]([NH2:1])[C:3]=3[N:4]=[CH:5]2)[O:27][C@H:26]([CH2:28][OH:30])[C@@H:24]([OH:25])[C@H:21]1[OH:22].[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[C:15](=[CH2:16])[C@H:14]([CH2:17][OH:18])[C@@H:13]([OH:19])[C@@H:12]1[F:20]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: C=C1[C@@H](n2cnc3c(N)ncnc32)[C@@H](F)[C@H](O)[C@H]1CO
Agent: [K+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(+)-(1R,2R,3R,5R)-3-(6-amino-9H-9-purinyl)-2-fluoro-5-(hydroxymethyl)-4-methylenecyclopentan-1-ol (15) Diisobutylaluminum hydride (DIBAL-H, 1.6 mL, 1.0 M in toluene) was added slowly into the solution of compound 14 (160.0 mg, 0.33 mmol) in anhydrous CH2Cl2 at −78° C. After 30 min at the same temperature, the reaction was diluted with isopropyl alcohol/chloroform (4:1) co-solvent (30 mL) and saturated potassium sodium tartrate solution (10 mL) was added. The mixture was stirred at room temperature for 2 h and the organic layer was collected. The aqueous layer was extracted with isopropyl alcohol/chloroform (4:1) co-solvent (3×10 mL) and organic layer were combined, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on a silica gel (MeOH:CH2Cl2=1:20 to1:10) to give adenosine analogue 15 (70.0 mg, 76%) as a white solid. mp: 215-218° C. (dec.) [α]25D +151.80° (c 0.23, CHCl3) UV (H2O) λmax 259.0 nm (ε 13998, pH 2), 260.0 nm (ε 15590, pH 7), 260.0 nm (ε 15579, pH 11); 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.06 (d, J=2.4 Hz, 1H), 5.86 (dd, J=2.4 and 25.6 Hz, 1H), 5.42 (t, J=2.4 Hz, 1H), 4.93 (td, J=3.2 and 52.4 Hz, 1H), 4.92 (s, 1H, partially buried inside the H2O peak), 4.40 (td, J=3.2 and 10.8 Hz, 1H), 3.88-3.76 (m, 2H), 2.78 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 156.0, 152.5, 149.9, 146.1 (d, J=1.0 Hz), 141.1 (d, J=5.2 Hz), 117.9, 111.8, 95.9 (d, J=186.0 Hz), 72.9 (d, J=22.9 Hz), 61.8 (d, J=3.4 Hz), 57.6 (d, J 17.2 Hz), 51.1. Anal. Calcd. for C12H14FN5O2: C, 51.61; H, 5.05; N, 25.08. Found: C, 51.74; H, 5.09; N, 24.92.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([F:16])[CH:4]=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([F:32])[C:29](O)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CCOC(OC(OCC)=O)=O>CN(C=O)C>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:27]=[C:28]([F:32])[C:29]([NH:1][CH2:2][C:3]2[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([F:16])[CH:4]=2)=[O:30])=[CH:25][CH:26]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(C=C(F)C(=O)O)cc1
Reactant: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Product: C=Cc1cc(CNC(=O)C(F)=Cc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 47.8 %

Procedure:
N-(4-Aminomethyl-2-fluoro-6-vinylphenyl)methanesulfonamide (1.1 eq, 0.15 mmol, 53.24 mg), 3-(4-tert-Butylphenyl)-2-fluoroacrylic acid (1 eq, 0.14 mmol, 30 mg), DEPC (1.2 eq, 0.17 mmol, 25.49 μl), and TEA (2 eq, 0.28 mmol, 39.09 μl) were added in DMF under argon atmosphere. The reaction mixture was stirred for 12 hrs. The reaction mixture was purified according to similar procedure of Example 21 to yield title product (30.0 mg, 48%).