Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.C(NC(C)C)(C)C>CS(C)=O>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[NH:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:17][CH2:18]3)[C:8]2=[O:19])[CH2:4]1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Reactant: Clc1nc2ccccc2o1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC(C)NC(C)C
Product: O=c1n(C2CC2)c2nccnc2n1[C@H]1C[C@H](Nc2nc3ccccc3o2)C1

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.1099 g, 0.390 mmol), 2-chlorobenzoxazole (0.088 ml, 0.768 mmol, Sigma-Aldrich Chemical Company, Inc.), and diisopropylamine (0.204 ml, 1.170 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO. The reaction was heated to 90° C. for 24 h The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 909% over 15 min. LCMS showed product was not isolated at ≧95% purity. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (25 g), eluting with a gradient of % to 5% MeOH in CH2Cl2, to provide the title compound (0.0590 g, 0.163 mmol, 42.4% yield). LCMS showed product peak at 1.604 min (m+1=362.9). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.02 (m, 2 H) 1.02-1.09 (m, 2 H) 2.52-2.58 (m, 1 H) 2.91-3.01 (m, 1 H) 3.18-3.30 (m, 2 H) 4.46-4.59 (m, 1 H) 5.11-5.23 (m, 1 H) 6.99 (td, J=7.73, 1.37 Hz, 1 H) 7.12 (td, J=7.63, 1.17 Hz, 1 H) 7.27 (dd, J=7.73, 0.68 Hz, 1 H) 7.36 (dd, J=7.82, 0.59 Hz, 1 H) 7.94-7.98 (m, 1 H) 7.99-8.02 (m, 1 H) 8.42 (d, J=6.46 Hz, 1 H)
Reaction SMILES: [CH2:1]1[O:13][C:12]2[C:3](=[C:4]([CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[C:5]([O:7][CH3:8])=[O:6])[O:2]1.[Br:16]Br>C(Cl)(Cl)Cl>[CH2:1]1[O:13][C:12]2[C:3](=[C:4]([CH:9]=[C:10]([Br:16])[C:11]=2[O:14][CH3:15])[C:5]([O:7][CH3:8])=[O:6])[O:2]1
Reactant: COC(=O)c1ccc(OC)c2c1OCO2
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(OC)c2c1OCO2
Yield: 93.2 %

Procedure:
Compound 122 (5.56 g, 25.6 mmol) was dissolved in anhydrous chloroform. Bromine (4.5 g, 28.5 mmol) was added dropwise over 2 hours at 5°-8° C. Then the mixture was maintained for an additional 2 hours at the same temperature. After the usual workup, 6.9 g of white solid 123 was obtained (88% yield). m.p. 165°-6° C. (crystallized from ethyl acetate). IR cm-1 1710 (s, C=O), 1425, 1400 (s, C--O); MS m/z (%): 288 (M+, 100), 290 (M+2, 96); 1H NMR δ ppm 3.91 (s, 3H, OCH3), 4.14 (s, 3H, ArOCH3), 6.10 (s, 2H, OCH2O), 7.65 (s, 1H, 6-ArH); Anal. (C10H9O5Br) C, H, Br.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CC(O)=O.C(OCC)C>[CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH2:13][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCCCc1ccc2c(c1)CCN2
Yield: 61.7 %

Procedure:
To a solution of the product of Step B (0.08 g; 0.35 mmol) in AcOH (1.5 ml) NaBH3CN was added at 0° C., with stirring. The resulting mixture was stirred for 2 h at room temperature, then diluted to 20 ml with diethyl ether and washed with 10% NaOH (2×5 ml), H2), brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; hexane/EtOAc; 9:1) to give the title compound (0.05 g; 62%) as a colourless syrup. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=7 Hz); 1.26 (m, 10H); 1.54 (m, 2H); 2.48 (tr, 2H, J=7.9 Hz); 2.98 (tr, 2H, 9.2 Hz) 3.52 (tr, 2H, J=9.2 Hz); 6.56 (d, 1H, 7.8 Hz); 6.83 (d, 1H, J=7.8 Hz); 6.93 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:27][CH:26]=1
Reactant: Brc1ccc(OCCCN2CCCCC2)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(OCCCN3CCCCC3)cc2)cc1
Yield: 27 %

Procedure:
A suspension of potassium carbonate (290 mg) and palladium tetrakistriphenylphosphine (49 mg) in a solution of 1-[3-(4-bromophenoxy)-propyl]piperidine (250 mg) and 4-methylbenzeneboronic acid (228 mg) in toluene (5 mL) is heated overnight at a temperature close to 100° C. The mixture is diluted with ethyl acetate (200 mL) washed with a saturated aqueous sodium bicarbonate solution (3 mL), dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with dichloromethane then dichloromethane/methanol/ammonia 99/1/0.5. Fractions containing the expected product are pooled, concentrated under reduced pressure and salted with oxalic acid to give 70 mg of 1-{3-[(4′-methylbiphenyl-4-yl)oxy]propyl}piperidine, oxalate as a white solid melting at 195° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([O:32][CH3:33])=[CH:25][C:24]=1[CH:34]=[CH2:35].C1(C=CC(O)=CC=1)O>C(O)(C)C>[Cl:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[C:26]([O:32][CH3:33])=[CH:25][C:24]=1[CH2:34][CH2:35][NH:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: C=Cc1cc(OC)c([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CN)cc2)CC1
Agent: Oc1ccc(O)cc1
Solvent: CC(C)O
Product: COc1cc(CCNCc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A stirred solution of 4-(4-aminomethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.531 g, 1.82 mmol), 1-chloro-4-methoxy-5-nitro-2-vinylbenzene (Example 50C) (0.3 g, 1.40 mmol) and quinol (61.8 mg, 0.562 mmol) in isopropyl alcohol (16 mL) was heated to 100° C. for 30 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on neutral silica gel using 2% methanol in DCM to give the title compound (0.460 g, 65%)
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[CH:20]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)([CH3:22])[CH3:21].ClCCl>N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH:20]([CH3:22])[CH3:21])=[CH:28][N:27]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: CC(C)c1ccc(N)nc1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (241 mg, 0.800 mmol) in pyridine (5 mL), stirred under nitrogen at room temperature, was added 5-isopropylpyridin-2-amine (54.5 mg, 0.4 mmol). The mixture was then stirred at room temperature overnight. Dichloromethane (25 mL) was added to the mixture and the organic phase washed with water (25 mL) and brine (25 mL) then dried using a hydrophobic frit. Solvent was removed in vacuo to give the crude product. This was purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient), to provide the title compound (39 mg) as an off-white solid. LCMS (2 min, formic) Rt 0.96 min, m/z (ES+) 402 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C1C(=O)N([Cl:18])C(=O)C1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([Cl:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1c[nH]c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 141 %

Procedure:
To a solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (1.8 g, 9.09 mmol) in 18 mL of DCM and 18 mL of DMF was added NCS (1.46 g, 10.9 mmol) at RT. The reaction mixture was stirred at RT overnight, then partitioned between EtOAc and brine. The organic layer was dried (MgSO4) concentrated to give 2.98 g of impure 2-bromo-7-chloro-5H-pyrrolo[2,3-b]pyrazine as a yellow oil which was used for the next step without any purification.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:8]([C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[O:9])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccncc1)c1ccc(F)cc1
Reaction time: 6 h
Yield: 75.5 %

Procedure:
To a stirred and cooled (ice-bath) solution of 141.5 parts of 4-pyridinecarbonyl chloride hydrochloride in 400 parts of fluorobenzene were added portionwise 399 parts of aluminum chloride. Upon completion, the whole was slowly heated to reflux and stirring at reflux was continued for 6 hours. The reaction mixture is cooled, poured onto crushed ice and acidified with 240 parts of a hydrochloric acid solution 10N. The layers were separated. The acid aqueous phase was washed twice with 180 parts of methylbenzene and strongly alkalized with a sodium hydroxide solution 60%. The product was extracted three times with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was dissolved in 900 parts of methylbenzene and the solution was treated with activated charcoal. The latter was filtered off and the filtrate was evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 152 parts (75.5%) of (4-fluorophenyl)(4-pyridinyl)methanone; mp. 85.5° C. (intermediate 25).
Reaction SMILES: [O:1]=[C:2]1[NH:20][C@@H:5]2[CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:8][CH2:9][C@@H:4]2[O:3]1.[O:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[C@@H:5]2[CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:8][CH2:9][C@@H:4]2[O:3]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1N[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@@H]2O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(C(=O)OCc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of (3aR,7aS)-benzyl 2-oxohexahydrooxazolo[4,5-c]pyridine-5(6H)-carboxylate (1.0 equiv.) in dichloromethane (0.09 M) was added BOC2O (1.1 equiv.), triethylamine (1.1 equiv.), and a catalytic amount of DMAP. The reaction was stirred at room temperature for one hour at which point it was concentrated under vacuo and filtered through a plug of silica gel eluting with ethylacetate. The product was dried under vacuo to give a white solid in 75% yield. LCMS (m/z): 277.2 (MH+), LC Rt=3.43 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14]2[S:15][CH2:16][C:17](O)([C:19]([F:22])([F:21])[F:20])[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]([F:21])([F:20])[F:22])[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CCNC(=O)Nc1cc(C2=NC(O)(C(F)(F)F)CS2)c(Br)cn1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
To a mixture of 1-(5-bromo-4-(4-hydroxy-4-(trifluoromethyl)-4,5-dihydrothiazol-2-yl)pyridin-2-yl)-3-ethylurea (Intermediate 41, 2.2 g, 5.32 mmol) in DCM (30 mL), TFAA (1.128 mL, 7.99 mmol) followed by TEA (1.113 mL, 7.99 mmol) were added. The reaction mixture was allowed to stir overnight at room temperature, then another 150 uL of TEA and TFAA were added and the reaction mixture was stirred for additional 3 h. The reaction was concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The layers were separated, and the organic layer was washed with sodium bicarbonate solution, water and brine, then dried over magnesium sulfate and concentrated under reduced pressure. The light yellow solid obtained was purified by normal phase (1% MeOH in dichloromethane to 3% MeOH in dichloromethane) to give 520 mg of the product. MS (ESP): 396 (M+1) for C12H10BrN3O; NMR: 1.07 (t, 3H); 3.11-3.17 (m, 2H); 7.24 (t, 1H); 8.35 (s, 1H); 8.50 (s, 1H); 8.77 (s, 1H); 9.34 (s, 1H)
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]1C=C[CH:48]=[C:47]([Cl:51])[CH:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:44]=[CH:45][CH:46]=[C:47]([Cl:51])[CH:48]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1cccc(CBr)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cccc(Cl)c3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-3-chlorobenzene and isolated as white solid (4.8 mg, 29%). MS (m/e): 407.4 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[N:26][CH:27]=1.O>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1)[O:19][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:30][CH:29]=2)=[N:26][CH:27]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: FC(F)(F)Oc1ccc(-c2ccc(CCl)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
15 mg (0.60 mmol) of 95% sodium hydride were added at 0° C. to a solution of 116 mg (0.50 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 144 mg (0.50 mmol) 5-chloromethyl-2-(4-trifluoromethoxy-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1, and a small amount of ether. The residue was purified by chromatography on silica (eluent: ethyl acetate/n-heptane 4:1) to give 136 mg (56%) of the title compound as white powder.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][CH3:16])[C:11]=1[CH3:12]
Reactant: CSc1ccccc1B(O)O
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
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: CC#N
Product: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (550 mg, 2.22 mmol), 2-(methylthio)phenylboronic acid (484 mg, 2.88 mmol), sodium carbonate (705 mg, 6.65 mmol), Pd(PPh3)4 (128 mg, 0.11 mmol), acetonitrile (5.2 mL), and water (1.3 mL) at 100° C. in a microwave reactor for 1 h. Purification by column chromatography (silica gel, 0-20% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline as a white amorphous solid. Mass Spectrum (ESI) m/e=336.1 (M+1).
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[O:16][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([NH2:22])[C@H:12]1[OH:13].[C:23]([O:27][C:28]([NH:30][C@H:31]([C:51](O)=[O:52])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:35][CH:34]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[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[O:16][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C@@H:14]([NH:22][C:51](=[O:52])[C@H:31]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:37][CH:38]=2)[NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:29])[C@H:12]1[OH:13]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
Product: CCOC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1NC(=O)[C@H](Cc1ccc(OCCCNC(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Yield: 70.5 %

Procedure:
Ethyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-O-(3-tert-butoxycarbonylaminopropyl)-L-tyrosylamino]-β-D-ribofuranuronate (770 mg) was prepared by reacting ethyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronate (462 mg) prepared in Example 63 with N-tert-butoxycarbonyl-O-(3-tert-butoxycarbonylaminopropyl)-L-tyrosine (906 mg) prepared in Preparation 7 (4) according to a similar manner to that of Example 64, mp. 125°-131° C. (dec.).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[S:8][C:9]([CH:12]=[CH:13][C:14]2[C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)=[CH:10][CH:11]=1)C.[OH-].[K+]>O1CCCC1>[S:17]1[CH:18]=[C:14]([CH:13]=[CH:12][C:9]2[S:8][C:7]([CH:6]=[CH:5][C:4]([OH:23])=[O:3])=[CH:11][CH:10]=2)[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]1=2
Reactant: CCOC(=O)C=Cc1ccc(C=Cc2csc3ccccc23)s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C=Cc1ccc(C=Cc2csc3ccccc23)s1
Yield: 43.8 %

Procedure:
A stirred mixture of 3-[5-[2-(benzo[b]thiophen-3-yl)ethenyl]thiophen-2-yl]-2-propenoic acid ethyl ester (5.47 g), 1N aqueous potassium hydroxide solution (50 ml) and tetrahydrofuran (60 ml) was heated at reflux overnight. The mixture was concentrated in vacuo, and the residue was acidified with 10% hydrochloric acid. The mixture was extracted with dichloromethane and ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was extracted (Soxhlet) overnight with ethyl acetate. The extract was reduced to a volume of 100 ml and cooled to give 2.2 g (44%) of product, mp 197°-198° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:18][O:19][CH3:20])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12]C)=[O:11].[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:18][O:19][CH3:20])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([OH:12])=[O:11]
Reactant: COCc1nc(Cl)c(-c2cc(C(=O)OC)ccc2C)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1nc(Cl)c(-c2cc(C(=O)O)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added methyl 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.4, 50 mg, 0.19 mmol) and sodium hydroxide (31 mg, 0.76 mmol) in methanol/water (3 mL/3 mL). The resulting solution was stirred for 12 hours at room temperature. The pH of the solution was adjusted to 1-2 with hydrogen chloride (6 M), then concentrated under reduced pressure to yield 150 mg (crude) of the title compound as the HCl salt as white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14][CH2:13]2>>[Cl:1][CH2:2][C:3]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:18])[NH:16]2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc2c1NC(=O)CC2
Product: COc1ccc(C(=O)CCl)c2c1NC(=O)CC2

Procedure:
By using chloroacetyl chloride and 8-methoxy-3,4-dihydrocarbostyril, there was obtained 5-chloroacetyl-8-methoxy-3,4-dihydrocarbostyril as a white powder having a melting point of 187°-188° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])=[CH:12][CH:11]=2)[CH:9]=1)=[N+]=[N-].Cl[Sn]Cl>CO.CCOC(C)=O>[NH2:1][CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])=[CH:14][CH:15]=2)[CH:9]=1
Reactant: [N-]=[N+]=NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1

Procedure:
To a solution of 1-(4-(4-(azidomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one prepared above (203 mg, 0.695 mmol) in MeOH (6 mL) and EtOAc (6 mL), SnCl2 2H2O (343 mg, 1.52 mmol) was added. After the mixture was heated to reflux for 1 h, it was concentrated in vacuo. The residue was purified by HPLC to give 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one (145 mg). MS 267 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C1COCC1>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH2:1][C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)=[O:34])=[CH:3][C:4](=[O:14])[O:5]2)=[CH:10][CH:9]=1)#[N:13]
Reactant: Cc1cc(=O)oc2cc(C#N)ccc12
Reactant: O=C=Nc1cccc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(CC(=O)Nc3cccc(Cl)c3)cc(=O)oc2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (673 mg, 3. 6 mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (5.4 mL). After 30 minutes 3-chloro-1-isocyanato-benzene (222.3 mg) was added into the reaction mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-100% ethyl acetate in hexanes to yield 2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(3-chloro-phenyl)-acetamide as a yellow solid.