Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH:14]3[CH:10]([CH2:11][NH:12][CH2:13]3)[CH2:9]2)[N:3]=1.[N:16]1[N:17]=[C:18]([C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23](O)=[O:24])[NH:19][CH:20]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH:14]3[CH:10]([CH2:11][N:12]([C:23]([C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[C:18]4[NH:19][CH:20]=[N:16][N:17]=4)=[O:24])[CH2:13]3)[CH2:9]2)[N:3]=1
Reactant: Cc1ccnc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4nnc[nH]4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 27 and 2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI) mass calcd. for C20H21N7O, 375.55; m/z found, 376.2 [M+H]+. 1H NMR (CDCl3): 8.18-8.04 (m, 3H), 7.55.7.42 (m, 2H), 7.39-7.33 (m, 1H), 6.39 (d, J=5.0 Hz, 1H), 3.96-3.79 (m, 2H), 3.77-3.63 (m, 2H), 3.62-3.55 (m, 1H), 3.46-3.37 (m, 2H), 3.15-3.06 (m, 1H), 3.05-2.98 (m, 1H), 2.95-2.90 (m, 1H), 2.33 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(O)CCC>CCOC(C)=O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: Brc1cccc(Br)n1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: COc1ccc(CNc2cccc(Br)n2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2,6-dibromopyridine 16-1 (15 g, 70 mmol), 4-methoxybenzylamine (25 mL, 191 mmol) and butanol (25 mL) was heated at 100° C. for 6 days. After cooling, EtOAc was added, the solids removed by filtration and the solution concentrated in vacuo. Purification of the residue by silica gel chromatography (Hexane:EtOAc 4:1) afforded the title compound 16-2 as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH:17]=1.[O:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:33][CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[O:24])=[CH:25][CH:26]=2)[CH:17]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)NC3CCOCC3)cc2)cn1
Yield: 13 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using tetrahydro-pyran-4-ylamine instead of cyclopropylmethylamine, to the title compound (16 mg, 13%) which was obtained as an off-white solid. MS: m/e=428.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH2:19][CH3:20])[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:11]=3[C:10]=2[O:23][CH3:24])=[N:6][CH:7]=1.[OH2:36].C[N+]1([O-])CCOCC1.[OH2:45]>CC(C)=O.C(Cl)Cl.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:3]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([C@@H:29]([OH:45])[C@H:30]3[OH:36])[C@@H:27]2[C:33]([NH2:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH2:19][CH3:20])[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:11]=3[C:10]=2[O:23][CH3:24])=[N:6][CH:7]=1
Reactant: O
Reactant: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)c2OC
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(N[C@@H]3[C@@H]4C[C@@H]([C@@H](O)[C@H]4O)[C@@H]3C(N)=O)n1)c2OC
Reaction time: 0.75 h
Yield: 67 %

Procedure:
0.16 M of Osmium tetraoxide in Water (50 uL) was added to (1S,2S,3R,4R)-3-[5-Chloro-2-(1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (152 mg, 0.306 mmol) and 4-Methyl-morpholine 4-oxide hydrate (65 mg, 0.48 mmol) in Acetone (10 mL) and Water (1.0 mL), and the reaction was stirred under an atmosphere of Nitrogen for 45 min. The reaction was diluted with DCM (15 mL) washed with water (2×5 mL) and brine (10 mL), dried over sodium sulfate and conc. in vacuo. Chromatography of the residue (ISCO 12 g SiO2, 0-10% MeOH:DCM) afforded (1R,2S,3R,4S,5S,6R)-3-[5-Chloro-2-(1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-5,6-dihydroxy-bicyclo[2.2.1]heptane-2-carboxylic acid amide as brown solids (110 mg, 67%). MP: 164-170° C.; LCMS: 531 (M+H); 1H-NMR (CDCl3): 8.40 (d, 1H, J=8.8 Hz), 7.92 (s, 1H), 7.38 (s, 1H), 7.16 (d, 1H, J=7.8 Hz), 7.01 (d, 1H, J=9.0 Hz), 5.73 (s, 1H), 5.37 (s, 1H), 4.32 (t, 1H, J=8.0 Hz), 3.97 (m, 1H), 3.83 (m, 1H), 3.80 (s, 3H), 3.49 (d, 1H, J=5.3 Hz), 2.98 (m, 2H), 2.51 (m, 1H), 2.44 (m, 1H), 2.39 (m, 1H), 2.28 (m, 3H), 2.06 (m, 1H), 1.91 (m, 1H), 1.12 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][Cl:16])[C:3]=1[N+:17]([O-])=O>CC(O)=O.[Fe]>[NH2:17][C:3]1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][Cl:16])=[C:5]([CH:10]=[CH:11][C:2]=1[Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1NCCCCl
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Cl)c(N)c1NCCCCl
Temperature: 80 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of methyl 4-chloro-2-[(3-chloropropyl)amino]-3-nitrobenzoate (275 mg, 0.895) and Fe (150 mg, 2.69 mmol) in AcOH (2.8 mL) was stirred at 80° C. for 1 h. AcOH (2.8 mL) and Fe (350 mg, 6.27) were added to the reaction mixture at room temperature, and the resultant mixture was stirred at 80° C. for 30 min, filtered through Celite and concentrated in vacuo. After water was added to the residue, the resultant mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on NH silica gel eluting with a 3% ethyl acetate/n-hexane mixture to afford a yellow oil (201 mg, 0.725 mmol, 81%).
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[NH2:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1>>[CH3:1][Si:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
In the manner of example 3, 11-(trimethylsilyl)undecyl bromide was reacted with ethyl 4-aminobenzoate to yield ethyl 4-[11-(trimethylsilyl)undecylamino]benzoate, m.p. 66°-68° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[CH3:25])[CH:5]=[CH:6][CH:7]=1.[Br:27]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCCC1.O>[Br:27][CH2:25][C:10]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:26])[C:14]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[S:17][C:13]=2[C:12](=[O:24])[N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cccc1Cn1c(C)nc(=O)c2sc(N3CCOCC3)nc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1Cn1c(CBr)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a 40 mL I-CHEM reaction vial equipped with a stirbar, was added Example 60, 4-[(3-chloro-2-methylphenyl)methyl]-5-methyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (1 g, 2.56 mmol), N-bromosuccinimide (0.569 g, 3.20 mmol), and 2,2′-azobis(2-methylpropionitrile) (0.084 g, 0.512 mmol). The solids were taken up in tetrahydrofuran (THF) (25.6 ml) and stirred overnight at room temperature. After overnight stirring, the reaction was diluted with water (˜10 mL) transferred to a separatory funnel and extracted with dichloromethane DCM (˜50 mL). The organic layer was dried over sodium sulfate and concentrated to a residue. The residue was re-dissolved in a minimum amount of DCM (˜2 mL) and injected onto a 25 g SNAP silica cartridge for purification (eluting with a gradient: 5%-75% THF (1% methanol (MeOH)) into DCM, over 30 column volumes). Fractions containing the desired material were pooled and concentrated to afford 5-(bromomethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (752 mg, 1.601 mmol, 62.6% yield). LC/MS Theoretical m/z MH+=470.78 Found: 470.8; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 3.46-3.56 (m, 4H) 3.66 (t, J=4.93 Hz, 5H) 4.46 (s, 2H) 5.58 (s, 2H) 6.53 (d, J=8.08 Hz, 1H) 7.14 (t, J=7.96 Hz, 1H) 7.37 (d, J=7.83 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>C1COCC1>[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)[C:4]3[C:9]([C:10](=[O:12])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:26][CH:25]=1
Reactant: Nc1cc(=O)c2cccnc2n1-c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(CBr)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CNc2cc(=O)c3cccnc3n2-c2cccc(C(F)(F)F)c2)cc1
Temperature: 80 °C
Yield: 3.4 %

Procedure:
A mixture of 2-amino-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (50 mg, 0.16 mmol), CsCO3 (160 mg, 0.49 mmol) and 4-methylbenzyl bromide (35 mg, 0.25 mmol) in THF (3 mL) was heated to 80° C. in a sealed tube for 16 h. The reaction was cooled to room temperature and quenched with water (3 mL). The mixture was extracted with CH2Cl2 (3×), and the combined organic extracts were dried with Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC (YMC-Pack Pro C18 Column, 150×20 mm I.D.; first run: 20-80% CH3CN in water, 11 min.; second run: 50-90% MEOH in water, 20 min.) to afford 2-[(4-Methylbenzyl)amino]-1-[3-(trifluoromethyl)phenyl]-1,8-naphthyridin-4(1H)-one (2.2 mg, 3%): LCMS RT: 2.75 min, MH+: 410.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][C@H]1CN(CC2C=CC(NC)=CC=2)CCN1C(OC(C)(C)C)=O>>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:24])=[CH:3][C:4]=2[CH3:23])[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: Cc1cc(N)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(C)c1

Procedure:
The title compound was prepared from D7 using a method similar to that described for D3.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8](=O)[C:9]2[CH:25]=[CH:24][CH:23]=[C:11]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=O)[CH:10]=2)=[CH:4][CH:3]=1.B.CC(O)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:25]=[CH:24][CH:23]=[C:11]([CH2:12][NH:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:10]=2)=[CH:27][CH:28]=1
Reactant: O=C(NCc1ccc(F)cc1)c1cccc(C(=O)NCc2ccc(F)cc2)c1
Agent: B
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Fc1ccc(CNCc2cccc(CNCc3ccc(F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a partially heterogeneous mixture of N1,N3-bis(4-fluorobenzyl)isophthalamide (5.1 g, 13.41 mmol) in THF (70 mL) at ice bath temp was added a cold solution of borane (100 mL of 1 M solution in THF) slowly. It was stirred at ice bath tem for 1 h. It was warmed to rt and stirred for 30 h at rt. The mixture was warmed to ˜60° C. and stirred for 2 h. To the mixture was added 5 mL of HOAc, stirred for 1 h and it was mostly concentrated. To the residue was slowly added 150 mL of MeOH and 150 mL of 1N HCl with stirring, stirred for 2 h at rt, heated at 65° C. for 30 min and it was mostly concentrated. The mixture was mixed with EtOAc and aq NaHCO3, the EtOAc layer was separated, washed with water, dried over MgSO4 and concentrated in vacuo to obtain the desired product (4.5 g, 95%) as a viscous material of crude product. This crude product was used directly for the next step without any further purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH2:18][CH2:19][CH:20]=[CH2:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[O:9]1[CH2:21][CH:20]1[CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CCCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: c1ccc(CCC2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of m-chloroperbenzoic acid (43.5 g, 151 mmol) in chloroform (250 ml) was treated with 4-phenyl-1-butene (20 g, 151 mmol). The reaction was stirred for 1 hour at room temperature and washed with sodium bicarbonate, sodium sulfite, and saturated sodium chloride. The solution was dried over sodium sulfate and evaporated to dryness to afford 3,4-epoxybutylbenzene (100%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:16]=[CH2:17])=[C:9]([C:12]([NH:14][NH2:15])=[O:13])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:21]=[O:22])C>C(OCC)(=O)C>[C:12]([C:9]1[CH:8]=[C:7]([CH:1]=[CH:2][C:21]=1[OH:22])[C:11]([NH:15][NH:14][C:12]([C:9]1[O:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]=1[CH:16]=[CH2:17])=[O:13])=[O:10])#[N:14]
Reactant: CN(C)C=O
Reactant: C=Cc1c(-c2ccccc2)coc1C(=O)NN
Solvent: CCOC(C)=O
Product: C=Cc1c(-c2ccccc2)coc1C(=O)NNC(=O)c1ccc(O)c(C#N)c1

Procedure:
A mixture of 4-phenyl-3-vinyl-2-furancarboxylic acid hydrazide (compound of Reference Example 39, 0.20 g) and the compound of Reference Example 63 (0.32 g) in DMF (5 ml) was stirred at 70° C. for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate, thereby giving 0.17 g of the desired compound. Melting point: 170-174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
Tert-butyl 4-(4-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (48 mg, 0.173 mmol) was dissolved in EtOH (2 ml), followed by addition of Pd (10 wt % on activated carbon, 5 mg), and then the resulting liquid was stirred at room temperature under hydrogen stream for 2 hours. The resulting reaction liquid was filtered, concentrated under reduced pressure, and dried under vacuum, to obtain 46 mg of colorless oil (95%).
Reaction SMILES: O1CCCC1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:13]([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])[CH2:14][C:15]#[CH:16]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[C:7]1([C:16]#[C:15][CH2:14][CH2:13][N:17]2[C:21](=[O:22])[C:20]3[C:19](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]2=[O:27])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Ic1ccccc1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1ccccc1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Under a nitrogen atmosphere, 35 ml of tetrahydrofuran, 3.06 g of iodobenzene, and 9.0 ml of triethylamine were added to 535 mg of dichlorobis(triphenylphosphine)palladium, 145 mg of copper iodide, and 3.00 g of N-(3-butynyl)phthalimide. The obtained mixture was stirred under reflux for 4 hours. After completion of the stirring, the reaction solution was cooled to a room temperature, and a solid was then filtrated. The filtrate was concentrated, and the residue was then purified by column chromatography (Wako Gel C-200; toluene:ethyl acetate=4:1), so as to obtain 3.70 g of a phthalimide compound.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(#N)C>[CH:1]1([CH2:6][C@@H:7]([C:8](=[O:9])[N:10]2[CH:14]([C:15]([NH:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Reactant: Nc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in acetonitrile (10 mL) at 0° C. was added 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (656 mg, 2.0 mmol) and N-methylmorpholine (0.29 mL, 2.6 mmol). The reaction was stirred for 2 hours at 0° C. Aniline (93 mg, 1.0 mmol) was added to the reaction, which was allowed to warm to room temperature and stirred for 3 hours. The solvent was then removed under reduced pressure, and water (5 mL) and DCM (15 mL) were added to the residue. The phases were separated. The aqueous phase was extracted twice with DCM (15 mL), and the combined organics were dried over sodium sulfate and concentrated. The resulting residue was purified by Combiflash silica gel chromatography (0-60% EtOAc in hex) to give 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-oxo-4-{5-[(phenylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoate (386 mg, 0.90 mmol, 90% yield) as a yellow oil. MS: 428 ([M+H]).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[C:25](OC2C=CC(NC(=O)OC(C)(C)C)=C(F)C=2)[CH:24]=[CH:23][N:22]=1>>[C:15]([O:14][C:13](=[O:19])[NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:25]2[CH:24]=[CH:23][N:22]=[C:21]([NH2:20])[C:26]=2[N+:27]([O-:29])=[O:28])=[CH:3][CH:4]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])c2ccccc12

Procedure:
The title compound was prepared from tert-butyl 4-hydroxynaphthalen-1-ylcarbamate (Regan, J. et al, J. Med. Chem., 2002, Vol. 45, No. 14, p. 2994) (3.9 g, 15 mmol) by the same method as described for compound (3a).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:17]([C:14]3[CH:13]=[CH:12][N:11]=[CH:16][CH:15]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: O=Cc1ccncc1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccncc1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with pyridine-4-carboxaldehyde in an analogous manner to that described in Example 1 to give 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(4-pyridyl)-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a pale yellow crystalline solid of melting point 218-219° C. (decomposition).
Reaction SMILES: C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:36])=[N:23][C:24]=2[N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][CH2:34][CH3:35])(=O)C.C(Cl)(C)=O>CC(O)=O>[Cl:36][C:22]1[N:21]=[C:20]2[C:25]([NH:26][CH:27]=[N:19]2)=[C:24]([N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH2:33][CH2:34][CH3:35])[N:23]=1
Reactant: CCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-2-chloro-6-(2-propylimidazol-1-yl)purine (4.99 g, 9.6 mmol) was dissolved in HOAc (400 mL). To the solution was added AcCl (4.0 mL, 4.42 g, 56.3 mmol), and the mixture was stirred at 65° C. for 1.5 h in a sealed flask (reaction almost complete, TLC). Volatiles were evaporated in vacuo, and the residue was washed (CH2Cl2), and dissolved in 0.1 N NaOH/H2O. Precipitation with CO2 gave 2-chloro-6-(2-propylimidazol-1-yl)purine (2.20 g, 88%). Recrystallization (MeOH) gave the pure material (1.93 g, 77%).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6]C)=O)#[C-:2].Cl.[F:9][C:10]1([F:15])[CH2:14][CH2:13][NH:12][CH2:11]1.C(N(CC)CC)C>CO>[F:9][C:10]1([F:15])[CH2:14][CH2:13][N:12]([C:4](=[O:6])[CH2:3][N+:1]#[C-:2])[CH2:11]1
Reactant: FC1(F)CCNC1
Reactant: [C-]#[N+]CC(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: [C-]#[N+]CC(=O)N1CCC(F)(F)C1
Yield: 60 %

Procedure:
To stirred and cooled (0° C.) methyl isocyanoacetate (96% technical grade, 345 mg, 3.48 mmol) was slowly added 3,3-difluoropyrrolidine hydrochloride (500 mg, 3.48 mmol), triethylamine (487 μL, 3.48 mmol) and MeOH (1 mL). The mixture was stirred for 15 h at RT and then concentrated. The resulting oil was coevaporated twice from EtOAc. 1-(3,3-Difluoropyrrolidin-1-yl)-2-isocyanoethanone VIB 01158 was obtained as a yellow oil (305 mg, 60% yield) and used in the next step without purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:32])[CH3:31]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)=O)C3)cc1

Procedure:
Compound dp was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with acetyl chloride. LC-MS: m/z=+439 (M+H)+.