Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O.C(N(CC)CC)C.C(Cl)(Cl)Cl.CO>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][C:20]([NH:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:21])=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C=Nc1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NCCc1c[nH]c2ccccc12)Nc1ccccc1
Reaction time: 2 h

Procedure:
Tryptamine (1.04 g, 6.5 mmol) was dissolved in a mixture of acetone (20 ml) and triethylamine (1 ml) under a nitrogen atmosphere. Phenyl isocyanate (852 mg, 7.15 mmol, 0.78 ml) was swiftly added dropwise at 0° C. and the mixture was then subsequently stirred for 2 h, while cooling with ice, and at RT overnight. A subsequent TLC in chloroform/methanol 20:1 showed only small amounts still of tryptamine. The mixture was concentrated i. vac. The residue obtained was purified by flash chromatography with 100 g of silica gel and chloroform/methanol 50:1→9:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH3:20])[CH2:17][O:18][CH3:19])[C:10]=1[NH2:21].[C:22](OC)(=[O:26])[C:23]([CH3:25])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:21]=[C:23]([CH3:25])[C:22](=[O:26])[N:15]([CH:16]([CH3:20])[CH2:17][O:18][CH3:19])[C:11]=2[N:12]=[CH:13][CH:14]=1
Reactant: COCC(C)Nc1nccc(-c2ccc(Cl)cc2Cl)c1N
Reactant: COC(=O)C(C)=O
Solvent: Cc1ccccc1
Product: COCC(C)n1c(=O)c(C)nc2c(-c3ccc(Cl)cc3Cl)ccnc21
Yield: 2.1 %

Procedure:
4-(2,4-Dichloro-phenyl)-N2-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine (0.13 g, 0.40 mmol) was dissolved in toluene (20 mL), followed by methyl pyruvate (0.081 g, 0.80 mmol) and heated at reflux overnight. The reaction was concentrated in vacuo and purified by reverse phase prep HPLC to yield 3.2 mg (2%) of 8-(2,4-dichloro-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 9): 1H NMR (300 MHz, CD3OD): δ 8.6 (d, 1H), 7.6 (s, 1H), 7.4–7.25 (m, 3H), 4.4 (m, 1H). 3.8 (m, 1H), 3.3 (s, 3H), 2.4 (s, 3H), 1.6 (d, 2H), 1.25 (s, 2H). MS (AP) m/z 378.3 [(M+H)+, 100].
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]>>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[C:21]3[S:17][C:18](=[O:23])[NH:19][C:20]3=[O:22])=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CSC(=O)N1
Reactant: CNc1cccc(-c2ccc(C=O)cc2)c1
Product: CNc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 91.7 %

Procedure:
In a manner similar to that of Example 1(f), starting with 2.9 g (13.7 mmol) of 3′-methylaminobiphenyl-4-carboxaldehyde and 1.6 g (13.7 mmol) of 2,4-thiazolidine dione, 3.9 g (91%) of the expected product are obtained.
Reaction SMILES: [CH:1]1([CH:9]([OH:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:1]1([C:9](=[O:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CC(O)C1C=CCCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)C1C=CCCCCC1
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 51.1 %

Procedure:
At 0° C., a solution of 1-cyclooct-2-enylethanol (1.4 g, 9 mmol) in dichloromethane (20 ml) was added to pyridiniumchlorochromate (2.35 g, 11 mmol) in dichloromethane (30 ml). The resulting mixture was stirred at 20° C. during 3.5 h and filtered through Celitee ®. The filtrate was concentrated and the crude product purified by flash chromatography (hexane/Et2O 6:1) to give 0.7 g of 1-cyclooct-2-enylethanone (55%).
Reaction SMILES: [NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1.[CH:36](=O)[CH3:37].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:36][CH3:37])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: COc1ccc(CNCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(OC)cc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-(4-methoxybenzylamino)pentyl)-piperidin-4-yl)methyl)benzamide (1.5 g) as starting compound, acetaldehyde (0.22 ml) and sodium cyanoborohydride (0.24 g) were reacted and treated in the same manner as in Example 136 to give 0.8 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(4-methoxybenzyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[H-].[Na+].Br[CH2:14][C:15]1[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C:17](=[O:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25]>CN(C=O)C>[NH2:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[N:7]=[CH:6][N:5]2[CH2:14][C:15]1[N:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[C:17](=[O:26])[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25]
Reactant: Nc1ncnc2[nH]cnc12
Reactant: Cc1ccccc1-n1c(CBr)cc2cccc(C)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
9H-Purin-6-amine (1901) (540 mg, 4.0 mmol) was dissolved in anhydrous DMF (20 mL). NaH (60% in mineral oil, 160 mg, 4.0 mmol) was added and the resulting mixture was stirred at RT for 30 min. 3-(Bromomethyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1610) (1.37 g, 4.0 mmol) was added. The reaction mixture was stirred at RT for 30 min, poured into ice-water (30 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (25 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-20% MeOH/DCM) to afford the desired product, 3-((6-amino-9H-purin-9-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1902, compound 5 of Table 4) (1.1 g, 70% yield) as a white solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1.[Br:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH:28]=[O:29].[Cl-].[NH4+]>CCCCCC.C1COCC1>[Br:24][C:25]1[CH:26]=[C:27]([CH:28]([OH:29])[C:13]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][CH2:16]2)[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: CC(C)(C)OC(=O)C1CCC1
Reactant: O=Cc1ccc(Cl)c(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c(Br)c2)CCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
21.65 ml (54.12 mmol) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution, cooled to from −20° C. to −30° C., of 7.6 ml (54.12 mmol) of diisopropylamine in 30 ml of abs. THF. After the addition had ended, the mixture was stirred at from −20° C. to −30° C. for another 30 min. The mixture was then cooled to −78° C., and a solution of 6.2 g (39.7 mmol) of tert-butyl cyclobutanecarboxylate in 10 ml of abs. THF was added dropwise at this temperature. After 4 h at −78° C., a solution of 7.9 g (36.1 mmol) of 3-bromo-4-chlorobenzaldehyde in 10 ml of abs. THF was then added. The reaction mixture was slowly warmed to RT overnight, saturated aqueous ammonium chloride solution was then added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→10:1). This gave 7.77 g of the target compound (56% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>C(O)C.O>[Na+:18].[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:13][CH2:14][C:15]([O-:17])=[O:16])[CH:7]=1
Reactant: NCC(=O)[O-]
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C([O-])CNc1cc(Cl)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 58.4 %

Procedure:
To a stirred solution of 1-chloro-2,5-difluoro-4-nitrobenzene (0.825 g, 4.26 mmol) in ethanol (8.0 mL), was added a solution of sodium glycinate (0.415 g, 4.27 mmol) in water (1.5 mL). The resulting suspension was refluxed for 60 h. The solution was cooled to room temperature and the precipitated bright orange solid was filtered, washed with cold ethanol (5 mL), and dried under vacuum to give 0.673 g (64%) title compound as a bright orange powder; 1H NMR (DMSO-d6) δ 3.50 (d, 2H, J=3.6 Hz), 7.04 (d, 1H, J=6.6 Hz), 8.01 (d, 1H J=9.9 Hz), 8.74 (s, 1H). The unreacted 1-chloro-2,5-difluoro-4-nitrobenzene was recovered almost quantitatively from the filtrate.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([O:10][CH2:11][C@:12]2([CH3:15])[CH2:14][O:13]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I:24][C:25]1[CH:26]=[N:27][NH:28][CH:29]=1>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([O:10][CH2:11][C@:12]([OH:13])([CH3:15])[CH2:14][N:27]2[CH:26]=[C:25]([I:24])[CH:29]=[N:28]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Ic1cn[nH]c1
Reactant: C[C@@]1(COC(=O)c2ccc([N+](=O)[O-])cc2)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@](O)(COC(=O)c1ccc([N+](=O)[O-])cc1)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
(S)-(2-Methyloxiran-2-yl)methyl 4-nitrobenzoate (2.0 g, 8.4 mmol) and cesium carbonate (4.12 g, 12.7 mmol) were added to a solution of 4-iodo-1H-pyrazole (1.64 g, 8.43 mmol) in DMF (30 mL). The mixture was stirred at room temperature for 14 h, then diluted with EtOAc, and washed with hydrochloric acid (1N). The organic layers were separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-60% EtOAc/Hexane) to afford (S)-2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)-2-methylpropyl 4-nitrobenzoate. MS ESI calc'd. for C14H15IN2O5 [M+H]+ 432. found 432.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22](O)[CH:21]=1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([O:19][C:22]1[CH:21]=[CH:20][C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reaction time: 6 h

Procedure:
10 g (40 mmol) of N-(benzyloxycarbonyl)-(L)-pyroglutamic acid and 5.84 g (40 mmol) of p-nitrophenol are dissolved in 100 ml of THF. A solution of 8.65 g (42 mmol) of N,N-dicyclohexylcarbodiimide in 40 ml of THF is run in at ordinary temperature, the mixture is stirred for 6 hours and filtered, the filtrate is evaporated, the residue is taken up with ethyl acetate, the mixture is filtered, the filtrate is evaporated and the residue is recrystallized from the same solvent. This gives 60% of a pure product of melting point=141°-2° C.; [α]D25 =-48.7° (C=1, THF).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[C:24]1([CH3:33])[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>CN(C=O)C>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([CH3:33])=[CH:25][CH:26]=3)=[O:32])[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)N2CCN(c3nc(N)nc4sc(-c5ccc(F)cc5)nc34)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.15 mmol) in DMF (1 ml) was added p-tolyl isocyanate (21 μl, 0.17 mmol) in DMF (0.3 ml). The reaction mixture was stirred for 2 hours at room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4. After removing the solvents in vacuo, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (31 mg, 44%).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:33]=[C:32]([CH3:34])[C:20]([O:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[C:19]([CH2:35][CH3:36])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:37][CH3:38])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C1COCC1.[Li+].[OH-]>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:33]=[C:32]([CH3:34])[C:20]([O:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:19]([CH2:35][CH3:36])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:37][CH3:38])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNCCOc1c(C)cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCNCCC(=O)O
Yield: 75.8 %

Procedure:
A solution of ethyl 3-((2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methyl-phenoxy)ethyl)amino)propanoate (88 mg, 0.168 mmol) in MeOH (0.5 mL), THF (0.5 mL) and 2 N aq. LiOH (0.2 mL) is stirred at rt for 2 h. The mixture is concentrated, diluted with 2 N aq. HCl (10 mL) and extracted four times with DCM (4×20 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (63 mg) as an off-white solid; LC-MS: tR=0.93 min, [M+H]+=495.12; 1H NMR (CDCl3): δ 8.37 (s br, 2H), 7.78 (s, 1H), 7.72 (s, 1 H), 7.43 (s, 1H), 7.20 (s, 1H), 4.07-4.18 (m, 2H), 3.99 (s, 3H), 3.34-3.42 (m, 2H), 3.16-3.34 (m, 3H), 2.62-2.76 (m, 4H), 2.33 (s, 3H), 2.09 (m, 2H), 1.81-1.94 (m, 4H), 1.68-1.79 (m, 2H), 1.27 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-])=O)[C:9]=2[OH:18])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[H][H]>[Pd]>[CH:1]1([NH:4][S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=2[OH:18])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1O
Yield: 99.3 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-cyclopropyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (740 mg, 2.53 mmol) was reduced with hydrogen and 10% Pd/C (350 mg) to form the desired product (660 mg, 99%). 1H NMR (MeOD-d4): δ 6.83 (m, 2H), 2.20 (m, 1H), 0.56 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:13][C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=3[N:18]=2)[C:5]([F:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[CH:31]2)=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CN1C(=O)CCC1.C(Cl)Cl.CO.CC(C)=O.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][C:14]1([CH3:21])[O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([F:22])=[CH:4][N:3]=[C:2]([NH:23][C:24]4[CH:33]=[C:32]5[C:27]([CH:28]=[CH:29][N:30]=[CH:31]5)=[CH:26][CH:25]=4)[N:7]=3)=[N:18][C:17]=2[NH:16][C:15]1=[O:19]
Reactant: Nc1ccc2ccncc2c1
Reactant: CC1(C)Oc2ccc(Nc3nc(Cl)ncc3F)nc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC1(C)Oc2ccc(Nc3nc(Nc4ccc5ccncc5c4)ncc3F)nc2NC1=O
Temperature: 100 °C
Yield: 15.5 %

Procedure:
A mixture of 1.6 g 2-chloro-5-fluoro-N4-[2,2-dimethyl-3,4-dihydro-3-oxo-pyrido[3,2-b][1,4]oxazin-6-yl]-4-pyrimidineamine, 800 mg of 7-aminoisoquinoline, 320 mg of palladium acetate, 320 mg of rac-Binap and 3.68 g cesium carbonate in 32 mL of 1,4-dioxane and 8 mL of NMP was heated at reflux at 100° C. overnight under argon. The reaction was cooled, diluted with CH2Cl2/MeOH and filtered. The filtrate was diluted with water and the organic phase evaporated to give the crude product which was dissolved in acetone/MeOH and evaporated onto silica gel. The material was purified by flash chromatography eluting isocratically with CH2Cl2/2 N ammonia solution in MeOH 15:1 to yield 330 mg of the title compound. 1H NMR (DMSO-d6): δ 8.91 (s, 1H), 8.48 (s, 1H), 8.28 (d, 1H), J=5.4 Hz), 8.16 (d, 1H, J=2.1 Hz), 7.82 (m, 2H), 7.68 (d, 1H, J=6 Hz), 7.51 (d, 1H, J=8.1 Hz), 7.30 (d, 1H, J=8.4 Hz), 1.43 (s, 6H); LCMS: purity: 99%; MS (m/e): 432 (MH+)
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:19][O:20]C(=O)C)[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:18])=[N:13][CH:14]=2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.C(O)(=O)C>[C:1]([O:4][CH2:5][CH:6]([CH2:19][OH:20])[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:18])=[N:13][CH:14]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CCn1cnc2cnc(N)nc21)COC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)OCC(CO)CCn1cnc2cnc(N)nc21
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
To a solution of 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (0.48 g, 1.5 mmol) in methanol (9 ml) was added anhydrous potassium carbonate (14 mg, 0.1 mmol) and the solution was stirred for 20 minutes. Two drops of glacial acetic acid were added, the solution was filtered and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (15:1, 10:1) to afford 9-(4-acetoxy-3-hydroxymethylbut-1-yl)-2-aminopurine as a white crystalline solid (124 mg, 30%), m.p. 166°-168°; νmax (KBr) 3440, 3220, 1720, 1650, 1615, and 1580 cm-1 ; δH [(CD3)2SO]1.68 (1H, m, 3'-H), 1.82 (2H, m, 2'-H), 1.98 (3H, s, CH3), 3.41 (2H, t, J4.8 Hz, D2O exchange gives d, CH 2 OH), 3.9-4.05 (2H, AB part of ABX, JAB 10.9 Hz and JAX =JBX 5.8 Hz, CH2OCO), 4.12 (2H, t, J 7.2 Hz, 1'-H), 4.62 (1H, t, J 5.0 Hz, D2O exchangeable, OH), 6.44 (2H, s, D2O exchangeable, 2-NH2), 8.07 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Observed M+, 279.1326. C12H17N5O3 requires 279.1331).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34](O)=[O:35])[CH:29]=1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:34]([C:30]2[CH:29]=[C:28]([CH3:27])[CH:33]=[CH:32][N:31]=2)=[O:35])[CH2:7]1
Reactant: Cc1ccnc(C(=O)O)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cc(C)ccn2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-methyl-pyridine-2-carboxylic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH:18]3[C:30]4[N:29]([CH2:31][C:32]#[N:33])[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22]=4[CH2:21][CH2:20][N:19]3[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[OH-].[Na+]>C(OCC)C>[NH2:33][CH2:32][CH2:31][N:29]1[C:30]2[CH:18]([C:14]3([C:11]4[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=4)[CH2:15][CH2:16][CH2:17]3)[N:19]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:20][CH2:21][C:22]=2[C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC#N)c3ccccc23)C1C1(c2ccc(Cl)cc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)C1C1(c2ccc(Cl)cc2)CCC1
Temperature: -5 °C

Procedure:
Lithium aluminium hydride (0.281 g, 7.41 mmol) was suspended in diethyl ether (40 mL). The slurry was cooled to −5° C. and tert-butyl 1-[1-(4-chlorophenyl)cyclobutyl]-9-(cyanomethyl)-1,3,4,9-tetrahydro-2H-b-carboline-2-carboxylate (2.35 g, 4.94 mmol) was added in small portions. After stirring at −5° C. for 1 h 2N sodium hydroxide solution (15 mL) was added dropwise. After 10 min additional 2N sodium hydroxide solution (60 mL) was added. The aqueous layer was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with water (30 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane, methanol). Yield: 0.16 g (7%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4](N)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[BrH:15]>O>[Br:15][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(N)cccc1F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1c(F)cccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Hydrobromic acid (48% in water, 140 mL) is added slowly to an aliquot of 11 (14.33 g, 101.5 mmol) cooled to 0° C. The resulting solid is broken up with a glass rod and stirred vigorously at 0° C. for 10 min. A solution of sodium nitrite (7.40 g, 107.2 mmol) in water (50 mL) is added slowly (˜1.5 h) to the stirred slurry containing 3-fluoro-2-methoxyphenylamine and hydrobromic acid, maintaining the temperature of the reaction mixture below 5° C. A purple solution of cuprous bromide (9.62 g, 67.1 mmol) in hydrobromic acid (48% in water, 50 mL) is added dropwise to the reaction mixture, maintaining the temperature of the reaction mixture below 5° C. The resulting reaction mixture is heated at 60° C. until the evolution of gas ceases (˜2.5 h). The reaction mixture is cooled to room temperature, and the product extracted with diethyl ether (6×150 mL). The combined organic extracts are washed with brine (3×150 mL), dried over magnesium sulfate, and evaporated under reduced pressure to give 1-bromo-3-fluoro-2-methoxybenzene as a brown oil. This product is of sufficient purity (≧95% by NMR spectroscopy) to use directly in the next synthetic step. 1H NMR (CDCl3): δ 3.95 (d, JH-F=1.5 Hz, 3H, OCH3), 6.88 (apparent t of d, JH-H=8.0 Hz, JH-F=5.5 Hz, 1H, H-5), 7.04 (d, JH-F=10.5 Hz, JH-H=8.0 Hz, JH-H=1.5 Hz, 1H, H-4), 7.30 (d of apparent t, JH-H=8.0 Hz, JH-H=1.5 Hz, JH-F=1.5 Hz, 1H, H-6). 19F{1H} NMR (CDCl3): δ −127.7 (s). 13C{1H} NMR (CDCl3): δ 61.4 (d, JC-F=5.0 Hz, OCH3), 116.2 (d, JC-F=19.5 Hz, C-4), 117.7 (d, JC-F=3.0 Hz, C-1), 124.5 (d, JC-F=8.0 Hz, C-5), 128.5 (d, JC-F=3.5 Hz, C-6), 145.7 (d, JC-F=12.5 Hz, C-2), 156.2 (d, JC-F=250.5 Hz, C-3).