Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:37]1([NH2:40])[CH2:39][CH2:38]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[N:8][N:7]4[C:2]([NH:40][CH:37]5[CH2:39][CH2:38]5)=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: NC1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn3c(NC4CC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
To a solution of 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.39 g, 0.93 mmol) in toluene (20 mL) was added successively racemic-BINAP (34.7 mg, 0.06 mmol), cesium carbonate (0.91 g, 2.8 mmol), cyclopropylamine (0.64 mL, 9.3 mmol) and palladium (II) acetate (8.3 mg, 0.04 mmol). The resultant mixture was heated under reflux for 8 hours. After cooling to room temperature the reaction mixture was partitioned between ether and water. The organic layer was washed with brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (3:1 hexanes-ethyl acetate) provided 3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-methoxyphenyl)pyrazolo-[1,5-a]pyridin-7-amine (0.30 g, 73%) as a pale yellow solid. 1H NMR (CDCl3): δ 7.95 (d, 1 H), 7.85 (d, 1 H), 7.56 (d, 2 H), 7.36 (t, 1 H), 6.99 (d, 2 H), 6.40 (d, 1 H), 6.33 (m, 2 H), 4.38 (m, 1 H), 3.88 (s, 3 H), 2.68 (m, 1 H), 2.09 (m, 2H), 1.81–1.57 (m, 6 H), 0.89 (m, 2 H), 0.75 (m, 2 H); MS m/z 441 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:35][CH:34]([N:36]([CH3:38])[CH3:37])[C:33]([CH3:40])([CH3:39])[CH2:32]2)[N:3]=1>CC(O)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:35][CH:34]([N:36]([CH3:38])[CH3:37])[C:33]([CH3:40])([CH3:39])[CH2:32]2)[N:3]=1
Reactant: CN(C)C1CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)CC1(C)C
Solvent: O
Solvent: CC(=O)O
Product: CN(C)C1CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)CC1(C)C
Yield: 51.3 %

Procedure:
A solution of [(2R)-3-(2-{2-chloro-6-[4-(dimethylamino)-3,3-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.0681 g, 0.117 mmol) in 4:1 HOAc-water (5 mL) was stirred for 56 h and then concentrated in vacuo. A solution of the residue in DCM (100 mL) was washed with sat. aq. NaHCO3 (30 mL), and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Gilson RPLC and crystallized from EtOAc-hexanes to provide [(2R)-3-(2-{2-chloro-6-[4-(dimethylamino)-3,3-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (0.0300 g, 51% yield, mixture of diastereomers) as a white solid. LCMS: (M+H)+: 500.3.
Reaction SMILES: [O-2].[Zn+2:2].[P:3](=[O:7])([OH:6])([OH:5])[OH:4]>[Zn].O>[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[Zn+2:2].[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[Zn+2:2].[Zn+2:2]
Reactant: O=P(O)(O)O
Agent: [O-2]
Agent: [Zn+2]
Agent: [Zn]
Solvent: O
Product: O=P([O-])([O-])[O-]
Temperature: 70 °C
Yield: 101.5 %

Procedure:
In a ball mill 438 g of zinc oxide and 4 g of metallic zinc (powder) are ground by the wet grinding method in the presence of 500 g of water, whereafter an additional 1,000 g of water are added thereto. The resulting slurry is heated to a temperature of 70° C. and under continuous stirring 350 g of phosphoric acid are added thereto (as calculated for 100% H3PO4). After 40 minutes the slurry is filtered, the residue is washed and dried to give 700 g of zinc phosphate (the yield is 98%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Cl:38])=[C:30]([CH:37]=2)[O:31][C@@H:32]([CH3:36])[C:33]([OH:35])=O)[C:20]([CH3:39])=[C:19]3[CH3:40])=[O:15])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:44][C:33](=[O:35])[C@@H:32]([O:31][C:30]1[CH:37]=[C:26]([CH:27]=[CH:28][C:29]=1[Cl:38])[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([C:14]([NH:13][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=3)[CH3:12])=[O:15])=[CH:24][CH:23]=2)[C:19]([CH3:40])=[C:20]1[CH3:39])[CH3:36]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C)n(Cc2ccc(Cl)c(O[C@@H](C)C(=O)O)c2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)n(Cc2ccc(Cl)c(O[C@@H](C)C(N)=O)c2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Yield: 89.3 %

Procedure:
A solution of (S)-2-(5-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoic acid (20 mg, 0.036 mmol), NH4Cl (19 mg, 0.36 mmol), HATU (14 mg, 0.036 mmol) and DIEA (25 μl, 0.144 mmol) in DCM (0.5 ml) was stirred at rt for 1 h. After concentration, the obtained oil was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to afford a white powder (18 mg). ESI-MS (m/z): 560/561/562 [MH]+.
Reaction SMILES: COC(C1OC(C2[Se]C=CC=2[C:15]([C:17]2[CH:21]=[CH:20][Se:19][C:18]=2[C:22]2[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:26]=2)=O)=CC=1)=O.[C:31]1([NH:37][NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1>C(O)(=O)C>[CH3:30][O:29][C:27]([C:24]1[O:23][C:22]([C:18]2[C:17]3[CH:21]=[CH:20][Se:19][C:15]=3[N:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:38]=2)=[CH:26][CH:25]=1)=[O:28]
Reactant: NNc1ccccc1
Reactant: COC(=O)c1ccc(-c2[se]ccc2C(=O)c2cc[se]c2-c2ccc(C(=O)OC)o2)o1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2nn(-c3ccccc3)c3[se]ccc23)o1

Procedure:
Compound 73 (3.8 g, 0.013 mole), phenylhydrazine 8 (5.0 g, 0.046 mole) and glacial acetic acid (1.5 ml) were allowed to react as in the preparation of compound 55 to afford compound 78. Yield: 0.62 g (12.8%); white needle crystals; mp 167-169° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([OH:26])=O)=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl.CN.[CH2:30]([N:32]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O.O>[NH2:1][C:2]1[C:3]([C:24]([NH:32][CH3:30])=[O:26])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)n1cc(-c2nc(C(=O)O)c(N)nc2-c2ccccc2)ccc1=O
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
A mixture of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylic acid (70 mg), methylamine hydrochloride (14.8 mg), 1-ethyl-3-[3′-(dimethylamino)propyl]-carbodiimide (34.1 mg), and 1-hydroxy-benzotriazole (29.7 mg) in CH2Cl2 (0.7 ml) was stirred at 25° C. for 4 hours. Water and EtOAc were poured into the mixture. The organic layer was separated, washed with water, sat. aq. NaHCO3, and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane-EtOAc then CH2Cl2—MeOH) and then crystallized from MeOH-IPE to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-N-methyl-5-phenyl-2-pyrazinecarboxamide (40 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([S:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:12])[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[C:1]([C:5]1[CH:10]=[C:9]([S:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:31])=[O:12])[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cc(S(=O)c2nccs2)cc(C(C)(C)C)c1O
Solvent: ClCCl
Product: CC(C)(C)c1cc(S(=O)(=O)c2nccs2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
2,6-Di-tert-butyl-4-(2-thiazolylsulfinyl)phenol (produced in Example 57) (0.87 g) was dissolved in 50 ml of dichloromethane and, with ice cooling and stirring, 1.89 g of 70% m-chloroperbenzoic acid was added, and stirring was further continued at room temperature for 30 minutes. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. Purification of the crude product obtained by silica gel column chromatography (chloroform) gave 0.50 g of the desired compound as a colorless solid.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][C:9]2[O:13][C:12]([C:14](O)=[O:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(Cl)[Cl:18]>S(Cl)(Cl)=O.CN(C=O)C>[ClH:18].[N:2]1([CH2:8][C:9]2[O:13][C:12]([C:14]([Cl:1])=[O:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(CN2CCOCC2)o1
Reactant: ClCCl
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(CN2CCOCC2)o1
Temperature: 25 °C
Yield: 83 %

Procedure:
A suspension of 5-morpholin-4-ylmethyl-furan-2-carboxylic acid hydrochloride in thionyl chloride with 2 drops of DMF was refluxed under N2 for 3 hours, then cooled to room temperature. Dry CH2Cl2 was added and solvents were evaporated in vacuo. The residue was triturated with dry CH2Cl2, and the resulting solid was filtered, washed with dry CH2Cl2 and dried in vacuo to give 373 mg (83% yield) of 5-morpholin-4-ylmethyl-furan-2-carbonyl chloride hydrochloride as a white solid. 1H-NMR (d6-DMSO) δ: 11.54 (broad s, 1H), 7.26 (d, 1H), 6.92 (d, 1H), 4.49 (s, 2H), 3.94 (m, 2H), 3.74 (m, 2H), 3.28 (m, 2H), 3.09 (broad s, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[OH:8].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[OH:8][C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[NH:1][C:10]1[CH2:14][S:13][C:12](=[O:15])[N:11]=1
Reactant: O=C1NC(=S)CS1
Reactant: N[C@H]1CCCC[C@@H]1O
Solvent: CCO
Product: O=C1N=C(N[C@H]2CCCC[C@@H]2O)CS1
Yield: 42.2 %

Procedure:
To a solution of (1S,2S)-2-aminocyclohexanol (1.00 g) in ethanol (30 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.17 g), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (786 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C@@H](CO)C(N1CCC(C2C(F)=CC(N3C[C@H](CNC4C=NC=CN=4)OC3=O)=CC=2F)=CC1)=O>>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][CH:12]=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccn1
Agent: O=C([C@@H](O)CO)N1CC=C(c2c(F)cc(N3C[C@H](CNc4cnccn4)OC3=O)cc2F)CC1
Product: CC(C)(C)OC(=O)Nc1ncccn1
Yield: 93.1 %

Procedure:
2-(Di-(t-butoxycarbonyl)amino)pyrimidine (5.2 g, 17.6 mM) was hydrolysed by essentially the technique for the appropriate intermediate of Example 22 to give the title product as a white solid (3.2 g). NMR (DMSO-d6) δ: 1.43 (s, 9H); 7.08 (t, 1H); 8.57 (d, 2H); 9.91 (s, 1H). MS (ESP): 196 (MH+) for C9H13N3O2
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.Br[CH2:20][CH2:21][O:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOC(C)=O>[CH3:23][O:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COCCBr
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCOc1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (400 mg, 1.65 mmol), 1-bromo-2-methoxyethane (436 mg, 3.14 mmol), potassium carbonate (434 mg, 3.14 mmol), and dimethyl sulfoxide (5 mL) was stirred at 135° C. overnight. After cooling, the mixture was diluted with EtOAc and washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-100% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:14]=1.[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>>[N+:15]([C:4]1[C:3]([O:2][CH3:1])=[CH:14][C:7]2[CH2:8][C:9](=[O:13])[NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)CC(=O)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(cc1[N+](=O)[O-])CCNC(=O)C2
Temperature: 0 °C

Procedure:
765 mg (4 mmol) of 8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one were added to a mixture of 15 ml of concentrated nitric acid and 1.5 ml of fuming nitric acid at a temperature between 3° and 5° C., while stirring. After stirring at this temperature for 30 minutes more, the mixture was poured into ice water, and the aqueous mixture was neutralized with potassium carbonate. The precipitate formed thereby was suction-filtered off, washed with water and dried. The yellow crystals were purified by chromatography on silica gel, using ethyl acetate as the eluant, to separate the corresponding 9-nitro- and 7,9-dinitro-isomers.
Reaction SMILES: C([Mg]CCCC)CCC.[CH3:10][Si:11](Cl)([CH3:13])[CH3:12].CC1N(C(N(C)C)=O)C1.[CH2:24]([O:26][C:27]([CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)=[O:28])[CH3:25].C(=O)([O-])O.[Na+]>C1COCC1.CCCCCCC.CCCCCC.O>[CH2:24]([O:26][C:27]([C@@H:29]1[CH2:34][CH2:33][C:32]([O:35][Si:11]([CH3:13])([CH3:12])[CH3:10])=[CH:31][CH2:30]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Agent: CC1CN1C(=O)N(C)C
Agent: CCCC[Mg]CCCC
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)[C@H]1CC=C(O[Si](C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
To (S,S)-bis α-methyl benzylamine (9 g, 40 mmol) in THF (200 mL) under argon was added dibutyl magnesium in heptane (20 mL, 1M) and the mixture heated to reflux. After 1.5 hours, the mixture was cooled to −78° C. and trimethylsilyl chloride (10.1 mL) and N,N-dimethylpropyleneurea (1.2 mL) added dropwise. After a further 20 minutes ethyl-4-oxocyclohexane carboxylate (2.87 mL, 18 mmol) was added dropwise. The reaction was stirred at −78° C. for 16 hours, then saturated sodium hydrogen carbonate (100 mL), water (100 mL) and hexane (200 mL) were added. The organic soluble material was purified by chromatography on silica gel eluting with 0-5% diethyl ether in hexane to give an oil (3.5 g, 80%).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:14][C:13]3[CH:15]=[C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:22])[CH:17]=[N:18][C:12]=3[NH:11][C:10](=[O:36])[CH2:9]2)=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C.CO.C(Cl)Cl>[CH3:35][N:23]([CH2:24][C:25]1[N:26]([CH3:34])[C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[N:18][C:12]2[NH:11][C:10](=[O:36])[CH2:9][NH:8][CH2:14][C:13]=2[CH:15]=1
Reactant: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)N(C)Cc4cc5ccccc5n4C)cc3C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CNCC(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A solution of (E)-3-[4-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (2.00 g, 3.92 mmol), from Example 65, in dichloroethane (80 mL) was cooled in an ice bath and treated with 1-chloroethyl chloroformate (0.47 mL, 4.31 mmol). After stirring at 0° C. under N2 for 30 min and then at room temperature for 30 min, the mixture was heated to reflux for 1.5 h. The mixture was allowed to cool and then concentrated to dryness. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3) gave a tan solid. The solid was suspended in methanol and heated to reflux for 2 h. The mixture was allowed to cool and the solid was isolated by filtration, dissolved in CH2Cl2, washed with 1 N NaOH, dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3 to 95:5) gave the title compound (0.70 g, 49%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.38-8.33 (m, 2H), 7.72-7.67 (m, 1H), 7.60-7.57 (m, 2H), 7.32-7.20 (m, 3H), 7.14-7.09 (m, 1H), 6.90-6.80 (m, 1H), 6.49-6.38 (m, 1H), 4.93-4.78 (m, 2H), 4.08 (s, 2H), 3.95 (s, 2H), 3.71 (s, 3H), 3.13-3.07 (m, 3H); MS (ESI) m/e 390 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>COCCOC.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>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(Br)cn1
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: COCCOC
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
439 mg (0.38 mmol) Pd(PPh3)4 was added under argon at room temperature (r.t.) to a solution of 823 mg (3.76 mmol) 5-bromo-pyridine-2-carbaldehyde in 30 ml 1,2-dimethoxyethane and stirred for 15 min. 14.5 ml (29.0 mmol) of 2 M sodium carbonate solution and 1.00 g (5.27 mmol) 4-trifluoromethyl-phenylboronic acid were added and the mixture heated to boiling temperature for 18 hours (h). The reaction mixture was cooled to room temperature (r.t.), filtered, and the filtrate evaporated. The residue was taken up with ethyl acetate, washed twice with water, dried over sodium sulphate and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 630 mg (48%) of 5-(4-trifluoromethyl-phenyl)-pyridine-2-carbaldehyde.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[O:6][C:7]1[CH:8]=[C:9]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=1)=O.[CH2:29]([NH2:32])[CH2:30][CH3:31].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[N+:26]([C:25]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:15])=[O:16])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:1][NH:32][CH2:29][CH2:30][CH3:31])([O-:28])=[O:27]
Reactant: O=Cc1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under N2, a mixture of N-[3-(3-formyl-4-nitrophenoxy)-phenyl]-benzenesulfonamide (0.0060 mol) and propylamine (0.0085 mol) in DCE (50 mL) was stirred at room temperature, then NaBH(OAc)3 (0.0080 mol) was added and the reaction mixture was stirred overnight at room temperature. A saturated NaHCO3 solution (50 mL) was added and the layers were separated. The organic layer was dried, filtered off and the solvent was evaporated. The residue was purified over silica gel filter (eluent: 98:2 CH2Cl2:CH3OH). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[OH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O>>[CH2:1]([NH:3][CH2:8][C:7]1[CH:6]=[C:5]([OH:4])[CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: O=Cc1cccc(O)c1
Reactant: CCN
Product: CCNCc1cccc(O)c1

Procedure:
prepared by reaction of ethylamine with 3-hydroxy-benzaldehyde
Reaction SMILES: [CH2:1]([NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][NH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:17][C@@H:18]1[C@@H:22]([CH2:23][OH:24])[O:21][C@@H:20](N2C=CC(=O)NC2=O)[CH2:19]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[F:17][C@@H:18]1[C@@H:22]([CH2:23][OH:24])[O:21][C@@H:20]([N:12]2[CH:11]=[N:10][C:9]3[C:13]2=[N:14][CH:15]=[N:16][C:8]=3[NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:19]1
Reactant: CCCCCCNc1ncnc2[nH]cnc12
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCNc1ncnc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 96 h
Yield: 29.6 %

Procedure:
6-Hexylamino-9H-purine (0.67 g, 2.6 mmoles, Sigma Chemical Company) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in potassium phosphate buffer (50 ml, 10 mM), pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 4 days, MeOH (175 ml) was added to the reaction. The reaction was applied to a column containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (92:8). Fractions containing product were pooled, concentrated, and then flash chromatographed again on silica gel (2.5×20 cm) with dichloromethane:acetone (9:1). Solvent was removed and lyophilization yielded 9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-(hexylamino)-9H-purine (29%) (0.22 g): mp 83° C.;
Reaction SMILES: [Cl-].[Al+3].[Li+].[Cl-].[Cl-].[Cl-].[Cl-].[Al+3].[Cl-].[Cl-].[O:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]#[N:29])[CH2:23][CH2:22]3)[C:15]=2[O:14][CH2:13][CH2:12]1.[OH-].[Na+]>CCOCC.O1CCCC1.C(Cl)Cl>[NH2:29][CH2:28][CH2:27][N:24]1[CH2:23][CH2:22][N:21]([C:20]2[C:15]3[O:14][CH2:13][CH2:12][O:11][C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH2:26][CH2:25]1
Reactant: N#CCN1CCN(c2cccc3c2OCCO3)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: NCCN1CCN(c2cccc3c2OCCO3)CC1
Yield: 95.3 %

Procedure:
A suspension of lithium aluminium chloride (8.2 g) in dry ether (170 ml) was treated dropwise with a solution of aluminium chloride (8.2 g) in ether (170 ml) under cooling. After stirring for half an hour at room temperature a solution of 1-(1,4-benzodioxan-5-yl)-4-cyanomethylpiperazine (9.4 g) in dry tetrahydrofuran (250 ml) was added dropwise at 15° C. After reflux for 1.5 h the mixture was cooled and conc. sodium hydroxide solution (40 ml) was added dropwise. Filtration and removal of solvent in vacuo gave an oil which was dissolved in methylene chloride and dried over magnesium sulfate. Removal of solvent in vacuo gave 1-(2-amino-1-ethyl)-4-(1,4-benzodioxan-5-yl) piperazine (9.1 g) as a viscous oil.