Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][CH2:20][F:21]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:19][CH2:20][F:21])([C:10]#[N:11])[C:12]#[N:13])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: N#CC(C#N)Cc1ccc([N+](=O)[O-])cc1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccc([N+](=O)[O-])cc1
Yield: 20.5 %

Procedure:
Using 0.40 g of (4-nitrobenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.10 g of 2-(4-nitrobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (47)).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH:12]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.C(=O)(O)[O-].[Na+]>C(#N)C.C(O)(=O)C>[C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:15]3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC1CCNCC1
Reactant: O=Cc1cc(-c2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of the compound prepared in Example 7 (500 mg), ethyl 2-(piperidin-4-yl)acetate (494 mg) and acetic acid (0.33 mL) in acetonitrile (15 mL) was stirred for 30 minutes at room temperature. Tetramethylammonium triacetoxyborohydride (2.28 g) was added and the reaction was stirred overnight. The reaction was poured into a saturated aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (675 mg) having the following physical data.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[N:20]=[CH:21][N:22]=[C:4]2[CH:3]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[N:5]2[N:20]=[CH:21][N:22]=[C:4]2[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: N#Cc1ccc(NCCNc2nc(Cl)cc3ncnn23)nc1
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: C1COCCO1
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3ncnn23)nc1
Temperature: 150 °C

Procedure:
60 mg (0.19 mmol) of 6-({2-[(7-chloro[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)amino]ethyl}amino)nicotinonitrile (Example 54A), 35.6 mg (0.19 mmol) of (2,4-dichlorophenyl)boronic acid and 21.6 mg (0.019 mmol) of tetrakis(triphenylphosphine)palladium(0) are introduced into a mixture of 4 ml of dioxane and 1.3 ml of saturated aqueous sodium carbonate solution under argon. The mixture is degassed with argon and then heated in a microwave at 150° C. for 30 min. Cooling is followed by filtration through an Extrelut® cartridge. Purification by preparative HPLC results in 15.3 mg (19% of theory) of the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11]O.P(Br)(Br)[Br:14].C([O-])(O)=O.[Na+]>C1COCC1>[Br:14][CH2:11][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=1[Cl:10]
Reactant: BrP(Br)Br
Reactant: COc1cc(Cl)c(CO)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(CBr)c(Cl)c1
Yield: 219.6 %

Procedure:
Dissolve (2,6-dichloro-4-methoxy-phenyl)-methanol (113 g, 545.76 mmol) in 1200 mL dry THF and cool to 0 deg under nitrogen. Add PBr3 (59.1 g, 218.3 mmol) under nitrogen and stir at 0° C. for 30 minutes. Pour into saturated aqueous NaHCO3 and extract with EtOAc. Dry and concentrate under vacuum to obtain 129.4 g product as an off-white solid. NMR (CDCl3) δ 6.88 (s, 2H), 4.73 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH:29]([C:31]1[O:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:34]4[O:35][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: O=Cc1ccc(B(O)O)o1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)o3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Yield: 43.6 %

Procedure:
To a stirred solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.2 g, 0.45 mmol) and (5-formylfuran-2yl)boronic acid (0.075 g, 0.542 mmol), in dioxane/water mixture (4 mL+1 mL), Cs2CO3 (0.368 g, 1.13 mmol) was added and solution purged with argon for 15 min. Pd(PPh3)4 (0.052 g, 0.045 mmol) was then added and argon was purged again for 10 min. The reaction mixture was heated at 100° C. for 2 h. On completion, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-methyl)-6-(5-formylfuran-2yl)-1H-indazole-4-carboxamide (0.09 g, 43.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:18][C:11]3[N:12]=[C:13]([CH3:17])[NH:14][C:15](=O)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:15]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:18][C:11]=2[N:12]=[C:13]([CH3:17])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Yield: 6 %

Procedure:
A solution of 6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (0.2 g, 0.77 mmol) and diisopropylethylamine (0.26 ml, 1.54 mmol) in POCl3 (4 ml) was stirred under N2 at 90° C. for 3.5 hours. The reaction mixture was allowed to cool down to room temperature and poured into an ice-bath. The aqueous phase was extracted with diethyl ether. The combined organic layers were washed with a half-saturated NaHCO3 solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (14 mg, 6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[CH2:11]([O:13][C:14](=[O:23])[C:15](=O)[CH2:16][C:17](=O)[CH:18]([CH3:20])[CH3:19])[CH3:12]>CCO.C1(C)C=CC=CC=1>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH:18]([CH3:19])[CH3:20])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:10]=1)=[O:23])[CH3:12]
Reactant: COc1ccccc1NN
Reactant: CCOC(=O)C(=O)CC(=O)C(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(C)C)n(-c2ccccc2OC)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
2-Methoxyphenylhydrazine (14.07 g, 81 mmol) in EtOH (100 mL) was added dropwise to a refluxing solution of 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (10 g, 53.7 mmol) in toluene (100 mL), under an argon atmosphere. The reaction mixture was stirred for 18 h at 100° C., allowed to cool to rt, concentrated, diluted with a saturated aqueous solution of sodium bicarbonate (250 mL), and extracted with EtOAc. The organic extracts were washed with a saturated aqueous solution of sodium bicarbonate, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5→7:3) to provide 10.1 g of the title compound. tR: 1.11 min (LC-MS 4);
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:28][CH:29]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)c2ccc(C(F)(F)F)cc2)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 4-Trifluoromethylbenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(4-trifluoromethylbenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:22])[C:5]([O:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH:14]([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[OH-].[Na+].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:22])[C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH3:19])[C:15]([OH:17])=[O:16])=[CH:20][CH:21]=2)=[N:6][CH:7]=1
Reactant: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture of 67.0 g (0.206 mole) of methyl 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionate, 350 ml of dioxan and 250 ml of 1N sodium hydroxide solution is stirred for 2 hours at 40° C. The reaction mixture is poured into a mixture of ice and 150 ml of 2N hydrochloric acid and extracted twice with ethyl acetate. The extracts are washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated by evaporation, affording 63.6 g (99% of theory) of 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionic acid with a melting point of 95°-97° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[N:7]=1>C(O)C>[CH:1]([NH:4][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[N:7]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.55 mL (29.96 mmol) of isopropylamine is added to a solution of 1.25 g (5.99 mmol) of 2-chloro-6-nitroquinoline in 50 mL of ethanol and the mixture is stirred for 18 hours at ambient temperature. Then the reaction mixture is heated to 65° C. in the microwave for 2 hours. The reaction mixture is then evaporated down, the residue is taken up in 20 mL of DMF, combined with 2.55 mL (29.96 mmol) of isopropylamine, and stirred for 18 hours at ambient temperature. The reaction mixture is evaporated down and the residue is combined with ethyl acetate and water. The organic phase is extracted twice with water. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is then removed. Yield: 0.75 g (54.1% of theory); C12H13N3O2 (M=221.25); calc.: molecular ion peak (M+H)+: 232; found: molecular ion peak (M+H)+: 232; Rf value: 0.48 (silica gel, petroleum ether/ethyl acetate (2:1)).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1.[H][H]>C(O)C.[Pd]>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(CN2C(=O)c3ccccc3Oc3ccccc32)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(CN2C(=O)c3ccccc3Oc3ccccc32)cc1
Yield: 94.5 %

Procedure:
Compound 416 (0.364 g, 0.912 mmol) was dissolved in ethanol (10.0 mL) and the palladium on charcoal (0.037 g, 10% w/w) was added. The reaction mixture was stirred over 1 atmosphere of hydrogen at room temperature for 1 hour. The catalyst was filtered and the filtrate was concentrated to afford title compound 417 (346 mg, 95%) that was used crude for next step. MS (m/z): 402.4 (M+H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH:24]([CH3:26])[CH3:25])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[C:27]([O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][C:18]=1[O:23][CH:24]([CH3:26])[CH3:25])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)Oc1cc(OCc2ccccc2)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(OCc2ccccc2)ccc1OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Triethylamine (4.27 mL, 30.7 mmol) was added to a solution of 4-(benzyloxy)-2-isopropoxyphenol (2.64 g, 10.22 mmol) in dry CH2Cl2 (40.9 mL) and the resulting solution was cooled to 0° C. Benzoyl chloride (1.54 mL, 13.29 mmol) was added dropwise and the reaction was stirred at 25° C. overnight. The reaction mixture was washed with water (50 mL). The aqueous layer was separated and extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give the crude product. This was azeoptoped with toluene to afford 4-(benzyloxy)-2-isopropoxyphenyl benzoate. LCMS calc.=385.1; found=385.0 (M+Na)+. 1H NMR (500 MHz, CHCl3): δ 8.25-8.21 (2 H, m), 7.66-7.60 (1 H, m), 7.52 (2 H, t, J=7.7 Hz), 7.47 (2 H, d, J=7.5 Hz), 7.44-7.39 (2 H, m), 7.39-7.33 (1 H, m), 7.12-7.05 (1 H, m), 6.73-6.68 (1 H, m), 6.60 (1 H, dd, J=8.7, 2.8 Hz), 5.07 (2 H, s), 4.54-4.43 (1 H, m), 1.27 (6 H, t, J=6.1 Hz).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[S:6][C:2]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[C:3]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2-c2ccncc2)cc1
Temperature: 120 °C
Yield: 23.1 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.2 g, 0.43 mmol) in 5 ml of anhydrous DMF:H2O (2:1) 4-pyridine boronic acid (0.108 g, 0.87 mmol), potassium phosphate (0.112 g, 0.51 mmol) was added. Then degassed the reaction mixture for the 10 minutes, and added dichlorobis [(triphenylphosphine)-palladium (II) (0.046 g, 0.06 mmol) and again degassed for 10 min. The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. DMF was distilled off, after cooling to r.t. water was added into reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.045 g, 49%). 1H NMR (DMSO-d6, 400 MHz): δ 3.80 (s, 3H), 5.59 (s, 2H), 6.94 (d, 2H, J=8.8 Hz (o-coupling), 7.14 (dt, 1H), 7.34 (d, 1H, J=6.0 Hz (o-coupling), 7.38 (d, 2H, J=8.8 Hz (o-coupling), 7.41-7.45 (m, 1H), 7.89 (broad s, 1H), 8.17 (s, 1H), 8.60 (dd, 1H) MS ES+ (454.12), HPLC (method 5) Rt=13.55 min.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:26][CH:25]=5)[CH2:20][CH2:19]4)[CH:8]3[N:9]=2)=[C:5]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)[N:4]=[CH:3]1.[H-].[Na+].O.[CH3:43]N(C=O)C>>[O:36]1[CH:37]=[CH:38][CH:39]=[C:35]1[C:5]1[N:4]=[CH:3][N:2]([NH:1][CH3:43])[C:10]2[C:6]=1[N:7]1[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)[CH:8]1[N:9]=2
Reactant: CN(C)C=O
Reactant: COCCOc1ccc(N2CCN(CCN3C(=O)N(C)N4C5=C(c6ccco6)N=CN(N)C5=NC34)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CNN1C=NC(c2ccco2)=C2C1=NC1N(CCN3CCN(c4ccc(OCCOC)cc4)CC3)C(=O)N(C)N21
Temperature: 21 °C
Reaction time: 3 h

Procedure:
A mixture of 5-amino-8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-1-yl]ethyl]-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one (0.1 g, 0.18 mmol) obtained in example 1, NaH (0.043 g, 0.18 mmol) and methyl iodode (0.1 ml, 0.18 mmol)in DMF (2 ml) were stirred at 21° C. for 3 hours. To the reaction mixture water (10 ml) was added and solid obtained was filtered. The crude product was purified by column chromatography to obtain 8-(2-furyl)-3-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-1-yl]ethyl]-1-methyl-5-(methylamino)-[1,2,4]triazolo[5,1-f]purin-2-one. (5 mg, 5%) as an off white solid.
Reaction SMILES: [O:1]([C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[N:14]=[C:15]=[S:16])[CH2:9]1)=[O:7])[C:2]([CH3:5])([CH3:4])[CH3:3].C[O:18][C:19](=O)[C:20]([NH2:31])([CH2:28][CH:29]=[CH2:30])[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[C:2]([O:1][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[N:14]2[C:19](=[O:18])[C:20]([CH2:28][CH:29]=[CH2:30])([CH2:21][C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[NH:31][C:15]2=[S:16])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:5]
Reactant: C=CCC(N)(Cc1ccncc1)C(=O)OC
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2N=C=S
Product: C=CCC1(Cc2ccncc2)NC(=S)N(C2C3CN(C(=O)OC(C)(C)C)CC32)C1=O
Yield: 87.9 %

Procedure:
Using the same procedure as described in Example 2B, 3-(tert-butoxylcarbonyl)-6-isothiocyanato-3-aza-bicyclo[3.1.0]hexane (23.4 mmol, prepared in 1A) and 2-amino-2-allyl-3-pyridin-4-yl-propionic acid methyl ester (11.6 mmol) were reacted to afford the title compound of 30A (4.37 g, 10.2 mmol, 88% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:24][CH2:23]1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8])([O-])=O>C(O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:24][CH2:23]1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8]
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reaction time: 8 h
Yield: 50.2 %

Procedure:
3-Nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide (1.5 g, 3.2 mmol) was taken in a mixture of ethanol/methanol (50.0 mL/20.0 mL). This was added to a flask containing Pd/C (5 wt %) (0.15 g). The solution was evacuated and nitrogen purged and stirred under a balloon of hydrogen for 8 h. LC-MS indicated completion of reaction. Reaction was stopped, evacuated and nitrogen purged and filtered on celite. The solvent was rotavaped out to give 3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide (0.7 g, 47%).
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C([NH:7][C:8]1[C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:16]2[C:11]([CH:12]3[CH2:25][CH:13]3[CH2:14][O:15]2)=[CH:10][CH:9]=1)=O>C(O)C>[NH2:7][C:8]1[C:17]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[C:16]2[C:11]([CH:12]3[CH2:25][CH:13]3[CH2:14][O:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)C(F)(F)F)ccc2c1OCC1CC21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1c(N)ccc2c1OCC1CC21
Yield: 54.7 %

Procedure:
Sodium borohydride (0.32 g) was added in portions to a stirred solution of tert-butyl (1aRS,7bSR)-5-(trifluoroacetylamino)-1,1a,2,7b-tetrahydro-cyclopropa-[c]chromene-4-carboxylate (Intermediate 123, 0.5 g) in ethanol (20 mL). The resultant mixture was stirred at room temperature for 1 hour then concentrated under vacuum. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether with a gradient of 2-4% to give tert-butyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.2 g) as a white solid.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[CH3:20])[C:10]2[N:21]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[S:23][C:9]=2[C:8](=[O:30])[N:7]=1)[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][CH:4]([C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[CH3:20])[C:10]2[N:21]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[S:23][C:9]=2[C:8](=[O:30])[N:7]=1)[CH3:5]
Reactant: Cc1c(Cl)cccc1Cn1c(C(C)N=[N+]=[N-])nc(=O)c2sc(N3CCOCC3)nc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1Cn1c(C(C)N)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(1-azidoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (48 mg, 0.108 mmol) in Tetrahydrofuran (THF) (1 mL) was added resin-bound triphenylphosphine (28.2 mg, 0.108 mmol) and the mixture was stirred at 60° C. overnight. The reaction was then quenched with water and stirred at 60° C. for 1 hr. The resin was removed by filtration and the filtrate was then extracted with dichloromethane. The organic solution was dried over sodium sulfate, filtered, and concentrated to provide the desired product as a brown solid. This crude material was purified on a silica gel column eluting with chloroform/(a solution of 2M ammonia in methanol) (99:1). The fractions containing product were combined, then concentrated to provide 5-(1-aminoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl) [1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (19 mg, 0.045 mmol, 42.0% yield). LC/MS m/z MH+=420 (theoretical), found=420.1, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (d, J=6.82 Hz, 3H) 2.48 (s, 3H) 3.53-3.63 (m, 4H) 3.72-3.85 (m, 5H) 4.02 (br. s., 1H) 5.42 (d, J=17.68 Hz, 1H) 5.78 (d, J=17.18 Hz, 1H) 6.49 (d, J=7.83 Hz, 1H) 7.07 (t, J=7.96 Hz, 1H) 7.34 (d, J=7.83 Hz, 1H)