Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:18][O:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[F:15])[N:7]=1.[Na+].[I-:20]>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:6]2[N:7]=[C:2]([I:20])[C:3]3[CH2:18][O:17][CH2:16][C:4]=3[N:5]=2)[CH:13]=1
Reactant: [I-]
Reactant: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)COC2
Agent: [Na+]
Product: Fc1ccc(Cl)cc1-c1nc(I)c2c(n1)COC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-2-(5-chloro-2-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (78 mg, 0.275 mmol, 1 eq) in 57% H(aq) (2 ml) at rt was added NaI (206 mg, 1.37 mmol, 5 eq). The reaction mixture stirred at rt overnight and then was poured onto ice. The product was extracted with chloroform and the aqueous layer was neutralized with NaHCO3 and extracted further with chloroform. The organic layers were combined washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude residue of 2-(5-Chloro-2-fluorophenyl)-4-iodo-5,7-dihydrofuro[3,4-d]pyrimidine which was not further purified.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[CH:7]([NH:15]C=O)[CH2:6][CH:5]1[CH2:18][CH3:19])(=[O:3])[CH3:2].Cl.C([O-])(O)=O.[Na+]>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[C@H:7]([NH2:15])[CH2:6][C@@H:5]1[CH2:18][CH3:19])(=[O:3])[CH3:2]
Reactant: CCC1CC(NC=O)c2cc(Br)ccc2N1C(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC[C@H]1C[C@@H](N)c2cc(Br)ccc2N1C(C)=O
Temperature: 75 °C
Reaction time: 0.67 h
Yield: 83 %

Procedure:
A suspension of (1-acetyl-6-bromo-2-ethyl-1,2,3,4-tetrahydro-4-quinolinyl)formamide (for a preparation see intermediate 4) (0.5 g, 1.538 mmol) in ethanol (4 mL) was treated with HCl (5N in water, 1 mL, 5.00 mmol) and the resulting mixture was stirred at 75° C. for 40 min under microwave irradiation then cooled to room temperature and basified with a saturated NaHCO3 aqueous solution (50 mL). The aqueous phase was extracted with AcOEt (3×50 mL). The combined organic phases were dried over MgSO4 then concentrated in vacuo to give (cis)-1-acetyl-6-bromo-2-ethyl-1,2,3,4-tetrahydro-4-quinolinamine (377 mg, 1.27 mmol, 83%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH:6]=[N:7][OH:8].CN(C=O)C.[Cl:14]N1C(=O)CCC1=O>[Cl-].[Na+].O>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](=[N:7][OH:8])[Cl:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=CC1CCCO1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ON=C(Cl)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
A 250 mL round-bottomed flask was charged with tetrahydrofuran-2-carbaldehyde oxime (2.0 g, 17 mmol) and DMF (100 mL). 1-chloropyrrolidine-2,5-dione (2.3 g, 17 mmol) was added and stirred at ambient temperature overnight. The reaction was poured into 1:1 brine:water (800 mL) and extracted with EtOAc (500 mL). The organic layer was washed twice with water, dried over sodium sulfate, filtered and concentrated to afford the title compound (2.6 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH:13]=O)=[CH:11][N:12]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C([SiH](CC)CC)C>C(Cl)Cl.FC(C(O)=O)(F)F>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH2:13][NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH2:22])=[CH:16][CH:17]=2)=[CH:11][N:12]=1
Reactant: O=Cc1cnc(Nc2ccccn2)s1
Reactant: Nc1ccc(N)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(NCc2cnc(Nc3ccccn3)s2)cc1

Procedure:
A solution of 2-(pyridine-2-ylamino)-thiazole-5-carbaldehyde (0.10 g, 0.49 mmol, WO2004/001059), benzene-1,4-diamine (0.105 g, 0.97 mmol) and triethylsilane (0.19 mL, 1.2 mmol) in CH2Cl2-TFA (3:1, 4 mL) was stirred at ambient temperature for 4 h. The reaction mixture was concentrated in vacuo and the residue partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The organic phase was washed with saturated aqueous NaHCO3 solution, brine, dried (MgSO4) and concentrated in vacuo. The crude product which contained the title compound along with the starting aldehyde and benzene-1,4-diamine was carried on directly into the next step.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]=O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:18](Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC>C(Cl)Cl.C(OCC)C.O1CCCC1.[Zn]>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[CH:18])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCc1ccc(CC=O)cc1
Agent: [Li]CCCC
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCc1ccc(CCCCCCCC)cc1

Procedure:
p-(n-Octyl)phenylacetaldehyde (1 mmole, prepared as described in paragraph A of this example) is dissolved in methylene chloride, and treated with carbontetrabromide (4 mmole), triphenylphosphine (4 mmole) and zinc dust (4 mmole) at room temperature. The reaction mixture is then diluted with ethyl ether and filtered. The filtrate is washed with water, dried and evaporated to give an oily residue. This residue is dissolved in tetrahydrofuran and treated with n-butyl lithium (2.1 mmole) at -78° C. for one hour and then at room temperature until the reaction ceases. The reaction mixture is poured onto water, the pH adjusted to 7, and extracted with methylene chloride. The methylene chloride extract is washed with water, dried and the solvent removed by evaporation. Distillation under reduced pressure affords p-(n-octyl)benzylacetylene.
Reaction SMILES: C(=O)(OC)O[CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH2:15]([NH:22][C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:4]=[CH2:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)OC/C=C/c1ccccc1
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: C=C[C@H](NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a solution of (E)-cinnamyl methyl carbonate (0.50 g) in THF (10 mL) at RT under N2 was added the (S)-(1,1′-Dinaphthyl-2,2′-di-(S,S)-1-phenylethylphosphoramidite* (0.140 g), [Ir(COD)Cl]2 (0.035 g) and benzylamine (0.557 g). The reaction mixture was stirred at reflux overnight, then cooled to RT. MP-TsOH resin (4.07 mmol/g, 2 g) was added to the reaction mixture and the resulting mixture stirred for 1 hr. The resin was then filtered from the reaction mixture and thoroughly washed with MeOH. The isolated resin was then washed separately with ammonia (7 N in MeOH) and the filtrate was concentrated to an oil. The crude material was purified via column chromatography (5% EtOAc/hexanes) to give the desired product (0.26 g, 93.5% ee, 44% yield). 1H NMR (300 MHz, CDCl3) δ 3.73 (s, 2H), 4.22 (d, 1H), 5.12 (d, 1H), 5.22 (dd, 1H), 5.89-6.01 (m, 1H), 7.21-7.38 (m, 10H). MS APCI, m/z=224 (M+1). LC/MS 1.79 min., Method A.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.N1C=CC=CC=1C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[NH4+].[Cl-]>O1CCOCC1.[Cu]I.C(OCC)(=O)C>[CH3:9][O:8][C:4]1[N:3]=[C:2]([CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cccc(Br)n1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1cccc(OC)n1
Temperature: 25 °C

Procedure:
A slurry of 2-bromo-6-methoxypyridine (1.8 g, 9.57 mmol), copper(I) iodide (0.16 g, 0.86 mmol), 2-picolinic acid (0.21 g, 1.72 mmol), cesium carbonate (4.7 g, 14.4 mmol) and diethyl malonate (4.4 mL, 28.7 mmol) in dioxane (15 mL) was heated at 95° C. for 4 days. After cooling to room temperature, ethyl acetate and saturated aqueous NH4Cl were added. The organic phase was separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated. The product was purified twice by flash chromatography (SiO2; heptane/ethyl acetate, gradient 0-80% and second chromatography using heptane/ethyl acetate gradient 0-20%) giving the product.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Cl)[N:24]=1.C(N(CC)C(C)C)(C)C>CCCCO>[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[C:25]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:14])[CH3:3])[N:24]=1
Reactant: Cc1cccc2cc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2cc([C@H](C)Nc3nc(N)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
(S)-3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 4704) (100 mg, 0.36 mmol), 2-Amino-6-chloropurine (compound 5401) (60.9 mg, 0.36 mmol) and N,N-diisopropylethyl amine (69 μL, 0.40 mmol) were suspended in n-BuOH (4 mL) in a sealed tube, and the resulting mixture was stirred at 100° C. for 48 h and then at 120° C. for 24 h. The mixture was allowed to cool to room temperature and concentrate in vacuo to remove n-BuOH. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was triturated with anhydrous ethyl ether and further purified by flash column chromatography on silica gel (eluting with 0-8% MeOH/DCM) to afford the desired product, (S)-3-(1-(2-amino-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one as a off white/yellow solid (5402, compound 323 in Table 4), (28 mg, 20%).
Reaction SMILES: C([NH:3][C:4](=[O:7])[CH:5]=[CH2:6])O.[CH2:8]([O:10][C:11](=[O:14])[CH:12]=[CH2:13])[CH3:9].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C=O>C(O)C.CC(C)=O>[CH2:8]([C:5](=[CH2:6])[C:4]([NH2:3])=[O:7])[OH:10].[CH2:8]([O:10][C:11](=[O:14])[CH:12]=[CH2:13])[CH3:9]
Reactant: C=CC(=O)NCO
Agent: C=CC(=O)OCC
Agent: C=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CC(C)=O
Product: C=C(CO)C(N)=O

Procedure:
56 g of N-methylolacrylamide were dissolved in 1000 ml of ethanol, then added with 23 ml of ethylacrylate and 0.36 g of dibenzoylperoxide and heated to reflux for 6 hours while stirring under nitrogen atmosphere. After cooling the reaction mixture was poured into acetone under good stirring. The polymer was filtered, washed and dried as usual. Yield: 62 g. Analytical results: free CH2O: absent; total CH2O: 19.10%; [η]: 0.12 dl/g in NaNO3N at 30° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:12]([N:11]([CH2:9][CH:5]1[CH2:6][CH2:7][CH2:8][CH:3]([NH2:2])[CH2:4]1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1CCCC(C(=O)N(Cc2ccccc2)Cc2ccccc2)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: NC1CCCC(CN(Cc2ccccc2)Cc2ccccc2)C1
Yield: 75.5 %

Procedure:
A solution of 3-amino-N,N-dibenzylcyclohexane-carboxamide monohydrochloride (0.848 g) in tetrahydrofuran (5 ml) was added dropwise to a suspension of lithium aluminum hydride (0.337 g, 8.89 mmol) in tetrahydrofuran (5 ml), and the resulting mixture was stirred with heating under reflux for 3 hours. The resulting solution was cooled on an ice bath, followed by adding dropwise thereto water (0.33 ml), a 2N-aqueous sodium hydroxide solution (0.66 ml) and water (1.0 ml) in that order. Thereafter, the insoluble material was removed by filtration using Celite. The solvent was distilled off from the filtrate under reduced pressure, followed by replacement with ethanol (once) and toluene (twice). Then, the residue was dried under reduced pressure to obtain 3-[(dibenzylamino)methyl]cyclohexanamine (0.550 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1([CH2:28][CH2:29][C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.CN(C)C=O>C(Cl)Cl.CO>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: O=C(O)CCc1ccccc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: O=C(CCc1ccccc1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 33.4 %

Procedure:
Preparation of example 38 from the title compound of Example 7 (0.030 g, 0.11 mmol), 3-Phenyl-propionic acid (0.025 g, 0.16 mmol), triethylamine (0.077 mL, 0.44 mmol), O(-7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (63 mg, 0.16 mmol) and N,N-dimethylformamide (0.05 M, 2.0 mL) was carried out analogously to Example 11. Silica gel chromatography (95:5 CH2Cl2/methanol) afforded the title compound (15 mg) as a yellow powder in 34% yield.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:21](=[O:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].O>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:21]([OH:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCCCC=O
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCC(O)c1cccc(OCc2ccccc2)c1
Temperature: -70 °C
Yield: 89 %

Procedure:
Under a nitrogen atmosphere, a solution of 17.0 grams (0.065 mole) of 3-(phenylmethoxy)phenyl bromide in 125 mL of tetrahydrofuran was stirred and cooled to -70° C. To this was added dropwise 28.0 mL (0.071 mole) of 2.5M n-butyllithium (in hexanes) during a 15 minute period. The reaction mixture temperature was maintained below -60° C. during the addition. Upon completion of addition, a solution of 11.5 grams (0.068 mole) of undecanaldehyde in 15 mL of tetrahydrofuran was added dropwise during a 5 minute period. Upon completion of addition, the reaction mixture was allowed to warm to 0° C. during a one hour period. The reaction mixture was again cooled to -60° C., and 100 mL of water was added. The reaction mixture was allowed to warm to ambient temperature, and then it was extracted with 200 mL of diethyl ether. The ether extract was washed with 50 mL of water, and then it was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 9:1 petroleum ether and diethyl ether, and 7:3 petroleum ether and diethyl ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 20.5 grams of 1-[3-(phenylmethoxy) phenyl]undecanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:21][C:20](=[O:22])[NH:19][N:18]=2)[CH2:13][CH2:12]1.O.O.Cl[Sn]Cl>CO>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[O:21][C:20](=[O:22])[NH:19][N:18]=3)[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)o1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1ccc(N2CCC(c3n[nH]c(=O)o3)CC2)c(F)c1
Yield: 82.6 %

Procedure:
To a stirred solution of 3,4-difluoro nitrobenzene (1b, 3.5 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(2-fluoro-4-nitrophenyl)-4-piperidine carboxylate (3b, 5.33 g, 86%). To a stirred solution of ester (3b, 5.0 g, 18 mmol) in ethanol, NH2NH2.H2O (2.25 g, 45 mmol) is added and refluxed for 12 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(2-fluoro-4-nitro phenyl)-4-piperidinecarbohydrazide (4b, 4.62 g, 91%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4b, 3.38 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.47 g, 40%). Nitro compound (5b, 1.23 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 920 mg, 83%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodi imide)) (0.19 g, 1 mmol) and amine compound (7e, 0.28 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-3-fluoro-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8e, 333 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]([C:13]3[C:14]([C:18]#[N:19])=[N:15][NH:16][CH:17]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:25][N:24]=1>CC(O)(C)C>[C:33]1([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([NH:1][C:2]3[CH:21]=[CH:20][C:5]([O:6][C:7]4[C:12]([C:13]5[C:14]([C:18]#[N:19])=[N:15][NH:16][CH:17]=5)=[CH:11][CH:10]=[CH:9][N:8]=4)=[CH:4][CH:3]=3)=[N:24][N:25]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: N#Cc1n[nH]cc1-c1cccnc1Oc1ccc(N)cc1
Solvent: CC(C)(C)O
Product: N#Cc1n[nH]cc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
In a 20-mL sealed tube was dissolved 4-(2-(4-aminophenoxy)pyridin-3-yl)-1H-pyrazole-3-carbonitrile (0.120 g, 0.433 mmol) in t-BuOH (1.0 mL). Then 1-chloro-4-phenylphthalazine (0.104 g, 0.433 mmol) was added and the mixture was stirred at 100° C. for 3 days. The reaction was cooled to RT, concentrated and purified on a Gilson reverse phase chromatography system. The title compound was extracted into CH2Cl2, washed 1× saturated NaHCO3 1×H2O, dried over Na2SO4, filtered through fritted funnel and concentrated. The title compound was further purified by silica gel chromatography using 10-100% EtOAc/Hexanes to afford 4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1H-pyrazole-3-carbonitrile as light yellow solid. MS m/z=482 [M+1]+. Calc'd for C29H19N7O: 481.51.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][CH:6]=[C:7]([C:13]([O:15]CC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:18]([C:13]([OH:15])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[N:5]2)=[CH:19][CH:20]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=CNc1cccc(N)c1)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(NC(C)=O)ccc2c1O
Temperature: 250 °C

Procedure:
10.5 Grams of diethyl 3-aminoanilino-methylenemalonate are dissolved in 80 ml of diphenyl oxide, 8 ml of acetic anhydride are added and the mixture is gradually heated to 250° C. and maintained under reflux for 10 minutes. The mixture is allowed to cool, 20 ml of ethanol are added and the solid is filtered off and washed with ethanol. The product is recrystallized in dimethylformamide and 4.6 grams of a solid are obtained, of melting point 295° to 300° C.
Reaction SMILES: NC1N=C(N)C2C(=NC=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)N=1.[CH:27]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[S:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.[NH2:44][C:45]1[N:46]=[C:47]([NH2:57])[C:48]2[CH:54]=[C:53]([CH2:55]Br)[CH:52]=[N:51][C:49]=2[N:50]=1>>[NH2:44][C:45]1[N:46]=[C:47]([NH2:57])[C:48]2[CH:54]=[C:53]([CH2:55][C:37]3[CH:36]=[CH:35][CH:34]=[C:33]4[C:38]=3[NH:39][C:40]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[S:32]4)[CH:52]=[N:51][C:49]=2[N:50]=1
Reactant: Nc1nc(N)c2cc(CBr)cnc2n1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: Br
Agent: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2cc(Cc3cccc4c3Nc3ccccc3S4)cnc2n1

Procedure:
9-[(2,4-Diaminopyrido[2,3-d]pyrimidin-6-yl)methyl]phenothiazine (Formula I: Ar=2,4-diaminopyrido[2,3-d]pyrimidin-6-yl; W=CH2; X=N; Z=S; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by starting from phenothiazine (159 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[NH:19].CC[O-].[Na+]>CCO>[F:16][C:17]([F:22])([F:21])[C:18]1[N:20]=[C:11]([OH:13])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:19]=1
Reactant: N=C(N)C(F)(F)F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C(F)(F)F)nc1O
Yield: 54.9 %

Procedure:
A solution of diethyl ethoxymethylenemalonate (35.0 g, 162 mmol), trifluoroacetamidine (18 g, 162 mmol) and NaOEt (11.0 g, 162 mmol) in EtOH (200 mL) was heated at reflux for 6 h. The reaction mixture was concentrated and H2O (48 mL) was added. The resulting solid was filtered, washed with Et2O (300 mL) and H2O (200 mL), and dried to give the title compound (21 g, 50% yield); m.p. >220° C. (dec.); 1HNMR (DMSO-d6) δ 8.38, 4.16 (q, 2H), 1.25 (q, 3H).