Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[C:8](OC(=O)C)(=[O:10])[CH3:9].[OH-].[Na+]>CC(C)=O>[C:8]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)NCCCN(C)C
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
A 51.1 g (0.50 mol) portion of N,N-dimethyl-1,3-diaminopropane was put into a flask and cooled to 5° C. while stirring in an atmosphere of nitrogen. Under ice-cooling, to this was added dropwise 51.1 g (0.50 mol) of acetic anhydride spending 1 hour. After completion of the dropwise addition, this was further stirred at 25° C. for 3 hours. Thereafter, the reaction mixture was again ice-cooled and 41.6 g (0.5 mol) of 48% sodium hydroxide aqueous solution was added dropwise thereto spending 15 minutes and then, after completion of the dropwise addition, 350 ml of acetone was added to the reaction mixture and allowed to stand at room temperature for 8 hours. Sodium acetate precipitated in the acetone solution was removed by filtration, acetone was evaporated under a reduced pressure and then 71 g of the remaining yellow oil was distilled under a reduced pressure to obtain the title compound as a transparent oil. Yield 62.4 g (0.433 mol; yield 86.8%, boiling point 116-118° C./0.64 kPa).
Reaction SMILES: ClCOC1C2C=CC=CC=2SC=1C(OC)=O.Cl[C:18]1[C:19]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:20]=2[S:21][C:22]=1[C:23](Cl)=[O:24].Cl.[NH2:33][CH2:34][CH2:35][SH:36].C1CCN2C(=NCCC2)CC1>CN(C=O)C.C(OCC)(=O)C.CO>[CH3:31][O:30][C:28]1[CH:27]=[CH:26][C:20]2[S:21][C:22]3[C:23](=[O:24])[NH:33][CH2:34][CH2:35][S:36][C:18]=3[C:19]=2[CH:29]=1
Reactant: NCCS
Reactant: COc1ccc2sc(C(=O)Cl)c(Cl)c2c1
Agent: COC(=O)c1sc2ccccc2c1OCCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2sc3c(c2c1)SCCNC3=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74 %

Procedure:
To a room temperature solution of methyl 3-chloromethoxy-benzo[b]thiophene-2-carboxylate (500 mg, 1.95 mmol) [prepared by reaction of the known 3-chloro-5-methoxy-benzo[b]thiophene-2-carbonyl chloride with methanol- [J. Med. Chem., 35:958 (1992)]] in 20 mL of DMF is added cysteamine-HCl (885 mg, 7.79 mmol) followed by DBU (2.33 mL, 15.58 mmol). The reaction mixture is stirred at room temperature for 1.5 hours then warmed to 70° C. The mixture is diluted with ethyl acetate and washed with aqueous HCl, water and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The crude product is recrystallized from hexane and ethyl acetate to provide 2,3-dihydro-9-methoxy[1]benzothieno[2,3-f]-1,4-thiazepin-5(4H)-one in 74% yield, mp 209°-209.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:10]=1[O:11][CH3:12])[C:5]([Cl:26])=[O:6]
Reactant: COc1c(Cl)cc(C(=O)O)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-chloro-4-methoxy-5-trifluoromethylbenzoic acid (300 mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.13 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (e).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].Cl[S:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11].ClCCl.C(OCC)(=O)C>N1C=CC=CC=1>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[O:8][S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:20][CH:21]=1)(=[O:12])=[O:11]
Reactant: [O-][n+]1ccccc1O
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(S(=O)(=O)On2ccccc2=O)cc1
Yield: 30 %

Procedure:
2-Hydroxypyridine-1-oxide (0.21 g, 1.9 mmol) was reacted with 4-(chlorosulfonyl)benzoic acid (0.62 g, 2.8 mmol) in 5 mL pyridine. The solvent was evaporated, leaving a yellow oil. Addition of 5 mL of dichloromethane followed by the addition of 5 mL of ethyl acetate allowed for precipitation of PZBG-1e in 30% yield (0.17 g, 0.57 mmol). 1H NMR (400 MHz, DMSO) δ=8.18 (d, J=8.8 Hz, 2H), 8.08 (d, J=8.4 Hz), 7.88 (dd, J1=7.6 Hz, J2=2 Hz), 7.45 (td, J1=8.2 Hz, J2=2 Hz, 1H), 6.50 (dd, J1=9.2 Hz, J2=1.6 Hz, 1H), 6.26 (td, J1=7 Hz, J2=1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ=166.5, 156.6, 141.5, 138.2, 137.9, 137.3, 131.2, 130.4, 122.8, 106.2. ESI-MS(−): m/z 294.26[M−H]−. Anal. calcd. for C12H9NO6S: C, 48.81; H, 3.07; N, 4.74. Found: C, 48.91; H, 3.37; N, 4.84.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1)#[N:2]>C(O)C.[OH-].[NH4+].[Ni]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][N:4]=1
Reactant: N#Cc1ccc(C(F)(F)F)cn1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCc1ccc(C(F)(F)F)cn1
Yield: 30.5 %

Procedure:
To a nitrogen flushed solution of 2-cyano-5-(trifluoromethyl)pyridine (Description 1; 8.0 g, 46.5 mmol) in a mixture of ethanol (100 ml) and ammonium hydroxide (25 ml) was added a spatula end of Raney Nickel and the resulting mixture hydrogenated at 50 psi overnight. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient rising from 2% MeOH in dichloromethane+0.5% NH4OH to 5% MeOH in dichloromethane+0.5% NH4OH to give the title compound (2.5 g, 30%) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(Cl)(Cl)Cl>[O-:42][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(-c4ccccn4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(-c4cccc[n+]4[O-])cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 14.5 %

Procedure:
To a suspension of N-[4—(2-pyridyl)phenyl]-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (400 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.25 g) at 0° C., and the mixture was stirred at room temperature for 70 hours. To the mixture was added sodium thiosulfate solution, and the mixture was stirred for minutes. The mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried with magnesium sulfate. The mixture was concentrated, purified with column chromatography (ethanol/ethyl acetate=1:1) to give crystals, which were dissolved in chloroform. The mixture was concentrated, and to the residue was added ethanol. Precipitated crystal was collected by filtration to give crystals, which were washed with ethanol to give N-[4—(1-oxidopyridin-2-yl)phenyl]-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 160) (60 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([N:11]3[CH2:15][CH2:14][CH2:13][CH:12]3[C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[F:23])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31]>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>[F:23][C:17]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=1[C@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Fc1ccc(F)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
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: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)cc1
Temperature: 150 °C

Procedure:
In step 6A-5, palladium tetrakis (25 mg, 0.02 mmol) was added to a solution of 3-bromo-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (6-6) (77 mg, 0.23 mmol), sodium carbonate (85 mg, 0.81 mmol), and 4-cyanophenylboronic acid (60 mg, 0.41 mmol) in 2 mL of dioxane and 0.5 mL of water contained in a microwave reaction tube. The resulting solution was heated in a microwave for 25 minutes at 150° C. and the yellow slurry was cooled to room temperature and filtered through a 0.2 μm nylon frit. The solvent was removed from the mother liquor and the remaining residue was reconstituted in methanol and further purified by preparative LC/MS. The desired fractions were dried to yield the desired product as a racemic mixture, which was then purified by chiral LC to yield (R)-4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile (6-7) as a chiral pure white solid along with (S)-4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile as a chiral pure white solid.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([N:13]1[C:17]2=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=[C:16]2[N:15]([CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[CH3:33])[N:26]([CH3:34])[CH:25]=2)[C:14]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>CO>[CH3:34][N:26]1[C:27]2[C:32](=[C:31]([CH3:33])[CH:30]=[CH:29][CH:28]=2)[C:24]([CH2:23][N:15]2[C:16]3[C:17](=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[N:13]([C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5][C:4]([OH:36])=[O:3])[C:14]2=[O:35])=[CH:25]1
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccc(C)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2c(n1)n([C@H](CC(=O)O)c1ccccc1)c(=O)n2Cc1cn(C)c2cccc(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a solution of (R)-3-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-5-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl]-3-phenyl-propionic acid ethyl ester (200 mg, 0.41 mmol) in MeOH (5 mL) was added 2N NaOH (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then treated with 1N HCl and extracted with CH2Cl2 twice. The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 144 mg (76%) of the title compound as off-white solid. LCMS, M++1, m/z: 455.00.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11](O[Si](C)(C)C)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:7]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=1[OH:29])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CCCCCC>[C:25]([C:7]1[CH:8]=[C:9]([CH:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]=1[OH:29])([CH3:26])([CH3:27])[CH3:28]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1cc(C(CCc2ccccc2)O[Si](C)(C)C)cc(C(C)(C)C)c1O
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(CCc2ccccc2)N2CCOCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a nitrogen-purged, 250 mL, three-neck, round-bottom flask were added the 148.9 grams of the 2,6-di-t-butyl-4-(1-trimethylsilyloxy-3-phenylpropyl)phenol produced in step (B) of this example, 67 grams of hexane, and 45.8 grams (0.53 mole) of morpholine. The mixture was stirred overnight at ambient temperature. After this time, the solvent was removed and the solids recrystallized from a solution of 5 percent toluene in hexane to give pure 2,6-di-t-butyl-4-(1-morpholino-3-phenylpropyl)phenol as a white crystalline solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:13][C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:5]=2[CH:6]=1.[Br:14]Br>O1CCCC1>[Br:14][C:2]1[CH:3]=[C:4]2[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][C:12]=3[NH:13]2)=[CH:6][CH:1]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)[nH]c1cnccc12
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)[nH]c1cnccc12
Yield: 65.8 %

Procedure:
A solution of norharmane (600 mg, 3.57 mmol) in tetrahydrofuran (THF; 50 ml) was treated with bromine (0.40 ml, 7.80 mmol) at RT while stirring. After stirring for 18 h at RT, the reaction was concentrated under reduced pressure and the resulting residue was sonicated in 10% aqueous Na2CO3 (100 ml). The product was filtered and washed with water to give 905 mg of crude product. The crude product was crystallized from xylenes to provide in two crops 580 mg of 7-bromo-β-carboline.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[Cl:13])(=[O:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:14])=[O:9])=[CH:6][C:5]=1[Cl:13])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(C(=O)O)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(C(C)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 4-acetyl-3-chlorobenzoic acid (synthesized by the method of Tetrahedron 1988, 44, 1631, 700 mg, 3.52 mmol) in N,N-dimethylformamide (4 mL) were added potassium carbonate (974 mg, 7.05 mmol) and iodomethane (658 μL, 10.57 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added water, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, filtered through Phase-separator (Varian Inc.), and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→75:25) to give methyl 4-acetyl-3-chlorobenzoate (707 mg, 94%) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH:29]([NH2:30])[S:40]([CH3:39])(=[O:42])=[O:41])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(OCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1nc(OCC(N)S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 131 (100 mg, 0.23 mmol) in CH2Cl2 (4 mL) was stirred under Ar at 230. Triethylamine (0.1 mL) was added followed by the addition of a solution of methanesulfonyl chloride (29 mg, 0.25 mmol) in CH2Cl2 (1 mL). The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-10% EtOAc/CH2Cl2 gave the title compound as a white-amorphous solid. mp 95-99°, LC MS m/z=505 (MH+). Retention time=2.02 min.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:6][CH:7]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)=[CH:6][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1OC1CCCC1
Reactant: NCc1ccccc1
Product: COc1ccc(-c2ccc(NCc3ccccc3)nn2)cc1OC1CCCC1
Yield: 92.1 %

Procedure:
14 g (46 mmol) of 3-chloro-6-(3-cyclopentyloxy-4-methoxyphenyl)pyridazine are heated in 74 g (0.69 mol) of benzylamine at 200° C. for 3 hours. The mixture is subsequently poured onto ice and extracted with dichloromethane, and the organic phase is dried with potassium carbonate and then concentrated. Petroleum ether (b.p. 50°-70° C.) is added to the residue, and the resulting precipitate is filtered off with suction and crystallized from ethyl acetate/cyclohexane. 15.9 g (92.4%) of 3-benzylamino-6-(3-cyclopentyloxy-4-methoxyphenyl)pyridazine of m.p. 116° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[N:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:17]1[N:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1cccnc1Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccnc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under N2 in a 250 mL round-bottomed flask fitted with a reflux condenser and magnetic stirrer, 3,4-dichlorophenol (2.9 g, 17.8 mmol) was added to a suspension of K2CO3 (7.0 g, 51 mmol) in 70 mL of anhydrous DMF. After stirring the mixture for 15 min., 2-chloronicotinaldehyde (2.4 g, 17 mmol prepared according to the method in J. Heterocycl. Chem. 1995, 32, 1595) was added and the mixture was heated to 90–100° C. for 5 h. After allowing the reaction to cool to room temperature overnight, the mixture was diluted with water and extracted three times with EtOAc. The aqueous layer was then extracted with additional EtOAc and the organic layers were combined, washed with water and brine and dried over Na2SO4. Removal of the solvent in vacuo gave a brown solid which was further dried under vacuum overnight and then recrystallized from EtOAc to give the title product as tan crystals, 1.6 g; m.p. 97–99° C. A second crop of tan crystals weighing 0.716 g was later obtained, and concentration of the filtrate provided an additional 2.65 g of nearly pure title product; δH (CDCl3, 400 MHz) 7.08 (1H, dd), 7.17 (1H, m), 7.43 (1H, d), 7.49 (1H, d), 8.25 (1H, dd), 8.33 (1H, dd), 10.50 (1H, s).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]3[CH:14]=[N:15][C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=4[O:28][CH3:29])=[N:17][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[NH2:54][CH:55]1[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]1.C(N(CC)CC)C>ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]3[CH:14]=[N:15][C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH:54][CH:55]5[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]5)=[O:25])=[CH:21][C:20]=4[O:28][CH3:29])=[N:17][C:6]2=3)[CH2:2][CH2:3][CH2:4]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CCC(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 24.3 %

Procedure:
A mixture of 0.059 g (0.00015 mole) of 4-(9-cyclobutyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-23), 0.07 g (0.000185 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.05 mL (0.0004 mole) of 4-amino-1-methylpiperidine, 0.1 mL of triethylamine and 3 mL of dichloromethane was stirred for 2.5 hours at ambient temperature. The mixture was concentrated under reduced pressure and the residue purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (10:90-100:0) to give 0.018 g of 4-(9-cyclobutyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-24).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([CH3:16])=[C:9]([C:13]([NH2:15])=[O:14])[NH:10][C:11]=1[CH3:12])=O.[N+]([O-])(O)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>COCCO>[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[C:8]([CH3:16])=[C:9]([C:13]([NH2:15])=[O:14])[NH:10][C:11]=3[CH3:12])[CH:4]=[CH:3][N:31]=2)=[CH:27][CH:28]=1
Reactant: N=C(N)Nc1ccc(F)cc1
Reactant: Cc1[nH]c(C(N)=O)c(C)c1C(=O)C=CN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1[nH]c(C(N)=O)c(C)c1-c1ccnc(Nc2ccc(F)cc2)n1
Temperature: 120 °C
Yield: 22.2 %

Procedure:
4-(3-Dimethylamino-acryloyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid amide (100 mg, 0.43 mmol), 4-fluorophenylguanidine nitrate (139 mg, 0.65 mmol) and K2CO3 (94 mg, 0.68 mmol) were partially dissolved in 2-methoxyethanol (5 mL) and heated at 120° C. for 18 h. The mixture was concentrated in vacuo and purified by SiO2 chromatography (EtOAc/MeOH gradient elution). The crude product was triturated in iPr2O to afford the title compound (31 mg) as a buff solid. M.p. 93.5–96.8° C. MS: [M+H+]=326.9 (C17H16FN5O requires 325.3). 1H-NMR (DMSO-d6) δ: 2.36 (s, 3H, CH3), 2.39 (s, 3H, CH3), 6.79 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 6.92 (br. s, 2H, NH), 7.07 (t, 2H, J=8.5 Hz, Ph-H), 7.76–7.78 (m, 2H, Ph-H), 8.36 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 9.41 (s, 1H, NH), 11.24 (br. s, 1H, NH).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:45])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([C:30]1[NH:34][C:33]3[CH:35]=[CH:36][C:37]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:38][C:32]=3[N:31]=1)=[N:18][N:19]2C1CCCCO1)=[O:13]>C(Cl)Cl>[F:45][C:9]1([F:8])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([C:30]1[NH:31][C:32]3[CH:38]=[C:37]([N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)[CH:36]=[CH:35][C:33]=3[N:34]=1)=[N:18][NH:19]2)=[O:13]
Reactant: O=C(Nc1cccc2c1c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc2[nH]nc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)c12)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
TFA (327 mg, 2.87 mmol) was added to solution of 2,2-difluoro-N-(3-(5-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)cyclopropane carboxamide (15 mg, 0.029 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (8 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.18 (d, 1H, J=8.0 Hz), 7.49 (d, 1H, J=8.8 Hz), 7.35 (m, 1H), 7.25 (d, 1H, J=8.0 Hz), 7.18 (s, 1H), 7.09 (d, 1H, J=7.6 Hz), 3.89 (m, 4H), 3.22 (m, 4H), 3.08-3.01 (m, 1H), 2.21-2.15 (m, 1H), 1.96 (m, 1H); ESI-MS [M+H]+: 439.1.