Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:23]1[N:28]=[C:27]([O:29][CH3:30])[C:26]([Cl:31])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:31][C:26]1[C:27]([O:29][CH3:30])=[N:28][C:23]([NH:1][C:2]2[CH:3]=[C:4]([C:9]3[S:13][C:12]([N:14]4[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]4)=[N:11][CH:10]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=2)=[N:24][CH:25]=1
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reactant: COc1nc(Cl)ncc1Cl
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1nc(Nc2cc(C)cc(-c3cnc(N4CCCNC(=O)C4)s3)c2)ncc1Cl
Temperature: 90 °C
Yield: 403.2 %

Procedure:
A sealed tube was charged with a stir bar, 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 75 mg, 0.248 mmol), 2,5-dichloro-4-methoxypyrimidine (44 mg, 0.248 mmol), potassium carbonate (69 mg, 0.496 mmol), Pd2(dba)3 (23 mg, 0.025 mmol), and XPhos (59 mg, 0.124 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed t-amyl alcohol (0.83 ml) was added and the tube was sealed and heated at 90° C. for overnight. The resulting slurry was diluted with methanol, absorbed onto 1.5 g of silica, and purified via silica gel chromatography (0-20% methanol in ethyl acetate) to afford 44 mg (1.0 mmol, 40% yield) of 4-(5-{3-[(5-chloro-4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-1,4-diazepan-2-one as a light yellow solid. MS APCI: [M+H]m/z 445.1. 1H NMR (500 MHz, dmso) δ 9.72 (s, 1H), 8.30 (s, 1H), 7.77 (s, 1H), 7.59 (t, J=5.0 Hz, 1H), 7.48 (s, 1H), 7.30 (s, 1H), 6.95 (s, 1H), 4.15 (s, 2H), 4.05 (s, 3H), 3.78 (m, 2H), 3.21 (m, 2H), 2.26 (s, 3H), 1.77 (m, 2H). rhSyk=+++
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(O)(C)C>[N+:8]([C:7]1[C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][OH:11])[C:15](=[O:20])[CH2:16]2)=[N:3][CH:4]=[CH:5][N:6]=1)([O-:10])=[O:9]
Reactant: O=C1CNCCN1CCO
Reactant: O=[N+]([O-])c1nccnc1Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1CN(c2nccnc2[N+](=O)[O-])CCN1CCO
Reaction time: 20 h
Yield: 33.7 %

Procedure:
A solution of 2-chloro-3-nitropyrazine (1.59 g, 10 mmol) in chloroform (20 ml) was added over 30 minutes to an icebath cooled solution of 4-(2-hydroxyethyl)piperazin-3-one (1.44 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in isopropanol (30 ml). After addition was complete, the reaction mixture was allowed to warm to 20°-25° and was stirred at this temperature for 20 hours. Solvents were removed under reduced pressure and the residue was partitioned between a saturated aqueous solution of sodium chloride and ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Flash chromatography over silica gel and elution with 5% methanol-95% chloroform gave 0.90 g (48.6%) of 1-(3-nitro-2-pyrazinyl)-4-(2-hydroxyethyl)piperazin- 3-one. An analytical sample, m.p. 117°-120°, was obtained upon recrystallization from ethyl acetatehexane.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6])=[CH:21][CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: FC(F)(F)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)CCCOc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C

Procedure:
464.5 g (1.95 mol) of 4-iodo-1,1,1-trifluorobutane, 390.4 g (1.95 mol) of 4-(benzyloxy)phenol and 539.5 g (3.90 mol) of potassium carbonate are dissolved in 3 L of NMP. The mixture is heated to 80° C. overnight. The solution is cooled to room temperature and the reaction mixture is extracted with ethyl acetate and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure to give 580 g of
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[CH2:14]([O:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of NaH (60%, 4.05 g, 101 mmol) in DMF (50 mL) was added 1,4-dioxaspiro[4.5]decan-8-ol (10 g, 63 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature, and treated with benzyl bromide (9.02 mL, 76 mmol). The mixture was heated to 50° C. overnight, diluted with EtOAc, and washed with water (×5). The organic layer was dried, concentrated, and purified by flash chromatography to afford the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Br:29])=[C:24]([CH3:30])[CH:23]=1)(=[O:20])[C:18]#[CH:19]>C1COCC1.[Cu]I>[N+:8]([C:4]1[CH:3]=[C:2]([C:19]#[C:18][C:17]([O:21][C:22]2[CH:23]=[C:24]([CH3:30])[C:25]([Br:29])=[C:26]([CH3:28])[CH:27]=2)=[O:20])[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: C#CC(=O)Oc1cc(C)c(Br)c(C)c1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(OC(=O)C#Cc2cccc([N+](=O)[O-])c2)cc(C)c1Br
Temperature: 65 °C
Yield: 28.6 %

Procedure:
1-Iodo-3-nitrobenzene (41.05 g, 164.3 mmol) in THF (100 mL) was degassed under reduced pressure at −78° C., and then nitrogen gas was introduced. To the solution was added K2CO3 (41.27 g, 298.6 mmol), CuI (2.27 g, 11.9 mmol) and PdCl2(Ph3P)2 (1.11 g, 1.57 mmol), and the mixture was stirred at 65° C. 4-bromo-3,5-dimethylphenyl propiolate (6-1) (37.79 g, 149.3 mmol) in THF (68 mL) was added by syringe pump over a period of 5.4 hr, and the mixture was stirred an additional 1 h after addition was complete. After being cooled to room temperature, the mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography. The fractions containing the desired compound were concentrated. To the concentrate added hexane and the precipitated solid was collected by filtration. The solid was washed with hexane and dried to give the title compound 6-2 (15.96 g, 29% yield) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].[C:21](OC(=O)C)(=[O:23])[CH3:22]>O>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]([C:21](=[O:23])[CH3:22])[CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C

Procedure:
4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydroquinoline (1.08 g) was heated at reflux in 10 ml of acetic anhydride for 2 h, cooled to RT, diluted with water (100 ml), neutralized to pH7 with NaHCO3 (solid) and extracted with EtOAc. The organic portion was washed with brine, removal of the solvents afforded 1-(4,4-dimethyl-7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone as a solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=1[C:9]([O:11]CC)=[O:10].[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1ccccc1N1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1N1CCCC1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of ethyl 2-(2-oxopyrrolidin-1-yl)benzoate (4.3 g) in methanol (30 mL) was added 8 N aqueous sodium hydroxide solution (6.9 mL) at room temperature, and the mixture was heated to 50° C., and stirred overnight. The reaction mixture was allowed to cool to room temperature, and neutralized with 6 N aqueous hydrochloric acid solution (3 mL), and the solvent was evaporated under reduced pressure. The resultant crystals were recrystallized from ethanol to give the title compound (2.58 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12]>C(Cl)Cl>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1)=[O:15])[CH3:12]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: CCN(CC)C(=O)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 44.5 %

Procedure:
4.2 g of Compound [II] was dissolved in 50 ml of methylene chloride, and 4.1 g of N,N-diethylcarbamoyl chloride was added to the solution. The mixture was heated under refluxing for 5 hours and cooled, followed by washing with water. The organic layer was collected, and the solvent was distilled off. The residue was subjected to crystallization by the addition of hexane. The crystals obtained were collected by filtration and dried to obtain 3.2 g of N,N-diethyl N'-(5-t-butyl-3-pyrazolyl)urea.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].Br[C:12]1[C:16]([Br:17])=[CH:15][S:14][C:13]=1[C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=O>CN(C)C=O>[Br:17][C:16]1[C:12]([S:10][CH2:7][CH2:8][CH3:9])=[C:13]([CH2:18][C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[S:14][CH:15]=1
Reactant: CCCS
Reactant: O=C(c1cccs1)c1scc(Br)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1c(Br)csc1Cc1cccs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cloudy solution of 80 mL of dimethylformamide containing 3.7 g of potassium-t-butoxide, under a nitrogen blanket and cooled to 0°,was added 3.0 mL of n-propanethiol. This mixture was stirred for 5 minutes and then 12 g of the product of Example 8 was added in one portion. After stirring for 3 hours at room temperature, the mixture was poured into 400 mL of ice-water and extracted with methylene chloride. The organic layer was washed with 1N NaOH (aq), water and dried (MgSO4). Filtration and concentration of the filtrate in vacuo afforded 7.5 g of the subject compound as a dark oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nc4cccc(-c5cccc(S(C)(=O)=O)c5)n4n3)cc2)CC1

Procedure:
[5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75 mg, 0.26 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (73 mg, 0.28 mmol) in a manner analogous to Example 77 to yield [5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:29][C:11]3[N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH2:17][CH2:18][CH2:19]OC4CCCCO4)[C:15](=[O:16])[C:10]=3[C:9]=2[CH:30]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)O)[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl.O>[F:49][C:48]([F:51])([F:50])[C:46]([O:52][CH2:19][CH2:18][CH2:17][N:14]1[C:15](=[O:16])[C:10]2[C:9]([CH2:30][C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[S:29][C:11]=2[N:12]([CH3:28])[C:13]1=[O:27])=[O:47]
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of 6-(3-chlorophenyl)-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetra hydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 4, Step 2, 50 mg, 0.078 mmol) in TFA (1 mL) was added triethylsilane (0.5 mL). The reaction was stirred at RT for 2 h then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydro thieno[2,3-d]pyrimidin-3(4H)-yl)propyl 2,2,2-trifluoroacetate (40 mg, 80.5% yield) as an oil. LCMS: MH+ 571 and TR=2.327 min. Used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([NH2:15])=[O:14])=[N:4][C:5]([C:9](O)([CH3:11])[CH3:10])=[C:6]([Cl:8])[N:7]=1.N1C=CC=CC=1.S(Cl)(C)(=O)=O.[H][H]>[Pd].C1COCC1.C(O)C>[Cl:1][C:2]1[C:3]([C:13]([NH2:15])=[O:14])=[N:4][C:5]([CH:9]([CH3:11])[CH3:10])=[C:6]([Cl:8])[N:7]=1
Reactant: CC(C)(O)c1nc(C(N)=O)c(Cl)nc1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CS(=O)(=O)Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)c1nc(C(N)=O)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 25.6 %

Procedure:
To a mixture of 3,5-dichloro-6-(1-hydroxy-1-methylethyl)pyrazine-2-carboxamide (2.64 g) and pyridine (30 mL), mesyl chloride (2.45 mL) was added under ice cooling. After stirring at room temperature for 5 hours, pyridine was distilled off under reduced pressure, and the resulting residue was partitioned using ethyl acetate and water. The resulting organic layer was washed with 10% aqueous citric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was distilled off to give a light brown syrup. To the light brown syrup, ethanol (60 mL) and THF (30 mL) were added, and then 10% palladium on carbon (0.7 g) was added and stirred at room temperature for 14 hours under 3 atmospheric pressure of hydrogen. After filtration through celite, the filtrate was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0 to 40:1). The resulting crude product was washed with diisopropyl ether to give 3,5-di-chloro-6-isopropylpyrazine-2-carboxamide (632 mg) as a white solid.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:38])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][S:28][CH:29]4[NH:34][C:33](=[O:35])[C:32](=[O:36])[NH:31][N:30]4[CH3:37])[O:24][CH2:23]2)[CH:17]([CH:39]([OH:41])[CH3:40])[C:16]3=[O:42])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:47].O>[Pd].O1CCOCC1>[Na+:47].[CH3:37][N:30]1[CH:29]([S:28][CH2:27][CH:25]2[O:24][CH2:23][CH:22]([S:21][C:20]3[CH:19]([CH3:38])[CH:18]4[N:15]([C:16](=[O:42])[CH:17]4[CH:39]([OH:41])[CH3:40])[C:14]=3[C:12]([O-:13])=[O:11])[CH2:26]2)[NH:34][C:33](=[O:35])[C:32](=[O:36])[NH:31]1
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CSC4NC(=O)C(=O)NN4C)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(CSC4NC(=O)C(=O)NN4C)C3)C(C)C12
Yield: 46.5 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.10 g of product from Example 86, 0.0135 g of sodium bicarbonate, 2 ml of water, 10 ml of dioxane, and 0.030 g of 10% palladium/carbon to give 0.038 g of the desired product.
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([OH:25])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:22])[NH2:21])=[O:13])(=O)C1C=CC=CC=1.N>O>[SH:9][CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([OH:25])=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:21])[NH2:22])=[O:13]
Reactant: N=C(N)NCCC[C@H](NC(=O)CCSC(=O)c1ccccc1)C(=O)O
Agent: N
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)CCS)C(=O)O
Reaction time: 1 h

Procedure:
Nα -(3-benzoylthiopropanoyl)-L-arginine (1 g.) is dissolved with vigorous stirring in a mixture of water (5 ml.) and concentrated ammonia (5 ml.). After one hour, the solution is extracted with ethyl acetate and concentrated to dryness in vacuo. The residue is chromatographed on a column of DEAE Sephadex [anion exchange resin derived from dextran (Mikes, supra, page 328)] (85 ml.) with a buffer of 0.005 M ammonium bicarbonate. The fractions containing the Nα -(3-mercaptopropanoyl)-L-arginine (as indicated by positive thiol and Sakaguchi Reaction) are pooled and lyophilized to remove ammonium bicarbonate, yield 200 mg., m.p. 230° (starts decomposing at 200°).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(C)OC)=[O:6].[CH2:15]([Mg]Cl)[CH2:16][CH2:17][CH3:18]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:5](=[O:6])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1cccc(Br)c1C
Reactant: CCCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCCC(=O)c1cccc(Br)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 3-bromo-N,2-dimethyl-N-(methyloxy)benzamide (2.55 g, 9.88 mmol) in anhydrous THF (28 mL) under nitrogen at −78° C. was added a butylmagnesium chloride (20% wt in THF/toluene, 6.94 mL, 11.90 mmol) drop-wise over 15 min. The resulting solution was stirred at −78° C. for 1 h, was allowed to warm to 0° C. and then stirred with slow warming to ambient temperature over 20 h. The reaction was then quenched with water (50 mL) and extracted with EtOAc (2×60 mL). Some saturated aqueous NH4Cl was added to disperse the emulsion formed. The resulting organic layer was then washed with brine (100 mL), dried (Na2SO4), filtered and reduced under vacuum. Purification by SPE (silica, 50 g cartridge), eluting with cyclohexane:EtOAc (gradient 49:1 to 9:1) afforded the title compound as a colourless oil (706 mg).
Reaction SMILES: C(OC([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:31][CH2:30][C:27]3([CH2:29][CH2:28]3)[C@H:26]([OH:32])[CH2:25]2)=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:32][C@@H:26]1[CH2:25][N:24]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][N:14]2[C:15](=[O:18])[CH2:16][CH2:17][NH:11][CH2:12][CH2:13]2)[CH2:31][CH2:30][C:27]21[CH2:29][CH2:28]2
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CCN1CCCC(=O)N1CCC2(CC2)[C@H](O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1CCNCCN1CCCC(=O)N1CCC2(CC2)[C@H](O)C1
Yield: 85 %

Procedure:
To 0.44 g (1 mmol) of 4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester in 10 ml of MeOH was added 0.05 g of 10% palladium on charcoal. The mixture was stirred under 1 atmosphere of hydrogen for 1.5 h after which time the reaction was filtered through Hyflo and concentrated, affording the titled compound in 85% yield as a colorless foam. MS: 310.4 (MH+).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O1CCCC1.C(OCC)(=O)C.O>[C:1]([NH:9][S:19]([C:16]1[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=1)(=[O:21])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)c1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.7 %

Procedure:
To a solution of benzamide (1.42 g) in tetrahydrofuran (50 ml) were added sodium hydride (611 mg) and 4-bromobenzenesulfonyl chloride (3.0 g), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give N-benzoyl-4-bromobenzenesulfonamide (2.1 g) as a colorless powder.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+].CC[N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>ClCCl.CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH2:36])=[O:25])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(N)=O)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.12 mmol), ammonium chloride (25 mg, 1.44 mmol), EDCI (36 mg, 0.18 mmol), HOBT (24 mg, 0.18 mmol) in dichloromethane (3 mL), DMF (0.5 mL) and Et3N (27 mg, 0.24 mmol) was stirred at room temperature for 16 h. The solution was concentrated in vacuo, washed with water (10 mL×3), purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=20:1) to give 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (24 mg, 48%) as a yellow oil. 1H NMR (300 MHz, DMSO): δ 9.67 (s, 1H), 8.85 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.13-7.99 (m, 3H), 7.68-7.59 (m, 2H), 7.49-7.42 (m, 2H), 6.73 (d, 1H, J=7.8 Hz), 6.08 (d, 1H, J=8.1 Hz), 4.25-4.21 (m, 1H), 3.60-3.57 (m, 1H), 3.44-3.38 (m, 1H), 2.06-1.95 (m, 3H), 1.67 (s, 1H), 1.08 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 414, tR=1.633 min, HPLC: 98.33% at 214 nm, 97.74% at 254 nm, tR=5.64 min.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:47])[N:41]([CH:43]2[CH2:46][O:45][CH2:44]2)[CH:42]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[CH:39][C:40](=[O:47])[N:41]([CH:43]4[CH2:46][O:45][CH2:44]4)[CH:42]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1ccc(Br)cn1C1COC1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C3COC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 5-bromo-1-oxetan-3-yl-1H-pyridin-2-one following a procedure analogous to that described in Example 35. LC (method 4): tR=0.97 min; Mass spectrum (ESI+): m/z=503 [M+H]+; 1H NMR (CDCl3) δ 1.05 (s, 3H), 1.12 (s, 3H), 1.48 (d, 3H), 2.10-2.22 (m, 5H), 2.34 (m, 1H), 2.83 (m, 1H), 4.72 (m, 2H), 5.10 (m, 2H), 5.63 (m, 1H), 5.83 (m, 1H), 6.57 (d, 1H), 6.97 (d, 2H), 7.12 (d, 2H), 7.20-7.32 (m, 5H), 7.49 (d, 1H), 7.65 (s, 1H).