Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1N1C2C3C=CC=CC=3N(CC(F)(F)F)C(=O)C=2C=N1.[F:26][CH:27]1[CH2:31][CH2:30][N:29]([C:32]2[C:37]([C:38]3[CH:39]=[CH:40][C:41]4[C:42]5[NH:56][N:55](C6CCCCO6)[CH2:54][C:43]=5[C:44](=[O:53])[N:45]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:46]=4[CH:47]=3)=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:28]1.[ClH:63]>O>[ClH:63].[F:26][CH:27]1[CH2:31][CH2:30][N:29]([C:32]2[C:37]([C:38]3[CH:39]=[CH:40][C:41]4[C:42]5[NH:56][N:55]=[CH:54][C:43]=5[C:44](=[O:53])[N:45]([CH2:48][C:49]([F:52])([F:51])[F:50])[C:46]=4[CH:47]=3)=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:28]1
Reactant: O=c1c2c(c3ccc(-c4cccnc4N4CCC(F)C4)cc3n1CC(F)(F)F)NN(C1CCCCO1)C2
Agent: Cl
Agent: O=c1c2cnn(C3CCCCO3)c2c2ccccc2n1CC(F)(F)F
Solvent: O
Product: O=c1c2cn[nH]c2c2ccc(-c3cccnc3N3CCC(F)C3)cc2n1CC(F)(F)F
Yield: 47 %

Procedure:
The product is obtained according to the procedure described in Step 1.7. starting with 7-[2-(3-fluoropyrrolidin-1-yl)pyrid-3-yl]-1-(tetrahydro-2H-pyran-2-yl-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-[2-(3-fluoropyrrolidin-1-yl)pyrid-3-yl]-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one, in the form of a white powder (hydrochloride. H2O; yield 47%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2O)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]=[CH:8]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2c1CCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc2c1CC=C2
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 4-nitroindan-1-ol (0.385 g, 2.15 mmol) and p-toluenesulfonic acid (5.0 mg, 0.03 mmol) in toluene (30 ml) was stirred and heated to reflux for 16 hours. After cooled to ambient temperature, the mixture was washed with aqueous sodium bicarbonate solution. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparatory TLC (hexane:ethylacetate 3:1) to afford 7-nitro-1H-indene (0.289 g).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:11]([C:14]1[C:22]2[NH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19][C:18]=2[CH:17]=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=1)([O-:13])=[O:12].[Na]>C(#N)C>[N+:11]([C:14]1[C:22]2[N:21]=[C:20]([C:23]([F:24])([F:25])[F:26])[N:19]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:18]=2[CH:17]=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc2nc(C(F)(F)F)[nH]c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc2c1nc(C(F)(F)F)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.5 g. of phenylsulfonyl chloride in 20 m. of anhydrous acetonitrile was added to a solution of 6.4 g. of 4-nitro-2,6-bis(trifluoromethyl)benzimidazole, sodium salt in 50 ml. of anhydrous acetonitrile. The mixture was stirred at room temperature for 2 hours, and the reaction mixture was filtered. The filtrate was evaporated to dryness under vacuum, and the residue was recrystallized from benzenepentane to yield 4-nitro-1-phenylsulfonyl-2,6-bis(trifluoromethyl)benzimidazole, m.p. 183°-185°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(I)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(I)ccc1CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Fluoro-4-iodo-1-methylbenzene (2.0 g, 8.6 mmol) was dissovled in carbon tetrachloride (10 mL), treated with N-bromosuccinimide (1.5 g, 8.6 mmol, 1 equiv) and benzoyl peroxide (9.0 mg, 0.004 equiv) and placed into an oil bath preheated to 80° C. for 3 hours. The mixture was cooled to ambient temperature, filtered and the filtrate was concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH:9]([C:17]1([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:30])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH:9]([C:17]1([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]1=[O:30])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:4])=[O:3]
Reactant: CC(C)CC1(C(CCO)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC1(C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Methanesulfonyl chloride (0.29 mL, 3.7 mmol) is added to a solution of tert-butyl α-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 4, step 2; 1.36 g, 3.37 mmol), triethylamine (0.52 mL, 3.7 mmol) and CH2Cl2 (8 mL) at 0° C. The mixture is stirred for 2 hours, washed with saturated NaHCO3 (2×10 mL), water (10 mL), dried (MgSO4), filtered, and concentrated to give 1.22 g (75%) of the title compound as a light yellow oil.
Reaction SMILES: FC(F)(F)C1N=C(S(C(F)(F)F)(=O)=O)NN=1.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].S([O-])([O-])(=O)=O.[Mg+2]>[N+](C)([O-])=O.CCOCC.[Sc]>[CH3:24][O:23][C:17]1[CH:22]=[CH:21][C:20]([C:25](=[O:27])[CH3:26])=[CH:19][CH:18]=1
Reactant: COc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: O=S(=O)(c1nc(C(F)(F)F)n[nH]1)C(F)(F)F
Agent: [Mg+2]
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: COc1ccc(C(C)=O)cc1
Temperature: 21 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
The catalytic effect of the scandium salt of 3-trifluoromethyl-5-trifluoromethanesulfonyl-1,2,4-triazole, obtained in Example 3, relative to a reaction was evaluated in the following manner. In 40 ml of anhydrous nitromethane, there is added 592 mg (700 mmoles) of the scandium salt of 3-trifluoromethyl-5-trifluoromethanesulfonyl-1,2,4-triazole, and 1.08 g (10 mmoles) of anisol and 2.04 g of acetic anhydride. After stirring during 10 min at 21° C., the reaction mixture was diluted with 50 ml of ether and the reaction was inhibited by 100 ml of a saturated solution of sodium bicarbonate NaHCO3. After filtration on Celite, the solution was extracted with three fractions of 50 ml ether, and the collected ether phase was washed with a saturated solution of potassium chloride. After drying the ether phase with magnesium sulfate and evaporation, 1.46 g of p-methoxyacetophenone (97% yield) was collected, with a purity characterized by a proton RMN higher than 99%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13].[Br:15]N1C(C)(C)C(=O)N(Br)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCCC>C(OC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][Br:15]
Reactant: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCCC
Solvent: COC(C)=O
Product: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Temperature: 75 °C
Yield: 64.1 %

Procedure:
A mixture of 2-methyl-6-nitro-benzoic acid methyl ester (99 g, 508 mmol), 1,3-dibromo-5,5-dimethylhydantoin (DBH) (80 g, 279 mmol), in methyl acetate (600 mL) was heated at 78° C. for 40 minutes, while stirred with a mechanical stirrer. Then a solution of 2,2′-azobisisobutyro-nitrile (AIBN) (4.2 g, 25 mmol) in methyl acetate (80 mL) was added and heated at 75° C. for 11 hours. The mixture was allowed to cool to 15° C. and stirred for 2 hours to age the precipitate. The suspension was filtered, washed with 10° C. methyl acetate (2×50 mL) to give a brown filtrate. To the filtrate, was added heptane (500 mL). The solution was washed with 2% brine (2×500 mL) and water (2×500 mL). The organic layer was concentrated to about 2 volumes, added t-butyl methyl ether (300 mL), heated at 70° C. for 15 minutes, cooled the solution to 53° C. over one hour, seeded with the product (about 250 mg) at 45° C., then at 20-25° C., while blowing nitrogen with a glass pipette overnight. The resulting suspension was filtered via a medium pore-sized funnel, washed with a pre-cooled 10° C. mixed solvent of heptane/MTBE (½ vol/vol) and suction dried in hood overnight to give 2-bromomethyl-6-nitro-benzoic acid methyl ester as an off-white solid (49 g, 35% yield). The solid was used in the next step without further purification.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:40][CH2:41][N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44][C:43]1=[O:49])[CH2:21][O:22][C:23](=[O:39])[C@H:24]([CH:36]([CH3:38])[CH3:37])[NH:25]C(OCC1C=CC=CC=1)=O)=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.C1CC=CCC=1>[Pd].C(O)(=O)C>[NH2:25][C@H:24]([C:23]([O:22][CH2:21][CH:20]([O:40][CH2:41][N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44][C:43]1=[O:49])[CH2:19][O:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH2:11])=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)OCn1ccc(N)nc1=O
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CC(=O)O
Product: CC(C)[C@H](N)C(=O)OCC(COC(=O)[C@@H](N)C(C)C)OCn1ccc(N)nc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cool mixture of 3.44 g of 2-((4-amino-1,2-dihydro-2-oxo-1-pyrimidinyl)methoxy)-1,3-propanediyl bis(N-((benzyloxy)carbonyl)-L-valinate) and 7 g of 10% palladium catalyst in acetic acid was slowly added 8.65 mL of 1,4-cyclohexadiene. The mixture was allowed to stir at room temperature for 18 h. The reaction mixture was filtered through a pad of Celite. The filtrate was then concentrated and dried in the lyophilizer for 48 h. The resulting beige foam was scraped off affording 2.38 g (68% as the acetic acid salt) of the title compound. The elemental analysis (showing 2 M of acetic acid and 1 M of water) UV, 1H, 13C-NMR spectra were consistent with the title structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=CC(C(=O)[C@H](C2C=CC=CC=2)C)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[C@H](C(=O)c1cc(F)cc(F)c1)c1ccccc1
Agent: C[C@H](C(=O)c1ccc(Cl)cc1)c1ccccc1
Product: C[C@H](Cc1cc(F)cc(F)c1)c1ccccc1
Yield: 87.3 %

Procedure:
A reaction was carried out in the same manner as in first step of Example 4-1 except that 31.0 g (126 mmol) of (S)-1-(3,5-difluorophenyl)-2-phenylpropane-1-one [H-Ph-CH(CH3)—CO-PhFF-H] prepared in first step was employed instead of (S)-1-(4-chlorophenyl)-2-phenylpropane-1-one [H-Ph-CH(CH3)—CO-Ph-Cl] in second step of Example 4-1 to obtain 25.4 g (110 mmol) of (R)-1-(3,5-difluorophenyl)-2-phenylpropane [H-Ph-CH(CH3)—CH2-PhFF-H] (yield: 87%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2I)[C:12](=[O:16])[C:13]#[C:14][CH3:15])[CH:5]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.S1C=CC=C1C(O)=O.[Cu]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13](=[C:14]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[CH3:15])[C:12]2=[O:16])[CH:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC#CC(=O)N(Cc1cccc(C(=O)OC)c1)c1ccccc1I
Agent: [Cu]
Agent: [Pd]
Agent: O=C(O)c1cccs1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2C(=O)C(=C(C)c3ccc(F)cc3)c3ccccc32)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 60.7 %

Procedure:
A mixture of 3-{[(2-iodo-phenyl)-(1-oxo-but-2-ynyl)-amino]-methyl}-benzoic acid methyl ester (0.5 g, 1.15 mmol), 4-fluorophenylboronic acid (0.32 g, 2.3 mmol), tetrakis(triphenylphosphine) palladium (0.13 g, 0.115 mmol) and copper thiophene-2-carboxylic acid (0.46 g, 2.42 mmol) in THF was stirred for 5 hours at 60° C. After removal of solvent, the residue was purified by flash chromatography, eluting with ethyl acetate/hexane=1:5 to afford the product 3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester (0.28 g, 60%) as a yellow solid. MS calcd. for C25H20FNO3 401.4, obsd. (ESI+) [(M+H)+] 402.2.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:34])[CH2:18][N:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:12]=1[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)Cl>CO.O1CCCC1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:34])[CH2:18][N:19]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:12]=1[NH:35][S:36]([CH3:39])(=[O:37])=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
Sodium borohydride (0.37 g, 9.7 mmol) was added in portions to a stirred solution of N-[2-benzyloxy-5-(2-dibenzylamino-1-oxo-ethyl)-phenyl]-methanesulfonamide (1.0 g, 1.9 mmol) in 20 mL of methanol/tetrahydrofuran (5:2) at room temperature and the resulting solution was stirred for 2 hours. Methylene chloride was added and the resulting solution was washed with aqueous sodium bicarbonate, dried over MgSO4 and the solvent was removed. Recrystallization from methylene chloride/hexanes gave the title compound as a crystalline solid; 1H NMR (300 MHz, CDCl3) δ 2.58 (d, J=6.7 Hz, 2H), 2.86 (s, 2H), 2.92 (s, 2H), 3.55 (d, J=13.5 Hz, 2H), 3.70 (d, J=13.5 Hz, 2H), 4.11 (s, 1H), 4.64 (t, J=6.7 Hz, 1H), 5.10 (s, 2H), 6.92 (d, J=8.5 Hz, 1H), 7.00 (dd, J=8.5, 2.0 Hz, 1H), 7.20-7.50 (m, 16H), 7.89 (brs, 1H); MS (ES) m/z: 517.1 (M++H); HRMS Calcd. for C30H32N2O4S(M+): 516.2083. Found: 516.2074.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[NH:5][C:4](=[O:12])[C:3]=1[NH:13][C:14]([C:16]12[CH2:23][CH:22]3[CH2:24][CH:18]([CH2:19][CH:20]1[CH2:21]3)[CH2:17]2)=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33](=[O:35])[CH3:34].O>CN(C)C=O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:32][C:33](=[O:35])[CH3:34])[C:4](=[O:12])[C:3]=1[NH:13][C:14]([C:16]12[CH2:17][CH:18]3[CH2:24][CH:22]([CH2:21][CH:20]1[CH2:19]3)[CH2:23]2)=[O:15]
Reactant: CCCn1c(N)c(NC(=O)C23CC4CC(CC2C4)C3)c(=O)[nH]c1=O
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(N)c(NC(=O)C23CC4CC(CC2C4)C3)c(=O)n(CC(C)=O)c1=O
Yield: 66 %

Procedure:
To a solution of 2.20 g (6.63 mmol) of 6-amino-5-(3-tricyclo[3.3.1.03,7 ]nonylcarbonylamino)-1-propyluracil (Japanese Published Unexamined Patent Application No. 173889/91) in 35 ml of dimethylformamide, 3.24 g (9.95 mmol) of cesium carbonate, 1.23 ml (13.3 mmol) of bromoacetone were added with stirring. The reaction mixture was stirred at 60° C. for 3.5 hours. The mixture was cooled, poured into 100 ml of water and extracted three times with 30 ml of chloroform. The organic layer was washed with 0.2M sodium thiosulfate aqueous solution, with water, with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluate: 2% methanol/chloroform) to give 1.70 g (yield 66%) of Compound I as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](Cl)([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[CH:6][N:7]=1.[Cl:13]C1N=CC(OC)=C(Cl)N=1.C([Mg]Br)=C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CC(C)=O.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[C:6]([Cl:13])[N:7]=1
Reactant: C=CC1(Cl)NC(Cl)=NC=C1OC
Reactant: COc1cnc(Cl)nc1Cl
Agent: C=C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C=Cc1nc(Cl)nc(Cl)c1OC
Reaction time: 5 h

Procedure:
2,6-Dichloro-5-methoxy-6-vinyl pyrimidine may be prepared using 2,6-dichloro-5-methoxy pyrimidine, which is commercially available. 2,6-Dichloro-5-methoxy pyrimidine (12.5 g, 69.8 mmol) was combined in a flask with THF (125 mL) and placed in a room temperature water bath. Vinyl magnesium bromide (78 mL, 76.8 mmol) was added in three portions. The mixture was stirred for 5 h. Acetone was added to quench any remaining Grignard reagent. DDQ (19 g, 83.8 mmol) was added to the mixture, and the mixture was stirred overnight. The mixture was then concentrated to remove the THF. Dichloromethane (DCM) was added, triturated, and allowed to stand over the weekend before being filtered, concentrated, and purified by column chromatography on silica gel using a 5-30% ethyl acetate/hexane gradient. This produced the title compound (7.95 g), which was observed to be a light yellow solid that turned grey in light.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].C(N(CC)CC)C.[Si:13]([O:20][C@@H:21]([C@@H:23]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[NH:25][C:24]1=[O:31])[CH3:22])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl>[Si:13]([O:20][C@@H:21]([C@@H:23]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[N:25]([Si:2]([CH3:4])([CH3:3])[CH3:1])[C:24]1=[O:31])[CH3:22])([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C
Temperature: 25 °C

Procedure:
First 22.8 ml of trimethylsilyl chloride and then 25.1 ml of triethylamine were added dropwise to a solution of 43.1 g of (3R,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-acetoxy-2-azetidinone in 450 ml of methylene chloride, maintained at 0° to 5° C. in an ice-water bath. The mixture was stirred at room temperature for 2 hous, then again cooled to 0° to 5° C. in an ice-water bath and filtered under suction. The filtrate was concentrated under reduced pressure. The residue was mixed with 300 ml of anhydrous ether and insolubles were filtered off. The solvent was stripped off from the filtrate, giving 52.8 g of crystalline (3R,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-acetoxy-1-trimethylsilyl-2-azetidinone.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[CH3:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:32]3[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H]1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
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
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CCCN1c1cccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)n1
Temperature: 100 °C
Yield: 89.4 %

Procedure:
A mixture of (S)-6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.08 g, 0.243 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.066 g, 0.268 mmol), Pd2(dba)3 (0.028 g, 0.049 mmol), X-phos (0.046 g, 0.097 mmol) and Na2CO3 (0.103 g, 0.992 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 15 g, 200-300 mesh, MeOH:dichloromethane=1:10) to afford (S)-4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (90 mg) as a yellow solid. LC-MS: [M+1]+=415, tR=1.660 min. This contained unidentified impurities and was used directly without further purification.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:17][N:18]1[N:22]=[C:21]2[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:20]2=[N:19]1)=O)C1C=CC=CC=1>CO.CCO.[Pd]>[NH2:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:17][N:18]1[N:22]=[C:21]2[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:20]2=[N:19]1
Reactant: CC(C)(C)OC(=O)N1Cc2nn(C[C@H]3NC(=O)[C@H]3NC(=O)OCc3ccccc3)nc2C1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2nn(C[C@H]3NC(=O)[C@H]3N)nc2C1
Reaction time: 1.7 h

Procedure:
Slurried tert-butyl 2-(((2R,3S)-3-(((benzyloxy)carbonyl)amino)-4-oxoazetidin-2-yl)methyl)-4,6-dihydropyrrolo[3,4-d][1,2,3]triazole-5(2H)-carboxylate (11.8 mg, 0.027 mmol) and Pd—C (5%, 2.3 mg) in MeOH/EtOH (740 μl, 1.7:1) under N2, whereupon the system was evacuated and backfilled with H2 (3×). After vigorous stirring for 1.7 h, the system was purged with N2 and the solids were filtered through a 0.45μ syringe filter. The filtrate was concentrated in vacuo and used as such without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([OH:12])=[CH:5]2.[CH3:13]N(C)C=O.CI>CO.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([O:12][CH3:13])=[CH:5]2
Reactant: CN(C)C=O
Reactant: Oc1cc2cc(Br)ccc2cn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CI
Product: COc1cc2cc(Br)ccc2cn1
Temperature: 25 °C
Reaction time: 0.27 h
Yield: 14 %

Procedure:
A mixture of 6-bromoisoquinolin-3-ol (606 mg, 2.70 mmol), silver carbonate (1.5 g, 5.3 mmol), and N,N-dimethylformamide (12 mL) was stirred at room temperature for 16 minutes. Methyl iodide (186 μL, 2.97 mmol) was added and the reaction was left stirring for 18 hours. The reaction was diluted with methanol and filtered through Celite. The filtrate was concentrated and purified by flash column chromatography to give the title compound (90 mg, 14%). +ESI (M+H+1) 240.0; 1H NMR (400 MHz, CDCl3, δ): 8.91 (s, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.43 (dd, J=8.8, 1.8 Hz, 1H), 6.90 (s, 1H), 4.02 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.CS(C)=O.[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15][CH2:14]1>C(OCC)(=O)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:20][CH2:19][CH:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCC1CCOCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Clc1cncc(NCC2CCOCC2)n1
Temperature: 75 °C
Reaction time: 6 h
Yield: 81.6 %

Procedure:
A mixture of 2,6-dichloropyrazine (950 mg, 6.38 mmol), DMSO (14 ml), TEA (1.067 ml, 7.65 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (771 mg, 6.70 mmol) was stirred at 75° C. for 6 hours, and the reaction progress was followed by LCMS. The crude reaction mixture was cooled to ambient temperature, diluted with 300 ml of ethyl acetate, washed with 1M NaOH soln. (1×), water (1×), saturated salt soln. (1×), dried with sodium sulfate, filtered, and concentrated to constant mass, giving 1185 mg of titled compound as free base, used without further purification. LCMS (m/z): 228.0 (MH+), retention time=0.73 min.