Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][N:13]([CH2:20][C@H:21]2[CH2:25][O:24]C(C)(C)[O:22]2)[C:14]3=[O:19])=[CH:4][C:3]=1[C:28]1[NH:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][N:32]=1.C(O)(C(F)(F)F)=O>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][N:13]([CH2:20][C@H:21]([OH:22])[CH2:25][OH:24])[C:14]3=[O:19])=[CH:4][C:3]=1[C:28]1[NH:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][N:32]=1
Reactant: CC1(C)OC[C@H](CN2CCc3c(Nc4ccc(Cl)c(-c5ncc(-c6ccccc6)[nH]5)c4)cccc3C2=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2cccc(Nc3ccc(Cl)c(-c4ncc(-c5ccccc5)[nH]4)c3)c2CCN1C[C@H](O)CO
Reaction time: 18 h

Procedure:
To a solution of (S)-5-(4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenylamino)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (210 mg, 0.40 mmol) in THF (1.6 ml) and water (0.4 ml) is added TFA (0.1 ml) at room temperature, and the reaction mixture is stirred for 18 hours. The reaction mixture is concentrated to dryness by rotary evaporation and the crude product is purified by preparative HPLC to afford (S)-5-(4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)phenylamino)-2-(2,3-dihydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one as an off-white solid. LC-MS m/z: 489.1 (M+1); 1H NMR 400 MHz (CDCl3) δ 7.76 (d, 1H, J=7.6 Hz), 7.67-7.63 (m, 3H), 7.40-7.32 (m, 4H), 7.27-7.20 (m, 3H), 6.71-6.68 (m, 1H), 3.89-3.87 (m, 1H), 3.66-3.53 (m, 6H), 2.82 (t, 2H, J=6.8 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=2[C:22]2[O:23][C:24]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:25]=3[CH:26]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CCC=CC=1>CO.[Pd]>[OH:31][C:28]1[CH:29]=[CH:30][C:24]2[O:23][C:22]([C:16]3[C:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)=[CH:20][C:19]([OH:21])=[CH:18][CH:17]=3)=[CH:26][C:25]=2[CH:27]=1
Reactant: Oc1ccc(-c2cc3cc(O)ccc3o2)c(-c2ccc(OCc3ccccc3)cc2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCCC=C1
Product: Oc1ccc(-c2cc(O)ccc2-c2cc3cc(O)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.1 %

Procedure:
A solution of 104 (0.13 g, 0.32 mmol) in MeOH (10 mL) was treated with 0.2 g 10% Pd/C and cyclohexadiene (1 mL) and stirred at rt for 24 h. The reaction was filtered through a bed of Celite, concentrated and chromatographed on silica gel (1:1 EtOAc/hexanes) and the product was obtained as an oil which crystallized upon addition of CH2Cl2 to yield 48 mg of yellowish needles: Mp=238-239° C.; 1H NMR (DMSO-d6) δ 9.87 (brs, 1 H), 9.54 (brs, 1 H), 9.08 (br s, 1 H), 7.64 (d, 1 H, J=8.5 Hz), 7.21 (d, 1H, J=8.7 Hz), 7.05 (d, 2 H, J=8.4 Hz), 6.84 (dd, 1 H, J=8.5 Hz, 2.5 Hz), 6.76 (d, 2 H, J=8.5 Hz), 6.69 (dd, 2 H, J=6.6 Hz, 2.4 Hz), 6.63 (dd, 1 H, J=8.7 Hz, 2.4 Hz), 5.84 (s, 1H); MS 317 (M−H)−.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1.[F:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([NH:23][C:24]2([C:27](O)=[O:28])[CH2:26][CH2:25]2)=[O:22])=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH:11][C:27]([C:24]3([NH:23][C:21](=[O:22])[C:20]4[CH:30]=[CH:31][C:17]([F:16])=[CH:18][CH:19]=4)[CH2:26][CH2:25]3)=[O:28])[C:4]2=[N:3][CH:2]=1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Reactant: O=C(NC1(C(=O)O)CC1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(F)cc1
Yield: 67.5 %

Procedure:
Combine (4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine (95.0 mg, 0.48 mmol), 1-[(4-fluorobenzoyl)amino]cyclopropanecarboxylic acid (128.0 mg, 0.57 mmol), and O—-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (218.0 mg, 0.57 mmol) in N,N-dimethylformamide (4 mL). Add diisopropylethylamine (0.21 mL, 1.19 mmol) and stir the reaction for approximately 16 hours at ambient temperature under nitrogen. Dilute the reaction with ethyl acetate, wash with saturated sodium bicarbonate and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure. Purify the residue by flash chromatography (3% ammonia (2M) solution in methanol/dichloromethane) to give the title compound (131.0 mg, 68%): MS (m/z): 405 (M+1).
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]1[N:25]([CH3:28])[CH2:26][CH2:27][C:18]21[CH3:29].[CH2:30]([O:32][C:33](=[O:39])[C:34](OCC)=[O:35])[CH3:31].[Cl-].[NH4+]>CCOCC>[O:35]=[C:34]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]1[N:25]([CH3:28])[CH2:26][CH2:27][C:18]21[CH3:29])[C:33]([O:32][CH2:30][CH3:31])=[O:39]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CN1CCC2(C)c3cc(Br)ccc3N(C)C12
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Tetramethylethylenediamine (TMEDA) (2.3 ml) and s-butyllithium (1.3M in cyclohexane, 11.7 ml) were added to anhydrous ether (8.0 ml) at -78° C. under nitrogen. A solution of 5-bromo-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (3.57 g) in anhydrous ether (10 ml) was added to the resulting reaction mixture at -78° C. via canula and stirred at this temperature for 1 hour and at -20° C. for 1 hour. The solution was then added via canula to a -78° C. solution of diethyloxalate (5.2 ml) in anhydrous ether (30 ml) under N2. The resulting mixture was held at -78° C. for 30 min, -20° C. for 2 hours and room temperature for 30 min. Saturated ammonium chloride solution (10 ml) was added and the organic and aqueous phases separated. The organic phase was washed twice with brine, dried (Na 2 SO4), filtered and concentrated under vacuum. The crude residue was purified using preparative high performance liquid chromatography (HPLC), (silica gel, sample loaded and eluted with 2% methanol in ethyl acetate). Concentration of the appropriate fractions afforded 1.6 g of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester, as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH:10](OCC)[O:11]CC)=[O:7])=[C:4]([Cl:19])[CH:3]=1.Cl.O>C1COCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH:10]=[O:11])=[O:7])=[C:4]([Cl:19])[CH:3]=1
Reactant: CCOC(CNC(=O)c1ccc(Br)cc1Cl)OCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=CCNC(=O)c1ccc(Br)cc1Cl
Reaction time: 24 h
Yield: 59.5 %

Procedure:
To a solution of 4-bromo-2-chloro-N-(2,2-diethoxyethyl)benzamide (14.88 g, 42.44 mmol) in THF (50 mL) was added 2N HCl (50 mL) at room temperature. After 24 hours, water (100 mL) was added to the mixture, then the mixture was extracted with ethyl acetate (100 mL×2), the organic layer was washed with water (50 mL), dried over MgSO4. Removal of the solvent, gave a title compound (6.98 g, 60% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:8]=[C:9]([CH2:15][C:16]([OH:34])([C:30]([F:33])([F:32])[F:31])[CH2:17][C:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])([CH3:20])[CH3:19])[NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH3:29])=[C:21]([C:18]([CH3:19])([CH3:20])[CH2:17][C:16]([OH:34])([C:30]([F:32])([F:33])[F:31])[CH2:15][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=3[CH:8]=2)[CH:26]=1
Reactant: CCOC(=O)c1cccc2[nH]c(CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2c(C(=O)O)cccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A solution of 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-4-carboxylic acid ethyl ester (220 mg, 0.470 mmol) in 10 mL of methanol was treated with a solution of potassium hydroxide (85 mg, 1.5 mmol) in 3 mL of water. The resulting mixture was stirred at room temperature for 4 hours, refluxed for 6 hours, cooled to room temperature, and concentrated in vacuo. The residue was treated with cold 1 N sulfuric acid and extracted with three 30 mL portions of dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 190 mg of the title product as a light cream solid (89% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:17][C:18](=[O:27])[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])(=O)[NH2:2].S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:17][C:18](=[O:27])[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])#[N:2]
Reactant: CCOc1c(C(N)=O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOc1c(C#N)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a solution of 3-carbamoyl-8-(2,6-dichlorobenzoylamino)-4-ethoxyquinoline (122 mg) in dimethylformamide was added thionyl chloride (53.9 mg), and the mixture was stirred for 30 minutes at ambient temperature. The mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 3-cyano-8-(2,6-dichlorobenzoylamino)-4-ethoxyquinoline (89.9 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[CH:24]([N:27]=[C:28]=[O:29])([CH3:26])[CH3:25]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:27]([CH:24]([CH3:26])[CH3:25])[C:28]2=[O:29])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)N=C=O
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(C(C)C)c(=O)n(C3CCCC3)c12
Yield: 53.8 %

Procedure:
1-Cyclopentyl-3-isopropyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and isopropyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 354 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 7.78 (d, 1H), 7.57 (t, 1H), 7.24 (d, 1H), 5.21 (p, 1H), 4.93 (m, 1H), 4.14 (s, 3H), 3.83 (m, 2H), 2.38 (m, 2H), 2.08 (m, 4H), and 1.15 (d, 6H) ppm.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([CH:28]1[CH2:31][CH2:30][CH2:29]1)[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:20][S:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:9][CH2:8]1.C[Al](C)C.[CH3:37][NH2:38]>C(Cl)Cl>[CH:28]1([N:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[C:14]4[C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:20][S:19][C:15]=4[N:16]=[CH:17][N:18]=3)[CH2:11][CH2:12]2)[CH2:4][C:3]([NH:38][CH3:37])=[O:2])[CH2:29][CH2:30][CH2:31]1
Reactant: CN
Reactant: COC(=O)CN(CC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1)C1CCC1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CNC(=O)CN(CC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1)C1CCC1
Temperature: 25 °C

Procedure:
The reaction was stirred for min and then allowed to warm to room temperature. After stirring for 30 minutes, methyl-2-[cyclobutyl-[[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-4-piperidyl]methyl]amino]acetate (37 mg, 0.082 mmol) in DCM (0.5 mL) was added dropwise and the reaction stirred for 2 h. A further 123 μL of trimethylaluminium and a further 123 μL of methylamine were added and the reaction stirred overnight at room temperature. The solvents were then evaporated and the residue purified by column chromatography eluting 0 to 5% v/v of 7 M ammonia/methanol in DCM to give 2-[cyclobutyl-[[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-4-piperidyl]methyl]amino]-N-methyl-acetamide as a colourless solid (6 mg). LCMS RT=3.01. M+1=450.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:40][N:41]([CH3:44])C=O>>[CH3:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=[C:10]([CH2:9][CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:28]2[N:29]([CH2:4][C:1]3[CH:3]=[CH:44][N:41]=[CH:40][CH:2]=3)[CH:30]=[CH:31][N:32]=2)[CH:18]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2ccncc2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (25 mg, 0.53 mmol), (4-bromomethyl) pyridine (14.1 mg 0.055 mmol, 1.05 equiv), and potassium carbonate (22.0 mg, 0.16 mmol) were combined in dimethylformamide (1.0 mL). After stirring at room temperature for 3 d, the solvents were removed and the residue purified by column chromatography to afford 23.0 mg (77%). Mass spec.: 563.3 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:20])[C@H:12]([C:17](O)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.O>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].COC(C)(C)C>[CH2:1]([O:8][C:9](=[O:10])[N:11]([C@@H:12]([C@@H:13]([CH3:14])[CH2:15][CH3:16])[CH2:17][OH:18])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC[C@H](C)[C@@H](CO)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-N-methyl-L-isoleucine (52.37 g, 187.5 mmol, 1 eq.) in tetrahydrofuran (524 mL, 0.35 M) was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 375 mL, 375 mmol, 2 eq.) slowly over 1 hour and the reaction was allowed to stir for 18 hours at room temperature. The reaction was cooled to 0° C. and water (30 mL) was added over 30 minutes. The reaction mixture was diluted with 1 M aqueous sodium carbonate solution (100 mL) and tert-butyl methyl ether (250 mL). The aqueous layer was back-extracted with tert-butyl methyl ether (100 mL). The combined organic layers were washed with 1 M aqueous sodium carbonate solution (100 mL), washed with brine (200 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to provide #1 (48.44 g, 97% yield) as a pale yellow oil, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers: δ 7.26-7.41 (m, 5H), [5.06 (AB quartet, JAB=12.9 Hz, ΔνAB=22.8 Hz) and 5.06 (AB quartet, JAB=9.0 Hz, ΔνAB=9.0 Hz), total 2H], [4.65 (t, J=5.3 Hz) and 4.59 (t, J=5.4 Hz), total 1H], 3.67-3.80 (m, 1H), 3.51-3.60 (m, 1H), 3.41-3.51 (m, 1H), 2.75 and 2.71 (2 s, total 3H), 1.49-1.64 (br m, 1H), 1.24-1.37 (br m, 1H), 0.90-1.02 (br m, 1H), 0.74-0.87 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@H:23]1[CH2:27][NH:26][C:25](=[O:28])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@@H:23]1[CH2:24][C:25](=[O:28])[NH:26][CH2:27]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NO[C@H]1CNC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C1C[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (25 mL) were added (4R)-4-(aminooxy)pyrrolidin-2-one 128 (0.12 g, 0.86 mmol, J. Med. Chem. 1997, 40(15), 2363-2373), 1-hydroxybenzotriazole (0.14 g, 1.10 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.10 mmol) and 4-dimethylaminopyridine (0.13 g, 1.08 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-7-oxo-N-{[(3R)-5-oxopyrrolidin-3-yl]oxy}-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 129 (0.22 g, 82%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]=[N:10][CH2:11][CH:12](C)C.[CH2:15](OCC(COCC1OC1)(COCC1OC1)COCC1OC1)C1OC1>CO>[CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH2:8][CH:9]=[N:10][CH:11]([CH3:12])[CH3:15]
Reactant: CC(C)CN=CCN1CCNCC1C
Reactant: C(OCC(COCC1CO1)(COCC1CO1)COCC1CO1)C1CO1
Solvent: CO
Product: CC(C)N=CCN1CCNCC1C
Temperature: 60 °C

Procedure:
To a 10 mL round bottom flask containing a stir bar was added methyl isobutyliminoethylpiperazine (726 mg, 3.44×10−3 moles, 3 equivalents) and 4 g MeOH. To this mixture at 25° C. was added pentaerythritol tetraglycidyl ether (307 mg, 0.853 mmol, 3.4 mmoles epoxide). This mixture was stirred and heated at 60° C. for 6.5 hours. To this mixture was added ethyl t-piperazine carbamate (537 mg, 3.4 mmol) and this mixture heated at 60° C., 16 hours, 60° C., 54 h with no adduct for the desired product at 906 or 833 (decarboxylated material). Another aliquot of monoblocked piperazine was added (1.5 g) and this mixture was heated at 70° C., 16 hours, 24 hours and 60 hours total with no sign of desired adduct. The 3:1 adduct at 748 amu was completely converted to 4:1 adduct at 993 amu by reaction of remaining equivalent imine in presence of a total of 16 equivalents of ethyl 1-piperazine carboxylate. This mixture was purified by tangential flow ultrafiltration using a 1K regenerated cellulose membrane at 20 psi as a 2-5% w/w mixture in MeOH to give 8-9 recirculations. The retentate was stripped of volatiles on a rotary evaporator followed by high vacuum to give 590 mg. The following scheme illustrates this reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([NH2:19])[N:18]=3)[N:15]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC>ClC(Cl)C.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[NH2:19][C:17]1[N:18]=[C:13]2[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:23](=[O:24])[C:22]4[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:21]=4[F:20])=[CH:3][CH:4]=3)=[N:15][N:14]2[CH:16]=1
Reactant: Cc1ccc(F)c(C(=O)O)c1
Reactant: Nc1ccc(C#Cc2ccc3nc(N)cn3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(F)c(C(=O)Nc2ccc(C#Cc3ccc4nc(N)cn4n3)cc2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To 6-[(4-aminophenyl)ethynyl]imidazo[1,2-b]pyridazin-2-amine, (30 mg, 0.12 mmol, 1 eq) and 2-fluoro-5-methylbenzoic acid (18.5 mg, 1 eq) in anhydrous dichloroethane (1 mL) under nitrogen atmosphere at room temperature was added 4-(dimethylamino)pyridine (2.94 mg, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (27.76 mg, 1.2 eq). After the reaction was stirred at 50° C. for 2 hours, it was diluted with chloroform, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (from CHCl3 to MeOH—CHCl3 1:25) to yield N-{4-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)ethynyl]phenyl}-2-fluoro-5-methylbenzamide as a yellow solid in amount of 7 mg.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[CH2:11]([Li])CCC.COS(OC)(=O)=O.[Cl-].[NH4+]>C(OCC)C>[CH3:11][C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: Cc1ccc(-c2cccs2)s1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a stirred solution of 32.0 grams (0.193 mole) of 2,2'-bithienyl in 150 mL of diethyl ether was cooled to -5°0 C., and 90.5 mL (0.226 mole--2.6M in hexanes) of n-butyllithium was added slowy dropwise. Upon completion of addition the reaction mixture was stirred at -5° C. for one hour, and then a solution of 27.8 grams (0.220 mole) of dimethylsulfate in 75 mL of diethyl ether was added very slowly dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred for 18 hours. After this time the reaction mixture was poured into 350 mL of an aqueous 10% ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined extracts were washed with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to yield 30.0 grams of 5-methyl(2,2'-bithienyl); b.p. 108°-113° C./1.9 mm.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[N:6]([CH2:14][CH3:15])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[N:6]([CH2:14][CH3:15])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)c(OC)cc21
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)c(OC)cc21
Yield: 69.9 %

Procedure:
Following a procedure analogous to 101b, 7-Amino-1-ethyl-8-methoxy-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (88 mgs) and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (84 mgs) gave the title compound as white solid 103 mgs (70%); 1H-NMR (CDCl3, 400 MHz) δ 8.43 (s, 1H), 7.94 (s, 1H), 7.39 (s, 1H), 6.76 (s, 1H), 6.47 (d, J=9.0 Hz, 1H), 6.29 (s, 2H), 5.54 (broad s, 1H), 5.32 (broad s, 1H), 4.56 (t, J=8.6 Hz, 1H), 3.92 (s, 3H), 3.83 (broad m, 2H), 3.09 (s, 1H), 2.83 (s, 1H), 2.51 (d, J=8.2 Hz, 1H), 2.29-2.25 (m, 3H), 2.09-2.05 (m, 2H), 1.68 (d, J=9.3 Hz, 1H), 1.34 (s, 6H), 0.91-0.85 (m, 3H); LC/MS:, found (M+H)+=525.28; MP:156-166° C.