Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([NH2:37])=[CH:35][C:34]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[N:28]1([C:31]2[C:36]([NH:37][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=3[CH3:24])=[CH:35][C:34]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:33][N:32]=2)[CH2:27][CH2:26][O:25][CH2:30][CH2:29]1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (70.0 mg, 0.190 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 8.21 (1H, d, J=7.8 Hz), 7.84 (1H, d, J=11.7.0 Hz), 7.80 (1H, td, J=7.5, 1.4 Hz), 7.70 (1H, td, J=7.7, 1.4 Hz), 7.54 (1H, br. s.), 7.50 (1H, d, J=9.4), 7.41 (1H, d, J=7.4 Hz), 7.06 (1H, ddd, J=13.5, 8.6, 2.5 Hz), 6.52 (1H, br. s.), 3.84-4.03 (4H, m), 3.70-3.83 (4H, m), 3.32-3.56 (2H, m), 2.87-3.19 (9H, m), 1.92 (3H, s). Mass Spectrum (ESI) m/e=596.2 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[S:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1>>[CH3:25][O:24][C:11]1[CH:12]=[C:13]([C:20]([F:21])([F:22])[F:23])[CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[C:10]=1[C:9]([NH:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[NH:1][CH:30]1[CH2:31][CH2:32][S:27][CH2:28][CH2:29]1)=[O:26]
Reactant: O=C1CCSCC1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1NC1CCSCC1

Procedure:
The title compound, white foam, MS: m/e=485.3 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and tetrahydro-4H-thiopyran-4-one.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]([NH:16][C:17]2[N:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25](OCC)=[O:26])=[N:21][CH:22]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C[O-].[Na+].Cl>CO>[CH2:1]([O:8][N:9]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]([NH:16][C:17]2[N:18]=[CH:19][C:20](/[CH:23]=[CH:24]/[C:25]([NH:31][OH:32])=[O:26])=[N:21][CH:22]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCC(=O)N(OCc3ccccc3)C2)cn1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCC(=O)N(OCc3ccccc3)C2)cn1)NO
Temperature: 0 °C
Reaction time: 4 h
Yield: 7.8 %

Procedure:
To a solution of ethyl (2E)-3-(5-{[(3R)-1-(benzyloxy)-6-oxo-3-piperidinyl]amino}-2-pyrazinyl)acrylate (200 mg, 0.50 mmol) in methanol (5 mL) was added hydroxylamine hydrochloride (175 mg, 2.52 mmol) at ambient temperature under nitrogen. After cooling, 1M sodium methanolate in methanol (5 mL) was added dropwise to the mixture over 1 h, the reaction mixture was stirred at 0° C. for 2 hrs and at ambient temperature for 4 hrs. The reaction mixture was adjusted to PH 6.0 with 1 mol/L hydrochloric acid and evaporated in vacuo. The residue was dissolved in ethanol and the precipitate was removed by filtration. The solvent was evaporated in vacuo. The residue was purified by preparative HPLC (CH3CN, 20% NH4HCO3/30%-90%, gradient) to give (2E)-3-(5-{[(3R)-1-(benzyloxy)-6-oxo-3-piperidinyl]amino}-2-pyrazinyl)-N-hydroxyacrylamide (15 mg, 8%) as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2([OH:18])[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]2)=[O:9])[CH:7]=1.CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][C:10]3([CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11]3)[C:8](=[O:9])[C:6]=2[CH:7]=1
Reactant: COC1CCC(O)(C(=O)c2cc(Br)ccc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=O
Temperature: 70 °C
Yield: 39.3 %

Procedure:
A mixture of (5-bromo-2-fluorophenyl)(1-hydroxy-4-methoxycyclohexyl)methanone (Intermediate 12 Step 2, 1.05 g, 3.17 mmol) and potassium tert-butoxide (0.445 g, 3.80 mmol) in THF (10 mL) was heated in a microwave reactor at 70° C. for 30 min. The solvent was removed in vacuo and the residue was purified by flash chromatography using a gradient of 0 to 15% EtOAc in hexanes to afford 388 mg (39% yield) of the title compound. 1H NMR (400 MHz, CDCl3): δ ppm 1.71 (m, 6H), 2.31 (m, 2H), 3.32 (m, 1H), 3.41 (s, 3H), 7.03 (d, J=9.20 Hz, 1H), 7.36 (t, J=8.80, 2.00 Hz, 1H), 7.77 (d, J=2.00 Hz, 1H); MS (ES+) m/z 312 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:20])=[C:11]([CH:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]3=[O:19])[N:12]=2)=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:20])=[C:11]([C:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]=3[O:19][CH3:21])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)CCC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC1=C(c2nc(-c3ccc(Cl)cc3)sc2C)C(=O)CC1
Temperature: 40 °C
Yield: 66.6 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-cyclopentane-1,3-dione (1.12 g, 3.66 mmol) in acetone (20 ml) was added potassium carbonate (1.04 g, 7.32 mmol), followed by iodomethane (455 μl, 7.32 mmol), and the reaction heated to 40° C. for 6 hours. The solvent was then removed from the crude reaction mixture under reduced pressure and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dry loaded onto silica and purified by flash chromatography to give 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-3-methoxy-cyclopent-2-enone (780 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][N:6]1[C:10]([C:11](O)=[O:12])=[CH:9][C:8]([CH3:14])=[N:7]1>CN(C)C=O>[CH3:5][N:6]1[C:10]([C:11]([Cl:3])=[O:12])=[CH:9][C:8]([CH3:14])=[N:7]1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(=O)O)n(C)n1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Cl)n(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (1.04 ml, 14.4 mmol) is added to a stirred solution of 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (0.5 g, 3.6 mmol) and dimethylformamide (3 drops). The reaction is stirred for 2 hours at room temperature and then for 2 hours at 80° C. The reaction is concentrated. The residue is dissolved in dichloromethane and then the solvent is evaporated to yield 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:24]1([NH2:34])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>FC(F)(F)CO>[C:24]1([NH:34][C:21]2[C:16]3[CH:15]=[C:14]([C:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH:12]=4)[NH:23][C:17]=3[N:18]=[CH:19][N:20]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: C1=C(c2cc3c(Nc4cccc5ccccc45)ncnc3[nH]2)CCNC1
Temperature: 80 °C

Procedure:
A sealed tube containing a solution of 4-(4-chloro-7H-pyrrolo[2,3-d]-pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (250 mg, 0.75 mmol), 1-naphthylamine (160 mg, 1.12 mmol) and trifluoroacetic acid (287 μL, 3.73 mmol) in 2,2,2-trifluoroethanol (5 mL) was heated at 80° C. and maintained at this temperature overnight. The product was poured into saturated NaHCO3 solution (50 mL) and the precipitate was filtered off, giving the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ=9.48 (1H, s), 8.14-7.92 (3H, m), 7.82 (1H, d, J=8.0 Hz), 7.64 (1H, d, J=7.2 Hz), 7.61-7.44 (3H, m), 6.40 (1H, s), 4.02 (2H, brs), 3.51 (2H, brs), 2.89 (2H, brs); MS (ES+): m/z 342.11 [MH+], HPLC: tR=1.71 min (MicromassZQ, polar—5 min).
Reaction SMILES: [K].[CH2:2]([C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(N(C)C)=O>O>[CH2:2]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Reactant: Brc1ccccc1
Agent: [K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCc1cccc(Oc2ccccc2)c1
Temperature: 150 °C

Procedure:
Into the round bottom flask containing potassium salt of 3-pentadecyl phenol is added bromobenzene followed by Cu powder and in a solvent, DMAc (dimethyl acetamide). The reaction mixture is heated at 150° C. for 6 h. After completion of the reaction, the obtained dark colored reaction mixture is poured into water and the Cu salts are removed by filtration. The filtrate is extracted in a solvent, washed with water and dried, purified to obtain arylated product, 1-pentadecyl-3-phenoxybenzene.
Reaction SMILES: Br[C:2]1[C:11]([CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:10][C:9]2[C:8]([CH3:24])([CH3:23])[CH2:7][CH2:6][C:5]([CH3:26])([CH3:25])[C:4]=2[CH:3]=1.[Cu][C:28]#[N:29]>CN1CCCC1.[OH-].[NH4+]>[C:28]([C:2]1[C:11]([CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])=[CH:10][C:9]2[C:8]([CH3:24])([CH3:23])[CH2:7][CH2:6][C:5]([CH3:26])([CH3:25])[C:4]=2[CH:3]=1)#[N:29]
Reactant: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(Br)cc21
Reactant: N#C[Cu]
Agent: CN1CCCC1
Agent: [NH4+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(C#N)cc21
Temperature: 175 °C
Yield: 60.7 %

Procedure:
To a solution of 9.0 g (20.5 mmol) of 2-bromo-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene in 70 mL of N-methyl pyrollidine was added 7.36 g (82 mmol) of copper (I) cyanide and the reaction mixture was heated to 175° C. After 16 hours the reaction mixture was cooled to room temperature and diluted with 10% aqueous ammonium hydroxide. The resulting salts were removed by filtration and washed with hot ethyl acetate. The filtrate was extracted with ethyl acetate and the combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution: 3-25% ethyl acetate/hexane) to give 4.8 g (61%) of 2-cyano-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[C:6]=1[CH3:13]>CS(C)=O.O>[CH3:1][O:2][C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[C:6]=1[CH3:13]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc[n+]([O-])c(C)c1C
Reaction time: 8 h

Procedure:
To a solution prepared by diluting 41.6 g (2.0 eq.) of a 28% aqueous solution of sodium methoxide with 200 mL of dimethylsulfoxide, a liquid containing 17.0 g of 4-chlor-2,3-dimethylpyridine-1-oxide dissolved in dimethylsulfoxide (70 mL) was added dropwise. The mixture was allowed to react for 3 hours at 40 to 50° C., and then was left to stand overnight at room temperature. 15 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then was concentrated to dryness under reduced pressure, to obtain 37.2 g of 4-methoxy-2,3-dimethylpyridine-1-oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6]C)=[C:4]([N+:10]([O-])=O)[CH:3]=1.NN.[CH3:15]O>[Ni]>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH3:15])([NH2:6])[CH:4]([NH2:10])[CH:3]=1
Reactant: CNc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CO
Agent: [Ni]
Agent: NN
Product: CC1(N)C=CC(Cl)=CC1N
Yield: 84 %

Procedure:
32.5 g (0.175M) of 4-Chloro-2-nitro-N-methylaniline of A above are added gradually to 24 g Raney-Nickel (wet) and 48 g hydrazine in methanol. A large amount of heat is generated. After the addition is complete, the solution is heated to reflux for 3 hours and filtered to remove the metal catalyst. The solvent is removed and the residue dissolved in methylene chloride. The methylene chloride solution is extracted with water and the mixture is filtered to remove the emulsion. The layers are separated and the methylene chloride layer is dried over anhydrous magnesium sulfate. After removal of the solvent, the residue is recrystallized from hexane. The substituted phenylenediamine weighs 22.6 g (84% yield) and has a melting point of 51°-2° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].Cl[C:11]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: Cc1cc(N)cnc1Br
Product: Cc1cc(Nc2ccc(Cl)cc2C(=O)O)cnc1Br
Yield: 24 %

Procedure:
Obtained (0.51 g, yield 24%) following the procedure described in Intermediate 13 starting with 6-bromo-5-methylpyridin-3-amine (5.35 mmol, 1.0 g) and 2,5-dichlorobenzoic acid (10.68 mmol, 2.04 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([N:32]1[CH2:40][CH2:39][CH:35]([C:36]([OH:38])=O)[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CN1CCOCC1.[NH2:48][C:49]1[N:50]=[CH:51][C:52](/[C:64](=[N:66]/[NH2:67])/[NH2:65])=[N:53][C:54]=1[C:55]1[O:56][C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])=[N:58][N:59]=1>CC(N(C)C)=O>[NH2:65]/[C:64](/[C:52]1[CH:51]=[N:50][C:49]([NH2:48])=[C:54]([C:55]2[O:56][C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])=[N:58][N:59]=2)[N:53]=1)=[N:66]\[NH:67][C:36]([CH:35]1[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:40][CH2:39]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)(C)c1nnc(-c2nc(/C(N)=N/N)cnc2N)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N/N=C(\N)c2cnc(N)c(-c3nnc(C(C)(C)C)o3)n2)CC1
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (74.3 g, 195.44 mmol) was added to a solution of N-Boc-isonipecotic acid (41.1 g, 179.15 mmol) and 4-methylmorpholine (35.9 mL, 325.74 mmol) in DMA (800 mL). The mixture was stirred for 10 minutes then (Z)-5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbohydrazonamide (45 g, 162.87 mmol) was added to the solution in one portion (exotherm observed from 22° C. to 27° C.). After a few minutes the product crystallised from the reaction mixture. The reaction mixture was removed from the vessel and filtered through a sinter. Additional DMA was added to wash product from the sides of the vessel (150 mL) and this was poured onto the filter cake. Isopropanol (600 mL) was added to the vessel and the remainder of the product in the vessel was suspended in this solvent using vigorous agitation. The isopropanol suspension was used to wash the filter cake once the DMA had been removed by suction. The filter cake was sucked dry then washed with MTBE and sucked dry once again. The filter cake was dried in vacuo to afford (Z)-tert-butyl 4-(2-(amino(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)methylene)hydrazinecarbonyl)piperidine-1-carboxylate (76 g, 95%) as a yellow solid: 1H NMR Spectrum: (DMSO-d6) 1.40 (9H, s), 1.46 (9H, s), 1.63-1.9 (2H, m), 2.33-2.6 (2H, m, obscured by DMSO signal), 2.63-3.03 (2H, m), 3.18-3.48 (4H, m, obscured by water signal), 3.88-4.11 (2H, m), 6.43 (2H, s), 7.76 (2H, br), 8.84 (0.5H, s), 8.87 (0.5H, s), 9.85 (1H, s); Mass Spectrum [M+H]+=488
Reaction SMILES: Cl[CH:2]([C:6](=[O:8])[CH3:7])[C:3](=O)[CH3:4].[CH:9]([NH2:11])=[O:10].[OH-].[Na+].[Na+].[Cl-]>O.C(O)=O>[C:6]([C:2]1[O:10][CH:9]=[N:11][C:3]=1[CH3:4])(=[O:8])[CH3:7]
Reactant: NC=O
Reactant: CC(=O)C(Cl)C(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CC(=O)c1ocnc1C
Temperature: 140 °C
Yield: 26.4 %

Procedure:
A mixture of 3-chloro-2,4-pentanedione (26.8 g), formamide (18.0 g), and formic acid (50.0 g) was heated in a 140° C. oil bath and refluxed for 4 hours. The resulting dark mixture was poured into 100 ml of water, basified with 50% NaOH solution, and saturated with NaCl. The mixture was extracted with ethyl ether (3×100 ml). The ether solution was dried over sodium sulfate and concentrated. The residue was vacuum-distilled to yield 6.59 g of 5-acetyl-4-methyloxazole as a colorless liquid, 84° C. (15 torr). NMR: 2.51 (s, 3H), 2.52 (s, 3H), 7.85 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:24])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)nc2c1Cl
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.2 %

Procedure:
A solution of 2-bromo-8-chloroimidazo[1,2-b]pyridazine-7-carboxamide (0.940 g, 3.41 mmol), (3S,4S)-benzyl 3-amino-4-ethylpyrrolidine-1-carboxylate (1.017 g, 4.09 mmol) and Hunig's Base (1.788 ml, 10.24 mmol) in DMF (3.0 ml) in a reaction vial was stirred at 90° C. for 2 h. The reaction solution was added slowly to a stirred ice-water resulting in a light tan precipitate. The suspension was stirred for 30 min at 0° C. After filtration, (3S,4S)-benzyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-ethylpyrrolidine-1-carboxylate was collected as a light tan solid (1.716 g, 3.52 mmol, 100% yield). ESI-MS (analytical LCMS Method A): m/z 489.1, 487.1 ([M+H]+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[C:19]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[NH2:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37].[OH-].[Na+].CC(O)C>C(Cl)Cl>[OH:37][CH2:36][CH:35]([NH:34][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][C:18]3[C:19]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)[CH2:38][OH:39]
Reactant: CN(c1ncccc1CNc1nc(Nc2ccc(CCl)cc2)ncc1C(F)(F)F)S(C)(=O)=O
Reactant: NC(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)O
Product: CN(c1ncccc1CNc1nc(Nc2ccc(CNC(CO)CO)cc2)ncc1C(F)(F)F)S(C)(=O)=O

Procedure:
A mixture of 7 (100 mg, 0.200 mmol), 2-amino-1,3-propanediol (90.9 mg, 0.998 mmol), sodium hydroxide (7.98 mg, 0.200 mmol) and 2-propanol (0.5 mL) was heated to reflux. After 30 minutes the mixture was cooled, treated with DCM, and washed with water. The organic phase was dried over MgSO4, filtered and concentrated. The resultant residue was then purified by column chromatography (silica gel; eluting with 6% MeOH/DCM with NH4OH), and the eluents containing the product were combined and concentrated to provide 8 as a white solid. Yield: 60.9 mg, 55%. MS+ 556.2. 1H NMR (500 MHz, d6-DMSO) δ: 9.48 (s, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 7.59 (m, 2H), 7.34 (m, 3H), 6.99 (d, 2H), 4.75 (d, 2H), 4.35 (t, 2H), 3.58 (s, 2H), 3.34 (m, 4H), 3.12 (s, 3H), 3.09 (s, 3H), 2.45 (m, 1H). FAK IC50: <0.000595 μM (Table 1, Example 389)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[NH:19][N:18]=[C:17]([I:20])[C:14]3=[N:15][CH:16]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.CS(O)(=O)=O>C(Cl)Cl.O1CCCC1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[CH:12]=[C:13]3[N:19]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][O:21]4)[N:18]=[C:17]([I:20])[C:14]3=[N:15][CH:16]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: C1=COCCC1
Reactant: COc1cc(OC)cc(-c2cnc3c(I)n[nH]c3c2)c1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)cc(-c2cnc3c(I)nn(C4CCCCO4)c3c2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A mixture of 6-(3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-b]pyridine (0.54 g, 1.4 μmmol), dihydropyran (0.39 mL, 4.2 mmol) and methanesulfonic acid (18 μL, 0.28 mmol) in methylene chloride (6 mL) and tetrahydrofuran (2 mL) in a sealed reaction vial was stirred at 50° C. for 3 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.60 g). LCMS (M+H)+=465.9.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[N:13]2)=[CH:10][CH:11]=1)=[O:5].[BH4-].[Na+].O>CO>[CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:14]=[N:13]2)=[CH:10][CH:11]=1)[OH:5]
Reactant: CC(C)CC(=O)c1ccc(-n2cc(C(F)(F)F)cn2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)CC(O)c1ccc(-n2cc(C(F)(F)F)cn2)nc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a 0° C. solution of 3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-one (1.4 g, 4.7 mmol) in methanol (20 mL) was added sodium borohydride (367 mg, 9.4 mmol). The resulting mixture was stirred at 20° C. for 1 hour. Water was added and the mixture was extracted with ethyl acetate (40 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give 3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butan-1-ol (1.4 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.82-7.79 (m, 2H), 4.82-4.77 (m, 1H), 1.83 (s, 1H), 1.75-1.64 (m, 2H), 1.47-1.43 (m, 1H), 0.88-0.92 (m, 6H).