Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)[NH2:2].Cl.O1CCOCC1.[F:20][C:21]([F:33])([F:32])[C:22](=O)[CH2:23][C:24]([C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)=O>C(O)C>[O:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[C:24]1[N:1]([C:3]2[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=2)[N:2]=[C:22]([C:21]([F:20])([F:32])[F:33])[CH:23]=1
Reactant: CCOC(=O)c1csc(NN)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1csc(-n2nc(C(F)(F)F)cc2-c2ccco2)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
To 28 (268 mg, 1.431 mmol) was added 4N HCl in dioxane (3.6 mL, 14.3 mmol) and 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (0.23 mL, 1.6 mmol). The resulting suspension was allowed to stir for 16 h at 100° C. Ethanol (1.4 mL) was added, and the mixture was stirred for 4 h at 100° C. Solvent was evaporated and the residue was purified by silica gel column chromatography with gradient of EtOAc (10-20%) in hexanes to afford 29 (203 mg, 20%) as an orange solid. LRMS (ESI): calc. 357.0; found 358.1 (MH)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:6]([CH2:14][C:15]([N:17]([O:19][CH3:20])[CH3:18])=[O:16])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=[CH2:5].S(OC)(O[CH3:25])(=O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:20][O:19][N:17]([CH3:18])[C:15](=[O:16])[CH2:14][N:6]([C@@H:3]([CH:4]=[CH2:5])[CH2:2][O:1][CH3:25])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: C=C[C@@H](CO)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C[C@@H](COC)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of (S)-tert-butyl 1-hydroxybut-3-en-2-yl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (Intermediate 250, 7 g, 24.28 mmol) in THF (75 mL) at 0° C. was added dimethyl sulfate (2.436 mL, 25.49 mmol) followed by LiHMDS (26.7 mL, 26.70 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred for two hours. The reaction mixture was then partitioned between ethyl acetate and water. The layers were separated and the organics were washed with saturated sodium bicarbonate, water and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (5%-30% ethyl acetate/hexanes) afforded the title compound as a clear oil (6.89 g, 91%).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[CH:17]=[C:18]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH:19]([CH3:21])[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6](/[CH:17]=[C:18](\[C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)/[CH:19]([CH3:21])[CH3:20])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(C)C(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2/C=C(\c2ccncc2)C(C)C)CCN(C)C1
Temperature: 25 °C

Procedure:
2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (0.08 g, 0.4 mmol), 4-(1-bromo-3-methylbut-1-en-2-yl)pyridine (0.1 g, 0.44 mmol), potassium phosphate (0.169 g, 0.797 mmol), L-proline (0.013 g, 0.113 mmol), and copper (I) iodide (0.015 g, 0.079 mmol) were mixed in DMF (5 mL) and purged with nitrogen. The contents were cooled to RT and poured into water. The precipitate obtained was filtered, dried and purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.50 (d, 2H), 7.60(d, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 6.95 (d, 2H), 4.60 (m, 1H), 4.30 (m, 1H), 3.80 (m, 1H), 3.50 (m, 1H), 3.10 (m, 1H), 3.05 (m, 5H), 2.38 (s, 3H), 1.38 (d, 6H).
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-:21])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[CH3:58][C:59]1[N:64]=[C:63]([NH:65][CH:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)[CH:62]=[CH:61][C:60]=1[N+:72]([O-:74])=[O:73]>CN(C)C=O.ClCCl.O1CCCC1>[CH3:58][C:59]1[N:64]=[C:63]([NH:65][CH:66]2[CH2:67][CH2:68][N:69]([C:19](=[O:21])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:22])([F:2])[F:23])=[CH:9][CH:8]=4)[CH2:15][CH2:14]3)[CH2:70][CH2:71]2)[CH:62]=[CH:61][C:60]=1[N+:72]([O-:74])=[O:73]
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: Cc1nc(NC2CCNCC2)ccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(NC2CCN(C(=O)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (35 mg; 0.11 mmol, prepared in accordance with Example 3), diisopropylethyl amine (174 μL; 1.0 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (37 mg; 0.1 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (6-methyl-5-nitro-pyridin-2-yl)-piperidin-4-yl-amine hydrochloride (27 mg; 0.1 mmol, prepared in accordance with Example 100) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 90 minutes at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (42 mg; 0.08 mmol). The structure was confirmed using Protocol II-A. Calculated mass=535; observed mass=535; HPLC retention time=3.39 min.
Reaction SMILES: FC(F)(F)C([O-])=O.C([NH:27][C:28]1[S:29][CH:30]=[C:31]([C:33](=[N:69][O:70][CH:71]([F:73])[F:72])[C:34]([NH:36][CH:37]2[C:67](=[O:68])[N:39]3[C:40]([C:51]([O:53]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:52])=[C:41]([CH:44]([CH3:50])[NH+:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:42][S:43][C@H:38]23)=[O:35])[N:32]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[NH2:27][C:28]1[S:29][CH:30]=[C:31]([C:33](=[N:69][O:70][CH:71]([F:72])[F:73])[C:34]([NH:36][CH:37]2[C:67](=[O:68])[N:39]3[C:40]([C:51]([O-:53])=[O:52])=[C:41]([CH:44]([CH3:50])[NH+:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:42][S:43][C@H:38]23)=[O:35])[N:32]=1
Reactant: CC(C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(F)F)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1)[NH+]1CCCC1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC(F)F)c3csc(N)n3)[C@H]2SC1)[NH+]1CCCC1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A solution of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(1-methyl-1-pyrrolidiniomethyl)-3-cephem-4-carboxylate trifluoroacetate (syn isomer) (1.25 g) in methylene chloride (4 ml) was stirred at 0°-5° C., and anisole (2.6 ml) and trifluoroacetic acid (5.2 ml) were added thereto. The mixture was stirred for one hour at 0°-5° C. To the reaction mixture was added diisopropyl ether, and the resultant precipitates were collected by filtration, washed with diisopropyl ether and dissolved in water (400 ml). The solution was subjected to column chromatography on macroporus non-ionic adsorption resin "Diaion HP-20" and the elution was carried out with 30% aqueous solution of methanol. The fractions containing the object compound were collected, concentrated in vacuo and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(1-methyl-1-pyrrolidiniomethyl)-3-cephem-4-carboxylate (syn isomer) (450 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH2:10][C:11]1[O:15][C:14]([CH2:16][S:17][CH2:18][CH2:19][NH2:20])=[CH:13][CH:12]=1)[CH3:9].CS[C:23](=[N:27][CH3:28])[NH:24][C:25]#[N:26]>C(#N)C.[N+]([O-])([O-])=O.[Ag+]>[C:25]([N:24]=[C:23]([NH:27][CH3:28])[NH:20][CH2:19][CH2:18][S:17][CH2:16][C:14]1[O:15][C:11]([CH2:10][N:8]([CH3:7])[CH3:9])=[CH:12][CH:13]=1)#[N:26]
Reactant: CN=C(NC#N)SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Agent: [Ag+]
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: CNC(=NC#N)NCCSCc1ccc(CN(C)C)o1
Reaction time: 16 h
Yield: 2.4 %

Procedure:
To a stirred suspension of potassium carbonate (20.7 g) in a solution of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (10.7 g) and N-cyano-N'-methylcarbamimidothioic acid methyl ester (7.1 g) in acetonitrile (107 ml) at 70° was added a solution of silver nitrate (9.35 g) in acetonitrile (20 ml) during 1 hr. The mixture was stirred for 16 hr, the solid filtered and the filtrate evaporated to dryness. The residue was dissolved in ethyl acetate (250 ml). A portion of this (10.5 ml) was washed with water (6 ml), the ethyl acetate layer evaporated to give a solid which was crystallised from isopropylacetate (1.75 ml) giving N"-cyano-N-[2-[[[5-(dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]-N'-methylguanidine (0.35 g) m.p. 79°-81.5°.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=O)[CH:21]=[N:22][CH:23]=1.O>C1COCC1>[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[CH:24]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[CH:21]=[N:22][CH:23]=1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: COc1cncc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/C=C/c1cncc(OC)c1
Temperature: 0 °C
Yield: 13.9 %

Procedure:
To a suspension of 3.12 g (78.1 mmol) of sodium hydride (60% in oil) in 30 mL of anhydrous THF is added, over 45 minutes, under argon and at 0° C., 16.4 g (78.1 mmol) of methyl (diethoxyphosphoryl)acetate in 10 mL of THF. Stirring is maintained for 30 minutes at 0° C. and 5.1 g (37.2 mmol) of 5-methoxypyridine-3-carbaldehyde in 20 mL of anhydrous THF are then added dropwise at 0° C. After cooling to room temperature, the reaction mixture is treated with 150 mL of water and then extracted with EtOAc (3×100 mL). The organic phases are combined, washed successively with water (2×20 mL), dried over Na2SO4, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAC gradient of 0 to 40% EtOAc. 1 g of methyl (2E)-3-(5-methoxypyridin-3-yl)prop-2-enoate is obtained in the form of a white powder.
Reaction SMILES: [C:1]([N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]1[CH2:10][C:9]([CH:11]=O)=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].Cl.[CH2:34]([O:36][NH2:37])[CH3:35]>CCO>[C:1]([N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]1[CH2:10][C:9](/[CH:11]=[N:37]/[O:36][CH2:34][CH3:35])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C:6]1=[O:20])(=[O:3])[CH3:2]
Reactant: CCON
Reactant: CC(=O)N(C(=O)OC(C)(C)C)N1CC(C=O)=NN(C(=O)OC(C)(C)C)C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCO/N=C/C1=NN(C(=O)OC(C)(C)C)C(=O)N(N(C(C)=O)C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[acetyl(tert-butoxycarbonyl)amino]-6-formyl-3-oxo-5H-1,2,4-triazine-2-carboxylate (192 mg, 0.500 mmol) and sodium acetate (45 mg, 0.55 mmol) in EtOH (1.0 mL) at room temperature was added O-ethylhydroxylamine HCl-salt (54 mg, 0.55 mmol). The mixture was heated to 70° C. and stirred for 2 h. The obtained reaction mixture was filtered hot and the solid residual washed with EtOH. The filtrate was concentrated to give the desired product which was used without further purification. LCMS (Method I) RT 1.94 min. [M+Na]+ 450.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C)C=O>[CH3:13][O:12][C:10](=[O:11])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[CH:16][N:17]([CH3:19])[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1ccc(OC)cc1
Solvent: CN(C)C=O
Product: COC(=O)C(=CN(C)C)c1ccc(OC)cc1
Temperature: 100 °C

Procedure:
Methyl 4-methoxyphenylacetate (3.3 g) was dissolved in N,N-dimethylformamide (3 cm3) treated with N,N-dimethylformamide dimethyl acetal (6 cm3) and heated at 100° C. for 18 h. The reaction was then cooled and evaporated under high vacuum to afford crude methyl-3-dimethylamino-2-(4-methoxyphenyl)propenoate (3.6 g) which was used without further purification. δH (250 MHz; CDCl3); 2.68 (6H, s), 3.62 (3H, s), 3.8 (3H, s), 6.82 (2H, d, J 8.7 Hz), 7.1 (2H, d, J 8.7 Hz) and 7.54 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16]>>[C:11]1(=[O:16])[C:10]2[NH:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:15]=2[CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccccc1
Reactant: O=C1CCCCC1=CO
Product: O=C1CCCc2c1[nH]c1ccccc21

Procedure:
2,3,4,9-Tetrahydro-1H-carbazol-1-one was prepared from aniline (2.9 g, 31 mmol) and 2-(hydroxymethylene)cyclohexanone (3.5 g, 28 mmol) in a similar manner as described in Example 1 to give 2.5 g (49%) of a brown solid. 1H-NMR (DMSO-d6): δ 11.6 (s, 1H), 7.66 (d, 1H), 7.38 (d, 1H), 7.30 (t, 1H), 7.07 (t, 1H), 2.90 (t, 2H), 2.56 (t, 2H), 2.15 (quint, 2H); MS m/z 186 (M+1).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH:7]([CH2:12][C:13]#[CH:14])[C:8]([O:10][CH3:11])=[CH2:9].C(N(CC)CC)C>C(Cl)Cl>[S:1]([O:6][CH:7]([CH2:12][C:13]#[CH:14])[C:8]([O:10][CH3:11])=[CH2:9])([CH3:4])(=[O:3])=[O:2]
Reactant: C#CCC(O)C(=C)OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCC(OS(C)(=O)=O)C(=C)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Mesyl chloride (1.73 ml) was added dropwise to a solution of 3-hydroxy-2-methoxy-1-hexen-5-yne (2 g) and triethylamine (3.32 ml) in methylene chloride (20 ml) under ice-cooling over a period of 10 minutes. After being stirred for 48 hours at room temperature the mixture was washed successively with water, aqueous sodium bicarbonate solution, and brine, dried over magnesium sulfate, and evaporated in vacuo to give 3-mesyloxy-2-methoxy-1-hexen-5-yne (3.45 g).
Reaction SMILES: Cl[Si]1(Cl)CCC1.[CH3:7][CH:8]=[CH:9][SiH:10]([O:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[O:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14]>>[CH2:13]([N:12]([CH2:15][CH3:16])[O:11][Si:10]1([O:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH2:7][CH2:8][CH2:9]1)[CH3:14]
Reactant: CC=C[SiH](ON(CC)CC)ON(CC)CC
Agent: Cl[Si]1(Cl)CCC1
Product: CCN(CC)O[Si]1(ON(CC)CC)CCC1

Procedure:
In accordance with the general procedure of Example 1, when 1,1-dichlorosilacyclobutane and methylvinylbis(diethylaminoxy)silane are reacted it is predicted that the title compound is formed.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:31]=[CH:30][C:18]([C:19]([NH:21][CH2:22][CH:23]4[CH2:27][O:26]C(C)(C)[O:24]4)=[O:20])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].CC(O)=O>O>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:31]=[CH:30][C:18]([C:19]([NH:21][CH2:22][CH:23]([OH:24])[CH2:27][OH:26])=[O:20])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc2ncc(-c3ccc(C(=O)NCC4COC(C)(C)O4)cc3)n2n1
Solvent: O
Solvent: CC(=O)O
Product: CCCCNc1ccc2ncc(-c3ccc(C(=O)NCC(O)CO)cc3)n2n1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
To 150 mg (0.355 mmol) of 4-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-benzamide was added 15 ml of AcOH and 5 mL of water and heated to 60° C. for 1.5 hr. It was concentrated and the crude was purified on the acetic PREP HPLC to yield 107 mg (79%) of the titled compound. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.00 (t, J=7.39 Hz, 3H) 1.42-1.55 (m, 2H) 1.66-1.76 (m, 2H) 3.40 (t, J=7.17 Hz, 2H) 3.43-3.52 (m, 1H) 3.56-3.65 (m, 3H) 3.84-3.93 (m, 1H) 7.24 (d, J=9.92 Hz, 1H) 7.96 (d, J=9.92 Hz, 1H) 8.00-8.05 (m, 2H) 8.23-8.28 (m, 2H) 8.30 (s, 1H); LRMS (ESI) m/e 384.0 [(M+H)+, calcd for C20H25N5O3 383.0]
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:20][Si](C(C)C)(C(C)C)C(C)C)[CH:5]=[C:6]([CH3:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[CH3:19][C:6]1[CH:5]=[C:4]([OH:20])[CH:3]=[C:2]([CH3:1])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([CH:16]([CH3:17])[CH3:18])[CH:10]=1
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Cc1ccc(F)c(C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc(C)c1Cc1ccc(F)c(C(C)C)c1
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 3,5-dimethyl-4-(4′-fluoro-3′-iso-propylbenzyl)triisopropylsilanoxybenzene in THF (10 mL) at 0° C. was added TBAF (1 M, 4.0 mL). The reaction mixture was stirred for 3 h, diluted with ethyl acetate 920 mL) and quenched with water (10 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:9) to afford 3,5-dimethyl-4-(4′-fluoro-3′-iso-propylbenzyl)phenol (450 mg, 61% for two steps): 1H NMR (300 MHz, CDCl3): δ 6.97 (d, J=7.4 Hz, 1H), 6.86 (m, 1H), 6.69 (m, 1H), 6.60 (s, 2H), 3.95 (s, 2H), 3.20 (m, 1H), 2.22 (s, 6H), 1.25 (d, J=6.4 Hz, 6H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:9); Rf=0.50.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1)(=O)=O.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:17]=2)[N:12]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1)C(F)(F)F
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccccc1-c1ccc2c(-c3ccnc(NC4CC4)n3)cnn2n1
Temperature: 100 °C
Yield: 51.7 %

Procedure:
To a solution of 3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yl trifluoromethanesulfonate (21.0 mg, 0.08 mmol) in DMF (1 mL) was added Pd(PPh3)2Cl2 (5 mg, 0.007 mmol), 2-chlorophenyl boronic acid (15 mg, 0.096 mmol), and Na2CO3 (21.0 mg in 0.5 mL water). The reaction mixture was heated at an oil bath temperature of 100° C. for about 12 hours. The mixture was cooled to RT and water (20 mL) was added. The aqueous layer was washed with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo and purified by silica-gel column chromatography (30% EtOAc/hexanes) to give the title compound as a brown solid (15 mg, 55%). 1H-NMR (300 MHz, CDCl3) δ 9.14 (d, 1H, J=9.2 Hz), 8.52 (s, 1H), 8.32 (d, 1H, J=5.3 Hz), 7.74-7.71 (m, 1H), 7.56-7.52 (m, 2H), 7.46-7.42 (m, 2H), 5.61 (bs, 1H), 2.88 (m, 1H), 0.89 (m, 2H), 0.66 (m, 2H); MS (ESI) (M+H)+ 363.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([CH2:15][O:14][C:12]2[C:11]([C:19]([F:22])([F:20])[F:21])=[CH:10][C:9]3[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)[CH:28]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(OCC3CC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-cyclopropylmethoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M176) (275 mg, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (170 mg, 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][C:9]=1[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23])([CH3:4])([CH3:3])[CH3:2].[CH3:25][CH2:26][C:27](=O)[CH2:28][CH3:29].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:13]([NH:14][CH:27]([CH2:28][CH3:29])[CH2:26][CH3:25])=[CH:12][CH:11]=[CH:10][C:9]=1[C:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(-c2cccc(N)c2NC(=O)OC(C)(C)C)c(C)c1
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(CC)Nc1cccc(-c2c(C)cc(C)cc2C)c1NC(=O)OC(C)(C)C
Reaction time: 0.75 h
Yield: 75.6 %

Procedure:
Under a nitrogen atmosphere was combined 5 ml of acetic acid, 205 mg (0.62 mmol) of the title compound of Example 4 and 126 μl (1.25 mmol) of 3-pentanone, followed by 890 mg (6.29 mmol) of powdered sodium sulfate (Na2SO4). The solution was allowed to stir for 20 minutes, at which point 158 mg (0.75 mmol) of sodium triacetoxyborohydride (NaBH(OAc)3) was added. The solution was allowed to stir for 45 minutes and was then quenched with aqueous bicarbonate (75 ml) and was extracted with ethyl acetate (2×30 ml). The organic extract was washed with water (1×25 ml) and then brine (1×25 ml), and then dried over Na2SO4, filtered and concentrated in vacuo to afford 232 mg of crude product, which was chromatographed on silica gel using 9:1 hexane:ethyl acetate to afford 186 mg (74.7%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:24][C@H:25]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:40]2[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=2)(=[O:32])=[O:31])[CH2:26]1)(C)(C)C>>[Cl:46][C:45]1[C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[S:30]([N:27]2[CH2:28][CH2:29][C@H:25]([OH:24])[CH2:26]2)(=[O:31])=[O:32])=[N:41][C:42]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:43][CH:44]=1
Reactant: COc1cc2c(cc1N)CCN(C[C@@H](C)O)CC2
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](O)C3)n1)CCN(C[C@@H](C)O)CC2
Yield: 29 %

Procedure:
In an analogous manner to Example 15N34, the product was prepared from (R)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol and {2-[(S)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. The product was isolated as a white solid (35 mg, 29%). mp: 199-201° C. MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.58-7.52 (m, 2H), 7.25 (t, J=8 Hz, 1H), 6.66 (s, 1H), 4.37 (br s, 1H), 3.88 (m, 4H), 3.42 (m, 3H), 3.31 (d, 1H), 2.91-2.52 (m, 10H), 2.27 (m, 1H), 1.17 (d, J=6 Hz, 3H).